Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias. There are currently no effective pharmacological therapies approved for the treatment of IPF. Despite the focus on targeting fibrogenic pathways, recent clinical trials have been largely disappointing. Progress is being made in elucidating key cellular processes and molecular pathways critical to IPF pathogenesis, and this should facilitate the development of more effective therapeutics for this recalcitrant disease. Emerging pathobiological concepts include the role of aging and cellular senescence, oxidative stress, endoplasmic reticulum stress, cellular plasticity, microRNAs, and mechanotransduction. Therapeutic approaches that target molecular pathways to modulate aberrant cellular phenotypes and promote tissue homeostasis in the lung must be developed. Heterogeneity in biological and clinical phenotypes of IPF warrants a personalized medicine approach to diagnosis and treatment of this lung disorder.

IMPORTANCE Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. OBJECTIVE To assess the effect of antimicrobial therapy on clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020).INTERVENTIONS Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if Ն50 kg, n = 126). No placebo was administered in the usual care alone group. MAIN OUTCOMES AND MEASURESThe primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. RESULTS Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%).CONCLUSIONS AND RELEVANCE Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease.

Background In May 2005 the lung allocation score (LAS) became the primary method for determining allocation of lungs for organ transplantation for those at least 12 years of age in the United States. During the pre-LAS period, black patients were more likely than white patients to become too sick or die while awaiting transplant. The association between gender and lung transplant outcomes has not been widely studied. Methods Black and white patients ≥18 years of age registered on the UNOS lung transplantation waiting list from January 1, 2000-May 3, 2005 (pre-LAS, n=8765) and May 4, 2005-September 13, 2010 (LAS, n=8806) were included; logistic regression analyses were based on smaller cohorts derived from patients listed in the first 2 years of each era (pre-LAS, n=2350, and LAS, n=2446) to allow for follow-up time. Lung transplantation was the primary outcome measure. Multivariable analyses were performed within each time period to determine the odds of dying or receiving a lung transplant within three years of listing. Results In the pre-LAS era, black patients were more likely than white to become too sick for transplantation or die within three years of wait list registration (43.8% vs. 30.8%; odds ratio [OR] 1.84; p<0.001). Race was not associated with death or becoming too sick while listed for transplantation in the LAS era (14.0% vs. 13.3%; OR 0.93; p=0.74). Black patients were less likely to undergo transplantation in the pre-LAS era (56.3% vs. 69.2%; OR 0.54; p<0.001) but not in the LAS era (86.0% vs. 86.7%; OR 1.07; p=0.74). Women were more likely than men to die or become too sick for transplantation within three years of listing in the LAS era (16.1% vs. 11.3%; OR 1.58; p<0.001), as compared to the pre-LAS era (33.4% vs. 30.7%; OR 1.19; p=0.08). Conclusion Racial disparities in lung transplantation have decreased with the implementation of LAS as the method of organ allocation; however, gender disparities may have actually increased in the LAS era.

ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov.

No abstract