Guideline: Infection Prevention and Control Guidelines for TB, MDR-TB and XDR-TB »
 

Sexually Transmitted Infections Diagnosis and Management

 

The syndromic approach to Sexually Transmitted Infection (STI) diagnosis and management is to treat the signs or symptoms (syndrome) of a group of diseases rather than treating a specific disease. This allows for the treatment of one or more conditions that often occur at the same time and has been accepted as the management of choice. This guide includes the current STI syndromic management algorithms.

STIs are preventable and many are treatable. Early access to care helps prevent further transmission to partners and from mother-to-child, acquisition of additional STIs, and decreases the risk of STI related complications. Screening for STIs at any and all health care visits, can promote STI prevention and management and provide an opportunity for additional health promotion and education. Where possible, STI screening and prevention should become routine and integrated into all health visits.

 

In order to perform a proper clinical assessment it is important to take a good sexual history and undertake a thorough ano-genital examination. The history should include questions concerning symptoms, recent sexual history, sexual orientation, type of sexual activity (oral, vaginal, anal sex), the possibility of pregnancy (females), use of contraceptives including condoms, recent antibiotic history, any drug allergies, and recent overseas travel.

General Measures

  • Counselling and education, including  HIV testing
  • Condom promotion, provision and demonstration to reduce the risk of STIs
  • Compliance/adherence with treatment
  • Contact treatment/partner management
  • Circumcision promotion with appropriate counselling concerning condoms
  • Contraception and conception counselling

 

Syphilis Serology

 

The Rapid Plasmin Reagin (RPR) measures disease activity, but is not specific for syphilis. False RPR positive reactions may occur, notably in patients with connective tissue disorders (false positive reactions are usually low titre < 1:8). For this reason, positive RPR results should be confirmed as due to syphilis by further testing of the serum with a specific treponemal test, e.g.:

  • Treponema pallidum haemagglutination (TPHA) assay
  • Treponema pallidum particle agglutination (TPPA) assay 
  • Fluorescent Treponemal Antibody (FTA) assay 
  • Treponema pallidum ELISA 
  • Rapid treponemal antibody test 

Screening can also be done the other way around starting with a specific treponemal test followed by a RPR in patients who have a positive specific treponemal test. This is sometimes referred to as the “reverse algorithm”.

Once positive, specific treponemal tests generally remain positive for life. The RPR can be used:

  • To determine if the patient’s syphilis disease is active or not,
  • To measure a successful response to therapy (at least a fourfold reduction in titre, e.g. 1:256 improving to 1:64), or
  • To determine a new re-infection 

Some patients, even with successful treatment for syphilis, may retain life-long positive RPR results at low titres (≤1:8), which do not change by more than one dilution difference (up or down) over time (so-called serofast patients).

Note:

  • Up to 30% of primary syphilis cases, i.e. those with genital ulcers may have a negative RPR.
  • The RPR is always positive in the secondary syphilis stage and remains high during the first two (infectious) years of syphilis.

 

 

Medicine Treatment

 

Early Syphilis Treatment

 

Check if treated at initial visit.

  • Benzathine benzylpenicillin, IM, 2 .4 MU immediately as a single dose
    • Dissolve benzathine benzylpenicillin, IM, 2 .4 MU in 6 mL lidocaine 1% without epinephrine (adrenaline) .

In penicillin-allergic patients:

  • Doxycycline, oral, 100 mg twice daily for 14 days

If penicillin-allergic and pregnant: Refer for penicillin desensitisation.

 

Late Syphilis Treatment

 

Check if treatment was commenced at initial visit.

  • Benzathine benzylpenicillin, IM, 2 .4 MU once weekly for 3 weeks .
    • Dissolve benzathine benzylpenicillin, IM, 2 .4 MU in 6 mL lidocaine 1% without epinephrine (adrenaline).

If penicillin-allergic and pregnant: Refer for penicillin desensitisation.

 

 

Syphilis in Pregnancy

 

Mother-to-child transmission of syphilis occurs in up to 40% of cases in untreated mothers. Untreated maternal syphilis may lead to miscarriage, stillbirth, non-immune hydrops fetalis, or congenital syphilis in the newborn. Syphilis may be asymptomatic in pregnant women with diagnosis made by positive serology, preferably with on-site rapid testing.

 

Referral

 

  • Neurosyphilis
  • Clinical congenital syphilis

 

 

Description

 

This is a viral infection which can be transmitted sexually and non-sexually. It is usually self-limiting but can be progressive in an advanced stage of immunodeficiency.

  • Clinical signs include papules at the genitals or other parts of the body.
  • The papules usually have a central dent (umbilicated papules).

 

 

Medicine Treatment

 

  • Tincture of iodine BP.
    • Apply with an applicator to the core of the lesions.

 

 

Description

 

The clinical signs include:

  • Warts on the ano-genital areas, vagina, cervix, meatus or urethra.
    • Warts can be soft or hard.

In most cases, warts resolve without treatment after 2 years in non- immunosuppressed patients.

 

 

General Measures

 

  • If warts do not look typical or are fleshy or wet, perform an RPR/VDRL test to exclude secondary syphilis, which may present with similar lesions.
  • Emphasise HIV testing.

 

 

Referral

 

All patients with:

  • Warts > 10 mm
  • Inaccessible warts, e .g . intra-vaginal or cervical warts
  • Numerous warts

 

 

Description

 

Infestation of lice mostly confined to pubic and peri-anal areas, and occasionally involves eyelashes.

The bites cause intense itching, which often results in scratching with bacterial super-infection.

 

 

General Measures

 

Thoroughly wash clothing and bed linen that may have been contaminated by the patient in the 2 days prior to the start of treatment in hot water and then iron.

 

Medicine Treatment

 

  • Benzyl benzoate 25%
    • Apply to affected area.
    • Leave on for 24 hours, then wash thoroughly.
    • Repeat in 7 days.

 

Pediculosis of the Eyelashes or Eyebrows

 

  • Petroleum jelly.
    • Apply to the eyelid margins (cover the eyelashes) daily for 10 days to smother lice and nits 
    • Do not apply to eyes.

 

 

Referral

 

All children with lice on pubic, perianal area and eyelashes to exclude sexual abuse.

 

1. INTRODUCTION

 

At no time in recent history has tuberculosis become of great concern as today. Despite highly effective drugs, disease and deaths due to Mycobacterium tuberculosis are increasing in South Africa, fuelled by the HIV epidemic. The most serious aspect of the TB epidemic has been the emergence of DR-TB in the country. DR-TB is a man-made problem, largely due to human error in any or all of the following:

  • Management of drug supply
  • Patient management
  • Prescription of chemotherapy
  • Patient adherence

Anti-TB drugs constitute a two-edged sword – while they kill the mycobacteria; they also select for naturally resistant mycobacteria. In this way, strains can become sequentially resistant to several agents and patients may also acquire further drug-resistant strains through re-infection or super- infection.

 

1.1. Definitions

 

 

DR-TB is a disease (usually pulmonary) caused by M. tuberculosis strains resistant to one or more anti-TB drugs.

  • MDR-TB is defined as resistance to rifampicin and isoniazid, with or without resistance to other first-line anti-TB drugs.
  • XDR-TB is defined as resistance to rifampicin, isoniazid, any fluoroquinolone and resistance to one or more of the following injectable anti-TB drugs: kanamycin,amikacin, and capreomycin.

Drug resistance is further classified according to the history of previous TB treatment:

  • Resistance in new patients (previously called ‘primary resistance’) is resistance in the cultures from patients with no history of previous TB treatment or patients who have received TB treatment for less than one month previously. Resistance in new patients provides a measure of the degree of transmission of M. tuberculosis strains.
  • Resistance in previously treated patients (previously called ‘acquired resistance’) refers to resistance in cultures from patients with one or more previous TB treatment episodes, of more than one month each. Previously treated patients are also often referred to as re-treatment cases.
  • Resistance levels in re-treatment are always higher than in new patients, and provide an indication of the extent to which patients were appropriately treated.

The terms ‘primary’ and ‘acquired’ have been discontinued as epidemiological terminology, as the exact causative nature of drug resistance in a patient is not always possible to assess. Patients may be erroneously labelled as having primary resistance if they do not disclose previous treatment for TB, while patients who fail treatment (and are therefore labelled to have acquired resistance) may have been infected with a resistant strain from the beginning or acquired resistance during treatment.

 

 

MDR-TB differs from non-tuberculosis mycobacteria (NTM). NTMs are commonly resistant to both isoniazid and rifampicin but should not be confused with MDR-TB. These Policy Guidelines are relevant for the management of DR-TB only and not for disease caused by NTM.

 

1.2 Development of Drug-Resistant TB

 

M. tuberculosis has the ability to undergo spontaneous, slow but constant mutation, resulting in resistant mutant organisms. This natural phenomenon is genetically determined and varies from drug to drug. The probability of spontaneous resistance to individual first-line anti-TB drugs is as follows:

  • Isoniazid: 1 in every 106 cell divisions
  • Rifampicin: 1 in every 109 cell divisions
  • Streptomycin: 1 in every 106 cell divisions
  • Ethambutol: 1 in every 105 cell divisions
  • Pyrazinamide: 1 in every 105 cell divisions

Usually, the chromosomal location of resistance to different drugs is not linked. Therefore, spontaneously occurring multidrug resistance is extremely rare. For example, the probability of mutation resulting in resistance to isoniazid is 10-6 and for rifampicin it is 10-9. The likelihood of spontaneous resistance to both isoniazid and rifampicin is the product of the two probabilities (i.e.,

10-15). Since the probability of naturally occurring resistant mutants is very low, a large bacterial load (e.g., in lung cavities) is needed for MDR-TB strains to emerge.

Drug resistance is the result of selection of resistant mutants in the bacterial population, due to killing of susceptible bacilli by anti-TB drugs. The problem is greatly exacerbated by inadequate treatment such as direct or indirect monotherapy, resulting from intake of a single anti-TB drug or from intake of several drugs with suboptimal concentrations. Susceptible bacilli are killed rapidly and resistant mutants are then able to multiply.

Erratic  TB treatment with first-line  drugs, either  through clinical error  (i.e., prescription  of inadequate drugs, adding one drug to a failing regimen or programme failure with high treatment non-compliance and default) can result in the emergence of resistance, including MDR-TB. Erratic treatment with second-line drugs can result in XDR-TB a virtually untreatable disease.

 

1.3. Situational Analysis

 

South Africa is the world’s third highest burden TB country, only lagging behind countries with significantly larger populations, such as China and India. South Africa is also ranked the fifth highest DR-TB high burden country. In addition, the numbers of MDR-TB and XDR-TB patients have increased due to the concurrent HIV epidemic and inadequate management of TB.  There has been a steady increase in cases since 2006, possibly due to increased case detection (Tables I and II). In 2010, the NHLS diagnosed 7 386 MDR-TB and 741 XDR-TB cases. The reason for the decrease in the number of cases between 2009 and 2010 is not clear.

 
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As shown in Tables I and II, KwaZulu-Natal and Western Cape notified the highest number of cases followed by Eastern Cape and Gauteng.

As shown in Table III, there is a wide gap between the number of MDR- and XDR-TB patients diagnosed, registered and started on treatment. In 2009, the programme did not start DR-TB treatment in approximately 50% of all diagnosed MDR-TB patients. The numbers diagnosed and started on treatment depend on the prevalence of drug-resistance and accessibility and efficiency of diagnostic and treatment services in the provinces.

 
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1.4. Framework for Managing Drug-Resistant TB

 

Management of DR-TB is organised around five components like the DOTS strategy, because the underlying principles are the same, namely:

  • Sustained government commitment;
  • Accurate, timely diagnosis through quality assured culture and drug susceptibility testing;
  • Appropriate treatment utilising second-line drugs under strict supervision;
  • Uninterrupted supply of quality assured second-line drugs; and
  • Standardised recording and reporting system.

 

1.5. Prevention of Drug-Resistant TB

 

Standardised First-line Regimens for New and Re-Treatment Patients

Ensuring cure of new smear-positive patients the first time will prevent significant development and subsequent spread of drug-resistant TB. This is only possible on a national scale by the use of standardised regimens. Every effort should be made to ensure that patients on regimen 2 (re- treatment) complete their treatment, as they are at a higher risk of developing drug-resistant TB.

Compliance to Treatment Protocols

Compliance with management guidelines as recommended by the National Department of Health ensures that adequate drugs, in the correct combinations and dosages, are prescribed for the correct period of time. Use of fixed combination drugs eliminates the likelihood of selection of drugs and inadequate dosing due to human error.

Patient Adherence and Supervision of Therapy

Adherence refers to how well patients complete the full course of prescribed medication. This often depends on adequate counselling, ongoing support, and access to the facility and attitudes of heath care staff. Directly observed therapy (DOT) during (at the very least) the intensive phase of treatment is the national policy. Excellent adherence during the intensive phase of treatment, during which time the total bacterial load in the patient is being reduced, is crucial to the prevention of drug-resistant TB. This is especially true for sputum smear-positive patients who have a high bacterial load. DOT in the follow-up phase is also important to help prevent relapse.

Drug Supply

The uninterrupted supply of anti-TB drugs to treatment points is crucial in preventing drug resistance.

 

2. LEGISLATIVE FRAMEWORK AND PUBLIC HEALTH ETHICS

 

The Department of Health is legally responsible for the control of TB, including DR-TB, as a public health issue and is required to operate within the context of the Bill of Rights enshrined in the Constitution of the Republic of South Africa, 1996. The Bill of Rights affords individual rights to every person and also balances competing rights and communal interests.

 

2.1. Rights protected by the Constitution

 

  • Freedom and security of the person: Violations of this right arise from enforced isolation or treatment.
  • Life: The right to receive treatment and the right of the uninfected to be protected from infection.
  • Health care: The right to health care services and emergency medical treatment.
  • Just administrative action: The right to be heard before a decision is made, which adversely affects individual rights.
  • Human dignity: The effects of detention and treatment on an individual’s dignity
  • Privacy: disclosure of a patient’s health status to others.
  • Equality: Discriminating between those who will receive treatment or be detained and those who will not.
  • Freedom of movement and residence: The effect of enforced detention and conditions of release.
  • Freedom of trade, occupation and profession: The effect of enforced detention and conditions of release.
  • Social security: The right to social security, including, if they are unable to support themselves and their dependents, appropriate social assistance.

 

2.2. Other Relevant Legislation

 

The following legislation provides a legal framework for the management of MDR-TB:

The National Health Act 61 of 2003

Chapter 2 of the Act emphasises the rights to emergency medical treatment; to have full knowledge of one’s condition, to exercise one’s informed consent, to participate in decisions regarding one’s health, to be informed when one is participating in research, to confidentiality and access to health records, of users to lay complaints about the service; and the rights of health workers to be treated with respect.

The Promotion of Administrative Justice Act 3 of 2000

Gives effect to the right to administrative action that is lawful, reasonable and procedurally fair and to the right to written reasons for administrative action as contemplated in section 33 of the Constitution of the Republic of South Africa, 1996.

The Occupational Health and Safety Act 85 of 1993

Provides for the health and safety of persons at work and the protection of employees against hazards through provision of a safe working environment by the employer.

The Compensation for Occupational Injuries Diseases Act 130 of 1993 and its Hazardous Biological Agent Regulations (21 December 2001)

Provides for the compensation for disability caused by injuries sustained and diseases acquired in the workplace by employees during their employment. This excludes the mines, which are provided for in a separate Act.

The Employment Equity Act 55 of 1998

Promotes equal opportunity and fair treatment in employment through the elimination of unfair discrimination.

Social Assistance Act 13 of 2004 and Regulations

Gives effect to the section 27 (1)(c) of the Constitution by providing for the rendering of social assistance to persons and mechanisms for the rendering of such assistance.

The Labour Relations Act 66 of 1995

Aims to promote economic development, social justice, labour peace and democracy in the workplace. It incorporates the code of good practice, which deals with some of the key aspects of dismissals for reasons related to conduct and capacity.

Basic Conditions of Employment Act 75 of 1997.

Provides for the minimum conditions of employment that employers must comply with in their workplace.

Promotion of Equality and Prevention of Unfair Discrimination Act, 2000

Promotes the principles of equality, fairness, social progress, justice, human dignity and freedom. It also prohibits unfair discrimination and unfair denial of access to healthcare services.

Promotion of Access to Information Act, 2000

Guarantees access to any information held by another person that is required for the exercise or protection of any rights. It also promotes the Constitutional right of access to any information held by the State and therefore impacts access to medical records and history.

Unemployment Insurance Act No 63 of 2001

Sections 14, 20, 36 provide for claims by the worker if unable to work because of illness.

 

2.3. Public Health Ethics

 

The Siracusa Principles on the Limitation and Derogation of Provisions in the International Covenant on Civil and Political Rights1 state, “Public health may be invoked as grounds for limiting certain rights in order to allow a state to take measures dealing with a serious threat to the health of the population or individual members of the population. These measures must be specifically aimed at preventing disease or injury or providing care for the sick and injured and that due regard shall be had to the international health regulations of the World Health Organization.”

 

2.3.1. International Health Regulations

The purpose and scope of these regulations is to prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks and which avoid unnecessary interference with international traffic and trade. Implementation is guided by the following principles:

  • With full respect for dignity, human rights and fundamental freedom of persons.
  • Guided by the Charter of the United Nations and the Constitution of WHO.
  • Guided by the goal of their universal application for the protection of all people of the world from international spread of disease.

The management and prevention of DR-TB requires cooperation by all affected and balancing of community and individual interests. Limitation of individual freedom of choice may be necessary to protect individuals as well as entire communities.

Individual freedom should however be carefully restricted and only when alternative approaches to preventing spread, are not likely to be effective. The following guiding principles should be observed in determining the restrictions:

  • Provide and manage treatment in accordance with the law.
  • Adopt the least restrictive practices that will allow the common good to be protected.
  • Ensure that restrictions are necessary and proportional to the need for protection.
  • Explore all less restrictive measures before implementing more intrusive public health measures.
  • Base intervention on scientific evidence that failure to implement the measure is likely to result in harm to the well-being of the public and society as a whole and not imposed arbitrarily.
  • Attempt to ensure that those impacted by restrictions receive support from the community (i.e., job security, financial support for individuals who are isolated and provision of food parcels and other necessities to their families, and protection against stigmatisation or unwarranted disclosure of private information).

A fair and standard process must be followed when making the decision to isolate people with confirmed MDR- and XDR-TB in order to achieve favourable outcomes. In order to achieve this, the following must be followed:

  • Ensure consistency in applying standards across people and avoid discrimination based on colour, religion and status.
  • Engage patients and their families in the decision-making process and ensure that they give consent.
  • Treat all patients with dignity and respect.
  • Communicate clearly in local language and culturally sensitive manner.
  • Ensure transparency, accountability and no hidden agendas.
  • Maintain impartiality and neutrality in the process of decision-making regarding management.

2.3.2. Patient Management Related Challenges

A number of factors need to considered and addressed when managing patients with DR-TB.

Patient

Some patients might refuse treatment and hospitalisation; other patients may wish to be treated but do not agree to be hospitalised. Some patients request discharge from MDR-TB units while still highly infectious. Decentralisation of MDR-TB care is a solution to this problem.

Community

Implications of continued employment for infectious patients, discharging patients who failed treatment back to communities and disclosure of patients’ condition to family, employer and close contacts need to be discussed with all affected parties. This requires that infection control strategies are implemented in the community to ensure protection of vulnerable groups (e.g., children, HIV-positive people) and intensive community mobilisation to increase awareness and address stigma.

Labour

Working in MDR-TB hospitals exposes staff to a high risk environment for infection, which is a cause for concern for HCWs often results in high staff turnover, refusal to work in high risk areas, and difficulties in recruiting staff. It is vital to ensure that adequate infection control measures are implemented, all staff is protected and occupational health services and compensation for workers who contract the disease are provided.

 

3. ORGANISATION OF SERVICES

 

The Policy Guidelines has been developed based on previous experience in Peru, current efforts at out-patient MDR-TB treatment in KwaZulu-Natal, and in the Western Cape. The Policy Guidelines describe the roles of the different levels of patient management.

 

3.1. Types and Functions of DR-TB Units

 

A DR-TB unit is a health facility where health professionals have been trained to initiate and manage the treatment of DR-TB patients. A DR-TB unit may be a (stand-alone) hospital, a DR-TB ward in a general hospital, or a DR-TB ward in a TB hospital or other specialised hospital.

Hospitalisation provides time for:

  • Initiating DR-TB and HIV treatment;
  • Monitoring the initial response to treatment and possibly adjusting medication;
  • Educating and counselling the patient on MDR-TB and HIV;
  • Assessing the household in preparation for discharge; and
  • Educating and counselling the family and other household members on DR-TB and HIV to optimise family support for the patient in treatment adherence and implementation of household infection control.

3.1.1. Provincial Level

The centralised DR-TB unit is also known as the “Provincial Centre of Excellence”. Each province has at least one hospital that is a specialised DR-TB unit. This hospital will perform a supporting and supervisory role for the MDR-TB outpatient programme in each province, and as the centre of excellence, provide technical advice to the decentralised MDR-TB sites.

Functions of the Centralised DR-TB Unit

  • Initiating treatment of all DR-TB cases after appropriate assessment;
  • Admitting DR-TB cases from the geographic area around the unit;
  • Ensuring hospitalisation of all XDR-TB cases until there are two successive negative TB cultures;
  • Assessing all DR-TB patients attending the clinic each month;
  • Providing DOT to all DR-TB patients attending the unit each day;
  • Recording and reporting to the provincial Department of Health;
  • Providing on-going training, support and supervision for all the facilities in the province;
  • Providing social support, rehabilitation, educational and skills building programmes for patients;
  • Providing education and counselling to all patients admitted in hospital;
  • Preparing a discharge plan for all patients and ensuring effective down referrals;
  • Monitoring DR-TB patients post discharge until completion of treatment and two years post treatment completion;
  • Monitoring  rational usage of second-line  drugs and ancillary drugs for side effects management;
  • Establishing and maintaining functional clinical management teams;
  • Compiling monthly, quarterly, six-monthly and annual reports of DR-TB patients started on treatment, their culture conversion and outcomes;
  • Providing technical assistance and capacity building to decentralised DR-TB units, and feeder clinics on management of DR-TB; and
  • Arranging patients’ evaluations at provincial patient review committees.

 3.1.2. Districts or Sub-Districts

Districts and sub-districts have administrative and management responsibilities in ensuring effective DR-TB services in the area. Their primary functions are to:

  • Trace all confirmed DR-TB patients and refer to the DR-TB hospital;
  • Ensure availability of drugs for the patient at the clinic or district hospital;
  • Establish an efficient patient retrieval system for patients who default DR-TB treatment;
  • Arrange transportation for patient evaluation and follow-up at the DR-TB hospital;
  • Appoint disease outbreak teams to conduct contact screening programmes for all close contacts of confirmed DR-TB patients six monthly for two years;
  • Conduct household assessments prior discharging patients from DR-TB units;
  • Monitor and evaluate DR-TB programme performance;
  • Ensure continuum of care for patients post discharge;
  • Ensure on-going psychosocial support for patients; and
  • Increase awareness and education about DR-TB among communities.

 
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Satellite MDR-TB Units exist to complement bed capacity of decentralised sites. They are essentially transitional and should be capacitated to become decentralised sites. Mobile teams are to be attached to PHC services but operate within the community.

3.1.3. Decentralised DR-TB Units

There will be a number of decentralised DR-TB units in each province, depending on the need, but at least one unit per district is required. These units will be responsible for the initiation and management of DR-TB patients in a defined geographical area, initially as inpatients, but then when appropriate, as outpatients. These units may consist of whole hospitals, wards or sections of existing provincial, district or sub- district level hospitals.

NOTE: Decentralised  DR-TB  units with adequate human resources and infrastructure capacity may initiate treatment and follow up on XDR-TB cases according to the national and provincial Department of Health’s discretion.At least one decentralised unit is required for each district.

Patients diagnosed with MDR-TB who are smear microscopy positive will be hospitalised at the decentralised DR-TB units for up to eight weeks or until they become smear negative on two consecutive tests. This is important given that most patients in South Africa with MDR-TB are co- infected with HIV and will need to commence treatment for both diseases.

Once a patient’s sputum smear microscopy is negative and they meet the criteria for outpatient treatment (see Figure 2), they may receive treatment while living at home. Smear positive patients who refuse admission but are willing to receive medication should still be treated.

Functions of the Decentralised MDR-TB Units

Districts and sub-districts have administrative and management responsibilities in ensuring effective TB and DR-TB services in their areas. Their primary functions are:

  • Initiating treatment of all MDR-TB cases after appropriate assessment;
  • Admitting DR-TB cases when indicated;
  • Providing transportation for patient evaluation and monthly follow up of all DR-TB cases attending clinic;
  • Tracing confirmed DR-TB patients and referring them to the DR-TB hospital;
  • Providing DOT to all DR-TB patients attending the unit daily;
  • Providing social support, rehabilitation, educational and skills building programmes for patients;
  • Providing education and counselling to all patients admitted to hospital;
  • Preparing a discharge plan for all patients and ensuring effective down referrals;
  • Monitoring DR-TB patients post discharge until completion of treatment and two years post treatment completion;
  • Ensuring availability of drugs and monitoring rational usage of second-line drugs;
  • Establishing and maintaining functional clinical management teams;
  • Recording and reporting to the provincial Department of Health;
  • Compiling monthly, quarterly, six monthly and annual reports of DR-TB patients started on treatment, culture conversion and outcomes;
  • Monitoring and evaluating DR-TB programme performance;
  • Providing technical assistance and capacity building to satellite MDR-TB units and feeder clinics on management of DR-TB;
  • Monitoring treatment side effects;
  • Ensuring referral of patients with XDR-TB, adverse drug reactions (ADRs) and complicated disease to the centralised DR-TB unit; and
  • Tracing all confirmed cases. 

 

 
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3.1.4. Satellite MDR-TB Units

Satellite units may be based at district or psychiatric hospitals, community health centres, or correctional services facilities. These are transitional structures that should have the capacity to become decentralised sites. Satellite MDR-TB units should exist to:

  • Admit and follow up MDR-TB patients initiated on treatment at decentralised sites; and
  • Serve patients who refuse to start treatment unless they are closer to home.

After the assessment and initiation of MDR-TB therapy (by a centralised or decentralised DR-TB unit), patients may be referred to a satellite MDR-TB unit where they will receive treatment and are monitored daily. Nurses, with the support of a doctor based at the centralised or decentralised DR-TB sites should monitor the health of the patient.

An improvement in the patient’s medical condition (e.g., weight gain, no fever, no cough, etc.) indicates that s/he is tolerating all MDR-TB drugs and HAART and is smear negative. Patients can be discharged to the community and continue receiving treatment either from the mobile team or their nearest primary health-care facility. At times MDR-TB treatment may be administered in institutions such as prisons, mining health facilities or psychiatric hospitals. The initial period of hospitalisation should be between two and eight weeks.

Initially the patient should return monthly to the decentralised DR-TB site for on-going management of their condition. When the programme is established and the staff at satellite MDR-TB sites are trained, it may be possible for patients in the continuation phase to be monitored monthly at satellite MDR-TB sites. Until then, the patient should travel once bi-monthly or quarterly to the decentralised DR-TB site.

Satellite MDR-TB units should not initiate MDR-TB treatment. They may eventually be upgraded to a decentralised MDR-TB unit if they have adequate and trained staff and infrastructure.

Functions of Satellite MDR-TB Units

  • Admitting all MDR-TB cases referred from centralised or decentralised DR-TB units;
  • Ensuring monthly follow up of all DR-TB patients attending the unit;
  • Providing DOT to all DR-TB patients attending daily;
  • Educating and counselling all patients admitted to hospital;
  • Preparing a discharge plan for all patients and ensuring effective down referrals;
  • Monitoring treatment side effects; and
  • Ensuring referral of patients with XDR-TB, severe ADRs, and complicated disease to the centralised DR-TB site.

 
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3.1.5. Primary Health Care Facilities

Primary health care (PHC) facilities play a significant role in providing injectables at clinics and DOT to all DR-TB patients in their areas. This must be integrated with the treatment of other TB and HIV patients. The existing TB nurses will be trained to handle these activities. It is not necessary to have dedicated DR-TB nurses at the primary health care level.

Patients who have access to a PHC clinic should utilise the health facility for their daily injections and DOT. The facility-based staff will monitor side effects and adherence; provide education on the disease, and monitor household infection control practices. Minor side effects such as nausea, vomiting and diarrhoea should be managed by the nurse at the facility, but the patient should be referred to the decentralised DR-TB unit for management of more serious side effects. In addition, the nurse at the facility should be responsible for contact tracing and serve as the link between the decentralised DR-TB unit and MDR-TB patients treated at the facility.

PHC facilities treating MDR-TB patients will be supported by the nearest decentralised DR-TB unit or the centralised DR-TB unit or provincial centre of excellence if it is closer to the facility.

Functions of Primary Health Care Facilities

  • Identifying high risk groups;
  • Screening and testing symptomatic high-risk groups;
  • Tracing patients with a confirmed diagnosis of DR-TB;
  • Notifying the district TB coordinator;
  • Providing initial counselling and education of the patient and family;
  • Preparing patient for hospital admission when indicated;
  • Coordinating referrals to the centralised and decentralised DR-TB units;
  • Ensuring monthly follow up of all DR-TB cases attending a clinic;
  • Providing DOT to all DR-TB patients attending daily;
  • Conducting contact screening of close contacts;
  • Following up patients initiated to start community-based treatment or patients who are post discharge from hospital;
  • Coordinating follow up visits in hospital;
  • Tracing treatment interrupters;
  • Collecting monthly sputum and other routine tests;
  • Monitoring treatment side effects and;
  • Ensuring referral of patients with XDR-TB, severe ADRs, and complicated disease to the centralised DR-TB unit.

Contact Tracing and Monitoring

Contact tracing and monitoring is an important role of the PHC facilities through the mobile teams and DOTS supporters. Measures for contact tracing and monitoring include:

  • Listing and examining all contacts and testing those with symptoms in accordance with existing TB protocols;
  • Re-testing contacts with symptoms for TB and drug susceptibility six-monthly for two years;
  • Ensuring that the MDR-TB patient is continuously screened for signs and symptoms; and
  • Offering HIV counselling and testing to contacts.

 
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3.1.6. Mobile Teams

Mobile teams are also called mobile MDR-TB units. These are units based at the PHC facility or a satellite MDR-TB unit. They provide injections to patients at their homes, supervise intake of oral tablets, and educate family about infection control.

Patients who are unable to access a health facility daily should, for the duration of the injectable phase of treatment, be visited daily at home (five times a week) by a mobile team, which should consist of a driver and nurse. During these visits, the team will administer injectable drugs, observe the patient taking their oral drugs, monitor side effects and adherence, provide education on the disease, and monitor household infection control practices. Minor side effects such as nausea, vomiting and diarrhoea should be managed by the nurse on the mobile team, but the patient should be referred to the decentralised DR-TB site for management of more serious side effects. The mobile MDR-TB unit should also be responsible for contact tracing and serve as the link between the decentralised DR-TB site and MDR-TB patients in the community. In some instances the mobile MDR-TB unit will also carry out TB programme activities such as tracing defaulters from the TB programme or giving re-treatment patients streptomycin injections.

Existing TB tracer teams may expand their mandate by taking care of MDR-TB patients. Again, these teams need to take care of all TB and HIV patients. Their scope should not be restricted to MDR-TB care.

Functions of Mobile Teams

  • Provide DOT to all DR-TB patients in the area;
  • Provide patient, family and community education on TB;
  • Monitor treatment side effects and referring to the nearest health-care facility when necessary; and
  • Maintain appropriate records.

 
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3.1.7. Community Level: DOTS Supporters/Caregivers

Depending on the local situation, the DOTS supporters may be community caregivers, community DOTS volunteers or family members. It should be noted that training is very important for this cadre of supporters, and compensation should be considered because DOT is the department’s core business. Family members should only be used as a last option because they may be coerced by other family members, making them less objective as community caregivers.

Patients and their designated household treatment supporters must be trained on the natural history of MDR-TB and HIV as well as in basic infection control (e.g., cough hygiene and the basic principles of isolation), MDR-TB medications, common side effects/toxicity, and the role of HIV in TB infection. Family planning during MDR-TB treatment should be encouraged. Community caregivers should provide on-going daily support to MDR-TB patients who are treated on an outpatient basis.

If the patient is on HAART, the patient and treatment supporter should receive literacy training according to current practice. This must be given by staff trained in MDR-TB and integrated TB and HIV care. Any training that takes place in the clinical setting will be separated in space and time from the HAART programme to avoid nosocomial transmission. In addition, education for the patient, household supporter, and possibly even the treatment supporter should be given at individual patients’ home by the mobile MDR-TB unit.

Given the important role of the treatment supporter, s/he should preferably be HIV-negative and have access to a support group and regular TB screening.

Functions of Community Level Services

  • Provide DOT to all DR-TB patients in the area;
  • Provide patient, family and community education on TB;
  • Monitor treatment side effects and referring to the nearest health-care facility when required; and
  • Maintain appropriate records.

Table IX describes the responsibilities of staff working at various levels of MDR-TB care.

 
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3.2. Management Teams/Committees at Different Levels

 

The provincial TB directorates are responsible for setting up management teams and committees to oversee the clinical management of DR-TB patients in the province.

3.2.1. Provincial DR-TB Review Committee

Each province should establish a management team to support and advice in difficult clinical cases, medico-legal and ethical issues such as termination of MDR-TB treatment in a patient who does not respond to treatment. This committee must be multi-disciplinary and should include medical officers and/or professional nurses from the DR-TB hospital, physicians, pathologists, paediatricians, cardio-thoracic surgeons, public health specialists, radiologists, civil society representatives, social workers, provincial management and a specialist in legal and ethical issues. Other representatives from government departments such as Social Development, Correctional Services, Military Health Services, South African Social Security Agency, and the mining industry may be included in this committee.

This committee advises and recommends on the following:

  • Appropriate clinical management of individual MDR- and XDR-TB patients;
  • Use of salvage regimens in individual patients with high-grade resistance;
  • Management of chronic drug resistant TB regarding termination of treatment and palliative care;
  • Management of patients who refuse treatment;
  • Management of infectious patients who do not cooperate with the health professionals and those who abscond from hospital or refuse to be admitted; and
  • Development of provincial criteria on pass-outs.
  • Identification and resolutions to health systems issues contributing to poor service delivery such as delays in culture results or shortages of medication.

3.2.2. District and Sub-District Level

At a district and sub-district level co-ordination of DR-TB activities will be done by the district and sub-district TB co-ordinators and the district TB team if there is one. This team will be responsible for:

  • Informing (PHC) staff of the latest developments regarding DR-TB;
  • Disseminating and training PHC staff on the latest guidelines regarding when sputum cultures should be taken so that patients with DR-TB are diagnosed as soon as possible;
  • Referring patients diagnosed with DR-TB to the decentralised unit for initiation of treatment;
  • Ensuring that PHC staff feel supported in their treatment of patients with DR-TB;
  • Ensuring that there are no interruptions in treatment as the patient moves from being an inpatient to receiving care in the community; and
  • Monitoring and referring patients receiving treatment in the community.

Patient support groups should be formed at all levels of care to enhance adherence.

 

3.3. Treatment Follow Up

 

DR-TB treatment should be monitored closely through daily DOTS and recording of patients taking their drugs and receiving injections. Sputum for smear microscopy and culture should be collected every month for the duration of treatment. Depending on where the patient receives care, daily DOTS and recording of patients taking their drugs and receiving injections should be done by the decentralised DR-TB site, mobile team or the satellite unit administering medication. Sputum collection and the monitoring of smear microscopy, culture and DST results should be conducted at the decentralised DR-TB site.

Adverse drug reactions should be monitored continuously by the facility where the patient receives treatment or the mobile team and DOTS supporters. ADRs should be assessed using a check-list and where necessary reported without delay to supervising unit. ADRs must be treated aggressively as this will enhance treatment adherence.

Details of the patient’s HIV status and HAART, including the commencement date and treatment regimen must be recorded in the patients’ notes. The clinical and laboratory evaluations that should be conducted monthly are listed in Table XI.

 
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3.4. Infection Control

 

3.4.1.  Home Infection Control

Mobile teams including DOTS supporters should educate patients and household members. Home infection control will be encouraged and monitored. Home infection control includes the following:

  • Ensuring adequate ventilation/open windows;
  • Isolating patient (own bedroom where possible);
  • Promoting cough hygiene;
  • Ensuring that patients use surgical mask during waking hours while at home or when meeting with others;
  • Refraining from close contact with children;
  • Maximising time in open-air environment (e.g., receiving visitors outside);
  • Advising all household members and regular contacts to undergo HIV tests;
  • Minimising contact with known HIV positive patients; and
  • Ensuring that household members are screened for TB and DR-TB every six months.

Infection Control during Home Visits

Mobile teams should decrease the risk of contracting DR-TB by adhering to the following infection control measures:

  • Wearing an N95 respirator (health workers and DOTS supporters);
  • Keeping home visits or clinical evaluations brief, and whenever possible, conduct these outside or in a well-ventilated room with as much distance as possible from the patient;
  • Educating the patient on cough hygiene and avoiding close contact;
  • Providing the patient with a surgical mask when close contact is required; and
  • Collecting sputum outside, observing prescribed infection control precautions.

3.4.2. Infection Control during Patient Transport

When transporting DR-TB patients, the following infection control measures should be observed:

  • Use compartmentalised vehicles separating the airspace of the driver from that of the passengers;
  • Open vehicle windows;
  • Provide surgical mask for patient;
  • Provide N95 masks for medical staff and driver; and
  • Educate patient.

Health workers who have contact with DR-TB patients should know their HIV status. If they do not, they should be encouraged to be tested for HIV. Health workers who are HIV-positive should commence ART when appropriate and be screened every six months for TB and have a TB culture done at the time of ART initiation and on an annual basis.

 

3.5. Building Treatment Capacity to Meet the Increasing Burden of MDR-TB

 

It is clear that cases of MDR-TB are on the rise in South Africa. To meet this need, treatment services are being expanded to decentralised treatment facilities and community-based programmes are being developed and expanded. It is imperative that innovative approaches to expand access to MDR-TB treatment are explored.

Nurse-initiated treatment programmes are an important option that has proven successful for HIV management throughout the world. Data on nurse-initiated TB/HIV treatment are beginning to emerge in conference proceedings. South African researchers have documented the successful integration of a nurse-based screening algorithm for pulmonary TB compared with physician diagnosis, and a randomised controlled trial is now underway to evaluate PALSA-Plus nurse-led management strategies throughout primary health-care clinics.

The mounting evidence for nurse management coupled with the continued expansion of community-based MDR-TB programs compels key stakeholders to consider the most appropriate approaches to address the epidemiologic circumstances facing the country.

 

3.6. Conclusion

 

Issues addressed in this Section, Organisation of Services, are also covered in the Multi-Drug Resistant Tuberculosis: A Policy Framework on Decentralised and Deinstitutionalised Management for South Africa. Our MDR-TB services are still medical practitioner-driven. All MDR-TB patients are being initiated on treatment by medical practitioners. Given the high burden of MDR-TB in the country, we will gradually phase in nurse-initiated MDR-TB component to address this challenge.

 

4. CASE FINDING STRATEGIES

 

4.1. Risk Groups for MDR-TB

 

Intensified case finding should be conducted among patients at high risk of MDR-TB based on the history. Specific elements of the history that suggest an increased risk for drug resistance are listed in the table below.

 
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4.2. Intensified Case Finding for MDR-TB

 

Routine culture and first-line DST should be done for the following groups of patients:

  • New TB patients who remain sputum smear-positive after two months of treatment or who become positive after five months of treatment.
  • All newly diagnosed re-treatment TB patients.
  • Symptomatic close contacts of confirmed MDR- and XDR-TB patients.
  • Symptomatic individuals from known high-risk groups, including HCWs, laboratory workers, prisoners, mine workers and HIV-positive individuals in high MDR-TB prevalence areas.

First-line DST should include testing for isoniazid and rifampicin mainly; ethambutol and streptomycin should not be included routinely as this does not change the management of MDR- TB patient.

Previously treated TB (retreatment) patients may have had DST results in the past that may no longer reflect the resistant pattern of the strain they have at the time of MDR-TB diagnosis.  DST should therefore be performed again in all patients who have received TB treatment since the date of their last DST result.

Young children may not be able to produce sputum specimens, therefore other measures such as gastric aspiration and/or induced sputum should be considered to obtain a specimen for confirmation of diagnosis. Children with TB disease who are close contacts of patients with MDR- TB may be started on MDR-TB treatment until it is confirmed that they do not have MDR-TB.

 

4.3. Intensified Case Finding Strategies for XDR-TB

 

All strains identified as MDR-TB should routinely undergo second-line DST in order to diagnose or rule out XDR-TB. In specific instances, (i.e. when  screening contacts of known XDR-TB patients), second-line DST should be requested together with first-line DST. The tests that should be conducted routinely are kanamycin, ofloxacin, capreomycin, moxifloxacin and ethionamide. Other tests may be conducted on request by the treating clinician.

 

5. DIAGNOSIS OF DR-TB

 

5.1. Introduction

 

In the majority of cases, the development of DR-TB is insidious and progresses over weeks and months. As a result, patients often ignore the symptoms or accept them as symptoms related to the daily stresses, lack of sleep and from being overworked, therefore delay seeking health care.

DR-TB may also be associated with other serious disorders, such as HIV infection, alcoholism, renal failure, diabetes mellitus, cancers and drug abuse. The signs and symptoms of these conditions and their complications can easily obscure those of DR-TB and can also result in considerable delays in diagnosis or in misdiagnosis, especially in patients with HIV infection.  It is therefore important that HCWs have a high index of suspicion for DR-TB as early diagnosis and initiation of treatment is critical in the prevention of amplification of resistance and extensive lung damage resulting in complicated forms of disease which are more difficult to treat.

 

5.2. Signs and Symptoms of DR-TB

 

The symptoms of DR-TB are the same as for drug-susceptible TB:

  • Cough
  • Chest pain
  • Dyspnoea
  • Haemoptysis
  • Systemic symptoms (i.e.,fever, chills, nights sweats, tiredness, anorexia, weight loss)

In addition to the systemic effects of DR-TB, there may be remote manifestations unrelated to the site of involvement. These include haematologic abnormalities, hyponatraemia and psychological disorders. The most common haematological manifestations include increases in the peripheral blood leukocyte count and anaemia. The increase in leukocyte count is usually slight, but leukemoid reactions and leukopenia may occur. An increase in the peripheral blood monocyte and eosinophil counts may also occur. Anaemia is common in disseminated DR-TB disease.

Extra-pulmonary DR-TB presents more of a diagnostic challenge because it involves relatively inaccessible sites, and depending on the organs involved, fewer bacilli can cause much greater damage.

 

5.3. Assessing a Patient for DR-TB

 

An initial evaluation for DR-TB should include:

  • A complete medical history
  • A physical examination
  • Bacteriological investigations to confirm the diagnosis

5.3.1.  Medical History

A proper history of the patient must be recorded. These should include the elements listed below.

  • History of presenting symptoms including cough and duration of the cough, sputum production, fever, night sweats, loss of appetite, unintentional weight loss (determine extent of weight loss and the time period), dyspnoea, chest pains, haemoptysis, abdominal pain, nausea, vomiting, diarrhoea, constipation, headache, peripheral leg pain, hearing loss, depression, anxiety.
  • Medical history should include previous TB episodes, previous treatment regimen, time to smear or culture conversion, treatment outcomes for each episode (if multiple) and participation in clinical trials, chronic medical illness such as other medical conditions such as diabetes mellitus, renal disease, malignancies, chronic malabsorption syndrome, prolonged corticosteroid therapy, immunosuppressive therapy and HIV infection, which may affect clinical management, allergies, pregnancy, last menstrual period, method of contraception, prior psychiatric illness, medication that the patient may be taking other than TB treatment.
  • Surgical history including any surgical procedures the patient has undergone and the reasons.
  • Work history should focus on any experience in the mining industry, stay in either TB hospital or prison and laboratory work.
  • Social history should include substance abuse (alcohol, tobacco and other drugs).
  • Previous confinement in a hospital, prison and duration should be noted.
  • Family history of TB, screening of close contacts, confirmation of disease in and treatment of contacts, history of DR-TB exposure should be noted.

All patients who do not know their HIV status should be offered counselling and voluntary testing.

It is important to determine the baseline clinical parameters on initiation of treatment in order to monitor the patient’s progress whilst on treatment and will enable early detection of any other co- morbid conditions that may require adjustment of the treatment regimen or ancillary treatment.

  • The initial physical examination must include the examination of the skin, head, neck, oropharynx, cardiovascular system, pulmonary system, abdominal organs, extremities, and nervous system. The vital signs (i.e., heart rate, blood pressure, respiratory rate, weight and height) must be recorded.
  • Laboratory and other baseline tests such as chest x-ray, urine pregnancy test (where indicated), urea and electrolytes, creatinine, full blood count, HIV test, liver function tests, audiometry and psychiatric evaluation where indicated.

5.3.2. Physical Examination

A physical examination is an essential part of the evaluation of any patient therefore all vital signs must be obtained. The physical signs cannot be used to confirm or rule out DR-TB, but can provide valuable information about the patient’s overall condition and other factors that may affect patient management.

The clinical presentation of patients with DR-TB is similar to those of patients with drug-susceptible TB, and patients often present with cavitary lung lesions.

5.3.3. Laboratory Diagnosis of MDR- and XDR -TB

MDR-TB is often suspected clinically when a patient has a persistently positive smear microscopy or culture result, or when a patient fails to respond to treatment despite documented good adherence. MDR- or XDR -TB can also be suspected when a person has had exposure to a confirmed or suspected MDR- or XDR -TB patient. Demonstrating in vitro resistance in the M. tuberculosis isolate from the patient is the only definitive diagnosis of MDR- or XDR-TB.

The quality of DST is of paramount importance and impacts directly on treatment. All laboratories performing TB culture and drug susceptibility testing must be part of a recognised external quality assurance programme including TB microscopy, TB culture and DST. The use of line probe assay is recommended. However, it must be noted that the line probe assay will only be done on TB smear positive patients or culture positive patients. Therefore the line probe assay does not replace conventional DST. Patients diagnosed on line probe assay will be started on treatment immediately. Conventional DST confirmation is not required.

5.3.3.1. Microscopy

Although direct microscopy is the cornerstone of diagnosis of pulmonary TB, it cannot distinguish between drug-susceptible and drug-resistant M. tuberculosis, or between different species of mycobacterium. The use of microscopy in DR-TB is limited to:

  • Evaluating the infectiousness of patients.
  • Triaging specimens for culture and DST.
  • Confirming that bacterial growth on culture are acid-fast bacilli and not contaminants.

The sensitivity of smear microscopy is in the region of 30% to 60% when compared to culture, as at least 5 000 to 10 000 organisms per ml of sputum need to be present to allow visualisation, as only a small amount of the sputum is actually viewed.  Nevertheless, the infectiousness of DR-TB patients correlates crudely with the number of AFB in the sputum smear as measured by conventional semi-quantitative methods, other factors being equal. Smear microscopy, however, cannot distinguish viable from nonviable bacilli, so its use in monitoring of progress on treatment is limited.  For example, even with adequate treatment, DR-TB patients may become culture negative but remain smear positive suggesting that the bacilli are non-viable.

The turnaround time for microscopy results should be less than 48 hours, depending on the work load and the transport time to the laboratory. Results must be reported as ‘positive/ negative for acid fast bacilli’ and quantified, as quantification may serve as an indication of disease severity.

5.3.3.2. Culture

Mycobacteria are slow growing organisms with a mean generation time of 12 to 18 hours, so culture results for TB may take several weeks. Mycobacteria also require special culture media. A variety of suitable culture media and differential tests for species identification are available. A commercial automated system using liquid media (BACTEC Mycobacterial Growth Indicator Tube (MGIT) 960; Becton Dickinson) is used as the culture medium of choice in the National Health Laboratory Service (NHLS). This system uses a fluorescence quenching-based oxygen sensor to detect mycobacterial growth.

Timeous transport of specimens to the laboratory is critical, as any delays will result in a decrease in the viability of the mycobacteria as well as contamination due to overgrowth of common respiratory bacteria. Specimens should therefore be kept cool during transportation or refrigerated at 4°C if

delays are anticipated. Inadequate decontamination process in the laboratory compromises the growth and isolation of mycobacteria. It can also adversely affect the culture yield.

Culture results are reported as positive or negative in the MGIT automated system, together with an indication of the time to positivity, which may be a reflection of the severity of disease. The results should always be correlated with the patient’s clinical condition, and investigations repeated if necessary.

False negative cultures may result from inadequate specimens, poor laboratory technique, and delayed transport of the specimens to the laboratory. Cross contamination of specimens may lead to false positive results.

5.3.3.3. Identification of M. tuberculosis

The overwhelming majority of mycobacterial isolates will be M. tuberculosis in HIV negative patients. However, the prevalence of non-tuberculous mycobacteria (NTM) can be higher in HIV positive patients.  Unless the species is confirmed as M. tuberculosis, mycobacterial isolates appearing phenotypically resistant to anti-TB drugs may not be DR-TB, but due to infection with NTM. Treatment of NTM is entirely different from DR-TB; therefore M. tuberculosis should always be confirmed following culture.

5.3.3.4. Drug Susceptibility Testing

Drug susceptibility testing (DST) is required to make a definite diagnosis of MDR-TB. DST can be done by several methods. The MGIT methodology distinguishes susceptibility from resistance by comparing growth in plain (control) medium to growth in medium to which specified concentrations of drugs have been added.

Limitations of DST

  • With conventional methodologies, growth detection, identification of M. tuberculosis and DST may take weeks or even months.
  • Different anti-TB drugs have different ‘critical concentrations’ (the breakpoint between calling a strain resistant or susceptible), which also depend on the culture medium used for DST.
  • DST for first-line anti-TB drugs has  been thoroughly studied and consensus reached on appropriate methodologies, critical drug concentrations, and reliability and reproducibility of testing. The intrinsic accuracy of DST varies with the drug tested: for first-line drugs DST is most accurate for rifampicin and isoniazid and less so for streptomycin and ethambutol.
  • DST for second-line anti-TB drugs (SLDs) is much more problematic and has not been standardised internationally, due to technical difficulties related to in vitro drug instability leading to drug loss.  Laboratory technique also influences DST results. In addition, the drug concentration defining resistance (critical concentration) is often very close to the minimal inhibitory concentration (MIC) required to achieve anti-mycobacterial activity, increasing the probability for misclassification of susceptibility or resistance and leading to poorer reproducibility of second-line DST results.
  • SLDs that are more stable in different test environments and have shown relatively good reproducibility are aminoglycosides, polypeptides, and fluoroquinolones. The reproducibility and reliability of DST for PAS, cycloserine, terizidone and thioamides are much more limited while the correlation of DST results with clinical response to treatment has not yet been established. In addition, the relevance of in vitro cross-resistance between drugs in the same group is difficult to interpret clinically.

HCWs treating patients with DR-TB must be aware of the limitations of DST and interpret the results with the constraints in mind.  TB organisms that test susceptible to specific drugs have a higher probability of responding effectively on treatment with those drug(s) than organisms that test drug-resistant.  Discrepant results must be interpreted with care.

5.3.3.5. The Use of GeneXpert in the Diagnosis of MDR-TB

GeneXpert MTB/RIF (GXP) is a relatively new diagnostic tool for TB diagnosis in South Africa. This test has an advantage over the existing TB smear microscopy because it has higher sensitivity, specificity and identifies many patients that would not have been diagnosed using TB microscopy. The Xpert MTB/RIF test reports MTB detected or not detected and also provides data on the state of susceptibility or resistance to rifampicin.

 
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All patients with GXP MTB positive results (rifampicin susceptible or inconclusive) will be started on TB treatment at the point of diagnosis.

All patients with GXP MTB positive results with resistance to rifampicin will be referred to MDR-TB facilities to commence MDR-TB treatment. The following steps will be followed at the MDR-TB facility regarding GXP MTB positive patients with resistance to rifampicin:

  1. Open patient’s file.
  2. Examine patient prior to starting treatment.
  3. Take a sputum sample for TB culture and DST for MDR-TB confirmation.
  4. Start MDR-TB treatment. Isoniazid (INH) may be included.
  5. Register these patients under the category MDR-TB ‘not confirmed’.
  6. Review MDR-TB treatment after receiving laboratory confirmation, meaning that MDR-TB treatment will be continued if diagnosis is confirmed; MDR-TB treatment maybe stopped if MDR-TB is not confirmed. However, as already outlined conventional culture and DST is an imperfect gold standard and therefore results should be interpreted in the clinical context and the possibility of falsely negative phenotypic DST should also be borne in mind. An experienced physician should be consulted if appropriate. A new and updated Xpert cartridge will become available late 2011 and this recommendation may be revised in the light on performance characteristics of the new cartridge.
  7. Review patient’s category in the register: change from MDR-TB not confirmed to MDR-TB confirmed upon laboratory TB culture and DST or Line Probe Assay (LPA); on the contrary the MDR-TB not confirmed will be de-registered or deleted from DR-TB register and recorded as drug-susceptible TB on ETR.net.

Note: When a sample is taken from GXP MTB positive rifampicin-resistant patients, the following will take place:

  1. The sample will be subjected to smear microscopy test
  2. All smear positive tests will be subjected to Line Probe Assay leading to a quick confirmation
  3. All smear negative samples will go through TB culture (MGIT) and later be subjected to LPA if the sample becomes culture positive and TB bacilli identified. This will take longer.
  4. If an organism is shown to be resistant to rifampicin and/or isoniazid, DST for second-line drugs (fluoroquinolone and aminoglycoside) will also be performed.

 
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6. MANAGEMENT OF PATIENTS WITH MONO- AND POLY- DRUG RESISTANT TB

 

6.1. Introduction

 

Patients with mono- and poly-drug resistant strains of M. tuberculosis are not classified as MDR- TB or XDR-TB. Mono-resistance is defined as resistance to a single first-line anti-TB drug, while poly-drug resistance is resistance to two or more anti-tuberculosis drugs other than both rifampicin and isoniazid.

 

Routine testing for mono- and poly-drug resistant TB in all TB patients is not recommended as the majority of patients with mono- or poly-drug resistant TB will be cured with standard first-line chemotherapy.

 

6.2. Treatment of Patients with Mono- and Poly-Drug Resistant TB

 

With the exception of streptomycin, definite randomised or controlled clinical trials have not been conducted to determine the best treatment options for various types of drug resistance. Recommendations are based on evidence from the pre-rifampicin era, observational studies, general principles of microbiology and therapeutics in TB, extrapolation from anecdotal evidence and expert opinion.

 

The design of regimens for mono- and poly-drug resistant TB requires experience and should be done under supervision of the provincial DR-TB clinical review committees. The treatment history, DST pattern and the possibility of strains of M. tuberculosis having acquired additional resistance should be considered before deciding on an appropriate regimen.         

 

Some of the specific issues that should be considered when designing an appropriate regimen are described below.

 

6.2.1. Timing of DST Results

 

 

Because of the inevitable delay in culture and DST, the DST result that prompts a change in treatment may not accurately reflect the bacterial population at the time it is reported as it reflects the bacterial population at the time that the sputum specimen was collected.  The treatment regimens for mono- and poly-drug resistant TB assume that the pattern of drug resistance has not changed during this interval and should not be used if further resistance to any of the drugs is suspected.

 

6.2.2. Use of Pyrazinamide DST Results

 

DST results for pyrazinamide are unreliable and resistance to pyrazinamide should be assumed depending on the prior treatment history; in this case an alternative regimen should be used. However, pyrazinamide should be considered for inclusion in the regimen in certain circumstances as a considerable proportion of patients could still harbour pyrazinamide susceptible strains.

 

6.2.3. Development of Further Resistance

 

Further resistance should be suspected if the patient was on the functional equivalent of only one or two drugs for one month or more. For example, pyrazinamide is not regarded as a good companion drug to prevent resistance. If the patient was only receiving rifampicin and pyrazinamide (due to resistance to isoniazid and ethambutol), resistance to rifampicin may develop. Therefore, it is crucial to determine which functional drugs the patient received between the time of specimen collection and the time of initiation of the treatment regimen.

 
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The regimens in Table XIII, which is a simplified table, are an adaptation of regimens suggested in the WHO guidelines.

All mono- and poly-drug resistant patients are to be recorded in the DR-TB register. All provinces that are still keeping them in the drug-susceptible register should put systems in place to address this matter.

Patients that are mono-drug resistant to rifampicin must be recorded as MDR-TB ‘not confirmed’.

Mono- and poly-drug resistant TB patients should be followed using:

  • TB microscopy  and TB culture every month during intensive phase until TB culture conversion.
  • TB microscopy and culture monthly during continuation phase
  • DST (repeated) if unsatisfactory clinical and biological progress after 3-4 months of treatment.

 

7. MANAGEMENT OF PATIENTS WITH MDR-TB

 

7.1. Introduction

 

Treatment of patients with MDR-TB involves second-line drugs. They are much more expensive, less effective and have more side effects than first-line TB drugs. The design of treatment regimens for patients with MDR-TB poses several challenges, complicated by a limited choice of second- line drugs, with greater toxicity and less efficacy.  As with drug-susceptible TB, the use of multiple drugs is imperative to prevent the development of additional resistance. Consideration of cross- resistance is also important when designing treatment regimens for MDR-TB.

Before the patient is referred to the MDR-TB hospital the following must be done at the diagnosing clinic:

  • Ensure that all details regarding the treatment are communicated to the patient; this will enable the patient to take an informed decision on consent to treatment.
  • Counsel and educate the patient and family member. This should include information on what MDR- or XDR-TB is, how one is infected, why one needs to be admitted to hospital, length of hospitalisation and the treatment, what is going to happen in hospital and what happens after discharge.
  • Address any patient concerns.
  • Verify patient’s physical and work address.
  • Enquire about close contacts at home or work.
  • Arrange for screening of and testing of all contacts.
  • Provide a checklist of things the patient will need to take with to hospital.
  • Make the necessary transport arrangements for the patient and a family member where necessary to the MDR-TB hospital.

 

7.2. Definitions of Terms used to Describe Treatment Strategies

 

Common treatment strategies include:

Standardised Treatment Regimen

Drug-Resistance Survey (DRS) data from representative patient population are used to base regimen design in the absence of individual DST. All patients in a defined group or category receive the same regimen. Not confirmed MDR-TB patients should be confirmed by DST whenever possible. In South Africa, we have a standardised regimen. All newly diagnosed MDR-TB patients receive a standardised regimen.

Standardised Treatment Regimen followed by Individualised Treatment Regimen

Patients on standardised regimen may be switched to an individualised regimen when other DST results become available. Each regimen is individually designed based on the patient’s previous history of anti-tuberculosis treatment and individual DST results.

Empiric Treatment followed by Individualised Treatment

Empirical treatment regimen is given to MDR-TB patients diagnosed on clinical grounds. DST of the presumed MDR-TB contact is considered as well as DRS data from the representative patient population. Commonly, an empirical regimen is adjusted when DST results on the individual patient become available

 

7.3 Standardised MDR-TB Regimen

 

The limited number of available second-line drugs imposes obvious limitations on the design of adequate MDR-TB treatment regimens. The most successful treatment regimens are those that include multiple drugs, which the patient had not previously received. A standardised MDR-TB regimen is recommended and this is based on the country-specific profiles of drug resistance and previous drug use of second-line drugs.

The design of the standardised regimen is based on first-line DST at diagnosis. DST of ethambutol and pyrazinamide do not have high reproducibility and reliability.

The standardised regimen consists of at least six months intensive phase treatment with five drugs:

Kanamycin/amikacin, moxifloxacin, ethionamide, terizidone and pyrazinamide taken at least six times per week during the injectable phase followed by a continuation phase treatment with four drugs moxifloxacin, ethionamide, terizidone and pyrazinamide) taken at least six times per week.

Levofloxacin will be used in patients who may not tolerate moxifloxacin.

Administration of the standardised regimen has been simplified across four weight bands to accommodate the formulations available in the country while complying with the international requirements for minimum, maximum and average dose per kg.

Ethambutol may be used as an additional item (sixth item in the standardised regimen) in areas with confirmed low prevalence to ethambutol resistance or in patients who have not received ethambutol for more than one month before DR-TB treatment.

The standardised treatment regimen described above applies only to MDR-TB patients previously treated with regime 1 or regime 2 of our TB programme, these are patients who have not been previously exposed to second-line anti-tuberculosis agents.

Patients who were previously exposed to second-line anti-tuberculosis drugs will require an individualised regimen based on two factors: firstly history of anti-TB drugs received and secondly DST results.

  • In principle, any agent not previously received by the patient is likely to be susceptible and any agent used for more than a month before is likely to be resistant.
  • Most MDR-TB patients who were exposed to first- and second-line anti-TB drugs and patients with resistance to an injectable or a fluoroquinolone will require drugs such as capreomycin, para-amino salicydic acid granules, moxifloxacin or levofloxacin, high dose INH and clofazimine among other drugs in their regimens.

 

 

7.4. Second-Line Drugs

 

The following first- and second-line drugs are available locally for the treatment of DR-TB.

Pyrazinamide and/or ethambutolare used in second-line treatment, given the limited number of second-line drugs available. Resistance to pyrazinamide is neither easy to acquire nor easy to prove by DST. Pyrazinamide has a bactericidal effect in an acid medium (bacilli inside macrophages), it should initially be used in combination with an aminoglycoside (active against multiplying bacilli outside macrophages) to obtain maximum effect.

Ethambutol is a valuable agent for preventing the emergence of resistance to other drugs. Ethambutol is no longer part of the standardised regimen due to lack of high reproducibility, reliability and high level resistance to MDR-TB strains.

Aminoglycocides: Kanamycin and amikacin are parenteral drugs that are structurally similar. Strains resistant to streptomycin are usually susceptible to kanamycin and amikacin. Resistance to kanamycin induces almost complete cross-resistance with amikacin and they should be considered as the same drug. Amikacin is as active as kanamycin and better tolerated, but much more expensive.

Polypeptide: Capreomycin is a cyclic polypeptide that differs structurally from kanamycin, amikacin and does not exhibit uniform cross-resistance with the aminoglycosides.

Thioamides: Ethionamide and prothionamide are two different presentations of the same active substance, with bacteriostatic activity against M. tuberculosis at therapeutic concentrations; they are bactericidal at higher concentrations. The pharmacokinetics of the two preparations is very similar, but prothionamide may be better tolerated. They induce complete cross-resistance and should therefore be regarded as the same drug.

Fluoroquinolones: Moxifloxacin is a preferred drug in the management of MDR- and XDR-TB. There is limited evidence that shows that strains resistant to ofloxacin may still be susceptible to moxifloxacin (i.e., there is not complete cross-resistance between these fluoroquinolones). Ofloxacin and levofloxacin will be used in patients younger than 8 years and adults who may not tolerate moxifloxacin.

Ciprofloxacin must not be used as an anti-tuberculosis agent in the management of DR-TB because of its weak efficacy compared with other fluoroquinolones.

Terizidone and Cycloserine: Terizidone is a combination of two molecules of cycloserine and they should therefore be regarded as the same drug. Terizidone and cycloserine are bacteriostatic at the recommended dosage. Both drugs have a high incidence of side effects, specifically related to central nervous system toxicity, and can precipitate focal or grand mal seizures with high serum concentrations. Psychotic disturbances and suicidal thoughts have been reported in patients with appropriate serum concentrations. Pyridoxine (150 mg) should be given together with terizidone or cycloserine to prevent neurological side effects. Both are valuable companion drugs in the prevention of resistance to other second-line drugs, since they do not have cross-resistance with other active TB drugs.

Para-aminosalicylic acid (PAS): PAS is a bacteriostatic agent, valuable in preventing resistance to other drugs. It is bulky, unpleasant to take and causes gastrointestinal disturbances; however, enteric-coated formulas are better tolerated.

 
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7.5. Other Drugs

 

Oral medications sometimes referred to as “third-line drugs” that have been used for the treatment of MDR-TB include thioacetazone, clofazimine, amoxicillin-clavulanate, macrolides (clarithromycin and azithromycin) and other rifamycins (rifabutin and rifapentine), imipenem and linezolid.

  • Thioacetazone is associated with the development of Stevens-Johnson syndrome in HIV- infected patients. In addition, it shows cross-resistance with ethionamide, prothionamide and isoniazid. It is therefore not recommended for use in this country.
  • Clofazimine, an antileprosy drug, which has been known to have in vitro activity against M. tuberculosis with unproven clinical efficacy. But a recent study from Bangladesh has shown that clofazimine is an important MDR-TB drug. This is the drug of choice among the others in this group.
  • Amoxycillin-clavulanate, clarithromycin and azithromycin have high minimal inhibitory concentrations (MIC) for most strains of M. tuberculosis relative to achievable serum concentrations, but clinical efficacy has again not been proven.
  • Rifabutin exhibits cross-resistance with rifampicin in up to 80% of patients, while rifapentine has complete cross-resistance with rifampicin.
  • Imipenem is a carbapenem. Carbapenems are very broad-spectrum antibiotics. A recent study showed activity against M. tuberculosis when given in combination with clavulanic acid. It is however an intravenous drug.
  • Linezolid is an oxazolidinone antibacterial. It showed good activity against M. tuberculosis in vitro and has been used with success in MDR/XDR-TB patients in several case reports. Linezolid should be considered if cost permits.

Therefore, none of these drugs are recommended for routine MDR-TB treatment. They can be used when it is difficult to design treatment regimen with drugs in Groups 1-4.  XDR-TB patients will require drugs in Group 5 to be part of their treatment regimen.

 

7.6. Second-Line Drug Groups

 

Second-line drugs are grouped according to efficacy, experience of use, and drug class, the different groups are described in table below:

 
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7.7. Standard Codes for Drugs and Regimens

 

Standard codes are used for MDR-TB treatment regimens. An MDR-TB regimen consists of two phases:

Phase 1: The intensive/injectable phase where a combination of injectable and oral drugs is used.

Phase 2: The continuation phase during which only oral drugs are used.

The number shown at the beginning stands for the phase duration in months, and is the minimum duration that phase should last. The number in subscript (i.e., ) is the number of drug doses per week. If there is no number in subscript, treatment is daily (a minimum of six times a week). The alternative drug(s) is indicated in brackets. The drugs in the higher groups are written first, followed by others in descending order.

Example of drug standard codes used to describe drug regimens

Regimen: 6Z-Km(Am)-Mfx-Eto-Trd/ 18Z-Mfx-Eto-Trd

The above regimen is 6 months intensive phase treatment with five drugs. The injectable drug is kanamycin, but there is an option for amikacin. The continuation phase is for at least 18 months with oral agents. Treatment is taken daily throughout the treatment period, which is twenty-four months in total.

 

7.8. Standardised Regimen for Adults (including children 8 years and older) MDR-TB Treatment

 

Intensive phase: at least 6 months, guided by TB Culture Conversion (treatment taken at least six times per week)

 

 
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Continuation phase: at least 18 months after TB culture conversion (treatment taken at least six times per week)

 
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7.9. Basic Principles of Treatment

 

  • Use five drugs in intensive or injectable phase and four drugs in continuation phase as per standard regimen. Drugs are administered at least six days per week.
  • Of the five drugs used in intensive phase: Give at least four drugs with either certain, or almost certain effectiveness. Drugs previously used for a month or more may not be included among drugs with certain effectiveness.
  • Each dose should be given under strict supervision throughout the treatment period.
  • Sputum specimens are taken every month for TB smear microscopy and culture
  • The duration of the injectable phase is guided by TB culture conversion.
  • TB culture conversion occurs when a patient obtains two consecutive negative TB culture results on sputum taken 30 days apart; the culture conversion date is the collection date of the first specimen that turned TB culture negative.
  • The injectable phase is determined by adding four months to the culture conversion date if
  • the total duration is less than six months then the patient should receive a total of six months injection because the injectable phase must be at least six months.
  • Capreomycin should be considered for use in patients with renal insufficiency, hearing loss, or peripheral neuropathy.
  • Pyrazinamide and fluoroquinolones should preferably be given once a day as the high peaks attained in once daily dosing may be more efficacious. Once daily dosing is also recommended for other second-line drugs; however, ethionamide, cycloserine, terizidone and para-amino salicylic acid are often given in divided doses during the day to facilitate patient tolerance.
  • Pyrazinamide may be used for the entire treatment period if the strain is thought to be susceptible to the drug.  Many MDR-TB patients have chronically  inflamed  lungs,  which theoretically produce an acidic environment in which pyrazinamide is active.
  • If patient’s organism is resistant to kanamycin or amikacin but susceptible to ofloxacin: add capreomycin, clofazimine and PAS.
  • It is further recommended that culture results, chest X-ray findings and the patient’s clinical status be taken into account in deciding whether or not to continue with the injectable drug for a longer period, particularly in patients for whom the susceptibility pattern is unknown, the effectiveness of the drug is questionable and those with extensive or bilateral pulmonary disease.
  • Intermittent therapy with the injectable drug - three times a week after an initial period of two to three months of daily therapy can be considered in patients who have been on the injectable for a prolonged period of time. Beyond six months and when toxicity becomes a greater risk to the patient.

 

 

7.10. Duration of Treatment

 

The recommended duration of treatment is guided by culture conversion and is determined by adding 18 months to the culture conversion date. Extension for up to 24 months may be indicated in chronic cases with extensive pulmonary damage.

 

7.11. Extrapulmonary MDR-TB Treatment

 

Extrapulmonary MDR-TB is treated using the same strategies and treatment duration as pulmonary MDR-TB. If the patient has symptoms suggestive of central nervous system involvement and is infected with MDR-TB, the drugs used should have adequate penetration into the central nervous system. Pyrazinamide, ethionamide, cycloserine and terizidone have good penetration; kanamycin, amikacin and capreomycin only show penetration in the presence of meningeal inflammation; and PAS has poor or no penetration.

 

7.12. Terminal Illnesses

 

Terminally ill patients, where circumstances permit, may be discharged for care by family members, with the consent of the family. Conditions, under which the patient may be discharged, include:

  • The patient will remain within the confines of his/her home.
  • There are no young children or persons with known HIV infection in the household who will be placed at risk.
  • All necessary measures would be taken to prevent spread of infection.
  • Access to the patient by other people will be restricted or controlled.

 

8. MANAGEMENT OF PATIENTS WITH XDR-TB

 

8.1. Introduction

 

By definition, two key classes of second-line anti-TB drugs are compromised in XDR-TB. Individualised treatment regimens are therefore essential and must be designed according to DST results and history of previous drug use.

A detailed clinical history can help suggest which drugs are likely to be ineffective; therefore you may need to obtain records from previous health care providers. The probability of acquired drug resistance increases with the duration of drug administration. In particular, evidence of clinical or bacteriological treatment failure during treatment is highly suggestive of drug resistance. If a patient has used a drug for more than a month with persistent positive smears or cultures, that drug should be considered as ‘probably resistant’, even if DST is reported as susceptible.

DST results should complement rather than invalidate other sources of data about the likely effectiveness of a specific drug. For example, if a history of prior anti-tuberculosis drug use suggests that a drug is likely to be ineffective due to resistance, this drug should not be relied on as one of the four core drugs in the regimen, even if the strain is susceptible in the laboratory. Alternatively, if the strain is resistant to a drug in the laboratory, but the patient has never taken it and resistance to it is extremely uncommon in the community, this may be a case of a laboratory error or a result of the limited specificity of DST of some second-line drugs.

Another important pitfall is that due to the delays in confirming the diagnosis, the patient may have already been started on a standard or empiric treatment by the time DST results become available from the laboratory. The possibility of further acquired resistance during this time must be considered. If there is a high probability of acquired resistance to a drug after the specimen for culture and DST was collected, this drug should not be counted as one of the four drugs in the core regimen.

XDR-TB patients have a much-reduced chance for cure and a very high risk of premature death; therefore, management of these cases should be prioritised using the same principles as those for MDR-TB. XDR-TB patients must be hospitalised, preferably at the MDR-TB hospitals.

 

8.2. Basic Principles of Treatment

 

There is currently no international consensus on the optimum duration of XDR-TB treatment; therefore, the same principles as for MDR-TB treatment apply, but clinical assessment of individual patients is required to decide on the termination of XDR-TB treatment.

The following principles must be applied when designing XDR-TB regimens:

  • At least four drugs expected or known to be effective or patient has not been exposed to should be included.
  • All patients should receive an injectable drug if susceptibility is documented or expected.
  • Other medications are added based on estimated susceptibility, drug history, efficacy, side- effect profile. Drugs to be considered are: PAS, ethionamide and terizidone.
  • A recent South African study undertaken in four provinces from South Africa, and confirmed in a recent meta-analysis, found that moxifloxacin improved outcomes in the face of ofloxacin resistance. The use of moxifloxacin is therefore recommended.
  • The use of thioacetazone is not recommended because of the high risk of skin rashes that
  • are more prevalent in HIV-positive individuals and can result in Stevens-Johnson syndrome and death. In addition, thioacetazone has cross-resistance with the thiomides (ethionamide and prothionamide) and is considered a relatively weak anti-TB agent. While thioacetazone is included among Group 5 drugs, it is the least used agent for the treatment of DR-TB and is not available in South Africa.
  • Newer rifamycins (e.g. rifabutin, rifapentine) have almost complete cross-resistance with rifampicin.
  • Group 5 drugs should be considered where in cases where adequate regimens are impossible to construct with available drugs from the other groups and you need to strengthen the regimen. The total dosage will depend on the degree of uncertainty and regimen will often contain five or more drugs. Clofazimine is the drug of choice among the group 5 drugs.

 
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The rationale for individualised regimens in the treatment of patients with XDR-TB is that they have to receive drugs that the strain is susceptible to and exclude those that they are resistant to. This is simple, but in practice the DST results for second-line drugs is too complex and the tests are not as sensitive as we would like them to be. As previously discussed the margin between the minimum inhibitory concentration and the critical concentration is narrow hence it is easy to misinterpret the results. The only accurate second-line DST tests are for kanamycin or amikacin and the fluoroquinolones.

Based on the above, the recommended standardised regimen for XDR-TB is as follows

but may be modified based on DST results:

6 Cm-Mfx-Eto-Trd -Z-PAS-Clofazimine/ 18 Mfx-Eto-Trd or Cs-Z –PAS/Clofazimine

 

8.3. Standardised Regimen for Adult XDR-TB Treatment

 
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The other reinforcing agents or agents with unclear efficacy (Group 5) may only be considered if the patient has a considerable resistance pattern which makes it difficult to construct an effective regimen using the first- and second-line drugs.

XDR-TB treatment for children is essentially like adults. Same drugs used in adults are to be administered to children with one exception: levofloxacin should be used in children younger than 8 years.

 

9. ROLE OF SURGERY

 

The treatment of MDR- and XDR-TB is primarily chemotherapy. There are, however, limited indications for surgery and these presume that the disease is mainly localised, unilateral and that there is adequate cardiopulmonary reserve. For patients with localised disease, surgery can significantly improve treatment outcomes, provided skilled thoracic surgery and excellent post- operative care are available. A multidisciplinary team approach should be employed when dealing with patients being considered for surgery.

Major indications

  • Persistence of positive sputum cultures and lack of radiographic and clinical improvement after six months of adequate therapy and patient adherence.
  • Relapse in the same site after a previous adequate course of chemotherapy in a patient who has been adherent.

Minor indications

  • In a patient who has undergone sputum conversion but the profile of drug resistance is so great (e.g., resistance to more than four drugs) that if relapse did occur it may be difficult to re- establish sputum culture conversion.
  • In a patient who has undergone sputum conversion but there is residual cavitation or gross lobe or lung destruction and hence the potential for relapse.

At least six months of treatment should be given before surgery is considered. In a patient who has not undergone sputum conversion, surgery should only be performed when there is no further possibility of an adequate chemotherapeutic regimen. The decision to perform surgery and the extent of surgery (lobectomy or pneumonectomy) should preferably be made after anatomical localisation of disease by CT scan. Often the apex of a lower lobe is involved together with a corresponding upper lobe and the former should also be removed. Minimal contra lateral disease is not a contra-indication to surgery. The role of PET-CT scans in guiding surgery remains unclear. Perfusion scans are useful in establishing how much functioning lung is likely to be removed. Basic spirometry (FEV1 and FVC) is adequate in assessing lung function in the majority of patients. Eligible patients should have a FEV1 > 0.8. If the FEV1 is acceptable, analysis of blood for HCT, ABG, urea and electrolytes, creatinine should be performed pre-operatively.  ECG is useful for excluding pulmonary hypertension which would contraindicate surgery. A pre-operative ECG should be routinely performed on patients older than 50 years and on patients with diabetes.

The resected part of the lung should be sent for histology, culture and drug susceptibility testing. Sputum cultures should be performed immediately post-surgery and then monthly until two consecutive negative cultures have been obtained. If the patient was culture-negative at the time of surgery the treatment should continue for at least 18 months after culture conversion. If the patient was culture positive, treatment should continue for another 24 months.

 

 

10. MANAGEMENT OF ADVERSE DRUG REACTIONS

 

10.1. Introduction

 

Almost all patients on MDR- and XDR-TB treatment will report adverse effects to the second-line drugs. Close monitoring of patients is necessary to ensure that adverse drug reactions (ADRs) are recognised and addressed quickly. The majority of ADRs are easy to recognise and patients will often volunteer this information. However, it is important to have a systematic approach to patient interviewing since some patients may be timid about reporting even severe ADRs. Other patients may be distracted by one side effect and forget to inform the health care provider about others. The timely and aggressive management of adverse effects of the second-line drugs greatly facilitates patient adherence.

 

 

10.2. Most Common Adverse Drug Reactions

 

Adverse drug reactions can be classified under the following categories:

  • Minor side effects
  • Toxic reactions
  • Hypersensitivity reactions
  • Idiosyncratic reactions
  • Other reactions

Since DR-TB patients receive combination chemotherapy, it is often difficult to determine which drug is the source of the undesired effect as drug-to-drug interactions may also produce adverse effects. Some ADRs present soon after treatment is initiated while others tend to manifest later.

The most common adverse reactions to second-line anti-TB drugs are described below.

Skin Reactions

Skin reactions ranging from pruritus to rashes and most severely to toxic epidermal necrolysis, sometimes accompanied by fever, may be caused by several agents. These are frequent among patients with HIV infection. In most cases desensitisation is successful, and the full range of medications can be re-introduced within one or two weeks.

Gastrointestinal Symptoms (nausea, vomiting, diarrhoea)

Symptoms such as nausea, pain and vomiting are common, but may be prodromal symptoms of hepatitis such as jaundice and therefore close clinical observation is mandatory. Gastrointestinal symptoms can usually be dealt with by taking the medication with a non-fatty meal or before going to bed. Monitoring of the response is important, if the symptoms do not subside, liver toxicity must be suspected and investigated.

Ototoxicity

Impaired hearing or impaired balance is virtually always due to the injectable agents. It is often, but not always, dose-dependent.  Audiometry should therefore be performed prior to initiation of treatment and repeated monthly or when indicated, throughout the intensive phase. Patients with pre-existing vestibulo-cochlear impairment should be counselled on the potential risks and informed consent obtained before these drugs are used. Patients complaining of hearing loss or impaired balance should be checked to establish that the dosage given is appropriate for weight and age, as toxicity increases with both.

Peripheral Neuropathy

Peripheral neuropathy, presenting as paraesthesia such as tingling and numbness, starting at the feet with proximal spread is the usual manifestation. Myalgia, weakness and ataxia may accompany these symptoms.

Peripheral neuropathy is usually due to cycloserine and terizidone and occurs more commonly

in malnourished or alcohol-dependent patients. Pyridoxine or amitriptyline is effective in treating peripheral neuropathy.

Electrolyte Wasting

Electrolyte wasting is a known complication of the injectable drugs, most frequently with capreomycin. It is generally a late effect that manifests after months of treatment, and is reversible once the injectable is suspended. Electrolyte wasting is often asymptomatic in the early stages but patients complain of muscle cramps and palpitations.

Psychiatric Symptoms

Infrequently, toxic psychosis, depression, suicidal ideation, anxiety and epileptic convulsions may occur with cycloserine and terizidone. Pyridoxine is usually effective for treating these cases.

Nephrotoxicity

This is a well-documented ADR of all injectable drugs, both the aminoglycosides and capreomycin. This ADR is occult (not obviously noted by taking the history of the patient or by physical examination) in onset and can be fatal.

Impaired Vision

This is most frequently caused by ethambutol.  Optic toxicity is not detectable byfundoscopy. Patients with impaired vision other than due to myopia, hyperopia or presbyopia should not be given ethambutol.

Osteo-articular Pain

Arthralgia is a ADR drug event resulting from the accumulation of uric acid caused by pyrazinamide. Acetyl salicylic acid commonly alleviates the symptoms.  Intermittent administration of Pyrazinamide will also reduce the effect of uric acid retention. Allopurinol is ineffective.

Hypothyroidism

Is a late effect provoked by PAS and ethionamide and physical symptoms can be subtle.  

 

10.3. Monitoring Adverse Drug Reactions

 

Laboratory screening is invaluable for detecting ADRs that are more occult. During the intensive phase of treatment, patients must be interviewed weekly about adverse reactions to the drugs and these recorded utilising the Adverse Drug Reaction Monitoring Form (Annexure I). This section will need more detail, especially in dealing with patients who are being managed under ambulatory care.

In the continuation phase the incidence of ADRs must be monitored monthly utilising the same Form. Line listings of these effects must be provided quarterly to the Provincial TB Coordinator. Serious ADRs which necessitate discontinuation of drugs must be noted in the Serious Adverse Drug Reaction Report  and a report  sent  within five calendar days  to the Medicines Control Council.

Drug intolerance and patient sensitisation should be managed according to the recommendations contained in these guidelines. Treatment supervisors should enquire about ADRs during every encounter with the patient.

Table XXII provides a guide on the number and frequency of laboratory tests that should be conducted to monitor the development of ADRs.

 
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10.4. Management of Adverse Drug Reactions

 

Of equal importance to the treatment regimen used is the proper management of ADRs. Second- line anti-tuberculosis drugs have many more adverse reactions than first-line anti-tuberculosis drugs.

Proper management of ADRs begins with pre-treatment patient education, when the patient should be informed in detail about the potential adverse effects that the drugs they are taking can cause, and when to notify the health-care provider.

Timely and aggressive management of ADRs is essential. Without it, mortality and permanent disability can be the result, in addition to patient non-adherence. Even if the ADRs are not particularly dangerous, prompt intervention is important. Patients may have significant anxiety about an adverse effect if they do not understand what is happening. This may in turn augment the severity of the adverse reaction (i.e., nausea and vomiting).

The following sequential steps for the management of ADRs are recommended:

1. Management of ADRs with Standardised Algorithms

Most ADRs can be managed with over-the-counter and common prescription drugs. If they are mild, continuing the treatment regimen, with the help of ancillary drugs where necessary is the best option.  Many ADRs disappear or diminish with time and patients should be encouraged to tolerate the effects until they subside. Psychosocial support is an important component of management of ADRs.

2. Reduced Dosage of Suspected Drug(s)

The adverse reactions of a number of second-line anti-tuberculosis drugs are highly dose dependent. If a patient cannot tolerate the regimen, the dosage of the suspected drug(s) may be reduced until the adverse reactions subside. If it is not clear which drug is the cause of the adverse effect(s), the dosage of each drug can be reduced sequentially until the culprit drug is identified. In this case, when the dosage of a second drug is reduced, the first drug of which the dosage was reduced should be returned to normal dosage. If reduction of dosage of individual drugs does not result in the disappearance of the ADRs, it may be necessary to reduce the dosages of multiple drugs simultaneously. However, due to the narrow therapeutic margins of second-line drugs, lowering the dose may affect the efficacy as well, so every effort should be made to maintain an adequate dose of the drug according to body weight.

3. Removal of Drug(s) from the Regimen

If reduced dosage does not alleviate the ADR it may be necessary to remove a drug from the regimen, or to replace the drug with another drug. This final option should be chosen only as a last resort, as it will affect the potency of a regimen.

Monitoring and management of ADRs may have to be more aggressive in patients with concomitant conditions such as:

  • Pregnancy and lactation;
  • Diabetes mellitus;
  • Renal insufficiency;
  • Acute or chronic liver disease;
  • Thyroid disease;
  • Mental illness;
  • Drug or alcohol abuse; and
  • HIV infection.

The following table summarises the most common ADRs, the offending drugs and their management strategies.

 
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11. RECOMMENDED DRUGS FOR THE TREATMENT OF ADVERSE DRUG REACTIONS

 

A number of ancillary medications and adjuvant therapies are used to manage ADRs, reduce morbidity and mortality and improve overall treatment outcomes in DR-TB patients.

 

11.1. Commonly Used Drugs and Supplements

 

The most commonly used drugs and supplements are:

Analgesics

Headaches are a common adverse effect of DR-TB treatment. It is important to rule out other causes such as meningitis, migraine and cluster headaches. Codeine with acetaminophen gives relief to moderate pain and also helps control cough. Stronger analgesics should be used as appropriate.

Corticosteroids

The adjuvant use of corticosteroids in patients on DR-TB treatment has been shown not to increase mortality and can help alleviate symptoms associated with severe respiratory insufficiency, central nervous system involvement and laryngeal TB. There is no evidence that one corticosteroid is better than another. Prednisone is commonly used, starting at approximately 1 mg/kg and gradually decreasing the dose by 10 mg per week. Stopping the prednisone abruptly can be dangerous in patients dependent on corticosteroids. Corticosteroids may also alleviate symptoms in patients with exacerbation of obstructive pulmonary disease. In these cases, prednisone may be given over one to two weeks, starting at approximately 1 mg/kg then tapering of the dose by 5-10 mg per day. Patients already using corticosteroids for other conditions should continue their use.

Pyridoxine

Pyridoxine is given as adjuvant therapy with cycloserine and terizidone to prevent neurological toxicity and should be provided at a dose of 150 mg/day. The dose may be increased to 300 mg/ day when ADRs related to cyloserine or terizidone use are experienced.

Vitamin and mineral supplements

Vitamins (especially vitamin A) and mineral supplements may be given when patients have deficiencies. If minerals are given they should be administered at least one hour before or after administration of fluoroquinolones, as zinc, iron and calcium can interfere with fluoroquinolone absorption.

Respiratory Insufficiency

Oxygen can be used to alleviate shortness of breath. Generally, it is indicated in patients with a pO < 55mmHg or O saturation < 89%, and should be titrated to raise the O Saturation to more than 90%. Oxygen is usually started at 2-4L/min via nasal cannula. If more than 5 L/min is needed, the oxygen should be delivered through a mask. Retention of CO2 can occur in some patients and should be checked when starting oxygen or increasing oxygen delivery. Corticosteroids and morphine also provide significant relief from respiratory insufficiency.

Bronchodilators

Bronchodilators alleviate shortness of breath and may suppress cough. Due to the high prevalence of residual lung disease in DR-TB patients, bronchodilators should be continued after completion of treatment.

Nutritional Support

In addition to causing malnutrition, DR-TB can be exacerbated by poor nutritional status. The second-line anti-tuberculosis drugs can also decrease the appetite, making adequate nutrition a greater challenge.

Nutritional support can take the form of providing foods parcels, and whenever possible should include a source of protein.

 
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12. TREATMENT IN SPECIAL SITUATIONS

 

12.1. Introduction

 

Co-existing or co-morbid conditions often render MDR-TB treatment even more problematic. The following situations require special attention in MDR-TB patients considered for treatment:

 

12.2. Oral Contraception Use

 

Birth control is strongly recommended for all women receiving DR-TB treatment because of the potential negative consequences for both mother and foetus of frequent and/or severe ADRs.

There is no contraindication to taking oral contraceptives with second-line anti-TB drugs. However, since oral contraceptives may have decreased efficacy due to potential drug interactions, other methods such as the use of medroxy-progesterone or barrier methods (e.g., diaphragm or condom) should be considered for use throughout the period of treatment.

If the patient opts for oral contraception, she should be made aware of the fact vomiting results in decreased absorption of the pill, and possible decreased efficacy. She should be advised not to take the pill at the same time with anti-tuberculosis treatment and that if vomiting occurs within the first two hours of taking the pill, she should use a barrier method of contraception.

 

12.3. Pregnancy

 

Female patients of childbearing age should be tested for pregnancy during initial evaluation. Second-line drugs are not contra-indicated in pregnancy but some of the drugs have teratogenic effects and the risk of not treating DR-TB may have serious consequences to both mother and foetus.

Pregnant patients should be carefully evaluated, taking into consideration the gestational age and the severity of the disease. The risks and benefits of treatment should be carefully considered. Apply the following principles:

Discuss condition and treatment plan with the patient

A discussion of risks and benefits need to take place. The benefits of initiating treatment upon diagnosis outweigh the risks of not starting treatment. Any concerns a patient may have in starting therapy or in using medicines while pregnant need to be addressed. If the patient agrees to start therapy, use three or four oral drugs with demonstrated efficacy and then reinforce the regimen with an injectable agent after the second trimester of pregnancy or immediately postpartum.

Avoid injectable agents

Aminoglycosides should not be used in the treatment of pregnant patients as they are particularly toxic to the developing foetal ear. Capreomycin may carry the same risk of ototoxicity, but it is a drug of choice if an injectable agent cannot be avoided.

Use of ethionamide

Ethionamide should be given with caution because it may increase the risk of nausea and vomiting associated with pregnancy and teratogenic effects have been observed in animal studies.

Table XXV shows the safety profile of the second-line drugs in pregnancy.

 
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12.4. Breastfeeding

 

Lactating Mothers

A woman who is breastfeeding and has active DR-TB should receive a full course of treatment, as timely and properly applied chemotherapy is the best way to prevent transmission of DR-TB to the baby.

Nursing Infants

In lactating mothers on treatment, most anti-tuberculosis drugs are found in the breast milk in minute concentrations compared to the therapeutic doses used in treating infants. However, the effects on infants of such exposure during the full course of treatment have not been established. Therefore, the use of infant formula is the only reasonable way to avoid any unknown adverse effects. However, the use of infant formula will depend on multiple factors, including the patient’s resources, safety of water supply, and bacteriological status of the mother. If the setting is not appropriate for infant formula, then breast-feeding may be considered.

The mother and baby should not be forced to stay apart. If the mother is smear-positive, she should consider using a mask when in close contact with the infant or leaving the care of the infant to family members until she is negative.

 

 

12.5. Children

 

Children with MDR- or XDR-TB generally have primary disease transmitted from a source adult case. Since children often have paucibacillary disease, they are seldom culture-positive. Nevertheless, every effort should be made to confirm MDR- or XDR-TB bacteriologically in children.

In culture-negative children who have clinical evidence of active TB and close contact with a person who has confirmed MDR- or XDR-TB, the child’s treatment should be guided by the DST results and history of TB drug exposure of the source case. There is limited reported experience on the use of the second-line medications for extended periods in children. Careful consideration of the risks and benefits of each drug should be made, but the child should be started on an effective regimen. Education and counselling of the patient and family is critical at the initiation of treatment. Given that MDR- and XDR-TB are life-threatening diseases, no drugs are absolutely contraindicated in children.

It should be noted that while fluoroquinolones have been shown to retard cartilage development in beagle puppies, experience in the treatment of children with cystic fibrosis and many MDR- TB cases over prolonged periods has failed to demonstrate similar effects in humans. It is now considered that the benefit of fluoroquinolones in treating MDR-TB in children outweighs the risks. Additionally, ethionamide, PAS, cycloserine and terizidone have been used effectively in children and are well tolerated.

In general, drug dosages should be based on the weight of the child. Monitoring monthly weight is therefore important in children with adjustment of the dosages as the child gains weight. All drugs, including the fluoroquinolones, should be dosed at the higher end of recommended ranges whenever possible.

 

 
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In children who are not culture-positive at the start of treatment, failure is difficult to assess. Children, as is the case in adults, should get monthly cultures of either gastric aspirates or (induced) sputum until they become culture-negative. Thereafter two-monthly specimens for culture should be obtained until completion of treatment if they had severe lung disease (same as in adults). Persistent abnormalities on chest radiograph do not necessarily signify a lack of improvement. Failure to gain weight or weight loss (less common) is of particular concern, and often one of the first (or only) signs of treatment failure. Monitoring weight gain would therefore assist in the early detection of treatment failure.

Anecdotal evidence suggests that adolescents are at high risk for poor adherence and poor treatment outcomes, perhaps due to biologic reasons (more advanced disease due to late diagnosis) and social factors (more problems with adherence due to peer pressure, behaviour, drug use, pregnancy, denial poor acceptance of illness). Early diagnosis, strong social support, individual and family counselling, and a close relationship with the medical provider may help improve outcomes.

 

12.6. Diabetes

 

The prognosis of treatment in a diabetic patient with uncontrolled glucose levels is poor. Therefore the responsibility falls on the physician and patient to ensure proper diabetic care and control. In addition, diabetes may potentiate ADRs, especially renal failure and peripheral neuropathy. Oral hypoglycemic drugs can be safely given with second-line drugs, but ethionamide and prothionamide may make it more difficult to control insulin dependent diabetes.

In the management of the diabetic patient with DR-TB, the following is recommended:

  • Medical follow-up: Diabetes must be managed closely throughout treatment.
  • Patient education: The basics on the diet, treatment compliance, weight control, exercise, and foot care should be communicated to the patients, together with the symptoms of hypo- and hyper-glycaemia and what to do when they occur.
  • Glucose monitoring

        - Goals for capillary blood testing: 80-120 mg/dl before meals; 100-140 mg/dl before bedtime; the range should be higher if patient has a history           of hypoglycaemia.

        - Patients may need a period of intensive glucose monitoring until these targets are attained. Once a patient is on a stable dose of insulin, blood             sugar may be monitored four times weekly to ensure that targets are being maintained.

        - If a patient is on oral anti-diabetic agents, sugar may be monitored twice weekly.

  • Regular monitoring

        - Creatinine and potassium should be monitored weekly for the first month and then at least monthly thereafter.

        - If the creatinine rises, creatinine clearance should be checked and the second-line anti-TB drugs should be adjusted accordingly. Once the dose             is adjusted, the creatinine should be checked weekly until it has stabilised.

        - HbA1C every three months if treatment changes or patient is not meeting target; every six months if stable. Target: HbA1C<7.

        - Retinal examination annually.

  • Screening and treatment for hypertension

        - Blood pressure measurements should be conducted monthly.

        - Hypertensive patients with diabetes should be started on an ACE-inhibitor.

  • Prevention of diabetic nephropathy

        - Adjust the dose of the injectable drug based on the creatinine clearance.

        - Consider using an ACE inhibitor in patients with albuminuria >300 mg/24 hours

 

12.7. Renal Insufficiency

 

Renal insufficiency due to longstanding tuberculosis infection itself or previous use of aminoglycosides is not uncommon. Great care should be taken in the administration of second- line drugs in the patient with renal insufficiency, and the dose and/or the interval between dosing should be adjusted based on creatinine clearance.

 
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The formula to calculate the creatinine clearance (CrCI) or the glomerular filtration rate (GFR) is as

follows:

Estimated Glomerular Filtration Rate (GFR): Men: (140 – age) x (ideal body weight in kg)

72 x (serum creatinine, mg/dl)

Women: (140 – age) x (ideal body weight in kg) x 0.85

72 x (serum creatinine, mg/dl)

Normal values for creatinine clearance are:

Men: 97 to 137ml/min

Women: 88 to 128ml/min

An example of adjusting the dose of a medication in renal insufficiency:

A male patient has a serum creatinine = 2.4, age = 59, ideal body weight = 53 kg. What should the dose of Kanamycin be?

Step 1: Calculate the Glomerular Filtration Rate (GFR)

= (140 – age) x (ideal body weight in kg)

72 x (serum creatinine, mg/dl)

= (140 – 59) x (53)

72 x 2.4

= 24.8 ml/min

Step 2: Refer to Table XXV and make the appropriate dose adjustment.

In this case the 24.8 ml/min falls below 30 ml/min. The dose of kanamycin given in Table XXV is 12-15 mg/kg. The dose to prescribe would be between 12 x 53 = 636 mg and 15 x 53 = 795 mg. It is reasonable to choose a dose between these two that is relatively easy to draw up from the vial. In this case, 750 mg three times a week is the logical choice.

Note:

• For this patient, every drug in the regimen should be examined and adjusted if necessary.

• The creatinine will need to be monitored periodically (often weekly or more frequently in the

patient with severe renal insufficiency) and doses readjusted for any change.

If this were a woman, the GFR = 24.8 x 0.85 = 21.1 ml/min.

Kanamycin dose: 12-15 mg/kg which works out to 636-795 mg, therefore 750 mg three times a week

(Adapted from:  World Health Organization. Guidelines for the Programmatic Management of Drug-resistant Tuberculosis (WHO/HTM/TB/2005.361), World Health

Organization: Geneva, Switzerland, 2006).

 

 

12.8. Liver Disorders

 

Pyrazinamide is the most hepatotoxic of the first-line anti-tuberculosis drugs. Of the second- line drugs, ethionamide, prothionamide and PAS are hepatotoxic, although less so than any of the first-line drugs. Hepatitis is quite rare with the fluoroquinolones, but may occur. In general, patients with chronic liver disease should not receive pyrazinamide. All second-line drugs can be used, however close monitoring of liver enzymes is advised, and if significant worsening of liver inflammation is seen, responsible drugs may need to be stopped.

Patients who are hepatitis virus carriers and those with a past history of acute hepatitis or excessive alcohol consumption can be started on second-line drugs provided there is no clinical evidence of chronic liver disease; however, hepatotoxic reactions may be more common in these patients and should be anticipated.

Uncommonly, a patient may have DR-TB and unrelated concurrent acute hepatitis. Clinical judgement is necessary in this instance - in some cases it will be possible to defer treatment until the acute hepatitis has resolved. In other cases, it will be necessary to start the treatment during the acute hepatitis phase in which case a combination of four non-hepatotoxic drugs will be the safest option.

 

 

12.9. Seizure Disorders

 

Some patients requiring DR-TB treatment may have past or present medical history of seizures. The first step is to determine whether the seizures are under control and if the patient is on any treatment. If the seizures are not under control, initiation or adjustment of treatment that the patient is taking will be needed prior to the start of DR-TB treatment. In addition, if other underlying conditions or causes of the seizures exist, they should be corrected.

Cycloserine and terizidone should be avoided in patients with uncontrolled seizures.  However, in cases where there is no option, cycloserine/ terizidone may be given and the treatment for seizures adjusted to control them. The risks and benefits of using cycloserine/ terizidone should be considered and discussed with the patient. When seizures present for the first time whilst patient is on DR-TB treatment, there is a good chance that they are related to one of the second- line drugs.

 

12.10. Substance Dependency

 

Patients who abuse alcohol and drugs should be started on a rehabilitation programme and if necessary adjuvant therapy given. Although complete abstinence from alcohol or drugs should be strongly encouraged, treatment is not contraindicated in people who abuse alcohol or drugs. If the treatment is repeatedly interrupted due to the patient’s addiction, then it should be suspended until successful rehabilitation or other measures to ensure adherence are established.

Cycloserine and terizidone will have a higher incidence of adverse reactions in the alcohol or drug- dependent patients, including seizures. However, if any of these drugs is considered important to the regimen, it should be used and the patient closely monitored for side effects, and adequately treated when necessary.

 

12.11. Psychiatric Disorders

 

It is prudent to have a psychiatrist conduct a psychiatric evaluation on all patients before the start of MDR-TB treatment, or at least on all patients with a history of psychiatric illness. The initial evaluation will document any pre-existing psychiatric condition and establish a baseline for comparison if new psychiatric symptoms develop while the patient is on MDR-TB treatment. Any identified psychiatric illness at the start or during treatment should be managed appropriately.

There is a high baseline incidence of depression and anxiety in patients with DR-TB, often related to the chronicity of the disease, confinement in hospital and other socioeconomic stressors. If a psychiatrist is not available, the treating physician should document any psychiatric conditions the patient may have at the initial evaluation.

Treatment of the psychiatric condition with the appropriate drugs, individual counselling, and/or group therapy may be necessary to manage the patients. Group therapy has been very successful in providing a supportive environment for DR-TB patients and may be helpful for patients with or without psychiatric conditions. The use of cycloserine or terizidone is not absolutely contraindicated for the psychiatric patient.  Adverse effects from these drugs may be more prevalent in the psychiatric patient, but the benefits often outweigh the potential higher risk of adverse reactions. Close monitoring is recommended if cycloserine or terizidone is used in patients with psychiatric disorders.

The hospital should have an organised system for management of psychiatric emergencies which include psychosis, suicidal ideation, and any situation involving the patient being a danger to him/ her or others. Referral mechanisms to deal with psychiatric emergencies (often to psychiatric hospitals with isolation facilities for infectious diseases) should be available twenty-four hours a day.

 

 

13. DRUG-RESISTANT TB AND HIV

 

13.1. Introduction

 

HIV co-infection is a significant challenge for the prevention, diagnosis, and treatment of MDR- and XDR-TB. Provider-initiated HIV counselling and testing should be routinely offered to all TB patients.

HIV is a powerful risk factor for development of all forms of TB including DR-TB. DR-TB is often associated with higher mortality rates in HIV infected when compared with the non-infected.

Diagnosis of DR-TB in HIV positive persons is difficult and all high risk HIV patients with TB should be screened for drug-resistance with DST. ART in addition to treatment of DR-TB has been reported to improve outcomes of DR-TB in HIV-infected.

The national guidelines on the use of ART should be considered in conjunction with the content of this chapter.

 

13.2. Clinical Features and Diagnosis of DR-TB in HIV-infected Patients

 

As with drug sensitive TB, the clinical presentation is influenced by the degree of underlying immunodeficiency. In the earlier stages of HIV infection, the pathology of DR-TB is similar to that seen in HIV negative people with smear positive pulmonary TB being the most commonly seen. As immunodeficiency progresses, extra-pulmonary TB disease becomes more common. Furthermore, clinical presentation may be masked by the existence of other opportunistic infections.

The diagnosis of DR-TB in HIV-positive persons is more difficult and may be confused with other pulmonary or systemic infections. Increasingly, the clinical presentation in advanced HIV is extra-pulmonary. This can result in misdiagnosis or delayed diagnosis of DR-TB, which may lead to advanced or complicated drug resistant TB disease and death.

Protocols for the diagnosis of DR-TB in HIV follow the same principles as for HIV-negative patients. Sputum culture and DST should be done on all high risk groups ( i.e., non-converters, all re-treatment patients, contacts of drug resistant TB). Every effort should be made to obtain a specimen in, even if extra-pulmonary TB is suspected.  Common sites of HIV-related extra- pulmonary DR-TB are the pleura, the lymph nodes and the pericardium. Blood cultures for tubercle bacilli sometimes yield positive results.

 

13.3. Management of Co-Infected Patients

 

DR-TB treatment is the same for HIV-positive and HIV-negative patients. However, MDR-TB and XDR-TB treatment is much more difficult and ADRs are much more common in HIV-positive patients. Mortality is high during treatment particularly in the advanced stages of immunodeficiency mainly due to advanced MDR- or XDR-TB disease and other HIV-related opportunistic infections. Patients already on ART when MDR- or XDR-TB is diagnosed should immediately be started on appropriate treatment.

The current scope of knowledge has not provided enough evidence to respond to all concerns related to treatment of patients co-infected with MDR- and XDR-TB and HIV. The main issues include:

  • Timing of initiation of ART in MDR- and XDR-TB patients (i.e., the appropriate time to initiate ART in MDR-TB patients is not known and depends on a careful calculation of risks and benefits).
  • Drug-drug interactions.
  • Overlapping toxicities.
  • Adherence to complicated treatment regimens.
  • Clinical management of co-infected patients.
  • The primary goal of ART is to decrease HIV-related morbidity and mortality:
  • The patient should experience fewer HIV-related illnesses.
  • The patient’s CD4 count should rise and remain above the baseline count.
  • The patient’s viral load should become undetectable (<50 copies/ml) and remain undetectable on ART.

 

13.3.1. Timing of Initiation of ART in Adult DR-TB Patients

 

All HIV-positive TB, MDR- and XDR-TB patients are eligible to start ART irrespective of CD4 cell count. Furthermore, these patients must be fast-tracked (ART initiation within 2 weeks of being eligible) for the initiation of ART.

Advantages of Starting ART Early

1. Reduced HIV related morbidity and mortality.

2. Increased survival of co-infected DR-TB patients

3. Slower progression to AIDS.

Issues to Consider when Initiating ART

1. Overlapping ADRs from ART and second-line drugs.

2. Complex drug-drug interactions.

3. Occurrence of immune reconstitution syndrome.

4. Treatment non-compliance associated with high pill burden.

The simultaneous initiation of ART and second-line drugs is associated with ADRs that may lead to the interruption of both DR-TB and/or ART. Deferred initiation of ART may help the clinician identify the potential cause of ADRs without neglecting the possibility of concurrent illness.

Two scenarios exist with regard to DR-TB and ART, depending on which condition manifests first:

1.Patient develops DR-TB while on ART

  • Start DR-TB treatment immediately.
  • Antiretroviral therapy should be continued throughout DR-TB treatment.
  • Monitor patient for ADRs, drug-drug interactions and combined toxicities; avoid using tenofovir and aminoglycosides because they are nephrotoxic.

Development of DR-TB is not indicative of ART failure. It is not a reason to stop either DR-TB or

ART or to change any of the regimens.

2.Patient presents with DR-TB before commencing ART

  • All patients must be started on ART irrespective of CD4 cell count. Moreover the initiation of ART must be fast tracked as soon the DR-TB treatment is tolerated.

 
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1. Why Infection Prevention and Control Guidelines?

 

Most people with undiagnosed, untreated and potentially contagious TB are frequently seen in health care facilities but are missed. In an area with high HIV prevalence, this poses a risk for HIV positive patients who are particularly vulnerable to TB with a 10% annual risk of developing TB compared to a 10% lifetime risk in those with normal immunity. The numbers of patients with diagnosed or undiagnosed TB, immune compromised patients (HIV positive, children <5 years/ malnourished, diabetic) presenting to our health facilities creates a potential for transmission of TB. People who are immune compromised may become infected or re-infected with TB if they are exposed to someone with infectious TB disease. They can progress rapidly from TB infection to disease – over a period of months rather than a period of years as is common for persons with a normal immune system.

An increased risk of TB has been documented amongst all categories of health care personnel (including facility staff, community health workers and volunteers) compared to the general population. The prevalence of HIV amongst health care personnel correlates with that in the general population. Health care personnel are at risk due both to frequent exposure to patients with infectious TB. The rising incidence of Multidrug-Resistance Tuberculosis (MDR-TB) and Extensively Drug-Resistance Tuberculosis (XDR-TB) with high mortality have led to a stronger focus on TB infection control.

It is the responsibility of management and staff to minimize the risk of TB transmission in health settings. Infection control measures should be established to reduce the risk of TB transmission to both the general population and to health care personnel. Since the majority of patients are seen at primary health care level, it is important to ensure that infection prevention and control measures are implemented not only in the hospitals but clinics, community health centers and community or household level.

 

2. How Tuberculosis is Transmitted?

 

Tuberculosis is spread from person to person by droplet nuclei that are produced when a person with pulmonary or laryngeal tuberculosis coughs/ sneezes and by aerosol-producing investigations such as bronchoscopy and sputum induction.

People with active tuberculosis generate droplets of different sizes. The larger droplets which contain higher numbers of bacilli do not remain airborne for long periods. If they are inhaled, they do not reach the alveoli because they are trapped by the mucous in the upper airway and from there transported by mucociliary action to the oro-pharynx and swallowed or expectorated. The smaller droplets which are 1 to 5 µm in diameter containing fewer (±1 - 5 bacilli), are highly infectious. They remain airborne for long periods of time in any indoor space. When inhaled they can easily reach the alveolar spaces within the lungs, where the organisms replicate. It is estimated that one cough can produce 3,000 droplet nuclei and a sneeze up to a million droplets; about 10 - 200 droplet nuclei are sufficient to cause infection. The most infectious people are those who have smear positive pulmonary TB (coughing up the bacilli), particularly with lung cavities. People with smear negative pulmonary TB cases are much less infectious and those with extra-pulmonary TB are almost never infectious, unless they have pulmonary tuberculosis as well.

 

In children  abacavir, lamivudine  and efavirenz  at appropriate dosage constitute the first-line regimen. Lopinavir/rotonavir will replace efavirenz in children younger than 3 years. Dosages are available in the national HIV guidelines.

 

13.4. Prophylaxis for Opportunistic Infections

 

3. How People are Exposed to TB Bacilli?

 

  • When someone with pulmonary TB coughs, invisible droplets containing TB bacilli are dispersed into the air;
  • The remain suspended in the air and fall at a rate of 12mm/hr; and
  • These droplets can then be inhaled by others.

Transmission generally occurs indoors, in dark, damp spaces where the bacilli can survive for several hours. Direct sunlight has a bactericidal effect on the tubercle bacilli. Close contact with a person who has infectious PTB for a prolonged time increases the risk of transmission.

 

Cotrimoxazole is highly effective in preventing:

  • Pneumocystis jirovecii pneumonia
  • Toxoplasmosis
  • Pneumococcus
  • Salmonella
  • Nocardia
  • Malaria

The provision of cotrimoxazole to HIV-infected individuals has resulted in a decrease in hospital admissions as well as mortality in TB patients. Current WHO policies require that all HIV-infected symptomatic (stage 2, 3 & 4) adults and children be given cotrimoxazole prophylaxis as part of a minimum package of care. HIV-infected DR-TB patients are usually in WHO stage 3 or 4 and therefore qualify for cotrimoxazole prophylaxis. Ideally cotrimoxazole should be initiated prior to ART on first adherence visit.

Given the higher likelihood of sulfa-related ADRs in HIV-positive patients (6-8 times greater than in the general population) sulfa-based prophylaxis should be started at least two weeks apart from MDR- or XDR-TB treatment and/or ART. This will allow differentiation between side effects from second-line drugs and cotrimoxazole.

Recommended dosages of cotrimoxazole

In Adults:

Cotrimoxazole 960 mg (two tablets single strength) daily

or

Trimethoprim 5 mg/kg plus sulphamethoxazole 25 mg/kg daily

 

4. What are the Factors that Determine the Likelihood of Transmission of M. Tuberculosis?

 

  • The number of organisms expelled into the air; and
  • The concentration of organisms in the air, determined by the volume of the space and its ventilation; and
  • The length of time an exposed person breathes the contaminated air

Once infected, the progression to active disease is dependent on the immune status of the individual.

 

5. What are the Key Factors for Progression to Active Disease?

 

In Children:

 

Body weight

 

Cotrimoxazole 40/200 mg/5ml

 

< 5 kg

 

2.5 ml

 

5 to 9.9 kg

 

5 ml

 

10 to14.9 kg

 

7.5 ml

 

15 to 21.9 kg

 

10 ml or 1 tab 80/400 mg

 

> 22 kg

 

15 ml or 1 ½ tab 80/400 mg

Patients on cotrimoxazole prophylaxis as well as antiretroviral drugs should continue the cotrimoxazole until their CD4 count increases to 350 or above and remains at this level for 3-6 months and then stop.  Patients with known hypersensitivity to cotrimoxazole could be given dapsone instead.

 

13.5. Immune Reconstitution Syndrome

 

  • Age: children <5 years of age and the elderly are less infectious as they have paucibacillary disease
  • HIV: people who are HIV positive and have a high CD4 count would be as infectious as HIV negative patients. Those with low CD4 count are considered less infectious as they would have paucibacillary disease.
  • silicosis,
  • diabetes mellitus,
  • malnutrition,
  • corticosteroids and other immuno-suppressive drugs and
  • smoking

 

6. What are the key Patient Factors that determine the Risk of Transmission?

 

The immune reconstitution syndrome occurs when the improving immune function unmasks a previously occult opportunistic infection (an infection that was present in the patient’s body, but was not clinically evident). Reactions usually occur within a median of 15 days after initiation of ART. They do not appear to be related to any particular regimen but are usually found in patients with advanced HIV. TB is a common immune reconstitution illness and MDR-TB or XDR-TB patients should be pre-emptively counselled about immune reconstitution syndrome.

Patients with advanced HIV, particularly those with a CD4 count < 50 cells/mm³ may become ill with an immune reconstitution illness during the first few weeks of ART, with symptoms of persistent fever, sweats, loss of weight, cough, shortness of breath, worsening pulmonary infiltrates, and decreasing visual acuity (to name but a few).

 

 

7. What are the Key Environmental Factors that determine the Risk of Transmission?

 
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  • Ventilation: Inadequate ventilation results in failure of air dilution or removal of infectious droplet nuclei thereby increasing the risk of transmission.
  • Duration of exposure: Spending eight continuous hours with an infectious person poses a higher risk than two hours or occasional contact.
  • Concentration of the droplet nuclei: The risk of transmission is higher if the concentration of the droplet nuclei in the air is high.
  • Space: The risk is higher in a small enclosed space.
  • Air circulation: Recirculation of air poses a risk when it contains infectious droplets.

 

8. How to Reduce the Risk of Transmitting TB Infection in Health care facilities?

 

Opportunistic infections may present in atypical ways during the phase of immune reconstitution. Management includes high doses of corticosteroids to contain symptoms: prednisolone or methylprednisolone 1 mg/kg for one to two weeks gradually reduced thereafter. It is not unusual to prolong the use of steroids or to restart if symptoms re-occur. Clinicians need to be cautious and attentive to the development of complications due to prolonged use of steroids (e.g. Cytomegalovirus infections).

Non-steroidal agents tend not to be helpful.

 

13.6. Patient Monitoring

 

8.1 What are the Key Management Control Measures?

 

The co-infected DR-TB/HIV patient poses a great challenge and requires intensive monitoring of drug interactions and additive toxicities. The complexity of ART and second-line drugs each with its own toxicity profiles (which may be potentiated during dual therapy) demands even more rigorous monitoring in co-infected patients. In addition, other opportunistic infections have to be prevented, monitored and treated.

Patients with DR-TB and HIV may require special socio-economic support. The treatment regimens are particularly hard to administer, the stigma of both diseases can result in serious discrimination, and the risk of mortality is very high.

The monitoring with chest x-rays, smear microscopy and cultures of patients is the same as for HIV-negative DR-TB patients. In patients receiving ART, CD4 counts should be measured at the time of diagnosis and every six months thereafter. A significant decrease in CD4 count is a decrease from baseline of 30% or more.

Viral load should be measured at baseline and at six-monthly intervals, provided that patients have reached virological goal (defined as a one-log/ 10-fold decrease). If this has not been achieved, an appropriate evaluation of virological failure should be done (assessment of adherence, potency, absorption, and viral resistance). A significant change in plasma viral load is a three-fold or 0.5 log increase or decrease.

ART also requires additional monitoring of tests not usually done in DR-TB treatment. For example, hematocrit and white blood cell count testing in patients on zidovudine, periodic monitoring of liver serum enzymes in patients on nevirapine, and testing of pancreatic enzymes in patients with abdominal pain taking stavudine or didanosine, are required.

 

13.7. Management of Adverse Drug Reactions

 

Infectiousness is dependent on the site of TB and extent of TB disease. Patients should be considered infectious if they have any of the following;

  • Cough
  • Sputum smear positive
  • Chest x-rays shows cavities in the lungs
  • Active affective TB Not on treatment
  • Just started TB treatment (on treatment less than a week)
  • Poor clinical response to TB treatment

 
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Introduction

 
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Many infections, and even non-infectious diseases, can cause fever and a haemorrhagic state. It is important to distinguish these conditions from viral haemorrhagic fevers (VHFs) caused by the so-called formidable or Class 4 viruses. The VHFs have in common a propensity for person-to-person spread and high mortality rates, which necessitate that special  infection  control  measures  (isolation  precautions)  should  be  instituted  when managing suspected or confirmed cases of the diseases, and work with the viruses is permitted only in biosafety level 4 (BSL4) laboratories. However, not all of the viruses associated with VHFs are uniformly lethal or spread readily between humans: some less pathogenic viruses are placed in Class 4 in countries from which they are absent in order to exercise control over their possible introduction.

 

Many parts of the world have endemic VHFs, and modern travel has made it possible for introduced cases to occur virtually anywhere. The most common VHF in  Southern Africa is caused by the tick-borne Crimean-Congo haemorrhagic fever (CCHF or Congo fever) virus, and approximately 5-20 cases of the disease are diagnosed in South Africa each year. Rift Valley fever, a zoonotic disease of sheep and cattle, also occurs in our region, but human infections are generally seen in the context of major outbreaks of disease in livestock which occur at irregular intervals of many years when exceptionally heavy rains favour breeding of the mosquito transmitters of the virus, and human-to-human transmission has not been recorded. The most recent large outbreak in South Africa was in 2010. In addition, the growing tendency for severely ill patients from countries in tropical Africa to seek medical attention in South Africa is leading to increased risk that cases of Lassa, Marburg and Ebola haemorrhagic fevers may be imported inadvertently. Fatal nosocomial infections have occurred in South African hospitals in the past, and to avoid further tragedies health care workers should maintain high standards of infection control and biosafety awareness at all times, and all patient care facilities should institute contingency plans for dealing with VHF patients.

 

The present document, an updated version of guidelines first prepared in 1985, is intended as a guide to the recognition and management of suspected and confirmed cases, and prevention of nosocomial spread, of the indigenous African viral haemorrhagic fevers. The recommendations are not binding except where reference is made to legislation, statutory regulations, or agreed protocol for dealings between separate organizations and institutions, each of which should draft and implement protocols adapted to their own needs.

 

 

2. REFERRAL OF VIRAL HAEMORRHAGIC FEVER PATIENTS

 
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After it was recognized in the 1980s that Congo fever is indigenous in South Africa, it was arranged that at least one provincial hospital within each province should be designated as a referral centre for the management of VHF patients, but circumstances have changed:

● It can  no  longer  be  assumed  that  VHF  patients  can  automatically  be  referred  to designated provincial hospitals.

● All private hospitals, and public tertiary and regional hospitals should be adequately resourced and prepared to handle VHF patients.

● All other  public  hospitals  must  have  access  to  public  referral  hospitals  that  are adequately resourced.

● It  is  the  responsibility  of  provincial  Department  of  Health  and  Hospital  Services, including  the  Coordinators  of  Communicable  Disease  Control,  to  formulate  and implement  provincial  policy  with  regard  to  referral  of  VHF  patients,  including  the designation of specific referral hospitals (see section 7).

● Previous versions  of  the  present  document  contained  a  list  of  designated  referral hospitals with contact details of persons with whom to liaise in order to arrange referral of VHF patients. Unfortunately this type of information is subject to abrupt changes, and hence the management of each hospital (specifically infection control officers) should establish for themselves what policy applies in their own province or sub region with  respect  to referral  of  VHF  patients,  and  keep  up-to-date  contact details  for  the  nearest  designated  VHF  referral  centre.  Do  not  be  caught unprepared.

 

 

3. BACKGROUND TO THE VIRAL HAEMORRHAGIC FEVERS

 

The managerial control provides a framework for the implementation of the infection prevention and control measures. This framework outlines interventions that must be implemented at all levels - national, provincial, district, facility and community.

1.    National and Provincial level managerial control activities include:

  • The development of minimum standards for health facility design which take airborne infection control into consideration.
  • Ensuring compliance to these standards for any new construction and renovations
  • Developing occupational health policies for staff working in the health facilities
  • Ensuring that regular TB medical surveillance for all health workers is conducted.
  • Building capacity for staff to conduct facility risk assessments and developing IPC plans
  • Ensuring that risk assessments are conducted in all health facilities annually
  • The development and distribution information, education and communication (IEC) materials on infection control health care workers and communities
  • Conducting social mobilization and awareness campaigns on TB infection control
  • Engaging civil society in TB prevention and control activities
  • Monitoring and evaluation of the implementation of the TB infection control measures.
  • Support operational research activities in TB IPC.

2.    District level managerial activities

  • The establishment of an Infection Prevention and Control committee and appoint infection prevention and control officer, where this exists ensuring that TB infection prevention and control is included in their responsibilities.
  • Appointment of an IPC Officer to coordinate the implementation of infection prevention and control programme within the district
  • Conduct health facility TB risk assessments annually
  • Review facility TB IPC plans annually
  • Provide occupational health services for all staff working in the health facilities
  • Monitoring the number of health staff diagnosed with TB monthly
  • Train and educate health workers on infection prevention and control measures.
  • Ensure availability of appropriate commodities for TB IPC
  • Monitoring of the implementation of TB Infection Prevention and Control interventions.
  • Facilitate operational research activities in TB IPC.

 

Viruses associated with haemorrhagic fevers (Table 3.1), fall into three groups with respect to their reservoir hosts and primary means of transmission, namely, rodent-associated viruses, arthropod-borne viruses, and viruses thought to be associated with bats.

 

3.1 Rodent-associated viruses

 

In general, HIV-positive patients have a higher rate of ADRs to both TB and non-TB medications and the risk of these increases with the degree of immunosuppression. Many of the medications used to treat DR-TB and HIV have overlapping, or in some cases additive, toxicity. Identifying the source of ADRs in patients taking treatment for both DR-TB and HIV is difficult.

When possible, avoid the use of agents with shared adverse effect profile. However, benefit of using drugs that have overlying toxicity outweighs the risk but there is a need to increase monitoring of ADRs in HIV infected DR-TB patients.

Some of the common overlying toxicities are:

  • Peripheral neuropathy
  • Central Nervous System toxicity
  • Depression
  • Gastro-intestinal intolerance
  • Hepatotoxicity
  • Skin rash
  • Renal toxicity
  • Electrolyte disturbances
  • Hypothyroidism etc.

 

The arenaviruses and hantaviruses cause chronic kidney infection in myomorph rodents (rats and mice) with excretion of virus in the urine, and humans become infected from contaminated food or household items, but there may also be occupational or recreational exposure to rodent excreta.

 

13.7.1. Hepatotoxicity

 

8.2 What are the Key Administrative Control Measures?

 

This is a common and potentially serious ADR. It is defined as:

  • An AST and ALT serum level of more than three times the upper limit with accompanying symptoms, or
  • An AST and ALT serum level of greater than five times the upper limit without accompanying symptoms.

If hepatitis develops, all potentially hepatotoxic drugs must be stopped, including pyrazinamide, antiretrovirals and cotrimoxazole. Serological tests for hepatitis A, B and C should be performed and the patient should be asked about exposure to alcohol and other hepatotoxins.  While the hepatitis is resolving it would be advisable to provide non-hepatotoxic drugs to continue the MDR-TB treatment, such as ethambutol and streptomycin. Treatment may be restarted when the AST, ALT and bilirubin levels have dropped below two times the upper limit of normal levels with significant improvement of symptoms.

 

13.7.2. Peripheral Neuropathy

 

Neuropathy may be caused by nucleoside analogues (ddI, d4T) and additive toxicity of ethionamide, cycloserine, terizidone and pyrazinamide when given with stavudine and/or didanosine has also been demonstrated. Pyridoxine 150 mg daily should be used in all HIV-infected patients receiving cycloserine/terizidone.

 

14. MONITORING AND EVALUATION OF PATIENTS WITH DR-TB

 

14.1. Introduction

 

MDR- or XDR-TB disease can be an emotionally devastating experience for patients and their families, while stigma related to the disease may interfere with adherence to treatment. In addition, the long duration of DR-TB treatment, combined with ADRs, may contribute to depression, anxiety and further jeopardise treatment adherence.

Monitoring the patient throughout the treatment period is therefore essential. The symptoms of DR-TB generally improve within the first few months of treatment. However, early resolution of symptoms is not an indication of cure, and recurrence of symptoms after sputum conversion may be the first sign of treatment failure. Laboratory evidence of improvement is therefore required, together with regular clinical assessment of the patient.

 

3.1.1   Lassa fever

Lassa fever is caused by an arenavirus that is confined to West Africa (Nigeria, Sierra Leone, Guinea and Liberia are particularly affected). Related viruses that occur in rodents elsewhere in Africa were not known to be pathogenic until the recent discovery of Lujo virus in southern Africa. Lassa fever infection is generally associated with a comparatively mild disease with fever and a death rate of 1-2% among cases in the community at large, but some patients develop haemorrhagic disease and deaths rates may approach 20% among hospitalised patients, or exceed 40% in nosocomial outbreaks. Person-to-person spread of infection, which occurs in the home and hospital, appears to require overt contact with infected tissues and body fluids. A physician from Nigeria who was evacuated for treatment in South Africa in 2007 proved to be suffering from fatal Lassa fever, but fortunately there were no secondary infections.

 

Clinical features of Lassa fever

The incubation period is usually 7-10 days (range 3-21 days). Over 80% of infections are asymptomatic or mild, but in the rest there is insidious onset of fever, chills, malaise, headache,  generalized  myalgia  and  prostrationWithin  2-3  days  patients  develop  sore throat vomiting,   abdominal   or   ches (retrosternal)   pains,   cough,   hypotension   and bradycardia. There is characteristic pharyngeal and tonsillar inflammation with vesicular or ulcerative lesions and whitish or yellowish exudate. Conjuctivae are injected, and there is lymphadenopathy,  muscle  tenderness,  pulmonary  rales,  and  sometimes  maculopapular rash. From day 5 patients may progress to severe sustained fever and toxaemia with haemorrhages (epistaxis, haematemesis, melaena), puffiness of the face and neck, serous effusions (hydrothorax), disorders of the central nervous system and shock.  The acute illness has a duration of 1-3 weeks. Deafness occurs in 25% of patients with some recovery in 1-3 months, and there may be loss of hair and an unsteady gait during convalescence.

 

Clinical pathology of Lassa fever

Early leucopenia may be followed by leucocytosis. Proteinuria is common. Abnormalities in platelet counts, prothrombin and clotting time are not marked, but there may be pronounced increases in serum levels of aspartate and alanine transaminases, lactic dehydrogenase and creatine kinase. Viraemia lasts about a week from the time of onset of disease but excretion of virus in urine may extend over 3-10 weeks.

 

 

Lujo virus: In September-October 2008, there was a nosocomial outbreak of infection with a new arenavirus, Lujo virus, in Johannesburg, involving 5 patients, 4 of whom died, with a clinical course similar to severe Lassa fever. The first patient was transferred from Zambia to South Africa for medical management and the source of her infection remains undetermined, although rodents are suspected. Three cases involved secondary spread of infection from the first patient, and there was one tertiary infection. The secondary and tertiary infections alloccurred before isolation precautions were implemented. Several arenaviruses cause hemorrhagic fevers in South America.

 

Clinical features of Lujo virus

Incubation period of 9-13 days; a prodomal illness characterized by fever, headache and myalgia, followed by diarrhoea and pharyngitis and a morbiliform rash on the face and trunk reported in three cases on day 6-8 of illness. Facial swelling occurred in three patients with marked pharyngeal ulceration reported in one patient. There appeared to be an initial clinical improvement after hospital admission in three patients, followed by sudden, rapid deterioration in all patients who died. Bleeding was not a prominent feature. One patient had a petechial rash and another had oozing of blood from venipuncture sites. One patient was treated with intravenous ribavirin and survived.

 

Clinical pathology of Lujo virus

At the time of admission all patients had thrombocytopenia (range: 42-104 x 109/L). Liver transaminases (AST and ALT) were raised in all five patients during the course of their illness.

 

 

14.2. Monitoring Progress of Treatment

 

Patients on MDR- or XDR-TB treatment need to be monitored closely for side effects and signs of treatment failure. There are essentially three components to treatment monitoring namely, clinical, laboratory and other investigations.

 
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3.1. Hantaviruses.

Several hantaviruses are associated with a group of diseases in Europe and Asia which are known collectively as haemorrhagic fever with renal syndrome (HFRS) (with fatality rates of <1-35%), while another group of hantaviruses is associated with the hantavirus pulmonary   syndrome   (HPS (fatalit rates   50% i Nort an Sout America. Hantaviruses have been poorly studied in Africa, and there is as yet little evidence that they occur here, except possibly for Seoul virus, thought to have been widely disseminated to sea ports with ship-borne rats and occurring in urban settings.

 

Clinical features of HFRS

 

There  are  4  clinical  forms  of  the  disease,  varying  in  severity  (<1-35%  fatal)  from nephropathia epidemica associated with Puumala virus in Scandinavia, through mild or rat- borne HFRS associated with Seoul virus infection which has been widely disseminated with ship-borne rats, to Far Eastern HFRS associated with Hantaan virus in Asia (also known as Korean haemorrhagic fever), and so-called Balkan HFRS associated with Dobrava virus. The incubation period is 2-3 weeks. Severe disease has five well-marked phases but these overlap and are obscured in mild disease. An initial febrile phase of 3-7 days is marked by high  fever,  chills,  malaise,  myalgia,  anorexia,  dizziness,  headache  and  ocular  pain, abdominal and back pain with tenderness in the renal area (peritoneal and retroperitoneal oedema), followed by characteristic flushing of the face neck and chest, with injection of the eyes, palate and pharynx which develops into a fine petechial rash and conjunctival haemorrhage. There is marked proteinuria. A hypotensive phase follows abruptly and lasts hours to 2 days, with tachycardia and classical shock: narrowed blood pressure, cold and clammy skin, dulled senses and confusion; one third of fatal patients enter irreversible shock at this stage. Proteinuria continues and there is mild haematuria, raised haematocrit level, leukemoid reaction  and  thrombocytopenia.  Onset  of  an  oliguric  phase  of  3-4 days  is marked by increasing blood urea and creatinine levels. Blood pressure begins to normalize but hypertension can result from the hypovolaemic state. There may be severe nausea and vomiting, and bleeding tendencies increase: epistaxis, conjunctival haemorrhage, cerebral and gastro-intestinal haemorrhage and extensive purpura. There is hyperkalaemia, hyponatraemia  and  hypocalcaemia.  There  may  be  central  nervous  symptoms  and pulmonary oedema, with 50% of fatalities occurring in this phase. A diuretic phase may last days to weeks, with diuresis of up to 3-6 litres per day, and marks the start of recovery. The convalescent phase lasts 2-3 months with progressive recovery of glomerular filtration rate.

 

Footnotes

i: Criteria for STI therapy in VDS: Unpublished surveillance data for VDS at Alexander Health Centre, Gauteng (2007-2012) shared by NICD: Centre for STI and  HIV .

ii: Metronidazole: Swedberg J, Steiner JF, Deiss F, Steiner S, Driggers DA .  Comparison of single-dose vs .  one-week course of metronidazole for symptomatic bacterial vaginosis .  JAMA .  1985 Aug 23-

30;254(8):1046-9 .

Metronidazole: Kissinger P, Secor WE, Leichliter JS, Clark RA, Schmidt N, Curtin E, Martin DH .  Early repeated infections with Trichomonas vaginalis among HIV-positive and HIV-negative women .  Clin Infect Dis .  2008 Apr 1;46(7):994-9 .

Metronidazole: Kissinger P, Mena L, Levison J, Clark RA, Gatski M, Henderson  H, Schmidt N, Rosenthal SL, Myers  L, Martin DH .  A randomized treatment trial: single versus 7-day dose of metronidazole for the treatment of Trichomonas vaginalis among HIV-infected women .  J Acquir Immune DeficSyndr .  2010 Dec 15;55(5):565-71 .

iii: Ceftriaxone: Newman  LM, Moran JS, Workowski KA .  Update on the management of gonorrhea in adults in the United States .  Clin Infect Dis .  2007 Apr 1;44Suppl 3:S84-101 .Review .

Ceftriaxone: Ito M, Yasuda M, Yokoi S, Ito S, Takahashi Y, Ishihara S, Maeda S, Deguchi T .  Remarkable increase in central Japan in 2001-2002 of Neisseria gonorrhoeae isolates with decreased susceptibility to penicillin, tetracycline, oral cephalosporins, and fluoroquinolones .  Antimicrob Agents Chemother .  2004 Aug;48(8):3185-7

Ceftriaxone: Tanaka M, Nakayama H, Tunoe H, Egashira T, Kanayama A, Saika T, Kobayashi  I, Naito S . A remarkable reduction in the susceptibility of Neisseria gonorrhoeae isolates to cephems and the selection of antibiotic regimens for the single-dose treatment of gonococcal infection in Japan .  J Infect Chemother .  2002 Mar; 8(1):81-6 .

Ceftriaxone: Deguchi T, Yasuda M, Yokoi S, Ishida K, Ito M, Ishihara S, Minamidate K, Harada  Y, Tei K, Kojima K, Tamaki M, Maeda S .  Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval .  J Infect Chemother .  2003 Mar;9(1):35-9 .

Ceftriaxone: Lewis DA .  Gonorrhoea resistance among men-who-have-sex-with-men: what’s oral sex got to do with it? S Afr J Epid Infect .  2013;28: 77 .

Ceftriaxone: Lewis DA, Sriruttan C, Müller EE, Golparian D, Gumede L, Fick D, de Wet J,Maseko V, Coetzee J, Unemo M .  Phenotypic and genetic characterization of the first two cases of extended- spectrum-cephalosporin-resistant Neisseria gonorrhoeae infection in South Africa and association with cefixime treatment failure .  J Antimicrob Chemother .  2013 Jun;68(6):1267-70 .

Ceftriaxone: Lewis DA .  The role of core groups in the emergence and dissemination ofantimicrobial-resistant N gonorrhoeae .  Sex Transm Infect .  2013 Dec;89Suppl4:iv47-51 .  Review .

Ceftriaxone: Health Protection Agency .  Gonoccocal Resistance to Antimicrobials Surveillance Programme (GRASP) Action Plan for England and Wales: Informing the Public Health Response . (Ed .^(Eds) (HPA, London, 2013)

Ceftriaxone: Bignell C, Fitzgerald M; Guideline Development Group; British Association for Sexual Health and HIV UK .  UK national guideline for the management of gonorrhoea in adults, 2011 .  Int J STD AIDS .  2011 Oct;22(10):541-7 .

Ceftriaxone: Centers for Disease Control and Prevention .  Cephalosporin-resistant Neisseria gonorrhoeae public health response plan .  (Ed .^(Eds) (CDC, Atlanta, 2012)

Ceftriaxone: Centers for Disease Control and Prevention .  Update to CDC’s Sexually transmitted diseases treatment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections .  MMWR Morb Mortal Wkly Rep .  2012;6: 590-594 .

iv: Azithromycin: Lau CY, Qureshi AK .  Azithromycin versus doxycycline for genital chlamydial infections: a meta-analysis of randomized clinical trials .  Sex Transm Dis .  2002 Sep;29(9):497-502 .

 

 

 

 

Azithromycin: Bignell C, Garley J .  Azithromycin in the treatment of infection with Neisseria gonorrhoeae .  Sex Transm Infect .  2010 Nov;86(6):422-6

Azithromycin: Stamm WE, Hicks CB, Martin DH, Leone P, Hook EW 3rd, Cooper RH, Cohen  MS, Batteiger BE, Workowski K, McCormack WM .  Azithromycin for empirical treatment of the non gonococcal urethritis syndrome in men .  A randomized double-blind study .JAMA .  1995 Aug

16;274(7):545-9 .

Azithromycin: Lister PJ, Balechandran T, Ridgway GL, Robinson AJ .  Comparison of azithromycin and doxycycline in the treatment of non-gonococcal urethritis in men .  J Antimicrob Chemother .  1993

Jun;31Suppl E:185-92 .

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Azithromycin: Manhart LE, Gillespie  CW, Lowens  MS, Khosropour CM,Colombara DV, Golden MR, Hakhu  NR, Thomas  KK, Hughes JP, Jensen NL, Totten PA .  Standard treatment regimens for non gonococcal urethritis have similar but declining cure rates: a randomized controlled trial .  Clin Infect Dis .  2013 Apr;56(7):934-42 .

Azithromycin: Handsfield  HH, Dalu ZA, Martin DH, Douglas  JM Jr, McCarty JM, Schlossberg D . Multicenter trial of single-dose azithromycin vs .  ceftriaxone in the treatment of uncomplicated gonorrhea .  Azithromycin Gonorrhea Study Group .  Sex Transm Dis .  1994 Mar-Apr;21(2):107-11 .

Azithromycin: Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher  M, Mmbando D, Samky E, Lyamuya E, Mabey D, Grosskurth H, Hayes R .  Single-dose azithromycin versus penicillin  G benzathine for the treatment of early syphilis .  N Engl J Med .  2005 Sep 22;353(12):1236-44 .

Azithromycin: Hook EW 3rd, Martin DH, Stephens J, Smith BS, Smith K .  A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis .  Sex Transm Dis .  2002 Aug;29(8):486-90

Azithromycin: McLean  CA, Wang  SA, Hoff GL, Dennis LY, Trees DL, Knapp JS, Markowitz LE, Levine WC .  The emergence of Neisseria gonorrhoeae with decreased susceptibility to Azithromycin in Kansas City, Missouri, 1999 to 2000 .  Sex Transm Dis .  2004 Feb;31(2):73-8

Azithromycin: Galarza PG, Abad  R, Canigia LF, Buscemi L, Pagano I, Oviedo  C, Vázquez  JA .  New mutation in 23S rRNA gene associated with high level of azithromycin resistance in Neisseria gonorrhoeae .  Antimicrob Agents Chemother .  2010 Apr;54(4):1652-3 .  doi: 10 .1128/AAC .01506-09 .

Azithromycin: Bignell C, Fitzgerald M; Guideline Development Group; British Association for Sexual Health and HIV UK .  UK national guideline for the management of gonorrhoea in adults, 2011 .  Int J STD AIDS .  2011 Oct;22(10):541-7 .

Azithromycin: Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC) .  Sexually transmitted diseases treatment guidelines, 2010 .  MMWR Recomm Rep .  2010 Dec 17;59(RR-12):1-110 . Erratum in: MMWR Recomm Rep .  2011 Jan 14;60(1):18 .  Dosage error in article text .

Azithromycin: Chisholm SA, Mouton JW, Lewis DA, Nichols T, Ison CA, Livermore DM .  Cephalosporin

MIC creep among gonococci: time for a pharmacodynamic rethink? J Antimicrob Chemother .  2010

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Azithromycin: de Jongh M, Dangor Y, Adam A, Hoosen AA .  Gonococcal resistance: evolving from penicillin, tetracycline to the quinolones in South Africa - implications for treatment guidelines .  Int J STD AIDS .  2007;18:697-699 .

Azithromycin: Manhart LE, Broad JM, Golden MR .  Mycoplasma genitalium: should we treat and how? Clin Infect Dis, 53 Suppl 3, S129-142 (2011) .

 

 

 

 

Azithromycin: Mena LA, Mroczkowski TF, Nsuami M, Martin DH .  A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitalium-positive urethritis in men .  Clin Infect Dis .  2009;48:1649-1654 .

Azithromycin: Amsden  GW, Gray CL .  Serum and WBC pharmacokinetics of 1500 mg of azithromycin when given either as a single dose or over a 3 day period in healthy volunteers .  J Antimicrob Chemother .  2001 Jan;47(1):61-6 .

Azithromycin: Sampson MR, Dumitrescu TP, Brouwer KL, Schmith VD .  Population pharmacokinetics of azithromycin in whole blood, peripheral blood mononuclear cells, and polymorphonuclear cells in healthy adults .  CPT Pharmacometrics Syst Pharmacol .  2014 Mar 5;3:e103 .

Azithromycin: Lewis DA, Maartens GM: Medicine  review: The use of azithromycin in the syndromic management algorithms for the management of sexually transmitted infections (STIs) in South Africa, 16 March 2014 .

Azithromycin: SAMF, 2012 edition .

v: Azithromycin: Pitsouni E, Iavazzo C, Athanasiou S, Falagas ME .  Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection during pregnancy: a meta-analysis of randomised controlled trials .  Int J Antimicrob Agents .  2007 Sep;30(3):213-21 .

vi: Lidocaine 1%: Contract circular HP02-2013AI (1August2013to31July2015): MCC registered package inserts of Kocef® 250 mg, 500 mg, 1 g; Rociject® 500 mg, 1 g; Oframax® 250 mg, 1 g

vii: Azithromycin (LAP): Savaris RF, Teixeira LM, Torres TG, Edelweiss MI, Moncada J, Schachter J .  Comparing ceftriaxone plus azithromycin or doxycycline for pelvic inflammatory disease: a randomized controlled trial .  Obstet Gynecol .  2007 Jul;110(1):53-60 .

Azithromycin (LAP/ SSW/ BUBO): Amsden  GW, Gray CL .  Serum and WBC pharmacokinetics of 1500 mg of azithromycin when given either as a single dose or over a 3 day period in healthy volunteers . J Antimicrob Chemother .  2001 Jan;47(1):61-6 .

Azithromycin (LAP/ SSW/ BUBO): Sampson MR, Dumitrescu TP, Brouwer KL, Schmith VD .  Population pharmacokinetics of azithromycin in whole blood, peripheral blood mononuclear cells, and polymorphonuclear cells in healthy adults .  CPT Pharmacometrics Syst Pharmacol .  2014 Mar

5;3:e103 .

viii: Metronidazole (LAP): Bignell  C, Fitzgerald M; Guideline Development Group; British Association for Sexual Health and HIV UK .  UK national guideline for the management of gonorrhoea in adults,

2011 .Int J STD AIDS .  2011 Oct;22(10):541-7 .

Metronidazole (LAP): Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC) . Sexually transmitted diseases treatment guidelines, 2010 .MMWR Recomm Rep .  2010 Dec 17;59(RR-

12):1-110 .  Erratum in: MMWR Recomm Rep .  2011 Jan 14;60(1):18 .  Dosage error in article text .

ix: Ceftriaxone 1 g + Azithromycin 2 g (MUS): WHO .  Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae .  2012 .

x: Gentamicin: Brown  LB, Krysiak R, Kamanga  G, Mapanje C, Kanyamula H, Banda B, Mhango C, Hoffman M, Kamwendo D, Hobbs M, Hosseinipour MC, Martinson F, Cohen MS, Hoffman IF . Neisseria gonorrhoeae antimicrobial susceptibility in Lilongwe, Malawi, 2007 .Sex Transm Dis .  2010

Mar;37(3):169-72 .

xi: Azithromycin (GUS): National STI Surveillance Programme, Centre for HIV & STIs, NICD/NHLS,

2006-2011

Azithromycin (GUS): Lewis D, Newton DC, Guy RJ, Ali H, Chen MY, Fairley CK, Hocking JS . Theprevalence of Chlamydia trachomatis infection in Australia: a systematic review and meta- analysis .  BMC Infect Dis .  2012 May 14;12:113 .

Azithromycin (GUS): World Health Organization .  Guidelines for the management of sexually transmitted infections .  WHO, Geneva .  2003 .

 

 

 

 

xii: Pregnancy/ breast feeding (GUS): Adult Hospital level STG, 2012 .

xiii: Lidocaine 1% (GUS/ Syphilis): Kingston M, French P, Goh  B, Goold P, Higgins S, Sukthankar A, Stott C, Turner A, Tyler C, Young H; Syphilis Guidelines Revision Group 2008, Clinical Effectiveness Group .  UK National Guidelines on the Management of Syphilis 2008 .  Int J STD AIDS .  2008

Nov;19(11):729-40 .  Erratum in: Int J STD AIDS .  2011 Oct;22(10):613-4 .

Lidocaine 1% (GUS/ Syphilis): Amir J, Ginat S, Cohen YH, Marcus TE, Keller N, Varsano I .  Lidocaine as a diluent for administration of benzathine penicillin G .  Pediatr Infect Dis J .  1998 Oct;17(10):890-3 .

xiv: Azithromycin (Bubo): Workowski KA, Berman S; Centers for Disease Control and Prevention

(CDC) .  Sexually transmitted diseases treatment guidelines, 2010 .MMWR Recomm Rep .  2010 Dec

17;59(RR-12):1-110 .  Erratum in: MMWR Recomm Rep .  2011 Jan 14;60(1):18 .  Dosage error in article text .

 

 

 

Clinical features of HPS

Persons who develop HPS are often healthy young adults, but may be of any age and either sex. The incubation period is 2-3 weeks and onset is marked by sudden development of fever, headache, severe myalgia and a cough, which may be productive in some instances. Gastrointestinal manifestations in some patients include abdominal pain, nausea, vomiting and diarrhoea. After 3-6 days of illness there is progressive tachypnoea, tachycardia and hypotension preceding the onset of acute respiratory distress with pulmonary oedema. Patients are generally hospitalized at this stage, but some die before they can be admitted. On admission patients may have proteinuria, leucocytosis with neutrophilia plus increased myeloid precursors and atypical lymphocytes, haemoconcentration, and thrombocytopenia, and increased prothrombin and partial-thromboplastin times, although there is no rash and very  seldom  a  tendency  towards  overt  or  internal  bleeding.  Withitwo  days  of  being admitted to hospital most patients develop diffuse bilateral interstitial and alveolar pulmonary infiltration and pleural effusions demonstrable on radiographs, with hypoxaemia, which necessitates intubation, mechanical ventilation and oxygen supplementation. Sometimes there is renal insufficiency and increased serum creatine kinase levels (evidence of skeletal muscle inflammation). Death generally occurs 6-8 days after the onset of illness, often withi48 hours of admission to hospital, but can range from 2 days after the observed onset of illness to more than two weeks. Fatality rates often exceed 40%, and incurable shock anmyocardial  dysfunction  may  contribute  to  the  high  mortality.  Autopsies  reveal  non-

cardiogenic pulmonary oedema and serous pleural effusions, with scant lymphoid infiltration of the lung tissue. Some survivors manifested transient diuresis, but otherwise they make an uneventful recovery without sequelae.

 

3.2 Arthropod-borne viruses (‘arboviruses’ or ‘insect-transmitted’ viruses)

 

Several haemorrhagic fevers are caused by arboviruses. These are diverse viruses, which have in common the fact that they are transmitted by blood-sucking arthropods (mosquitoes, midges, sand flies and ticks), with various wild and domestic animals serving as reservoir hosts (infected animals which serve as sources of virus for infecting the arthropod vectors). Only a few arboviruses cause haemorrhagic disease.

 

3.2.1   Crimean-Congo haemorrhagic fever (CCHF or Congo fever)

 

Congo fever is the most frequently observed haemorrhagic fever in South Africa. It is caused by a tick-borne virus, which occurs widely in Africa, Eastern Europe and Asia, within the distribution range of its main vectors, ticks of the genus Hyalomma. These are known as bont-legged ticks in South Africa on account of the distinctive brown and white bands on their legs. The disease is seen most frequently in the Northern Cape, Free State and North West Provinces where the drier climate favours the bont-legged ticks, but cases may occur anywhere in the country: patients infected in the Free State have become ill in KwaZulu- Natal, and abattoir workers have developed the disease within the cities of Cape Town and Johannesburg. The disease has an approximately 30% fatality rate and humans acquire infection from tick bite or from contact of broken skin with fresh infected blood and tissues of livestock (sheep, cattle, ostriches), which themselves undergo benign infection. Meat, which has been bled out and hung to mature according to proper slaughterhouse procedures, is not  infectious,  and  cooking  destroys  the  virus.  About  5-20  cases  othe  disease  are diagnosed in South Africa each year, and two South Africans are known to have acquired infection during visits to Namibia and Tanzania. In addition, a patient from the DRC with unrecognised CCHF was treated in South Africa; the diagnosis was only established after his death but fortunately there were no secondary infections. Infection can occur in hospitals where medical staff comes into contact with the blood of patients (needle sticks) or blood-tinged body fluids; there have been three such incidents in South Africa involving 6 nurses, a surgeon and a laboratory technologist, with 3 fatalities. There is no vaccine. 

 

 

 

Clinical features of Congo fever

The incubation period commonly ranges from 1-3 days after tick bite, to 5-6 days after contact with infected blood or other tissues, but may occasionally be longer. People are not always aware of being bitten by ticks (look for ticks or bite marks, including on the scalp and between toes), but infection can also be acquired from merely squashing ticks between the fingers. In contrast to the necrotic eschars that occur at the site of the bites in tick bite fever (rickettsiosis), there may only be slight bruising at bite sites in Congo fever. Unlike many other arbovirus diseases, a high proportion of infections are symptomatic. Onset is usually very sudden, with severe headache, dizziness, neck pain and stiffness, sore eyes, photophobia, fever, rigor and chills, followed rapidly by myalgia with intense backache or leg pains, nausea, sore throat and vomiting. There may be non-localized abdominal pain and diarrhoea at an early stage. Fever is often intermittent and patients may undergo sharp changes of mood over the first two days, with feelings of confusion and aggression. By da2-4 patients may exhibit lassitude, depression and somnolence, and have a flushed appearance with injected conjunctivae or chemosis. Tenderness localizes in the right uppequadrant of the abdomen, and hepatomegaly may be discernible. Tachycardia is commoand patients may be slightly hypotensive. There may be lymphadenopathy, plus enanthema and petechiae of the throat, tonsils and buccal mucosa. A petechial rash appears on the trunk and limbs by day 3-6 of illness, and this may be followed rapidly by the appearance of large bruises and ecchymoses, especially in the anticubital fossae, upper arms, axillae and groin. Oozing of blood from injection or venipuncture sites, epistaxis, haematemesis, haematuria, melaena, gingival bleeding and bleeding from the vagina or other orifices may commence on day 4-5 of illness, seldom earlier. There may also be internal bleeding, including retroperitoneal and intracranial haemorrhage. Severely ill patients enter a state of hepatorenal and pulmonary failure from about day 5 onwards and progressively becomes drowsy, stuporous and comatose. Jaundice may become apparent during the second week of illness. The mortality rate is approximately 30% and deaths generally occur on day 5-14 of illness. Patients who recover usually begin to improve suddenly on day 9-10 of illness, but asthenia, conjunctivitis, slight confusion and amnesia may continue for a month or longer.

 

Clinical pathology of Congo fever

During the first few days of illness there may be leucocytosis or leucopenia, and elevated aspartate and alanine transaminases, gamma-glutamyl transferase, lactic dehydrogenase, alkaline phosphatase and creatine kinase levels, while bilirubin, creatinine and urea levels increase and serum protein levels decline during the second week. Thrombocytopenia, elevation of the prothrombin ratio, activated partial thromboplastin time, thrombin time, elevation of D-dimers and fibrin degradation products, as well as depression of fibrinogen and haemoglobin values are evident very early in the illness, indicating that disseminated intravascular coagulopathy is an early and central event in the pathogenesis of the disease. During the first 5 days of illness any of the following clinical pathology values are highly predictive of fatal outcome: leucocyte counts 10x109/L; platelet counts 20x109/L; AS200U/L; ALT 150U/L; APTT 60 seconds; and fibrinogen 110mg/dL. Leucopenia does not have the same poor prognostic connotation as leucocytosis at this early stage, and all clinical pathology values may be grossly abnormal after day 5 of illness without necessarily being indicative of a poor prognosis. Viraemia is usually detectable during the first week of illness (range 1-13 days), and viral nucleic acid can be detected in serum by RT-PCR for up to 16 days after onset. Antibody response is rarely demonstrable in fatal illness, and thus detection of antibody is generally a favourable sign.

 

3.2. Rift Valley fever (RVF)

RVF is a mosquito-borne virus disease of livestock in Africa and Madagascar which affects mainly sheep and cattle, and causes massive outbreaks of abortion and death of young animals at irregular intervals of years when particularly heavy rains favour the breeding of the vectors. Humans acquire infection from contact with infected tissues of farm animals, or less frequently from mosquito bite. Most patients experience benign illness with fever, some with ocular sequelae (usually transient scotomas, but sometimes permanent blindness) and only <1% develop fatal haemorrhagic disease, hepatitis or encephalitis. Nevertheless, outbreaks can be massive and the disease has caused large numbers of human deaths on occasion. The last major outbreak in South Africa occurred in 2010, and particularly affecting farms in Eastern Cape, Free State and Northern Cape Provinces with some spread to the Western Cape, North West and Gauteng Provinces. There were 230 lab confirmed human cases and 26 deaths but is likely that there were a significant number of asymptomatic cases who were not tested. In 1985, one patient infected in Angola and two infected in Zambia were treated in South Africa. In 2000-1, the disease was recognized outside of the African region for the first time in a large outbreak in Saudi Arabia and Yemen. Curiously, there are no records of human-to-human transmission of the virus, although very high levels of virus occur  in  the  blood  of  patients  so  that  transmission  by  needle  stick  is  possible.  An experimental human vaccine produced in the USA was formerly used on a limited scale in people with occupational exposure to infection in the livestock industry and in laboratories, but it is not currently available.

 

Clinical features of RVF

The incubation period is generally 2-6 days, and the majority of infections are either mild (recognized only in serosurveys or as laboratory infections), or present as moderate to severe febrile illness with sudden onset of severe retro-orbital pain and headache, photophobia, suffused conjunctivae, myalgia, arthralgia, prostration, nausea and tenderness of the liver without hepatomegaly. Fever and prostration often last only 2-3 days, or the disease may run a diphasic course over two weeks. Ocular complications occur in 5-20% of cases 1-3 weeks after onset of illness. Decreased visual acuity or scotomas are associated with retinal haemorrhages, exudate and macular oedema. Vision usually improves over a period of 1-3 months as lesions resolve, but occasionally there can be detached retina and blindness. Less than 0.5% of patients develop encephalitis or haemorrhagic disease with high death rates. Encephalitis occurs as a complication 1-2 weeks after the acute febrile disease,   and   patient may   succum o underg sudden   or   protracted   recovery. Haemorrhagic fever with or without neurologic disease, can supervene within a week after the acute febrile stage. There is extensive liver necrosis in these cases, and there may be marked anaemia following massive epistaxis, haematemesis and melaena. Petechiae, ecchymoses and jaundice may be evident.

 

Clinical pathology of RVF

 

There is usually leucopenia, hyperbilirubinaemia, thrombocytopenia, prolongation of clotting parameters and markedly raised serum transaminases. Viraemia commonly lasts 2-3 days but has been recorded for up to 11 days.

 

3.2. Chikungunya, yellow fever and dengue viruses

 

These viruses circulate between mosquitoes and non-human primates (monkeys and apes) in forests, but have the unusual ability among arboviruses of utilizing humans as their sole vertebrate hosts in urban outbreaks of disease. Although infections with these three viruses can take a haemorrhagic form, they have not been associated with human-to-human spread, and their main importance is as differential diagnoses for VHF.

 

Chikungunya (CHIK) virus causes outbreaks of illness characterized by fever and joint pain in rural locations where baboons and monkeys occur in Africa, mainly in East Africa, but including South Africa, particularly the Limpopo and Mpumalanga Lowveld, and northern KwaZulu-Natal coast. Pain in a particular joint may last for up to two years after the acute illness. Severe and haemorrhagic forms of the disease have been recorded in a minority of patients in Asia and the Indian Ocean islands where the virus causes large urban epidemics. Chikungunya has been diagnosed in South African tourists returning from abroad, and it is theoreticall possible   tha such   a   patien could   initiate   urban   outbreak involving transmission by local mosquitoes, particularly in KwaZulu-Natal. There is no vaccine.

 

Yellow fever (YF) is a well-known mosquito-borne virus, which causes outbreaks of fatal disease with necrotic hepatitis in South America, West Africa, and less frequently East Africa, but it has never been recorded south of Angola. Suitable mosquito vectors occur in eastern South Africa. The fact that a very effective vaccine is available, and is used on international travellers, tends to limit the potential for tourists to spread infection to remote locations, but it is possible that sick patients could be evacuated for treatment in South Africa. Nosocomial infection has never been described, although in endemic areas mosquito transmission could also affect health care workers.

 

 

Dengue (DEN) is a mosquito-borne virus which causes massive outbreaks of disease with fever, and joint and muscle pains throughout the tropics in South America, the Caribbean, East and West Africa, Indian Ocean islands, India and South East Asia. There are four sub- types of the virus, and a small proportion of patients may develop haemorrhagic disease or a shock syndrome, particularly the very young and the aged, or those who suffer sequential infection with a second sub-type of the virus after an interval when immunity to the initial infection is waning. This latter phenomenon involves so-called immune-enhancement of infection. Suitable mosquito vectors exist in eastern South Africa, and it is theoretically possible for the virus to be introduced into the country and for epidemics to occur here.  The disease has been diagnosed in South Africa on a few occasions in recent years in people who had visited India, the Far East, or Indian Ocean islands. There is no vaccine.

 

3.3 Viruses believed to be associated with bats

 

Introduction

 

There is emerging evidence that the filoviruses (filament-shaped or thread-like viruses), Marburg (MBG) and Ebola (EBO), are associated with bat reservoir hosts. Outbreaks of human disease have sometimes resulted from known contact with infected tissues of non- human primates (chimpanzees and gorillas), but since these animals are equally as susceptible to fatal infection as are humans, it is surmised that they are unlikely to be reservoir hosts. Marburg virus appears to be confined to Africa, whereas the Reston sub- type of Ebola virus, which apparently causes benign infection in humans, was discovered in monkeys imported into the USA from the Philippines. In Africa, Marburg and Ebola viruses appear to be endemic in the tropical region roughly within the area enclosed by Zimbabwe, Angola, Ivory Coast and Kenya: Marburg outbreaks are known to have originated in Uganda, Kenya, DRC, Zimbabwe and Angola, while outbreaks caused by the Sudan, Zaire and Ivory Coast sub-types of Ebola virus have occurred in Sudan, Democratic Republic of Congo, Uganda, Gabon, Congo Republic and Ivory Coast. Two young Australians who are thought to have become infected while hitchhiking in Zimbabwe, developed Marburg disease in South Africa in 1975, and a nurse in Johannesburg acquired infection from them. A doctor, who became infected from contact with Ebola patients in Gabon in 1996, came to South Africa for treatment, and a nurse acquired fatal infection from him.

 

 

Clinical features of Marburg and Ebola fevers

The incubation period is generally 7-10 days (range 2-21 days) and the duration of clinical disease is of similar duration, but convalescence is prolonged. There is sudden onset of fever, severe headache (often frontal initially), sore throat, chest and/or abdominal pain, myalgia, arthritis, malaise, fatigue, nausea and anorexia. Signs exhibited by patients include oral/throat lesions, persistent diarrhoea and vomiting, dehydration, dry cough, conjunctivitis and non-itching maculopapular rash of trunk and limbs with onset on about day 5 of illness and desquamation 4-10 days later. The rash may be difficult to discern in dark-skinned patients, but the desquamation is more apparent and may involve palms and soles. There may be splenomegaly and non-icteric hepatitis with epigastric tenderness. Pregnant women may abort. The more severe and fatal cases progress to a haemorrhagic state by day 5-8 of illness with bleeding from needle puncture or scarified sites, mouth/gingival bleeding, haematemesis,   melaen an epistaxis.   Central   nervou system   symptom include aggressive and altered behaviour, confusion and somnolence. Dehydration is severe in the absence of administration of fluids.

 

 

Hepatitis B is an important  public health issue in South Africa (SA). Prior to the introduction of the hepatitis B vaccine into the South African Expanded Programme of Immunisation  (EPI) in 1995, prevalence rates of this disease were 0.3 - 15%.[1] However, unlike countries such as Taiwan,[2] SA has had no catch-up vaccination programme to ensure complete vaccination coverage. In addition, the HIV/AIDS pandemic has had a potentially deleterious influence on the natural history of patients co-infected with HIV and the hepatitis B virus (HBV).[3]

The spectrum of disease and natural history of chronic HBV infection is diverse, ranging from a low viraemic immune control state to progressive chronic hepatitis, with the potential for the ensuing complications of cirrhosis, liver failure and hepatocellular carcinoma (HCC).[4] As understanding of the natural history of chronic hepatitis B increased over the past decade, there have been significant therapeutic advances. The decision to treat and the choice of therapy is dependent on both the phase of chronic infection and patient factors.

This guideline draws on the recently published guidelines by the American Association for the Study of Liver Disease (AASLD), the European Association for the Study of the Liver (EASL), the Asia-Pacific Association for the Study of the Liver (APASL), National Institutes of Health (NIH) and the World Gastroenterology Organisation (WGO).[5-9]  It serves as an attempt to contextualise practice guidelines on the management of chronic hepatitis B in SA.

 

Pathogenesis and natural history

 

Clinical pathology of Marburg and Ebola fevers

There  may  be  transient  leucopenifollowed  by  marked  leucocytosis,  reduced  platelet counts, raised transaminases, proteinuria and low haemoglobin values. Viraemia has been detected up to day 17 of illness, but persistence of virus has been demonstrated in some organs (liver, and eye with uveitis) for several weeks, and excretion in semen has been recorded for up to 12 weeks after onset of illness.

 

See Table 1. Hepatitis is an enveloped partially double-stranded DNA virus belonging to the Hepadnaviridae family. It is 100 times more infectious than HIV and can be transmitted by perinatal, percutaneous and sexual exposure.[10] Close person-to-person contact is an important form of transmission, most notably among children in highly endemic areas, such as in SA.[5,10]

Liver injury due to hepatitis B is mainly caused by cellular immune mediated mechanisms with cytotoxic T lymphocyte lysis of infected hepatocytes. The magnitude of the individual’s adaptive cellular immune response to HBV-related antigens determines the outcome of acute HBV infection, as well as the degree of liver injury. Chronically infected patients are unable to sustain an immune response to HBV and may experience intermittent episodes of hepatocyte destruction in an attempt to clear virally infected hepatocytes, in what can be termed ‘flares’. Note that, during the acute infection, hepatitis B does not appear to induce an intra-hepatic innate immune response. Instead, it acts as a ‘stealth’ virus early in the infection.[9]

Age is also an important host factor determining the risk of chronicity. Following acute exposure to HBV, 90% of neonates born to hepatitis B ‘e’ antigen (HBeAg)-positive mothers, 20 - 50% of infants and children under the age of 5 years, and <5% of adults will develop chronic hepatitis B infection.[11,12] Viral variants may also influence the course and outcome of the disease. In addition, and only rarely and in the setting of profound immune suppression, the virus can be directly cytopathic.

In choosing an appropriate management strategy, a clear understanding of the process of hepatitis B viral replication, as well as the natural history of chronic hepatitis B, is vital:

Following acute exposure, the HBV enters the hepatocyte and is imported into the nucleus. The partially doubled-stranded DNA is repaired to form a circular extra-chromosomal molecule called the covalently closed circular DNA (cccDNA),[13] which is the transcriptional template for the viral messenger RNAs (mRNAs). The RNA form of the genome is encapsidated together with the reverse transcriptase, and reverse transcription occurs within the cytoplasm. Cytoplasmic viral capsids containing mature viral DNA are either transported to the nucleus, thereby replenishing cccDNA, or bind to HBV surface antigens which have accumulated in the endoplasmic reticulum, bud through the cellular membranes and are secreted from the hepatocyte non-cytopathically, as virions.

Hence, even if the individual clears hepatitis B surface antigen (HBsAg), the hepatocyte still harbours cccDNA. This is the basis of occult HBV infection, which is defined as detectable HBV DNA in the liver and a very low level (<200 IU/ml) of HBV DNA in the blood of those previously exposed to HBV, viz. HBsAg negative and hepatitis B immunoglobulin G core antibody (anti- HBc IgG) positive. The clinical significance of occult HBV is that immunosuppression may lead to reactivation in these patients. HBV DNA can also integrate into the cellular genome during chronic infection, as a result of random insertion of viral DNA into the host genome, by host processes during failed repair of the partially double-stranded DNA. This integrated DNA plays no role in viral replication, but plays an important and ill-defined role in the development of HCC.

 
2017_03_1490121826-4595.JPG
 

4. DIAGNOSIS

 

4.1 Clinical diagnosis of VHF

 

There are 5 phases of chronic infection which are not necessarily sequential and are of variable duration.[6,14]

1. The immune tolerant phase is characterised by HBeAg posi- tivity, high levels of viral replication (high serum HBV DNA), normal transaminases, minimal or no hepatic necroinflammation and no or slow progression to fibrosis. During this phase, the rate of spontaneous HBeAg loss is low. This phase, which is more common and more prolonged in individuals infected perinatally or under the age of 5 years, frequently persists into early adulthood and is frequent in SA.

2. The immune clearance phase (HBeAg-positive chronic hepatitis B) is characterised by HBeAg positivity, but lower levels of viral replication. The transaminases are elevated and histologically there is more severe necroinflammation and more rapid progression of fibrosis. This phase may last several weeks to years and, if successful, a sustained HBeAg seroconversion will occur with the development of anti-HBe. A successful HBeAg seroconversion is more likely to occur in individuals infected during adulthood.

3. The inactive HBV carrier or latency state (immune control phase) follows successful HBeAg to anti-HBe seroconversion and is characterised by very low (<2 000 IU/ml) or undetectable HBV DNA levels and normal transaminases. As a result of immunological control of the infection, these patients have a good prognosis, with a much lower risk of progression to cirrhosis or HCC. HBsAg loss and seroconversion to anti-HBs may occur spontaneously at a rate of 1 - 3% per year.

4. Five to 15% of individuals in the inactive HBV carrier state will develop HBeAg-negative chronic hepatitis B. This reactivation phase represents a later phase in the natural history of the disease and is more common in older men. Nucleotide substitutions in the precore and/or basal core promoter regions of the HBV genome result in HBV variants that are unable to express HBeAg, or which do so at very low levels. This phase is characterised by HBeAg negativity, fluctuating transaminases and HBV DNA levels, significant necroinflammation and progressive fibrosis. Low levels of hepatitis B immunoglobulin M core antibody (anti-HBc IgM) may be detected.

It is important, but often difficult, to distinguish this phase from the inactive HBV carrier state. Patients with HBeAg-negative chronic hepatitis B have a high risk of progression to cirrhosis, which may in turn lead to decompensation and the risk of HCC. At least 1 year follow-up, with 3 - 4-monthly monitoring of alanine transaminase (ALT) and HBV DNA levels, is required to confidently distinguish these two phases of the disease.[15-17]

Individuals in the inactive HBV carrier state may also revert back to HBeAg positivity and develop HBeAg-positive disease.

5. Occult HBV infection is the term used to describe those cases where patients have cleared surface antigen but have detectable plasma HBV DNA. Serologically they are HBsAg negative, hepatitis B surface antibody (HBsAb) positive and anti-HBc IgG positive, yet they are positive for HBV DNA, albeit at very low levels (invariably <200 IU/ml). While no liver disease is associated with occult infection, these individuals are at very high risk of reactivation of HBV with immune suppression, e.g. during use of rituximab (MabTheraR), and require prophylactic antiviral therapy.

 

Diagnosis

 

In diagnosing chronic hepatitis B, HBV serological markers and HBV DNA levels must be carefully and correctly interpreted, to accurately decide on the phase of the chronic infection so that appropriate management, if required, can be instituted.

 

3.1 HBV serological markers[5,18]

 

Signs and symptoms of VHF

Early signs and symptoms are non-specific, and patients may present with fever, headache, conjuctivitis, pharyngitis, myalgia (especially lower back pain), vomiting, abdominal pain and diarrhoea. Recognition of the syndrome is easier once patients develop a petechial rash or ecchymoses, and other haemorrhagic signs such as epistaxis, haematemesis and melaena. There may be rapid progression to multi-organ failure, altered mental state, jaundice and shock.

Important information to bear in mind during clinical diagnosis

Not all patients with VHF bleed, and it is more important to recognize a syndrome that may include bleeding, nosocomial transmission, evidence of thrombocytopenia and hepatic dysfunction, notably raised transaminases.

Clinicians can seek advice from the medical officer on duty at the National Institute for Communicable Diseases (NICD) (cellular telephone number 082 883 9920).

More than 90% of suspected cases of VHF prove to be severe forms of common diseases. Many of the diseases mistaken for VHF are treatable if diagnosed early. There must be systematic elimination of differential diagnoses (see section 4.2).

Failure to institute appropriate safety precautions can have severe consequences. However, the unnecessary institution of isolation precautions is expensive and highly disruptive.

By the time that VHF is suspected patients have often received prior medical attention during which certain clinical pathology and microbiological tests may have been performed (see section 4.2).

Obtaining a history of possible exposure to infection can be crucial to diagnosing VHF. Relatives and cohorts often provide more reliable information than severely ill patients.

 

HBsAg:

  • General and screening marker of infection
  • First serological marker to appear
  • Surrogate marker for transcriptionally active cccDNA
  • Infection is considered chronic if HBsAg persists for >6 months.

HBeAg:

  • Indicates active replication of virus
  • Absent or low in pre-core or basal core promoter mutations.

Anti-HBc total (HBcAb total):

  • Includes both IgG and IgM HBcAb.

IgG anti-HBc:

  • Most sensitive marker of past exposure to HBV as anti-HBs may be undetectable if HBV infection was acquired in childhood, as is common in SA.

IgM anti-HBc:

  • Marker of acute infection or reactivation
  • Strongly positive in acute infection and possible low positivity in reactivation or flare.[19]

Anti-HBs (HBsAb)

  • Recovery and/or immunity to HBV
  • Detectable after immunity is conferred by HBV vaccination.

Anti-HBe (HBeAb)

  • Usually indicates HBeAg to anti-HBe seroconversion and that the virus is no longer replicating
  • Also present in HBeAg-negative chronic hepatitis, with active replication due to mutants.

 

 

Virological evaluation of HBV infection

 

  • Serum HBV DNA quantification
  • HBV genotype
  • HBV resistance testing.

 

 

Role of HBV DNA testing [18]

 

  • Can differentiate chronic HBeAg-negative disease from the inactive latency state (HBV DNA <2 000 IU/ml)
  • Differentiates between occult hepatitis B (IgG anti-HBc positive, HBV DNA positive, but <200 IU/ml) and resolved infection (IgG anti-HBc positive, anti-HBs positive, HBV DNA negative)
  • Changes in HBV DNA levels used to monitor response to therapy
  • In patients adherent to therapy, increasing HBV DNA levels indicate the emergence of resistant variants
  • HBV DNA levels correlate with disease progression.[20-23]

 

 

Immunological markers, DNA levels and ALT in HBV infection [16,24]

 

See Table 2.

 

Detailed and accurate information required during diagnosis

●    Age,  sex,  and  place  of  residence  of  the  patient  (VHF  infection  has  not  yet  been confirmed to have occurred within South Africa in a child <10 years old).

●   Chroni medical   condition an medication,   including   recen dru an dosage adjustments.

●    History  of  the  current  illness,  including  results  of  prior  medical  and  laboratory investigations.

●   Occupation of the patient and possible exposure to infection as in:

§    Health care anlaboratory workers who tended,  or processed specimens from, patients with confirmed or suspected VHF or undiagnosed fever compatible witVHF; and

§    Contact  with  animals  or  animal  tissues  by  abattoir  workers,  veterinarians,  farm workers, hunters, taxidermists, or persons who work with hides and skins.

●   Non-occupational contact with known or suspected cases of VHF, or undiagnosed fever.

●   Non-occupational contact with animals or their tissues including blood.

●   Residence in or recent travel to tropical or rural environments.

●   Handling or being bitten by ticks or insects, especially mosquitoes.

●   Recent travel to a country known or likely to be endemic for VHF, particularly involving rural environments and contact with animals or insects - but remember that some rodent- associated and mosquito-borne VHF viruses can occur in urban environments (see section 3).

●   Record exact details of:

§    The date/s of potential exposure/s to infection.

§    The date of onset of illness (incubation periods are <1 week for arbovirus infections including Congo fever, but up to 3 weeks for arenavirus, hantavirus and filovirus infections - see section 3).


§    The dates and types of all specimens previously taken and submitted for laboratory examination.

§    The results of all clinical pathology and microbiological tests already performed (see section 4.2).

 
2017_03_1490122246-1941.JPG
 

Assessment of liver disease prior to therapy [5,6,16]

 

See Table 3.

 
2017_03_1490122293-9747.JPG
 

Features that support a diagnosis of VHF

●   Short duration and rapid progression of the disease: i.e. acute rather than chronic illness.

●   Lack of evidence in the patient's history or physical examination, which excludes VHF.

● Laboratory evidence of leucopenia, thrombocytopenia, coagulation abnormalities, and raised serum transaminases, but leucocytosis can occur in CCHF, Lassa, Marburg and Ebola haemorrhagic fevers, and relatively normal platelet counts can be seen in Lassa fever.

·    The progression of the illness and the timing of bleeding in relation to the onset of symptoms  may  be  important  in  guiding  the  diagnosis  of  VHF  versus  alternativdiagnosis. For example: patients with Congo fever typically bleed three to five days aftethe onset of illness while patients with meningococcal disease typically bleed within 24 hours after the onset of symptoms.

 

Features which tend to exclude a diagnosis of VHF

Normal platelet counts and normal serum transaminase levels render VHF unlikely. Confirmation of an alternative diagnosis, e.g. a positive blood culture may also render VHF unlikely. However, it is important to remember that bacterial septicaemia can occur as a complication to VHF, and in areas where malaria is endemic patients may test positive for malaria on blood smears while suffering from other infections, including VHF.

 

A scoring system found to be useful in the diagnosis of Congo fever in South Africa is presented in Table 4.1, and a document on answers to frequently asked questions about the disease, compiled for people involved in the livestock industry, is included as Appendix 1.

 

The outcome of the initial assessment may be inconclusive, but the aim should be to decide whether or not to proceed on the assumption that VHF may be involved. The disruptions and expense caused by false alarms should be balanced against the potentially dire consequences of failure to recognize VHF.

 

For submission of specimens for specific laboratory confirmation of VHF see section 4.3.

 

Clinical history and physical examination

 

Include family history of HBV infection and HCC.

 

Assessment of the severity of the liver disease

 

4.2 Differential diagnosis of suspected VHF

 

Procedure to follow when VHF is suspected

When VHF is suspected, it is important to obtain and interpret the results of all medical examinations and laboratory tests already performed, but warn laboratory personnel of the suspected diagnosis and ensure that further laboratory tests are only performed with appropriate biosafety precautions (see section 6.2). Another crucial step to take is to ensure that all specimens previously submitted to laboratories are retained for onward transmission to NICD along with newly collected specimens for specific VHF diagnostic tests (see.section

4.3).

 

Diseases commonly confused with VHF

 

Malaria, trypanosomiasis, relapsing fever, plague, yellow fever, other arbovirus infections and leptospirosis, especially after travel to or residence in rural or tropical areas (malaria is most common and can be rapidly fatal if not treated, but it also occurs together with other infections including VHF).

 

Bacterial  septicaemias  resemble  VHF  and  can  be  rapidlfatal  if  not  treated;  most commonly caused by meningococci, but also by a wide variety of Gram-positive and - negativ bacteria,   an includ typhoid,   anthrax,  an Capnocytophaga   species (dysgonic fermenter 2) infection after dog bite, (septic abortion and tuberculosis with haemoptysis can also resemble VHF).

 

Rickettsioses: tick bite fever (TBF), Q fever, typhus; TBF often occurs in town dwellers who visit rural environments, but can also result from exposure to kennel ticks in urban settings, even where dogs are kept indoors in apartment buildings; TBF can run a fatal course very similar to Congo fever, but has an incubation period of 7-10 days after tick bite as compared to 1-3 days for Congo fever, there is usually a necrotic eschar at the site of the tick bite in TBF and the petechial rash extends to palms and soles; TBF can be treated with broad-spectrum antibiotics.

 

Hepatitis A, B, E, and less often C (westerners travelling in Africa often develop hepatitiA).

 

Fulminant systemic herpes simplex virus infection with hepatitis (with/without vesicular rash); about 60 cases have been seen in RSA with high fatality, mostly in ostensibly healthy young adults; extremely high transaminase levels which may fall terminally after virtually complete destruction of hepatocytes. Less common are severe cytomegalovirus, E-B virus or varicella-zoster virus infections, or haemorrhagic measles.

 

HIV seroconversion sickness, or HIV/AIDS with secondary infections, especially septicaemias.

 

Drug sensitivities and overdoses including anticoagulants (warfarin), other poisons and toxins including haematoxic snake bite envenomation (e.g. boomslang), industrial and agricultural chemical poisoning.

 

Malignant disease, e.g. leukaemia, lymphoma. Idiopathic thrombocytopenic purpura.

 

Heat stroke.

 

 

Interpretation  of  clinical  pathology  results  for  differentiating  VHFs  from  other diseases

 

Full haematological examination: Findings compatible with VHF include leucopenia, thrombocytopenia, anaemia, altered clotting parameters and increased fibrin degradation products or D-dimers, but disseminated intravascular coagulopathy also occurs in many other conditions, including septicaemia. Granulocytosis suggests bacterial infection, but leucocytosis can occur in CCHF, Lassa, Marburg and Ebola haemorrhagic fevers (see section 3), and in leukaemia.

 

Examination of a stained blood smear: Malaria, trypanosomiasis, other haemoparasitic diseases and certain bacterial septicaemias (meningococcus, Capnocytophaga, anthrax) can  be  diagnosed,  and  differential  white  cell  counts  can  be  performed  to  provide  an indication of leucocytosis/granulocytosis, leucopenia, leukaemia, anaemia, and even thrombocytopenia.

 

Bacteriological blood cultures: It is important that blood cultures should be performed to exclude septicaemia. Samples should be taken before antibiotic therapy is instituted. Septicaemia can be secondary to many conditions including pneumonia, gastroenteritis, perforated ulcers, and abscesses or wound infections.

 

Clinical chemistry tests: Raised serum transaminase levels occur commonly in VHF, and to a lesser extent also raised bilirubin levels, but jaundice and hepatocellular damage have many causes. Extremely high transaminase and bilirubin levels occur in systemic herpes simplex infection with hepatitis. Evidence of severe liver damage is a poor prognostic sign. Proteinuria is common in VHFs, notably in Lassa fever.

 

Specific serodiagnostic tests for non-VHF diseases: Serological tests results should be interpreted with caution, taking into account the sensitivity and specificity of the test and the stage that they are performed during the course of the illness. Notably negative results using the currently available tests for tick bite fever may not exclude the disease. Anti-HA IgM, HbsAg, HBeAg and Anti-HBc are important screening tests for hepatitis A and B. Serodiagnostic tests are available for leptospirosis, salmonellosis, measles, herpesvirus infections and many other diseases which could be confused with VHF. Rapid serum latex agglutination tests can be used to detect bacterial antigen in meningococcal septicaemia.

 

More than one pathology may be present in a patient, and epidemiological information and clinical laboratory findings should guide the diagnostic process.

 

4.3 Laboratory verification of VHF

 

Specific diagnostic tests for the formidable (Class 4) VHFs are performed only by the Special Pathogens Unit (SPU) at NICD. It is essential that arrangements are made directly  with  one  of  the  SPU  laboratory  diagnosticians  before  specimens are submitted (Laboratory telephone numbers 011 386 6339, 082 903 9131, 082 908 8042 an 08 90 8046;   NIC Hotline   08 88 9920) particularly   where   urgent investigations  are  warranted  after  normal  work  hours  (07h30-16h00  Monday  to Friday). The staff must be informed of the means of transport of the specimens, tracking or waybill numbers, and expected date and time of delivery.

 

4.3.1 Source and nature of specimens: Clinical laboratories

All  specimens  that  may  have  been  submitted  to  haematology,  microbiology,  clinical chemistry and other laboratories before VHF was suspected must be traced and redirected to NICD for virological examination. These specimens are important because VHF viruses are often only present in blood and other tissues in the early stages of the disease, and may be absent later.

 

Live patients

Specimens to be taken from live patients specifically for the investigation of suspected VHF should include 5-10ml of clotted blood and 5ml of blood taken with EDTA/sequestrene (lavender top). Throat swabs in viral transport medium may also be useful. Daily samples collected from patients in whom a diagnosis of VHF has already been confirmed provide valuable information, but need not be submitted for urgent tests; the samples can be kept refrigerated and sent to NICD in batches by routine laboratory delivery services with appropriate packaging (see 4.3.2 below).

 

 

 

1.   Infection control plan

Each facility must have a written TB Infection Prevention and Control plan that outlines a protocol for the prompt recognition, separation, provision of services, investigation for TB and referral of patients presenting with TB symptoms or confirmed TB disease. The plan will include, but not be limited to, the following measures:

  • Early recognition of people with TB symptoms through symptomatic screening of all patients entering facility or soon after arrival. A staff member should be assigned to screen patients using the TB screening tools (adult and children). The form must be completed and included in the patients file. Presumptive TB cases should be investigated immediately.
  • People with chronic cough must wait in a designated, well-ventilated waiting area, for example in outdoor waiting areas, or a well-ventilated section of the waiting area.
  • They must be educated on cough hygiene and provided with a face mask or tissue to cover their mouth and nose when coughing. Tissues and facemasks should be provided in the waiting areas and discarded in the bins after use. Hand washing should be encouraged after contact with respiratory secretions.
  • Fast tracking confirmed TB cases coming for follow up appointments or to take/ collect their treatment to ensure that they spend as little time as possible in the facility.
  • Educating health care personnel, patients and communities to seek health care early when symptoms of TB are present and to protect themselves and others e.g. through appropriate cough hygiene and good ventilation in the household.
  • Improved TB and HIV integration in the health facility, with symptomatic TB screening of HIV positive patients at routine clinical visits and appropriate tests for those who are symptomatic, to aid early diagnosis.

•    Training of facility staff on IPC plan

Infection prevention and control is effective only if all staff working in a facility understands the importance of the infection prevention and control policies and their role in implementing them. Training should include the following:

  • Basic concepts of M. tuberculosis transmission and pathogenesis;
  • Risk of TB transmission to health care workers and staff;
  • Symptoms and signs of TB;
  • Impact of HIV infection on increasing risk of developing TB disease and the importance of TB as a major cause of disease and death in PLWHA;
  • Importance of the infection prevention and control plan and the responsibility that each staff member has to implement and maintain;
  • Specific infection prevention and control measures and work practices that reduce the likelihood of transmitting TB;
  • Measures staff can take to protect themselves from TB; and
  • TB disease surveillance among HCW

•    Community education and awareness. Educate communities and patients on the following:

  • To recognize symptoms of TB and promptly seek health care;
  • To undergo HIV Counselling and Testing;
  • Cough hygiene; and
  • Prevent ion of transmission in the community

•    Surveillance of TB disease among health workers

Surveillance of TB among Health Care Workers serves as an indication of performance of IPC Plan. All facility staff must be included in the TB medical surveillance programme in line with Occupational Health and Safety Act (Act No. 85 of 1993). This medical surveillance programme consist of the following main components:

  • Pre-aemployment medical: Baseline screening and testing for M. tuberculosis infection for all newly employed HCWs as part of the pre-employment. This serves as a baseline for comparison in the event that a person contract TB disease. It provides an opportunity to identify high risk individuals (HIV, diabetes etc) for appropriate placement and enables early detection and initiation of treatment.
  • Periodic medical: Sceening and testing for TB every six months. This should also be conducted as part of outbreak investigations.
  • Exit medical: Screening and testing for TB disease to exclude undiagnosed TB disease at the time of leaving the facility and ensure early treatment.
  • Training of staff on TB medical surveillance programme, and
  • Education of staff on the importance of using the service.

All staff with confirmed infectious TB disease pose a risk of transmitting TB infection and should be initiated on treatment promptly.

•    Administrative Control Strategies to prevent TB transmission in Health Care settings

In general, administrative control measures have the greatest impact on preventing TB transmission and they are the first priority in any setting regardless of available resources. These measures aim to reduce the droplet nuclei in health facilities by eliminating the generation of droplet nuclei and risk of exposure. The administrative control activities include;

  • Early recognition of people with TB symptoms through screening of all patients entering the health facility
  • Separation of people who are coughing from the other patients, this will require identification of a well- ventilated area that can be used as a sub-waiting area.
  • Prompt investigation for TB in symptomatic patients
  • Sputum test results must be followed up and patient started on treatment immediately if diagnosed with TB.
  • Educating all patients on respiratory hygiene
  • Isolation of confirmed TB patients

 

Corpses

There is usually reluctance to proceed with a full autopsy until VHF can be excluded, and there is a widespread misconception that post mortem procedures may only be performed with the consent of relatives. However, in terms of the Health Act 61 of 2003 autopsy and removal of organs or tissues 'for determining the cause of death’ may be authorized by the medical practitioner in charge of clinical services in the hospital or authorized institution, or of the mortuary, or by a medical practitioner authorized by the person in charge of such hospital or authorized institution. Minimal specimens taken to eliminate VHF should include blood collected by cardiac puncture and liver samples taken with a biopsy needle; some liver should be placed in fixative for histopathological examination and some placed in a small volume of viral transport medium or physiological saline for virological examination. If possible, some liver tissue should also be placed in 2.5% glutaraldehyde fixative for electromicroscopy. The specimens can be taken in the ward where the death occurred or in a mortuary. Blood tends to ooze from needle puncture sites and these should be taped or sealed (e.g. Opsite®, S & N Pharmaceuticals Pty Ltd). The body should be decontaminated and sealed in double stout plastic body bags as discussed in section 6.5.

 

Labels attached directly to the primary specimen containers (e.g. blood tubes) should be marked clearly with the name of the patient and date of collection of the sample. For removal from the patient facility or mortuary, the specimens should be double-wrapped in zip-lock specimen bags or ordinary clear plastic bags and labeled appropriately, preferably with biohazard stickers to alert staff to the contents, and should be delivered by hand directly to the laboratory responsible for forwarding the specimens to NICD.

 

It may be useful to have a histopathologist examine rapidly fixed (heated formalin) and sectioned liver specimens. Bacterial septicaemia can sometimes be recognized and differentiated from liver disease due to VHF or other causes. Lack of liver lesions suggests that VHF is not involved.

 

  • Liver profile including total bilirubin, conjugated bilirubin, ALT, aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT)
  • Full blood count (FBC) including a differential count
  • Serum albumin and international normalised ratio (INR) to assess synthetic function.

 

 

Viral serology

 

  • HBsAg, anti-HBs, HBeAg and anti-HBe
  • IgG anti-HBc (if assessing for occult HBV or previous cleared infection).

 

 

Viral replication

 

Serum HBV DNA quantified with real-time polymerase chain reaction (PCR).

 

Look for other co-factors

 

  • Viral co-infection: HCV, HIV
  • Non-alchoholic fatty liver disease/alcoholic liver disease
  • Iron overload
  • Drug/toxin-induced injury

 

 

Liver biopsy

 

A liver biopsy is required to assess the degree of necroinflammation and fibrosis and is helpful in assessing the contribution of one or more comorbidities. It is generally indicated if the ALT is elevated and/or HBV DNA is >2 000 IU/ml, or when interferon- based therapy is being considered. A biopsy is useful in the SA context to assess the need for treatment, as there has often been a prolonged immune tolerant phase and liver enzymes may be only marginally elevated. A liver biopsy is not required in patients with clinical evidence of cirrhosis or when nucleos(t)ide analogue (NUC) therapy is indicated, regardless of the grade of activity or stage of fibrosis. The risk of severe complications with liver biopsy is low (1/4 000 - 10 000).

 

Ultrasound of the liver and doppler studies of the portal vein

 

Goals and endpoints of therapy [5,6,16]

 

4.3.2   Packaging of specimens for transfer to NICD

 

UN/WHO  approved  shipping  containers  for  hazardous  specimens  are  commercially available, e.g. SAF-T-PAK®, or else safe packaging can be improvised as indicated in the text box below (Figures 4.1; 4.2):

 

8.3 What are the Environmental Control Measures?

 

Environmental controls are used to prevent the spread and reduce the concentration of droplet nuclei in the air. The managerial and administrative control must be in place for the environmental controls to be effective. The types of controls implemented will vary from one facility to another based upon the results of the risk assessments. There are three main types of environmental controls namely;

  • Ventilation (natural and mechanical)
  • High Efficiency particulate air filtration (HEPA)
  • Ultraviolet germicidal irradiation (UVGI)

 

See Table 4. HBV infection cannot be eradicated completely with current available therapies because of the persistence of cccDNA, which acts as a viral reservoir in infected hepatocytes.[25] Even so, an ideal endpoint of treatment would be to achieve viral eradication with sustained HBsAg loss, with/without seroconversion to anti-HBs antibodies, as HBsAg is a surrogate marker for transcriptionally active cccDNA.[26,27] However, this is as yet uncommon and hence a broad goal of therapy is to prevent or reverse disease progression to cirrhosis, end-stage liver disease or HCC. This can be achieved by suppressing HBV replication, with a consequent improvement in necro- inflammation and fibrosis that lowers the risk of cirrhosis and HCC. [20-22,28] 

Once cirrhosis is established, preventing decompensation, HCC or death is the primary treatment goal. In those patients with early decompensation,  suppression of HBV replication can improve synthetic function and decrease the Child-Pugh/model for end-stage liver disease (MELD) score, and may delay the need for liver transplantation.  In those with end-stage liver disease, suppression of HBV replication prior to transplantation reduces the risk of recurrence.

 

 
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8.4 How to Ensure Proper Ventilation?

 
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Ventilation is the movement and the replacement of air in a building with air from the outside or with re circulated air that has been sanitized. When fresh air enters a room, it dilutes the concentration of droplet nuclei in room air.

 

The method used for transmitting specimens to NICD depends on the urgency with which diagnostic tests are required, proximity to NICD, and the availability and speed of routine delivery services for transmitting specimens to NICD as operated by the NationaHealth Laboratory Service (NHLS) and private companies (e.g. Ampath, Lancet)

For the delivery of specimens for urgent tests from within a few hours distance by road from NICD, it may be necessary to assign a specific vehicle and driver. This applies even to hospitals within close proximity to NICD since routine specimen delivery routes are operated at certain times of day only. Sometimes relatives of patients are willing to deliver specimens when no other rapid means of transport is available. Specimens should be delivered directly to members of SPU staff (contact telephone numbers: 011 386 6339, 082 903 9131, 08908 8042, 082 908 8046; NICD Hotline 082 883 9920), or after hours left with the security guards at the entrance to NICD by prior arrangement with SPU staff (for map see Figur4.6).

 

For  delivery  of  specimens  from  longer  distances  it  may  be  possible  to  utilize  routine laboratory delivery services, or a commercial courier service using scheduled road or air transport and door-to-door delivery, depending on the urgency with which tests are required. However, deliveries after normal work hours, and particularly at weekends, can be difficult to arrange.

 

Follow up specimens from patients in whom the diagnosis has already been confirmed or sera from healthy contacts of VHF patients which are sent for routine screening and do not require urgent tests, can be sent to NICD by regular laboratory delivery services with appropriate packaging.

 

4.3.3   Laboratory tests

If emergency tests are warranted and appropriate arrangements have been made ahead of time with SPU staff (telephone numbers 011 386 6339, 082 903 9131, 082 908 8042 an082 908 8046; NICD Hotline 082 883 9920) tests can be performed after normal work hours, which are 07h30-16h00 on weekdays only.

 

4.3. Interpretation of results

 

In the acute phase of the disease, cases of VHF are diagnosed by identifying virus antigen or nucleic acid in the specimens, or by isolating (culturing) live virus. Virus antigen detection tests are used for certain diseases only and take 3-8 hours to complete. Detection of virus nucleic acid by reverse transcription-polymerase chain reaction (RT-PCR) takes 6-12 hours from the time of receiving the specimen in the laboratory, depending on whether or not there is need for nested (second round) tests. Isolating virus in culture can sometimes be achieved within 2 days but usually takes a week or longer.

 

In the convalescent phase of the disease, cases of VHF are diagnosed by identifying an antibody response. Preliminary IgG antibody tests can be completed within two hours of receipt of specimens and IgM tests within 3 hours, but overnight tests produce more reliable results.

 

All serum samples (acute and convalescent) are routinely tested for antibodies to the full range of African VHF viruses. This is because the clinical histories received are sometimes inaccurate, particularly with respect to the date of onset or duration of illness.

 

It is extremely important to remember that even acute specimens for which virus antigen,  RT-PCR  and  antibody  tests  are  all  negative,  occasionally  yield  virus  in culture some days later. Failure to appreciate this possibility has led to serious misunderstandings in the past.

 

Sometimes it is necessary to submit a further sample to clarify an ambiguous finding. For example, detection of IgG antibody on its own, without virus or IgM antibody, could indicate past infection not connected to the current illness, but sometimes IgG can appear in circulation slightly before IgM during convalescence.

 

It is almost equally important to eliminate a possible diagnosis of VHF as it is to confirm a diagnosis rapidly: failure to detect virus or viral nucleic acid in serum during the first 7 days of illness, or to demonstrate antibody two weeks after onset, constitutes a fair indication that one of the known African VHFs is not involved. However, viraemia may be of very short duration or absent. Hence, negative findings on samples taken early in the course of disease should be supported by antibody tests on further specimens taken in convalescence.

 

 

In emergencies results are made known telephonically or by fax as soon as possible, with written confirmation following later (remember to include contact details for the person to whom results should be reported when submitting specimens).

 
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5. IMMEDIATE ACTION TO BE TAKEN AFTER CLINICAL DIAGNOSIS OF VHF

 
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As soon as the decision is made to proceed on the basis of a presumptive diagnosis of VHF, measures should be applied to minimize exposure of medical staff, other patients and relatives. Whatever is ultimately decided concerning the management of the case, the immediate course of action should be to:

●      Inform the management and infection control officers at the medical facility concerned of the existence of the suspected case of VHF.

●     Isolate the patient and apply infection precautions as best as can be managed undethe circumstances in cooperation with infection control staff (see section 6.3). The precautions must remain in force until the possibility of VHF has been excluded or the

patient is no longer under care at the facility concerned.

●      Administer such life-saving therapy as may be necessary and possible, e.g. blood/fluid therapy.

●     Take steps to verify the diagnosis (see sections 4.3).

●      Cooperate with infection control officers in preparing a list of staff members who have had contact with the patient or fomites, including ambulance, laboratory and cleaning personnel - the contacts must be informed of the risks and precautions to be taken, and placed  under  observation  (see  section  7  for  definitions  of  exposure,  contact  anobservation).

●     Notify the National Director of Communicable Disease Control (CDC) and the relevanProvincial Coordinator of CDC of the existence of the suspected case of VHF so that they can investigate the circumstances surrounding the incident, place relatives and

cohorts and other contacts of the patient/s under observation if indicated, and take necessary actions to control any potential outbreak of VHF in the community at large (see section 7.2 for contact details of the officials).

●      Decide whether the patient is to be retained at the primary hospital, or whether to seek transfer to a hospital more suited to managing the case. Decisions to transfer VHpatients cannot be taken unilaterally; see section 7.1 for the criteria and mechanismfor reaching decisions on referral.

●      Assess the status of the patient as either low, moderate or high risk with respect to the probability that VHF is involved, the likely outcome of the disease, and the feasibility osafe transfer - sometimes the process of transfer poses too great a threat to the life of the patient or the safety of the personnel involved:

 

 

 

Low risk patients

This category has febrile disease with features suggestive of VHF (e.g. thrombocytopenia), but are not necessarily severely ill and lack a history of contact with known VHF patients or animals (other than long-term pets), or animal tissues, or ticks and mosquitoes, and have not left an urban environment for at least 3 weeks prior to onset of illness. There are no haemorrhages, and risk of spread of infection is assessed as low.

 

Moderate risk patients

This category has febrile disease with features suggestive of VHF, and are not necessarily severely ill, but have visited or resided in a tropical or rural environment, or have had contact with animals or animal tissues, or ticks and mosquitoes during the 3 weeks preceding onset of illness. They have not had direct contact with known VHF patients or fomites (see section 7.3) but may have an indirect association with such patients, e.g. they have worked, resided in or visited the same places as VHF patients. Although there may be no haemorrhages, it is assessed that infection with a VHF agent may be involved.

 

High-risk patients

This category is severely ill with fever and haemorrhagic manifestations (this criterion is sufficient to place patients in the high risk category). In addition, they may have visited or resided in a tropical or rural environment, or have had contact with animals, animal tissues or ticks and mosquitoes during the 3 weeks preceding onset of illness. Alternatively, they may not necessarily be severely ill, but have had definite exposure to VHF  (see  section  7.3).  This  includes  a)  hospital  and  laboratory  staff  who  have developed illness within 3 weeks* of last known contact with a confirmed VHF patient or fomites associated with such patients, and b) relatives and close associates of known VHF patients. (*The interval is 2 weeks for arbovirus diseases such as Congo fever, bu3 weeks for Lassa, Marburg and Ebola haemorrhagic fevers.)

 

1. Natural ventilation is created by the use of external natural forces such as wind. It is however difficult to control the direction of the airflow as this depends on the wind speed or direction. It relies on open windows and doors to allow the air to move in and out of the room. Designing waiting areas and examination rooms in such a way they maximize natural ventilation can help reduce the spread of TB. Open air shelters with a roof to protect patients from sun and rain can be used as waiting areas.

2. Directional airflow: Fans can be used to enhance flow of air in and out of the room when installed in the windows or wall opening where there are inadequate windows. They can also be used to exhaust air outside, away from people. For example, in a room which has a door/ window on one side and nothing on the opposite side, when the door/ window is kept open, the overall effect of installing fans on the opposite side is to draw in fresh air through the front of the building and exhaust air out.

It is therefore important to be mindful of the direction of airflow in a room to ensure that the sitting arrangement is such that air will blow from behind the health care worker over the patient and out of the room.

 
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3. Mechanical ventilation: This is created using an air supply or an exhaust fan to force air exchange and to drive airflow. Such ventilation works by generating negative or positive pressure in the room to drive air changes. To be effective, all doors and windows must be kept closed, with controlled air leakage into or out of the room.

 

8.5 What is High Efficiency Particulate Air (Hepa) Filtration?

 

High efficiency particulate air filters are capable of removing 99.97% of particles that are 0.3 microns or greater in diameter. They are used to clean air which is recirculated to other areas of a facility, or recirculated within a ward/room, for rooms where there is no general ventilation system, where the system is incapable of providing adequate airflow, or where increased effectiveness of room airflow is required.

HEPA filtration may have a place as an additional measure to adequate ventilation in booths or enclosed areas designed for sputum collection/ induction. Portable units are available but have not been evaluated adequately to determine their role in tuberculosis infection control.

However, recirculating air from areas intended to isolate a patient with tuberculosis is not recommended and these units are also expensive and need regular engineering attention.

 

8.6 What is Ultraviolet Germicidal Irradiation (UVGI)?

 

Priority should be given to achieving adequate ventilation. Where this is not possible because of climatic conditions for example where it gets very cold in winter or during the night and it is not feasible to keep windows opened or the design of the building makes it impossible to ensure adequate ventilation, UVGI may be considered as an adjunctive measure.

UVGI is dependent on room air mixing to be effective because contaminated air must be circulated to the irradiated upper part of the room where the organisms can be rapidly inactivated. Several studies have shown that well-designed UVGI upper room devices can disinfect mycobacteria in conditions that have an equivalent of 10–20 air changes per hour. It is ineffective in humid and dusty environments. UVGI devices have to be installed properly for maximum effect; testing and maintenance must be conducted regularly.

Upper UVGI devices are hazardous if not properly designed or installed. The NIOSH guidelines recommended the occupational exposure limit of 6mJ/cm2 over an 8 hour period for a short wave ultraviolet irradiation (254 nm). It has been reported that exposure above this limit may result in erythema/ photo dermatitis and photo- keratitis and/or conjunctivitis.

 

9. What is the Role of Infection Prevention and Control Committee (IPC Committee)?

 

The IPC committees as articulated in the National Infection Prevention and Control Policy and Strategy, 2007 should provide oversight for TB infection prevention and control.

The roles and responsibilities of this committee in relation to TB IPC are to:

  • Ensure development of the Infection Prevention and Control plans
  • Provide technical support on TB prevention and control to district and facilities
  • Review TB surveillance data trends (including MDR and XDR-TB)
  • Advise on potential outbreaks and management thereof.

 

10. What is the Role of Infection Prevention and Control Teams (IPC Teams)?

 

The hospital IPC Team as articulated in the National Infection Prevention and Control Policy and Strategy, 2007 should supervise and coordinate TB IPC activities in hospitals and clinics within its catchment area.

 

11. What is Personal Respiratory Protection?

 

Personal protection refers to the use of respirators that contain a special filter material that protects the wearer from inhaling the bacilli. They are used as the last resort where the managerial, administrative and environmental controls have not completely eliminated the risk. The use of respirators can further reduce this risk in these settings.

1. Respirator masks: Respirator masks are designed to filter out the droplet nuclei thus protecting health care workers and visitors from inhaling the droplet nuclei. They are most appropriately used for short-term protection against high-risk exposures e.g. during sputum inducing procedures and bronchoscopy. The recommended respirator is the type that covers the mouth and nose and is fitted with a special particulate filter to filter out very small particles. NIOSH certified N95 or greater or E.U. specified filtering face piece FFP2 or greater are recommended for use in health care settings.

These face masks have a capacity to filter small particles thus protecting against inhaling infectious droplet nuclei. The N95 respirator has a filter efficiency level of 95% or more against particulate aerosols oil free when tested against 0.3 μm particles. The “N” indicates that the mask is not resistant to oil; the “95” refers to a 95% filter efficiency. The FFP2 respirator has a filter efficiency level of 94% or more against 0.4 μm particles and is tested against both oil and oil free aerosols.

Fit testing must be performed on all health care workers to determine which type or size of respirator fits properly. It makes use of a noxious substance that is sprayed in a hood covering the head

  • If the individual can smell the substance, it means the respirator does not fit well
  • If the individual cannot smell the substance, it means the respirator fits well.

Once the correct type and size has been determined for an individual, fit testing does not need to be repeated.

 
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11.1 How to Put on and test Seal an N95 Respirator Mask?

 

  • Wash your hands using soap and water or clean with hand sanitizer
  • Inspect the mask to ensure that it is not damaged.
  • Cup the respirator in your hand with the nosepiece at your fingertips, allowing the headbands to hang freely below your hand    Position the nosepiece under your chin with the nosepiece up
  • Pull the top strap over your head resting it high at the back of your head. Pull the bottom strap over your head and position it around your neck below your ears
  • Place fingertips of both hands at the top of the metal nosepiece. Mould the nosepiece (using two fingers of each hand) to the shape of your nose.
  • Cover the front of the respirator with both hands, being careful not to disturb its position.
  • Exhale sharply and adjust if leaking
  • Inhale deeply and adjust if leaking

 
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Seal checking is performed to check if the respirator is sealing the face off properly and that air is not leaking between the face and the respirator. This should be done every time the respirator is worn.

  • Positive seal-check: Exhale sharply. A positive pressure inside the respirator means that there is no leakage. If there is leakage, adjust the position and/or the tension straps. Retest the seal. Repeat the steps until the respirator is secured properly.
  • Negative seal-check: Inhale deeply. If there is no leakage, negative pressure will make the respirator cling to your face. Leakage will result in loss of negative pressure due to air entering through gaps in the seal. Adjust the position and/or the tension straps and check for damage. Retest the seal. Repeat the test until the respirator is secured properly.

 

14.2.1. Clinical Evaluation

The patient must be evaluated by the doctor weekly during the injectable phase and monthly during the continuation phase. Different scenarios need to be considered. During admission, regular medical ward rounds must be conducted. This may be every second day, twice a week or weekly for stable patients; nursing care must be provided daily and the patient record card updated. Patients who are very sick or critical need to be reviewed on a daily basis by the doctor.

A focused assessment of the patient should be conducted looking at any respiratory distress, gastro-intestinal disturbances, drug intolerance or ADRs, progression of hearing loss or tinnitus, and neuro-psychiatric effects. A physical exam should be conducted and routine laboratory tests or any other tests that may be indicated at the time.

Weight, height and body mass index (BMI) are also important parameters to monitor. Weight needs to be measured every week during injectable phase, then monthly during continuation phase. Height is to be measured at baseline while BMI need to be looked weekly during admission especially for patients with BMI<18.5.

14.2.2. Bacteriological Investigations

Culture and smear conversion are the most important indicators of patient improvement. Smear microscopy and bacteriological culture are therefore used to monitor patient progress throughout treatment and should be performed monthly. Microscopy is useful as a good indicator of patient progress; however, it cannot distinguish viable organisms from those that are non-viable. Culture is therefore necessary to monitor treatment progress. One sputum specimen should be sent monthly to the NHLS for smear microscopy and culture (not DST).

Definition of Conversion

Two types of conversion are considered for DR-TB patients (i.e., smear conversion and culture conversion); both require that the smear or culture be positive at the beginning of treatment.

  • Smear conversion is defined as two consecutive negative ‘smears’, taken at least 30 days apart. Time to conversion is calculated as the interval between the date of treatment initiation and the date of the first of the two negative consecutive smears (the date of sputum specimen collection should be used).
  • Culture conversion is defined as two consecutive negative ‘cultures’, taken at least 30 days apart. Time to conversion is calculated as the interval between the date of treatment initiation and the date of the first of the two negative consecutive cultures (the date sputum specimen collection should be used).

Patients that are culture and smear negative at the commencement of treatment for whatever reason(s) do not get counted in the cohort reporting of culture or smear conversion.

Sputum conversion is slower when using second-line anti-tuberculosis drugs. Culture results showing a few colonies should not be automatically regarded as negative in DR-TB patients, nor should a single positive culture preceded by multiple negative cultures be regarded as treatment failure.

Culture conversion is not equivalent to cure.  A significant proportion of patients may initially convert and later revert to being culture positive, depending on the initial burden of disease and the level of resistance. For these reasons, cultures should be done regularly throughout the duration of treatment.

14.2.3. Other Laboratory Tests

These are liver function tests, serum creatinine, serum potassium, thyroid stimulating hormone. These tests are used mainly to monitor the development and the management of ADRs.

All patients with DR-TB must be offered HIV tests if they do not know their HIV status.

A pregnancy test in females patients of child bearing age is also important on admission and when necessary. Patients spend long periods on treatment after admission; hence it is important to consider pregnancy tests in females who are not on contraception.

14.2.4. Chest X-Rays

Chest x-ray films should be taken whenever the patient’s clinical condition worsens, or whenever surgical intervention is being considered. The chest x-ray film results may remain unchanged or show only slight improvement, this does not mean the patient is not improving on treatment therefore; no changes in treatment should be made on the basis of chest x-ray films alone.

The chest x-ray films must be evaluated using a standardised scoring system at the following intervals:

  • At diagnosis;
  • After completion of the intensive phase of treatment or at six months;
  • Every six months; and
  • At treatment completion.

The chest x-ray film is divided into six zones by the mediastinum and horizontal lines through the 2nd and 4th anterior rib shadows. Each zone is described according to disease and cavitation, as follows:

Scoring System for the Evaluation of Chest X-Rays

 

 
2017_03_1490155689-7176.png
 

 

 

 

 

Disease (a)

 

 

 

Score

 

No disease

 

:

 

Leave blank

 

0

 

< 50% of area affected

 

:

 

< 

 

1

 

≥ 50% of area affected

 

:

 

> 

 

2

 

 

Cavitation (b)

 

 

 

Score

 

No cavitation

 

 

Leave blank

 

0

 

Single cavity, <2 cm diameter

 

:

 

1a

 

0.25

 

Single cavity, 2-4 cm diameter

 

:

 

1b

 

0.50

 

Single cavity, >4 cm diameter

 

:

 

1c

 

1.00

 

Multiple cavities, largest <2 cm diameter

 

:

 

2a

 

0.50

 

Multiple cavities, largest 2-4 cm diameter

 

:

 

2b

 

1.00

 

Multiple cavities, largest >4 cm

 

:

 

2c

 

2.00

 

A composite score is calculated by adding the disease and cavitation scores for each zone, as follows:

 

Zones affected

 

1

 

2

 

3

 

4

 

5

 

6

 

Disease (> / <)

 

 

 

 

 

 

 

Score (a)

 

 

 

 

 

 

 

Cavitation

 

 

 

 

 

 

 

Score (b)

 

 

 

 

 

 

 

Total score (a+b)

 

 

 

 

 

 

The following table presents a summary of parameters to be considered for DR-TB patient monitoring.

 

 

 

 
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14.3. Patient Education and Counseling

 

Education, counselling and emotional support are particularly important, much as in any other chronic life-threatening illness. On-going intensive counselling will also help to ensure good adherence to the treatment regimen and increase the likelihood of a successful outcome.

Patients and their families should also be informed on an on-going basis about MDR- or XDR- TB, its spread, prevention, treatment, potential ADRs, the need for treatment compliance and early testing for MDR- and XDR-TB for other family members should they develop symptoms. Information can be provided by physicians, nurses, community health workers and other health care providers at every encounter with the patient. Information and educational materials should be appropriate to the literacy levels of the population and should also be culturally sensitive.

 

14.4. Treatment Compliance

 

Patients with DR-TB may more likely have had problems with treatment non-compliance in the past. In addition, treatment compliance is made more difficult by prolonged multidrug treatment regimens with drugs that have serious ADRs. Monitoring patient compliance and support measures to facilitate adherence are therefore particularly important.

MDR-TB treatment and, to a lesser extent XDR-TB treatment, can be successful with high overall rates of treatment compliance when adequate support measures are implemented.  Patient support groups and family support for the patients may help improve this.

Since the patients often have only one last chance for cure and there is a serious public health consequence if treatment fails, it is imperative that all patients receive their treatment under strict DOT after discharge from the hospital either in the community or at health facilities. This should be provided in such a way that it does not introduce undue burdens to patients and their families. Long distances and difficulties accessing services may all contribute to treatment interruption.

The first choice for providing community care to DR-TB patients is to use HCWs where possible. When human or financial resources do not permit the use of HCWs, trained community members can serve as effective treatment supporters. However, community members need intensive training, on-going supervision and support by health professionals.

Irregular or noncompliant patients continue to pose a challenge to nurses and community health workers particularly following discharge from hospital, therefore any non-compliance should be addressed as soon as it is detected. The patient must be counselled again and any issues that may be contributing to the non-compliance addressed. If the current arrangement for DOT does not suit the patient the patient anymore, a more suitable arrangement must be agreed upon. The patient must also be assessed for:

  • Any psychiatric symptoms, and referred to a psychologist/psychiatrist for further assessment if necessary.
  • Alcohol and drug abuse and referred for rehabilitation programmes.

Socio-economic factors that could contribute to non-compliance such as lack of money for transport, lack of food which may exacerbate some of the gastro-intestinal effects on taking medication must also be investigated. Where these apply the social worker must be contacted.

When all measures have been taken and the patient is not consistent with taking the medications, a decision should be taken to discontinue treatment.

 

14.5. Maintaining Confidentiality

 

The HCW and community health worker must maintain strict confidentiality at all times to ensure and maintain the patient-provider relationship, as treatment is lengthy. In some cases this may entail arranging a system where the patient receives medication without the knowledge of others.

 

14.6. Social Support

 

The provision of social support to patients may improve chances of adherence to therapy. The social worker must conduct an assessment of the patient’s home environment and ensure that social support is provided for the family members where needed. If the patient was employed, with the patient’s consent arrangements may be made with the employer to provide the necessary leave of absence from work whilst the patient is hospitalised thereby sustaining the monthly income of the patient. Patients who are substance abusers must be started on rehabilitation programmes with intensive counselling as treatment compliance tends to be poor in this group of patients. Organisations such as SANCA can assist with provision of these programmes.

Patients who qualify for social grants or disability grants should be assisted to access these grants. Those who are breadwinners, or who have lost income as a result of admission in hospital and their families are in distress should be assisted to access other benefits – social relief of distress grant, an extension beyond the stipulated six months may need consideration for those patient who need longer hospitalisation (i.e. non-converters/treatment failures).

The social worker should also negotiate with the employers to encourage them to offer the patient “paid” sick leave as far as reasonably possible or lodge an application for access to the

‘unemployment insurance fund’ (UIF) on behalf of the patient whilst hospitalised. An application may be lodged on behalf of the patient who is a breadwinner to access free municipal services through the use of the indigent policy. This is an avenue designed for non-affording people to benefit on basic services like water, electricity and waste removal amongst others. In terms of chapter nine of the Municipal Systems Act, a municipality in relation to the levying of rates and other taxes and the charging of fees for municipal services, it must within make provision for indigent debtors that is consistent with its rates, tariff policies, financial and administrative capacity.

Some of the patients may develop hearing loss due to prolonged use of aminoglycosides or capreomycin resulting in permanent disability and may require disability grants. Applications should therefore be processed as soon as confirmation of deafness is confirmed. 

 

14.7. Management of Treatment Interruption and Default

 

When a patient refuses to continue treatment every effort should be made to convince the patient to continue treatment. This should include explaining the implications of discontinuing treatment, importance of completing the treatment and addressing the reasons for wanting to stop treatment and other patient concerns. In most cases this is due to the side effects and addressing these more aggressively by providing ancillary treatment and rescheduling the doses might help. An evaluation of the patient should be conducted and this must include an assessment of the patient for any psychiatric illness and/or substance abuse and the patient must be referred accordingly when these exist. Where socio-economic factors are contributing to this, they should be addressed. When all these measures fail, and the patient insists on stopping treatment, the patient should sign a refusal of hospital treatment (RHT) form (Annexure 4).

A patient is regarded as having defaulted treatment if s/he has been missed treatment for two consecutive months.  Every effort should be made to recall patients who abscond or interrupt treatment for a day or two, to persuade them to resume treatment. A home visit should be conducted to find out why the patient has defaulted after two days and to ensure that treatment is resumed promptly and effectively. The situation should be addressed in a sympathetic, friendly, and non-judgmental manner. Every effort should be made to address the patients’ concerns or reasons for interruption or abscondment to prevent it from happening again.

In patients where treatment has to be restarted following abscondment, default or interruption, the following should be considered:

  • Commitment of patient to treatment completion;
  • Clinical condition of the patient; and
  • Duration of treatment interruption or default.

A full physical examination must be conducted and sputum specimen obtained for microscopy, culture and DST, a chest x-ray must be done and compared with previous ones for extent of disease. Counselling of the patient must be conducted and patient must sign the patient consent form before treatment initiation.

The treatment will depend on the stage at which the patient interrupted treatment and the clinical condition of the patient on return for treatment. Patients who interrupt treatment for more than six months must be clinically evaluated for active disease and if found to have active disease, must be started on a new treatment regimen based on their resistance pattern. If there is no active TB disease, the decision on treatment must be made by the clinical review committee. If not started on treatment, the patient must be followed up regularly for signs of relapse.

 
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14.8. End of Intensive Phase of Treatment

 

The decision to stop the injectable drug should be made following the review of the clinical picture, smear and culture results, chest x-ray films. The injectable drug can be stopped when:

  • Patient has completed a minimum of six months of intensive phase treatment.
  • Two consecutive negative culture results.
  • At least four drugs to which the strain is still sensitive and are usable.

In patients with high grade resistance, extensive lung disease and in whom the regimen contains only four drugs including the injectable, the injectable may be used for a minimum of 12 months after culture conversion or throughout the treatment period.

 

14.9. If There is No Improvement at Four Months of Treatment

 

If a patient shows minimal or no improvement at the end of the injectable phase, the patient must be re-evaluated as follows:

  • Evaluate treatment compliance.
  • Repeat chest x-ray.
  • Repeat sputum smear microscopy, culture

     - If culture is still positive  repeat first- and/or second-line drug susceptibility testing. Resistance amplification or treatment failure must be considered.

 
2017_03_1490156701-5293.JPG
 

14.10. Recurrence of Positive Cultures after Culture Conversion

 

Re-appearance of single or multiple positive smears or cultures should be considered as possible evidence of treatment failure. Therefore, patients should be re-evaluated to determine the course of action. The DST should be repeated to determine whether this is a different strain from the initial one or there has been resistance amplification. During this period two or more drugs should be added to the regimen whilst awaiting DST results.

If the strain and resistance profile is similar to the initial one, this could be treatment failure in which case the treatment may be modified based on resistance profile, or extended until the patient has had 18 consecutive months of negative cultures.

If the strain and resistance profile is completely different from the initial one, this could be due to contamination or a new infection, the latter being the least likely. The cultures should be repeated twice and documented as negative before concluding that this is due to contamination.

 

14.11. Treatment Completion

 

The patient is considered to have completed treatment when s/he has completed at least 18 months of treatment after culture conversion and 24 months for those who had extensive lung damage at the initiation of treatment. Bacteriological, clinical, and radiological information must be considered when determining the end of treatment for MDR- and XDR-TB.

 

14.12. Follow-up After Treatment Completion

 

Patients who complete a full course of MDR- or XDR-TB treatment should be followed up for at least two years after cure. The follow up visits must be conducted every six months and should mainly focus on:

  • Assessing the patient for symptoms and signs of relapse.
  • Conducting smear and culture every six months.
  • Conducting radiographic evaluation as needed for development of respiratory symptoms.
  • Monitoring response to ancillary medicines in patients who had residual lung disease.

Patients should be advised to report to the nearest clinic when they experience symptoms of TB at any stage. Patients failing to come for appointments must be traced. Therefore knowledge of each patient’s residence during the follow-up phase must be obtained.

 
2017_03_1490156902-9591.JPG
 

14.13. MDR- and XDR-TB Treatment Failures

 

Treatment failures are considered when no response to treatment is seen at six months of treatment (i.e., if bacteriological conversion is not seen or if clinically deterioration is evident). Re-assessment of the regimen and treatment plan, and formulation of a new plan of action are necessary. Avoid adding one or two drugs to an apparently failing regimen, instead redesign the regimen with four effective drugs. Once a patient gets two or more new drugs included in the regimen, with or without omission of certain drugs; this should be considered as a new regimen. The patient will receive an outcome of treatment failure and recorded in a new treatment cohort.

14.13.1. Patients with Suspected MDR-TB Treatment Failure

Patients who show clinical, radiological, or bacteriological evidence of persistent active disease or re-appearance of disease after six months of treatment should be evaluated for possible failure. In addition, patients who show rapid clinical deterioration before month 6 should also be evaluated.

The following steps should be taken for patients with suspected treatment failure:

  • The treatment card should be reviewed to confirm adherence of patient to treatment. The healthcare worker should investigate whether the patient has taken all the medicines. A non-confrontational interview should be undertaken without the presence of the treatment supervisor.
  • A non-confrontational interview with the treatment supervisor should be done in the absence of the patient. Questions should be asked to rule out possible manipulation of the treatment supervisor by the patient. If this is suspected, the treatment supervisor should be switched to another patient and the patient assigned a new treatment supervisor.
  • The treatment regimen should be reviewed in relation to medical history, contacts, and all available treatment reports. If the regimen is deemed inadequate, a new regimen should be designed.
  • The bacteriological data should be reviewed. Often the smear and culture data provides the strongest evidence that a patient is not responding to therapy. A single positive culture in the presence of otherwise good clinical response is not necessarily indicative of treatment failure, especially if follow-up cultures are negative or the number of colonies is decreasing. Positive smears with corresponding negative cultures may reflect dead bacilli, thereby not indicating treatment failure. Repeated negative smear and culture results in a patient with clinical and radiological deterioration may indicate that disease other than DR-TB is also affecting the patient.
  • Other illnesses that may decrease absorption of medication (like chronic diarrhoea) or may result in immune-suppression (like HIV) should be excluded.

14.13.2. Patients with Apparent MDR-TB Treatment Failure

There is no single indicator that determines whether treatment is failing; however, a point is reached when it is clear that the patient is not going to improve. Signs that indicate treatment failure include:

  • Persistent positive smears or cultures after 8 months of treatment;
  • Extensive and bilateral lung disease with no option for surgery;
  • High-grade resistance with no option to add additional agents; and
  • Deteriorating clinical condition that usually includes weight loss and respiratory insufficiency.

All these signs need not be present to declare failure of the treatment regimen; nevertheless, cure is highly unlikely when they all exist. Of note is that the epidemiological definition of treatment failure for recording outcomes is often different from the process of suspending treatment in a patient when it is failing. The epidemiological definition is an outcome to account for the patient in treatment cohort analysis. The clinical decision to suspend treatment is one made after all other options have been explored, and cure of the patient has been determined to be highly unlikely.

 

14.14. Suspending Treatment

 

MDR- or XDR-TB treatment can be terminated provided that appropriate counselling has been offered to the patient, and the patient has been heard before a final decision is made. Termination of treatment should be considered in the following circumstances:

  • Where the patient no longer consents to receiving treatment.
  • Where there is a negligible chance of success, even where the patient wishes the treatment to continue. This would apply to those who are chronic defaulters in whom the treatment may not be effective, may result in amplification of resistance, treatment failure or patients with advanced terminal disease.

Suspension of treatment should only be considered after all other options for treatment have been explored as this is a delicate situation and difficult for family members and caretakers, but it is especially difficult for the patient as treatment is often viewed as his/her only hope. Psychosocial support must be rendered to the patient and family.

If the DR-TB clinical management team is confident that all medications have been taken and that there is no possibility of adding other drugs or surgery, the treatment should be considered a failure and suspension of therapy recommended or provision of palliative care.

The decision to suspend treatment should be made by the provincial DR-TB review committee based on all evidence provided on the patient. The team should recommend a treatment plan. Conditions under which treatment may be suspended include:

  • The patient’s quality of life is poor, particularly when medications used in DR-TB treatment have considerable side effects, and continuing them while the treatment is failing may cause additional suffering.
  • Continuing treatment that is failing can amplify resistance in the patient’s strain, resulting in resistance to all available anti-tuberculosis drugs.  This ‘super-resistant strain’ can be transmitted to others.

A consultative process with the patient and family should take place. Both parties should be made to understand and accept the decision for suspension of treatment and alternative care offered. Depending on the patient’s condition this can be provided at home, hospital or hospice. Usually this process takes a number of visits and occurs over several weeks. Home visits during the process offer an excellent opportunity to talk with family members and the patient in a familiar environment. Treatment should not be suspended before the patient understands and accepts the reasons to do so, and agrees with the supportive care offered. The household should be assessed for risk of infection and family educated on measures to take to minimise transmission risk of infection and patients should be advised to avoid contact with the general public and especially with susceptible persons, such as young children or HIV-infected individuals.

 

14.15. Palliative/Supportive Care

 

A number of palliative measures can be implemented once DR-TB treatment is suspended. Supportive measures are summarised below.

  • Pain control. Paracetamol or codeine with paracetamol gives relief to moderate pain. Codeine also helps control cough; other cough suppressants can be added. If possible, stronger analgesics, including morphine, should be used when indicated.
  • Relief of respiratory insufficiency.  Oxygen can be used to alleviate shortness of breath. Morphine also provides significant relief from respiratory insufficiency and should be offered if available.
  • Nutritional support. Often small and frequent meals are best for a terminally ill person. Intake will decrease as the patient’s condition deteriorates. Treat nausea and vomiting or any other conditions that interfere with nutritional support.
  • Regular medical visits. When treatment is stopped, on-going medical and psychological support to the patient must be provided, through regular visits by the medical team. Depression and anxiety, if present, should be addressed.
  • Continuation of ancillary medicines. All necessary ancillary drugs should be continued as needed.
  • Hospitalisation, hospice care or nursing home care.  Looking after a terminally ill family member at home can be quite difficult. Hospice care should be offered to families who want to keep the patient at home. Inpatient care should be available for those patients where home care is not possible.
  • Preventive measures.  Oral care, prevention of bedsores, bathing and prevention of muscle contractures should be ensured for all patients as part of care. Regular scheduled movement of the bedridden patient is very important.
  • Infection control measures. The patient who is taken off of DR-TB treatment because of failure often remains infectious for long periods of time. Infection control measures should be continued.

 

15. MDR- AND XDR-TB CONTACTS

 

15.1. Introduction

 

The opportunity to halt the spread of MDR- and XDR-TB in the communities, to diagnose and treat the disease early is often lost because close contacts of MDR- and XDR-TB patients are not investigated.

Close contacts are defined as persons living in the same household, or who spend many hours a day together with the patient in the same indoor space. While data is limited, studies have shown that close contacts of MDR- and XDR-TB patients often have MDR- and XDR-TB disease respectively and should be appropriately managed.

 

15.2. Evaluating the Risk of MDR-TB in Contacts

 

Factors that should be considered when investigating patient contacts include:

  • The likelihood of infection in contacts thought to be newly infected.
  • The likelihood that the contact, if infected, will develop active disease.

“Contacts before the initiation of treatment” that have had exposure to a patient with active disease and are likely to be newly infected should be evaluated to assess the likelihood of the actual infection being an MDR- or XDR-TB strain of M. tuberculosis. Factors that should be considered include:

  1. Infectiousness of the index patient: MDR-or XDR-TB patients who cough and are sputum smear-positive are substantially more infectious than those who do not cough or are sputum smear-negative.
  2. Closeness and intensity of the exposure: Persons who share air space with a patient with active disease for a prolonged time (e.g., a household member, hospital room mate) are at higher risk for infection than those who have a brief exposure. Exposure in a small, enclosed, poorly ventilated space is more likely to result in transmission of infection than exposure in a large, well-ventilated space. Exposure during cough-inducing procedures (e.g., sputum induction, bronchoscopy) may greatly increase the risk of transmission of infection.
  3. Likelihood of exposure to persons with drug-susceptible TB: In immuno-competent persons, the risk of developing TB is highest within the first two years following infection, after which this risk declines markedly. In general, 5%-10% of infected immuno-competent persons will develop active disease within the first two years. Child contacts of patients with MDR- or XDR-TB (especially those under two years of age) are at increased risk of getting infected and develop TB disease.

The most potent factor that increases the probability of developing active disease following infection is impaired immunity, such as that seen in HIV infection.  It should be remembered, however, that there are many other medical causes of impaired immunity, including:

  • Malnutrition.
  • Congenital syndromes.
  • Certain haematological diseases.
  • Endocrine diseases.
  • Renal disease.
  • Diabetes mellitus.
  • Patients on immunosuppressive drugs (steroids, anti-cancer chemotherapy) or radiation therapy.

 

15.3. Managing Asymptomatic Contacts of MDR- and XDR-TB Patients

 

The use of second-line drugs for preventive therapy in MDR- or XDR-TB contacts is not recommended. To date, no controlled clinical trials have been conducted to assess the efficacy of treatment for latent MDR- or XDR-TB infection. Close monitoring of asymptomatic patients for development of symptoms is therefore more appropriate, particularly in high TB burden settings where many different tubercle strains (most often drug-susceptible) are circulating.  Given the real possibility that contacts may have been infected by drug-susceptible strains, it is acceptable practice to manage asymptomatic contacts of DR-TB patients in the same way as contacts of drug-susceptible TB patients.

Asymptomatic contacts of smear-negative MDR- and XDR-TB patients should be managed according to the standard recommendations for contacts of drug-susceptible TB patients

Asymptomatic contacts of smear-positive MDR- and XDR-TB cases should be rapidly identified and screened. Child contacts aged five years and younger should be considered for isoniazid preventive therapy irrespective of health status and tuberculin response.

Asymptomatic child contacts aged five years and younger and HIV-infected children irrespective of age should be considered for isoniazid preventive therapy.  All of these children should be examined clinically with Mantoux tuberculin skin test and a chest radiograph done. If there is any evidence of disease, specimens (from any appropriate source) should be obtained for culture and DST before commencement of anti-TB treatment according to the DST of the likely adult source case (that is MDR- or XDR-TB treatment if adult source case has MDR- or XDR-TB). If the children are well and chest radiographs are normal, all exposed and infected children (therefore irrespective of TST result) should receive preventive therapy (isoniazid 15 mg/kg/day for 6 months). However, isoniazid preventive therapy often fails in these children. Therefore regular two-monthly follow-up for symptoms (and CXR if indicated) should be done for first 6 months and 3-6 monthly thereafter for a minimum of two years.

In children older than five years and HIV negative adults, a strongly reactive tuberculin test indicates infection but not necessarily disease. The decision to start these persons on preventive (drug- susceptible) treatment depends on clinical history, examination and investigation.

Contacts of MDR/XDR-TB patients should report the first symptoms of possible TB and a careful risk assessment should be made. Sputum should be sent for smear, culture and DST. A chest X-ray should also be done.

Contacts that are HIV-positive should be followed up every six months for a period of two years and encouraged to report symptoms of TB as soon as they become evident.

 

 

15.4. Managing Symptomatic Contacts of MDR/XDR-TB Patients

 

15.4.1. Adult Contacts

All symptomatic close contacts of MDR- or XDR-TB cases should be examined immediately. If the contact appears to have active tuberculosis disease, culture and DST should be performed. While awaiting DST results, an empiric regimen based on either the resistance pattern of the index case or the most common resistance pattern in the community may be started.

If the work-up of a symptomatic adult is negative for TB, a trial of a broad-spectrum antibiotic that is not active against tuberculosis such as trimethoprim/sulfamethoxazole can be used. If the patient continues to be symptomatic, chest computed tomography, and/or directed bronchoscopy for smear and culture should be considered. If these diagnostic tools are not available or the results are not conclusive a diagnosis should be made with the clinical information at hand. If the initial work up is not suggestive of active tuberculosis, but the contact remains symptomatic, physical examinations should be repeated, together with monthly smears and cultures and repeat chest X-rays as needed.

15.4.2. Child Contacts

MDR- and XDR-TB should be suspected in the following situations with children:

  • Who are contacts of a patient with confirmed MDR- or XDR-TB.
  • Who are contacts of patients who died of tuberculosis while on treatment and there are reasons to suspect it was MDR- or XDR-TB.
  • With bacteriologically proven TB that are not responding to first-line drugs despite treatment compliance.

In children, the diagnosis of TB is more difficult than in adults. Symptoms of TB in young children can  be non-specific (e.g. chronic  cough or wheeze, failure to thrive and  recurrent fevers). Bacteriologic confirmation may be difficult to obtain due to the inability of children to produce sputum, the paucibacillary nature of paediatric TB, and the increased likelihood of extra-pulmonary TB in children. While every effort should be made to establish a bacteriologic diagnosis by DST in a child with suspected MDR/XDR-TB, it is not always possible.

Symptomatic child contacts of MDR/ XDR-TB patients should receive:

  • A medical evaluation, including history and physical examination.
  • Skin testing with tuberculin purified protein derivative (PPD).
  • A chest X-ray. Computerised tomography is sometimes helpful, especially in documenting complications due to hilar adenopathy.
  • Culture and DST: If the child is very young or cannot expectorate sputum, sputum induction with chest percussion or gastric aspiration should be performed.

If the tuberculin skin test is >5 mm, chest X-ray is negative and gastric aspirate or sputum culture is negative, the child can be treated with a broad spectrum antibiotic that is not active against tuberculosis, such as trimethoprim/sulfamethoxazole. The child should be followed up closely, with monthly evaluations that include sputum or gastric aspirate culture and chest X-rays, until three months of negative cultures or resolution of the symptoms occurs. If the patient’s clinical condition is highly suggestive of tuberculosis or progressively worsens, empiric treatment designed according to the DST pattern of the strain from the index case based may be started.

 

16. RECORDING AND REPORTING

 

16.1. Introduction

 

The information system for DR-TB is an extension of the TB information system and defines the minimum tools to monitor the management of DR-TB patients effectively. This information system allows the managers at different levels to monitor programme performance by following the distribution and trends in MDR-TB notification and treatment outcomes of patients started on Regimen IV. It does not include the detailed information that HCWs may need to manage individual patients, which is, however, contained in the patient clinical records and other forms used in the hospitals and clinics.

Particular attention must be paid to full documentation of patient particulars and every effort must be made to ensure that all patients are seen regularly by the management team during the treatment period to ensure a comprehensive management plan. The patient, facility records must be completed daily and updated monthly on the paper based and electronic DR-TB register (EDRWeb). Each hospital must have a person responsible for data management and compile case finding, case holding and treatment outcome reports.

 

16.2. Case Definitions for MDR-TB and XDR-TB

 

Case definitions for MDR- and XDR-TB are used to:

  • Allow proper patient registration and epidemiological notification;
  • Facilitate case allocation to appropriate treatment categories;
  • Facilitate case evaluation according to site, bacteriology and treatment history; and
  • Evaluate programme performance through cohort analyses.

A case of MDR-TB is defined as a patient with bacteriologically proven TB whose disease is due to bacilli showing in vitro resistance to rifampicin and isoniazid, with or without resistance to other first-line anti-TB drugs.

MDR-TB diagnosed through DST is also called “Confirmed MDR-TB”.

Not confirmed MDR-TB cases are patients commenced on MDR-TB treatment after a decision of a provincial DR-TB review committee or DR-TB practitioner on the basis of clinical presentation, radiological findings and medical history indicating a high probability of MDR-TB. It is worth noting that it is difficult to make a laboratory diagnosis of MDR-TB in children (see chapter 12).

Patients who have mono-resistance to rifampicin through GeneXpert or conventional DST will be registered as “not confirmed MDR-TB” because they receive MDR-TB treatment. These patients will later be changed to “confirmed MDR-TB” when laboratory confirmation becomes available.

A case of XDR-TB is defined as a patient with bacteriologically proven TB whose disease is due to bacilli showing in vitro MDR together with resistance to any fluoroquinolone plus resistance to one or more of the following injectable anti-TB drugs: kanamycin, amikacin, and capreomycin.

History of previous TB treatment allows categorisation of MDR and XDR-TB patients into three categories. These categories are essential for epidemiological monitoring of the DR-TB epidemic and help to identify patients that may be at risk. The patient categories are shown in the following table.

 
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Site of disease is classified according to pulmonary or extra-pulmonary involvement:

  • Pulmonary MDR- and XDR-TB refer to disease involving the lung parenchyma only.
  • Extra-pulmonary MDR- and XDR-TB refer to organs other than the lungs.
  • A patient with both pulmonary and extra-pulmonary MDR- and XDR-TB constitutes a case of pulmonary MDR- and XDR-TB.
  • The case definition for extra-pulmonary MDR- and XDR-TB in several sites depends on the site with the most severe form of disease.

Severity of disease is classified according to bacteriological status (smear or culture, positive or negative) at diagnosis.

 

16.3. Data Collection Tools and Flow of Information

 

The DR-TB data collection tools are similar to the TB data tools; others are the same such as suspect register and the referral forms. This section describes the core set of tools that are used for patient management and surveillance.

 
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16.3.1. DR-TB Treatment Card

HCWs administrating drugs daily to the patient must use this card to complete all the necessary demographic and management information about the patient.  This card should be completed when a patient is started on DR-TB treatment and updated daily. It should remain in the MDR-TB hospital and a patient follow up card issued when the patient is discharged from the hospital, but must be updated monthly when the patient comes for follow up at the hospital.

The card contains the following sections:

  • Basic demographic information: Name, gender, age, at least two physical addresses (patient, next of kin or friend, work) as well contact details.
  • DR-TB register number and date of registration.
  • Previous tuberculosis treatment episodes: All TB episodes that the patient has had should be recorded here for both sensitive and resistant TB.
  • Previous medical history: History of any other medical condition for which the patient might be taking medication or previously took medication for as well as substance abuse must be recorded. This must include history of previous admission to a hospital, imprisonment and working in the mines.
  • Patient category: There are eight possible groups: new, relapse, treatment after default, treatment after failure of first treatment, treatment after failure of re-treatment, transfer in, and other (previously treated but the outcome is unknown).
  • Site of disease: The affected organ must be specified in patients with extra-pulmonary TB disease. The International Classification of Diseases (ICD 10) Codes should be used.
  • Drug resistance history: The number refers to whether it was a new, primary or re-treatment (after default/failure/relapse).
  • Regimen and doses: The initial treatment regimen is recorded on the treatment card, as well as any changes and adjustments in treatment.
  • Sputum results for microscopy and culture: Monthly monitoring of smear and culture is required. The date and results of any DST conducted are recorded on the treatment card.
  • Drug susceptibility results: The date and results of any DST conducted are recorded on the treatment card.
  • Record of daily administration of drugs: Each end every dose of oral or injectable drugs administered to the patient is recorded in this section.
  • Adverse drug reactions: Any ADR that the patient experiences are graded and recorded. Any drug adjustments, adjuvant therapy or additional drugs for the management of side effects must be recorded.
  • Clinical progress notes: Weight, laboratory test results and chest x-ray findings monitoring these items can be recorded on the treatment card in the monthly drug administration section in the last column.
  • Outcome of treatment: At the end of treatment the outcome should be recorded on the treatment card according to the outcome definitions.

16.3.2. DR-TB Treatment Follow-up Card

This card records the same information as the treatment card but when the patient is discharged from the hospital or referred to another hospital, s/he takes this card to the receiving facility. The health care worker at the clinic updates the information on the card daily during follow up care and the information on this card is used to update the hospital treatment card on a monthly basis. The receiving clinic should notify the hospital when patient arrives at the clinic by completing the referral acknowledgement slip and sending it back to the hospital or by facsimile or telephonic confirmation where possible.

16.3.3. DR-TB Register

This register records all patients who receive treatment for drug resistant TB including mono- and poly-resistance. It is used to monitor patient progress while on treatment and allows for evaluation of the programme through quarterly, six-monthly and annual analysis of case finding, culture conversion and treatment outcomes.

The registers must be kept in all MDR-TB hospitals (central and peripheral). The information from the patient treatment card is entered into the register and should be updated daily for new patients registered and monthly for smear and culture results and treatment outcomes.

All patients in whom DR-TB have been confirmed must be registered in the DR-TB register, even if they have not started treatment. The following is recorded in the DR-TB register:

  • DR-TB register number: This is a unique patient identification number for patients that enter DR-TB treatment.
  • Date registered.
  • Name, sex, date of birth, address.
  • District TB register number.
  • Site of disease: Pulmonary (vs) extra-pulmonary.
  • Registration category: There are eight possible groups – new, relapse, treatment after default, treatment after failure of first treatment, treatment after failure of re-treatment, transfer in, and other (previously treated but the outcome is unknown).
  • Second-line drugs already received: Yes or no.
  • DST:  Date and results. Patients may have had more than one DST. The diagnostic DST (which resulted in the patient being registered as a MDR- or XDR-TB patient) is entered. The full DST history is recorded on the treatment card. Follow-up DST results are not recorded in the register.
  • Reason for being registered as DR-TB. Reasons include mono- or poly-resistant TB, confirmed or not confirmed MDR-TB, confirmed or not confirmed XDR-TB. If the patient is not started on treatment the reason is given in the subsequent column.
  • The DR-TB regimen: The date and the initial regimen are recorded.
  • Smear and culture monitoring results: Date and result.
  • Final outcomes: At the end of treatment the outcome should be recorded on the treatment card according to the outcome definitions.
  • Comments. This section is reserved for any additional information

16.3.4. Patient Identity Card

Once a patient is diagnosed with DR-TB, a patient identity card should be completed at the same time that the treatment card is completed, and be kept by the patient.  The card contains the following:

  • Demographic details (name, age, sex, address).
  • DR-TB register number.
  • Registration group.
  • Essential treatment information (start date, regimen, ADRs, clinical progress).
  • Health centre where the patient will receive treatment.
  • Dates of appointments.

16.3.5. Request for Sputum Examination

The top of the form is identical to the form used in DOTS programmes, while the middle part is used for requesting culture and DST. The bottom part is used for reporting the results. The same form is returned to the treating unit with the results.

 

16.4. Treatment Outcome Definitions

 

The outcome definitions are based on bacteriological culture as a monitoring tool:

  • Cure: A patient who has converted (with 2 consecutive TB culture negative taken 30 days apart), and has remained TB culture negative, has completed treatment and has been consistently culture-negative for five consecutive months in the final twelve months of treatment. If one positive culture is reported during that time and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative cultures, taken at least thirty days apart. This outcome is restricted to confirmed pulmonary DR-TB patients.
  • Treatment completed: A patient who has completed treatment but does not meet the definition for cure due to lack of bacteriologic results (i.e. less than five cultures were performed in the final twelve months of treatment).
  • Death: A patient who dies from any cause while on DR-TB treatment.
  • Treatment default: A patient who interrupts DR-TB treatment for two or more consecutive months for any reason.
  • Treatment failure: A patient who has had two or more of the five consecutive cultures taken in the final twelve months and are positive, or if any one of the final three cultures are positive. Treatment failure may be observed in patients who do not respond to treatment after 6 to 8 months of effective treatment. Such patients will be put on a different treatment regimen after receiving an outcome of failure and be allocated to a new treatment cohort.
  • Transfer out: A patient who has been transferred to a reporting unit in another province and for whom the treatment outcome is unknown.
  • Treatment stopped due to ADRs: A patient who develops ADRs while on DR-TB and could not continue treatment in spite of the management of the ADRs as per protocols and the decision has been taken to stop treatment.
  • Treatment stopped due to other reasons; A patient who could not continue on DR-TB treatment for any other medical reason than ADRs, and a decision to stop treatment was made.
  • Still on treatment: A patient who for any reason is still on treatment at the time of submission of treatment outcome report.

 

16.5. Cohort Analysis of Treatment Outcome

 

Details of all patients identified with DR-TB should be recorded in the register. The register must clearly identify MDR/XDR-TB patients from those with other forms of drug resistance and those that are not confirmed MDR/XDR-TB.

An MDR/XDR-TB cohort is defined as a group of patients registered with MDR/XDR-TB during a specified time period (i.e., one year).  The date of the diagnostic DST result and treatment start date should also be recorded in the register but it is the date on which the patient is registered that determines to which cohort the patient belongs. All diagnosed MDR/ XDR-TB patients should be offered treatment. If any patients are left untreated, the reasons for exclusion should be explicitly delineated. Some examples of reasons for exclusion from treatment include:

  • Died before treatment was initiated.
  • Patient unwilling/refuses treatment.
  • Drug supply shortage.
  • Limited health facility access.
  • Clinical reasons.
  • Social reasons.

Cohort analysis of treatment outcomes should be performed on all patients started on treatment DR-TB treatment, regardless of treatment duration. They should be stratified by the case registration groups; further sub-analysis of cohorts according to HIV status, history of previous second-line drug use, DST pattern, and regimen utilised is also useful.

The analysis of MDR/XDR-TB treatment outcomes should be performed 24 months after the last patient enrolment date in the cohort (interim outcome) and at 36 months (final outcome report) All patients should be assigned the first outcome they experience for recording and reporting purposes The analysis at 36 months will be directed at patients who were still on treatment after 24 months of treatment. There is no need to review outcomes of the entire cohort.

Patients still on treatment at the end of a designated cohort treatment period must also be explicitly identified as such, and whether they were culture-positive or negative at the time of the cohort analysis.

 

16.6. Quarterly Report of DR-TB Case Finding

 

The quarterly report is divided into five tables. The tables report the following information:

  • Table 1: Numbers of M/XDR-TB patients detected in the laboratory during the quarter.
  • Table 2: Numbers of Confirmed and not-confirmed M/XDR-TB cases started on treatment during the quarter.
  • Table 3: HIV and ART status of M/XDR-TB patients started on treatment during the quarter
  • Table 4: Proportion of MDR-TB detected, started on treatment and reasons for not starting treatment
  • Table 5: Proportion of XDR-TB detected, started on treatment and reasons for not starting treatment

This report is completed with a delay of one quarter, to allow for culture and DST results to be ready.  For example, DR-TB patients registered during the first quarter of a year (01 January to 31 March) should be reported in the quarter 3 report. In this report the date when the patient first enters the DR-TB register (registration date) is used, and not the date when the patient starts DR- TB treatment.

Preliminary Six-month Interim Outcome Assessment Form

Each defined cohort should have an interim or preliminary outcome report. This report should be developed by the central DR-TB unit or the decentralised DR-TB unit. This report looks at the number of confirmed M/XDR-TB patients with a smear and/or TB culture negative by the sixth month of treatment. If there is no result at month 6, the fifth month result should be considered.

Annual Report of Treatment Outcome of DR-TB Cases

This report shows the final results of treatment by year of treatment started, for all cases as well as for cases stratified by smear and culture results and patient registration category.

Since treatment is of long duration, the results will reflect the management of treatment during a prolonged period in the past. To assess quicker changes in default, failure, deaths etc., optional forms for preliminary outcomes are also available. An electronic system will generate these reports much easier.

 

17. HEALTH CARE WORKERS AND DR-TB

 

17.1. Introduction

 

TB is an occupational disease and HCWs have the legal right for a safe working environment where adequate protection is provided against infection. The onus rests on the employer to provide a safe working environment or alternative employment for HCWs with HIV infection, or other medical conditions leading to compromise immunity, which are therefore at greater risk.

Section 14 of the Occupational Health and Safety Act outlines the general duties of employees, including:

  • The employees must take reasonable care when carrying out work and to co-operate with the employer in creating a safe and health-working environment.
  • The employees must comply with the procedures of the organisation in the interests of safety and health.
  • The employees must report unsafe conditions and incidents or injuries to own self or other employer in the same shift.
  • The employees may not interfere or misuse any equipment that may be provided by the employer to reduce a risk.

Section 8 of the OHSA outlines the general duties of employers, these include:

  • Providing and maintaining a safe and healthy working environment with equipment that is not hazardous to the employees or any other person.
  • Removing hazards where possible.
  • Reduce risk where possible.
  • Control the risks at a tolerable level when the risk is inherent to the business.
  • Monitor the controls to ensure efficacy.
  • Medical surveillance is recommended where certain hazardous exposures occur, notably noise above 85 decibels (dB), chemical and biological agent exposure.
  • Informing employees of the nature and severity of the risks to which they are exposed and the necessary safe working procedures, which include the use of, appropriate personal protective equipment (PPE).
  • Training of employees in safe working procedures and the correct use of PPE.
  • Enforcing compliance with the OHSA.

 

Hazardous Biological Agents Regulations

These regulations were passed in December 2001 and they legally entrench infection control. A hazardous biological agent (HBA) is defined as any micro-organism, cell culture, and human endo-parasite, genetically modified which may cause infection, allergy, toxicity, or create hazard to human health. These are classified into four groups as shown in the following table.

 
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The employer has a duty to classify any HBA not listed in the schedules in the most appropriate grouping.

Section 4 deals with dissemination of information and training and this ranges from understanding the risk of infection to personal protection and engineering controls, the necessity for personal air sampling, medical surveillance, good housekeeping, personal hygiene and safe working procedures.

Section 5 deals with the duties of persons exposed to a HBA focusing mainly on the prevention of uncontrolled release of an agent (in this case M. tuberculosis), adherence to instructions regarding environmental and health practices and the disposal of materials containing the agent (M. tuberculosis) including the decontamination and disinfection requirements.

Sections 6, 7, and 8 places the onus on the employer to ensure that risk assessments are conducted, exposure monitored on a regular basis and medical surveillance of the employees are provided. The medical records of employees and risk assessment must be safely kept for a period of 40 years (Section 9).

Sections 10 and 11 address the control measures for prevention of exposure and the use of personal protective equipment.

Section 15 deals with special measures for health facilities, to prevent spread of infection in instances where patients may present with unknown or undiagnosed infections by implementing regulated infection control measures.

Compensation for Occupational Injuries and Diseases Act, 130 of 1993

The Compensation for Occupational Injuries and Diseases Act provides for compensation of HCWs who contract DR-TB, where the employee has contracted the disease and that such a disease has arisen out of and in the course of his or her employment involving the handling of or exposure to patients with DR-TB. Employees are entitled to compensation if they are injured while working or contract any work-related disease. The types of compensation paid to workers for injuries or diseases are:

  • Medical aid
  • Temporary disablement
  • Permanent disablement
  • Fatalities

An employee or someone on his behalf has the responsibility to report a disease, in writing, to the employer as soon as possible after a doctor’s diagnosis. If they fail to do this within 12 months of diagnosis, he/she will lose any rights to benefits (Section 43).

Employers must complete and submit the Employer’s Report of an Occupational Disease (W.Cl.1) to the Compensation Commissioner within 7 days after an injury and within 14 days of being notified of the diagnosis of a disease. Subsequently, the following reports must be submitted:

  • First Medical Report for an Occupational Disease (W.Cl.22).
  • Claim for Compensation for an Occupational Disease (W.Cl.14).
  • Progress Medical Reports (W.Cl.22) until the worker’s illness is stable.
  • Final Medical Report of an Occupational Disease (W.Cl.26) once the worker is stable.

The Commissioner has the responsibility to acknowledge the receipt of the documentation, register the claims and make the decision to accept liability or not and employer and employee informed accordingly. The Commissioner may refuse to award the whole or a portion of compensation and may hold the employer responsible for medical costs in cases where wilful misconduct or neglect of either the HCW or the employer could be proven.

The COIDA, Schedule 3 lists TB as compensable only in the following work situations:

  • Crystalline silica (alpha quartz) as found in the mines.
  • M. tuberculosis or NTMs (Non-tuberculous, mycobacteria) transmitted to an employee during the performance of health care work from a patient suffering from active open tuberculosis.

 

17.2. Infection Prevention and Control

 

Nosocomial infections are mainly due to delayed diagnosis of TB and confirmation of DR-TB and delayed start of appropriate treatment, which contributes to prolonged infectiousness. Inadequate or delayed isolation of suspects and patients, poor ventilation, lack of respiratory protective equipment and inadequate sputum collection procedures can result in exposure of HCWs, other patients and visitors to infection.

Priorities of Infection Control (for in-patients and out-patients)

There are three levels of infection control measures:

  • Administrative (managerial): Aims to reduce health care worker and patient exposure.
  • Environmental: Aims to reduce the concentration of infectious particles.
  • Personal respiratory protection: Protects HCWs in areas where the concentration of infectious particles cannot be adequately reduced by administrative and environmental controls.

Administrative controls are the most important and together with environmental controls will reduce but not eliminate the risk. Therefore in some high risk areas personal respiratory protective equipment may be used by people entering the high risk areas.

 

17.2.1. Administrative Controls

The first and most important level of infection control is the use of administrative measures to prevent infectious particles from being generated, thereby reducing the exposure of HCWs to M. tuberculosis. Important administrative measures include:

  • Developing and implementing an effective infection control plan to ensure rapid identification, isolation, testing and treatment of DR-TB suspects and patients;
  • Implementing effective work practices;
  • Educating, training and counselling HCWs about TB; and
  • Screening HCWs for TB disease and infection.

17.2.2. Environmental Controls

Environmental controls are the second-line of defence for the prevention of nosocomial transmission of DR-TB. When employed in conjunction with administrative controls, environmental controls can be effectively used to reduce the concentration of infectious particles to which HCWs or patients are exposed. Environmental controls are therefore most important in areas where there may be exposure to highly concentrated infectious particles, such as wards containing XDR-TB patients, wards containing large numbers of infectious MDR-TB patients, sputum induction areas, bronchoscopy suites, laboratories performing culture and susceptibility testing, and autopsy rooms.

The best way of reducing high concentrations of infectious particles in the work environment is through the following principles:

Ventilation

Adequate ventilation may be achieved by:

  • Open windows that maximise natural ventilation and dilute the air (the simplest and least expensive technique).
  • Overhead fans, which may be used to further enhance natural ventilation in settings where windows can remain open.
  • Exhaust fans which control the direction of air flow to prevent contamination in the areas adjacent to the infectious source and open windows and overhead fans are insufficient.
  • Exhaust ventilation systems that provide at least six air changes per hour and prevent contaminated air from escaping into ‘clean’ parts of the facility. The most common way, in which such ventilation can be established is through the use of negative pressure ventilation, in which a room is kept at negative pressure relative to the surrounding area and air is drawn into the room from the corridor and exhausted directly outside.

Air Sanitisation

Air sanitisation is through air filtration or ultraviolet germicidal irradiation (UVGI). Use of UVGI to kill infectious organisms or air filtration methods to remove infectious particles may be an option in some facilities where additional measures need to be implemented to further minimise risk. However, there is little evidence if any to prove the effectiveness of these methods.

Laboratory studies show that M. tuberculosis is killed if the organisms are sufficiently exposed to UV light. For UVGI to be effective, contaminated air must come into contact with the light rays, which may be a major problem in areas where air circulation is poor, and its effectiveness may be limited in areas where the humidity is high or in dusty areas. A final major limitation to the use of UVGI is the inability to assess its effectiveness in the field, especially given the various types of available products, positions in rooms, and variability of room air mixing in various settings.

If UVGI is installed, a regular program of maintenance is essential.  Responsibility should be assigned to ensure that the lamps are dusted periodically and changed at regular intervals. Also, it is important to periodically assess airflow to ensure that airflow patterns maximise the killing of the mycobacteria by UVGI. The quality of UVGI lamps is very important. Usually a good lamp will last 5 000 to 10 000 hours (7 - 14 months), after that, the irradiance drops off rapidly. Irradiance should be measured regularly with a radiometer.  In addition, care must be taken to minimise risk to HCWs and patients who, if inadequately protected, may get skin and eye irritation due to exposure to UV light if not properly installed.

17.2.3. Personal Respiratory Protection Equipment

Because neither administrative nor engineering controls can provide complete protection, the third-line of defence against nosocomial DR-TB transmission is the use of personal protection. This can prevent the wearer from spreading or acquiring the infection, depending on the type of equipment. The only types available for DR-TB are masks and respirators.

Surgical masks

Surgical masks are meant to prevent the spread of micro-organisms from the person wearing the mask to others by trapping large wet particles near the source, which in this case is the mouth. They do not provide adequate protection to the wearer from inhaling infectious droplet nuclei in the air. Masks usually have limited filtration capacity and are loosely fitted over the mouth and nose, allowing free entrance of aerosolised mycobacteria.

Although not the highest priority intervention, disposable masks can be used to reduce aerosols generated from potentially infectious DR-TB patients. They should therefore be considered for use by suspected and confirmed DR-TB patients.

Respirators

Respirators are a type of mask that covers the mouth and nose; they contain special filter material and are designed to fit tightly to the face to prevent leakage between the face and the edge of the mask. Respirators are designed to filter very small particles, including airborne mycobacterium. An industrial mask with a 1µm particle size and a filter efficiency of more than 95% is recommended. Disposable particulate respirators are the simplest and recommended devices to be used.

For a respirator to be effective there must be a tight seal between the mask and the wearer’s face.  If the respirator does not fit correctly, infectious particles will likely follow the path of least resistance and any leak between the face and the mask is a potential entry point for infectious droplet nuclei. Each individual should therefore be “fit tested” to ensure that an appropriate model is used for each worker and minimise the risk of leakages.

Disposable respirators are relatively costly, but may be re-used if well maintained (i.e., proper handling when wearing and removing them, good storage). They should be discarded when they become soiled, wet, or appear to lose their structural integrity, such that a tight seal can no longer be maintained between the edge of the mask and the face.  The main factors responsible for their deterioration are humidity, dirt, and crushing. The durability of these devices varies among designs and products, and the extent of use. There is often a trade-off between durability and cost. If respirators are to be re-used, they should be stored in an open, clean, dry location. Plastic bags should never be used since they retain humidity.

In all facilities training on the correct use of the respirators including putting them on and removing them, there must be procedures for:

  • Selecting respirators for use in the facility.
  • Storing and re-use of the respirators.
  • Evaluating the effectiveness of the use of respirators.
  • Fit testing to ensure correct fit of respirator.

 

17.3. Specific Measures for Prevention of Nosocomial Infection

 

Specific measures for preventing the spread of nosocomial infection:

 

Assign  infection  control  officers  who  will be  responsible for developing, implementing, monitoring and evaluating infection control plans.

Establish a multidisciplinary infection control committee comprising of an infection control officer, microbiologist, medical practitioner/physician, pharmacist, housekeeping supervisor/ manager food service manager, laundry service manager, maintenance manager and hospital manager.

Conduct risk assessments to evaluate the risk for transmission in each area and occupational group within the facility. These must be repeated annually to evaluate the effectiveness of the infection control interventions. Classification of risk for a facility, specific area, occupational group should be based on the profile of TB in the community, the number of infectious TB patients admitted or seen the area or ward, the estimated number of infectious TB patients an occupational category is exposed to, results of PPD test conversions among HCW and possible person-to-person transmission of M. tuberculosis.

  • Develop an infection control plan based on the risk assessment. This should include the development and implementation of policies or protocols for early identification, diagnosis and treatment of patients who may have infectious TB.
  • Provide prompt triage for and appropriate management of patients who may have infectious TB in the outpatient department. Ensure that staff:

      o Vigorously identify patients with active TB disease.

      o Conduct symptomatic screening of symptomatic patients.

      o Develop and use symptomatic screening tool.

      o Maintain a separate waiting area for TB suspects.

      o Provide tissues to cover the mouth when coughing and sneezing.

      o Use surgical masks to prevent spread of infectious particles when coughing or sneezing into the immediate surrounding areas.

  • Promptly initiate and maintain TB isolation for persons who may have infectious TB and admitted in the wards.

      o Include indications for isolation in policies for initiating isolation.

      o Designate a person to decide on initiation and termination of isolation.

      o Implement isolation practices in the facility.

      o Monitor isolation practices.

      o Manage patients who do not adhere to isolation practises.

      o Development and adhere to criteria for discontinuing isolation.

  • Effectively plan for discharge, which should include a confirmed outpatient appointment with the provider who will ensure continuum of care until the patient is cured, placement into case management (DOT) or outreach programmes, ensure systems to supply drugs.
  • Plan, install and evaluate ventilation and other engineering controls to reduce the risk of exposure to M. tuberculosis.
  • Plan, implement, maintain and evaluate a respiratory protection programme.
  • Educate and train HCWs about TB, effective methods for preventing transmission of infection and the benefits of medical surveillance programmes.
  • Develop and implement a programme for periodic counselling and screening for HCWs for latent infection and active disease.
  • Ensure that all HCWs know the importance of compliance to infection control interventions to minimise risk of exposure to infectious agents.
  • Offer alternative employment to HCWs who have a health condition that compromises cell mediated immunity when placed in high risk areas.
  • Ensure that information provided by HCWs regarding their HIV status is treated confidentially.
  • Ensure prompt evaluation of nosocomial transmission, including PPD test conversions or active TB in HCWs, epidemiological association of cases among workers, patients, contacts of patients or HCWs who have TB but were not promptly identified and isolated. The aim of epidemiological investigation is to:
  • Determine the likelihood that the transmission of and infection with MDR-TB have occurred in the facility.
  • Determine the extent to which M. tuberculosis has been transmitted.
  • Identify people who have been exposed and infected, enabling them to start treatment early.
  • Identify factors that could have contributed to the transmission and infection and to implement appropriate interventions
  • Evaluate the effectiveness of any interventions that are implemented and to ensure that exposure to and transmission of M. tuberculosis has been terminated.
  • Report all people confirmed with DR-TB and ensure adequate discharge follow up and the continuum of care.

 

17.4. Conducting Risk Assessment

 

The risk of infection with TB depends on the severity of disease in the source case and on prolonged, intensive exposure to this case. It follows, therefore, that all HCWs are not at equal risk of acquiring infection, and that for many cadres of HCWs the risk is almost equal to that of the general community. The following categories of risk may be summarised as follows:

 

 

Risk category

 

Definition

 

High risk

 

HCWs in prolonged close contact with infectious (smear-positive) MDR- TB cases (e.g., nursing staff and other medical staff in MDR-TB hospitals and wards).

 

HCWs involved in aerosol-producing procedures, e.g. pulmonary physicians, respiratory technicians and other medical staff performing bronchoscopy, sputum induction, tracheal intubation, aerosolised pentamidine therapy and autopsy procedures.

 

HCWs who are immuno-compromised and who are involved in regular

MDR tuberculosis patient management.

 

Medium risk

 

HCWs in primary health care centres who are involved in sputum collection procedures from tuberculosis suspects.

 

HCWs in prolonged close contact with retreatment tuberculosis patients, especially if such patients have a history of more than one previous treatment episodes and a record of poor adherence.

 

Low risk

 

HCWs in primary health care centres involved in management of tuberculosis patients on therapy.

 

Health care facility support staff, such as porters, cleaners and administrative staff.

 

HCWs in general hospitals and community health centres.

 

17.5. Infection Control Plans

 

The development of the infection control plan is based on the results of the risk assessment. The plan should be specific for each area and occupational group in the facility. A facility may have a combination of low, intermediate, and high-risk areas or occupational groups at the same time.

Irrespective of the level of risk, the following principles must apply:

  • Provide on-going education and training on the transmission and pathogenesis of TB, the consequences of DR-TB, the infection control measures implemented in the facilities and importance of compliance to these.
  • Stress a continuous awareness of risk situations and avoidance thereof.
  • Promote HIV testing due to the increased risk of acquiring tuberculosis among HIV- positive people.
  • Offer alternative employment to staff who are immuno-compromised.
  • Implement universal infection control procedures (including safe waste disposal) in all health care facilities.
  • Strictly adhere to cough hygiene.
  • Collect sputum in an open area or cough booths where available.
  • Ensure that in-patients who are coughing are in a single ward with good outside ventilation. The door must remain shut and the windows open as far as possible if the ward is not under negative pressure.

17.5.1. Cough Hygiene

The prevention of DR-TB focuses on both the infectious patient (and infected material) and on the HCW at risk of getting infected.

All patients should be instructed to cover their mouths and noses with a handkerchief, surgical mask or a tissue when coughing and other forms of forced expiration. After use, these materials should be disposed of in small plastic or paper refuse bags, which should be regularly changed and discarded into larger refuse bags for incineration. Alternatively, 5% concentrations of an iodine-containing solution or a hypochlorite solution containing 10 000 ppm active chlorine should be used for disinfection and disposal.

HCWs should wear particulate respirators which are impermeable to droplet nuclei when nursing patients or collecting sputum.

17.5.2. Sputum Collection

Collection of sputum specimens should take place in the open air on the sunny side of the ward. A special veranda should be built for this purpose in the case of bad weather. The correct procedure for sputum collection must be implemented and patients must be observed during the collection. The HCW should:

  • Stand directly behind the patient so as to minimise droplet infection exposure.
  • Ensure that the patient holds the container as close as possible to the mouth.
  • Ask the patient to close the container immediately after expectoration.
  • Ensure that all sputum jars are labelled prior to collection taking place to minimise handling of specimens.
  • Wear gloves when handling specimens.
  • Wash hands with appropriate disinfectant if hands have contacted sputum without gloves.
  • Ensure that the lids of sputum containers are properly closed to avoid spillage.
  • Follow correct procedures if breakage or spillage occurs: gloves should be worn, spillage covered with paper towel and wiped up and area cleaned with warm water and detergent, area then should be wiped with hypo-chlorite solution.
  • Ensure that all specimens are placed in a plastic bag.

The HCW should also follow these protective measures:

  • Wear disposable apron, gloves  and  particulate filter respirators during  cough inducing procedures.
  • Follow correct hand washing before and after each patient contact.
  • Wash all instruments in the ward to remove respiratory secretions before being sent to CSSD.
  • Ensure that all resuscitation equipment is in order and no mouth-to-mouth resuscitation is conducted.
  • Supply each patient with a disposable sputum mug with a lid and sputum mugs must be replaced three times per day.

17.5.3. Isolation Practices

Isolation wards for the following categories of patients must be available in the MDR-TB hospitals to prevent cross infection with different or new strains of M. tuberculosis:

  • New patients admitted into a ward must be isolated from those who have been on treatment for more than two weeks.
  • MDR-TB patients must be isolated from XDR-TB patients.
  • Children should be kept separate from adults.
  • Very sick patients should be admitted in a ward separate from stable patients.

In hospital settings, isolation may be stopped after a patient has three negative sputum smear microscopy results taken on three separate occasions, and shows maintained clinical improvement, including resolution of cough. If sputum smears in MDR- and XDR-TB patients remain consistently positive but repeated sputum cultures are negative, consideration can also be given to removing them from isolation if they have also shown clinical improvement. Positive smear and negative culture may be due to dead bacilli visualised during microscopy.

17.5.4. Medical Surveillance Programme

Medical surveillance programmes are in existence for all employees. The objectives of surveillance programmes are to:

  • Establish the baseline of TB infection status of the workers;
  • Identify those with latent TB infection and offer them preventive therapy to decrease their risk of developing active TB;
  • Identify workers with active TB disease and initiate TB treatment immediately;
  • Document conversion rates, those who are initially negative and then later become positive;
  • Investigate the possible source of infection for all converters;
  • Notify district and provincial health authorities; and
  • Monitor the effectiveness of the infection control program.

The elements of the medical surveillance programme include the following:

  • Pre-placement.
  • On-going surveillance.
  • Exit.
  • Post-employment.

Baseline Health Assessment of Employees

This includes medical history of the employee relating to past tuberculosis disease, BCG vaccination status, underlying medical conditions which may increase susceptibility of the employee to tuberculosis and previous contact with people/patients with confirmed tuberculosis.

Sputum microscopy and culture must be done for all symptomatic employees, including the following baseline tests:

  • Chest X-ray
  • Mantoux tuberculin skin test (TST)
  • Lung function tests
  • Glucose blood and urine levels
  • Hepatitis B

Provider-Initiated Counselling and Testing (PICT)

HCWs should be counselled about the risks of working with DR-TB patients, the necessary precautions that must be taken, and the substantially increased risks if they are, or become, HIV positive. Voluntary HIV counselling and testing should be offered on the basis that alternative working environments will be sought for those who are HIV positive and who wish to minimise their risk of infection with DR-TB. Any disclosure of HIV status should be voluntary, made to a designated health care provider, and held in the strictest confidence.

On-going Surveillance

Table XXXIII shows the recommended frequency of on-going medical surveillance based on the facility, and activity risks

 
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HCWs should declare information on their health status in the form of answers to specific questions relating to the early signs and symptoms of tuberculosis. These include cough for longer than three weeks, weight loss (i.e., unexplained loss of 10% or more of body weight), anorexia, night sweats and the frequent occurrence of colds or other respiratory infection episodes in recent weeks. When these are present the individual must be investigated for TB.

The following tests should be conducted routinely:

  • Full size chest x-ray examinations must be conducted for evidence of recent tuberculosis disease. Individuals exhibiting changes on serial examination should be evaluated for tuberculosis, both clinically and microbiologically.
  • Tuberculin skin test to detect converters. Individuals with TST reactions of <10mm should be re-tested. Strongly positive reactors with skin test diameters of >15 mm and recent skin converters should be evaluated clinically and microbiologically.

Post-exposure Monitoring

If any HCW has been exposed to an infectious DR-TB patient for more than two hours or to aerosolised infected material (e.g. in autopsy rooms), their monitoring files should be consulted and their chest x-ray and TST records reviewed. The HCW should also be carefully monitored clinically. Eight weeks after the exposure episode, a chest x-ray examination should be performed, together with a TST in cases where the previous reaction diameter was <10 mm.

Record Keeping

Each worker should have a confidential disease-monitoring file in which screening procedures for tuberculosis, the minimum physical examination and tests to be conducted, as well as other health-related data, including records of results of tests conducted and updates of any changes in the health status of the worker are recorded.

Other essential information that should be recorded includes:

  • Name, job title, position, placement in facility, shift and hours worked.
  • Date of employment in the health facility.
  • Results of baseline assessment.
  • Results of regular ongoing assessment.
  • Record of reported TB exposure.
  • Results of post-exposure screening.
  • Management plans for treatment and follow-up of workers with confirmed disease
  • Management and follow-up of workers on preventive therapy.
  • Counselling provided to the HCW.

As a general rule, HCWs who contract DR-TB through work should not be dismissed on the basis of incapacity at the expiry of their paid sick leave. A fair procedure should be followed, including an investigation into the nature and extent of the incapacity, the effects of treatment, and alternatives to dismissal. This would usually result in extended sick leave being granted. The provision of extended sick leave to an employee, at least on an unpaid basis or at less than full pay, in order to undergo treatment for MDR-TB would be regarded as fair. Fairness can only be tested in the circumstances of each particular case, and factors such as disability insurance and ill-health retirement benefits as alternatives would be relevant.

 

1. INTRODUCTION

 

The aim of this document is to outline an approach to the management of a case of meningococcal disease, in order to strengthen the knowledge of the organism, the disease, the management of cases and contacts and encourage an appropriate public health response.

The key sources of information in this document were the following:

  1. WHO Fact sheet No. 141 Meningococcal Meningitis, May 2003
  2. Guidelines for the public health management of meningococcal disease in the UK PHLS September 2002.
  3. Control of Communicable Diseases Manual, 18th edition ed: David Heymann, 2004 American Public Health Association
  4. The Craigavon Infection Control Manual. N Damani/J Keyes
  5. Morbidity and Mortality Weekly Report (MMWR)- Prevention and Control of Meningococcal Disease, May 27th 2005.

 

2. CAUSATIVE AGENT

 

Vieusseaux first described “cerebrospinal fever” in 1805 when an outbreak swept though Geneva, Switzerland. Reports throughout the 19th century confirmed the episodic, epidemic nature of the disease tending to affect young children and military recruits living in barracks. The causative agent, Neisseria meningitidis (the meningococcus), was identified in 1887 when Weichselbaum reported finding a new organism in the cerebrospinal fluid of six post-mortem cases during an epidemic. He called the organism “diplococcus intracellular meningitis”, to distinguish it from the intracellular diplococcus gonorrhoea identified by Neisser in 1879.

Meningococci are classified according to the characteristics of their polysaccharide capsule. Thirteen serogroups of N. meningitidis have been identified and five (A, B, C, W135 and Y) are recognized to cause epidemics. The pathogenicity, immunogenicity, and epidemic capabilities differ according to the serogroup. The identification of the serogroup is important for surveillance purposes and decisions about public health responses.

 

3. RISK FACTORS

 

3.1 The Agent

 

Neisseria meningitidis (the meningococcus) commonly colonises the nasopharynx without causing disease. Strains associated with invasive disease have acquired certain virulence factors, which are, as yet, poorly understood.

 

3.2 The Host

 

Medical conditions that commonly predispose individuals to invasive disease include:

  • Deficiencies of the terminal components of the complement system
  • Functional or anatomical asplenia

 

3.3 The Environment

 

The risk of infection is related to the nature and duration of contact. Household contacts of a case of meningococcal disease have a 400 - 800 fold increased risk of infection compared to the general population. Household overcrowding, coexisting viral infection and especially exposure to tobacco smoke also increase the risk. However despite perceived risk, only 0.5% of cases are associated with a household contact. When fairly large numbers of first year university/ technikon students, military or police recruits live together in residences, hostels or barracks they also have a 3 times higher incidence of disease than in the general population.

 

4. PATHOGENESIS OF DISEASE

 

Humans are the only natural host of meningococcus. The transmission of N. meningitidis is directly from person to person by droplet spread or intimate contact with nasopharyngeal secretions. Nasopharyngeal carriage of meningococci is much more common than invasive meningococcal disease. Nasopharyngeal carriers rather than patients with meningococcal disease are generally the source of new infections.

Studies in the United States and the United Kingdom show that between 5-10% of the population carry N. meningitidis at any given time. Carriage rates increase from about 2% in children under five to 25% in the late teens. Carriage is increased in smokers, overcrowded households, new military recruits and in first year residents of university hostels. Asymptomatic carriage of meningococcus is an immunising event and systemic immunity (serum antibodies) develops about 14 days after acquisition of meningococci. Invasive disease develops in the minority of people who carry meningococcus and usually occurs in the first 3 to 5 days after acquisition of meningococci. In these individuals the organisms in the nasopharynx evade the immune system and this result in blood stream invasion and dissemination especially to the brain.

The incubation period is 3 - 4 days (range 2 to10).

 

5. EPIDEMIOLOGY OF MENINGOCOCCAL DISEASE

 

5.1 Global picture

 

Meningococcal disease occurs sporadically in small clusters throughout the world. In temperate climates there is a seasonal pattern to disease with an increased incidence in winter and early spring. Changes in patterns of disease and serogroups are characteristic of meningococcus and highlight the importance of ongoing surveillance. Serogroups B and C account for a large majority of cases in Europe and the Americas. Serogroup C is also responsible for large outbreaks in Africa, South America and Asia. In the African meningitis belt serogroup A predominates with smaller epidemics caused by serogroup C and recently with serogroup W135. Serogroup A is usually the cause of meningococcal disease in Asia. In South Africa the pattern of meningococcal disease is characterised by sporadic cases throughout the year with occasional small clusters and a definite seasonal increase in winter and early spring.

 

5.2 The African Meningitis Belt

 

The highest burden of meningococcal disease occurs in the “Meningitis Belt”, an area stretching from Senegal in the west to Ethiopia in the east (Figure 1). This region has an estimated total population of 300 million people and is characterized by particular climatic and demographic conditions. During the dry season (December to June) dust storms increase the risk of upper respiratory tract viral infections. In addition, large numbers of people travel back and forth to the Hajj and to regional markets, so that crowding is exacerbated. Serogroup A diseases predominates and seasonal incidence rates vary between 1 and 20/ 100 000 annually. Every 8 to 12 years, with the waning of herd immunity, attack rates increase to 100 to 800 per 100 000 population with some communities reporting rates as high as 1000 per 100 000. The spread of a new epidemic-prone strain of serogroup W135 has been linked with the Hajj pilgrimage, causing high morbidity and mortality, particularly in West Africa. Following these Hajj- related outbreaks, since 2000, vaccination with a quadrivalent meningococcal vaccine has become mandatory for travellers to Saudi Arabia.

During endemic periods the highest attack rates are observed in young children, while during epidemics, older children, teenagers and young adults are also affected. In 1996, the meningitis belt experienced the largest recorded outbreak of epidemic meningitis in history, with over 250 000 cases and 25 000 deaths reported. Between that crisis and 2004, over 223 000 new cases of meningococcal meningitis were reported to the World Health Organization. In 2002, the outbreaks occurring in Burkina Faso, Ethiopia and Niger accounted for about 65% of the total cases reported in the African continent.

 
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5.3 Meningococcal Disease in South Africa

 

It is important to recognise the difference between the epidemics that occur in the “meningitis belt” and the sporadic seasonal increase in cases seen in South Africa. Increases in sporadic cases and outbreaks of meningococcal disease tend to occur in late winter and early spring in South Africa and outbreaks may especially occur in mines, correctional and detention facilities, academic institutions, and displaced communities. The total number of cases notified in South Africa has decreased steadily from around 2000 cases in 1972 to less than 500 cases in 2005. Under-notification after laboratory confirmation is the key factor.

The National Institute for Communicable Diseases (NICD) data on laboratory-confirmed cases indicate high incidences in the Gauteng and the Western Cape provinces. The incidence rates as reported are highest in the less than five-year-old age group. In the Western Cape serogroup B tends to be the most common serogroup. Outbreaks have been linked to the mining areas of Gauteng and North West provinces with serogroup A, and to a lesser extent, serogroup C predominating. As identified by the Respiratory and Meningeal Pathogens Reference Unit (RMPRU) of the National Institute for Communicable Diseases (NICD), since 2003, an increase in the number of cases of serogroup W135 has been reported in Gauteng province. This has been associated with a decrease in serogroup A disease.

 

5.4 Carriage of Meningococci

 

About 5 to 10% of people carry meningococci in their nasopharynx, very few will become ill due to the organism to some extent depending on risk factors mentioned above. Transmission of meningococci is higher in closed populations such educational institutions, prisons, army camps and is facilitated by climatic and living conditions such as winter, crowding and poor ventilation. In households and closed populations the carriage rate is significantly higher (20-70%). Carriage is more often in adolescents and young adults, lasts about 3 to 4 months and results in an immunological response and generates herd immunity.

 

6.CLINICAL FEATURES

 

Meningococcal disease presentation may be non-specific in the early stages and a high index of suspicion should be maintained. Disease presentation may also be acute and rapidly progressive. Key symptoms such as fever, headache and neck stiffness may be absent or slow to develop, particularly in young infants with meningococcal meningitis. Only 50% of patients present with meningococcaemia, and a rash is usually but not always present.

 
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6.1 Clinical features of meningococcal meningitis

 

Although sudden onset of illness with rapid progression to shock does occur, more commonly meningococcal disease is of a less dramatic nature and therapy is often effective. The disease may present initially as a flu-like illness with fever, malaise, headache, muscle pain, nausea or vomiting. Features of disease may include the following:

  • Neck stiffness
  • Photophobia
  • Prostration
  • Vomiting
  • Impaired consciousness
  • Hypotension
  • Raised intracranial pressure

In infants particularly (less than 1 year old), the onset may be insidious and classical signs absent. The diagnosis should be suspected in young children in the presence of vomiting and fever, irritability, and, if still patent, raised anterior fontanel tension. With early diagnosis and appropriate management, the mortality rate of meningococcal meningitis is between 5% and 10%, however persistent neurological damage occurs in about 10 to 20% of survivors.

 

6.2 Clinical features of meningococcal septicaemia

 

disease may present initially as a non-specific upper respiratory illness e.g. pharyngitis, followed by fever, headache, joint pain, vomiting, neck stiffness and photophobia. The haemorrhagic rash is a distinctive feature of meningococcal septicaemia and is indicative of severe disease, where the mortality rate may be as high as 50%. Although the rash is typically haemorrhagic or petechial in nature, it can also resemble the maculopapular rash of viral infections. In many cases the petechial rash will start on the buttocks, back of the legs and conjunctivae. The rash typically does not blanch on pressure and the petechiae may be difficult to see in the early stages, particularly in dark skin (checking the conjunctivae, soles and palms may in such cases reveal the petechiae). Remember the rash may be absent.

The onset of illness can be very rapid and, in 5-10% of cases, the disease may be fulminant within a few hours of onset. Cases may present with hypotension, shock, confusion, coma and death. Disseminated intravascular coagulation (DIC) may also occur. Such patients often respond poorly to antimicrobials, steroids, or vasopressor agents and usually require admission to an intensive care unit.

 

6.3 Clinical Differentiation

 

The clinical differential diagnosis of bleeding and fever with or without neurological signs includes:

  • Viral haemorrhagic fevers (notably Crimean Congo Haemorrhagic Fever for South Africa)
  • Severe tick bite fever
  • Rift Valley fever
  • Severe sepsis – caused by Gram-negative or Gram-positive bacteria
  • Fulminant malaria
  • Fulminant hepatitis
  • Advanced HIV infection with AIDS related complications
  • Leukaemia and other malignancies.

 

7. LABORATORY INVESTIGATIONS

 

7.1 Blood Culture

 

Blood must be collected in blood culture specimen bottles using strict aseptic technique (s) from all suspected cases and sent to the laboratory as quickly as possible. Specimens should reach the laboratory within 3-4 hours and not beyond 24 hours. Ideally two sets (taken from different sites and at different times) of blood cultures should be submitted prior to antibiotic therapy but treatment should not be delayed in order to obtain specimens. Even in cases of meningitis, blood for culture must be collected. About 1-5 ml of blood is needed in children and 5-10 ml in adults. Ideal volumes may vary depending on the blood culture system in use. Laboratories can be consulted for optimal blood volumes. Specimens must be kept at room temperature (not in a refrigerator) whilst awaiting transport to the laboratory.

If the clinical picture is compatible with meningococcal septicaemia, do not delay giving penicillin or ceftriaxone if laboratory confirmation cannot be immediately obtained. Early use of antibiotics in this setting can be lifesaving.

 

7.2 Cerebrospinal fluid (CSF)

 

Cerebrospinal Fluid (CSF) Examination and Culture

A lumbar puncture should be performed for suspected meningitis where no contraindications exist. In the primary care setting a lumbar puncture does not need to be done. Emphasis should be placed on administration of lifesaving care and urgent transfer to a referral hospital.

In adults

Where lumbar puncture is not contraindicated and can be safely performed; this should be done, as it provides valuable diagnostic information on the specific cause of meningitis.

In Children

The clinical signs indicating the presence or absence of raised intracranial pressure in children are notoriously inaccurate and should never be relied upon. A lumbar puncture is not indicated in a child with clinical meningococcemia even if meningism is found. A lumbar puncture should never be done if there is any suggestion of impaired level of consciousness. 

A blood culture and urgent treatment based on clinical assessment is more appropriate.

Contraindications to lumbar puncture in adults

Lumbar puncture is contraindicated in patients with raised intracranial pressure. Classical signs of RAISED INTRACRANIAL PRESSURE such as bradycardia, papilloedema or hypertension are often absent, especially in children. Neurological imaging, e.g. CT scanning should be considered before doing a lumbar puncture in all patients who have signs of:

  • Raised intracranial pressure (impending cerebral herniation) with focal neurological signs or papilloedema.
  • New onset seizures and an abnormal level of consciousness should prompt a careful examination to exclude raised intracranial pressure.
  • Intracranial pathology with mass effect. Signs include:

        •Deep coma (Glasgow Coma Scale (GCS) less than 13),

        •Sudden deterioration of level of consciousness,

        •Decerebrate or decorticate posturing

        •Neurogenic hyperventilation

        •Unequal dilated or poorly reactive pupils and

        •Absent doll’s eye reflex

Lumbar puncture should also be delayed in patients with haemodynamic instability (low blood pressure or uncorrected bleeding tendency).

 
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Transport and processing of CSF

The CSF should be kept as close to body temperature as possible whilst awaiting transport. The meningococcus is highly susceptible to heat, cold and direct sunlight. So the specimen should not be refrigerated, left on the window sill or transported in a hot car boot!

Tests to be requested on the cerebrospinal fluid (CSF) include:

  • Protein and glucose determination (a blood glucose should also be done)
  • Direct microscopy (cell count and Gram stain)
  • Culture and antibiotic susceptibility testing

If HIV infection is suspected an Indian ink stain and cryptococcal latex antigen test for cryptococcal meningitis should also be requested.

 
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The typical findings in CSF of adults may include the following:

  • White blood cell count: often above 1000 cells/mm3 with 60% polymorphonuclear cells*
  • Protein level: >0.80g/l (should be <0.45 g/l in normal CSF)
  • CSF glucose concentration 2/3 lower than blood glucose
  • Gram stain showing Gram-negative diplococci (intra and/or extracellular).

* may be low in immunocompromised patients

 

7.3 Aspirates from other normally sterile sites specimens, skin rash aspirate or biopsy culture

 

should be taken as clinically indicated, but if culture from these sites yield meningococci, this would confirm invasive disease.

 

7.4 Oropharyngeal swabs

 

Oropharyngeal swab specimens are less likely to be affected by prior antibiotic use, and may assist in making the diagnosis when used in conjunction with other laboratory test results and the clinical characteristics of presenting disease. In the absence of isolation of meningococci or positive PCR results from normally sterile sites, a positive culture from an oropharyngeal swab does not confirm disease, and may only reflect asymptomatic carriage.

Non-culture diagnostic tests

Polysaccharide antigen testing

Rapid detection tests for bacterial antigen using latex agglutination may give false positive and false negative results and should be interpreted with caution. They should not be routinely requested on all CSF specimens but reserved for certain circumstances e.g. patients in whom antibiotic therapy has been given prior to lumbar puncture, which may result in a negative culture.

PCR (polymerase chain reaction)

PCR-based assays for detecting specific DNA sequences of N. meningitidis are available at the meningococcal reference laboratory at the National Institute for Communicable Diseases, Johannesburg. The test has been validated and performs well for CSF and blood specimens; however, specimens from other normally sterile site can also be tested. Whole blood (EDTA or other unclotted specimen) and/or CSF specimens can be sent for PCR if cultures are negative, if the diagnosis is suspected and facilities for culture are not available, or if specimens are taken after commencing antibiotics. Direct communication with the laboratory in Johannesburg (011 555 0315/ 0327/ 0316) will assist in the urgent transportation of the specimen and expedited testing.

Skin scrapings/impression smears

The practice of performing skin scrapings and impression smears for Gram stain from the petechial/purpuric site is not recommended. A negative Gram stain does not exclude the diagnosis. In addition (Neisseria) species may form part of normal skin flora and will resemble meningococci on Gram stain thus yielding false positive results.

Post-mortem specimens

Post-mortem specimens can be taken to confirm an ante-mortem suspected diagnosis of meningococcal disease, or may be a way of establishing the cause of illness and death in cases with undiagnosed infection. These specimens may be especially useful for sudden, unexplained deaths, especially in infants and young adults. Spleen and heart blood cultures can be submitted and processed similar to routine blood cultures, especially if performed as soon as possible after death (ideally within 15 hours). Post- mortem CSF can also be submitted to a microbiology laboratory for processing. Ideally specimens should be taken at the start of the post-mortem examination, and every effort should be made to avoid contamination. Non-culture diagnostic tests may be very important if meningococcal disease is suspected, and specimens should be submitted for PCR in addition to culture (see above for details).

 

8 INFECTION CONTROL

 

Infection control measures for cases of meningococcal disease include:

  • Isolation of patients in a side ward with standard precautions AND respiratory droplet precautions. These patients may be transferred when necessary to a general ward 24-48 hours after receiving adequate treatment with a drug that will reliably eliminate nasopharyngeal carriage (ceftriaxone/cefotaxime). Patients on penicillin alone can only be moved from isolation after being given chemoprophylaxis to eradicate nasopharyngeal carriage.

 

  • Standard (universal) precautions must always be observed:

       – Gloves should be worn for all contacts with blood, body fluids, secretions and excretions (except sweat); non-intact skin and mucous membranes.

       – Hand washing with medicated soap before and after any patient contact. Hand washing before and after donning gloves.

       – If procedures are likely to generate splashes, eye protection, a mask and impermeable gowns/aprons should be worn. 

       – Needles and other sharps should not be re-capped and must be disposed of in designated puncture-resistant sharps containers.

  • Respiratory droplet precautions (used in addition to standard precautions as above):

       – Isolate the patient in their own room

       – Use standard surgical masks when working within one meter of the patient.

       – Use eye protection if exposed to oral or respiratory secretions.

       – Use a closed suction system.

 

11.2 How to Remove an N95 Mask?

 

  • Wash hands using soap and water
  • Avoid touching the front part of the mask with wet and greasy hands
  • Support the front part of the mask and remove by lifting the top and then the bottom elastic over the head.

Respirators are disposable but can be re-used repeatedly over the course of an 8 hour shift for up to 5 days, if they are properly stored in a clean dry place, used by one person, not soiled or wet, do not contain holes, tears or damaged in any other way. If the respirator has been breached it must be disposed of and a new respirator should be used.

Things to avoid

  • Do not write on the mask.
  • Do not store in a plastic bag
  • Do not leave mask hanging around your neck.
  • Do not fold and do not share

 
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Note: isolation of patients is recommended for at least 24-48 hours after adequate antibiotic treatment (for elimination of carriage) and patients should not be admitted into an overcrowded ward.

If a side ward Is not at all possible, decrease the risk of spread by ensuring Standard (universal) precautions, drawing the curtains around the bed and keeping the distance between the bed of this patient and the others more than I meter.

 

9. TREATMENT OF PATIENTS WITH MENINGOCOCCAL DISEASE

 

MENINGOCOCCAL DISEASE IS A MEDICAL EMERGENCY AND TREATMENT SHOULD NOT BE DELAYED.

Pre-hospital treatment consists of antibiotics (ceftriaxone/cefotaxime) and fluid resuscitation of shocked patient before moving them from the primary care facility. Treatment should not be delayed due to difficulties in performing lumbar punctures, delays in neuro-imaging or unavailability of results. The choice of antibiotics is determined by their ability to adequately penetrate the cerebrospinal space and the susceptibility of the organism. The recommended first line drug of choice for proven meningococcal septicaemia or meningitis is IV benzyl penicillin for 5-7 days. However, wherever possible, ceftriaxone or cefotaxime should always be used for empiric therapy for suspected bacterial meningitis (Table 2). Patients with proven meningococcal meningitis and established significant beta-lactam allergy should receive chloramphenicol.

 
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* Vancomycin should be added where high level penicillin resistance is anticipated (MIC≥2).

** Listeria monocytogenes is a relatively uncommon cause of bacterial meningitis in SA but should be considered. This organism is inherently resistant to cephalosporins and requires ampicillin ± gentamicin for effective treatment.

 

10. PUBLIC HEALTH RESPONSE

 

Every suspected case of meningococcal disease should prompt an urgent response to include:

  • Immediate telephonic notification to local health authority by health care worker in the facility (nurse or clinician); followed by written notification
  • Rapid investigation of the case
  • Classification of the case according to case definitions (see below)
  • Identification of close contacts for all confirmed and probable cases
  • Provision of required post exposure prophylaxis to close contacts
  • Identification of other cases in same institution or community that may suggest a cluster

 

10.1 Case definitions

 

Classification of cases using the following case definitions will determine the need for public health action. Confirmed and probable cases all require a public health response as outlined below.

10.1.2 Cases requiring public health action 

Confirmed case

Clinical diagnosis of meningitis, septicaemia or other invasive disease (e.g. orbital cellulitis, septic arthritis)*

AND at least one of the following:

  • Neisseria meningitidis isolated from a normally sterile site
  • Gram-negative diplococci in a normally sterile site
  • Meningococcal antigen in blood, CSF
  • Meningococcal DNA in normally sterile site

*Meningococcal conjunctivitis should also be managed as per invasive meningococcal disease

Probable case

Clinical diagnosis of meningitis and/or septicaemia where the public health physician, in consultation with the physician and microbiologist, considers that meningococcal infection is the most likely diagnosis.

NOTE: These definitions should be used by public health personnel in assessing requirements for further public health action. Health care workers are not required to classify cases as above but should rather notify ALL patients in whom a diagnosis of meningococcal disease is being considered. DO NOT WAIT for laboratory confirmation before notifying.

 

10.2 Cases not requiring public health action

 

Possible case

Clinical diagnosis of meningitis or septicaemia or other invasive disease where the doctor or nurse concerned, in consultation with the clinician and microbiologist, considers that diagnoses other than meningococcal disease are at least as likely. This category includes cases that may have been treated with antibiotics but whose probable diagnosis is viral meningitis.

In such cases, prophylaxis for contacts is not indicated.

Infection in non-sterile sites

Isolation of meningococci from sputum or from swabs taken from nasopharynx or genital tract is not by itself an indication for public health action as asymptomatic carriage in the respiratory and genital tract is common. However, when assessed together with other clinical and microbiological parameters, a positive throat swab may increase the index of suspicion of a probable case, especially if the isolate is a virulent strain. Meningococcal pneumonia alone is not an indication for public health action but may carry a low risk of transmission in healthcare settings especially to the immunocompromised. In SA, the majority of cases of meningococcal pneumonia reported to the RMPRU have been accompanied by evidence of invasion in blood or CSF and these would always require public health action. The response to a single case can usually be managed between the hospital staff and the local health department concerned based on the guidelines/ policy available. Consultation with a medical microbiologist and infectious disease specialist is recommended.

Management of contacts of a case requiring public health action

About 97% of cases are sporadic and have no identifiable contact. Meningococcal disease rarely spreads directly from person to person. The disease is the result of a complex interaction of the bacteria, the environment and the host. While the risk even for close contacts of cases is low, it is 400-800 times higher in people who live in the same household as the index case. This is mostly likely to be due to infection spreading in the household from an asymptomatic carrier to another family member rather than from the index case.

The increased risk in household members compared to the general population is thought to be likely due to genetic susceptibility in the family, increased exposure to virulent bacteria and environmental factors such as exposure to tobacco smoke. The risk is highest in the 48 hours after the index case presents. Close surveillance for household and intimate contacts is important so that early signs of possible disease, such as fever, are recognised and treated.

Indications for chemoprophylaxis (Defining close contacts)

The following information is based on published studies of disease incidence and risk. It must be remembered that taking drugs carries a risk of side effects which, although small, can be serious and may be greater than the risk of disease.

Chemoprophylaxis should be offered to close contacts of confirmed/probable cases, irrespective of vaccination status (see case definitions above).

Close contacts requiring prophylaxis include:

  • Those who have had prolonged close contact with respiratory secretions of the case in a household type setting during the seven days before onset of illness. Examples of such contacts would be those living and/or sleeping in the same household, those such as pupils, students, members of the military or police sleeping in the same dormitory or, sharing a kitchen where they prepare food together or sharing the same bathroom in a hostel, barracks or residence.
  • Those who have had transient close contact with a case require prophylaxis only if they have been directly exposed to large droplets or secretions from the respiratory tract within 10 days of a case becoming ill or admitted to hospital. This also applies to health care staff and ambulance or emergency personnel.

Prophylaxis is NOT routinely indicated following a single case for (unless already identified as close contacts as above):

  • All staff and children attending same nursery school or crèche
  • All pupils or students in same school or classroom or tutorial group
  • All work or school colleagues
  • All friends
  • All residents of nursing/residential homes
  • Dry kissing on cheek or mouth (Intimate kissing would normally bring the contact into the respiratory contact category).
  • All individuals attending the same social function
  • All passengers travelling in same plane, train, bus, or car

Household contacts and overnight visitors

Those who live in the same household or are intimate contacts of the index case should all receive chemoprophylaxis. Chemoprophylaxis should be given as early as possible, preferably within 24 hours of identification of a case. It may still be effective if given up to 10 days after the presentation of the index case if delays are unavoidable. Overnight visitors to the home of the index case within 7 days before the onset of illness should also be given prophylaxis.

Educational settings Following a single case, chemoprophylaxis is recommended for close contacts only (see definitions above). This will usually include close friends who may share eating utensils or meet the other criteria for a close contact. Usually this does not mean the whole class, but only selected individuals within the class. It may be more difficult to define a close contact amongst younger children in preschools/crèches but where possible post exposure prophylaxis should be limited to those who meet these criteria. Clusters, even in preschools are rare. The naturally immunizing strains in the nasopharynx which provide protection and may be eradicated by indiscriminate use of chemoprophylaxis.

Workplace

The risk in the workplace is generally even less than in educational settings. Chemoprophylaxis is not recommended except in exceptional circumstances i.e.: individuals meeting the criteria for “close contacts” of the case.

Passengers on public transport

Transient contact such as sitting next to a case before an acute illness occurred, on a bus, train, taxi or aeroplane does not usually pose a special risk and does not justify routine prophylaxis. These situations should be discussed with experts and managed accordingly. Prophylaxis on aeroplanes and other public transport is sometimes given to passengers immediately adjacent, in front and behind the index case, especially if travelling times are prolonged. Passengers should also receive an information leaflet with information regarding signs and symptoms and informed to seek immediate medical attention if they become symptomatic. The degree of contact with the index case will guide decision-making in these cases.

Health care settings

Health care workers should reduce exposure to large particle droplets by wearing surgical masks and using closed suction systems, especially when carrying out mouth and airway procedures, so that chemoprophylaxis is not needed. Health care workers who have had contact with large particle droplets/secretions of patients during procedures such as mouth-to-mouth resuscitation or endotracheal intubation, at the time of hospital admission, should receive chemoprophylaxis.

Health care workers in contact with a patient but not exposed to droplets/secretions do not usually qualify for chemoprophylaxis. A hospital ward is not equivalent to a household setting. Balanced risk assessment should be done in a case of immunocompromised contacts that may be at increased risk for invasive disease such as those who have anatomical or functional asplenia. Such individuals should receive pre-exposure prophylaxis with quadrivalent meningococcal vaccine as well as post exposure chemoprophylaxis when indicated.

It is useful to remind anxious staff, especially those that do not qualify for post exposure prophylaxis, that all drugs carry side effects; and that this risk is likely to be greater than the risk of disease; and that overuse of antibiotics leads to the development of resistance.

Drugs used for chemoprophylaxis

Any of the three possible chemo-prophylactic treatments may be given (Table 3).

 
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11. MENINGOCOCCAL VACCINES

 

Polysaccharide quadrivalent vaccines against N. meningitidis serogroups A, C, W135 and Y are used in South Africa. A bivalent vaccine comprising serogroups A and C only, is also available. The main recipients of the quadrivalent vaccine are Hajj pilgrims to Mecca.

The serogroup A component of polysaccharide vaccines is effective from 3 months of age and protection persists for about 3 years. Protection afforded by the serogroup C, W-135 and Y is of shorter duration and offers poor protection in children less than 18 months. Vaccines only provide adequate protection 10 to 14 days following vaccination. Protein conjugate vaccines are more effective than polysaccharide vaccines in children under 2 years of age and have activity against nasal carriage of meningococci.

The development of vaccines against serogroup B has faced many challenges. Serogroup B polysaccharide is poorly immunogenic, even when conjugated to a protein carrier. Although outer membrane vaccines show some promise, strain-specific differences in outer-membrane proteins suggest that these vaccines may still not provide protection against all serogroup B meningococci.

Recent W-135 epidemics in West Africa have led to the use of a trivalent A C W135 vaccine.

Following several serogroup C meningococcal outbreaks in the United Kingdom, a conjugate C vaccine has been introduced into the routine childhood immunization programme, resulting in a dramatic drop in meningococcal disease incidence, Serogroup C conjugates have also been used to control serogroup C epidemics, notably in Canada.

 

11.1 Recommendations for use of meningococcal vaccine in South Africa

 

12. How to Ensure Infection Prevention and Control in Congregate Setting?

 

1. TB wards

One of the most effective means to reduce the risk of transmission of M. tuberculosis in hospital settings is to manage TB patients in the outpatient setting whenever possible. Many patients can be managed entirely as outpatients, thereby avoiding hospitalization and the risk of exposing other patients and staff. If hospitalized, patients should be re-evaluated frequently for possible discharge with continuation of treatment as outpatients. Ideally, infectious TB patients should be isolated from other patients to prevent others from being exposed to the infectious droplet nuclei that they generate. If sputum smear is performed at the time of admission, those who have positive sputum smear results, and thus most infectious, should be isolated or separated from other TB patients already on treatment.

The hospital administration should ensure that:

  • There is a limited number of areas (preferably none) in the facility where exposure to potentially infectious TB patients may occur.
  • Separate wards for confirmed infectious TB patients are established. These wards should be located away from wards with non-TB patients, especially wards with paediatric or immuno-compromised patients.
  • In the outpatient setting, early identification, diagnosis, and treatment of TB cases is the highest priority.
  • X-ray  departments  schedule  inpatient  chest  x-ray appointments  for  patients  with  confirmed  or unconfirmed PTB during non-peak times.
  • Surgical masks are provided to coughing patients to wear when leaving isolation wards for any reason and in crowded waiting areas.

Isolation may be in patient’s homes, hospitals, or at designated TB or MDR-TB hospitals. Isolation is voluntary however; it may be legally enforced where a patient poses a risk to the public. Patients should remain in isolation until they are not infectious. People with infectious tuberculosis who are ill must be admitted in separate wards from other patients and their movement restricted to prevent the spread of infection. Ideally patients with suspected or confirmed infectious PTB should be admitted in a single ward that has;

  • Monitored negative air pressure
  • 6 –12 air changes per hour
  • Appropriate discharge of room air to the outside
  • Monitored high efficiency filtration of room air before the air is circulated to other areas of the hospital.
  • Simple extraction fan providing at least 6 air changes per hour or
  • Open windows and adequate ventilation.

When single wards are not available the patient should be placed in a ward with patients who are infected with the same micro-organisms. Patients at the same stage of treatment may be admitted in the same wards – cohorting. The same environmental measures as mentioned above apply in such a ward.

2. Patient transportation

The ventilation system in the ambulance should be circulate air within the vehicle but facilitate dilution by bringing in air from outside. If the vehicle has a rear exhaust fan, the fan must be on during transport. Air should flow from the front of vehicle, over the patient, and out through the rear exhaust fan.

After transporting the patient the vehicle must be ventilated by opening all doors and windows switching on the fans to flush out the air inside the vehicle.

If patient transport vehicles are used to transport a patient with infectious TB disease;

  • If possible separate the infectious patients from other patients.
  • The patient must wear a surgical mask
  • Ensure that all windows are open.
  • Educate patients in transit, driver and the accompanying staff on the use of masks and respirators.

3. Correctional facilities

Compared with the general population, TB prevalence is higher among inmates and it is associated with a higher prevalence of HIV infection, overcrowding, suboptimal ventilation, longer duration of potential exposure and limited access to health care services. TB is a public health concern in correctional facilities; employees and inmates are at high risk of infection. All correctional facilities must therefore have a written TB infection prevention and control plan based on the TB risk assessment report.

 

13. What is the Role of Advocacy, Communication and Social mobilisation (ACSM)?

 

ACSM is an integral part of infection control activities. The ACSM activities should focus on the following:

  • Imparting knowledge about the benefits as well as consequences of not implementing TB IPC measures in a given setting
  • Mobilizing communities to demand infection control measures for prevention of the spread of TB infection.
  • Mobilisation of resources to fund infection control activities.
  • IEC material: Develop TB IPC posters and pamphlets with clear and consistent messages.
  • Awareness and education campaigns: Identify key populations to target for TB awareness and infection prevention campaigns. These include schools, correctional services, mines and informal settlements and key populations to conduct
  • Media coverage
    • Make use of TV slots, radio and newspapers to communicate concise and consistent messages on TB infection prevention and control.
    • Engagement of all relevant stakeholders (e.g. Metrorail, Busses, taxis) to advocate Infection Prevention and Control
    • Branding of taxis on infection prevention messages
    • Bill boards in strategic points on Infection Prevention messages - short, consistent messages.

 

14. How to Conduct TB Risk Assessment?

 

The TB risk assessment is conducted as a first step in the process of developing the TB infection control plan for a facility. The seven principles of the risk assessment using the Hazard Analysis Critical Control Point (HACCP) risk analysis are:

  • Planning based on the HACCP process and determine what sections of the risk assessment tool will be used.
  • Assemble a multi-disciplinary risk assessment team
  • Establish procedures for documentation of all activities and the results of the assessment.
  • Establish procedures for validation and verification of the interventions currently being implemented and that they are periodically reassessed.
  • Conduct a hazard analysis by investigating all patient pathways to identify critical control points
  • Determine the appropriate IC intervention implemented for each critical control point by using the risk assessment questionnaire
    • Evaluate the management of the infection control plan in the facility in order to reduce risk against infection
    • Evaluate compliance with the use of personal protection
    • Evaluate  facility  environmental  controls  and  maintenance  practices,  and  determine  their effectiveness
    • Establish what monitoring plan for the applied IC intervention has been implemented at each of the critical control points
  • Identify and recommend corrective action.

 

6. MANAGEMENT OF VHF PATIENTS

 

6.1  Medical management of VHF patients

 

The medical management of VHF patients is a subject on which it is difficult to obtain consensus of opinion, and detailed analysis lies beyond the scope of the present document. The following remarks represent an attempt to summarize experience gained mainly in the management of Congo fever patients in South Africa.

.

6.1. Antiviral therapy

 

Antiviral compounds

Ribavirin is a synthetic nucleoside analogue, which has been shown to be of use in treating hantavirus and arenavirus (Lassa fever) infections. There is evidence to suggest that it is of benefit in treating Congo fever patients but the findings are not conclusive, mainly because too few patients have been placed on therapy sufficiently early in the course of the disease for meaningful analysis: since deaths occur from day 5 of illness onwards the disease must be recognized and treated early.

 

In practice, ribavirin therapy has only been attempted in patients with severe disease and a poor prognosis. In order to reach an early decision to institute therapy, it should be noted that during the first 5 days of illness in Congo fever any of the following pathological values are predictive of fatal outcome: leucocyte count 10x109/L; platelet count 20x109/L; AS200U/L; ALT 150U/L; APTT 60 seconds; and fibrinogen 110mg/dL. After day 5 of illness any value may be grossly abnormal without necessarily being indicative of a poor prognosis.

 

 

The oral preparation of ribavirin is registered in South Africa for the treatment of viral hepatitis. The drug would therefore be used ‘off- label’ for the treatment of CHF or Lassa fever. The trade name is Copegus, a Roche product, available in 200mg tablets. Ideally all severely ill patients should be treated with the intravenous formulation of ribavirin, but unfortunately it is not currently available in South Africa. It generally has to be sourced and imported when required. Table 6.1 and 6.2 shows the recommended dosage for adults and children.

 
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Oral ribavirin treatment of CCHF reported by Fisher-Hoch et al. (14): 4000 mg/d d1-4, 2400 mg/d d5-10.

 

Ribavirin can cause bone marrow depression, raised serum bilirubin values, nausea and malaise, but these effects are generally overshadowed by the signs and symptoms of VHF. Moreover, the drug is teratogenic in animal models, but its use should still be considered in pregnant patients given the potential for lethality in severe infections.

 

Congo fever patients have generally succumbed or recovered before completion of 10 days of treatment, resulting in early termination of the treatment.

 

No other chemotherapeutics are available for the treatment of VHFs, and the use of ribavirin is indicated only for the treatment of hantavirus, arenavirus and Congo fever virus infections. Use of ribavirin is considered to be contraindicated in Rift Valley fever as some patients treated  in  Saudi  Arabia  in  2000  succumbeto  late-onset  viral  encephalitis,  but  the association with ribavirin is not clear.

 

Prophylactic use of ribavirin

Oral ribavirin has been used prophylactically in persons deemed to have been exposed to infection with hantaviruses, arenaviruses and Congo fever virus, but the side effects of the drug can cause confusing and distressing illness which is particularly inconvenient when several people are affected. Hence it is advised that prophylaxis should be strictly limited to instances where there are strong indications that there has been exposure to infection, such as needle stick with blood known to be infected. The dosage for prophylaxis is the same as for treatment of infection.

 

Interferon

 

It has been demonstrated that interferons have significant antiviral activitiy against VHF agents in vitro and in animal models, and that there may be high levels of interferon expression in VHF patients. There appears to be no information on the value of interferon therapy in VHFs, but it is cautioned that its use in VHF patients poses difficult clinical challenges.

 

6.1. Immune plasma therapy

 

There is no controlled experimental evidence to indicate that the use of immune plasma is of benefit in VHF, and persons who have recovered from Congo fever generally have low neutralizing antibody activity in their serum which is unlikely to be of therapeutic value.

 

6.1. Supportive treatment

 

Monitoring of vital functions

This should include temperature, pulse and respiration rates, chest auscultation and fluid balance  (liquid  intake/urinary  output).  The  necessity  for  and  frequency  of  additional monitoring is dictated by the severity of the disease/condition of the patient and whether or not a ventilator and drugs such as diuretics are being used. Laboratory tests to support patient management include full blood counts (with platelet plus haemoglobin values), coagulation, liver function, glucose, creatinine, urea, electrolyte, blood gases and pH determinations on appropriate blood samples.

 

A chest X-ray should be taken on admittance of the patient and repeated if respiratory distress or suspected secondary infection occurs.

 

Haemoglobin replacement

This may be considered when blood haemoglobin levels fall to 8-10g/dL, but some patients tolerate such low levels quite well, and it is more important to treat on the basis of signs and symptoms of anaemia (respiratory distress) than purely on haemoglobin levels.

 

Although fresh blood may be transfused, it is better to use red blood cell concentrate to treat the anaemia of VHF. This helps prevent fluid overload and development of the respiratory distress syndrome. Modern additives to red cell concentrates adequately maintain the levels of phosphates which modulate the oxygen affinity of haemoglobin, so it is not essential to use fresh blood. As a rough guide, one unit of red cell concentrate should raise the haemoglobin level of an average adult by lg/dL.

 

Treatment of disseminated intravascular coagulopathy (DIC)

Contrary to our earlier perceptions, DIC appears to be an early and prominent feature of CCHF and other VHFs. There are two views on treatment of DIC: one holds that the administration of coagulation factors merely adds fuel to the fire, while the other advocates judicious replacement of coagulation factors. The latter opinion appears to be most widely favoured.

 

 

 

 

The use of heparin is considered to be useful in the early hypercoaguable stage of DIC, when there is accelerated partial thromboplastin time (PTT) and decreased prothrombin ratio (PR), but is of no value once the fibrinogen level falls. However, most cases of VHF are not diagnosed sufficiently early for use of heparin to be of value. Moreover, the use of the drug requires constant monitoring of the response and is best avoided by the inexperienced.

 

Thrombocytopaenia is a common feature of VHFs and occurs regularly in CCHF. There is agreement on the need for replacement of platelets, but this should be done only if thrombocytopaenia is accompanied by purpura and active bleeding such as epistaxis, or if platelet counts fall below 20x109/L.

 

A bag of platelet concentrate contains approximately 0.5 - 1.0X10 11 platelets in about 50 ml of plasma. The dosage of platelet concentrate is 1 bag/10kg body mass and transfusion services can be requested to pool the total dose, e.g. 7 bags can be supplied as 1 bag o350 ml, which can be administered rapidly (10 minutes). Transfusion services ordinarily supply platelets of appropriate ABO group specificity. The treatment may be repeated over a period of days if the patient's platelet level continues to decline or remains critically low.

 

If there is manifest consumption of other coagulation factors (abnormal PTT and PR levels, fibrinogen level <0.8g/L), administer fresh frozen plasma (FFP) or fresh dried plasma (FDP)at the rate of 10ml/kg body mass for the first dose. The treatment may be repeated if the patient continues to bleed or if coagulation factor levels remain markedly abnormal. As a general rule, 2-3 units of FFP or FDP should be administered to augment coagulation factors for every 10 units of red cell concentrate given to the patient.

 

Fibrinogen is not available as a separate product, but apart from its administration in FFP and FDP, it (and other factors) can also be administered in the form of cryoprecipitate. One bag of wet cryoprecipitate contains about 250 mg of fibrinogen and a bottle of dried cryoprecipitate, called anti-haemophilia factor (AHF), which is derived from a pool of 4-6 units of wet cryoprecipitate, contains approximately 1 g of fibrinogen. About 1-2 g fibrinogen (10 bags of wet cryoprecipitate) may be administered as a first dose.

 

Prothrombin complex concentrate (PCC, factor IX complex, Proplex) may be indicated following liver damage. It contains 200 units factor IX in a10 ml volume and a dose of 1 U/kg should increase the blood level of the factor by approximately 1%. Vitamin K should also be administered.

 

Intravenous fluids

Plasma is used to replace coagulation factors, not merely for volume expansion, but it is expensive and haemodynamic goals can be achieved with artificial colloids or even crystalloids. Iso-osmotic albumin solution (4%) may be used for volume expansion. Although

20% albumin has been used to treat hypoproteinaemia following liver damage in CCHF, it is considered  better  to  use  an  enteral  feed  that  provides  sufficient  calories  and  proteiaccording to body mass. If the gut is unavailable for enteral nutrition parenteral feeding may be necessary.

 

Hypoglycaemia was thought to be of critical importance in a number of CCHF patients iSouth Africa and blood glucose levels should be monitored carefully in severely ill patients.

 

Other therapy

There  is  no  information  on  the  effectiveness  of  steroids  to  allay  the  cytokine  storm’ underlying the DIC in VHF patients, but there is some support for this approach from animal models. If used, the dose should not exceed 200-300mg hydrocortisone daily. The use of non-steroidal anti-inflammatory drugs is not recommended.

 

Antacids, painkillers, relaxants and tranquillisers are administered as indicated.

 

Antibiotic prophylaxis is generally not indicated, however many patients will have received antibiotics prior to the diagnosis having been made. As with all patients in the ICU regular screening for colonization and infection is necessary.

 

Counselling of patients and relatives is mandatory as this is a highly stressful situation.

 

6.2  Clinical pathology monitoring of VHF patients

 

Requirements

Hospitals which manage suspected or confirmed cases of VHF should have available the services of a laboratory able to conduct the following tests:

●   A minimum range of screening tests to eliminate non-VHF diseases:

§  Full blood count.

§  Examination of blood smears for parasites and bacteria.

§   Blood cultures for septicaemia.

●    Haematological  and  clinical  chemistry  tests  to  monitor  treatment  and  progress  of patients:

§  Full blood counts (including platelet and haemoglobin values).

§  Coagulation studies.

§  Liver function tests.

§  Blood glucose tests.

§  Creatinine, urea, electrolyte determinations.

§  Blood gases and pH determinations.

 

§  Cross matching studies for transfusions.

 

Ideally  the  tests  should  be  conducted  by  a  small  team  of  experienced  volunteer technologists in a room set aside for the purpose within an existing laboratory, but since the occurrence of VHF is sporadic the expenditure to equip a dedicated unit is not justified. Consequently, the required tests are often conducted within routine laboratory facilities temporarily set aside for the purpose as required.

 

Operational procedures

Technologists who conduct clinical pathology tests on specimens from VHF patients should be trained in the donning, removal, and disposal of personal protective equipment (PPE), and entry and exit procedures from infected areas, as described under isolation precautions for VHF patients (see section 6,3).

 

Only volunteer team members should be present during the testing of specimens from suspected or confirmed VHF patients, and as far as possible manipulation of specimens should be performed in biohazard laminar flow safety cabinets (class IIA).

 

Duty registers should be kept, with staff subjected to the same monitoring as other medical personnel  dealing  with  VHF  patients,  and  incidents  constituting  potential  exposure  to infection, including injuries and spillages, should be dealt with as described in sections 6.4 and 7.

 

Decontamination of laboratory equipment including auto analyzers should follow standaroperating procedures developed from manufacturer’s instructions.

 

Decontamination of laboratory floors, walls and work surfaces, and disposal of waste materials, should follow procedures described in section 6.4.

 

Specimens for monitoring of VHF patients should be preserved at least until the patient is discharged or a diagnosis is established in a deceased patient, and should then be disposed of in a safe manner (autoclaved or sent for incineration). However, specimens should be offered to the Special Pathogens Unit (SPU) at the National Institute for Communicable Diseases (NICD) rather than destroyed, since much valuable information is gained from the examination of serial samples from VHF patients.

 

Ideally a separate clotted blood sample should be taken daily from confirmed VHF patients for submission to NICD, but these can be submitted together when the patient is discharged.

 

 

6.3 Isolation precautions (formerly known as barrier-nursing procedures)

 

Although the VHFs are seldom encountered, the consequences of being unprepared can be extremely serious. All medical institutions should formulate and implement contingency plans for isolating and managing VHF patients, even on a temporary basis. The aims should be to:

 

●   Identify facilities and resources which can be utilized for isolating and managing VHpatients.

●    Provide health care workers with training and instructions specific to their duties so that they are able to act in an informed manner when suspected cases of VHF are encountered.

●    Train all staff members to recognize potential cases of VHF, but ensure that critical assessment of such cases is performed by experienced clinicians and infection contropersonnel.

●   Train suitable volunteers in isolation precautions. Experience has shown that wheVHF occurs in an institution where        there has been no prior discussion of VHFs and  training  in  isolation  precautions  it  may  be  extremely  difficult  to     obtaivolunteers. Do not be caught unprepared.

●    Ensure  that  infection  control  personnel  monitor  safety  practices  during  isolation precautions and place staff who are in contact with VHF patients or fomites under observation (see section 7.3).

●    Establish proper channels of communication so that relevant members of staff at all levels are informed promptly of the existence of a suspected case of VHF, or of thimpending arrival at a hospital of such a patient, and of all key developments in the handling of the case.

●    Extend the system of communication to outside officials who need to be kept informed, such as Communicable Disease Control officials of the national and provincial Departments of Health (see section 7).

●   Make provision for well-informed responses to enquiries from news media (see sectio7).

 

Facilities

The minimum accommodation required for isolation precautions consists of one room in which the patient may be isolated and an ante-room or adjacent room where staff can don and remove personal protective equipment (PPE). Ideally, isolation units should have separate entrance and exit (clean and dirty) channels, and it is advantageous if the ante- room has a hand-basin and if ablution facilities are located in convenient proximity to the patient's room. The equipments and supplies required in the patient isolation room are listed in Table 6.3 below. Since VHF patients are often in need of intensive care, the isolation unit may need to consist of a cubicle or section of an ICU ward which can be closed off.

 

In addition to the patient room and ante-room there should be:

●    An area suitable for a nursing station where staff wait when not in direct attendance on the patient.

●   An area or room for storing supplies and equipment.

●    A  room  or  enclosed  area  for  changing  from  street  clothes  into  surgical  theatre  or equivalent clothing.

●    An observation room/ward in which to place high risk contacts of VHF patients who become sick, i.e. potential but unconfirmed secondary cases (such a facility is seldom

required).

●    A two-way communications system between the patient isolation room and the nursing station if necessary.

 

 

 

●    Purpose-buil isolation  facilities   shoul theoretically  hav negativ pressure  air- conditioning systems with high-efficiency particulate air (Hepa) filters on the exhaust ducts, but there are very few such units in the world and these are at major research facilities. It was speculated that 2 nurses who did not have direct contact with patients, but handled fomites such as bedpans, acquired Congo fever infection as a result of virus assing through an air-conditioning system during a nosocomial outbreak in South Africa in 1984, but there was no proof that this had occurred, and there is no evidence that air-conditioning systems constituted a hazard in the isolation of a further 200 VHF patients in  South  Africa,  or  ilarge  outbreaks  managed  by  international  response  teams elsewhere in Africa. Hospitals encounter suspected VHF patients so infrequently that it is not feasible to build dedicated patient isolation units and keep them vacant on standby. Instead, it is necessary to identify suitable facilities which remain in normal use and can be utilized for isolation of patients as the need arises.

 
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Much of the PPE is available in disposable plastic or paper form at all hospitals and clinics. Up to 25 changes of protective clothing may be required per day in nursing a patient during the critical phase of VHF illness (not all patients become severely ill or exhibit bleeding tendencies). Some hospitals utilize mended and condemned linen and theatre clothes for nursing VHF patients, but dye the items an obvious colour to help ensure that they are disposed of safely. Ideally, hospitals should keep stocks of the essential items in readiness, but this involves dedication of funds and secure storage space, plus rotation of perishable items. Alternatively, stocks should be secured immediately an emergency arises. Formidable epidemic disease packs (FED packs) containing virtually all of the above PPE items are available  commercially,  and  customized  packs  can  be  prepared  to  order  or  within  the hospital.

 

Safety equipment

It is notable that international teams operating under the auspices of the World Health Organization to control outbreaks of Marburg and Ebola haemorrhagic fevers in Africa use only standard PPE items specified above. Almost all VHF patients in South Africa have been nursed without special safety equipment, and all nosocomial infections occurred before the patients were placed under conditions of isolation precautions.

 

In the past, some hospitals in South Africa acquired special safety equipment for protection of staff against nosocomial infection, ranging from containment bed isolators, full-face respirators (gas masks) to battery-operated positive-pressure ventilated respirators (pappers’). There are disadvantages associated with each of these items: bed isolators are very expensive and occupy a large floor space; gas masks are tiring to use and tend to become fogged, thus reducing visibility and efficiency; pappers require expensive semi- disposable hoods and interfere with the use of stethoscopes.

 

 

Nevertheless, the use of pappers may be warranted for particularly hazardous procedures, such as intubation of VHF patients under intensive care. Hoods may be re-used by the same staff member for successive entries into the patient isolation room provided they are disinfected on exit from the isolation room as described below (they should be marked with the name of the user). Power supply points will be required in the ante-room for re-charging batteries, plus a rack or coat hooks for hanging respirators and hoods when not in use.

 

Personnel

Ideally, specifically trained, volunteer staff should be used for nursing VHF patients, and personnel who were in contact with the VHF patient/s before isolation precautions were implemented should be utilized first to limit potential exposure of further members of staff. Select persons of calm disposition able to cope with the stress of nursing VHF patients under strict isolation precautions.

 

Nosocomial infections can almost invariably be traced to fundamental lapses in technique, such as needle-sticks, against which most safety equipment cannot protect. Fatigue causes mistakes and hence adequate numbers of staff should be delegated to nursing patients under conditions of strict isolation precautions without seriously depleting the rest of the hospital or unnecessarily exposing too many individuals to VHF. If the nursing load is too heavy, as when multiple patients are involved, it may be necessary to suspend some or all- routine functions of the hospital. Counselling of staff (plus patients and families) should be offered to alleviate stress.

 

 

Shifts should be limited to a maximum of 8 hours (6 hours are preferable) to ensure a high degree of efficiency. Intensive nursing of critically ill VHF patients may require 3-5 persons per shift, 1-2 of whom are in the patient's room on a 1-2 hourly rotation. Low profile nursinof  moderately ill patients requires less  staff  and often it  is unnecessary to maintain a constant presence in the patient's room.

 

In addition to the staff members who are directly in attendance on the patient, one member of the nursing or administrative staff should remain outside of the isolation area to control communications, logistics and access to the isolation suite. In large hospitals it may be necessary to use security officers to control access to the isolation suite.

 

Domestic and any other staff who have not been specifically instructed in isolation precautions must be excluded from the isolation suite.

 

All medical and auxiliary staff (ambulance and laboratory personnel) who come into contact with a suspected or confirmed VHF patient or fomites, either before or after the institution of isolation precautions, must be placed under observation (see section 7). This should be done formally but the precautionary nature of the measure should be explained carefully.

 

Incidents constituting possible exposure to infection, e.g. needle sticks or other direct contact of skin with patients blood or body fluids, must be recorded and promptly brought to the attention of the hospital's infection control team to decide on any action to be taken (see section 7).

 

Baseline blood counts plus serum transaminase tests may be performed for persons who have had contact with a VHF patient or fomites, and serum samples should be kept frozen for later use if suspected infection occurs. However, this should be limited to persons with definite  exposure  to  infection  such  as  a  needle-stic with  known  infected  blood. Indiscriminate bleeding of contacts generates undue concern and unreasonable demands from people who have not had genuine exposure to infection.

 

Placing a patient into isolation

Explain to the patient and family that isolation precautions are being instituted and make an effort to reassure them. The donning of protective clothing by medical personnel can have a demoralizing effect on lay people.

 

Establish from the clinician in charge whether or not the patient's immediate family will be permitted to visit the patient (under supervision and with proper protective clothing). Inform the family accordingly and arrange for instruction in correct use of protective clothing.

 

Ensure that all staff are informed that the patient is being placed into isolation, institute control  over  access  to  the  isolation  suite  and  display  appropriate  warning  notices. Henceforth only specifically authorized personnel may have access to the patient and all staff must wear protective clothing when tending the patient.

 

The patient is transferred to the isolation room on his/her bed, and all other items of equipment required from the original ward (e.g. locker, ventilator, monitor, etc.) are moved with the patient. The procedure for receiving VHF patients from outside the hospital is described in section 7.

 

All non-essential items, including the patient's records, are left in the original ward and are decontaminated in the prescribed manner by personnel wearing protective clothing (see section 6.4). New patient records are started and kept outside of the isolation room.

 

 

All other patients who were in the original ward with the VHF patient are transferred, preferably to a single other ward, so that the original ward can be decontaminated (sesection 6.4). Sometimes it is more convenient to leave the VHF patient in the original ward and convert it into an isolation room.

 

Ensure that the infection control team prepares a register of all persons deemed to have had contact with the VHF patient/s and places contacts under observation (see section 7.3).

 

 

Ensure that a duty register is kept of all staff shifts and visits to the patient, to ensure traceability of contact with the patient.

 

 

Dressing for entering the patient isolation room


In a change-room or other suitable area close to the entrance to the isolation suite, staff remove all jewellery and replace their street clothes with surgical theatre tops and trousers, or equivalent cover-all garments (washable fabric or disposable), plus canvas or similar slip- on shoes. These clothes are worn for the duration of the work shift and are used to move around in the vicinity of the isolation suite, but an extra layer of protective clothing is donned in the ante-room for entry into the patient isolation room:

●   Long-sleeved, waterproof, disposable gown.

●   Vinyl or rubber apron if more than light duties are involved, e.g. bleeding patients.

●    Two pairs of latex surgical gloves, one worn over the other - the cuffs of the outer pair of gloves should be pulled over the cuffs of the gown and taped in place with masking taparound the wrist.

●   Disposable balaclava-type cap.

●   Disposable face-mask, e.g. N95 – cannot be used with facial hair (beards).

●   Goggles or acrylic visor, or disposable visor.

●    A disposable combination visor-face mask can replace a separate mask and goggles or visor.

●   Alternatively, a positive-pressure ventilated respirator (papper) with hood could replace the balaclava, face-mask and goggles or visor.

●    Two pairs of overshoes, one over the other, or heavy duty plastic bags taped to the trouser legs, or waterproof boots.

 

Needles,   other   sharp   objects,   patient' blood,   blood-contaminated   discharges   and equipment  soiled  with  blood  constitute  the greatest  danger  and  must  be  handled  with extreme care. Gloved hands contaminated with patient's blood or discharges should be dipped into 500 ppm chlorine disinfectant solution (see section 6.4) kept in the isolation room. Gloves must be checked frequently for tears or punctures and if the patient bleeds profusely, both inner and outer gloves must be changed hourly and the hands washed thoroughly in soap and water or surgical scrub disinfectant.

 

 

 

Procedure for leaving the patient isolation room

The procedure for leaving the isolation room must be followed strictly to prevent contamination of personnel and the environment. Double refuse or autoclave bags (heavy duty), which are used to receive discarded protective apparel, are placed one inside the other in a bin or holder in the ante-room with 20-30 cm of the top of the bags folded back over the rim of the bin or holder to form a clean margin when the bag is sealed. The bin is placed close to the door leading from the patient isolation room.

 

 

On leaving the patient isolation room, the outer overshoes are removed and placed in the disposal bag. Waterproof overshoes or boots may be dipped into a bucket/tray of 500 ppm chlorine disinfectant (see section 6.4) before being removed. The outer gloves are dipped or washed in 500 ppm chlorine disinfectant (see section 6.4), peeled off and discarded into the disposal bag. The inner gloves are used to remove the other items of protective wear and to place them in the disposal bag as follows:

●    Goggles or acrylic visors are removed and placed in 500 ppm chlorine disinfectant (see section 6.4).

●   Disposable combination visor-masks are discarded into the disposal bag.

●    If a positive-pressure respirator is being worn, an assistant in the ante-room swabs or sprays the outer surface of the hood with 500 ppm chlorine disinfectant (see section 6.4and with gloved hands helps to remove the respirator; the swabbed hood is hung on a hook or rack to dry; the respirator itself is hung or placed on a suitable surface anconnected  to  a  battery  charger.  Respirator  hoods  are  marked  with  the  names  of individual members of the team for re-use, and are discarded for incineration or safe disposal when no longer required.

Facemasks and balaclava caps are removed and placed in the disposal bag.

●    Next, aprons and gowns are removed and folded or rolled in the process so that outside surfaces are on the inside and they are placed in the disposal bag.

●   The inner pair of overshoes and finally the inner gloves are removed and placed in the disposal bag, and the hands are washed thoroughly with soap and water or surgical scrub disinfectant (use of ethyl or isopropyl alcohol is not recommended for disinfection of the hands in nursing VHF patients).

●    The inner and outer top rims of the disposal bags are sprayed with 500 ppm chlorine disinfectant (section 6.4) and sealed by a gloved assistant, conveniently with plastic cable-ties obtainable from electrical or hardware stores, or with adhesive tape.  The double bags are sealed into a third bag, or several layers of bags if necessary to prevent leakage. It is useful if the outer bag is colour-coded, e.g. red, to indicate that it contains biohazardous material due for incineration. However, red bags are commonly used for waste in hospitals.

●    The  outer  bag  is  labeled  with  biohazard  stickers  and  sent  for  incineration  under supervision,  or  sealed  into  the  container  of  a  commercial  biohazardous  materials disposal contractor, e.g. Sanumed®.

●    Surgical theatre clothes or equivalent cover-all garments and footwear are removed in the outer change room and discarded into laundry or disposal containers as appropriateand staff don their street clothes. Preferably, staff should be able to take a shower bath before leaving the isolation area.

 

 

 

Procedures for dealing with potentially hazardous incidents

All incidents constituting possible exposure to infection, such as needle stick injuries and splashing with patients body fluids must be recorded and reported to infection control staff to decide on appropriate action, and an Employer’s Report of an Accident Form (Compensation for Occupational Injuries and Diseases Act, 1993) must be completed and submitted.

 

First aid procedures should be applied as considered necessary, eg bleeding of needle stick or sharp instrument injury sites should be encouraged and wounds bathed in copious 500 ppm chlorine disinfectant (see 6.4).

 

Infection control staff in consultation with senior clinicians and management should decide whether staff members potentially exposed to infection should be placed in quarantine (section  7),  subjected  to  prophylactic  treatment  (section  6.1),  or  simply  kept  under observation (section 7).

 

Patient care facilities should be subjected to routine disinfection, but overt spillages of hazardous materials should be dealt with as they arise (section 6.4).

 

Discharge of patients

Provided they are well, Congo fever, Rift Valley fever and other arbovirus disease patients can be removed from strict isolation precautions, or even discharged from hospital, two weeks after onset of illness, but they should remain under supervision and refrain from strenuous activity for a month or more, depending on their progress. Meningism, encephalitis and ocular lesions can occur as late complications of Rift Valley fever.

 

Patients with a diagnosis of any of the other African haemorrhagic fevers should be nursed in isolation for at least 3 weeks after onset of illness. Sexual transmission of Marburg virus in semen has been recorded two months after recovery of the patient and the same could probably occur with Ebola virus. Excretion of Lassa fever virus in urine has been observed to occur over a period of a few weeks, and hence the discharge of Lassa fever or Lujo virus patients from hospital should be made consequent upon failure to isolate virus or to detect viral nucleic acid by RT-PCR in three consecutive urine samples collected on separate days. The same would apply to haemorrhagic fever with renal syndrome (HFRS) patients, but culture of the viruses is difficult and erratic.

 

Recovery from VHF may be marked by prolonged convalescence and it is advisable that patients should be kept under casual surveillance for about 3 months. They should be warned of the possibilities of their transmitting infection through intimate contact during this time.

 

 

If convenient, serum samples from recovered patients should be sent for monitoring of antibody levels at intervals after recovery as opportunity arises; useful diagnostic information on the duration of IgM and IgG responses is accumulated in this manner. Patients should be approached about the possibility of donating immune plasma once they are fully recovered, for preparation of control reagents for diagnostic tests, or for possible therapeutic use. Offers to donate plasma can be discussed with the Special Pathogens Unit at NICD (telephone numbers 011 386 6339, 082 903 9131, 082 908 8042 and 082 908 8045).

 

6.4  Disinfectants and decontamination

 

The use of disinfectants is not a substitute for sterilization by physical means, especially heat as in autoclaving or incineration. However, there are many situations where it is necessary to resort to the use of disinfectants, and the present discussion is limited to requirements for managing VHF patients. The use of brand names does not imply recommendation of a product to the exclusion of similar preparations. It should be remembered that mechanical cleansing is an integral part of proper disinfection: excess organic matter rapidly reduces the efficacy of disinfectants.

 

Choice of general disinfectant

Inorganic  chlorine,  in  the  form  of  diluted  household  bleach,  has  been  used  as  the disinfectant  of  choice  in  controlling  outbreaks of  VHF  in  Africa  because  it  is  effective, relatively inexpensive and readily available. However, inorganic chlorine corrodes metals and tends to degrade fabrics. Brand-name household bleaches contain 5% sodium hypochlorite and are diluted as follows for use:

 

A 10% aqueous solution of household bleach (one part bleach plus 9 parts water) yields 0.5% hypochlorite, or approximately 5000 ppm chlorine, and is used for disinfecting overt spillages of contaminated materials, excreta (organic wastes) and surfaces of corpses.

 

A 1:100 aqueous solution of household bleach (one part bleach plus 99 parts water, or

1 part of 10% diluted bleach plus 9 parts of water) yields 0.05% hypochlorite, or approximately 500 ppm chlorine, and is used for disinfecting gloved hands, walls and floors without overt spillages of contaminated materials, clothing, bedding, equipment and instruments, and the outer surfaces of sealed plastic bags containing infected or contaminated materials.

 

One or two crystals of potassium permanganate (Condys crystrals) can be added to undiluted household bleach to impart a pink colour to the diluted solutions of disinfectant for easy identification. Fresh stocks of diluted disinfectant should be prepared daily.

 

Organic’ chlorine formulations which contain a detergent, an anti-corrosive agent and chlorine incorporated in or complexed to organic molecules (chloro-cyanurates and chloramines) offer clear advantages over inorganic hypochlorite. A dry granular preparation of this type is sold in South Africa as Biocide D (6g granules per sachet), or as Biocide D Extra (30g granules per sachet) (Johnson Diversey, Germiston):

 

Twenty sachets of Biocide D Extra (600g) dissolved in 10 litres of water yields 0.5% hypochlorite, or approximately 5000 ppm chlorine, and is used for disinfecting overt spillages of contaminated materials, excreta (organic wastes) and surfaces of corpses.

 

Two sachets of Biocide D Extra (60g) dissolved in 10 litres of water yields 0.05% hypochlorite, or approximately 500 ppm chlorine, and is used for disinfecting gloved hands, walls and floors without overt spillages of contaminated materials, clothing, bedding, equipment and instruments, and the outer surfaces of sealed plastic bags containing infected or contaminated materials.

 

Fresh solutions should be prepared daily.

 

 

Disinfectant solutions should be clearly labelled with the concentration of active ingredient and date of preparation.

 

Choice of hand disinfectant

Gloved hands are generally rinsed in 500 ppm chlorine, and although this can also be used to rinse bare hands, it is recommended that when surgical gloves are removed after nursing or transportation of VHF patients, or performance of clinical pathology tests, the hands should be thoroughly washed with soap and water, or with a surgical scrub preparation. Ethyl or isopropyl alcohol preparations are not recommended for disinfection of the hands in managing VHF patients, although they can be used as skin disinfectants for injection of patients.

 

Decontamination and disposal of hazardous items

A specific individual in each nursing shift, or ambulance crew transporting a VHF patient, should be responsible for supervising decontamination and disposal of biohazardous items. All items leaving the isolation unit (patient's room and anteroom, or ambulance) should be enclosed in double layer autoclave bags (or more layers if necessary to prevent leakage) and sealed with cable ties or adhesive tape. The outer surface should be labelled with biohazard stickers and swabbed with 500 ppm chlorine disinfectant.

 

Disposable items should be sent for incineration under supervision and re-useable items for autoclaving. Crockery and cutlery used for feeding VHF patients should ideally be of the disposable type and incinerated along with food wastes.

 

Bedpans and other containers with patient secretions, excretions and other wastes such as vomitus and blood, should be flooded with copious 5000 ppm chlorine disinfectant, left for at least 30 minutes, and sealed into adequate layers of leak-proof autoclave bags or other secure secondary containers (e.g. stainless steel container). The outer surfaces of the bags or containers should be swabbed with 500 ppm chlorine disinfectant, labelled with biohazard stickers and the items removed for autoclaving and cleaning. Autoclaved wastes can be flushed into municipal sewers. After flushing, bedpans are cleaned with 500 ppm chlorine disinfectant. Thoroughly disinfected wastes (prolonged exposure to copious disinfectant) can also be discarded into sealed disposal pits, or buried.

 

It is convenient to use chemical toilets instead of bed pans for ambulant patients.

 

Vinyl, rubber and other items which are degraded by autoclaving could be discarded and incinerated, or subjected to prolonged immersion in 500 ppm chlorine disinfectant.

 

The hoods of battery-operated positive-pressure ventilated respirators (pappers’) are discarded for incineration at the termination of patient treatment, and the respirators are swabbed with 500 ppm chlorine disinfectant, and sealed into labelled bags and sent for gaseous sterilization.

 

Hypodermic and intravenous needles should be used with great care, discarded into rigid- walled disposal containers, flooded with a 5000 ppm chlorine disinfectant (see 6.4), sealed into leak-proof bags, labelled and sent for incineration.

 

Used linen and cloth items of protective wear should be sealed into labelled bags and autoclaved before laundering, but consideration should be given to incinerating grossly contaminated items such as bloodstained mattresses and pillows. Items, which are not visibly soiled, could be soaked in 500 ppm chlorine disinfectant for 30 minutes before laundering. Persons laundering cloth protective apparel or bedding used for VHF patients should don personal protective equipment (PPE) as described for isolation precautions (see section 6.3).

Vomitus, blood and other overt spillages on floors and similar impervious surfaces should be flooded with 5000 ppm chlorine disinfectant, covered with paper towels and left for 30 minutes before removal.

 

Floors of VHF patient isolation units should be mopped and drains flushed with 500 ppm chlorine disinfectant daily, or whenever there is spillage of potentially contaminated material. Rinsed mops should be soaked in 500 ppm chlorine disinfectant for 30 minutes. At the termination of  patient treatment the walls and all impervious surfaces in isolation units (lockers and tables) should be swabbed in addition to the disinfection of floors and drains. The same procedures should be applied to mortuaries and laboratories handling corpses or samples of suspected or confirmed VHF patients.

 

Patient records, which have been kept in an infected environment, can be bagged and autoclaved, or the information preserved by other means, e.g. copied from records, taped to a window or glass partition, or transmitted via telephone.

 

6.5 Disposal of corpses

 

Corpses  of  suspected  VHF  patients  may  be  processed  for  immediate  disposal  if  an etiological diagnosis has been confirmed. If a diagnosis has not been established, then in terms of the Health Act 61 of 2003 certain medical practitioners are empowered to authorize the performance of an autopsy to determine the cause of death, as described in section 7 othis document. Usually the autopsy procedures are limited to collecting blood by cardiac puncture and taking liver samples with biopsy needles.

 

After the autopsy specimens have been taken, the corpse may be held under refrigeration in a mortuary if the facilities exist, while laboratory investigations to eliminate VHF proceed. This usually takes a week, and if a diagnosis of VHF is eliminated, it may be deemed safe and/or necessary to proceed with a full autopsy to establish the cause of death.

 

For disposal, corpses are washed with 5000 ppm chlorine disinfectant (see section 6.3 above). Orifices are plugged with gauze and puncture sites are taped or sealed (Opsite®, S & N Pharmaceuticals Pty Ltd). The corpse is enclosed in an impervious body bag and sealed (it is advantageous if the body bag has an air-valve). The attendants change protective clothing, swab the body bag with fresh disinfectant and seal the corpse into a second impervious body bag. After disinfection of the outer body bag, the corpse can be removed fostorage in a mortuary or placed in a coffin for disposal. If impervious body bags are not available, adequate layers of stout plastic shrouds may be used.

 

The shrouded corpse should be placed in a coffin packed with absorbent material (sawdust) which is moistened with 5000 ppm chlorine disinfectant (see 6.4). The coffin should be sealed and wiped with 500 ppm chlorine disinfectant (see 6.4). The corpse should be cremated or buried under the supervision of a representative of the provincial Department of Healt an Hospital   Services,   more   specificall the   office   o th Coordinator   of Communicable Disease Control.

 

7. NOTIFICATION AND CONTROL OF OUTBREAKS OF VHF

 

7.1  Transfer of VHF patients

 

7.1.1 Arranging transfer of VHF patients

Reasons for and against transfer of VHF patients

Patients are often transferred through one or more hospitals before VHF is suspected. However, once VHF is suspected or confirmed, the following points must be taken into consideration:

 

Indications for transfer of VHF patients

The most important reason for transferring a patient is the need for better medical care. Another valid reason is to achieve greater safety in isolation and nursing of patients. Thus, there are stronger grounds for moving moderate or high risk patients to better facilities, but low risk patients are easier to move safely (see section 5 for discussion of risk categories). The  existence  of  a  conveniently-located  referral  centre  which  has  been  specifically designated  and  equipped  to  receive  VHF  patients,  is  an  obvious  incentive  to  transfer patients.

 

Contraindications to the transfer of VHF patients

Patients should not be moved when their condition does not allow this to be achieved safely: the process may unduly threaten the life of the patient,  or involve too great a risk of spreading infection. It is inadvisable to move patients when there appears to be a continuing outbreak of infection, as in common source outbreaks in abattoirs or on farms, or when there has been definite exposure of contacts (as in nosocomial needle sticks), or when secondary cases have already become manifest. The inference is that further cases may arise and that transfer of patients merely results in creating two or more potential centres of infection where contacts have to be placed under observation. Under certain circumstances, therefore, it is better to second trained staff and the required equipment to the primary hospital, than it is to move patients.

 

Reaching a decision on transfer of VHF patients

Decisions are reached with greatest facility where a framework for consultation has been organized as a matter of preparedness. Thus, a pre-arranged panel within the primary hospital should perform the initial clinical evaluation and decide whether there are indications for seeking transfer of patients. The panel should include clinicians, infection control and management representatives. Advice can be sought from the medical officer on duty at the National Institute for Communicable Diseases (NICD) (NICD Hotline 082 883 9920).

 

Once it has been decided to seek transfer of a patient, it should only be necessary to contact one person per telephone at the referral hospital. This person should be authorized to take decisions on accepting transfer of VHF patients, or be able to obtain decisions rapidly. Experience has shown that decisions can be reached with suitable expediency (see requirements  for  a  VHF  referral  centre  on  the  following  pages).  Arrangements  for transporting the patient should be made at the same time (see 7.1.2 and 7.1.3 below).

 

If the primary hospital does not have information available on provincial policy with regard to referral of VHF patients, or contact details for a referral hospital, information can be sought from the provincial Coordinator of Communicable Disease Control (see section 7.2), who must in any event be informed of transfers of VHF patients.

 

7.1.2 Non-ambulance transport of low risk VHF patients

Before VHF is diagnosed, patients are usually transported to doctors’ rooms or hospital without special precautions. Once VHF is suspected, patients should not be transported without specific precautions to prevent spread of infection. However, there is generally room for judicious improvisation in transporting VHF patients in the early stages of disease. For instance, when febrile illness first occurs in a known VHF contact, there appears to be no valid objection to the patient being taken to hospital in the vehicle of a relative with whom the patient has already had close contact. The safety of those in attendance should nevertheless remain a prime consideration and patients who are severely ill, or who are vomiting or manifesting haemorrhagic signs, should only be transported by an ambulance crew using appropriate personal protective equipment (see 7.1.3 below).

 

7.1.3 Transport of VHF patients by ambulance

There appear to be no strong reasons for the transportation of suspected or confirmed VHpatients by air within South Africa, and this has not occurred during the past decade.

 

Administrative considerations

As recommended for hospitals, ambulance and emergency medical services are advised to ensure that staff is trained in the recognition of VHFs, assessment of the condition of patients, and in essential isolation precautions for safe transportation of patients (see 6.3). This applies particularly, but not exclusively, to ambulance crews, which provide a service for designated VHF referral hospitals. Ambulance crews tasked with the transport of VHF patients at referral centres should ideally be composed of volunteer personnel, and be contactable through  a designated individual to whom all requests for transport  of  VHF patients should be channelled.

 

Equipment

Ambulance and emergency medical services should keep stocks of personal protective equipment (PPE), most conveniently in the form of formidable epidemic disease (FED) packs, each containing:

§ Disposable gown 1

§ Disposable balaclava type cap 1

§ Dust goggles 1 (alternatively a clear acrylic visor or disposable visor)

§ Disposable plastic aprons 2

§ Theatre masks, moulded 2

§ Surgical gloves 2 pairs

§ Overshoes 2 pairs

 

In addition, there should be decontamination (DECON) packs each containing:

§ Plastic autoclave bags (preferably red) 10

§ Sharps disposal container

§ Biocide D Extra or equivalent disinfectant, 50 sachets

§ Biohazard labels

§ Felt tip marker pen

§ Masking tape 1 roll

§ Plastic cable ties for sealing bags 12 (obtainable from electrical/hardware stores)

§ Paper towels 4 rolls

§ 10 litre plastic bucket (it is a good idea to mark 1 litre graduations on the bucket)

 

Ambulances despatched to transport suspected or confirmed VHF patients should carry 10 FED and 2 DECON packs. Although the ambulance should be stripped of non-essential equipment, it should carry a suction unit, a complete oxygen supply unit and the standardrange of equipment for management of patients. Items could be sealed into plastic bags witadhesive tape and opened only if required.

 

Battery-operated  positive-pressure  ventilated  respirators  (pappers)  (e.g.  Racal  ‘Dust Master, Delta Health & Safety, Kempton Park) with disposable hoods could replace the balaclava, face mask, goggles or visor in high risk situations. Two pappers are required per ambulance crew, and they must be maintained in working order with batteries charged at the base from which the ambulance operates. Pappers can generally be used for up to 8 hours with fully charged batteries. The disposable hoods are relatively expensive.

 

Operational procedures for the transportation of VHF patients by ambulance

A minimum ambulance crew of 3 members is required for the transportation of a VHF patientThe  clinician  requesting  transport  should  advise  the  ambulance  team  of  the condition of the VHF patient and of the appropriate protective measures to be taken, eg:

§ Conscious patient, no vomiting, no active visible haemorrhage, in full control of urinary bladder and bowel function - ambulance crew to use protective clothing as contained in FED packs; and

§ Patient  with  disturbed  level  of  consciousness,  vomiting,  possible  haemorrhages  or pulmonary involvement, not in control of urinary bladder or bowel functions - the use obattery-operated positive-pressure ventilated respirators (pappers) with hoods in place of the balaclava cap, masks and goggles or visors is advisable, particularly if there is to be nebulization, suctioning, intubation and manual ventilation of the patient.

 

The donning and removal of PPE and the use of pappers for safe transport of VHF patients should follow the routines described for isolation precautions for VHF patients in hospitals, with disposal of soiled items into double autoclave bags, sealed with cable ties or adhesive tape and labelled with biohazard stickers (see sections 6.3; 6.4). Re-usable items should be bagged separately from disposable items. Sharp instruments, particularly needles, should be used with great care and disposed of into appropriate sharps disposal containers.

 

On arrival at the location of the patient, the 3 crew members should all don protective clothing, but the driver should avoid contact with the patient and act as a liaison between the other 2 crew members and local hospital staff to ensure safe transfer of the patient into the ambulance.

 

Five of the FED packs should be carried in the driver's compartment and these could be made available to the personnel at the referring hospital if necessary for use in transferring the patient and in decontaminating afterwards (information on hospital decontamination procedures can be found in section 6.4 of this document).

 

 

Before transferring the patient, the crew should re-assess his/her condition and if necessary consult the clinical team at the referral hospital per telephone if there has been marked deterioration. Patients must be brought by wheeled bed or hospital trolley to the ward entrance and then transferred to the ambulance stretcher, to minimize further contamination of the hospital, and passages should be kept clear during transit of the patient. The receiving hospital should be given an estimated time of arrival by the ambulance crew, and the patient should be taken by shortest route to the appropriate ward through passages which are kept clear during the transit.

 

Decontamination of the ambulance and disposal of hazardous items

Crew members decontaminating ambulances should don PPE as contained in FED packs. During or after transport of a VHF patient, vomitus, blood and other spillages should be flooded with disinfectant at a concentration of 5000 ppm available chlorine (20x30g sachets of Biocide D Extra/10L water - see section 6.4), and covered with paper towels for at least 30 minutes before being wiped up. Overt spillages should never be sprayed with disinfectant.

 

Containers with secretions, excretions and other wastes such as vomitus and blood, should be  flooded  with  copious  chlorine  disinfectant  at  a  concentration  of  5000  ppm  (20x30g sachets of Biocide D Extra/10L water - see section 6.4) for at least 30 minutes.

 

All items leaving the ambulance should be enclosed and sealed in adequate layers of autoclave bags to prevent leakage. The outer surfaces of the bags should be wiped with chlorine disinfectant at a concentration of 500 ppm (2x30g sachets of Biocide D Extra/10L water - see section 6.4) and labelled to indicate that the bags contain biohazardous material. Disposable items should be sent for incineration under supervision and re-usable items sent for autoclaving.

 

The ambulance interior should be swabbed, including fittings, with chlorine disinfectant at a concentration of 500 ppm (2x30g sachets of Biocide D Extra/10L water - see section 6.4). It is convenient  to  dispense 500 ppm chlorine disinfectant from rigid-walled plastic spray bottles for cleaning surfaces which are not visibly contaminated.

 

Crew members who decontaminate ambulances should remove their PPE as described for isolation precautions during nursing of VHF patients in hospitals, with disposal of soiled items into double autoclave bags, sealed with cable ties or adhesive tape and labelled with biohazard stickers (see sections 6,3; 6.4).

 

7.1.4 Importation of VHF patients and transportation by air

South Africa accepted transfer of an American citizen with suspected Ebola fever from Zaire (DRC) in 1976 (laboratory tests proved to be negative), but since then it appears that no country has granted permission for the intentional importation of suspected or known cases of VHF, although technically countries could not exclude their own citizens. However, there have been many unwitting importations of VHF patients worldwide, sometimes resulting in the occurrence of fatal nosocomial infections, also in South Africa.

 

As with other countries, South African regulations pertaining to the importation of suspected or known cases of VHF are intended to give effect to the International Health Regulations o2005 (IHR 2005), which aim to control national and international  spread of contagious

diseases.

 

The importation of patients into South Africa by air occurs in two ways:

 

Intentional importation of patients – patients who are referred for medical attention are often assisted by evacuation companies which operate their own air ambulance services, but which may utilize scheduled commercial airline flights for ambulant patients with non- contagious conditions.

§    It is the responsibility of the aeromedical assistance company to ensure that visas are obtained for patients if necessary from the Department of Home Affairs.

§    If the patients condition is considered to be non-contagious (eg traumatic, surgical, obstetric or neoplastic) the pilot of the medical evacuation flight need only submit a general declaration (GENDEC) by facsimile to the Port Health Officer (PHO) at the port of intended entry, most often O.R.Tambo or Lanseria airports.

 

§    If a contagious disease (or suspected VHF) is involved, the aeromedical assistance company (pilot) must obtain prior clearance for importation of the patient through submission of a duly completed request form AC1 by facsimile to the PHO at the intended  port  of  entry.  The  PHO  must  obtain  expeditious  clearance  from  the provincial Directorate of Health and Hospital Services (specifically the office of the Coordinator of Communicable Disease Control), which may in turn consult, or at least must notify, the national Ministry of Health. In practice, the referring clinicians in the country of origin of the patient, the aero-medical assistance company, as well as health authorities and the referral hospital within South Africa, often seek advice from the medical officer on duty at the NICD (NICD Hotline 082 883 9920) in instances where VHF may be involved.

§    The PHO informs the pilot or person who made the request of the decision to permit or decline permission for importation of the patient by facsimile of form PH1, with a reference number. In general, requests for importation of suspected or known caseof VHF will be declined unless there are exceptional circumstances, eg a SoutAfrican citizen is involved.

 

Aeromedical assistance companies, and hospitals which accept patients from abroad, are well advised to comply strictly with the legal requirements for their own safety and the safety of others, as well as to avoid liability to prosecution or litigation. Aeromedical assistance companies have the same obligations as hospitals and ambulance services to ensure that staff is trained in the recognition of VHFs, assessment of the condition of patients, and in essential isolation precautions for safe transportation of patients (see 6.3).

 

Air ambulances should have available the same safety equipment as recommended for road ambulances (e.g. PPE FED packs and DECON packs, plus pappers) (section 7.1.3 above), and apply the same operational principles in transporting patients as described for ambulances. The use of pappers is particularly advisable if there is to be nebulization, suctioning, intubation and manual ventilation of potential VHF patients within the confined space of an air ambulance.

 

Although most instances of intentional importation of potential cases of VHF have involved Gauteng airports commonly utilized for medical evacuation of patients from tropical Africa, the increasing tourist trade and the institution of direct flights to remote destinations implies that  vigilance  should  be  maintained  at  alSouth  African  airports.  Management  of  a suspected VHF patient on arrival at the port of entry is discussed  below    (see    procedure below on the arrival of a flight with a suspected or known VHF patient).

 

 

 

Unintentional importation of VHF patients - patients who are being medically evacuated to South Africa ostensibly for non-contagious diseases may develop signs and symptoms suggestive of VHF or other formidable infectious disease (eg avian influenza) in transit. It also occurs that patients suffering from suspected VHF (or other notifiable disease) travel to South Africa on scheduled flights on their own initiative, sometimes specifically to seek medical attention here, without declaring their illness to the airline. Hence, aircrew members on commercial and medical evacuation flights should be trained to recognize the following signs and symptoms suggestive of VHF (or other formidable infectious diseases) in passengers:

§      Fever (≥38.5C)

§      Severe headache

§      Abnormal sweating

§      Rapid breathing

§      Excessive coughing

§      Severe vomiting

 

§      Diarrhoea

§      Bleeding - eg nosebleed or vomiting blood

The crew should attempt to isolate the patient and to avoid contact between the patient (or secretions and excretions) and other passengers as best as can be managed under the circumstances.

 

The pilot should notify the control tower at the airport of intended arrival of the existence of the patient on board, and the tower should arrange for the flight to be met by a PHO. The crew should complete form AC2 for notification of symptoms of a patient/sick passenger transported per aircraft to South Africa, and this should be handed to the PHO on arrival.

 

Screening procedures to detect febrile patients are increasingly being instituted within international airports following the occurrence of the SARS and avian influenza pandemics of recent years, and this represents a further method by which potential imported cases of VHF may be detected.

 

Procedure on the arrival of a flight with a suspected or known VHF patient

The flight must be met by port health officials, including a medical officer if necessary, to assess the patient and the likelihood that VHF is involved, and the doors kept closed (no disembarkation allowed) until formalities have been completed. A duly completed form AC2 should be handed to the PHO if relevant.

 

Prior arrangements for patients arriving on medical evacuation flights to be transported by ambulance and admitted to referral hospitals, should be permitted to proceed with due warning to the aircraft crew, ambulance crew and the hospital concerned that VHF may be involved, so that appropriate safety procedures can be instituted. If a suspected VHF patient arrives on a scheduled flight without prior arrangements for admission to a hospital in South Africa, the PHO should arrange for transportation and admission of the patient to a hospital designated   fo medica managemen o VH patient (ther shoul be   standing arrangements for PHOs to refer patients to designated hospitals through liaising with authorized contact persons at the hospital – see 7.1.1: reaching a decision on  transfer of VHF patients).

 

There should be a designated area within the airport for temporary isolation of patients awaiting transport to a designated hospital. The pilot should permit the public address system to be used to inform the crew and passengers calmly and factually that there is an ill person on board and to explain the precautionary measures which are being taken, before disembarkation is allowed.

All passengers and crew members should be given an information sheet plus a Health Alert

 

Notice which is to be handed to a medical clinician should the person develop febrile illness within the ensuing 3 weeks. Contact details for those crew members and passengers on the aircraft deemed to have been exposed to possible infection should be recorded by the PHO and given to the office of the provincial Coordinator of Communicable Disease Control (along with a complete passenger list) so that the persons at risk can be placed under observation if deemed necessary (see section 7). In deciding which persons may have had contact with the patient or secretions and excretions in such a manner as to have been exposed to possible infection (see definitions in section 7) it is advisable to include passengers seated in same row (aisle to aisle) as the patient, plus those seated in the two rows behind and the two rows in front of the patient.

 

People deemed to have been exposed to possible infection should be especially well briefed on the precautionary measures and their responsibilities, if necessary in a room in the airport. The PHO should assess the need for disinfection of affected parts of the aircraft cabin and arrange for this to be conducted as described for ambulances (see under 7.1.3 above).

 

The use of transport isolators for conveyance of passengers by air

Transport isolators are not available except through the military services.

 

7.1.4 Importation of VHF patients into South Africa by land and sea

The importation of VHF patients into South Africa by land seems less likely than by air, but did occur in 1975 when two people who had been hitch-hiking in Zimbabwe developed Marburg disease shortly after entering South Africa, with the subsequent occurrence of nosocomial infection in a health care worker in Johannesburg.

 

There appears to be a real but small risk of importing cases of VHF into South Africa by sea, with the rat-borne Seoul hantavirus being the most likely candidate. Moreover, there are well-documented instances where crew members and passengers of ships sailing from tropical destinations were found to be suffering from mosquito-borne infections such as yellow fever and dengue fever. It is believed that a ship sailing down the east coast of Africa ignited a large epidemic of dengue fever in Durban in 1926 (before the causative agent of the disease was known). Consequently, PHOs at sea ports of entry should maintain the same  vigilance  and  apply the  same  principles  of  VHF  control  as  prescribed for  major airports, including awareness of the possible importation of disease through disembarkation of passengers and crew members at ports, as well as through medical evacuation of sick persons from ships at sea by boat or helicopter.

 

7.2 Notification of cases of VHF

In terms of regulations promulgated under Health Act 61 of 2003, the VHFs are category A notifiable diseases which should be reported to the Department of Health by telephone within 24 hours of being diagnosed, with written notification on form GW17/5 (Figure 7.1) to follow within 5 days. However, it is important for implementation of control measures that additional information should be supplied, including details of clinical presentation, and this can be achieved conveniently by use of a checklist such as shown in Figure 7.2.

 

Notification should be made by the health care professional tending the patient as soon as possible after it has been decided to proceed on the assumption that VHF may be involved, or after a diagnosis of VHF has been confirmed, depending on which occurs first.

 

Reports should be made to the National Department of Health, Directorate: Communicable Disease Control (CDC), Pretoria, plus the relevant Provincial Coordinator of CDC listed in Table 7.1 below. The National Department of Health will notify World Health Organisation (WHO).

 
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7.3 Public health response to VHF outbreaks

 

7.3.1 Immediate responsibilities of Provincial CDCs during outbreaks of VHF:

●    Ensure that correct laboratory and autopsy investigations are undertaken to establish an aetiological diagnosis (see section 4.3).

●    Investigate the source of the outbreak.

●    Trace and place under observation all VHF contacts in the community at large, beginning with the family and cohorts of VHF patients (see below for definitions of contact and observation).

●    Ascertain whether the hospital authorities are treating VHF patients under appropriate conditions of isolation precautions, and whether the hospital infection control staff havtraced and placed all health care workers who have had contact with the patient/s ofomites under observation.

●    Participate as necessary in the decision-making process as to whether VHF patients should be treated in the primary hospital (the hospital where the diagnosis of VHF was first  suspected)  or  should  be  transferred  to  a  referral  hospital,  and  help  facilitate approved transfers (see section 7.1).

●    Supervise disposal of corpses of VHF patients (see section 6.3.3).

●    Convene a VHF Outbreak Control Committee if necessitated by the circumstances of the outbreak as indicated below.

●    Collate information and disseminate it to those who need to be kept informed, including news media as discussed below.

●    Take any further action as may be appropriate and necessary to attain containment ancontrol of the VHF outbreak, and ensure that no fundamental steps or procedures are overlooked.

 

Key References

 

Indications for convening a VHF Outbreak Control Committee

Hospital staff and provincial CDC personnel can manage small outbreaks of indigenous VHF. For example, where only one person develops Congo fever after being bitten by a tick it may only be necessary for provincial CDC officials to warn family members and cohorts of the patient to take precautions against exposure to ticks and blood of livestock, and to place persons potentially exposed to infection under observation for 2 weeks. The virus is widely distributed in South Africa and it makes no sense to quarantine properties.

 

In contrast, the investigation and control of large outbreaks, or introduced exotic infections (diseases not indigenous to South Africa), may require recruitment and coordination of large teams. Thus, the diagnosis of Ebola fever in a nurse in Johannesburg in 1996 necessitated a search for the source patient, and the identification and screening of about 1,500 potential contacts of the patients at two hospitals and in the community at large, resulting in 350 persons being placed under 3 weeks observation and subjected to intensive investigation if they became sick. It was necessary to co-opt administrators of the affected hospitals plus a quarantine   facility infectious   disease   consultants,   epidemiologists,   military   medical personnel, local health authorities, plus members of ambulance, laboratory, mortuary and blood transfusion services, with operations coordinated by a VHF Outbreak Control Committee which held daily meetings to monitor the situation. Control of the 2008 outbreak of nosocomial infection with the novel Lujo virus in Johannesburg required similar coordination.

 

A multi-disciplinary approach is crucial in public health when responding to large VHF outbreaks. This includes doctors, nurses, epidemiologists, laboratory technicians, environmental health specialists, administrations etc. The response should be organised by forming different sub-committees with roles and responsibilities as shown in Table 7.2 below.

 
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Swanepoel, R. (1985) Recognition and management of viral haemorrhagic fevers: a handbook and resource directory. Sandringham: National Institute for Virology, Department of Health, South Africa.

Swanepoel, R. (1987) Recognition and management of viral haemorrhagic fevers: a handbook and resource directory, 2nd edition. Sandringham: National Institute for Virology, Department of Health, South Africa.

CDC.(1988) Management of patients with suspected viral hemorrhagic fever. MMWR; 37 (no. S-3);1-15.

CDC. (1995) Notice to Readers Update: Management of Patients with Suspected Viral Hemorrhagic Fever - United States. MMWR; 44(25);475-479.

CDC and WHO. (1998) Infection Control for Viral Haemorrhagic Fevers in the African Health Care Setting. Atlanta: CDC.

Siegel JD, Rhinehart E, Jackson M, Chiarello L, and the Healthcare Infection Control Practices Advisory Committee, CDC. (2007) Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings

National Guidelines on Epidemic Preparedness and Response. (2009) Department of Health, South Africa.

 

7.3.2 Tracing of contacts

The purpose of tracing VHF contacts and placing them under observation is to control spread of infection and thus to terminate an outbreak. The office of the relevant provincial Coordinator of CDC is ultimately responsible for tracing and observation of contacts. In practice, infection control officials within hospitals where VHF patients are treated assume responsibility for placing health care workers who have had contact with the patient/s or fomites under observation, and this is done irrespective of whether or not contact took place before or after isolation precautions were instituted.

 

Concurrently, provincial CDC teams operate within the community at large to trace the movements of the VHF patient/s for up to 3 weeks prior to onset of illness in order to establish the source of infection, and to prepare a list of all contacts who are at risk of developing the disease and need to be placed under observation (a period of 3 weeks prior to onset of illness applies for Marburg, Ebola, Lassa and Lujo fevers, but 2 weeks is appropriate for Congo fever and other arbovirus diseases, see section 3).

 

Definitions

An outbreak of VHF is the occurrence of one or more cases of VHF.

 

An  index  patient  in  an  outbreak  of  VHF  is  the  first  patient  in  whom  the  disease  is recognized, and is not necessarily the primary case, i.e. is not necessarily the first person to have become infected in the outbreak. Recognition of the disease in the index patient results in the discovery of the outbreak.

 

A multiple case outbreak of VHF can arise when there is secondary human-to-human spread of infection from a primary case.

 

Common-source outbreaks occur when more than one primary case of infection arises from exposure to a natural source of infection, e.g. infected animal tissues.

 

A source patient is a patient from whom transmission has occurred to produce secondary infection/s.

 

A contact is a person who has been exposed to an infected person, animal or contaminated environment in such a manner as to have had the opportunity to acquire infection.

 

A case contact is a person who has been exposed to an infected person or his/her secretions, excretions, blood or other tissues in such a way as to be at risk of acquiring infection.

 

A source contact is a person who has been exposed to the same external (non-human)

source/s of infection as an infected person.

 

Low risk contacts have had slight or indirect contact with a VHF patient or other source of infection on a single or few occasions.

 

Moderate risk contacts have had close and prolonged contact with a VHF patient or other source of infection. This category includes intimate friends of a VHF patient, relatives and health care workers.

 

High-risk contacts have had what is judged to be definite exposure to VHF infection, e.g. needle-stick with blood from a confirmed case of VHF or similar exposure to animal tissues in a common-source outbreak.

Exposure to infection which constitutes contact for purposes of VHF control includes association with an infected person at any time from onset of fever until 3 weeks later in any of the following ways:

§            Sharing the same residence.

§            Face-to-face contact (1 metre).

§            Skin or mucous membrane contact or penetrating injury with the patient's secretions,  excretions,  blood  or  other  tissuesThis  includes  exposure  to animal tissues or insect bites in situations where such exposure is considered to be the source of infection.

 

In tracing and assessing persons potentially exposed to infection, interviews should be based on questionnaires prepared specifically for the circumstances of the outbreak under investigation (see Figure 7.3 for an example). Persons assessed as having been exposed to infection as defined above, are included on a list of contacts to be placed under observation.

 

7.3.3 Observation of contacts

Observation of contacts of VHF consists of recording temperatures twice daily for 3 weeks (21 days) from the last date of contact with a VHF patient or fomite, and monitoring for signs and symptoms of illness. A 21 day observation period is appropriate for Marburg, Ebola, Lassa and Lujo fevers, but 14 days is adequate for Congo fever, which has a shorter incubation period.

 

Rift Valley fever also has a short incubation period, but the virus seldom causes serious or haemorrhagic disease and person-to-person spread has not been recorded, so active observation is not essential.

 

Persons with ongoing exposure to infection, such as health care workers engaged in nursing of VHF patients, remain under observation while exposure continues to occur, and are kept under observation for the requisite 14 or 21 day period after the last date of potential exposure to infection.

 

Active observation involves contacts being seen twice daily by a medical official charged with this responsibility. Passive observation entails the contact reporting (e.g. by telephone) on their own status to the observation officer. Passive observation is sometimes applied to contacts deemed to be reliable, e.g. health care workers, but this must not be permitted when VHF is involved.

 

It is important to note that the term observation is used in preference to surveillance since the terms active surveillance and passive surveillance are used in a different sense to denote monitoring of a population for the occurrence of a disease either actively through sampling a sub-population or passively through simply testing samples submitted voluntarily to the laboratory.

 

Contacts should be seen at pre-arranged venues and times, which could include their place of employment, e.g. a hospital, or their place of residence, e.g. a farm, and specific arrangements must be made for monitoring of contacts at weekends or other times of absence from duty. All contacts must be seen twice daily at fixed times and any unexplained absences from work or home must be investigated.

 

No medical official should be responsible for monitoring more contacts than can be conveniently managed; in large outbreaks 10 contacts per monitor has been found to be convenient. Temperatures and illnesses reported by contacts should be recorded on a standard list (see an example presented as Figure 7.3), but care should be taken not to ask leading questions: let the contacts describe how they feel.

 

 

Low to moderate risk contacts of VHF (see definitions in 7.3.2 above), including health care workers, may be kept under active observation in their normal environment and employment, but should not leave the town/district until the observation period has ended. This provision is enforceable in law. High-risk contacts of VHF (see definition in 7.3.2 above) must be kept under active observation or placed under quarantine in a suitable facility for the duration of the quarantine period.

 

It is not universally agreed that there is a need to confine high risk contacts to a quarantine facility, provided they are kept under strict active observation. At most, confinement to a quarantine facility should be applied selectively to those considered to be in imminent danger of developing infection, e.g. medical staff who have had a needle-stick injury with blood known to be infected, or those who have developed non-specific illness, e.g. fever and headache.

 

Quarantine facilities need not necessarily be in the same complex as VHF isolation units. Old infectious disease hospitals in isolated localities are ideal, and since confinement of essentially healthy people may be involved, it is advantageous to have access to an outdoor area.

 

Any contact who develops fever (temperature of 38°C or over) or signs and symptoms suggestive of VHF, must be placed in isolation and treated as a suspected case.

Although monitoring of individual patients ceases on completion of the requisite 14 or 21 day period after the last date of potential exposure to infection, outbreaks are only declared to be over after twice the duration of this period has passed, 28 or 42 days since the last knowpotential exposure of any person to infection. Hospital infection control and provincial CDpersonnel must continue to monitor the situation during this precautionary period.

 

Counselling of contacts and health care workers should be considered to counter stress during outbreaks.

 

7.4 Communication with the media

News media can be disruptive during outbreaks of VHF through disseminating incorrect and alarmist information, and through making undue demands on the time of officials who are heavily engaged in controlling the outbreak. However, with proper planning and liaison, the media can be utilized to dispel misconceptions and to disseminate useful information. This is best achieved by conducting communications with the media on an organized basis, and issuing factual, non-sensational statements through specially appointed spokespersons who confine themselves to their areas of competence. For example:

§    Spokespersons for the national and provincial Departments of Health can report on control measures, VHF policy and the status of an outbreak.

§    Members of NICD staff can provide background information on VHFs, including

distribution and occurrence of the diseases, sources of infection, means of spread and mortality. It is useful to have succinct fact sheets on the diseases available for distribution.

§    Senior administrators and clinicians in hospitals treating VHF patients can issue suitably guarded statements on the clinical status of patients, bearing in mind the

rights of patients and relatives to preserve their privacy and anonymity.

 

Information must first be made known to those who have need of it, e.g. it is unacceptable for clinicians or relatives of patients to hear of laboratory findings on the radio, or for officials of the Department of Health to learn of the existence of an outbreak of VHF in the press. Although it is useful to issue approved press statements at set times, it is advisable to have well-informed spokespersons readily available to the media. Refusing to communicate or withholding information does not remove misconceptions. However, officials should not volunteer sensitive information to outsiders or to the media.

 

7.5 Long-term responsibilities of Provincial CDCs include:

●    Drafting contingency plans for managing single or multiple case outbreaks of VHF in the province.

●    Formulating policy as to whether cases of VHF should to be referred to a specifically designated hospital, or whether they should be managed in the hospital where the

diagnosis is first suspected. In practice, decisions will vary with individual circumstances.

●    Acting in conjunction with the provincial Department of Health and Hospital Services to identify and secure the use of facilities and resources needed for managing outbreaks

and delegating responsibilities, including the designation of specific hospitals as VHF

referral centres (see section immediately below).

●    Assisting health care facilities to institute planning and training of health care workers in the recognition, transport, isolation and nursing of patients.

 

Requirements for a VHF referral centre include:

●   Tertiary care hospital which has been specifically designated for referral of VHF patients.

It is usually possible to adapt space within a hospital to serve as an isolation unit for nursing of VHF patients with little or no structural alteration (see section 6.3.1).

●    Laboratory unit capable of performing essential clinical pathology tests for monitoring the treatment of VHF patients. It is best to use an existing laboratory, preferably but not

necessarily within the same complex as the patient isolation unit (see section 6.2).

 

●    Quarantine facility for high-risk contacts of VHF patients, such as health care workers who develop non-specific illness after known exposure to infection. Such persons are moved into the isolation unit if a diagnosis of VHF is confirmed. A quarantine facility is seldom required, and it need not be in the same complex as the isolation unit.

●    Mortuary with facility for refrigerated storage of  corpses until a diagnosis has been confirmed. This need not be within the same complex as the isolation unit and does norequire special facilities provided that the corpse is properly disinfected and shrouded.

●    Clinicians,  nurses,  infection  control  and  laboratory  personnel  trained  for  evaluation, management, nursing and laboratory monitoring of VHF patients with due isolation precautions.

●    A senior person, logically a clinician (plus an alternate), authorized to take decisions on accepting transfer of VHF patients, with appropriate consultation if necessary.

●    An ambulance service with paramedical teams equipped and trained for safe transport oVHF patients.

●    Personal protective and safety equipment required for transport and nursing of VHpatients.

 
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Endpoints of treatment: HBeAg- positive disease

 
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The ideal endpoint is sustained HBsAg loss due to therapy, with/without the development of anti-HBs.

 
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15. What are the Infection Prevention and Control Measures for Household?

 

Patients who have confirmed infectious TB disease are frequently sent home after starting initiation of treatment, even though they are still infectious. At the time of diagnosis they have most likely transmitted infection to household members. Therefore steps must be taken to prevent further spread of infection at home and to screen all household contacts for TB disease or infection. Community health care workers who provide services in the patient’s homes must be trained on the following;

  • educating patients regarding the importance of reporting symptoms or signs of TB disease early and the importance of reporting any adverse effects to treatment
  • counselling of patients on treatment adherence
  • administering DOT and providing support to the patient
  • precautions to be taken when collecting sputum
  • educate the patient and family members on cough hygiene and importance of ventilation
  • the importance of using N95 masks when entering a home/ room of a person with confirmed or suspected infectious TB
  • the importance of undergoing routine medical screening for TB disease and screening for risk factors

1. Administrative controls

  • Ensure treatment compliance at home: Care and support must be provided to the patient by community health workers.
  • Screen all close contacts for TB symptoms: people who are symptomatic must be investigated for TB, children less than 5 years and all people living with HIV in the household must be offered IPT.
  • Education: Educate patients, family members, care providers, and close contacts on the importance of isolation and infection control measures to be implemented at home.
  • Hospital isolation: Patients with confirmed infectious TB disease and family support or homeless must be admitted and isolated in the hospital. This will ensure that risk of infecting others is minimized and treatment compliance.

2. Environmental controls

Windows and doors must be kept open (weather permitting) to increase the ventilation and dilution of infectious droplet nuclei in the house. If a sputum sample needs to be collected at home, this must be done in a well- ventilated preferably outside.

3. Personal protective equipment

  • Patient: Mask: Patients do not need to wear masks at home once they are on adequate treatment (after two weeks of appropriate treatment). Give patients surgical masks and advise them to wear them at home if necessary, during transportation and medical consultations until they are no longer infectious.
  • Healthcare Worker: Respirator: Healthcare workers should wear respirators when entering the home of a patient with infectious TB disease or when transporting a patient with infectious TB. The respirators should be NIOSH-approved (N-95 or higher) or E.U. specified filtering face piece FFP2. Healthcare workers should be provided with respirators after appropriate education and testing.

 
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TB Infection Control measures in the home environment

STEPS TO BE TAKEN BY PATIENTS TO PREVENT TRANSMISSION OF TB IN THE HOME.

 PRECAUTIONARY MEASURES FOR HEALTH- CARE WORKERS

 Cover their mouth and nose when coughing or sneezing

 

Instruct patients to cover their mouth and nose with a tissue when coughing or sneezing

 

Where possible, sleep alone and not in a room with other household members

Wear a respirator when visiting the home of a patient with infectious TB disease or when transporting a patient with infectious TB disease in a vehicle

 

Refrain from having visitors in the home until they are noninfectious.

 

Collect specimens in a well-ventilated area, away from other household members

 

 

1. Introduction

 

The hepatitis C virus (HCV) is a global public health problem and a leading cause of chronic liver disease1 and the past decade has seen several significant advances in the management of persons infected with the virus.

The prevalence of HCV infection in South Africa is not known but has been estimated to be between 0.12 and 1.7 %.3

Phylogenetic analysis of the HCV has revealed 6 main genotypes and most published data relate to genotypes 1, 2 and 3. Genotypes 4, 5 and 6 however represent > 20 % of HCV infections worldwide. Genotype 5 is found predominantly in South Africa4,5 where it represents up to 40 % of all HCV genotypes.

Chronic hepatitis C is an important cause of end stage liver disease and individuals with HCV-related cirrhosis have a 30% risk of developing hepatic decompensation in 10 years and a 1 – 3 % per annum risk of developing hepatocellular carcinoma (HCC).6

Male gender, infection at an advanced age, obesity7, consumption of > 50 g alcohol per day8 and co-infection with the human immunodeficiency virus (HIV)9 are predictive of more rapid progression to fibrosis.

This document is based largely on the American Association for the Study of Liver Diseases (AASLD) 2009 Practice Guidelines and aims to provide clinicians with evidence based approaches to the management of HCV infection. It is recognized that reasonable physicians may deviate from the strategy and remain within acceptable standards of treatment.

 

11.1.1 Pre-exposure vaccination 

This can be used to protect individuals at risk (e.g. travellers to areas in Africa where there are epidemics, the military, and pilgrims to the Meningitis belt and to Saudi Arabia). Travellers to areas affected by meningococcal outbreaks are advised to be vaccinated. Pilgrims to the Hajj and Ramadan Omra, and visitors to Saudi Arabia must obtain a quadrivalent vaccine (against A, C, Y, W135) at least ten days prior to their arrival in the country.

Individuals who are at risk of severe disease or may be at increased risk of occupational exposure should also be offered quadrivalent vaccine. This includes:

  • persons with functional or anatomical asplenia
  • individuals with terminal complement deficiencies
  • laboratory staff in reference laboratories who routinely work with N. meningitidis

11.1.2 Pre-exposure vaccination for university students and boar ding schools 

Vaccination is not currently routinely recommended for 1st year students moving into university residences in SA. However, students and their parents should be informed of the existing very small risk, which could be decreased through vaccination. The disease incidence rate for incoming students into residences compared to the general population in the US in 1999 was 4.6/100 000 compared to 1.7/100 000 person years. Currently there are no local SA data to quantify this risk.

11.1.3 Post exposur e vaccination 

Close contacts of cases that have been given chemoprophylaxis can later be offered appropriate vaccine once the serogroup has been confirmed. This will extend the period of protection. Vaccine can be given up to 4 weeks after exposure as a preventive measure for close contacts; it does not have to be given as an urgent procedure. Use of vaccine does NOT replace the immediate need for chemoprophylaxis in close contacts as the serogroup will be unknown and vaccine does not offer immediate protection.

 

12. DETECTION OF AN OUTBREAK

 

Outbreaks tend to generate high levels of public alarm, especially as these are unpredictable and can develop quickly. Recognition of an outbreak of meningococcal disease particularly in the community can be challenging. Careful but rapid epidemiological investigation and calculation of attack rates is essential in determining whether an outbreak exists and its extent.

Look out for:

  • An increased rate of disease in defined populations and/or an absolute increase in cases
  • A cluster of patients in a particular age group
  • A shift in the age distribution of cases

 

12.1 Classification of cases for determining incidence/attack rates

 

Reported cases should be classified as follows, to allow accurate determination of rates of disease within the population concerned:

Sporadic case

A single case with no known history of close contact with another case

Primary case

A case with no known close contact with another case

Co-primary case

A close contact in whom disease develops within 24 hours of onset of illness in the primary case

Secondary case

A close contact of a primary case who becomes ill more than 24 hours after onset of illness in primary case.

 

 

12.2 Definition of an outbreak

 

12.2.1 Organisation/institutional outbreak 

  • Two or more probable or confirmed cases during a 4 week interval in a group which makes sense epidemiologically (if cases are laboratory confirmed – serogrouping should be the same).

        OR

  • Three cases of confirmed or probable meningococcal disease in ≤ 3 months of the same serogroup (if available) with a history of a common affiliation but no close contact giving a primary disease attack rate of ≥ 10 cases/100 000 persons.

(Reference: Guidelines for the public health management of meningococcal disease in the UK PHLS September 2002, Vol. 5 No 3 reprint 187 - 204 plus appendices)

12.2.2 Community-based outbreak 

  • Three cases of confirmed or probable meningococcal disease within a three month interval of the same serogroup (if available) in persons who live in the same area AND who have not had close contact with each other and do not share a common affiliation. Giving a primary disease attack rate of ≥ 10 cases/100 000 total community population. The population should include recognised political boundaries most closely related to the residences of these cases.
  • The numerator is the number of confirmed cases in the population at risk caused by strains of the same serogroup and that are not distinguishable. Count primary cases together with related co-primary and secondary cases as a single case.
  • The denominator is the population at risk. This population should be clearly defined and make sense to the people who live within and without the selected boundaries. It may not be easy to define such a population. Examples are a rural town/village or a secondary school with its feeder schools.

 

13. MANAGEMENT OF OUTBREAKS

 

13.1 Managing outbreaks in an institution/organisation

 

13.1.1 First steps in investigation 

In educational settings, where a second case has occurred, the risk of a third case may be as high as 30-50%. A prompt investigation of all suspected clusters/outbreaks is essential. When two or more cases are reported from the same institution within a four week period, careful and rapid assessment should be made:

A site visit is recommended by the response team to:

  • Confirm the information available on cases
  • Ensure that all close contacts of cases have already received prophylaxis where indicated
  • Obtain copies of laboratory results and/or clinical notes and review these.
  • Obtain details on serogroup results if available from the RMPRU of the NICD (see contact numbers). If cases are different serogroups they should be managed as sporadic cases.
  • Make a line listing of suspected cases and classify them according to case definitions:

      - Confirmed

      - Probable

      - Possible

  • List the characteristics of the cases in terms of person, time and place.
  • A review of the epidemiological information on each case should be obtained and analysed. (See annexure A)
  • Cases should be classified according to definitions (see above) as:

      - Primary

      - Co-primary and

      - Secondary

  • The number of primary cases should be used to determine the attack rate within the institution. This requires information about the population at risk for use in the denominator. This is not always easily determined in an institution/organisation. The population at risk should make sense epidemiologically and have meaning for the people involved and this is used as the denominator
  • The case fatality rate (number of deaths over the total number of cases) should also be determined

* A primary case with its related co-primary and/or secondary cases is counted as only 1 case in calculating rates of meningococcal disease.

13.1.2 Options for control of institutional clusters/outbreaks 

The public health management options for an institutional outbreak may include:

  • No further action e.g.; if after thorough investigation only two possible cases are identified
  • Giving out information only
  • Giving out information and offering wider prophylaxis in the institution.

13.1.2.1 Role of chemoprophylaxis 

The main decision to be taken is whether to offer wider prophylaxis, and, if so, when and to whom. The evidence on risk suggests a need to act promptly. The target group for chemoprophylaxis should be a discrete group, for example, children and staff of the same preschool group, children of the same school year, children or students who share a common social activity, or a group of friends.

Some considerations in decision-making

  • If two possible cases attend the same institution, whatever the interval between

cases, prophylaxis – for any contacts – is not indicated.

  • If two confirmed cases exist but are caused by different serogroups of meningococcus, they should be regarded as two sporadic cases, whatever the interval between them. Only close contacts of each respective case should be offered chemoprophylaxis.
  • If a cluster/outbreak is confirmed in an institution (based on the criteria discussed above) and cases are from an identified subgroup e.g.; the same class, prophylaxis should be offered to that group.
  • If a cluster/outbreak is confirmed but is not confined to a well define subgroup, advice should be sought from the National Directorate: Communicable Disease Control (012 395 8096) or the NICD (011 386 6000/082 883 9920 - 24 hour Outbreak Hotline) regarding options for control.
  • During outbreaks, information should be given out widely within the institution as appropriate
  • For confirmed clusters/outbreaks among children at preschool groups and primary schools, staff should normally be included in the target group (there is some evidence of increased risk) but not usually in outbreaks among students at secondary schools, colleges, universities (here there is no evidence of increased risk amongst staff).
  • If unsure of the appropriate response always seek expert advice from National Directorate: Communicable Disease Control (012 395 8096) or the NICD (011 386 6000/082 883 9920 - 24 hour Outbreak Hotline).

13.1.2.2 Role of meningococcal vaccine in institutional outbreaks 

For a cluster involving two or more cases of confirmed serogroup group A, C, Y or W135 infections in an institution, quadrivalent polysaccharide vaccine may also be considered for all individuals over the age of two years who were given chemoprophylaxis in order to extend protection. For an outbreak involving a broader institutional community, vaccine is usually preferable, as mass chemoprophylaxis has not been shown to be effective in this setting.

13.1.2.3 Use of nasopharyngeal swabs during outbreaks Obtaining nasopharyngeal swabs for detection of carriage of outbreak strains is not recommended in acute outbreaks because decisions have to be taken before results are available and because carriage rates often bear no relationship to the risk of further cases. In addition a single negative swab does not exclude carriage.

NB: Closing an institution or school is not advised as no reduction in risks would be expected (levels of contact among social networks are unlikely to be reduced and may in fact be increased by closing an institution). Also the success of any intervention will be improved if school/institution attendance is high.

 

13.2 Managing outbreaks in the community

 

2. Diagnosis

 

Identification of these outbreaks can be difficult and must be differentiated from an increase in sporadic disease. In order to do this, detailed epidemiological investigation of cases and calculation of attack rates is essential. In smaller populations, absolute numbers of cases rather than rates of disease may be more accurate. The calculation of age specific attack rates is useful to assess a potential target group for vaccination and the feasibility of such interventions.

Active case finding in the community should be commenced. An alert should be communicated to local general practitioners (GPs), paediatricians, out-of-hours services, clinics and hospitals with a clinical case definition in order to ensure all cases are identified, treated and reported promptly.

If it is established that an outbreak exists, decisions regarding appropriate intervention should be taken by the response team. Seek advice from national experts at the National Directorate: Communicable Disease Control (012 395 8042/8096) or the National Institute for Communicable Diseases (NICD): 011 386 6000/082 883 9920 (24 hour outbreak hotline).

One of the major challenges of interventions in community outbreaks is the difficulty in defining and reaching the target population. It is useful to try to define this group by population boundaries and age group. Such boundaries are often arbitrary but attempts should be made to use existing administrative boundaries e.g.: district, sub-district and/ or region that will make sense to the people who live in the area.

13.2.1 Role of chemoprophylaxis 

Community wide chemoprophylaxis is not recommended as it has not been shown to be of value. All close contacts of individual cases should be given prophylaxis as per the standard protocol.

13.2.2 Role of meningococcal vaccine 

This should be considered in community outbreaks due to serogroup A, C, Y or W135 depending on the serogroup, age group of affected population, geographic boundaries and feasibility. Such decisions should be made after careful assessment of all information by the full outbreak response team and in consultation with relevant experts.

13.2.3 Communications during outbreak 

An agreed public relations strategy is usually required, especially if high levels of interest are anticipated or already evident. This may include:

  • Telephone help-lines
  • Controlled media access to intervention sites
  • Regular coordinated press briefings and press conferences

 

13.3 Major meningococcal epidemics

 

Such a population wide epidemic has not occurred in southern Africa and seems unlikely in the foreseeable future. For an overview of recommendations of how major meningococcal epidemics should be managed see the Weekly Epidemiological Record 22 September 2000, No. 38, 2000, 75, 305–312. Available at http://www.who.int/wer and the Control of Communicable Disease Manual 18th ed. 2004. American Public Health Association.

 
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16. ANNEXURE C: FACTSHEET FOR SCHOOLS/ INSTITUTIONS

 

What is meningococcal infection?

Meningococcal disease is a serious illness caused by a bacterium known as Neisseria meningitidis (meningococcus).

Meningococci are bacteria, which, if looked for, can be found at the back of the throat or nose in about 5 to 20% of healthy adults and children. Only rarely do meningococci overcome the body’s defences and cause serious illness. Such carriage may actually prevent the spread of meningococci and subsequent disease.

When disease does occur, the bacteria usually cause inflammation of the lining of the brain (meningitis) or spread throughout the body via the blood (septicaemia or blood poisoning).

There are five different serogroups of meningococci that cause most disease (A, B, C, W135 and Y). Most cases occur in Gauteng and in Western Cape Province (WCP). In Gauteng serogroups A and W135 cause about 70% of the meningococcal disease, while in WCP the vast majority are due to serogroup B.

Who catches meningococcal infection?

Crowding, passive smoking, low socio-economic status and a preceding viral throat infection, being a new military recruit or first year student in a residence are risk factors. It is not known why some people become ill while others remain symptomless ‘carriers’ of the bacteria.

Most cases occur in children under four years of age. The next highest incidence is recorded for teenagers between 15 and 19 years of age.

95% of cases occur without any connection to other cases (sporadic cases), sometimes two or more cases are connected by those affected having close contact (outbreaks). In some areas, such as west and north Africa there are large periodic epidemics.

How can you suspect someone has meningococcal infection?

A person can become very ill very quickly.

 

Warning signs in children or adults include:

  • Sudden onset of a high fever,
  • Severe headache,
  • Dislike of bright lights (photophobia), Vomiting,
  • Painful joints,
  • Fits or Drowsiness leading to coma

Not all the symptoms may be present

 

In babies illness may be less obvious eg:

  • Fever while the hands and feet are cold,
  • High pitched moaning or whimpering,
  • Blank starring, inactivity, hard to wake up, Suddenly doesn’t want to eat,
  • Neck retraction with arching of the back
  • Pale and blotchy complexion

 

Septicaemia occurs if the bacteria enter the bloodstream. A characteristic rash develops and may start as a cluster of pinprick blood spots under the skin, spreading to form bruises under the skin. The rash can appear anywhere on the body. It can be distinguished from other rashes by the fact that it does not fade when pressed under the bottom of a glass (the drinking glass test). Many people with meningococcal infection may not have the rash.

How do you catch meningococcal infection?

Meningococcus is not highly infectious.

The bacteria are passed by close and fairly prolonged contact, so family members of a case and others who have close contacts with a case may be spreading the same germs. This usually means household or intimate kissing contacts.

Close contact in residential accommodation, such as student halls of residence, and schools can also give the opportunity for the spread of infection.

As the meningococci bacteria cannot survive for long outside the human body, infection cannot be caught from water supplies, swimming pools, or buildings.

How serious is meningococcal infection?

The bacteria only rarely give rise to meningococcal disease. But when they do, infection spreads rapidly and is fatal in about 10% of cases (can be up to 50% with septicaemia). If infection is diagnosed early and treated promptly most people make a full recovery. However, about 1 in 8 people who recover experience some long term effects. These can include headaches, stiffness in the joints, epileptic fits, deafness and learning difficulties.

Can you prevent meningococcal infection?

Meningococcal disease rarely spreads directly from person to person. Over 95% of cases are sporadic and have no identifiable contact. While even in close contacts the risk is low, it is highest in people who live in the same household as the person who became ill, but this is most likely to be due to infection spreading in the household from an asymptomatic carrier to another family member rather than from the person who became ill.

The risk is highest in the 48 hours after the index case presents. Watching household and intimate contacts is important so that early signs of possible meningococcal disease, such as fever, are recognised and treated urgently.

Who should take preventive drugs?

Antibiotics are recommended only for close respiratory contacts of a case

(a) Those who have had prolonged close respiratory type contact (possibly breathing in a fair amount of respiratory droplets) with the case in a household type setting during the seven days before onset of illness. Examples of such contacts would be those living and/or sleeping in the same household, those such as pupils, students, members of the military or police sleeping in the same dormitory, sharing a kitchen where they prepare food together, sharing eating utensils or sharing the same bathroom in a hostel, barracks or residence.

(b) Those who have had transient close contact with a case – but only if they have been directly exposed to close coughing or intimate kissing contact with large droplets or secretions from the respiratory tract within 10 days of a case becoming ill or admitted to hospital. This could include those close enough to have shared items like food and eating utensils, such as close friends at school (but not the whole class). This rule should also apply to children and teachers in crèches.

Prophylaxis NOT usually indicated for: (unless already identified as close contacts as above)

  • All staff and children attending same nursery school or crèche
  • All pupils or students in same school or classroom or tutorial group
  • All work or school colleagues
  • All friends
  • All residents of nursing/residential homes
  • Dry kissing on cheek or mouth. (Intimate kissing would normally bring the contact into the close contact category.)
  • Attending the same social function
  • All those travelling on the same plane, train, bus, or car

The advice above is based on local and international assessment of risk in contacts of actual cases. It must be remembered that taking drugs carries a risk of side effects – which although small can be serious and greater than the risk of disease!

How soon can a child be back at school after meningococcal infection?

All cases of meningococcal meningitis and septicaemia must be notified to the local health authority. Once a child has recovered from meningococcal infection and has been treated to clear the infection, they can return to school. There is no reason to exclude any healthy siblings or other close contacts of the case from school.

Adapted from the Health Protection Agency website: www.hpa.org.uk/infections/topics

 

The 2 classes of assays used in the diagnosis and management of HCV infection are

  • Serologic assays that detect specific antibodies to the HCV (anti-HCV)
  • Molecular assays that detect viral nucleic acid (HCV RNA).

All persons suspected of having acute or chronic hepatitis C or are at increased risk of HCV infection should be tested for anti-HCV.

HCV RNA testing should be performed in

  • Individuals who are anti-HCV positive.
  • Patients in whom antiviral treatment is being considered.
  • Patients with unexplained liver disease whose anti-HCV is negative and are suspected of having acute hepatitis C or are immunocompromised.

Historically qualitative molecular assays have been more sensitive than quantitative molecular assays but, with the increasing sensitivity of the latter, this is no longer the case. For monitoring purposes it is important to use the same laboratory test before and during therapy.

HCV genotyping should be performed in all HCV-infected persons prior to Interferon based treatment in order to plan for the dosage and duration of therapy and to estimate the likelihood of a response.

A liver biopsy should be considered if the treating physician requires information on the fibrosis stage for prognostic purposes or to make a therapeutic decision. It is furthermore useful in identifying that subset of patients with significant fibrosis but normal transaminases and to exclude co-existing liver disease.

Iron overload10  and steatosis11,12  reduce the likelihood of achieving a sustained virologic response (SVR) and should be treated prior to embarking on treatment with Pegylated Interferon (Peg-IFN) and Ribavirin. An SVR can now be achieved in almost 90 % of patients with genotypes 2 and 3 and, in this subset, a liver biopsy need only be done if there is clinical evidence of cirrhosis.

Currently available non-invasive tests may be useful in defining the presence or absence of advanced fibrosis in persons with chronic HCV infection but should not replace the liver biopsy in routine clinical practice.13

 

17. ANNEXURE D: FACT SHEET FOR HEALTH CARE WORKERS – for general distribution Meningococcal Disease

 

A rapid review of primary care and public health measures

Introduction 

Neisseria meningitidis (the meningococcus) is an important cause of meningitis and septicaemia in children and young adults around the world. Meningococcal disease generally occurs sporadically in small clusters around the world with major epidemics limited to certain geographical areas. Meningococcal disease is caused by Neisseria meningitidis (meningococcus). Serogroups A, B, C, Y and W135 are recognised to cause epidemics. In South Africa cases occur year round with definite seasonal increases in late winter/early spring.

Humans are the only natural host of meningococcus. The transmission of N. meningitidis is directly from person to person by droplet spread. Asymptomatic carriage of meningococcus occurs at a rate of 10% in the general population and up to

25% in young adults. Nasopharyngeal carriage of meningococci is much more common than invasive meningococcal disease. The meningococcus does not survive for any significant period in the environment.

The response to a case or cases should be based on a clear understanding of how the organism spreads, produces disease, the clinical picture it presents, what health care is available and what the appropriate public health response is.

Over 95% of meningococcal cases are sporadic and have no identifiable contact. Nasopharyngeal carriers rather than patients with meningococcal disease are generally the source of new infections. The disease is the result of a complex interaction of the bacteria, the environment and the host. While the risk even for close contacts of cases is low, it is highest in people who live in the same household as a case of meningococcal disease. This is mostly likely to be due to infection spreading in the household from an asymptomatic carrier rather than from the index case. The incubation period is 3-4 days (range 2-10).

Clinical Clues 

Early symptoms and signs include malaise, fever and vomiting. Headache, photophobia, drowsiness or confusion, joint pains and a typical haemorrhagic rash of meningococcal septicaemia may develop. A high index of suspicion should always be maintained. Fever and a low blood pressure or slow pulse should heighten the index of suspicion. Early on, the rash may look like rubella or measles. The classic rash is petechial or purpuric in nature and does not fade if you push a drinking glass against it. The rash may be absent.

Patients may present in a comatose state and disease can be very rapidly progressive. In some patients symptoms may be non-specific. Presentation in young infants may include vomiting, pyrexia, irritability and, if still patent, raised anterior fontanelle tension.

The most common serious clinical presentations of meningococcal disease include meningococcal meningitis and meningococcal septicaemia/ meningococcaemia.

Clinical Management 

SUSPECTED MENINGOCOCCAL DISEASE IS A MEDICAL EMERGENCY AND TREATMENT SHOULD NOT BE DELAYED.

Wherever possible ceftriaxone or cefotaxime should always be used for empiric therapy for suspected bacterial meningitis. The recommended drug of choice for proven meningococcal septicaemia or meningitis is IV benzyl penicillin for 5-7 days.

Patients with known or suspected meningitis should be isolated at the time of admission in a single bedded ward with standard AND respiratory droplet precautions. These patients may be transferred to a general ward 24-48 hours after receiving adequate treatment with a drug that will reliably eliminate nasopharyngeal carriage [ceftriaxone/ cefotaxime]. Patients on penicillin alone can only be moved from isolation after being given chemoprophylaxis to eradicate nasopharyngeal carriage

Laboratory investigations 

Do not delay treatment if a blood culture or CSF specimen cannot be immediately obtained.

Specimens should be kept at room or body temperature and away from direct sunlight. Do not refrigerate specimens

Blood culture:

Blood should be collected, using strict aseptic technique, from all suspected cases in blood culture specimen bottles and sent to the laboratory as quickly as possible. Specimens should if at all possible reach the laboratory within 3-4 hours, but not beyond

24 hours. Ideally two sets of blood cultures should be submitted prior to antibiotic therapy. Even in cases of meningitis, blood cultures are useful for diagnosis. About 1–3 ml of blood is needed in children and 5–10 ml in adults.

Cerebrospinal Fluid CSF:

If meningococcal disease is suspected a lumbar puncture is not indicated in the primary care setting and should be considered on arrival at a hospital.

Lumbar puncture should only be performed where no contraindications exist.

The classical clinical signs (bradycardia, papilloedema or hypertension indicating the presence or absence of raised intracranial pressure in children are notoriously inaccurate and should never be relied upon. A lumbar puncture should never be done in a child if there is any suggestion of an impaired level of consciousness. Adult patients with raised intracranial pressure, suspected focal intracranial pathology or who are immune compromised, should have a brain imaging before lumbar puncture. Contraindications for lumbar puncture include focal intracranial pathology or severe brain swelling on imaging, uncorrected bleeding tendency or a low blood pressure.

Cerebrospinal fluid should be sent for protein, glucose, direct microscopy (cell count and Gram stain) culture and antibiotic susceptibility. Rapid bacterial antigen detection tests should not be used routinely as they are not always reliable. They can be used for specific indications.

Skin scrapings

Skin scrapings/impression smears

Skin scrapings and impression smears for Gram stain from the petechial/purpuric site are not recommended as the test tends to give false positive and false negative results.

Notification 

The name and household contact details of a case of the meningococcal disease should be reported immediately by telephone to the Local or District Health Department - for urgent contact follow up. The notification form (GW17/5) should also be completed.

Chemoprophylaxis 

Non-pregnant adults: Ciprofloxacin, rifampicin and ceftriaxone are all effective in reducing the nasopharyngeal carriage rate and are therefore recommended for chemoprophylaxis. Ciprofloxacin offers a major advantage in terms of compliance. Ciprofloxacin is an effective drug for prophylaxis and is the drug of choice for non- pregnant adult contacts.

Children: Rifampicin is the drug of choice where it is available and four doses can be supervised. Ciprofloxacin and ceftriaxone are acceptable alternatives. Ceftriaxone is a painful injection (especially in children), which is often given with lignocain to children.

Pregnancy: Ceftriaxone is the first choice in pregnancy.

Management of contacts

Over 95% of cases of meningococcal disease occur in those without any contact with a case. This means the risk of disease even in close contacts is low, however it is slightly higher than the general population.

Chemoprophylaxis should be offered to all close respiratory contacts (defined as people who have had close, prolonged contact with the case), as soon as possible, i.e. preferably within 24 hours after the diagnosis of the index case, but can be effective up to 10 days. It is recommended in the following situations:

(a) Those who have had prolonged close respiratory type contact with the case in a household type setting during the seven days before onset of illness. Examples of such contacts would be those living and/or sleeping in the same household, those such as pupils, students, members of the military or police sleeping the same dormitory, sharing a kitchen where they prepare food together or sharing the same bathroom in a hostel, barracks or residence.

(b) Those who have had transient close contact with a case – only if they have been directly exposed to close coughing or intimate kissing contact with large droplets or secretions from the respiratory tract within 10 days of a case becoming ill or admitted to hospital. This also applies to health care staff and ambulance or emergency personnel.

(c) Index case should also receive prophylaxis to eliminate nasopharyngeal carriage (unless they have already been treated with ceftriaxone/cefotaxime) as soon as they are able to take oral medication.

Prophylaxis is NOT generally indicated for: (unless already identified as close contacts as above)

• All staff and children attending same nursery school or crèche

• All pupils or students in same school or classroom or tutorial group

• All work or school colleagues

• All friends

• All residents of nursing/residential homes

• Dry kissing on cheek or mouth. (Intimate kissing would normally bring the contact into the respiratory contact category.)

• Food or drink sharing or similar low level of salivary contact

• All those attending the same social function

• All travellers on the same plane, train, bus, or car

Healthcare workers

Health care workers (HCWs) should avoid exposure to droplets by wearing surgical masks and using a suction which does not ventilate into the room, when carrying out airway procedures (i.e. endotracheal intubations/airway management, or examination of the oropharynx), on all patients with suspected meningococcal septicaemia or meningitis.

Chemoprophylaxis is recommended only for those HCWs who have been in direct contact with droplets of respiratory secretions (i.e. mouth or nose is directly exposed to large particle droplets/ secretions) and who have not used appropriate barrier precautions. General medical or nursing care of cases is not usually an indication for prophylaxis

Chemoprophylaxis: Antibiotic options

One of the following:

Non-pregnant Adults

1. Ciprofloxacin 500mg Single Dose/os.

2. Rifampicin 600mg 12 hourly/os x 4 doses

3. Ceftriaxone 250mg Single Dose Im

Pregnant adults

Ceftriaxone 250mg Single Dose Im

Children

1. Ciprofloxacin 10mg/kg single dose/os

2. Rifampicin 10mg/kg 12 hourly/os x 4 doses

3. < 12 years, 125mg Ceftriaxone single dose Im.

Immunization of contacts

If serogroup A, C W135 or Y has been isolated from a case, polysaccharide quadrivalent vaccine may extend the period of protection for close contacts ≥2 years of age that have already received chemoprophylaxis. The cost of such vaccination is at the person’s own expense.

Chemoprophylaxis must always be given regardless of vaccination status.

Surveillance

All contacts should be advised on the early symptoms and signs and advised to report these promptly.

Managing a cluster of cases

When two or more cases of meningococcal disease occur in any institution, such as a school or military barracks etc. within a 4-week period, and these are due to the same serogroup this should be considered an outbreak and managed accordingly. (See section 13 Management of Outbreaks in the main document).

Adapted with permission from: The Craigavon Infection Control Manual edited by

N Damani/J Keyes.

 

18. REFERENCES

 

1. Burke P, Burne SR Allergy associated with ciprofloxacin. BMJ [serial on the internet] 2000;320:679. Available from: http://www.bmj.com/content/320/7236/679.full

2. Biluka OO, Rosenstein N. Prevention andcontrol of meningococcal disease. MMWR [serialon internet] 2005;54( RR-7):1 - 21. Available from: http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr5407a1.htm

3. Cooke RP, Riordan T, Jones DM, Painter MJ. Secondary cases of meningococcal infection among close household contacts in England and Wales 1984 –7. BMJ [serial on the internet] 1989;298:555 - 8. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1835902/?tool=pubmed

4. Edwards EA, Devine LF, Sengbusch CH, Ward HW. Immunological investigations of meningococcal disease. Scand J infect Dis 1977;9:105 - 110.

5. Fischer M, Hedberg K, Cardosi P, Plikaytis BD, Hoesly FC, Steingart KR, et al. Tobacco smokeas risk factor for meningococcal disease. Paediatr Infect Dis J 1997;16:979 - 838.

6. Flexner S. The results of serum treatment in thirteen hundred cases of epidemic meningitis. J Exp Med 1913;17:553 – 576.

7. Heyman LD, editor. Control of Communicable Disease Manual 18th ed. American Public Health Association; 2004.

8. National Institute for Communicable Diseases [homepage on the internet] Communicable Diseases Communique [serial on the internet]September 2003. Available from: http://www. nicd.ac.za/?page=communique&id=56

9. Public Health Laboratory Service, Public Health Medicine Environmental Group, Scottish Centre for Infection and Environmental Health. Guidelines for the public health management of meningococcal disease in the UK. Commun Dis Public Health 2002 ;5(3):178 - 80.

10. Recommendations of the Advisory Committee on Immunization Practices. Meningococcal disease and college students. MMWR [serial on the internet] June 30, 2002; 49 (RR07):11 – 20. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4907a2.htm

11. Rosenstein NE, Perkins BA, Stephens DS, Popvic T, Hughes JM. Meningococcal Disease. N Engl J Med 2001;344( 18):1378 – 88.

12. Stuart JM, Cartwright KA, Dawson JA, Rickard J, Noah ND. Risk factors for meningococcal disease: a case control study in south west England. Community Medicine 1988;10:139 - 146.

13. The Northern Ireland Infection control Manual. [homepage on the internet] Communicable Diseases [database on the internet] Available from: http://www.infectioncontrolmanual.co.ni/ diseases/meningitis.html

14. World Health Organization [homepage on the internet] Meningococcal Meningitis Fact Sheet 141, 2003 [database on the internet]. Available from: http://www.who.int/mediacentre/factsheets/2003/fs141/en/

15. World Health Organization [homepage on the internet] International Travel and Health.

Chapter 6: Vaccine-preventable diseases and vaccines [database on the internet] Available from: http://www.who.int/ith/en/

 

19. COMMUNICABLE DISEASE CONTROL COORDINATORS OFFICES

 

3. Treatment of chronic hepatitis C

 

PROVINCE

ADDRESS

TEL.NO

FAX.NO

National

Department of Health

Private Bag x828, PRETORIA, 0001

(012) 395 8096

(012) 395

8905/6

Northern Cape

Department of Health, Northern Cape Province

Private Bag x5049,

KIMBERLEY, 8301

(053) 830 0526

(053) 830 0655

North West

Department of Health, North West Province Private Bag x2068,

MMABATHO, 2735

(018) 397-2600

(018) 397 2627

Limpopo

Department of Health, Limpopo Province Private Bag x9530,

POLOKWANE, 0700

(015) 293 6281

(015) 291 3899

Western Cape

Department of

Health, Western Cape

Province

P O Box x2060, CAPE TOWN, 8000

(021) 483 6062

(021) 483 2682

Eastern Cape

Department of Health, Eastern Cape Province Private Bag x0038,

BHISHO, 5605

(040) 609

94232

(040) 609 3597

Free State

Department of Health, Free State Province

P O Box x517, BLOEMFONTEIN,

9300

(051) 408 1734

(051) 408 1417

 

PROVINCE

ADDRESS

TEL.NO

FAX.NO

Gauteng

Department of Health, Gauteng Province Private Bag x085, MARSHALLTOWN,

2107

(011) 355 3867

(011) 355 3338

Mpumalanga

Department of Health, Mpumalanga Province Private Bag x1128,

NELSPRUIT, 1200

(013) 766 0000

(013) 766 3473

KwaZulu-Natal

Department of Health, KwaZulu-Natal Province

Private Bag x9051,

PIETERMARITZBURG,

3200

(033) 395 2051

(033) 342 5830

 

The goal of therapy is to prevent complications and death from
HCV infection.

The currently recommended therapy of chronic hepatitis C
infection is the combination of a Peg-IFN and Ribavirin.14-16

Treatment should be considered in all adults with confirmed chronic hepatitis C and particularly in those who are at increased risk of developing cirrhosis. For patients in whom liver histology is available, treatment is indicated if advanced fibrosis (F2 or F3 according to the METAVIR scoring system) is present. As with all decisions in medicine, a balance must be struck between the benefit and risk of therapy and fibrosis is not a prerequisite for treatment.

Symptomatic cryoglobulinaemia is an indication for anti- viral therapy regardless of the stage of liver disease.

Additional factors that may influence the decision to treat are age, occupations in which there is a risk of transmission to others, quality of life, co-morbidities, the potential for serious side effects and the likelihood of treatment success.
Treatment may worsen psychiatric disorders and, in such patients, a pre-treatment psychiatric evaluation and close follow-up are mandatory.

Treatment is currently contraindicated in

  • Age less than 2 years.
  • Untreated thyroid disease.
  • Autoimmune hepatitis or other autoimmune condition known to be exacerbated by Peg-IFN or Ribavirin.
  • Decompensated liver disease.
  • Severe concurrent medical disease such as severe hypertension, significant coronary artery disease, heart failure, chronic obstructive pulmonary disease, poorly controlled diabetes mellitus.
  • Pregnancy or an unwillingness to use adequate contraception.
  • Major uncontrolled depressive illness.
  • Known hypersensitivity to drugs used to treat HCVinfection.
  • Solid organ transplantation (heart, lung or kidney).

Obesity is believed to play a role in the progression of fibrosis in HCV-infected individuals and may adversely affect treatment outcome. Patients with a BMI > 25.0 kg/m2  should therefore be advised to lose weight.

Excessive alcohol consumption results in rapid progression of fibrosis, enhances viral replication and may interfere with treatment. Although no consensus exists, it seems reasonable to recommend either the complete cessation of alcohol intake or restricting its use whilst on treatment. Alcoholics should be abstinent for at least 1 year before commencing anti-viral treatment.

All patients with chronic hepatitis C should be screened for hepatitis A and B and, if not immune, offered vaccination.

Venesection is recommended in patients in whom a liver biopsy reveals significant iron overload.

There is no evidence that herbal products have a role in the treatment of patients with acute or chronic hepatitis C.

Because of the slow evolution of chronic hepatitis C, treatment responses are defined by surrogate virologic parameters rather than clinical endpoints.
The major predictors of a SVR are viral genotype and pre- treatment viral load.14-16 SVR rates are higher in genotypenon-1 infections (predominantly genotypes 2 and 3) and in those with a viral load of < 600,000 IU/mL. Other less consistently reported baseline characteristics associated with a favourable response are female gender, age < 40 years, lower body weight (< 75 kg), the absence of insulin resistance, ALT levels > 3 times the upper limit of normal and the absence of bridging fibrosis or cirrhosis.

Patients with HCV-related cirrhosis, who achieve an SVR regardless of genotype, should continue to be monitored at 6 to 12 month intervals for the development of HCC.17

A RVR is highly predictive of achieving a SVR independent of genotype and regardless of treatment regimen.18,19

Failure to achieve at least a pEVR is the most robust means of identifying non-responders in patients with genotype 1 infection.15,20-22 As less than 3 % of such individuals achieve an SVR, this is an indication to stop treatment. The clinical utility of an EVR is less helpful in patients with genotypes 2 and 3 infection since a majority of such individuals clear the virus by
12 weeks and respond to therapy.

 

4. Treatment of HCV genotypes 1 and 4 infection

 

Duration of treatment: 48 weeks.

Therapeutic options

Peginterferon α-2a 180 μg per week subcutaneously + Ribavirin according to body mass (≤ 75 kg: 1,000 mg per day; < 75 kg but ≤ 90 kg: 1,200 mg per day; < 90 kg: 1,400 mg per day).15

or

Peginterferon α-2b 1.5 μg/kg per week subcutaneously + Ribavirin according to body mass (< 65 kg: 800 mg per day; ≥ 65 kg but ≤ 85 kg: 1,000 mg per day; < 85 kg but ≤ 105 kg:
1,200 mg per day; < 105 kg: 1,400 mg per day).14,24

Treatment may be discontinued

  • In patients who do not achieve at least a pEVR
  • In patients who achieve a pEVR but are still HCV RNA positive at week 24.

In patients in whom viral clearance is delayed (HCV RNA becomes negative between weeks 12 and 24), consideration should be given to extending therapy to 72 weeks.25,26

Patients in whom treatment is continued through 48 to 72 weeks and whose HCV RNA is negative at end of treatment should be retested for HCV RNA 24 weeks later to establish whether an SVR has been achieved.

 

Introduction of this chapter

 

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Chapter One

 

Sub Heading for Chapter Once

 

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Test Chapter Three Heading

 

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