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Rationale: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age, sex and comorbidity matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and comorbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 2.27, 1.39−3.71). Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

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The transforming growth factor-beta (TGFbeta) family of mediators consists of five closely related isoforms, of which three are present in mammals. TGFbeta1 has been shown to exert a biphasic effect on the proliferation of several cell types, including fibroblasts, with stimulation at low concentrations and inhibition at higher concentrations. The stimulatory effects are well characterized, but the mechanisms by which TGFbeta1 inhibits cell proliferation are incompletely understood. In the present study we have compared the effects of all three mammalian TGFbeta isoforms on human lung fibroblast proliferation, and have elucidated the role of the TGFbeta-induced synthesis of prostaglandin E2 (PGE2) in mediating their actions. All three isoforms stimulated fibroblast proliferation with maximal effects at 5 pg/ml (0.2 pM) and an order of potency of TGFbeta3 > TGFbeta2 > TGFbeta1. At higher concentrations, proliferation declined, and at 40 pg/ml and above all isoforms inhibited fibroblast proliferation. Again TGFbeta3 was the most potent, but there were no significant differences between the inhibitory effects of TGFbeta1 and TGFbeta2. Addition of indomethacin, an inhibitor of PGE2 synthesis, did not alter the proliferative activity of any of the TGFbeta isoforms, but completely overcame their inhibitory effects, restoring the stimulatory actions observed at lower TGFbeta concentrations. All TGFbeta isoforms stimulated PGE2 synthesis; TGFbeta3 was approximately twice as potent as TGFbeta1 and TGFbeta2, each of which had similar effects. These data suggest that the inhibition of fibroblast proliferation at higher concentrations of TGFbeta isoforms may be mediated by autocrine stimulation of PGE2 synthesis.