Examination of Protective Factors Against Severe Malaria
Examination of Protective Factors Against Severe Malaria
This study, sponsored by the National Institutes of Health and the University of Bamako in
 Mali, Africa, will examine factors that may protect against progression of malaria from mild
 to severe disease. Infection with the malaria parasite causes disease ranging in severity
 from mild or no symptoms to severe. A better understanding of what factors protect against
 disease progression may help scientists develop improved methods of disease prevention and
 treatment. The objectives of this study are to:

 -  Identify differences in protective factors for severe malaria in Malinke children
 residing in two Mali villages, Kela and Kangaba. Genetic variations in hemoglobin
 proteins called HbS and HbC appear to confer protection against severe disease in some
 children but not others. HbC appears to protect young Malinke children living in Kela,
 but not in nearby Kangaba, while HbS protects children in Kangaba but not in Kela. In
 addition, deficiency of an enzyme produced by red blood cells called G6PD protects
 males, but not females, from severe malaria.

 -  Investigate how fetal hemoglobin (HbF) may protect against malaria in infants and
 determine how HbS, HbC, G6PD deficiency, and beta-thalassemia trait affect the rate of
 HbF decline during the first 2 years of life.

 Children under 11 years of age who seek medical care at Kangaba or Kela health centers for
 symptoms of malaria may be eligible for this study. Each will be screened with a medical
 history, physical examination and blood test. In addition, healthy infants born to women
 referred to field site clinics may be enrolled for the newborn study. Participants undergo
 the following procedures:

 Children with mild malaria are treated with artesunate and amodiaquine. Those with severe
 malaria are treated with quinine. Blood is collected by finger prick every day for 4 days to
 evaluate the response to treatment and for genetic testing. Some blood is stored for future
 research related to malaria.

 Newborns have a heel or finger prick at 1, 3 and 6 months to collect a small blood sample for
 genetic testing. In addition, at the time of birth, a small amount of blood is collected from
 one of the blood vessels of the placenta. Some infants may be followed up to 2 years, with
 additional drops of blood taken at 12, 18 and 24 months. Some of the blood is stored for
 future research related to 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:

 1. All malaria patients enrolled in the case-control study will be less than 11
 years old.

 2. 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.

 3. 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.