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Figure 8.3 The erythrocytic cycle

ciparum, P. vivax and P. ovale malaria and every 72 h in P. malariae infection. However, it should be noted that in P. falciparum infection in immunologically naive subjects, very high parasitaemia will occur before synchronisation develops and thus this form of malaria rarely exhibits the classical periodic fever (see below).

Upon invasion of the erythrocyte, malaria parasites extensively remodel the cell, both externally and internally, making structural modifications necessary for their survival and proliferation. The most obvious ultrastructural alteration to the parasitised erythrocyte (pRBC) membrane is the appearance of electron-dense protrusions or 'knobs' (in P. falciparum and P. malariae) about 100 ^m in diameter (Luse and Miller, 1971). These knobs are thought to consist of several parasite polypeptides, including P. falciparum erythrocyte membrane protein 1 (PfEMP1), and are the sites where pRBCs bind to other cells, particularly erythrocytes (producing the phenom enon termed 'resetting') and vascular endothelium (cytoadherence). Several parasite-derived polypeptides, including PfEMPl, rosettins/rifins, sequestrins and modified band 3 are inserted into the erythrocyte membrane, resulting in considerable loss of deformability of the erythrocyte. PfEMPl is a 200-400kDa variable multidomain polypeptide which is encoded by the multiple var gene family (Smith et al., 1995; Su et al., 1995). It is likely that the different domains function independently; hence, PfEMP1 would appear to be a highly antigenically variable ligand with multiadhesive properties, allowing binding of pRBCs to a wide range of receptors, including intercellular adhesion molecule 1 (ICAM-1), chondroitin sulphate A (CSA) and CD36 on endothelia and heparan sulphate-like glycosaminog-lycans (HS-like GAGs), complement receptor 1 (CR1, CD35) and CD36 on erythrocytes (Baruch et al., 1996, Barragan et al., 1999). There are several other receptors

Figure 8.4 Conceptual diagram of epidemiology

for which the PfEMPl is the likely (but not definite) parasite ligand, such as blood group antigens A and B on erythrocytes and thrombospondin and CD31 on en-dothelia. Rosettins or rifins are parasite-derived low molecular weight polypeptides encoded by the large rif multigene family (Fernandez et al., 1999). Their abundance on the pRBC surface suggests that they contribute significantly to antigenic variation; other possible roles for these proteins are still being investigated. Special channels or pores are created by the parasite in the erythrocyte membrane to enable the acquisition of nutrients.

A proportion of the multiplying parasites develop into the sexual form, the gametocytes. The male and female gametocytes are taken up by mosquitoes, in which fertilisation occurs. The zygote develops into an oocyst, which ruptures to release about 1000 sporozoites into the mosquito body cavity. These sporozoites migrate to the salivary glands, and a further bite allows the life cycle to be completed (Figure 8.2).

Epidemiology

Malaria was once widespread in the world but the sponsored malaria eradication campaign of the 1960-1970s, sponsored by the World Health Organization (WHO), resulted in its eradication from most parts of central America. Europe was declared malaria-free in 1976. In many countries of Asia, malaria became an uncommon disease but in recent years has begun to return. The risk of malaria is highest in sub-Saharan Africa where there remain many areas of intense transmission.

The term 'endemic malaria' is used to describe an area where there has been a constant incidence both of cases and of transmission of malaria over a number of years. Endemicity is said to have ceased if there has been no evidence of transmission in the area over at least 3 years. If the vector is still present in the area, malaria remains potentially endemic. The malariogenic potential of the area then depends on its receptivity (i.e. number of new cases of malaria that could theoretically originate from one single imported case) and vulnerability (i.e. rate of entry of imported cases). Levels of endemicity may be classified as follows:

• Holoendemicity. Perennial transmission of high degree. Considerable immunity in all age groups, particularly adults.

• Hyperendemicity. Intense but seasonal transmission. Immunity insufficient to prevent clinical malaria.

• Mesoendemicity. Varying intensity of transmission depending on local circumstances.

• Hypoendemicity. Little transmission with minimal effects on population.

Not all female mosquitoes carry malaria parasites. The proportion of infected mosquitoes influences the endemicity of infection. Once sporozoites are injected into a human host, infection is not inevitable; indeed, only approximately half of infective bites will result in infection. Of these, only a proportion will result in clinical disease, and an even smaller amount will be serious and result in death if untreated (Figure 8.4). The risk of malaria is also influenced by other vector factors. Mosquitoes bite between dusk and dawn and thus travellers who protect themselves during this period are at much lower risk of acquiring infection. Mosquitoes are positively attracted to heat and smells emitted by the human body. Also, mosquitoes have a limited flight range of approximately 500 metres; hence, siting of housing estates away from breeding areas, the use of larvicides and environmental control where mosquito breeding habitats are destroyed can do much to reduce the risk of malaria. In endemic countries most serious disease is found in children under the age of 5 years. Since recurrent bouts of infection result in partial immunity, adults living in endemic areas are able to control the degree of parasitaemia and minimise the pathological consequences. Travellers who travel to endemic areas are immunologically naive and are thus at risk of severe disease.

Malaria appears some time after travel to an endemic area. The incubation period is shortest for P. falciparum (9-14 days) and longest for P. malariae (18-40 days or longer). Clinical disease is unlikely to occur in less than 9 days. The majority of cases occur within 3 months and almost all within 1 year of return from an endemic area. There are reports of malaria occurring many years after this time but this is very unusual.

Clinical Features

The incubation period of malaria varies from 9 days to more than 1 year. Clinical infection commences with a prodromal illness characterised by fever, myalgia and weakness. Patients then develop a 'flu-like illness with high temperature, weakness and prostration, often accompanied by a cough. Some patients may develop diarrhoea due to parasites in mesenteric vessels. Periodic fevers, with the classical cold and hot stage, may develop in patients with vivax or ovale malaria but is often absent in falciparum disease—the diagnosis has been missed in many patients by doctors who have assumed this fever pattern is essential for the diagnosis of malaria. The cold stage lasts 15-60 min, and is characterised by an inappropriate feeling of cold and apprehension. The patient is usually shivering, has a rapid low-volume pulse and exhibits intense peripheral vasoconstriction despite a high core temperature. The hot stage lasts 2-6 h, during which the patient suffers unbearable heat, running temperatures of 40-41 °C. Other characteristics include confusion, delirium, severe headache, nausea, prostration and postural syncope. Vomiting and diarrhoea may also feature, adding confusion to the clinical picture. The patient has a rapid, bounding pulse and dry, flushed, burning skin. Febrile convulsions are particularly common in children. This is followed by defervescence over 2-4 h, accompanied by profuse sweating, whereupon the exhausted patient sleeps. P. vivax, P. ovale and P. malariae infection may progress but the severity of symptoms is limited by parasitaemia. In contrast, P. falciparum infection may progress rapidly, and patients may develop the serious complications set out below in a matter of hours.

Complications of P. falciparum Malaria

The most serious complication of P. falciparum infection is cerebral malaria, which is most common among children aged 3-4 years. This is caused by massive sequestration of pRBCs, often accompanied by uninfected red cells in the cerebral vasculature—a phenomenon unique to P. falciparum. This massive sequestration is the result of upregulation of endothelial cytoadherence receptor expression by a variety of cytokines, including tumour necrosis factor a (TNF a) and interferon y (IFNy) (Jakob-sen et al., 1995). These cytokines also upregulate nitric oxide production, which causes local damage at sites of sequestration (Green et al., 1994). In cerebral malaria, overproduction of these cytokines and nitric oxide is stimulated by the glycophosphatidylinositol (GPI) anchor of several transmembrane toxins (Gowda and Davidson, 1999). Patients with cerebral malaria present with fever, a disordered level of consciousness, confusion or inappropriate behaviour, which progresses rapidly to generalised convulsions, coma and death. Retinal haemorrhages are seen in 15% and these are associated with a bad prognosis. The typical neurological pattern in adults is that of a symmetrical upper neuron lesion and absent abdominal reflexes; however, patients, particularly children, may be hypotonic. The cerebrospinal fluid (CSF) opening pressure is often raised in children, with cerebral herniation sometimes occurring (Newton et al., 1991). Cerebral malaria carries a mortality of 15-20% in areas where good standards of management are available, most deaths occurring within 24 h of admission. Patients who recover become rousable after being comatose for 30-40 h. Neurological sequelae, such as focal epilepsy, mononeuritis multiplex, cranial nerve palsies, mental deficit, behavioural disturbances and generalised spastic-

ity, occur in more than 10% of children but are much less common in adults (Molyneux et al., 1989).

Sequestration also occurs in several other organs, with parasitisation being greatest in the brain, heart, liver, lung and kidney.

The intense haemolysis that may occur in severe malaria may be associated with haemoglobinuria, resulting in the syndrome known as blackwater fever. This used to be a common manifestation of severe malaria, but hae-moglobinuria is now usually the result of intravascular haemolysis brought on by oxidant antimalarial drugs in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

A rare but severe form of malaria, termed 'algid malaria', is characterised by cardiovascular collapse. In some patients with algid malaria, Gram-negative bacteraemia has been documented.

Other complications of malaria include anaemia, hepatic and renal dysfunction (failure is rare), hypoglycaemia (> 5% of children with severe malaria), metabolic (largely lactic) acidosis, haemostatic disturbances and adult respiratory distress syndrome (ARDS) which carries a mortality in excess of 50%.

Malaria should form part of the differential diagnosis of any patient presenting with fever following travel to a malaria-endemic country. Because the parasites may adhere to microvasculature throughout the body, it has the capacity to mimic almost any infectious disease. Patients frequently have a mild cough and this may be mistaken for pneumonia, especially when travel occurs during the winter months in temperate countries or during influenza epidemics, where the clinical symptoms and signs may resemble a lower respiratory tract infection. Intestinal symptoms, which are common, may result in a false diagnosis of enteric infection. Symptoms of cerebral malaria may be mistaken for CNS infection and behavioural abnormalities or confusion may be blamed on alcohol misuse. In surveys of fatal cases of malaria, in almost all instances fatal outcome is associated with delayed diagnosis.

Diagnosis

Diagnosis of malaria is made simply by taking samples of capillary blood for morphological diagnosis. Parasites are found in the blood when the patient is febrile and for more than 4 h afterwards. A malaria examination must be undertaken on any patient complaining of fever who has recently travelled to a malaria-endemic area. Further samples should be taken in the presence of fever and the diagnosis should not be excluded unless three satisfactorily taken negative blood films are obtained. In the laboratory, capillary blood is examined by a Romanowsky-stained thick and thin film. The thick film is a 1 ^l blood spot which places many red cells together, the lysis of these cells that occurs during the staining process making the parasites apparent (Figure 8.5). This technique has the effect of concentrating the blood and hence increasing the

Figure 8.5 Giemsa-stained thick film showing malarial parasites. x 1000
Figure 8.6 Giemsa-stained thin film showing several ring trophozoites. x 1000

sensitivity of the tests. A satisfactorily prepared thick film, examined by a competent microscopist, has a sensitivity of about 0.0004% (Bruce-Chwatt, 1984). It is most suitable for returning travellers in whom parasitaemias may be low. However, thick film examination is technically demanding, as parasites may be difficult to identify; only experienced technologists should perform the test. The thin film is useful in speciating the parasite and defining the degree of parasitaemia (Figure 8.6).

Conventional blood film examination has been modified in attempts to improve rapidity of diagnosis, particularly when parasitaemias are low. The refinements introduced have sought to concentrate pRBCs by centrifugation of heparinised blood, density gradient cen-trifugation and selective magnetic separation, and facilitate identification by the use of fluorochrome stains. One such commercially available centrifugation/fluoroch-rome technique is the quantified buffy coat (QBC) technique (Spielman et al., 1988). This technique is easy to perform and rapid, but requires specialised equipment (a microcentifuge and fluorescence microscope) and a supply of costly QBC tubes. The sensitivity of the QBC technique is similar or slightly better than that of conven tional microscopy.

Rapid immunological antigen detection methods for falciparum malaria are now available using dipstick technology. In the Parasight-F test, a monoclonal antibody captures the falciparum antigen P. falciparum histidine-rich protein II (PfHRPII). A positive result is indicated by a visible line on the dipstick produced by a second, labelled, anti-HRPII antibody (Shiff et al, 1993). One problem with tests based on HRPII detection is the persistence of HRPII antigenaemia after effective treatment; this makes the test unreliable for the identification of treatment failures. There are newer tests based on the detection of parasite-specific lactate dehydrogenase— these have the advantages of being able to diagnose infection with any of the malarial parasites, and of becoming negative with effective treatment (Makler et al., 1998). Although commercially available, these tests have not been evaluated as thoroughly as the Parasight-F test in the field. These methods approach the sensitivity and specificity of conventional blood film examination but have the advantage that they are much less time-consuming (the Parasight-F test takes only 10min) and do not require an experienced parasitologist or any additional equipment for their use. They may be of particular value in hospitals which have a low throughput of samples for malaria diagnosis.

Treatment

The treatment of malaria depends on the species of parasite identified, its drug susceptibility profile, the level of parasitaemia and severity, and any factors pertinent to the patient in question. Patients infected with P. vivax, P. ovale, P. malariae and chloroquine-susceptible P. falciparum should be treated with chloroquine, which may be administered either orally, in uncomplicated malaria, or parenterally (by intravenous, intramuscular or subcutaneous routes) in severe disease (Tables 8.2-8.5). Chloroquine is a 4-aminoquinoline which has marked, rapid blood schizontocidal and gametocytocidal activity. Against sensitive parasites, chloroquine is more potent than quinine, usually requiring fewer doses to clear para-sitaemia (White et al., 1989). Chloroquine is also better tolerated; however, rapid intravenous administration causes life-threatening arrythmias, hypotension, seizures and cerebral oedema. Hence, oral administration is preferred. Haemolysis occurs in patients with hereditary defects of the pentose phosphate shunt, most commonly G6PD-deficiency. Methaemoglobinaemia may also occur. The most common side-effect of chloroquine in dark-skinned people is pruritus, which can affect compliance. Other adverse effects include dizziness, rash and blurring of vision. In susceptible patients, severe attacks of acute intermittent porphyria and of psoriasis may be precipitated.

Since P. vivax and P. ovale have a latent hypnozoite stage in the liver (see above) against which chloroquine is inactive, radical cure can only be achieved by the addition

Table 8.2 Antimalarial chemotherapy for uncomplicated falciparum malaria (modified from Hommel and Gilles, 1998)

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