Prognostic factors for mortality in invasive pneumococcal disease in adult: a system review and meta-analysis

Risk factors associated with mortality in invasive pneumococcal disease remain unclear. The present work is a meta-analysis of studies that enrolled only patients with invasive pneumococcal disease and reported on mortality. Potentially eligible reports were identified from PubMed, CHAHL, and Web of Science, comprising 26 reports in total. Overall mortality for invasive pneumococcal disease was reported as 20.8% (95% confidence interval (CI) 17.5–24%). Factors associated with mortality were age (odds ratio (OR) 3.04, 95% CI 2.5–3.68), nursing home (OR 1.62, 95% CI 1.13–2.32), nosocomial infection (OR 2.10, 95% CI 1.52–2.89), septic shock (OR 13.35, 95% CI 4.54–39.31), underlying chronic diseases (OR 2.34, 95% CI 1.78–3.09), solid organ tumor (OR 5.34, 95% CI 2.07–13.74), immunosuppressed status (OR 1.67, 95% CI 1.31–2.14), and alcohol abuse (OR 3.14, 95% CI 2.13–4.64). Mortality rates with invasive pneumococcal disease remained high, and these findings may help clinicians provide appropriate initial treatment for this disease.

Outcomes. Potential prognostic factors were defined in this study as any clinical information related to mortality such as age, sex, underlying diseases, focus of infection, and place of infection acquisition. Risk factors for 30-day and in-hospital mortalities were analyzed separately if > 3 articles were found in each subgroup.
Quality assessment. Two reviewers independently assessed the methodological quality of selected studies using the Newcastle-Ottawa Scale quality assessment to evaluate the quality of observational studies. Disagreements among reviewers were discussed, with agreement reached by consensus 10 . Statistics. All analyses were performed using Review Manager version 5.3 (Cochrane Collaboration, Oxford, UK). Figures illustrated using Review Manager were adjusted as necessary. Prognostic factors for 30-day and inhospital mortality rates were merged because of their similarity after meta-analysis. Heterogeneity evaluated using I 2 statistics was interpreted as follows: I 2 = 0%, no heterogeneity; I 2 > 0% but < 25%, minimal heterogeneity; I 2 ≥ 25% but < 50%, mild heterogeneity; I 2 ≥ 50% but < 75%, moderate heterogeneity; and I 2 ≥ 75%, strong heterogeneity 11 .

Results
Study search. Of these 26 articles identified, 2 demonstrated data from two independent populations ( Fig. 1). Our analysis thus eventually extracted data from 16 countries for 27,742 patients with IPD, of whom 5810 died.
Characteristics of included studies. The 26 articles were published between 2000 and 2020, reported from Spain and the United States (n = 3 each), Canada, Japan, Israel, South Korea, the Netherlands, the United Kingdom, and Taiwan (n = 2 each), and 6 other countries (n = 1 each) 6, . Two articles from Sweden and Georgia were multi-country studies compromising patients from 5 and 10 countries (Table 1). Twenty-one studies assessed either only adults or only adults plus adolescents ≥ 15 years old. Six studies included patients with IPD at any age. Six studies included only patients with HIV infection. Only two studies discussed status of HIV infection separately and the remaining four studies classified HIV as one condition defining an immunosuppressed status. Eight studies did not discuss the status of pneumococcal conjugate vaccination, seven studies revealed missing data for vaccination status, and nine studies discussed vaccination status (vaccination rates, 0-54.5%). No study identified a relationship between vaccination and mortality in multivariable analysis. Thirteen studies discussed in-hospital mortality as an outcome, twelve studies discussed 30-day mortality rates, and one study discussed 28-day mortality rate. The median in-hospital mortality was 23.0% (95% confidence interval (CI) 17.2-27.2%) and the median 30-day mortality rate was 18.9% (95% CI 13.9-23.9%). The overall mortality rate from IPD included in this study was 20.8% (95% CI 17.5-24.0%). Median Newcastle-Ottawa Scale score was 6, suggesting that most studies were of acceptable quality.

Discussion
Despite the wide adoption of pneumococcal conjugate vaccination, the overall mortality rate from IPD has remained high, at 20.8%. This meta-analysis revealed older age (> 64 years old), septic shock, immunosuppressed status, underlying chronic diseases, solid organ tumor, alcohol abuse, nursing home, and nosocomial infection were prognostic factors for mortality from IPD. These results appear useful in understanding prognostic factors for mortality due to IPD because of the solid methodology in accordance with the MOOSE statement, with statistical power supported by more than 27,000 subjects.
Aging is a major risk factor for the development of virtually every lung disease, increasing both morbidity and mortality, while morbidities and mortalities from other prevalent diseases have declined or remained stable 37 . The conventional nuclear family model is becoming increasingly uncommon, and the majority of elder care is provided by relatives, albeit with varying patterns of involvement and responsibility across family structures 38 . Residence in a nursing home and nosocomial infection have been associated with the progression of aging. Comorbidity also plays an important role in affecting mortality. This study identified underlying chronic diseases, solid organ tumor, and immunosuppressed status as important factors to clinical progress.
Septic shock is a frequent complication of pneumococcal infection and causes high rates of morbidity and mortality 39 . The presence of septic shock on admission was the most strongly associated with risk of mortality www.nature.com/scientificreports/ among those factors. Unlike prognostic factors that cannot be changed, such as age, facility, and underlying diseases, outcomes might be improved with medical intervention for septic shock. Alcohol abuse is another preventable risk factor for pneumococcal disease, particularly among young adults 40 . This study also revealed alcohol abuse as a risk factor for mortality. Pneumococcal vaccination with PCV13 or PPV23 in adults is cost-effective and should be considered a priority for decision-makers 41 , and status of vaccination varied widely among studies (0-54.5%). Pneumonia vaccination was another effective means of preventing IPD, but much work remains to be done to increase the acceptance of pneumonia vaccination.

Limitations
Several limitations to this study must be considered when interpreting the results. Given the nature of the disease in question, only a limited number of prospective studies were able to be enrolled. There posed a substantial risk for selection bias, due to the nature of observational study and risk factors analyzed in this manuscript were selected post-hoc. Second, the definition of mortality in articles as in-hospital or 30-day mortality was merged together in some risk factors, due to limited numbers of articles. Third, prognostic factors for mortality differed markedly between articles. Fourth, the forms of vaccine status for studies included in this meta-analysis varied. Fifth, the effects of serotype and antibiotic resistance were not discussed in the present investigation.

Conclusion
IPD still shows high mortality rates and the presence of septic shock represents one of the most important prognostic factors for mortality in IPD. Unlike prognostic factors that cannot be changed, such as age, facility, and underlying diseases, early intervention for septic shock might improve the mortality in IPD.