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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the National Institute of Allergy and Infectious
Diseases and the National Cancer Institute, National Institutes of
Health, Bethesda, MD; the Hematology Laboratory and Malaria Research
and Training Center, Department of Epidemiology of Parasitic Disease,
Faculty of Medicine, Pharmacy and Odonto-Stomatology, Bamako, Mali; and
the Division of Geographic Medicine, University of Maryland School of
Medicine, Baltimore, MD.
The malaria hypothesis proposes a survival advantage for
individuals with hemoglobin variants in areas of endemic
Plasmodium falciparum malaria. Hemoglobin C (HbC) is a
possible example in West Africa, where this hemoglobin has a centric
distribution with high frequencies among certain populations including
the Dogon ethnic group. To test whether HbC is associated with
protection from malaria, we performed a case-control study in the Dogon
of Bandiagara, Mali. HbC was present in 68 of 391 (17.4%) of
uncomplicated malaria control cases, whereas it was detected in only 3 of 67 cases (4.5%) of severe malaria (odds ratio [OR], 0.22;
P = .01). Further, HbC was present in only 1 of 34 cases
(2.9%) with cerebral manifestations, the most common presentation of
severe malaria in this population (OR, 0.14; P = .03).
Episodes of uncomplicated malaria and parasitemias (4800-205 050/µL)
were identified in cases of homozygous HbC (HbCC), which indicates that
P falciparum parasites are able to efficiently
replicate within HbCC erythrocytes in vivo. These findings suggest that
HbC does not protect against infection or uncomplicated malaria but can
protect against severe malaria in the Dogon population of Bandiagara,
Mali. The data also suggest that the protective effect associated with
HbC may be greater than that of HbS in this population.
(Blood. 2000;96:2358-2363) More than 50 years ago, Haldane1
suggested that protection against malaria was conferred to individuals
by a form of thalassemia. Since that time, the observed overlaps in the
geographic distributions of malaria with hemoglobinopathies and other
red blood cell disorders have been cited in support for the hypothesis
that malaria has been an important evolutionary force in selection of
these variants.2 Epidemiologic and in vitro support for
the malaria hypothesis is best documented for the
thalassemias3-5 and sickle hemoglobin (HbS),6-10 which in different regions of Africa, the
Middle East, and Asia are maintained in a state of balanced
polymorphism because of the protective effect of the heterozygous state
against severe disease. Hemoglobin E (HbE) has also been associated
with a reduced prevalence of severe Plasmodium falciparum
malaria, with the odds of severe complications being 15%-20% of those
found for homozygous hemoglobin A (HbA).11
The malaria hypothesis has been invoked to explain the observed
frequency of HbC in certain populations of West Africa, although epidemiological evidence has been contradictory.12-16 One
study suggested an increased immunoglobulin response in individuals heterozygous for HbC.17 The presence of heterozygous HbC,
however, was not found to correlate with reductions of P
falciparum infections or parasite
densities.12-14,17,18 Further, 2 clinical studies involving small numbers of HbC-trait individuals in some ethnic groups
did not show significant evidence of reduced rates of severe disease.15,16 Although individuals homozygous for HbC
(HbCC) were not observed in these studies, thereby leaving the
possibility of protection from malaria by the HbCC state unresolved,
these findings have not supported the possibility of a balanced
polymorphism in which positive selection by malaria for HbC may counter
negative selective pressures from the morbidity of the HbSC
state,19 the occasional pathologic developments in
the HbC homozygous state,20 and a possible reduced
reproductive fitness of the The HbC and HbS mutations both occur in the 6th position in the
Background
Diagnosis and classification of cases
Patients with uncomplicated malaria and parasitemia of Ep < 1 × 105/µL (control cases) were treated with chloroquine in an outpatient oral drug efficacy study (C. V. Plowe et al, unpublished data, 2000). Patients with severe malaria or parasitemia of Ep > 1 × 105/µL were placed under intensive care with treatment that included parenteral fluids, quinine, glucose, and antibiotics, as judged appropriate. Hemoglobin typing Hemoglobin types were determined by analysis of red blood cell lysates using cellulose acetate electrophoresis at an alkaline pH. Cellulose acetate plates (Helena Laboratories, Beaumont, TX) were stained with Ponceau red (Geimsa, St Louis, MO), yielding clear discrimination of hemoglobins A, F, S, and C/A2. Although HbC comigrates with HbA2 during electrophoresis, the presence of the HbC-trait was evident by its relative abundance in heterozygous and homozygous individuals. Homozygosity for HbC was also confirmed retrospectively for 1 of 7 cases from a frozen sample of preserved erythrocytes by citrate-agar electrophoresis (Helena Laboratories) and quantitative measurements of hemoglobins F, A2, and C by cation-exchange high-precision liquid chromatography (HPLC) using the variant -thalassemia short program
(Bio-Rad Laboratories, Hercules, CA). HbAS samples identified by
electrophoresis were confirmed with metabisulfite sickling tests.
Statistical analysis Demographic, clinical, and treatment profiles were recorded on case record forms, transferred to computer files, and analyzed by standard software including EpiInfo 6.0 (the Centers for Disease Control and Prevention, Atlanta, GA), Instat 2.03 (GraphPad Software, San Diego, CA), and Microsoft Excel (Microsoft, Seattle, WA). Parasitemias were log-transformed for statistical analysis. The controls for all comparisons were defined as uncomplicated malaria cases with parasitemia of Ep < 1 × 105/µL. We used the 2-tailed Fisher exact test, 2-tailed Student and Welch t tests, Mann-Whitney U (Wilcoxon rank sum) test, one-way analysis of variance (ANOVA), or Kruskal-Wallis nonparametric test as appropriate. Comparison statistics included the Mantel-Haenszel weighted odds ratio (OR), exact 95% confidence limit (CL), Mantel-Haenszel summary chi-square, and P values. P < .05 was considered statistically significant. Statistical power for comparisons was calculated using the observed OR and a 1-sided type I ( ) error rate of 0.05.
During the 2 transmission seasons of 1997 and 1998, the study team evaluated 3645 patient presentations for symptoms of illness. Of these presentations, 789 cases fit the definition of uncomplicated malaria, and 89 cases met the criteria for severe malaria. The ethnic representation among all malaria cases was 63% Dogon, 13% Peulh, and 24% other ethnic groups including Bambara, Ouolof, and Sonrhai. Approximately equal percentages of the uncomplicated and severe malaria cases had a record of self-treatment with antimalarial remedies prior to presentation to the Medicine Center (44% and 48%, respectively, with this information available for 213 cases). Of the 789 uncomplicated malaria cases, 50% were male and 50% were female, whereas 55% of the 89 severe cases were male and 45% were female. Among the 89 severe malaria cases, 67 occurred in the Dogon (Table
1). The 22 cases in other ethnic groups
were not of sufficient number to independently test for a significant
association between HbC and a reduced prevalence of severe malaria, and
these cases are not detailed in this report. As expected, patients with
severe malaria were significantly younger and more anemic than controls with uncomplicated malaria. Of the 67 severe Dogon cases, 34 cases (51%) presented with cerebral manifestations, 12 (18%) with severe anemia, 18 (27%) with hyperparasitemia
(Ep > 5 × 105/µL), 6 (9%)
with respiratory distress or shock, and 6 (9%) with severe
prostration. Different manifestations of severe malaria thus overlapped
at presentation in 9 of the 67 cases. The severe malaria cases in the
Dogon were more likely to be from rural areas surrounding Bandiagara
than were the uncomplicated malaria control cases (28% vs 6%,
respectively; P < .000 000 1) (Table 1). Complete residential information was not available for 16% of the study population.
As a baseline for analysis of hemoglobin type prevalences in this
study, we first compared the distribution of hemoglobin types in the
Dogon cases of uncomplicated malaria with those reported from an
extensive survey of hemoglobinopathies in the Dogon
country.22,23 The results of this comparison showed that
the reported prevalences of HbAA, HbAC, HbCC, and HbAS were
indistinguishable from the prevalences of 80.0% HbAA, 15.9% HbAC,
1.5% HbCC, and 2.6% HbAS found in the Dogon cases of uncomplicated
malaria (chi-square test with 3 degrees of freedom,
P = .95) (Table 2).
Estimated gene frequencies from the above observations in the
uncomplicated malaria controls (
Table 3 presents the distribution of
hemoglobin types among the severe and uncomplicated cases of malaria in
the Dogon. The percentage of cases with HbC (ie, HbAC and HbCC) in
cases of severe malaria (4.5%) was significantly lower than the
percentage in uncomplicated control cases (17.4% =
15.9% + 1.5%; OR, 0.22; 95% CL, 0.04-0.74;
P = .01). The 7 homozygous HbCC cases all presented with
uncomplicated malaria.
The prevalence of HbAS was not found to be significantly different in the Dogon groups with severe and uncomplicated malaria (OR, 1.91; 95% CL, 0.31-8.92; P = .59) (Table 3). Cerebral manifestations were identified in 2 of the 3 severe malaria HbAS cases. Comparisons of mean parasitemia by hemoglobin type relative to HbAA
among the Dogon population are presented in Table
4. Among the uncomplicated malaria
control cases, uncomplicated cases with
Ep > 1 × 105/µL, or severe
malaria cases, there was no significant difference in mean parasitemia
between the HbAC or HbAS cases and the HbAA cases.
Table 5 presents the results of the
calculated ORs and P values for the prevalences of HbC and
HbS in the severe malaria syndromes among the Dogon cases listed in
Table 3. In this analysis, the total prevalence of HbC (HbAC plus HbCC
presentations) was found to be significantly reduced in the cerebral
manifestations group (OR, 0.14; 95% CL, 0.00-0.89;
P = .03). The numbers of cases were not sufficient to
determine whether the prevalence of HbC differed significantly in
severe anemia, hyperparasitemia, respiratory distress or shock, or
severe prostration.
The Dogon presenting for this study showed a somewhat higher prevalence
of severe malaria than the Peulh and other ethnic groups (data not
shown). Residence data indicated a possible catchment effect because
the proportion of Dogon severe cases from rural areas (28%) was
significantly higher than the proportion of uncomplicated control cases
from rural areas (6%; P < .000 000 1) (Table 1). To
reduce a possible bias resulting from the selective referral of very
ill children from remote, predominately Dogon villages outside
Bandiagara, we compared the hemoglobin prevalences in urban severe
malaria cases against those in randomly matched urban uncomplicated
malaria control cases. Although this smaller sample size reduced the
statistical power for this comparison from 73% (type II error of 0.27)
(Table 3) to 53% (type II error of 0.47), the results remained
consistent with protection against severe malaria by HbC (OR, 0.22;
95% CL, 0.02-1.00; P = .06) (Table
6).
We also analyzed the prevalence of splenomegaly in uncomplicated
malaria controls and severe malaria cases by hemoglobin type (Table
7). Splenomegaly was found to be
significantly more frequent in cases of severe malaria in the Dogon
(P < .001) (Table 7). No instances of splenomegaly were
detected in the 7 CC cases presenting in this study.
The results of this study indicate that HbC is associated with
protection against the severe form of P falciparum malaria in the Dogon of Bandiagara, Mali. In this ethnic group, the prevalence of HbC was significantly lower among cases of severe malaria than among
cases of uncomplicated malaria. The protective effect indicated by the
calculated OR of 0.22 would correspond roughly to an 80% reduction in
the risk of severe malaria. As 16% of the Dogon population in
Bandiagara carry at least 1 HbCC individuals with P falciparum infections were readily found, including 1 case with Ep = 205 050/µL, a parasitemia that corresponds to approximately 5% infected erythrocytes in the bloodstream. These findings show that P falciparum can infect and proliferate within the bloodstream of the HbCC homozygote even though P falciparum parasites have been reported not to proliferate in HbCC erythrocytes under in vitro conditions.29,30 None of the 7 HbCC cases manifested severe or life-threatening complications of malaria. This study was not designed to determine whether HbC was associated with a protection against uncomplicated malaria. However, the fact that the prevalence of HbC in the malaria control group is similar to that observed in the Dogon community does suggest lack of a major effect from HbC on parasite infection and uncomplicated malaria. Prevalences of 15.9% HbAC and 1.5% HbCC in the uncomplicated malaria control cases compare closely to reported average rates of 14.9% HbAC and 1.1% HbCC in the Dogon population.22,23 These findings further suggest a parallel between HbC in the Dogon and HbS in other ethnic groups, which in the heterozygous state protects not so much against the occurrence of P falciparum infection and uncomplicated malaria as against the severe forms of the disease.8 In the cases of uncomplicated malaria among the Dogon, mean parasitemias among the HbAC, HbCC, or HbAS hemoglobin types did not significantly differ relative to the HbAA type (Table 4), which is consistent with previous studies.12-14,17,18 The relatively high proportion of Dogon cases presenting with severe malaria in this study may reflect selection bias from a catchment effect and may thus indicate a limitation in the study design with regard to residential criteria for enrollment.31 Separate analysis of this catchment effect and incorporation of 2 matched uncomplicated controls for each urban severe malaria case confirmed the OR for a protective effect of HbC against severe malaria. Although this strategy was used to minimize possible confounding variables, we recognize that differences in such factors as the prevalence of the HbC trait, entomologic inoculation rates, or self-treatment with antimalarial remedies could have affected prevalences of severe malaria in this analysis. Severe anemia was found to be relatively infrequent in our study, so the number of cases was insufficient to test whether the HbC trait is associated with protection against this manifestation of severe malaria. In contrast to reports from other regions of Africa, where severe anemia (defined as a hemoglobin of less than 50 g/L [5 g/dL]) was present in 30%-80% of severe malaria cases,8,32,33 only 18% of the severe cases in Bandiagara presented with a comparable degree of anemia. Possible roles of other genetic loci affecting malaria susceptibility, parasite transmission intensity, prior antimalarial treatment, nutritional differences, and other factors in anemia have yet to be explored. In The Gambia in West Africa, we note that a reduced prevalence of anemia but not of cerebral malaria was linked to the human leukocyte antigen (HLA)-DRB1*1302 haplotype, and the HLA-B53 allele was associated with protection from both forms of the severe disease.8 Of the 16 HbAS Dogon cases in the study, 3 cases presented with
manifestations of severe malaria, and 2 of these cases presented with
convulsions. While additional studies will be required to establish the
risk of severe malaria in Dogon children with HbAS, these cases raise
the question whether there is a less relative selection for HbAS by
malaria in Dogons than for HbAC and HbCC. Such a possibility would be
consistent with the fact that incidences of HbS and HbC are 3% and
16%, respectively, in the Dogons, which is different from the
respective incidences of 20% HbS and 3% HbC in the Malinke
group34 from which the Dogons are thought to have migrated
500-800 years ago.35 Genetic differences between these
populations or regional environment factors affecting protection by HbS
or HbC may account for the contrast in the current findings from our
previous study of a predominantly Bambara study group in Bamako,
Mali,15 and those from another large study in The Gambia.8 Linkage disequilibrium in these different
populations may also be present between the
The possibility that protective effects associated with different hemoglobin mutations may vary among different human populations is consistent with other reported findings. Early or vigorous development of malaria immunity has been associated with protection of sickle cell trait and thalassemia,36-40 and ethnic variations in the immunological response to P falciparum infection and rates of the clinical episodes of malaria are described from clinical studies in West Africa.41,42 Differences in the prevalence of splenomegaly from malaria infection have been found among West African populations.43,44 Specific environmental influences and diets (eg, the effect of fava beans in the case of HbE)45 may also contribute to the selection of hemoglobin variants. Investigations of questions raised by these observations should provide fundamental information on factors that affect the distribution of hemoglobinopathies and determine the disease manifestations of severe malaria.
We thank the residents of Bandiagara, Mali; the Bandiagara Traditional Healers group; Dr Chiaka Diakite and the staff of the Traditional Medical Center in Bandiagara for their help and encouragement; Boureima Ouologuem and Akouni Dougnon for their assistance; the Regional Malaria Control Program at Mopti, Mali; and Robert W. Gwadz and Richard K. Sakai for their efforts in the support of this work.
Submitted February 7, 2000; accepted May 30, 2000.
Supported in part by the US Agency for International Development (USAID) through the Health and Human Resources Analysis for Africa (HHRAA) Program and through the USAID Mission, Bamako, Mali.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Thomas E. Wellems, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 4, Rm 126, 4 Center Dr, MSC 0425, Bethesda, MD 20892-0425; e-mail: tew{at}helix.nih.gov.
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 F. Tokumasu, R. M. Fairhurst, G. R. Ostera, N. J. Brittain, J. Hwang, T. E. We |
Top
Abstract
Introduction