Diagnosis

As severe malaria is the progression of uncomplicated malaria, its diagnosis is similar to that of uncomplicated malaria plus observations of danger signs. 

As noted in WHO's Management of Severe Malaria, the most important element in the clinical diagnosis of malaria is a high index of suspicion. 

Gold standard: microscopy

  • Where microscopy is unavailable or unfeasible, a rapid diagnostic test (RDT) should be used.

In the absence of diagnostic facilities, a patient diagnosed with severe malaria based on clinical suspicion should be started on antimalarial treatment without delay, while other diagnoses are also considered.

Monitoring of parasitaemia at least every 12h is important during the first 2–3 days of treatment in order to assess parasite response to the antimalarial medicine, especially in South-East Asia where resistance to artemisinin and the partner drugs is emerging.

Obtaining a parasitological diagnosis does not resolve the diagnostic problem, especially in high transmission areas, where asymptomatic parasitaemia is common and may be incidental in any severe illnesses.

(Tropical Medicine & International Health - Special edition: Severe Malaria) 

Attention should be paid to:

  • Residence and travel history indicative of exposure, or the possibility of "airport malaria" (exposure in non-endemic areas)
  • Possibility of induced malaria (through transfusion, transplantation or use of contaminated needles)
  • Diseases presenting similar symptoms that are also common in malaria-endemic countries
  • In children, convulsions due to malaria must be differentiated from febrile convulsions

Signs of danger

Given the rapid progression and potential fatality of severe malaria, any patient who is severely ill or possibly has severe malaria requires immediate supportive care and should be given parenteral antimalarial drug treatment. Treatment should not be delayed by diagnostic tests or limited by definitions if severe malaria is suspected. Danger signs that may be presented in patients with severe malaria include:

  • Impaired consciousness or coma
  • Prostration (generalized weakness so that the patient is unable to sit, stand or walk without assistance)
  • Multiple convulsions: more than two episodes within 24h
  • Deep breathing and respiratory distress (acidotic breathing)
  • Acute pulmonary oedema and acute respiratory distress syndrome
  • Circulatory collapse or shock
    Systolic blood pressure < 80mm Hg in adults and < 50mm Hg in children
  • Acute kidney injury
    Clinical jaundice plus evidence of other vital organ dysfunction
  • Abnormal bleeding

Note that these manifestations can occur singly or, more commonly, in combination in the same patient.

Microscopy

Photo: WHO

Given the rapid progression and potential fatality of severe malaria, any patient who is severely ill or possibly has severe malaria requires immediate supportive care and should be given parenteral antimalarial drug treatment. Treatment should not be delayed by diagnostic tests or limited by definitions if severe malaria is suspected. Danger signs that may be presented in patients with severe malaria include:

  • Impaired consciousness or coma
  • Prostration (generalized weakness so that the patient is unable to sit, stand or walk without assistance)
  • Multiple convulsions: more than two episodes within 24h
  • Deep breathing and respiratory distress (acidotic breathing)
  • Acute pulmonary oedema and acute respiratory distress syndrome
  • Circulatory collapse or shock
    Systolic blood pressure < 80mm Hg in adults and < 50mm Hg in children
  • Acute kidney injury
    Clinical jaundice plus evidence of other vital organ dysfunction
  • Abnormal bleeding

Note that these manifestations can occur singly or, more commonly, in combination in the same patient.

Rapid Diagnostic Tests

Photo: Anne Jennings

Malaria Rapid Diagnostic Tests (RDTs) are based on the detection of different antigens produced by the parasite.

The tests are not quantitative, and the correlation between antigen concentration and parasitemia is not fully understood, so these do not provide information on the parasite density, which is an important parameter in monitoring a patient being treated for severe malaria.

Difference between RDT tests based on different antigens:

HRP-2 based tests

  • Detect only P. falciparum
  • Have the highest sensitivity
  • The HRP2 antigen often persist more than 6 weeks after elimination of parasites, as such leading to false positive tests
  • Because of this antigen persistence, these tests cannot be used to monitor response to treatment

pLDH based tests

  • Can detect the different species of malaria
  • The antigen persist only a short time after elimination of parasites (50% still positive 2 days after the elimination of the parasites, exceptionally up to two weeks)
  • Because of the antigen persistence, this test is not recommended to monitor response to treatment

HRP2 deletion

HRP2-detecting tests have shown instances of less sensitivity in parasites that express little or no target antigen, resulting in false negative results. Reports stemming from several countries in South America and Africa have confirmed identification of P. falciparum parasites with PfHRP2/PfHRP3 gene deletions, not expressing PfHRP2 and/or PfHRP3.

Suspect resistance if:

  • The sample tests negative on an HRP2 test line of at least two quality-assured malaria RDTs AND
  • Tests positive on the pan- or Pf-pLDH test line if a combination test is used AND
  • Microscopy confirms as positive for P. falciparum by two qualified microscopists

Implications:

  • Alternative RDTs will have to be procured
  • Revise case management decisions
  • Re-training in algorithms and RDTs
     

Actions to undertake with suspected false negatives:

  1. Investigate for PfHRP2/3 deletions
  2. Suspected PfHRP2/3 gene deletions should be informed to the NMCP and WHO
  3. Determine the prevalence in the affected country and neighboring countries
  4. Well-preserved specimens can be useful when identifying geographical location of HRP2/HRP3-deleted parasite populations