Risk factors for invasive pneumococcal disease in adults: a systematic review and meta-analysis

BackgroundThe burden of invasive pneumococcal disease (IPD) in adults remains high despite vaccination programs. Age is currently used as a prime criterium for defining target groups for prevention. To support effective intervention programs, we studied the relative importance of risk conditions that influence susceptibility to adult IPD. MethodsWe conducted a systematic search in PubMed and Embase and included all original studies published before June 2024. We extracted the reported risk estimates for IPD in adults with risk conditions, compared to the general population (PROSPERO ID 417980). Meta-analyses were performed for risk conditions that were substantiated by more than one study, using pooled incidence rate ratios with 95% confidence intervals (IRRs (95%CIs)) as primary outcome. FindingsOf the 2833 reports screened, 56 were included in the systematic review, and 45 supported the meta-analyses. The included articles reported more than 50 different risk factors for adult IPD. We synthesized 21 risk clusters for meta-analyses. The highest IRRs (95%CIs) for adult IPD were reported in immunocompromising conditions: transplant recipients 30{middle dot}75 (17{middle dot}64-53{middle dot}60), asplenia 24{middle dot}29 (18{middle dot}63-31{middle dot}65), HIV positive status 21{middle dot}87 (15{middle dot}72-30{middle dot}43), and haematological malignancy 20{middle dot}78 (9{middle dot}94-43{middle dot}47). Increasing age itself mediated minor risk sizes. At lower age the risk conditions conferred relatively higher risk ratios. Chronic kidney disease in adults <65 year old posed an IRR (95%CI) of 18{middle dot}40 (11{middle dot}38-29.74), compared to 5{middle dot}12 (2{middle dot}08-12{middle dot}63) among those over 65. IRRs >10 were also observed for compromised cerebrospinal fluid barrier and Downs syndrome. The overall quality of evidence was very low, mainly due to a high risk of bias and large between-study heterogeneity. Several studies indicated that patients with multimorbidity can accumulate risk for IPD. InterpretationThis meta-analysis provides the relative importance of all reported risk factors for adult IPD. How risk conditions interact in cases of multimorbidity remains largely unknown. FundingRadboudumc Community for Infectious Diseases encouragement Grant. Research in context Evidence before this studyCurrent evidence lacks a systematic overview of risk factors for adult IPD that allows assessment of their relative importance. It is largely fragmented into single observational studies or reviews that focus on specific host qualities. Added value of this studyOur comprehensive overview provides insight in the quantity, quality, and validity of evidence that supports risk conditions for adult IPD. In our meta-analyses we identified conditions that contribute to the risk of adult IPD, yet may ask for better appreciation. These include pronounced relative risk sizes in younger adults living with risk conditions, cumulative risks from multi-morbidity, and protective effects from healthy ageing. Implications of all the available evidencePopulations that likely benefit from greater attention for prevention of IPD are the younger adults living with risk conditions - especially chronic kidney disease, homeless individuals, and those with Downs syndrome. In combination with absolute risk sizes, the provided risk ratios indicate the adult populations most vulnerable to IPD. In addition, risk sizes inform study designs concerning effectiveness of preventive strategies.