Examination of Protective Factors Against Severe Malaria

Our previous case-control study (protocol #01-I-N020) established that hemoglobin (Hb) C protects against severe malaria in the Dogon ethnic group of Mali, West Africa. We believe that abnormal display of major parasite virulence antigens (PfEMP-1) on the surface of HbC erythrocytes accounts for this protection. Whether this mechanism mediates protection by other mutant erythrocytes remains to be investigated. The principal objective of the current protocol has been to investigate whether HbC also protects against severe malaria in the Malinke of Kela, which historically gave rise to the Dogon. Our preliminary data from protocol #02-I-N285 suggest that HbC but not HbS (sickle trait) protects the young Malinke children of Kela, with the opposite being true for the Malinke children of Kangaba, a nearby village. To confirm these novel preliminary findings and to investigate candidate mechanisms of protection, our ongoing case-control study requires an additional 150 severe malaria patients who are less than 5 years old, of Malinke ethnicity, reside in either Kangaba or Kela villages, and have normal G6PD activity. Children less than 11 years old and diagnosed with either severe (case) or uncomplicated (control) malaria will be tested for hemoglobinopathies and G6PD deficiency. Severe and uncomplicated malaria patients will be treated with parenteral quinine or oral artemisinin combination therapies, respectively, which are standard of care in Mali. Principal outcome measures will include a comparison of the frequency of HbC, HbS, and G6PD deficiency between cases and controls; with odds ratios and 95% confidence intervals determining the degree and statistical significance of severe malaria protection.

• INCLUSION CRITERIA:

• All malaria patients enrolled in the case-control study will be less than 11 years old.
• Uncomplicated malaria: Axillary temperature greater than 37.5 degrees Celsius or history of fever, signs and symptoms of malaria (e.g. headache, body aches, malaise), asexual parasite density less than 500,000 per microliter of blood, no criteria of severe malaria (see next paragraph), and no other etiologies of febrile illness (e.g. respiratory tract infection, cellulitis) on clinical examination.
• Severe malaria: Asexual parasite density greater than or equal to 100,000/uL or parasitemia of any density plus any one of the following: coma (defined as Blantyre coma score less than or equal to 2), convulsions (witnessed by investigator), severe prostration, severe anemia (hemoglobin less than 5 g/dL), respiratory distress, hypoglycemia (serum glucose less than 40 mg/dL), jaundice/icterus, shock (systolic blood pressure less than 50 mmHg, rapid pulse, cool extremities), cessation of eating and drinking, repetitive vomiting.

Exclusion criteria

Patients who are parasitemic yet are found by clinical examination to have another etiology of febrile illness (e.g., respiratory tract infection, cellulitis) will not be formally enrolled into the protocol, but may be treated for both malaria and their coexisting infection by the study team.