Fibrotic Hypersensitivity Pneumonitis (fHP) often presents a progressive fibrosing (PF) phenotype. Elevated levels of both circulating monocytes and alveolar macrophages have been pointed to play a role in the pathogenesis of idiopathic pulmonary fibrosis, but no substantive data exists regarding their contribution on PF-HP.

We performed a multicenter analysis of a retrospective cohort of 210 patients with fHP to determine predicting variables of early (<2 years) PF phenotype or death. The relationship between baseline circulating monocyte count, or bronchoalveolar lavage (BAL) macrophages, and outcome was assessed using bivariate and multivariable models. Results were then validated in a prospective cohort of 64 patients, enriched with 17 cases of acute exacerbations, and correlated with soluble markers, including serum levels of MCP-1 examined by ELISA.

High monocytes and BAL macrophages counts were independent predictors of early progression or death (controlled for ILD-GAP score and UIP-like pattern in HRCT). The median overall survival was significantly shorter for patients with monocyte count higher than 0.94x10⁹ cells/L (62 vs. 89 months; HR 2.28, 95%CI 1.19-4.36) and BAL macrophages higher than 65% (66 vs. 123 months, HR 2.69, 95%CI 1.55-4.67). In the prospective cohort, early mortality correlated with high monocyte count and elevated serum levels of MCP-1 and other M1-polarizing cytokines.

Our study shows that monocyte/macrophage-driven inflammation are associated with worse outcome in fHP, indicating the potential of future therapeutic approaches that target monocytes recruitment to lungs. It further suggests that MCP-1 levels may provide prognostic significance as biomarker.