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September 30, 2019

Prevalence of Immunodeficiency in Children With Invasive Pneumococcal Disease in the Pneumococcal Vaccine Era: A Systematic Review

Author Affiliations
  • 1Infectious Diseases Unit, The Royal Children’s Hospital, Melbourne, Parkville, Australia
  • 2Department of Allergy and Immunology, The Royal Children’s Hospital, Melbourne, Parkville, Australia
  • 3Department of Paediatrics, The University of Melbourne, Parkville, Australia
  • 4Infectious Diseases & Microbiology Research Group, Murdoch Children’s Research Institute, Parkville, Australia
JAMA Pediatr. 2019;173(11):1084-1094. doi:10.1001/jamapediatrics.2019.3203
Key Points

Question  What is the frequency of primary immunodeficiency in children with invasive pneumococcal disease since the availability of pneumococcal vaccine?

Findings  In this systematic review of 17 studies that included 6022 unique patients with primary invasive pneumococcal disease, children older than 2 years without a known predisposing condition presenting with their first episode of Streptococcus pneumoniae meningitis or pneumonia or recurrent invasive pneumococcal disease had rates of primary immunodeficiency as high as 26%.

Meaning  This study’s findings suggest that immune evaluation may need to be considered in all children older than 2 years presenting with invasive pneumococcal disease, including assessment for immunoglobulin deficiency, specific antibody deficiency, complement disorders, and asplenia.


Importance  Despite increasing access to vaccination, invasive pneumococcal disease (IPD) is responsible for approximately 826 000 deaths worldwide in children younger than 5 years each year. To allow early identification and prevention, an improved understanding of risk factors for IPD is needed.

Objectives  To review the literature on the prevalence of primary immunodeficiency (PID) in children younger than 18 years presenting with IPD without another predisposing condition and to inform guidelines for immunologic evaluation after the first episode of IPD based on published evidence.

Evidence Review  A literature search of PubMed, Embase (inception [1974] to February 28, 2019), and MEDLINE (inception [1946] to February 28, 2019) was conducted using the terms Streptococcus pneumonia, Streptococcus pneumoniae, pneumococcal infection, Streptococcus infection, pneumococcal meningitis, immunodeficiency, immune response, immunocompromised, susceptib*, precursor, predispose*, recurren*, newborn, neonat*, infan*, toddler, child, preschooler, adolescen*, and pediatric. Publications reporting original data on immunodeficiency in children with microbiologically confirmed primary or recurrent IPD were included. Strength of clinical data was graded according to the 5-point scale of the Oxford Centre for Evidence-Based Medicine.

Findings  In 6022 unique children with primary IPD, 5 of 393 (1.3%) to 17 of 162 (10.5%) of all children and 14 of 53 (26.4%) of those older than 2 years had a PID identified. Higher rates of PID, up to 10 of 15 (66.7%), were found in children with recurrent IPD. Antibody deficiency was the most common immunodeficiency, followed by complement deficiency, asplenia, and rarer defects in T-cell signaling. The site of infection was a key indicator for the risk of underlying PID, with the greatest risk of PID in children with meningitis or complicated pneumonia.

Conclusions and Relevance  Results of this study suggest that invasive pneumococcal disease, and particularly recurrent IPD, is an important marker of underlying PID in children without other risk factors. The findings also suggest that children older than 2 years with pneumococcal meningitis or complicated pneumonia and all children with recurrent IPD should be referred for an immune evaluation.

Trial Registration  PROSPERO identifier: CRD42017075978

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