By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: Even in the era of newborn screening, pneumococcal vaccination, and penicillin prophylaxis, children with sickle cell disease continue to be at risk of morbidity and mortality from invasive pneumococcal disease, mostly from non-vaccine serotypes.

SOURCE: Oligbu G, Collins S, Sheppard, et al. Risk of invasive pneumococcal disease in children with sickle cell disease in England: A national observational cohort study, 2010-2015. Arch Dis Child 2017 Dec. 27. doi:10.1136/archdischild-2017-313611. [Epub ahead of print].

Sickle cell disease is associated with vaso-occlusion and functional asplenia with negatively altered antibody production, poor opsonization, and decreased phagocytosis. This leads to increased susceptibility to infection with encapsulated bacteria, including pneumococcus. Without special protective intervention, children with sickle cell disease, as compared to healthy peers, have a 600-fold increased risk of invasive pneumococcal disease. Use of pneumococcal polysaccharide vaccines led to reduced but still significant risk. The advent of a 7-valent pneumococcal conjugate vaccine further reduced the risk of invasive pneumococcal disease in children with sickle cell disease in the United States. Subsequently, a 13-valent pneumococcal conjugate vaccine was used in an effort to prevent pneumococcal disease more successfully. The authors reviewed outcomes of children identified by newborn screening to have sickle cell disease during the era of the 13-valent vaccine to determine current risks of invasive disease.

Annual birth cohorts of children born between September 2010 and August 2014 who developed illness associated with pneumococci identified in a normally sterile site (such as blood, spinal fluid, and pleural fluid) were evaluated. There were 881 cases of invasive pneumococcal disease, and 12 of those children had sickle cell disease (11 with homozygous hemoglobin SS [HbSS], one with combined heterozygous hemoglobin SC [HbSC]).

Each of the 11 HbSS children had received appropriate 13-valent pneumococcal vaccine, but only one of the two who became ill after 24 months of age had received the recommended 23-valent polysaccharide pneumococcal vaccine around the time of the second birthday. Three of the 11 children (27%), two who had been born prematurely, died. Serogroup 15 was implicated most commonly, including each fatal case and eight of 11 cases overall. One child had a vaccine strain of illness but was only 3 months old at the time of the infection, and so had only received one vaccine dose. The child with HbSC was infected with a non-vaccine strain (33F) in the second year of life and recovered from the infection.

With good data about the number of children born in England during the study and the number who screened positive for sickle cell disease, the authors could calculate relative risks. The risk in the overall birth cohort was 32 per 100,000 children compared with 1,571 per 100,000 children with HbSS. (The risk was 329 per 100,000 for those with HbSC.)

The 49-fold increase in risk of invasive pneumococcal disease in the era of screening, prophylaxis, and vaccination was still less than the 600-fold risk without protective interventions. Of note, the only child with infection by a pneumococcal serotype included in the 13-valent vaccine had been only partially immunized due to young age. It is concerning that three of the 11 infected children with HbSS died even though their infections were with penicillin-sensitive germs.

The authors highlight the importance of strict adherence to penicillin prophylaxis starting by 3 months of age in children with sickle cell disease. This is essential since most of the remaining cases of invasive pneumococcal disease are by pneumococcal strains not included in the current conjugate vaccines.

COMMENTARY

The seminal study about the value of penicillin prophylaxis for children with sickle cell disease was published in the New England Journal of Medicine in 1986.1 Two-hundred fifteen children younger than 3 years of age were randomized to receive penicillin V potassium (125 mg by mouth twice daily) or placebo. After about 15 months of follow-up, the study was terminated early when preliminary analysis revealed an 84% reduction in pneumococcal sepsis in penicillin-treated children (13 of 110 untreated children developed sepsis [with three deaths] vs. two of 105 treated children [with no deaths]).1 Based on that study and as advised by the authors, newborn screening for sickle cell disease became standard in the United States, and penicillin prophylaxis by 4 months of age through at least 3 years of age was implemented for children with sickle cell disease.

Beginning in 2000, 7-valent pneumococcal conjugate vaccines became available for infants in the United States, and the 13-valent conjugate vaccines became available a decade later.2 The 23-valent polysaccharide vaccine still was given at 2 years of age.2 A single-center study in the United States from 2000-2014 identified 11 cases of invasive pneumococcal disease (estimated 417 per 100,000 person-years, similar to the English study with 1,571 per 100,000 children over five years).2 Interestingly, the U.S. study was similar to the English study, with all isolates being sensitive to penicillin and the vast majority (89%) due to non-vaccine strains of pneumococcus.2 However, unlike in the United Kingdom, the majority of the U.S. children with pneumococcal disease were older than 5 years of age; this raises the question of continuing penicillin prophylaxis well beyond the fifth birthday.

While the benefits of penicillin prophylaxis are clear, the target population and duration of treatment are less certain. Everyone suggests prophylaxis for children with HbSS and even combined heterozygotic children with both sickle cell and beta thalassemia hemoglobin. In addition, some use limited data,3,4 as compatible with Oligbu’s study, to suggest prophylaxis also for children with HbSC disease. There is variation between centers regarding how long penicillin should be used, but continuation commonly is suggested until at least 5 years of age.3,4,5

However, penicillin prophylaxis is not used widely in some African countries.4 A mathematical modeling study of the cost-effectiveness of newborn screening and prophylactic interventions for children with sickle cell disease showed that it would cost only $184 for each saved year of healthy life if preventive measures were implemented in high-risk African countries.6

The risk of sickle cell disease varies between African countries; Nigeria and the Democratic Republic of Congo account for half of the 228,000 babies born with sickle cell disease each year in Africa.6 By this modeling study, the mean life expectancy for African children with sickle cell disease without screening and preventive intervention is 1.7 years in rural areas and 6.7 years in urban areas.6 With screening and preventive strategies, the life expectancy rises to about 27 years.6

Of course, prophylactic penicillin is not effective if it is not given. A systematic review found that prophylactic penicillin was used as prescribed only 40-44% of the time.7 Beliefs about safety and effectiveness of the medication compromised adherence, but increased parental knowledge correlated with better adherence.7

Thus, the new study of invasive pneumococcal disease in patients with sickle cell disease reminds us that screening, penicillin prophylaxis, and vaccination combine to be very effective in preventing serious illness and death. However, the risk of serious infection in patients with sickle cell disease still is too high, even in resource-rich countries. Improvements depend on adherence to medical recommendations and on extending the reach of medical care to rural areas of sub-Saharan Africa.

REFERENCES

  1. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314:1593-1599.
  2. Martin OO, Moquist KL, Hennessy JM, et al. Invasive pneumococcal disease in children with sickle cell disease in the pneumococcal conjugate vaccine era. Pediatr Blood Cancer 2018;65:e26713.
  3. Rankine-Mullings AE, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev 2017;10:CD003427.
  4. Sabota A, Sabharwal V, Fonebi G, et al. How we prevent and manage infection in sickle cell disease. Brit J Haematol 2015;170:757-767.
  5. Yawn BP, Buchanan GR, Afeny-Annan AN, et al. Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033-1048.
  6. Kuznik A, Habib AG, Munube D, et al. Newborn screening and prophylactic interventions for sickle cell disease in 47 countries in sub-Saharan Africa: A cost-effectiveness analysis. BMC Health Serv Res 2016;16:304.
  7. Walsh KE, Cutrona SL, Kavanagh PL, et al. Medication adherence among pediatric patients with sickle cell disease: A systematic review. Pediatrics 2014;134:1175-1183.