A93-01 Respiratory Long Covid: Fibrotic Versus Airway Phenotypes and Response to Biologic Therapy

Rationale Long COVID is a prevalent and often disabling condition. Respiratory symptoms affect over 50% of patients, yet the pathobiology, diagnostic evaluation, and treatment strategies for Respiratory Long COVID (RLC) remain undefined. Here, we sought to delineate RLC phenotypes to enable mechanism-based diagnosis and therapy. Methods We conducted a retrospective analysis of two cohorts of patients evaluated at the Yale Center for Lung Diseases between 11/1/2020 and 11/1/2025 for RLC, defined as > 12 weeks of respiratory symptoms following SARS-CoV-2 infection. Data were abstracted via standardized manual chart review. Cohort 1 included 102 individuals who underwent comprehensive pulmonary evaluation, including chest imaging for parenchymal injury and bronchoprovocation testing (BPT) via mannitol (PD15) and/or methacholine challenge (PD20) per ATS/ERS standards. Cohort 2 comprised 146 patients treated with asthma biologics (49/146 received >1 therapy, yielding 200 treatment instances). The primary outcome was clinical response, defined by the treating provider’s assessment after >12 weeks of therapy. Results In Cohort 1, parenchymal injury was observed in 23/102 patients (22.5%), predominantly among those hospitalized for acute COVID (15/23, 65.2%). Persistent fibrotic post-COVID interstitial lung disease (PC-ILD) was rare (7/102, 6.9%). Patients without parenchymal injury showed a high prevalence of airway hyperreactivity (AHR) on BPT (51/79, 64.6%). Notably, AHR was common in PC-ILD as well (11/23, 47.8%). Patients with BPT+ post-COVID small airway disease (PC-SAD) demonstrated low rates of bronchodilator reversibility (BDR, 4.8%), peripheral eosinophilia >300/microliter (6.6%), IgE >150 IU/mL (20.0%), FeNO >25 ppb (22.9%), pre-existing asthma (30.6%), and exacerbations (8.1% with ≥1 systemic corticosteroid-requiring exacerbation/year). Onset of PC-SAD was associated with extrapulmonary symptoms such as fatigue (72.6%) and cognitive dysfunction (48.4%). In Cohort 2, patients with PC-SAD showed limited response to anti-IL5 and anti-IgE biologics (22/59, 37.3%; 3/8, 37.5%), intermediate response to anti-IL4R (44/73, 60.3%), and a superior response to anti-TSLP therapy (56/60, 93%, Fisher’s exact, two-sided, p < 0.001 vs each other class). Conclusions In the Yale RLC cohort, fibrotic PC-ILD was uncommon. The predominant phenotype was a T2-low, BDR-negative small airway disease associated with multisystem complaints and infrequent exacerbations. We propose to call this condition PC-SAD. AHR on BPT was a key diagnostic biomarker and anti-TSLP biologics yielded a significant therapeutic response in our cohort. To our knowledge, this is the first report to link a quantitative Long COVID biomarker to a mechanistically targeted therapy with demonstrated clinical benefit. This pathophysiology-informed ‘treatable trait’ framework provides a rational strategy for managing RLC and warrants prospective evaluation.