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Background: The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population., Methods: In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m 2 ) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m 2 ) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ 2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588., Findings: Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group., Interpretation: In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients., Funding: Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals., Competing Interests: Declaration of interests J-MN reports grants from the French Ministry of Health and Roche, during the conduct of the study; personal fees from AstraZeneca and Boehringer Ingelheim; and non-financial support from Boehringer Ingelheim. SJ reports personal fees from Actelion, Association pour les Insuffisants Respiratoires de Bretagne, AstraZeneca, Bristol Myers-Squibb, Boehringer Ingelheim, Chiesi, Galacto Biotech, Genzyme, Gilead, GlaxoSmithKline, LVL Medical, Mundipharma, Novartis, Pfizer, Roche, and Savara-Serendex; and received funding for clinical trials from Bellorophon Therapeutics, Biogen, Olam Pharm, and Pliant Therapeutics. RB reports grants from Boerhinger Ingelheim and Roche; and personal fees from Boerhinger Ingelheim, Roche, Sanofi, and SAvara. AB has received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, and Sanofi-Regeneron; has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MedinCell, Merck, Novartis, Roche, and Sanofi-Regeneron; and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi-Regeneron, and Vertex. PB reports personal fees from AstraZeneca, Boehringer, Chiesi, Novartis, Roche, Sanofi, Stallergene, and Teva. SM-A reports personal fees from Boerhinger Ingelheim and Roche. FG reports grants from Resmed; personal fees from Actelion, Cidelec, Novartis, Nyxoah, Resmed, and Sefam; and non-financial support from Asten, Boehringer Ingelheim, Novartis, Nyxoah, and Sefam. SD reports personal fees from Boehringer Ingelheim. AT reports personal fees from Bristol Myers Squibb and Chiesi; and travel accomodation fees from AstraZeneca, Boehringer Ingelheim, Teva, and Vitalaire. PYB reports grants from Laboratoire Boehringer Ingelheim and Laboratoire Roche; and personal fees from Laboratoire Boehringer Ingelheim and Laboratoire Roche. MPD reports personal fees from Boehringer Ingelheim; and non-financial support from Roche. GB reports non-financial support from Boehringer Ingelheim France, Novartis Pharma, and Roche. LW-S reports personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Roche, and Sanofi; and non-financial support from Boehringer Ingelheim and Roche. CC reports grants from Santelys; personal fees from Boehringer Ingelheim; and non-financial support from Roche. DV reports personal fees from Boehringer Ingelheim and Roche. BC reports personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Genzyme, Roche, and Sanofi; non-financial support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Roche, and Sanofi; and grants from Boehringer Ingelheim and Roche. VC reports personal fees from Actelion, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Fibrogen, Galapagos, Galecto, Merck Sharp & Dohme, Novartis, Promedior, Roche, Sanofi, and Shionogi; grants from Boehringer Ingelheim; and non-financial support from Actelion, Boehringer Ingelheim, Promedior, and Roche. TS reports personal fees from AstraZeneca, Bayer, BMS, Novartis, and Sanofi; and grants from AstraZeneca, Amgen, Bayer, Boehringer, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Novartis, and Sanofi. HN reports grants from Boehringer Ingelheim and Roche/Genentech; personal fees from Actelion Pharmaceuticals, Boehringer Ingelheim, Galapagos, and Roche/Genentech; and was the investigator of a clinical trial for Galecto Biotech AB, Gilead, Novartis, and Sanofi, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Anti-PD1 immunotherapies have become an essential treatment for bronchial cancer. According to published studies, PD1 and PD-L1 inhibitors have a better toxicity profile than chemotherapy. Nevertheless, some immune related toxicities can be potentially severe, such as induced interstitial lung disease (ILD). Currently, ILD patients are excluded from clinical trials using immunotherapy in lung cancer. IPF is the most frequent and severe form of ILD. Lung cancer represents a major complication of this disease and to date few data exist on the safety of immunotherapy in this context. We report 3 cases of IPF with lung cancer treated by nivolumab. All had a clinically mild to moderate IPF. The patients had received at least one line of chemotherapy before nivolumab and had progressive, metastatic lung cancer. Two patients experienced rapid cancer progression without immune toxicities. The third had a partial response but developed grade III immune colitis that led to discontinuation of the treatment. None developed lung toxicity or worsening of IPF on CT during follow-up, and death was always related to progression of the cancer. In our series of three patients with IPF, nivolumab was well tolerated with regard to their pulmonary condition. As inflammation and autoimmunity are probably marginal mechanisms in the pathogenesis of IPF, we do not believe that the presence of IPF should definitely disqualify potential candidates for treatment with nivolumab. Decisions should be taken, case-by-case, in selected patients without severe IPF and with no evidence of autoimmunity. In view of the epidemiology of lung cancer in IPF and the critical role of immunotherapy in the management of lung cancer, studies of prospective cohorts are urgently needed in this population., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background: Acute exacerbation is a substantial cause of death in patients with idiopathic pulmonary fibrosis with poorly described prognostic factors., Objectives: To review the features associated with acute exacerbation of idiopathic pulmonary fibrosis and assess its prognostic factors., Methods: Thirty-seven occurrences of acute exacerbation of idiopathic pulmonary fibrosis were retrospectively reviewed in the medical records of 27 patients. Clinical presentation, radiographic studies, pulmonary function tests, laboratory data, treatment, and outcome were analyzed., Results: Acute exacerbation of idiopathic pulmonary fibrosis occurred more frequently between December and May (75.7%) than between June and November (24.3%) (p = 0.01). In-hospital mortality was 27% and median survival was 4.2 months (range 0.2-36.6). Significant differences between nonsurvivors and survivors included the time elapsed between their admission and the initiation of treatment for acute exacerbation (6 vs. 3.1 days, p = 0.04), lactate dehydrogenase levels at admission (801 vs. 544.6 IU/l, p = 0.002), impairment of the prior forced vital capacity (51.2 vs. 65%, p = 0.01) and diffusing capacity for carbon monoxide (21.7 vs. 34%, p = 0.01). Furthermore, the evolution of gas exchange in the first 10 days after the initiation of treatment was associated with in-hospital and long-term mortality., Conclusions: Acute exacerbations of idiopathic pulmonary fibrosis are more frequent during winter and spring. The time between admission and initiation of treatment is a new reported prognostic factor that should be investigated further. This finding highlights the need for a fast diagnostic approach that should probably be standardized. Early gas exchange modifications reflect the response to treatment and predict the prognosis., (Copyright © 2011 S. Karger AG, Basel.)

Background: In idiopathic pulmonary fibrosis (IPF) the distribution and spatial-temporal progression of fibrotic changes may be influenced by general or locoregional conditions. From this perspective, patients with asymmetrical disease (AIPF) may be unique., Methods: This retrospective study included 32 patients (26 men, mean ± SD age 69 ± 7 years) with AIPF, as defined by an asymmetry ratio (most affected--least affected fibrosis score)/(most affected + least affected fibrosis score) >0.2. The global fibrosis score was the average of the right and left scores. Patients with AIPF were compared with 64 matched controls with symmetrical IPF., Results: Patients with AIPF did not differ from controls in global fibrosis score and forced vital capacity, but carbon monoxide transfer factor was less decreased (52 ± 19% vs 43 ± 13%, p=0.009). The rate of gastro-oesophageal reflux and acute exacerbations was significantly higher in patients with AIPF (62.5% vs 31.3%, p=0.006 and 46.9% vs 17.2%, p=0.004, respectively). In patients with AIPF the right side was more likely to be involved (62.5%); the median asymmetry ratio was 0.5 (range 0.24-1). Although the global fibrosis score worsened significantly in all 23 patients with AIPF with serial high-resolution CT scans (p<0.0001), pulmonary fibrosis remained asymmetrical in all except three. During follow-up, 15 patients with AIPF experienced 18 acute exacerbations. The first episode was virtually unilateral, occurring in the most affected lung in 10 patients (66.7%). Survival was similar between patients with AIPF and controls., Conclusion: AIPF may be related to locoregional factors including gastro-oesophageal reflux which may be responsible for both disease expansion and the occurrence of acute exacerbations.