Increased risk of invasive bacterial infections in African people with sickle-cell disease: a systematic review and meta-analysis

Summary

Children with sickle-cell disease are at great risk of serious infections and early mortality. Our Review investigates the association between sickle-cell disease and invasive bacterial disease among populations in Africa. We systematically searched published work extracted data on pneumonia, meningitis, and bacteraemia by sickle-cell disease status. Most studies identified lacked a control group and did not use best laboratory methods for culturing fastidious bacteria. Only seven case-control or case-cohort studies provided data on the association between invasive bacterial disease and sickle-cell disease status. For all-cause laboratory-confirmed invasive bacterial disease, the pooled odds of sickle-cell disease was 19-times greater among cases than controls. For disease caused by Streptococcus pneumoniae, the pooled odds of sickle-cell disease was 36-times greater; and for Haemophilus influenzae type b disease it was 13-times greater.

Introduction

Sickle-cell disease encompasses various combinations of abnormal haemoglobin genes that include at least one copy of the gene for haemoglobin S paired with another structural β-chain haemoglobin variant or β-thalassaemia gene. People living in Africa have the highest burden of sickle-cell disease, predominantly due to four types of abnormal haemoglobin combinations: haemoglobin SS (sickle-cell anaemia), haemoglobin SC, haemoglobin Sβ+ thalassaemia, and haemoglobin Sβ0 thalassaemia.¹ Every year 230 000 infants with sickle-cell anaemia are born in Africa, representing 60% of all births worldwide associated with severe haemoglobin disorders.² The prevalence of haemoglobin S varies by country and is highest in equatorial Africa where Plasmodium falciparum malaria is endemic. People that are heterozygotes or carriers of the haemoglobin S trait are protected against serious complications of malaria in early childhood.3, 4 This relative advantage among people that are heterozygotic for the sickle-cell gene maintains the presence of the gene in populations living in malarial areas despite the survival disadvantage of inheriting the homozygous state of sickle-cell anaemia, illustrating the concept of a balanced polymorphism.³ Up to 25% of adults in some countries such as Nigeria, Gabon, and the Democratic Republic of the Congo are heterozygous for haemoglobin S,5, 6, 7 and greater than 1% of infants are born with sickle-cell anaemia (figure 1).⁹

Children with sickle-cell anaemia have an increased risk of mortality that peaks between the ages of 6 months and 3 years in both low-income and high-income settings.2, 10, 11, 12, 13, 14 In Africa, an estimated 6·4% of deaths in children younger than 5 years are attributable to sickle-cell anaemia; in west Africa the population-attributable risk might be as high as 9%.1, 15

Increased early mortality among children with sickle-cell disease is primarily due to increased risk of infection. Immune function is compromised in sickle-cell disease because of deficiency in serum opsonin activity, abnormal neutrophil kinetics, and repeated sickling in the spleen that leads to loss of splenic function.11, 16 These immunological deficiencies render children with sickle-cell disease particularly vulnerable to malaria and infections from encapsulated bacteria such as Streptococcus pneumoniae (the pneumococcus). The greater risk of early invasive pneumococcal disease has been well documented: in the USA, before the introduction of pneumococcal conjugate vaccine, children with sickle-cell disease younger than 3 years had a 53-times greater risk of invasive pneumococcal disease compared with the general population.¹⁷ Comprehensive care with parental education, penicillin prophylaxis, pneumococcal vaccination, and aggressive treatment with intravenous antibiotics for febrile episodes has increased the life expectancy of people with sickle-cell disease in developed countries and the Caribbean to 45–55 years.12, 18

Life expectancy among African people with sickle-cell disease is probably less than 20 years.¹⁹ Some studies have questioned the relative importance of the pneumococcus as a cause of bacterial infection in African people with sickle-cell disease and, therefore, the applicability of antipneumococcal strategies used in developed countries and the Caribbean to African settings.20, 21 The objective of this Review is to summarise the data from Africa on the association between sickle-cell disease and invasive bacterial disease, with a focus on the pneumococcus. The implications of these findings for the care of patients with sickle-cell disease in Africa and the introduction of pneumococcal conjugate vaccine are discussed.