Severe Acute Respiratory Failure After Immune Checkpoint Inhibitor Therapy: Risk Factors and Outcomes

Project Summary Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, offering durable responses in previously untreatable malignancies. However, their use is associated with immune-related adverse events, including pulmonary toxicities such as severe acute respiratory failure (ARF). In fact, ARF is a leading cause of ICU admissions among ICI-treated patients. Despite the increasing prevalence of these events in ICI-treated patients, little is known about the specific clinical and biomarker risk factors for ARF or the impact of specific ARF etiologies on survival outcomes. Existing studies primarily focus on checkpoint inhibitor pneumonitis (CIP), an adverse event associated with ICI therapy. However, these studies often overlook the broader spectrum of ARF etiologies in ICI-treated patients. Consequently, there is a critical need to identify high-risk profiles and evaluate how ARF etiologies, both CIP and non-CIP, influence survival outcomes following ICI therapy. This proposal aims to address these gaps through two specific aims. Aim 1 will identify clinical and biomarker risk factors, including smoking history, pulmonary disease, cancer type/stage, treatment-related characteristics, and blood biomarkers (neutrophil-to-lymphocyte ratios [NLR], absolute lymphocyte counts [ALC], and monocyte counts), associated with ARF in a retrospective cohort of 5,800 ICI-treated patients using real-world clinical data from the Johns Hopkins Precision Medicine Analytics Platform (PMAP). Aim 2 will assess survival outcomes and recovery metrics stratified by ARF etiology, particularly CIP versus non-CIP ARF, to quantify their prognostic impact. This aim involves adjudicating 360 cases of ARF using a rigorous multidisciplinary approach, integrating structured data and clinical review to classify ARF etiologies comprehensively. By addressing key gaps in understanding ARF in ICI-treated patients, this proposal aims to improve early identification of high-risk patients, optimize management of respiratory complications, and provide actionable data to refine monitoring strategies. This research also provides exceptional training in risk factor analysis, advanced survival analysis, and interdisciplinary collaboration, establishing the groundwork for an independently funded research career dedicated to improving outcomes for patients with pulmonary toxicities associated with novel cancer therapies.