BALF gene expression profiling reveals a fibrosis associated innate immune activation bias in persistent post-COVID-19 ILD

Survivors of coronavirus disease 2019 (COVID-19) can experience long-term lung complications (pulmonary sequelae), but the underlying mechanisms remain unclear. Although most patients with COVID-19 lung injury eventually recover essentially completely, some experience significant residual damage. To investigate the underlying differences, we analyzed, using bronchoalveolar lavage fluid (BALF), the alveolar immune cell compartments of a group of patients with post-COVID-19 interstitial lung disease (ILD) 6 mo after acute COVID-19. Patients were categorized into two groups, based on high-resolution computed tomography (HRCT) evaluation a year later: those with persistent HRCT abnormalities compatible with fibrosis (persistent post-COVID-19 ILD, <i>n</i> = 6) and those with resolved lung lesions (resolved post-COVID-19 ILD, <i>n</i> = 13). In addition, six patients with preexisting ILD were included in the study, after recovery from COVID-19. Bulk RNA transcriptomics analyses of BALF cells revealed innate immunity and inflammation pathways of neutrophil and monocyte chemotaxis to be enriched in patients with persistent HRCT abnormalities post-COVID-19, consistent with an increase in monocyte-like cell recruitment in the lungs. Profibrotic secreted phosphoprotein 1 (<i>SPP1</i>) gene expression was significantly upregulated similar to other fibrotic lung diseases. Conversely, patients with resolved post-COVID-19 ILD showed enhanced BALF cell gene expression signatures, indicative of adaptive immune response activation. BALF gene expression patterns of low T-cell activation, high profibrotic macrophage activation, and neutrophil chemotaxis were similarly observed in patients with preexisting fibrotic ILD following COVID-19. These findings suggest that immune response imbalance leading to prolonged activation of innate immunity and subdued adaptive immune responses may be associated with persistent post-COVID-19 ILD and the development of pulmonary fibrosis.<b>NEW & NOTEWORTHY</b> Survivors of COVID-19 can experience long-term lung complications. We compared bronchoalveolar lavage fluid (BALF) cells from patients who recovered from COVID-19 lung injury and those who experienced significant long term residual damage. A prominent gene expression profile of increased monocyte chemotaxis coupled to decreased T cell activation was observed in persistent fibrotic post-COVID-19 ILD. These findings suggest that prolonged activation of innate immunity and subdued adaptive immune responses may be associated with persistent post-COVID-19 ILD and pulmonary fibrosis.