Severe falciparum malaria is defined by the demonstration of asexual forms of P. falciparum in a patient with a potentially fatal manifestation or complication of malaria in whom other diagnoses have been excluded.
Even though the complications are almost unique to P. falciparum infection, that DOES NOT mean that all cases of P. falciparum malaria invariably develop complications. The case fatality of P. falciparum malaria is around 1 per cent and this accounts for more than half a million deaths per year all over the world; 80% of these deaths are caused by cerebral malaria.
In 1990, the World Health Organization (WHO) established criteria for severe malaria and these were revised in the year 2000 to include other clinical manifestations and laboratory values that portend a poor prognosis based on clinical experience in semi-immune patients (Table 1). The major complications of severe malaria include cerebral malaria, pulmonary edema, acute renal failure, severe anemia, and/or bleeding. Acidosis and hypoglycemia are the most common metabolic complications. Any of these complications can develop rapidly and progress to death within hours or days.
The presentation of severe malaria varies with age and geographical distribution. In areas of high malaria transmission, severe malaria mainly affects children under five years of age. The mortality rate is higher in adults than in children but African children develop neuro-cognitive sequelae following severe malaria more frequently. In children, the complications include metabolic acidosis (often caused by hypovolaemia), hypoglycaemia, hyperlacticacidaemia, severe anaemia, seizures and raised intracranial pressure and concomitant bacterial infections occur more frequently. In adults, renal failure and pulmonary oedema are more common causes of death.
In many patients, several of these complications exist together or evolve in rapid succession within a few hours. In clinical practice, patients must be assessed for any of these signs or symptoms that suggest an increased risk for developing complications and must be treated immediately. In various studies risk factors for severe malaria and death include age greater than 65 years, female sex (especially when associated with pregnancy), nonimmune status, coexisting medical conditions, no antimalarial prophylaxis, delay in treatment, and severity of the illness at admission (coma, acute renal failure, shock, pulmonary edema, coagulation disorders). In tropical countries with a high transmission of malaria (hyperendemic areas), severe malaria is predominantly a disease of young children (1 month to 5 years of age).
Predisposing factors for complications and death from P. falciparum malaria:
In various studies, risk factors for severe malaria and death include age greater than 65 years, female sex (especially when associated with pregnancy), nonimmune status, coexisting medical conditions, no antimalarial prophylaxis, delay in treatment, and severity of the illness at admission (coma, acute renal failure, shock, pulmonary edema, coagulation disorders). In tropical countries with a high transmission of malaria (hyperendemic areas), severe malaria is predominantly a disease of young children (1 month to 5 years of age).
Thrombocytopenia is the most common laboratory abnormality (60% of cases), followed by hyperbilirubinemia (40%), anemia (30%), and elevated hepatic aminotransferase levels (25%). The leukocyte count is usually normal or low, but neutrophilia with a marked increase in band forms (left shift) is present in the majority of cases. The erythrocyte sedimentation rate, C-reactive protein, and procalcitonin are almost invariably elevated. The severity of malaria corresponds to the degree of the laboratory abnormalities. In one study of travelers who returned from the tropics, thrombocytopenia and hyperbilirubinemia had a positive predictive value of 95% for malaria.
Severe manifestations and complications of P. falciparum malaria
In a patient with falciparum malaria in whom other diseases have been excluded, the presence of one or more of the following manifestations is sufficient for a diagnosis of severe falciparum malaria.
|Table 1: Indicators of severe malaria and poor prognosis [1,3-5]|
|Initial World Health Organization criteria from 1990 |
|1. Cerebral malaria:||Unarousable coma not attributable to any other cause, with a Glasgow Coma Scale score ≤9; Coma should persist for at least 30 min after a generalized convulsion|
|2. Severe anemia||Hematocrit <15% or hemoglobin < 50 g/l in the presence of parasite count >10000/µl|
|3. Renal failure||Urine output <400 ml/24 hours in adults (<12 ml/kg/24 hours in children) and a serum creatinine >265 µmol/l (> 3.0 mg/dl) despite adequate volume repletion|
|4. Metabolic (Lactic) Acidosis/acidosis||Metabolic acidosis is defined by an arterial blood pH of <7.35 with a plasma bicarbonate concentration of <22 mmol/L; hyperlactatemia is defined as a plasma lactate concentration of 2-5 mmol/L and lactic acidosis is characterized by a pH <7.25 and a plasma lactate >5 mmol/L.|
|5. Pulmonary edema or acute respiratory distress syndrome (ARDS)||Breathlessness, bilateral crackles, and other features of pulmonary oedema. The acute lung injury score is calculated on the basis of radiographic densities, severity of hypoxemia, and positive end-expiratory pressure|
|6. Hypoglycemia||Whole blood glucose concentration of less than 2.2 mmol/l (less than 40 mg/dl).td|
|7. Hypotension and shock (algid malaria)||Systolic blood pressure <50 mmHg in children 1-5 years or <70 mm Hg in patients ≥5 years; cold and clammy skin or a core-skin temperature difference >100C|
|8. Abnormal bleeding and/or disseminated intavascular coagulation||Spontaneous bleeding from the gums, nose, gastrointestinal tract, retinal haemorrhages and/or laboratory evidence of disseminated intravascular coagulation.|
|9. Repeated generalised convulsions||≥3 generalized seizures within 24 hours|
|10. Haemoglobinuria||Macroscopic black, brown or red urine; not associated with effects of oxidant drugs or enzyme defects (like G6PD deficiency)|
|Added World Health Organization criteria from 2000 |
|11. Impaired consciousness||Various levels of impairment may indicate severe infection although not falling into the definition of cerebral malaria. These patients are generally arousable|
|12. Prostration||Extreme weakness, needs support|
|13. Hyperparasitemia||5% parasitized erythrocytes or > 250 000 parasites/µl (in nonimmune individuals)|
|14. Hyperpyrexia||Core body temperature above 400C|
|15. Jaundice (Hyperbilirubinemia)||Serum bilirubin of more than 43m mol/l (2.5 mg/dl).|
|16. Fluid and electrolyte disturbances ||Dehydration, postural hypotension, clinical evidence of hypovolemia|
|17. Vomiting of oral drugs||Patients with persistent vomiting may have to be admitted for parenteral therapy.|
|18. Complicating or associated infections||Aspiration bronchopneumonia, septicemia, urinary tract infection etc.|
|19. Other indicators of poor prognosis ||Leukocyte count >12,000/cumm; high CSF lactate (>6 mmol/l)and low CSF glucose; more than 3-fold elevation of serum enzymes (aminotransferases); increased plasma 5′-nucleotidase; low antithrombin III levels; peripheral schizontemia; papilloedema/retinal oedema|
|20. Malarial Retinopathy||A large, prospective autopsy study of children dying with cerebral malaria in Malawi found malarial retinopathy to be a better indicator of malarial coma. Similar retinopathy in an adult has also been reported.|
Differential Diagnosis: The differential diagnosis of fever in a severely ill patient is broad. Coma and fever may result from meningoencephalitis or malaria. Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness, photophobia, Kernig sign) but the patient may be opisthotonic. As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture should be performed to exclude this condition. There is also considerable clinical overlap between septicaemia, pneumonia and severe malaria – and these conditions may coexist. In malaria endemic areas particularly, where parasitaemia is common in the young age group, it is often impossible to rule out septicaemia in a shocked or severely ill obtunded child. Where possible, blood should always be taken on admission for culture, and if there is any doubt, empirical antibiotic treatment should be started immediately along with antimalarial treatment.
Evaluation of the Patient
Malaria is a very simple disease to diagnose and treat; yet it claims more lives than any other infectious disease in the world. It is therefore very essential that every case of malaria be assessed thoroughly.
General: Functional status, prostration, breathlessness, level of consciousness, hydration, toxicity, puffiness of face and lids, etc.
Vital signs: Pulse rate, blood pressure (hypotension), temperature (hyperpyrexia), respiratory rate (tachypnoea, acidotic breathing).
Other signs: Pallor, Jaundice, Cyanosis, Edema, etc.
Abdomen: Liver, spleen, bowel sounds – Tender hepato/ splenomegaly is more common in acute malaria.
Respiratory system: Basal crackles, wheezes; sometimes, associated pneumonia and its bronchial breath sounds.
C.N.S.: Level of sensorium, convulsions, neck stiffness, ocular fundii, any focal deficits.
Hemoglobin: Anemia is common in malaria. Rapid reduction in level of hemoglobin is seen in falciparum malaria and less than 7 g/ dl should be a warning.
Total leukocyte count: It can vary from low to high, and neutrophilic leukocytosis is common in severe malaria with or without associated bacterial infection. Leukopenia is seen in severe malaria with septicemia, and chronic hypersplenism.
Platelet count: Thrombocytopenia is common in P. falciparum and P. vivax malaria, but it does not correlate with the severity of the infection.
How to do a parasite count?
Thick film: The density of malarial parasites can be read against the leukocytes and an approximate parasite count can be calculated.
- Count the number of asexual forms of the parasite ( rings, trophozoites and schizonts) against 100 leukocytes and multiply by 75, this gives an approximate total per micro liter (mm3).
- The average leukocyte count per microscopic field is about ten. Therefore, multiply the average number of parasites per field by 750, this also gives an approximate total per micro liter.
Thin film: Count the number of parasites within 1000 red blood cells and divide this by 10. This gives the percentage of parasitemia.
A parasite count of 100000 or more per mm3 (or 5% and more) is considered as severe infection.
Blood Glucose: Hypoglycemia is a common problem encountered in malaria and may remain undetected because the symptoms and signs of hypoglycemia viz. sweating, tachycardia etc., are even otherwise seen in malaria. It is very important to monitor the blood glucose levels once at least 6 hours in falciparum malaria, particularly if the patient is pregnant or is receiving quinine.
Moderate elevation in blood urea and creatinine are common. Significant increase is suggestive of renal impairment.
Hyperbilirubinemia is common in malaria, particularly due to hemolysis. Some patients with falciparum malaria may have very high levels of conjugated bilirubin due to associated hepatocyte dysfunction.
Serum albumin levels may be reduced, some times markedly.
Serum aminotransferases, 5′ – nucleotidase and lactic dehydrogenase are elevated.
Prothrombin time and partial thromboplastin time are elevated in 20% of patients with cerebral malaria. Some may have features of disseminated intravascular coagulation.
Hyponatremia is common and needs careful management.
Lactic acidosis is seen in severely ill patients, especially in patients with hypoglycemia and renal dysfunction. It can be suspected if there is a wide anion gap.
Urine examination may show albuminuria, microscopic hematuria, hemoglobinuria and red cell casts. With massive intravascular hemolysis, urine may be black in colour.
- Persistence of fever even after 48 hours of initial treatment.
- Continuously worsening headache.
- Persistent vomiting.
- Any complications of P. falciparum malaria– altered sensorium, convulsions, anemia, jaundice, hyperpyrexia, bleeding and clotting disorders, breathlessness, high coloured urine etc.
- Patients who are at higher risk for development of complications of P. falciparum malaria-extremes of age, pregnancy etc.
- Patients who appear sick and prostrated
- Significant dehydration
- Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria. Critical Care 2003;7:315-323 Available at http://ccforum.com/content/7/4/315
- Njuguna PW, Newton CR. Management of severe falciparum malaria. J Postgrad Med [serial online] 2004;50:45-50. Available at http://www.jpgmonline.com/text.asp?2004/50/1/45/6653
- World Health Organization: Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990;84(suppl 2):S1-S65.
- World Health Organization: Severe falciparum malaria. Trans R Soc Trop Med Hyg 2000;94(suppl 1):S1-S90.
- Management of Severe Malaria: A practical handbook. Second edition. World Health Organization. Geneva, 2000. Available at http://apps.who.int/malaria/docs/hbsm.pdf
- Guidelines for the treatment of malaria. World Health Organization. Geneva, 2006. pp 41-61. Available at http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf
- Jagannath Sarkar et al. Risk factors for malaria deaths in Jalpaiguri district, West Bengal, India: evidence for further action. Malaria Journal 2009;8:133 Available at
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