Is Sickle Cell Trait a Risk Factor for Invasive Pneumococcal Disease?

Amoateng-Adjepong, Yaw

doi: 10.1097/EDE.0b013e3181d7e1f4
Infectious Diseases: Commentary

From the Yale University School of Medicine, New Haven, CT.

Correspondence: Yaw Amoateng-Adjepong, Yale University School of Medicine; Categorical Internal Medicine Residency Program, Bridgeport Hospital, Yale New Haven Health, 267 Grant Street, Bridgeport, CT 06610. E-mail:

Article Outline

There has been a long-held notion that, unlike the homozygous sickle cell disease (Hemoglobin SS), sickle cell trait (Hemoglobin AS) is a completely benign condition with no significant morbidity.1 That viewpoint is increasingly being challenged by numerous case reports of associated complications.2,3 In this issue of E pidemiology, Poehling et al present convincing data of modest increase in the incidence of invasive pneumococcal disease (IPD) in Tennessee children with sickle cell trait (incidence = 140 cases per 100,000 child years [95% confidence interval {CI} = 99/100,000–192/100,000]) compared with those with normal hemoglobin (81 cases per 100,000 child years [67/100,000–97/100,000]) in 1995–2003—periods before and after the 2000 recommendation for routine use of the heptavalent pneumococcal conjugate vaccine (PCV7) in US children.4 Sickle-cell-disease children had invasive pneumococcal disease incidence of 1076 per 100,000 child years for that same period. Adjusted for age, sex, time, and other high risk conditions, there was a 42% excess risk in black children with sickle cell trait compared with black children with normal hemoglobin (adjusted relative risk [aRR] = 1.42 [95% CI = 1.01–2.0]), and 77% excess compared with white children with normal hemoglobin (1.77 [1.22–2.55]). Similar increases were observed in children with Hemoglobin C trait. The invasive pneumococcal disease rates fell for all groups in the post-PCV7 period. This paper by Poehling et al4 represents the first comprehensive study of invasive bacterial disease incidence in the sickle cell trait population.

These findings raise very interesting questions. Could the observed increases be due to unexplained confounding? Can these findings be replicated in other sickle cell trait populations? Might sickle-cell-trait persons experience similar increases in the incidence of other bacterial infections (invasive salmonella, meningococcal, and hemophilus influenzae type B) that are known to burden homozygous sickle cell disease patients? What is the probable mechanism for such an increase?

The magnitude of the increase in invasive pneumococcal disease incidence in sickle cell trait was small compared with the 13-fold increase in the sickle cell disease children. Nonetheless, the consistent pattern of increase in the periods before and after PCV7, and after adjusting for known high-risk conditions such as black race, asthma, and young age, suggest the observed increase is real and unlikely to be explained either by chance or by unidentified confounding.

The observed increase in invasive pneumococcal disease rate in sickle-cell-trait children is of great public health significance. Sickle cell trait is present in at least 300 million people worldwide, with prevalence reaching 30%–40% in Africa, southern India, and portions of the Arabian Peninsula.2 These regions carry the heaviest global burden of pneumococcal, meningococcal, hemophilus influenzae type B, and salmonella infections.5–7 Pneumococcal disease alone accounts for 11% of all mortality in HIV-negative children.5 Whether the high prevalence of sickle cell trait in these regions accounts for part of the invasive pneumococcal disease and other infectious disease burden needs to be studied. It is gratifying that there was 82% reduction in the invasive pneumococcal disease incidence in the sickle-cell-trait children in the post-PCV7 period. Unfortunately, however, few countries in the regions with high sickle-cell-trait prevalence have PCV7 as part of their national childhood immunization coverage. The excess incidence of invasive pneumococcal disease in sickle-cell-trait children suggests targeted PCV7 vaccination of children with sickle cell disease alone is not sufficient, and that all children in these countries need to be vaccinated with PCV7.

The primary mechanisms for increased rates of invasive encapsulated bacterial infections in persons with homozygous sickle cell disease is due to the early functional hyposplenism, abnormality of the alternate pathway of complement activation (leading to opsonophagocytic defect), and to decreased levels of specific circulating antibodies.8 Splenic function in individuals with sickle cell trait is generally preserved, except in conditions of extreme hypoxia. Also, comparative studies found normal levels of circulating immunoglobin and complement activity in sickle-cell trait individuals. The probable mechanisms for such invasive pneumococcal disease increase in the sickle-cell-trait population will need further inquiry.

In summary, Poehling et al4 finding of increased invasive pneumococcal disease incidence among children with sickle cell trait is an unexpected addition to the emerging complications of sickle cell trait. It raises very interesting research questions that are worth exploring, and it challenges the dominant theory of sickle cell trait as a completely benign condition.

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YAW AMOATENG-ADJEPONG is a practicing pediatrician, internist and epidemiologist. He is an Assistant Clinical Professor of Medicine at Yale University School of Medicine and Associate Program Director of the Categorical Internal Medicine program at Bridgeport Hospital. He has a special interest in sickle cell trait and coauthored a recent review of complications associated with sickle cell trait.

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