Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis

Abstract

Background: Haemoglobinopathies can reduce the risk of malaria syndromes. We aimed to quantify the relation between different haemoglobin mutations and malaria protection to strengthen the foundation for translational studies of malaria pathogenesis and immunity.

Methods: We systematically searched the Medline and Embase databases for studies that estimated the risk of malaria in patients with and without haemoglobinopathies up to Sept 9, 2011, and identified additional studies from reference lists. We included studies that enrolled mainly children or pregnant women and had the following outcomes: Plasmodium falciparum severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and Plasmodium vivax malaria. Two reviewers identified studies independently, assessed quality of the studies, and extracted data. We produced odds ratios (ORs; 95% CIs) for case-control studies and incidence rate ratios (IRRs; 95% CIs) for prospective studies. We did the meta-analysis with a random-effects model when equivalent outcomes were reported in more than one study.

Findings: Of 62 identified studies, 44 reported data for haemoglobin AS, 19 for haemoglobin AC and CC, and 18 for α-thalassaemia. Meta-analysis of case-control studies showed a decreased risk of severe P. falciparum malaria in individuals with haemoglobin AS (OR 0·09, 95% CI 0·06-0·12), haemoglobin CC (0·27, 0·11-0·63), haemoglobin AC (0·83, 0·67-0·96), homozygous α-thalassaemia (0·63, 0·48-0·83), and heterozygous α-thalassaemia (0·83, 0·74-0·92). In meta-analysis of prospective trials only haemoglobin AS was consistently associated with protection from uncomplicated malaria (IRR 0·69, 95% CI 0·61-0·79); no haemoglobinopathies led to consistent protection from asymptomatic parasitaemia. Few clinical studies have investigated β-thalassaemia, haemoglobin E, P. vivax malaria, or pregnancy-associated malaria.

Interpretation: Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous α-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia. Through attenuation of severity of malaria, haemoglobinopathies could serve as a model for investigation of the mechanisms of malaria pathogenesis and immunity.

Funding: US National Institute of Allergy and Infectious Diseases.

Figure 1

Study identification flowchart

Figure 2

Unadjusted individual and summary Odds Ratios for specific malaria syndromes by haemoglobin variants Abbreviations: CI, confidence interval; Hb, haemoglobin ^a Not included in meta-analyses because prevalences of HbAS in cases and controls were not reported. All Odds Ratios (ORs) are for comparison with healthy controls. The data markers represent either ORs from individual studies (circles) or summary ORs for subgroup data (diamonds) that were generated by random-effects meta-analysis of individual studies (squares). For individual studies included in meta-analyses, the size of the square data marker is relative to the weight of the study. The I² statistic is a measure of the heterogeneity of the individual study estimates which were meta-analyzed, and was calculated using the Mantel-Haenszel method. ORs for individual studies may differ from those in Table S1 or in the original published studies because they were calculated from raw data and are thus unadjusted.

Figure 3

Individual and summary incidence rate ratios of P. falciparum syndromes in prospective studies of children with haemoglobinopathies Abbreviations: CI, confidence interval; Hb, haemoglobin. All incidence rate ratios (IRRs) compare patients with the variant listed to patients with either HbAA or the αα/αα genotype. Summary measures (diamonds) were computed using random-effects Poisson meta-regression of individual studies (squares). ^a Studies had overlapping cohorts. Because the cohort in Williams et al (2005) subsumes that of Williams et al (2005), only data from Williams et al (2005) was included in the meta-analyzed summary IRR for uncomplicated malaria in HbAS children. ^b Summary IRR of uncomplicated malaria in HbAS compared with HbAA children from five studies.^{,- c} Summary IRR of uncomplicated malaria in HbAC compared with HbAA children from two studies.^{, d} Summary IRR of uncomplicated malaria in homozygous or heterozygous α-thalassaemic compared with non-thalassaemic children from three studies [Williams 1996, Williams 2005 (NG), Crompton 2008].^{,, e} Detected by polymerase chain reaction.