Bronchoalveolar lavage fluid cytokine-based clustering identifies prognostically relevant cytokine phenotypes across interstitial lung diseases

Background Existing classification systems for interstitial lung diseases (ILDs) are limited and do not fully reflect the underlying biological drivers. We sought to identify cytokine-defined ILD subgroups based on bronchoalveolar lavage fluid (BALF) cytokine profiles and to examine their clinical relevance, particularly their association with prognosis.Methods We reanalyzed a BALF cytokine dataset from 84 patients with ILDs, including idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), cryptogenic organizing pneumonia, sarcoidosis, idiopathic inflammatory myopathy-associated ILD, and RA-ILD. Cytokine concentrations were measured using a multiplex bead-based assay. We used hierarchical clustering, principal component, correspondence, cosine similarity, and discriminant analyses to identify cytokine-defined subgroups and examine their clinical associations.Results We identified three cytokine-level-defined clusters: Clusters 1, 2, and 3, characterized by globally high, intermediate, and low cytokine levels, respectively. Clusters 1 and 3 were associated with poor and favorable prognoses, respectively. Cytokine-defined clusters did not fully correspond with conventional disease categories, although Cluster 3 predominantly included patients with sarcoidosis. RA-ILD was mainly distributed in Clusters 1 and 2 together with IPF, iNSIP, COP, and IIM-ILD. However, RA-ILD was distinguished by relatively elevated interleukin-17 and granulocyte-macrophage colony-stimulating factor levels.Conclusions BALF cytokine profiling can identify cytokine intensity-defined ILD subgroups that are associated with prognosis and are not fully captured by conventional disease classification. Although RA-ILD shares cytokine features with IPF and iNSIP, it also exhibits distinct immune characteristics. These findings suggest that intrapulmonary cytokine profiling could facilitate ILD stratification.