3. BACKGROUND TO THE VIRAL HAEMORRHAGIC FEVERS
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
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.
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 prostration. Within 2-3 days patients develop sore throat, vomiting, abdominal or chest (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.
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) (fatality rates ≥50%) in North and South 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.
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. Within two 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 within 48 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 and myocardial 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 of the 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 day 2-4 patients may exhibit lassitude, depression and somnolence, and have a flushed appearance with injected conjunctivae or chemosis. Tenderness localizes in the right upper quadrant of the abdomen, and hepatomegaly may be discernible. Tachycardia is common and 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; AST ≥200U/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.
3.2.2 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 patients may succumb or undergo 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.
3.2.3 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 theoretically possible that such a patient could initiate urban outbreaks 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
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, melaena and epistaxis. Central nervous system symptoms include aggressive and altered behaviour, confusion and somnolence. Dehydration is severe in the absence of administration of fluids.
Clinical pathology of Marburg and Ebola fevers
There may be transient leucopenia followed 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.