To perform a systematic literature review of the prevalence of primary immunodeficiency (PID) among pediatric patients with primary or recurrent invasive pneumococcal disease (IPD) and to identify factors associated with risk of PID diagnosis.

Pediatric cases (18 years or younger) of primary or recurrent IPD from 17 studies (prospective, retrospective and case-control published between 1997 and 2018).

The authors identified publications in PubMed, Embase, and Medline using standardized criteria (original data, 5 or more pediatric cases confirmed by isolation of Streptococcus pneumoniae from a sterile site via culture or polymerase chain reaction (PCR), and data on PID diagnosis). The primary outcome was prevalence of PID diagnosis, which was reported in all studies; 5/17 had a standardized immune evaluation. Authors reported cases of acquired or secondary immunodeficiency. History of pneumococcal vaccination infection site was considered when data were available.

Primary IPD was evaluated in 12 papers (n = 6022 cases); the prevalence of PID in this group ranged from 1.3% (5/393) to 26.4% (14/53). Recurrent IPD was evaluated in 5 articles; the prevalence of PID ranged from 10.5% (17/162) to 66.7% (10/15). Other underlying causes included acquired immunodeficiencies and immunosuppression. Pneumococcal vaccination rates varied from 6.7% to 75%. In populations with higher vaccination rates, among children older than 2 years, prevalence of PID diagnosis among IPD cases was higher, and increased when the 13-valent pneumococcal vaccine replaced the 7-valent vaccine. PID was more likely in IPD cases involving meningitis and complicated pneumonia.

Immunologic workup is warranted in children age 2 years and older with no predisposing conditions who present with pneumococcal meningitis, pneumonia or recurrent IPD. Workup should include evaluation for immunoglobulin deficiency, specific pneumococcal antibody deficiency, complement disorders and asplenia. Less common causes included X-linked agammaglobulinemia, T-cell signaling defects, and toll-like receptor signaling defects, among others.

Early diagnosis of PID can be challenging, and delay in diagnosis can lead to appreciable morbidity and mortality. Given the low prevalence of IPD and PID, this is challenging to study. This systematic review leverages existing data to address this question. Based on the study, the prevalence of PID diagnosis in IPD patients is sufficiently high to warrant workup in many IPD cases, and the authors highlight that age, site of infection (eg, pulmonary, CNS), and IPD recurrence should increase clinical suspicion for an underlying PID (or other cause of immunosuppression). Until more prospective studies with standardized workup are done, this can guide hospitalists and outpatient pediatricians in identifying patients who would benefit from workup and provides guidelines for preliminary screening. The authors highlight relevance in the setting of increased uptake of the 13-valent pneumococcal vaccine, which may make IPD cases more likely to reveal underlying PID or other cause of immunodeficiency.