Pathogenesis: The disease malaria is characterized by its long persistence in infected individuals in endemic areas, with characteristic recrudescences or relapses, sometimes after years of subclinical infection. However, infections in highly susceptible individuals, such as children, pregnant women and travellers, can produce acute severe and even fatal disease. Clinical expression is characterized by cyclic paroxysms of fever/chills (produced by host inflammatory responses), haemolysis and erythrophagocytosis (resulting in anaemia), and organ hypoperfusion due to ischaemia (arising through cytoadherence of infected cells to vascular endothelia, disseminated intravascular coagulation, erythrocyte rosetting, and haemozoin pigment accumulation). Vague prodromal signs may first develop prior to parasitaemia, including headache, anorexia and mild fever. Thereafter, characteristic febrile paroxysms and haemolytic anaemia develop and become progressively worse. Depending on the parasite species involved, severe complications may arise, including splenic rupture, cerebral signs, haemolytic anaemia, cardiac, pulmonary and renal failure. Paroxysms coincide with intraerythrocytic parasite developmental cycles (tertian = 2 day cycle, quartan = 3 day cycle) and may be accompanied by dizziness, nausea, vomiting, delirium, hepato/splenomegaly, leucopenia and thrombocytopenia. Infected cells are removed from the circulation by erythrophagocytosis during passage through the spleen. Some uninfected cells may also be removed if damaged or coated with debris or parasite antigens, thus exacerbating anaemic conditions. As the parasites grow within erythrocytes, they ingest and digest haemoglobin leaving behind characteristic dark pigment deposits, termed haemozoin (metabolic byproducts containing the indigestible iron-containing part of the haemoglobin molecule). Haemozoin may accumulate in organs and tissues resulting in impaired function. Infected erythrocytes (especially by P. falciparum) develop sticky protrusions by which they adhere to vascular endothelial cells, or clump together, resulting in restricted blood flow, ischaemia and end-organ anoxia.

P. falciparum causes malignant tertian malaria (sometimes known as malaria tropica), a severe disease with high parasitaemia because the parasites infect both young and mature erythrocytes. Symptoms appear 8-12 days after infection, being vague for 3-4 days (aches, pains, headache, fatigue, anorexia) then becoming acute in onset (fever, severe headache, nausea, vomiting, epigastric pain) with paroxysms exhibiting a periodicity of <48 hours. Schizogony often occurs in vessels in organs so disease severity may not correlate with parasitaemia. Various complications may arise due to ischaemic changes, including cerebral malaria (comatose), bilious remittent fever (hepatomegaly), dysentery (malabsorption diarrhoea), algid malaria (circulatory collapse) and blackwater fever (haemoglobinuria). Cerebral malaria occurs when capillaries are blocked by infected erythrocytes causing small haemorrhages which rapidly increase in size (conspicuous in retina). Symptoms include abnormal behaviour, fits, change in level of consciousness, coma, elevated cerebrospinal fluid (CSF) pressure, and classic decerebrate rigidity associated with hypoglycaemia. There are often neurological sequelae, such as hemiparesis, cerebral ataxia, cortical blindness, hypotonia, mental retardation, generalized spasticity, or aphasia.

P. malariae causes benign quartan malaria, a moderately severe disease with reduced parasitaemia because parasites only infect mature erythrocytes. The incubation period ranges from 27-40 days, with vague symptoms developing for 3-4 days (headache, photophobia, muscle aches, anorexia) followed by severe paroxysms of chills and fevers every 72 hours (long chill stage, more severe symptoms during fever stage). Proteinuria is common in infected individuals and a nephrotic syndrome may develop in children.

P. vivax and P. ovale cause benign tertian malaria, a moderately severe disease with high parasitaemia as both species preferentially infect reticulocytes (young erythrocytes). P. vivax infections are clinically similar to those of P. ovale, but they are more severe and relapses occur more frequently. Symptoms appear 7-10 days after infection and are vague for 3-4 days (headache, photophobia, muscle aches, anorexia), developing to steady or irregular low-grade fever then paroxysms with a regular 48 hour cycle. Many patients exhibit slow irregular recovery over 3-8 weeks but relapses may occur after weeks/months/years. Splenomegaly is evident during the first few weeks of infection and leukopenia is usually present. Severe complications are rare but P. vivax infections can sometimes include cerebral malaria with neurological signs, haemolytic anaemia, renal failure and pulmonary failure.

Mode of transmission: Infections are vector-borne, being transmitted by female mosquitos, mainly Anopheles spp. Although 390 mosquito species are found worldwide, only a few are considered to be important vectors. Only the female mosquitoes feed on blood as they require high protein diets in order to reproduce and lay rafts of eggs. The mosquito is not simply a vector, it acts as the definitive host in which sexual reproduction of the parasite occurs. Gametocytes ingested during feeding undergo fertilization forming an ookinete then an oocyst which produces numerous sporozoites eventually infecting the salivary glands. Sporozoites are injected into new hosts when the mosquito next feeds as saliva has anticoagulant properties and prevents blood from clotting in the mouthparts. Once a mosquito is infected, it is infected for life and continues to transmit infections.

Differential diagnosis: Diagnosis is conventionally made by a combination of clinical symptomatology and the detection of parasites in thick or thin peripheral blood smears stained with one of the Romanowsky’s stains, usually Giemsa’s, Leishman’s or Field’s stains. Fluorochrome stains have also been used to detect parasites in blood samples, but the morphological features of the stages detected are often obscure. It is important that infections by individual parasite species be differentiated as it impacts on treatment and prognosis. All infections should be considered to be immediately life-threatening, and a complete clinical history should be taken (symptoms/signs), including history of travel, transfusions, recreational drug use, and previous medications (especially anti-malarials). Immunoserological tests have also been developed and several fluorescence, haemagglutination and enzyme immunoassays are being used, particularly for mass screening. Molecular biological techniques using polymerase chain reaction (PCR) amplification of gene fragments have also been developed and have shown great potential for the detection of drug resistance in Plasmodium.

Treatment and control: A variety of drugs have been developed for therapeutic (treatment) and prophylactic (preventive) use. While most enjoyed years of efficacy, there are now widespread problems with drug resistance amongst the parasites. Early explorers noticed that Peruvian Indians used brews from ‘fever bark’ (Cinchona) trees to stave off fevers. The active drug quinine was isolated from the bark around 1820 and this become the mainstay for malaria treatment throughout the world, essentially based on Cinchona tree plantations in tropical colonies. Supply shortages due to the World Wars prompted research on synthetic drugs. Pamaquine, mepacrine and chloroquine were developed in the 1930s, proguanil in the 1940s, and pyrimethamine in the 1950s. Chloroquine, in particular, was found to be highly effective, cheap to produce and had low toxicity. However, resistance to chloroquine emerged in the 1960s and soon spread around the world. Sulphonamides were developed in the 1960s, mefloquine and a series of related drugs in the 1970s, and artemisinin was discovered in a Chinese herbal remedy in the 1980s. A holistic and strategic approach to the treatment of infected individuals is required based on whether suppressive, radical or preventive treatment is required, and the level of drug resistance present. Antimalarial drugs of choice are primaquine, chloroquine (despite the emergence of chloroquine-resistant strains), sulfadoxine, pyrimethamine, mefloquine, quinine and tetracycline. Preventive measures based on vector control programmes had many early successes (including those using DDT), but the rapid emergence of insecticide resistance (and the recognition of the toxicity of DDT and its prohibition) have led to the resurgence of malaria in many countries. At present, the best protection is the avoidance of mosquito bites, using screens, bed nets, insect repellants, and residual insecticide sprays.

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