gms | German Medical Science

Introduction: Community-acquired pneumonia (CAP), most often caused by pneumococci, is a major public health problem, especially affecting persons older than 60 years of age or those with certain underlying medical conditions. The effectiveness of 23-valent pneumococcal polysaccharide (PPV23) vaccination, which has been used in the past three decades for prevention of pneumococcal diseases, including pneumococcal CAP (pCAP), is controversial. Since March 2015, a 13-valent pneumococcal conjugate vaccine (PCV13) is approved for prevention of pCAP, for which efficacy was shown in a double-blind-randomized study in general population of more than 80,000 subjects.

Aim of this study was a systematic review (SR) and meta-analysis (MA) of available evidence for PPV23 efficacy and safety in adults according to the current German STIKO recommendation using randomized controlled trials (RCTs).

Methods: We performed a literature research in Cochrane, MEDLINE, and EMBASE for RCTs investigating the efficacy and safety of PPV23 vaccination in adults.

Selection criteria for the trials addressed the recommendations of the “Ständige Impfkommission” (STIKO) for adults, investigating PPV23 vaccination in adult patients, aged ≥18 and <60 years with underlying diseases or healthy subjects ≥ 60. Although also included in the recommendation, Human immunodeficiency virus (HIV)-positive participants were excluded from the review.

Outcome definitions were diverse between available published RCTs. Prior to data extraction, individual outcome parameters were discussed with medical experts and linked to following clinical endpoints for the SR: all-cause community acquired pneumonia (CAP), presumptive pneumococcal CAP, presumptive vaccine type (VT) pCAP, bacteraemic/invasive pCAP, bacteraemic/ invasive VT pCAP, death from any cause, death from pneumonia, death from pneumococcal pneumonia, local events and systemic events.

Meta-analyses were performed using random-effect models to address possible heterogeneity in an adequate way. For binary data, odds ratios were used as effect measure and for continuous data (standardized) mean differences were calculated. Heterogeneity was statistically tested by calculation of I-square. In case of a derived I-square above 0.5, no common effect estimate is presented. Reason for heterogeneity is assessed on clinical considerations by assessing meta-analyses on subgroups only. If subgroup analysis solved heterogeneity, those estimates were used. Odds ratios were calculated along with 95%-confidence intervals. Meta-analyses were conducted using the Cochrane Review Manager Version 5.3.

Results: Out of 18 RCT, five RCTs met the inclusion criteria for the SR (Alfageme et al., 2006, Furumoto et al., 2008, Kawakami et al., 2010, Maruyama et al., 2010, Oertqvist et al., 1998).

Meta-analysis demonstrated a marked and significant heterogeneity in the assessment of all-cause CAP and pCAP. Heterogeneity could be solved by subgroup analysis in the first case: heterogeneity could be explained by outlying results deriving from Maruyama et al. No meta-analysis could be conducted for pCAP.

The meta-analysis revealed that the PPV23 intervention compared to placebo was not efficient in the prevention of the following clinical endpoints: all-cause CAP (OR [95%-CI]: 0.95 [0.76; 1.19]), presumptive VT pCAP (1.04 [0.06; 16.67]), bacteraemic/invasive pCAP (0.18 [0.03; 1.03]), bacteraemic/ invasive VT pCAP (0.21 [0.02; 1.77]), death from any cause (1.05 [0.85; 1.29]) and death from pneumonia (0.66 [0.42; 1.05). There was a significant PPV23 treatment effect in the number of deaths due to pneumococcal pneumonia (0.04 [0.00; 0.61]; p=0.0214); however, this result needs to be treated with caution as pneumococcal pneumonia might be presumptive. For pCAP, a common estimate was not evaluable.

Discussion: The meta-analysis clearly demonstrated a significant heterogeneity in the assessment of all-cause CAP. This heterogeneity could be solved by assessing the subgroup of clearly defined CAP-cases only. As a consequence, Maruyama et al were to be excluded from the analysis of all-cause CAP. In this trial, all participants were nursing-home residents, so cases reported were cases of nursing-home acquired pneumonias (NHAP), a disease that clearly differentiates from “community acquired” pneumonia” (CAP).