Neurology · Medical Literature
Immunomodulation for stroke-associated pneumonia: a systematic review of mechanistic insight and emerging therapeutic strategies in animal models.
Abstract
Stroke-associated pneumonia (SAP) is a major infectious complication that increases mortality after stroke. Stroke-induced immunosuppression has been proposed as a key driver of SAP, supporting the rationale for immunomodulation. This review systematically outlines the immunopathology of SAP and evaluates immune-targeted strategies. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Web of Science, and Embase for studies on the immune mechanisms and immunomodulatory therapies for SAP. We included 38 studies. Evidence from preclinical models indicates that stroke severity disrupts immune homeostasis, driving SAP through a multi-layered network. Systemic immunosuppression is primarily mediated by sympathetic nervous system (SNS) overactivation, inducing splenic atrophy, lymphocyte apoptosis, and impaired innate immune cells (e.g., iNKT cells), whereas the hypothalamic-pituitary-adrenal (HPA) axis appears to contribute less critically. Furthermore, sustained activation of the cholinergic anti-inflammatory pathway (CAP) may impair pulmonary antimicrobial defense. Active intercellular suppression, as exemplified by monocyte-mediated T cell death, has been identified as a potential mechanism that further compromises immunity. Emerging evidence also implicates disruption of the gut-lung axis (e.g., intestinal barrier dysfunction and microbial dysbiosis), local pulmonary alterations, and dysregulation of key immune molecules (e.g., α-MSH, CD147) as potential contributors to SAP development. Interventions targeting these mechanisms (e.g., iNKT cell activator) have shown promise in preclinical models. This review systematically synthesizes the mechanistic basis of SAP and identifies emerging immunomodulatory interventions. While preclinical evidence is encouraging, most strategies remain experimental, and their clinical translation requires considerable further validation.
Clinical relevance
Stroke-associated pneumonia (SAP) is a major infectious complication driving post-stroke mortality, yet its immunopathological underpinnings remain incompletely characterized and no immune-targeted therapy has been validated for clinical use. This systematic review addresses a critical translational gap by synthesizing mechanistic evidence from 38 preclinical studies, informing the rationale for immunomodulatory intervention in a high-risk neurological population. Given the absence of proven prophylactic strategies beyond standard care, neurologists and intensivists managing acute stroke patients urgently need a framework to anticipate immune vulnerability and evaluate emerging therapeutics.
Key findings
1. Stroke-induced systemic immunosuppression is primarily driven by sympathetic nervous system (SNS) overactivation, leading to splenic atrophy, lymphocyte apoptosis, and impairment of innate immune effectors including invariant natural killer T (iNKT) cells — identifying SNS as the dominant immunosuppressive axis over the hypothalamic-pituitary-adrenal (HPA) axis, which appears to contribute less critically. 2. Sustained activation of the cholinergic anti-inflammatory pathway (CAP) was identified as a mechanism that impairs pulmonary antimicrobial defense, implicating vagal anti-inflammatory signaling as a paradoxical contributor to SAP susceptibility. 3. Active intercellular immunosuppression via monocyte-mediated T cell death was identified as a distinct mechanistic layer further compromising adaptive immunity in the post-stroke period. 4. Gut-lung axis disruption — encompassing intestinal barrier dysfunction and microbial dysbiosis — emerged as a contributing pathway to SAP development, extending the immunopathological model beyond the central and pulmonary compartments. 5. Dysregulation of specific immune molecules, including alpha-melanocyte-stimulating hormone (α-MSH) and CD147, was implicated as a potential contributor to post-stroke immune vulnerability and SAP pathogenesis. 6. Immunomodulatory interventions targeting iNKT cell activation demonstrated preclinical promise; however, all 38 included studies were animal models, and no quantitative effect sizes, confidence intervals, or p-values were reported in the abstract, precluding meta-analytic precision estimates. NOTE: Specific effect sizes, CIs, p-values, and NNT/NNH were not reported in the available abstract; the above findings reflect qualitative mechanistic evidence as synthesized across included preclinical studies.
Practice implications
Clinicians managing acute stroke patients should recognize that SNS overactivation represents the dominant immunosuppressive mechanism driving SAP, suggesting that early risk stratification based on stroke severity — which correlates with the degree of immune homeostasis disruption — may identify patients most likely to benefit from future immune-targeted prophylaxis. iNKT cell activators and strategies that preserve intestinal barrier integrity represent the most mechanistically supported candidate interventions emerging from preclinical models, though none are currently validated for clinical use and should not be administered outside of formal trial protocols. Pending clinical translation, practitioners should maintain a high index of suspicion for SAP in patients with severe strokes, optimize existing antimicrobial stewardship practices, and monitor for signs of infection with awareness that standard inflammatory markers may be blunted in the context of post-stroke immunosuppression.