Comorbidities were identified in 15% of PCV7-eligible children in England and Wales, with malignancy/immunosuppression and congenital heart disease each accounting for one quarter of reported comorbidities. Compared with PCV7-IPD cases, the prevalence of comorbidity was significantly lower for IPD cases caused by the 3 additional PCV10 serotypes and higher for non-PCV13 IPD cases. Overall CFR was low and independently associated with meningitis and comorbidity but not with infecting serotype group.
The comorbidities in the cohort reported here are typical of children considered at higher risk for IPD (6
). Other population-based studies that had differing definitions for comorbidities and age ranges have reported comorbidities in 10%–36% of children with IPD (7
). In Massachusetts, USA, 16% of 578 children <18 years of age who had IPD during 2001–2007 had comorbidity (mainly immunosuppression) (9
). The US Active Bacterial Core surveillance program identified comorbidity in only 3% of childhood IPD cases before PCV7 introduction in 1998–99, but this proportion increased to 7% in 2006–07 (p = 0.003), with similar increases in adults and the elderly; this finding suggests that the replacing serotypes after the decline in PCV7-IPD might be less virulent and thus more likely to infect vulnerable children with comorbidities (14
). The lower prevalence of comorbidities in the Active Bacterial Core surveillance might be explained partly by inclusion of children who had blood cultures performed in an outpatient setting, whereas blood cultures in the United Kingdom are almost always taken in the hospital and, therefore, capture more severe IPD cases (4
). Moreover, changes in clinical practice after PCV7 introduction, such as fewer blood cultures from previously healthy children with fever seeking outpatient care, might have contributed to the increased comorbidity prevalence between the 2 periods in the United States (14
In the cohort reported here, the 3 extra PCV10 serotypes were more likely to affect healthy children. Serotypes 1, 5, and 7 (which are included in both PCV10 and PCV13) are known to be highly invasive and mainly affect previously healthy persons but appear to cause less severe disease, as determined by various clinical severity scores and requirement for intensive care, and have a lower CFR (15
). In children, a meta-analysis of 7 different datasets found that serotypes 1, 5, and 7 were infrequently isolated among carriage strains but had the highest potential for invasive disease, whereas serotypes that were more likely to be carried (e.g., 6B, 19F, and 23F) were less likely to be invasive (16
A higher prevalence of comorbidity was identified for IPD cases caused by the 11 additional PPV23 serotypes as well as non-PPV23 IPD cases, suggesting that the remaining serotypes after PCV13 introduction in the United Kingdom might be less virulent. In England and Wales, PPV23 uptake for high-risk persons is low, particularly for children (17
), and is consistent with the low PPV23 vaccination rates observed among children with comorbidities in the IPD cohort reported here. That such a low proportion of high-risk children were vaccinated with the nationally recommended PPV23 and 2 of the 4 PPV23-vaccinated case-patients had IPD resulting from 1 of the PPV23 serotypes is concerning and merits further investigation on the use of polysaccharide vaccines in high-risk persons.
In keeping with other studies, PCV7 vaccine failure (3.9%) was uncommon (18
), and nearly one third of case-patients had comorbidities. A recent study in the United States reported 4% of 753 IPD cases diagnosed during a 27-month period as PCV7 vaccine failures, with 37% of the case-patients with vaccine failure having comorbidities (20
). In that study, PCV7-vaccinated children with comorbidities were almost 3× more likely to develop PCV7-IPD than were vaccinated children without comorbidities, even after we controlled for various confounders (20
). In another case–control study in the United States that involved 782 children 3–59 months of age who had IPD, vaccine effectiveness of >
1 PCV7 dose against PCV7-IPD was 96% (95% CI 93%–98%) for healthy children and 81% (95% CI 57%–92%) for children with comorbidities (21
). Similar estimates of 97% (95% CI 92%–98%) and 88% (95% CI 78%–94%), respectively, were obtained by using the indirect cohort (Broome) method to measure direct protection afforded by PCV7 (22
). In the United Kingdom, where a 12-month catch-up campaign offering PCV7 to all children <2 years of age was introduced at the same time as routine infant vaccination, vaccine effectiveness estimated by using the indirect cohort method was similar for children with comorbidities and healthy children receiving the nationally recommended immunization courses, albeit with wide confidence intervals for the different comorbidities and immunization schedules (3
In our study and the US studies, serotypes 6B and 19F were predominantly responsible for PCV7 vaccine failures. Similarly, recurrent IPD was reported in only 9 children (0.7%) and, like vaccine failure, was more likely to occur in children with comorbidities. The relatively long duration between episodes and the different infecting serotypes suggest re-infection rather than persistent infection as a consequence of, for example, inadequate or inappropriate therapy. Before routine pneumococcal vaccination, a US population-based surveillance study reporting 318 cases of recurrent IPD identified persons with HIV and children <5 years of age with chronic illness as the 2 main risk groups (23
). A more recent US study reported recurrent IPD in 90 of 4,067 children with IPD over 12 years, with comorbidities identified in >80% (24
). Recurrent IPD cases declined significantly after PCV7 introduction, although age at re-infection or proportion with comorbidities during the pre- and post-PCV7 periods did not differ (24
). Despite the smaller age range and shorter follow-up period, our study supports the low risk for recurrent IPD after PCV7 introduction, even though we are unable to compare with pre-PCV7 rates. Although 5 of 9 children with recurrent IPD had no reported comorbidities, some could have undetected immunologic abnormalities, as was identified in a child with fatal IPD who had IRAK-4 deficiency, for example (25–27
). Children in whom IPD developed, particularly because of vaccine failure, should be carefully assessed, and children who have a history of >1 serious invasive infection should be investigated for possible immune deficiency along with their close family members because further infections possibly could be prevented through appropriate immunization and/or antimicrobial prophylaxis.
The extensive follow-up of IPD cases, particularly the fatal cases, helped us to more accurately estimate CFR and assess IPD-associated deaths. Overall, IPD-associated CFR was low and independently associated with comorbidity and meningitis. The finding that meningitis was diagnosed in one quarter of mainly healthy children is concerning given the significantly higher CFR and association with the most severe long-term neurodevelopmental complications (reported in >30% of survivors) among pathogens causing bacterial meningitis in children (28
Like all large-scale epidemiologic studies, our study has limitations. Not all hospital laboratories in England and Wales routinely report or submit clinical isolates to the HPA. However, by combining multiple data sources and actively requesting submission of invasive pneumococcal isolates to the HPA national Reference Laboratory for confirmation and serotyping, we believe that our surveillance captures most laboratory-confirmed IPD cases and, because the same surveillance method has been in place since PCV7 introduction, enables comparison of trends over time. The study is also limited by the relatively short follow-up period for identifying vaccine failure cases and recurrent episodes. However, given the significant decline in carriage of PCV7 serotypes (29
), we are unlikely to see many cases of PCV7-IPD, particularly in young children where vaccine coverage remains high (30
). The changing pattern of IPD after PCV7 introduction emphasizes the need for continued epidemiologic and molecular surveillance across all age groups. In addition to assessing the role of PPV23 in protecting children with comorbidities, further studies are required to develop new strategies and vaccines with broader coverage to prevent IPD in children who are most susceptible and reduce deaths associated with pneumococcal meningitis.