Are available as co-formulated tablets containing 20 mg of artemether and 120 mg of lumefantrine. The recommended treatment for persons weighing more than 34 kg is 4 tablets twice a day for 3 days

One of the following ACTs is currently recommended: artesunate + amodiaquine, artesunate + sulfadoxine–pyrimethamine, artesunate + mefloquine, or artemether–lumefantrine. The choice of ACT in a country or region will be based on the level of resistance of the partner medicine in the combination.

Severe falciparum malaria (Table 65.2)

Two classes of drug are currently available for the parenteral treatment of severe malaria: the cinchona alkaloids (quinine and quinidine) and the artemisinin derivatives (artesunate, artemether and artemotil). Recent evidence ^4,⁵ suggests superior efficacy of artesunate over quinine in adults. The dosage of artemisinin derivatives does not need adjustment in vital organ dysfunction.

Table 65.2 WHO recommendations for treatment of severe P. falciparum malaria

Artesunate

2.4 mg/kg i.v. or i.m. given on admission (time = 0), then at 12 hours and 24 hours, then once a day is recommended in low transmission areas or outside malaria endemic areas. If artesunate is not available, quinine i.v. should be used.

For children in high transmission areas, one of the following antimalarial medicines is recommended as there is insufficient evidence to recommend any of these antimalarial medicines over another for severe malaria:

• artesunate 2.4 mg/kg i.v. or i.m. given on admission (time = 0), then at 12 hours and 24 hours, then once a day

• artemether 3.2 mg/kg i.m. given on admission then 1.6 mg/kg body weight per day

• quinine 20 mg salt/kg on admission (i.v. infusion or divided i.m. injection), then 10 mg/kg every 8 hours; infusion rate should not exceed 5 mg salt/kg per hour

Following initial parenteral treatment, once the patient can tolerate it, current practice is to switch to oral therapy and complete a full 7 days of treatment. In non-pregnant adults, doxycycline (3.5 mg/kg per day) is added to quinine, artesunate or artemether and should also be given for 7 days. During pregnancy or in children, clindamycin is used instead of doxycycline.

In patients with features of severe malaria, a mixed infection with falciparum should be assumed even if only a benign species is identified in the film. Occasionally, severe malaria can occur with vivax species. If the clinical suspicion is high, a therapeutic trial of antimalarial treatment is justified, even if the film is negative.

Severe malaria leads to severe septic shock, and the principles of management are the same including resuscitation and provision of supportive treatment. These patients are at risk of acute lung injury but do need adequate fluid resuscitation. Convulsions must be actively treated. Complications should be managed as they present. The threshold for dialysis should be low. Pneumonia and bacterial septicaemia are also common, and should be recognised and treated.

Exchange blood transfusion (EBT) has been used in severe malaria. However, recent WHO guidelines ³ do not recommend EBT, and note the lack of consensus on indications, benefits and dangers involved, or on practical details such as the volume of blood that should be exchanged. Traditional indications for EBT if pathogen-free compatible blood is available are:

• parasitaemia > 30%, even in the absence of clinical complications

• parasitaemia > 10% in the presence of severe disease, especially cerebral malaria, acute renal failure, ARDS, jaundice and severe anaemia and/or poor prognostic factors (e.g. elderly patient, late stage parasites (schizonts) in the peripheral blood)

• parasitaemia > 10% and failure to respond to optimal chemotherapy after 12–24 hours

OTHER FORMS OF MALARIA

Treatment of other forms of malaria is outlined in Table 65.3.

Table 65.3 WHO recommendations for treatment of P. vivax, ovale and malariae malaria

Uncomplicated P. vivax malaria

Chloroquine 25 mg base/kg divided over 3 days, combined with primaquine 0.25 mg base/kg, taken with food once daily for 14 days is the treatment of choice for chloroquine-sensitive infections. In Oceania and Southeast Asia the dose of primaquine should be 0.5 mg/kg.

Amodiaquine (30 mg base/kg divided over 3 days as 10 mg/kg single daily doses) combined with primaquine should be given for chloroquine-resistant vivax malaria.

Complicated P. vivax malaria

Treatment is the same as severe P. falciparum malaria.

P. ovale and malariae malaria

Treatment is the same as uncomplicated vivax malaria but without primaquine for malariae.

PROGNOSIS

Data are largely derived from endemic areas where presentation with convulsions, acidosis or hypoglycaemia is associated with a poorer outcome. Mortality in an artesunate-treated severe falciparum malaria group in one trial ⁵ was still high (15% vs. 22% in quinine-treated patients). In cerebral malaria, mortality is around 20%. The prognosis of cerebral malaria is frequently determined by the management of other complications such as renal failure and acidosis, but neurological sequelae are increasingly recognised.

TUBERCULOSIS

EPIDEMIOLOGY

Tuberculosis continues to be a devastating disease worldwide, with an estimated 8 million new cases and 2.6–2.9 million deaths annually. Medical conditions which predispose to tuberculosis include HIV infection, silicosis, diabetes, chronic renal failure/haemodialysis, malnutrition, solid organ transplant, gastrectomy, jejunoileal bypass, injection and inhalational drug abuse, alcoholism, chronic pulmonary disease and prolonged steroid use. Social factors such as institutional living conditions (nursing homes, homeless shelters, prisons), urban dwelling and poverty are associated with an increased risk of tuberculosis.

PATHOGENESIS

Tuberculosis (TB) is usually caused by Mycobacterium tuberculosis and four others (M. bovis, M. africanum, M. microti and M. canetti) grouped in the Mycobacterium complex. The genus Mycobacterium consists of many different species, all of which appear similar on acid-fast staining.

Inhalation of tubercle bacilli leads to one of four possible outcomes: immediate clearance of the organism, primary or progressive primary disease, chronic or latent infection, and reactivation disease. Latent infection refers to the presence of tuberculous infection (positive tuberculin reaction) without the disease.

The majority of primary TB infections are asymptomatic; clinical pneumonia occurs in 5–10% of adults with a higher incidence in children and those suffering from HIV infection. M. tuberculosis microfoci that have remained dormant after primary infection may undergo reactivation resulting in secondary TB, often referred to as reactivation disease. This is responsible for 90% of TB in patients not infected with HIV.

CLINICAL SPECTRUM

The manifestations of TB are protean and TB should be considered in the differential diagnosis of all patients with fever of unknown origin, night sweats, or unexplained weight loss. Besides the lungs, it can also involve the central nervous system, peritoneum, pericardium, gastrointestinal and genitourinary tract, bone and joints, lymph nodes and skin. Occasionally it can be disseminated in the form of miliary tuberculosis.

PULMONARY TUBERCULOSIS

Typically, reactivation disease starts in the apex of one or both lungs, leading to chronic inflammation and fibrosis. Pulmonary TB is often asymptomatic initially, though cough, dyspnoea and haemoptysis are useful clues. Hilar lymphadenopathy is the most common pulmonary presentation in children. It may occasionally present very late as extensive disease in both lungs with severe lung damage including cavitation, and pneumothoraces.

Sputum, induced sputum, bronchial washings and transbronchial biopsy of infiltrates should be performed to isolate the organism. Computed tomography (CT) is more sensitive than chest radiography for detection of infiltrates, cavities, lymphadenopathy, miliary disease, bronchiectasis, bronchial stenosis, bronchopleural fistula and pleural effusion.

Tuberculous pleural effusion

Pleural TB may result in pleural effusion, pleural empyema with or without bronchopleural fistula. Thoracocentesis and pleural biopsy should be performed. Positive cultures are found in less than 25% of cases. Pleural biopsy shows granulomatous inflammation in approximately 60% of patients. However, when culture of three biopsy specimens is combined with histological examination, the diagnosis can be made in up to 90% of cases. Pleuroscopy-guided biopsies increase the yield in pleural sampling.

The pleural fluid should be examined for total protein and glucose content, WBC count and differential, and fluid pH. Raised adenosine deaminase (ADA) levels have been found to be useful in the diagnosis, with levels more than 70 U/l in pleural fluid strongly favouring tuberculous aetiology and levels less than 40 U/l making it less likely; ADA also has a good negative predictive value. However, ADA assay should not be considered as an alternative to biopsy and culture.⁶ Raised γ-interferon has also been found to be useful. The clinical utility of PCR testing in tuberculous pleural effusion is limited.⁷

TUBERCULOUS MENINGITIS

Tuberculous meningitis ⁸ remains the most serious relevant manifestation of TB to the intensive care physician. Tuberculous meningitis results from haematogenous spread. There is a thick gelatinous exudate around the sylvian fissures, basal cisterns, brainstem and cerebellum.

The majority of patients with TB meningitis have had recent contact with TB, followed by a prodrome of vague ill-health lasting 2–8 weeks. Later, signs and symptoms of meningeal irritation appear. Cranial nerve palsies occur in 20–25% of patients and papilloedema may be present. Choroidal tubercles are rare but almost pathognomonic. Visual loss due to optic nerve involvement may occasionally be the presenting feature. There may be focal neurological deficit such as hemiplegia; extrapyramidal movements and seizures are other manifestations. As the disease progresses, cerebral dysfunction sets in and the mortality approaches 50%.

Diagnostic algorithms have been suggested but they are unlikely to provide sufficient assurance to confidently exclude other diagnoses.^9,¹⁰ The key is a high degree of clinical suspicion, especially in the critically ill. In one study, TB meningitis was considered as a diagnosis in only 36% of cases and only 6% received immediate treatment.¹¹

Definitive diagnosis of TB meningitis depends upon the detection of the organism in CSF, either by smear examination or by bacterial culture. The yield from smear is variable, but generally low. Culture of the CSF for the organisms is not invariably positive. Raised ADA level is not specific.

The sensitivity and specificity of a commercial nucleic acid amplification assay for the diagnosis of TB meningitis are 56% and 98% respectively.¹² Careful bacteriology is as good as, or better than, the commercial nucleic acid amplification assays, but molecular methods may be more useful when antituberculous drugs have already been commenced. However, the diagnosis of TB meningitis cannot be excluded by these tests, even if both are negative.⁸

CT or magnetic resonance imaging (MRI) of the brain, which are sensitive but not specific, may reveal thickening and intense enhancement of meninges, especially in basilar regions. Hydrocephalus and tuberculomas may also be present. Infarcts due to either vasculitis or mechanical strangulation of the vessels by the surrounding exudates are detected in up to 40%. The radiological differential diagnosis includes cryptococcal meningitis, cytomegalovirus encephalitis, sarcoidosis, meningeal metastases and lymphoma.

TUBERCULOUS EMERGENCIES

• Massive haemoptysis

• Respiratory failure

• Pericardial tamponade

• Small intestinal obstruction

• Tuberculous meningitis

• Status epilepticus due to tuberculomas

DIAGNOSIS OF TUBERCULOSIS

Once considered, isolate the patient and sample all potential sites for acid fast staining and culture. Pleural, peritoneal, pericardial and other fluids must be cultured and analysed for differential cell count, protein, glucose and ADA. Histological examination for granulomatous infection is useful in bronchial, pleural, peritoneal and skeletal tissues. Peritoneal biopsies are best obtained via laparoscopy. Newer culture media have reduced the time for culture to 2 weeks.

Nucleic acid amplification (NAA) tests amplify target nucleic acid regions that uniquely identify the M. tuberculosis complex, and are available as commercial kits or in-house assays. They can be applied to clinical specimens within hours. Based on current evidence, NAA tests cannot replace conventional diagnostic approaches using microscopy and culture.

The current status of NAA tests is summarised below:

• NAA tests, in general, have high specificity and positive predictive value; they are useful in ruling in rather than ruling out TB.

• A positive NAA test in smear-positive patients can differentiate M. tuberculosis from non-tuberculous mycobacteria (NTM); treatment can then be started.

• The interpretation of a smear-positive/NAA-negative test is controversial.

• Treatment can be started in smear-negative/NAA-positive patients with a high clinical suspicion, particularly when prompt treatment is imperative.

• If clinical suspicion is high, TB is not excluded by both a negative smear and NAA.

• NAA results may remain positive for months. This method should be used only for initial diagnosis and not follow-up.

Serodiagnosis of tuberculosis, despite remaining a poor confirmatory tool in areas of low incidence, may be useful in exclusion of disease.

Drug susceptibility tests should be performed on initial isolates from all patients in order to identify an effective antituberculous regimen, and may have to be repeated if the patient remains culture positive after 3 months.

TREATMENT OF TUBERCULOSIS

Local guidelines are of paramount importance and advice should be sought. The commonest regimen used is isoniazid (5 mg/kg) and rifampicin (10 mg/kg) for 6 months with the addition of pyrazinamide (15–30 mg/kg) and ethambutol (5–25 mg/kg) for the first 2 months. It has been suggested that instead of ethambutol, prothionamide is preferable as a fourth drug in tuberculous meningitis. Steroids are generally recommended in tuberculous meningitis ^13,¹⁴ and pericardial tuberculosis.

DRUG-RESISTANT TUBERCULOSIS

This is an increasing problem. Multidrug-resistant tuberculosis (defined as resistance to two or more of the first-line antituberculous drugs, usually isoniazid and rifampicin) can be primary (no prior antituberculous therapy) or secondary (development of resistance during or after chemotherapy).

Diagnosis depends upon collection of adequate specimens for culture prior to the initiation of antituberculous therapy. In critically ill patients, rapid diagnosis of drug resistance is of paramount importance. With the improvements in the culture methods and the availability of newer techniques, including phage-based assays, rapid identification of resistance is possible.¹⁵ When resistance is present to two or more first-line agents, parenteral aminoglycoside (streptomycin, amikacin, etc.) and fluoroquinolones are generally added. Specialist microbiological advice should be sought.

TYPHOID FEVER

Typhoid fever is caused by Salmonella typhi and less commonly by paratyphi A, B and C. Even non-typhoidal salmonellae have occasionally been isolated.¹⁶ Typhoid fever, common in South and South-East Asia, is almost exclusively caused by fecal–oral spread. In the developed world, cases are either seen in international travellers or occasionally caused by infected food.

DIAGNOSIS ¹⁹

Anaemia, leukopenia/leukocytosis and deranged liver function are common. Blood cultures are positive in up to 80% of cases, and are the investigation of choice; 10–15 ml yields higher success than smaller volumes.²⁰ Though culturing urine, stool, rose spots and duodenal contents is useful, bone marrow culture is the most sensitive, and its yield remains unchanged up to 5 days after commencement of treatment.²¹

Serodiagnosis using Widal tests has limited clinical value. Commercial serological tests such as Typhidot-M and Tubex, which detect IgM antibodies against different S. typhi antigens, have a higher sensitivity and specificity.²² Nested PCR is very promising in the diagnosis of typhoid fever.

TREATMENT ²³

In both uncomplicated and complicated typhoid fever, the treatment of choice is the fluoroquinolones (ciprofloxacin or ofloxacin 15 mg/kg for 5–7 days in uncomplicated and 10–14 days in complicated infections). In fluoroquinolone-resistant cases, azithromycin, cefixime or ceftriaxone can be used. There is some concern in using fluoroquinolones in children as they have been shown to cause cartilage toxicity in immature animals, but this appears largely unfounded in clinical trials.^24,²⁵

Dexamethasone reduces mortality in severe typhoid fever: delirium, obtundation, stupor, coma, or shock.²⁶ Ileal perforation, which may occur late, classically in the third week of febrile illness, requires prompt surgical intervention, and segmental resection has been recommended as the procedure of choice.^27,²⁸

CHOLERA

Cholera is caused by enterotoxin-producing Vibrio cholerae.²⁹ The incubation period varies from 12 hours to several days. The clinical case:infection ratio is about 1:10. It starts abruptly with painless watery diarrhoea associated with vomiting and painful muscle cramps. Vomiting may be the first symptom before diarrhoea.

Stool examination shows neither leukocytes nor erythrocytes. Dark field microscopy examination may reveal rapidly motile, comma-shaped bacilli in fresh stool. Commercial assays detecting O antigen in stool samples, which take less than 5 minutes, are now available and are as sensitive and specific as stool culture. Aggressive rehydration is the mainstay of treatment; very large quantities of fluid may be needed. Adjunctive antimicrobial therapy is effective in shortening the duration of diarrhoea. Single dose doxycycline (300 mg) or single dose ciprofloxacin (1 g) is very effective, but azithromycin has recently been shown to be superior.³⁰

LEPTOSPIROSIS

This is caused by Leptospira interrogans. It occurs due to exposure to contaminated water. The disease has an incubation period of 7–10 days with a range of 2–20 days. It has two phases: the septicaemic phase and the immune phase. Clinical features include conjunctival suffusion or haemorrhages (useful diagnostic clue), uveitis, severe muscle tenderness, non-oliguric renal failure, hypokalaemia, hepatic dysfunction, pulmonary haemorrhage, ARDS, myocarditis, rhabdomyolysis, thrombocytopenia, DIC, haemorrhage into the skin and internal organs, and digital gangrene. Weil’s syndrome is characterised by hepatorenal dysfunction, bleeding diathesis and pulmonary involvement.

Diagnosis is made with isolation of the organism by culture (blood, urine, CSF) or serology using the gold standard microscopic agglutination test (MAT). Both culture and serology should be attempted if available, and local microbiological advice should be sought. Treatment is with penicillin G or ceftriaxone. In penicillin-allergic patients, doxycycline can be used.

DENGUE FEVER

EPIDEMIOLOGY AND PATHOGENESIS

It is estimated 100 million cases of dengue fever and 250 000 cases of dengue haemorrhagic fever occur each year throughout the world.³¹ The causative agent is a flavivirus with four distinct serogroups, and it is transmitted by the bite of Aedes mosquitoes. Two patterns of transmission have been recognised: epidemic due to isolated introduction of dengue to a region, usually due to a single serotype, and hyperendemic, referring to the continuous circulation of multiple dengue virus serotypes.

Following a mosquito bite, viraemia begins and usually lasts up to 7 days. Infection with one of the four serotypes (primary infection) provides life-long immunity against that serotype but not against the other serotypes (secondary infection). Epidemiological studies have suggested that the risk of severe disease (dengue haemorrhagic fever/dengue shock syndrome) is significantly higher in secondary than primary infection.

CLINICAL FEATURES

The clinical presentation varies from mild febrile illness to severe haemorrhagic fever. Most infections are asymptomatic. WHO classifies dengue infection as undifferentiated fever, dengue fever (DF) and dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS).

Dengue fever has an incubation period of 3–14 days and is characterised by the sudden onset of fever, severe headache, retro-orbital pain on moving the eyes, and fatigue. It is often associated with severe myalgia and arthralgia (breakbone fever). Maculopapular rash, flushed facies and injected conjunctiva are common. Haemorrhagic manifestations can occur in DF and should not be confused with DHF.

Dengue haemorrhagic fever occurs primarily in children < 10 years and is characterised by plasma leakage syndrome and haemoconcentration (20% or greater rise in haematocrit), pleural effusion or ascites. The diagnosis is made if the following symptoms and signs are present: bleeding, a platelet count < 100 000 per mm³ and plasma leakage. Haemorrhagic manifestations without evidence of plasma leakage do not constitute DHF. The mechanism underlying the profound capillary leak in DHF but not in DF is poorly understood. It is important to watch for the onset of DHF which typically occurs 4–7 days after the onset of the disease, approximately at the time of defervescence. Decrease in platelet count and rise in haematocrit are useful clues.³²

Dengue shock syndrome is characterised by profound hypotension and shock.

DIAGNOSIS

Dengue should be suspected in all febrile patients who live in, or have returned from, endemic areas in the preceding 2 weeks. Leukopenia, thrombocytopenia with a positive tourniquet test, and raised AST are frequently seen; the former two tests have the highest sensitivity (about 90%) for the diagnosis of early dengue.³² A positive tourniquet test cannot differentiate DHF from DF.

IgM immunoassay allows rapid confirmation of the diagnosis. If it is negative, particularly in the first 6 days of the illness, the diagnosis should not be ruled out. Acute and convalescent sera should be analysed by haemagglutination assay or IgG immunoassay for a fourfold rise in titre. Virus isolation and reverse transcriptase PCR (RT-PCR) are available but are usually not used in the clinical setting.

TREATMENT

Supportive therapy for shock, especially appropriate and prompt fluid replacement, can reduce mortality. WHO guidelines on fluid management are available.³³ In DSS, steroids have not been shown to be useful.³⁴ Once capillary leakage abates, fluid overload and pulmonary oedema can become problematic.

HANTA VIRUS

Hantaviruses are rodent viruses distributed worldwide, with over 150 000 cases being registered annually. There are two major clinical syndromes: hantavirus cardiopulmonary syndrome (HCPS) and haemorrhagic fever with renal syndrome (HFRS). Both are acquired by exposure to aerosols of rodent excreta.

HANTAVIRUS CARDIOPULMONARY SYNDROME

The incubation period is about 3 weeks. There are two phases: the prodromal phase is characterised by a relatively mild febrile illness, typically lasting 3–5 days, and the cardiopulmonary phase is characterised by severe, rapidly progressive respiratory failure. In the latter phase, acute pulmonary oedema due to increased capillary permeability occurs. Progress from the prodromal to cardiopulmonary phase is dramatic. In severe cases, significant myocardial depression also occurs, resulting in low cardiac output and hypotension. Acute renal failure can occur. The combination of thrombocytopenia, myelocytosis, haemoconcentration, lack of significant toxic granulation in neutrophils, and more than 10% of lymphocytes with immunoblastic morphological features is highly sensitive and specific. Enzyme-linked immunosorbent assay (ELISA) for IgM and IgG antibodies is useful in the diagnosis. Hantavirus can also be detected by tissue RT-PCR. Immunohistochemical staining of tissue reveals hantaviral antigen. Treatment is mainly supportive with intravenous fluids, inotropes, mechanical ventilation, extracorporeal membrane oxygenation and blood products. Intravenous ribavirin is probably ineffective in the treatment of HCPS in the cardiopulmonary stage.³⁵

HAEMORRHAGIC FEVER WITH RENAL SYNDROME

This is characterised by fever, renal failure and haemorrhagic manifestations. The disease has five progressive stages: febrile, hypotensive, oliguric, diuretic, and convalescent. Non-specific constitutional symptoms are followed by shock, oliguria, DIC and haemorrhagic manifestations. Diagnosis is made using ELISA for IgG and IGM antibodies. Treatment is supportive, including renal support. Ribavirin has been found to be useful.³⁶

ARBOVIRAL ENCEPHALITIS

Viruses transmitted to human beings by the bites of arthropods (especially mosquitoes and ticks) are major causes of encephalitis worldwide. Although different viruses can cause encephalitis, an antigenically related group of flaviviruses accounts for a major proportion of cases. These include mosquito-borne diseases such as Japanese encephalitis, West Nile virus encephalitis, St Louis encephalitis, Murray Valley encephalitis ³⁷ and tick-borne encephalitis. Viral encephalitis is characterised by a triad of fever, headache and altered level of consciousness. Other common clinical findings include disorientation, behavioural and speech disturbances, and focal or diffuse neurological signs such as hemiparesis or seizures. The incubation period is usually 5–15 days. Other manifestations include recurrent seizures, including status epilepticus, a flaccid paralysis resembling that of poliomyelitis, and parkinsonian-type movement disorders. Flavivirus encephalitis is usually diagnosed by IgM capture ELISA.Treatment is supportive. Interferon-α, ribavirin and intravenous immunoglobulin have all been tried with mixed success.

VIRAL HAEMORRHAGIC FEVERS (VHF)

EPIDEMIOLOGY

Lassa virus, Rift valley fever, Congo–Crimean haemorrhagic fever, haemorrhagic fever with renal syndrome, Marburg and Ebola viruses, yellow fever and dengue haemorrhagic fever are some of the most important viral haemorrhagic fevers. Increased vascular permeability is the primary defect. Petechial haemorrhages are usually associated with fever and myalgias. Later, frank mucous membrane haemorrhage may occur, with accompanying hypotension, shock and circulatory collapse. Multisystem organ failure can occur. There is a wide variation in the relative severity of the clinical presentation.

At least four of the haemorrhagic fevers – Lassa fever (LF), Ebola virus, Marburg virus and Congo–Crimean haemorrhagic fever (CCHF) – are capable of person-to-person transmission through close contact with infected blood and other body secretions. Epidemiological studies of VHF in humans indicate that, although possible, the airborne route does not readily transmit infection from person to person.

CLINICAL FEATURES

The patient will have either been in an endemic area or been in contact with someone from an endemic area. Viral haemorrhagic fevers ³⁸ generally have an abrupt onset with an incubation period < 10 days. The incubation period can be up to 21 days. They present as acute febrile illnesses with a prodrome that often includes severe headache, dizziness, flushing, conjunctival injection, myalgia, lumbar pain and prostration. Gastrointestinal symptoms with nausea, vomiting, abdominal pain and diarrhoea may occur.

Leukopenia or leukocytosis, thrombocytopenia and elevated serum aminotransferases may be evident early in the disease; a petechial rash may appear on days 3–10. Coagulation profiles become progressively more abnormal, and overt haemorrhagic features of the disease (ecchymoses, epistaxis, gingival bleeding, melaena, haematuria, etc.) may supervene from day 5 onward, or sometimes even earlier. Multiple organ failure supervenes and death may ensue. Clinical improvement becomes apparent towards the end of the second week of illness in patients who survive.