Protocol: Pharmacological Interventions for Preventing Pneumonia in Older Adults at Risk of Frailty-Associated Pneumonia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Pneumonia in frail older adults is an important clinical challenge in the context of global population aging. In Japan, pneumonia and aspiration pneumonia were the fifth and sixth leading causes of death in 2024, with mortality rates of 66.6 and 52.9 per 100,000 population, respectively (17). The development of pneumonia in frail older adults is multifactorial, involving interacting vulnerabilities such as dysphagia, impaired cough reflex and airway clearance, immune dysfunction, malnutrition, and sarcopenia (18). Although pneumonia in this population has traditionally been discussed primarily in terms of aspiration pneumonia, the lack of consistent diagnostic criteria and its complex multifactorial pathophysiology have prompted the proposal of frailty-associated pneumonia (FAP) as a broader clinical concept (18). Pneumonia may also contribute to a self-perpetuating cycle in which impaired swallowing and physical function increase susceptibility to infection, while infection further accelerates functional decline and frailty (18). Preventive approaches include vaccination, oral care, swallowing rehabilitation, nutritional support, and interventions to maintain physical function; however, the benefits and harms of pharmacological strategies for preventing pneumonia in older adults at increased risk of FAP remain uncertain (19). Several pharmacological interventions have been investigated for the prevention of pneumonia or aspiration pneumonia in vulnerable older adults, including nicergoline (20), angiotensin-converting enzyme inhibitors (21), cilostazol (22,23), the Japanese Kampo medicine Hange-koboku-to (Banxia Houpu Tang) (24), and mosapride (25). These interventions have been proposed to reduce pneumonia risk through different mechanisms, including enhancement of swallowing and cough reflexes, modulation of airway-protective mechanisms, and improvement of gastrointestinal motility. Randomized controlled trials (RCTs) have suggested potential benefits for some of these interventions; however, the available evidence is derived from heterogeneous populations, interventions, and outcome definitions. Moreover, the balance between potential preventive benefits and drug-related adverse events remains uncertain in older adults with the vulnerabilities relevant to FAP. Previous systematic reviews, including those by Loeb and colleagues in 2003 (26) and Santos and colleagues in 2021 (27), primarily evaluated interventions for preventing aspiration pneumonia in older adults at risk of aspiration. These reviews predated, or did not explicitly incorporate, the broader concept of FAP and therefore did not systematically evaluate the applicability of the evidence to older adults with frailty-related vulnerabilities beyond aspiration risk alone. In addition, because frailty and related vulnerabilities were not consistently assessed in earlier RCTs, an updated synthesis requires explicit consideration of the clinical characteristics of study populations and the applicability of the available evidence to FAP. Evaluation of the benefits, harms, and certainty of evidence for individual pharmacological interventions is therefore needed to inform clinical decision-making and guideline development. We therefore aim to conduct a systematic review of RCTs, with meta-analyses where appropriate, to evaluate the benefits and harms of pharmacological interventions for preventing pneumonia in older adults at increased risk of FAP.