Malaria: Symptoms, Criteria of Severe Malaria, Diagnosis, Treatment by NJE

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Malaria is a parasitic infection caused by five species of Plasmodium (P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi), the last species only recently being described as a human pathogen. It is a major killer on the world stage, with around a million deaths per year, mainly affecting children in sub-Saharan Africa.

Although it is endemic in most parts of the tropical world, the intensity of transmission varies widely with Africa and, in particular, West Africa suffering the greatest parasite burden. As repeated infection leads to clinical immunity, the burden of malaria falls predominantly on children in areas of intense transmission but affects all age groups in areas with less intense, more seasonal malaria. Only one species, Plasmodium falciparum, is frequently lethal. The other species rarely kill, but P. vivax causes substantial morbidity on a global scale.

What are the Signs and Symptoms of Malaria

If the diagnosis of malaria is not to be missed, a detailed travel history must be taken in patients with a febrile illness. Falciparum malaria usually causes symptoms within 1 month of return from endemic areas, but the other species may not manifest for several months.

Although a fever, or history of a fever, is almost invariable in patients with malaria, the hallmark of this disease is the absence of specific features. Chills, sweats, and rigours are common, but false localizing symptoms, such as cough or diarrhoea, may mislead the unwary clinician.

Physical signs, apart from fever, are few in uncomplicated infection, although jaundice, splenomegaly, and hepatomegaly occur in a significant minority.

Laboratory findings are helpful, with thrombocytopenia in around 60% of patients. A mild normocytic anaemia or a raised bilirubin are also common, whereas the white cell count is almost invariably normal or low.

Severe malaria

Severe malaria, almost always caused by P. falciparum, usually manifests as cerebral malaria, severe anaemia, acute respiratory distress syndrome (ARDS), acute renal failure, or shock. Table 6.15 lists the WHO defining features of severe malaria. Although jaundice is associated with severe malaria, its sole presence is not a good predictor of poor outcome.

The following groups are at higher risk of severe malaria and death: pregnant women, non-immune Caucasians, patients with asplenia or sickle cell disease, patients more than 60 years old, and cases with parasitaemia >2%.

•  Cerebral malaria presents as drowsiness or confusion but may rapidly progress to an unrousable coma. Focal neurological signs, such as decerebrate posturing and disconjugate eye movements, may develop in the later stages.

•  Severe anaemia is mainly a disease of children presenting with respiratory distress secondary to cardiac failure, often with associated metabolic acidosis.

•  ARDS/pulmonary oedema in malaria is indistinguishable from the syndrome caused by bacterial sepsis. It may develop 1 or 2 days into treatment and is associated with a mortality of up to 50%.

•  Acute renal failure in malaria is secondary to acute tubular necrosis. The mortality associated with this condition is low in regions where renal replacement therapy is available, and renal function usually returns to normal after several weeks.

•  Shock is uncommon in severe malaria and may reflect concomitant bacteraemia (a well-known complication of the condition).

•  Hypoglycaemia is less common in adults than children with severe malaria. It is, however, a common side effect of parenteral quinine treatment.

Pregnant women are particularly at risk from malaria, especially in the third trimester. They have increased susceptibility to severe malaria and have a particular predisposition to ARDS and hypoglycaemia.

What are the criteria for defining severe malaria

WHO criterionDefinition
Cerebral malariaUnrousable coma or inability to sit up
Severe anaemiaHaemoglobin <5 g/dL
Acute renal failureSerum creatinine >265 
micromoles/L or renal output <0.4 
mL/kg per hour
AcidosisArterial pH <7.3
ShockSystolic blood pressure <90 mmHg
HypoglycaemiaBlood glucose <2.2 mmol/L
Spontaneous bleeding ± DICStandard criteria
Pulmonary oedema or ARDS Standard criteria

How Diagnosis the Malaria

Once the diagnosis of malaria is suspected, an EDTA blood specimen for analysis should be collected without delay. Although thick and thin blood films stained using Giemsa remain the mainstay of parasitological diagnosis of malaria, many laboratories in the developed world use immune chromatographic tests (ICT). PCR-based methods are usually restricted to research or reference laboratories.

In general, ICT tests have very good diagnostic accuracy for P. falciparum but perform less well for the other species. In laboratories experienced in the diagnosis of malaria, thick films, QBC tests (a fluorescence-based microscopic screening test), and ICT kits have a very good negative predictive value for falciparum malaria.

Where the clinical suspicion is high, particularly in patients who may have self-treated or who have been taking chemoprophylaxis, up to three films may be necessary to exclude the diagnosis. Empirical treatment of patients for malaria is rarely appropriate in view of the high sensitivity of available diagnostic tests.

What are the Management of Malaria

Severe falciparum malaria

The first question to answer in patients with falciparum malaria is ‘Does this patient have the severe disease?’ This involves a detailed clinical examination, paying attention to the cardinal features of severe malaria, plus, where facilities exist, a full blood count, renal and liver profile. The parasitaemia provides some prognostic value, although the relevance of a particular level will vary, depending on the immune status of the individual.

Current UK guidelines recommend treating all patients with parasitaemia more than 2% as severe malaria, with parenteral quinine. However, a threshold level of 5% for parenteral treatment has been suggested by other authorities. Most recently two large randomized trials, one in adults in South East Asia and the other in children in Africa, have clearly shown that, compared with quinine, artesunate significantly reduces the mortality from severe malaria. Thus artesunate is now the drug of choice for this condition. A coagulation screen, arterial blood gases, blood cultures, chest radiograph, and baseline ECG should also be obtained in ill patients. Severe malaria should be managed in a high dependency or critical care environment where possible. Exchange transfusion is generally not recommended, especially when patients are treated with artesunate, a rapidly acting antimalarial.

•  Fluid resuscitation. Although some degree of fluid depletion is common in patients with malaria, haemodynamic compromise is uncommon. Thus, unlike the management of bacterial sepsis, these patients should receive relatively cautious fluid resuscitation.

•  Intravenous artesunate. 2.4 mg/kg on admission, then at 12 h and 24 h, then once daily until the blood film is clear of parasites. The course should be completed with an agent, such as artemether-lumefantrine (Riamet®) or atovaquone-proguanil eg Malarone®).

•  If artesunate is unavailable, give intravenous quinine, with a loading dose of 20 mg/kg (maximum 1.4 g) intravenous quinine dihydrochloride in 500 mL 5% glucose (or 0.9% sodium chloride), infused over 4 hours, followed 8 hours later with a maintenance dose of 10 mg/kg (maximum 700 mg) in 500 mL 5% glucose (or 0.9% sodium chloride) infused over 4 hours every 8 hours. A loading dose should NOT be given if the patient has recently taken mefloquine or quinine. Patients need ECG monitoring (as quinine prolongs the QTc interval) and frequent blood glucose measurements (as quinine causes hypoglycaemia). Once able to swallow, patients should be converted to oral quinine 600 mg TDS to complete 7 days. This should then be followed by doxycycline 200 mg od or clindamycin 450 mg three times daily for a further week.

•  Consider antibiotics if there are signs of shock (e.g. ceftriaxone 2 g daily intravenously). Uncomplicated falciparum malaria Although UK guidance recommends inpatient management for all cases of falciparum malaria, there is accumulating evidence that ambulatory treatment is safe in selected cases. Decisions to manage these patients without hospital admission, however, should only be taken in consultation with infection specialists.

Uncomplicated infection is effectively treated with a 7-day course of oral quinine plus doxycycline 200 mg daily or clindamycin 450 mg three times daily. The second drug is given because compliance with 7 days of quinine is poor due to side effects. Pregnant women should be treated with the quinine/clindamycin combination, as doxycycline is contraindicated. Outside of pregnancy, however, better compliance is likely with the following preferred regimens:

•  Atovaquone-proguanil (e.g Malarone®) four tablets daily for 3 days, or

•  Artemether-lumefantrine (Riamet®) four tablets, then four tablets at 8, 24, 36, 48, and 60 hours.

Non-falciparum malaria

Patients with non-falciparum (benign) malaria can usually be managed as outpatients. For all parasites, chloroquine remains the treatment of choice, given as follows:

•  600 mg stat, followed by 300 mg at 6, 18, and 42 hours. Two species P. ovale and P. vivax have a stage called the hypnozoite that develops in the liver. This form of the parasite is resistant to chloroquine therapy and leads to the phenomenon of relapses, if not specifically treated. Primaquine treatment is, therefore, necessary to achieve radical cure, given as 15 mg daily for P. ovale and 30 mg daily for P. vivax for a total of 2 weeks.

Primaquine frequently causes haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Consequently, the G6PD level must be checked before primaquine is prescribed; if the level is low, seek expert advice.P. malaria and P. knowlesi are reliably cured with chloroquine alone. The latter, however, frequently causes severe disease, for which intravenous artesunate is probably the drug of choice, as for P. falciparum.

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