Examination of Protective Factors Against Severe Malaria
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Malaria; Severe Malaria
Status: Active, not recruiting
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)
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.
Official title: Multidisciplinary Studies of Malaria Protection by Hemoglobinopathies and G6PD Deficiency in Mali
Study design: N/A
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
Minimum age: N/A.
Maximum age: 10 Years.
- INCLUSION CRITERIA:
1. All malaria patients enrolled in the case-control study will be less than 11
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
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.
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.
Locations and Contacts
Malaria Research and Training Center, Bamako, Mali
Bard H. The postnatal decline of hemoglobin F synthesis in normal full-term infants. J Clin Invest. 1975 Feb;55(2):395-8.
Starting date: August 2005
Last updated: April 26, 2008