Malaria

From Ganfyd

Disease caused by the protozoa Plasmodium and spread by the Anopheles mosquito It is one of the most important diseases in the world in terms of mortality and morbidity. It is a particular problem in sub-Saharan Africa, but is also seen in South and South East Asia. Malaria deaths continue to rise at a time when non-malarial deaths are falling, mainly due to waning efficacy of available medicines, despite the arrival of new agents. Resistance continues to be a major problem and a vaccine remains elusive. The prevalence of fake medicines in endemic countries is another major problem.

Probably The Ague, or Shaking Fever, backalong.

Anopheles mosquitoes capable of carrying the disease exist in England, but the climate is currently too cool at some times of year for the malarial parasite to complete its lifecycle. As global warming bites, it may return to temperate areas such as Exeter, England, where in Roman times it was present.

Malaria has been with human beings for a long time in evolutionary terms, as seen in the numerous genetic mutations that occur for the express benefit of conferring partial immunity eg sickle cell trait, G6PD, hereditary spherocytosis. At the same time, the parasite has evolved multiple ways of avoiding the immune system, which is why developing a vaccine has proved so difficult. It is likely that our immune system has also evolved in response to pressure from the organism eg HLA B53 confers 40% protection vs severe malaria.

Aetiology

• Plasmodium falciparum - causes the most severe disease, predominates in Africa, widespread resistance, but no liver stage.
• Plasmodium vivax/ovale - cause less severe disease, predominates in Asia, resistance rare, liver stage
• Plasmodium malariae - causes less severe disease, predominates in Asia, resistance rare, but no liver stage

The parasite sporozoite form is injected with salivary secretions into the human host. It circulates until it reaches hepatocytes, where it replicates and forms clusters called schizonts. These release trophozoites into the blood stream, where red cells are infected and further replication occurs. Disease only appears once widespread haemolysis has occurred, usually 3 weeks or more after initial infection.

A proportion of trophozoites transform into gametocytes. When these are ingested along with human blood by another mosquito, they can then continue the life cycle in the mosquito. In P vivax and ovale, longlasting hypnozoites may persist in the liver, which can be responsible for late reactivation of disease.

Clinical

In endemic areas, intermittent asymptomatic low level parasitaemia is seen commonly. Children are the most at risk of severe disease:

• cerebral malaria
• severe haemolysis
• ARDS
• acidosis

Even in adults with relative immunity, however, malaria causes recurrent, usually self-limiting, episodes of mild disease and is also responsible for chronic anaemia.

In non-endemic disease, particularly travellers or people who have lost their immunity by long term lack of exposure after emigration, the infection is more likely to manifest with disease and the disease is more likely to be severe. Symptoms develop at least 3 months after exposure, but suspect the diagnosis in those at risk for up to 1 year after exposure (although falciparum usually presents within 3 months).

Cerebral Malaria

Usually affects young children, who present febrile in coma, +/- seizures. But often multisystem dysfunction. Meningitis is the main differential.

Prognosis related to presence of recurrent seizures, raised intracranial pressure, metabolic derangement.

There is a need to identify at risk cases not just severe because high mortality before quinine is started.

• Mild malaria
  • Present with fever, anaemia, splenomegaly. The periodicity of the fever depends on the species - falciparum tends to demonstrate daily spikes, vivax/ovale may spike every 2-3 days, malariae may spike every 4-5 days.
• Moderate risk
  • Parasitaemia >5% (not very well correlated, and not really relevant for non-falciparum)
  • Sickle cell disease (who have worse outcomes, despite being relatively protected!)
• High risk
  • Pregnancy
  • Asplenic or splenic dysfunction
  • Acidosis (BE >-8)
  • Hyperkalaemia (>5.5mmol/L)
  • Hypoglycaemia
  • Impaired conscious level

Kussmaul breathing predicts acidosis & death.

Investigations

Do not wait for the results of tests if symptoms/signs suggestive, since falciparum can be rapidly aggressive. Malarial retinopathy has recently been described and may turn out to be a useful diagnostic tool.

Blood tests

The blood smear is the classic test. Thin smears are best for identifying the particular type of malaria and the percentage parasitaemia (percentage of erythrocytes infected), but thick smears are more sensitive. Repeat testing is important - sensitivity is only 70% on a single smear, but rises to over 95% with 3 smears.

New molecular based tests are expensive but are less reliant on operator experience.

• HRP2 (histidine rich protein) is specific to falciparum.
• pLDH versions are available for falciparum and vivax.
• Aldolase is a pan-specific antigen, but probably not as sensitive as the others.

HRP2 alone is probably most appropriate for high prevalence area where non-falciparum tends to be co-infection.

Radiology

Treatment

See also UK malaria treatment guidelines.^[1]

Adjunctive

• Surprisingly, shock usually responds to just 1 bolus of fluid. Excessive fluid resuscitation is likely to precipitate cardiac failure in severe anaemia, may exacerbate anaemia and raised intracranial pressure. Albumin appears to be superior to crystalloid.
• Oxygen for respiratory distress, glucose if hypoglycaemia.
• Poor evidence for exchange transfusion - consider for persistent acidosis or multiorgan failure, sickle cell.
• Seizures: follow standard guidelines. Partial, subtle seizures are common. No evidence to support prophylactic phenobarbitone.

Antimalarials

The non-falciparum malarias are still mostly sensitive to chloroquine, which can be given orally for 3 days. G6PD deficiency should be excluded before chloroquine treatment is started in patients at risk. Treatment must also address eradication of liver stage hypnozooites, for which primaquine is usually given.

In falciparum malaria, quinine is the drug of choice. It can be given orally but as it is extremely bitter compliance may not be good - use Malarone (proguanil + atovaquone), or Co-artemether (with lumefantrine = Riamet). Mefloquine resistance means that the BNF no longer recommends it. 7 days of quinine should be followed a single dose of Fansidar (if likely to be sensitive), or by 5 days clindamycin or 7 days doxycycline.

WHO now recommends use of the newer artemisin derivatives (originally discovered in China) which have proved to be much more effective in terms of rate of clearance of parasitaemia (they are active against all stages of the parasite life cycle) and can be given intramuscularly, rectally as well as by other routes.

In view of the problem of resistance, combination treatment is likely to be necessary for endemic areas. The rapid action of artemisin makes in less susceptible to the development of resistance, but reports of resistance in South-east Asia have already been reported.^[2]

Resistance to Malaria

Heterozygotes for haemoglobinopathies eg HbS have relative resistance to the Malarial parasite. This is due to the reduced lifespan of the red cells, and this relative resistance is also presumably the reason for the prevalence of hereditary spherocytosis etc, and G6PD deficiency.

Prevention

Prevention of bites is the first step. Anopheles tend to bite in the evening. Skin should be covered, and repellent sprays/coils etc used. Eradication of mosquitoes with DDT was extremely successful in many areas.

Chemoprophylaxis

See Malaria prophylaxis

Prophylaxis is recommended for those travelling to at-risk areas. The recommended combination of drugs varies according to location.

See HPA guidance.^[3]

Vaccination

There are several barriers:

• Antigens of the different life cycle stages differ
• Need to generate v high immune response
• Need to overcome escape mechanisms

The GlaxoSmithKline experimental malaria vaccine Mosquirix is expected to complete late-stage trials in 2011 involving 16,000 people. The company hopes to seek approval for the vaccine in 2012.^[4]

RTS,S/AS02D was an early candidate vaccine showing an efficacy of about ~30%. A change in the adjuvant component appears to have improved efficacy in infants. Early reports of this newer candidate vaccine, RTS,S/AS01E, which targets the circumsporozoite protein, has shown an efficacy of about 56% over a median follow-up period of 8 months.^[5]

Sporozoite vaccine in Mozambique reduces clinical malaria by 22% only, and only for 2-3 months. PfEMP1 is main antigen for natural antibody but high levels of variation.

Probably best to go for T cell stimulating vaccine to knock out infected liver cells. Prime boost strategy = fowlpox vaccine first then modified viral vector eg adeno or smallpox. Current Kilifi trial.

Combination probably more effective but likely to be too expensive for Africa.

Post-exposure Prophylaxis

Regular treatment in pregnancy is beneficial.

Notification

ICD code

ICD-10_-_A00-B99#.28B50-B64.29_Protozoal_diseases

External links

• HPA page on malaria
• CDC page on malaria

References