Immunomodulatory therapies in community-acquired pneumonia: a protocol for a systematic review and network meta-analysis.

INTRODUCTION: Community-acquired pneumonia is the leading global cause of infection-related death. A subset of patients with pneumonia develops aberrant immune responses, resulting in harmful inflammation, tissue damage and significant mortality. Immunomodulatory therapies aim to blunt this dysregulated immune response and reduce resultant injury. No consensus exists on the use or impacts of immunomodulatory therapies in the management of community-acquired pneumonia. This protocol describes the methods we will use to undertake a systematic review and network meta-analysis of the effects of immunomodulatory therapies on the mortality of patients with community-acquired pneumonia. METHODS: We will undertake a systematic review and network meta-analysis investigating the use of immunomodulatory therapies in community-acquired pneumonia. Our protocol has been developed and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and prospectively registered with PROSPERO (CRD42024565301). The primary objectives of this work are to compare the impact of immunomodulatory therapies on 28-day and 90-day mortality in adult patients admitted to hospital with a primary diagnosis of community-acquired pneumonia. The secondary objectives of this work are to identify any differences in the effectiveness of these immunomodulatory therapies in managing community-acquired pneumonia of differing aetiology and severity.We will conduct a literature search of Medline, Embase, Scopus, Web of Science and Global Health for all relevant articles until 30 June 2024. All observational, interventional and epidemiological studies published in English will be included, and each type of study design will be examined separately. All studies will have their titles and abstracts independently screened by two reviewers, followed by a full article eligibility review and data extraction. A third reviewer will adjudicate any disagreements. Data extracted will include, but not be limited to, the study design, country in which it was undertaken, patient characteristics (eg, age, sex, cause of CAP, severity of CAP), details regarding the immunomodulatory therapy and dosing used and the 28-day and 90-day mortality of each study arm. ANALYSIS: The risk of bias will be assessed using the Risk of Bias in Non-randomised Studies - of Exposure tool for non-randomised studies and the Cochrane Risk of Bias 2 tool for randomised control trials. The quality of evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations for network meta-analysis framework. A quantitative synthesis of data is planned for 28-day and 90-day mortality rates.We will fit a random-effects network meta-analysis model that includes random effects for between-study heterogeneity and for inconsistency. This will be done using the metafor package for R. We will use a contrast-based approach, modelling estimated treatment effects using reference treatments. In the case of the primary objective, this will be the log odds ratio (OR) of mortality in one treatment compared with another.Each type of study design will be examined separately. Treatments using the same immunotherapy at different doses may be grouped if appropriate. ETHICAL APPROVAL AND DISSEMINATION: This will be a systematic review of published literature; therefore, ethical approval is not required. To ensure communication of our findings, we will publish our results in a peer-reviewed journal and present our findings at appropriate local, national and international meetings. PROSPERO REGISTRATION NUMBER: CRD42024565301.