Introduction: Unclassifiable interstitial lung disease (uILD) represents a heterogeneous subgroup of interstitial lung diseases characterized by overlapping features, in which a confident diagnosis cannot be established despite comprehensive evaluation, representing approximately 10–20% of cases.
Objectives: To characterize patients with uILD at the time of multidisciplinary discussion in order to better understand this heterogeneous phenotype.
Materials and Methods: A multicenter retrospective chart review was conducted between January-2015 and January-2026, identifying patients with a diagnosis of uILD established at multidisciplinary discussion. Patients were characterized regarding demographics, exposures, comorbidities, lung function and diagnostic procedures.
Results: A total of 75 patients were initially classified as uILD, most commonly due to the absence of biopsy (49.1%) or histological–radiological discordance (41.3%). The mean age at diagnosis was 68.5 years, with a predominance of males (70.7%) and current or former smokers (57.4%).
Comorbidities included diabetes mellitus (25.3%), gastroesophageal reflux (18.7%), heart failure (12%), and asthma (10.7%). Environmental exposures were frequent, particularly to birds (48%), moisture/mold (34.7%), and poultry (17.3%).
Dyspnea (74.7%) and cough (57.3%) were the main presenting symptoms, with inspiratory crackles detected in 74.7% of patients. At baseline, median of FVC was 78.3% [69.1-97.5] and DLCO 53.5% [43.4-64.6]; 22.9% had suspected pulmonary hypertension based on echocardiographic findings, and 14.7% required supplemental oxygen (long-term and/or portable).
Bronchoalveolar lavage was performed in 81.3% of patients, with lymphocytosis observed in 21.3%. Lung biopsy was performed in 53% patients, most commonly transbronchial lung cryobiopsy (n=34).
Median follow-up was 25 months [13.5–48.5], with an overall mortality of 24%, predominantly due to respiratory causes.
Conclusions: uILD remains a heterogeneous and clinically relevant entity. This cohort highlights the burden of smoking, comorbidities, and environmental exposures, along with substantial mortality, underscoring the need for improved diagnostic and therapeutic strategies.