Researchers unveiled results from impactful clinical trials for the first time, including the GRAIL, AZ-SWED, and FIBRONEER-IPF randomized clinical studies, and the Watch the Spot pragmatic trial, during “Breaking News: 2025 Clinical Trial Results in Pulmonary Medicine” on Sunday at the ATS 2025 International Conference.

Preventing CMV Reactivation in Critical Illness

Renee D. Stapleton, MD, PhD, ATSF, professor of medicine at the University of Vermont Robert Larner, MD, College of Medicine, presented “unexpected and unexplained” findings from the GRAIL phase 3 study of ganciclovir to prevent cytomegalovirus (CMV) reactivation in critically ill patients with sepsis.

Contrary to expectations, ganciclovir prophylaxis did not increase respiratory support-free days (RFDs). It was associated with higher mortality in critically ill, CMV-seropositive immunocompetent adults with sepsis-associated respiratory failure.

In the previously completed GRAIL phase 2 study, Dr. Stapleton and colleagues found that ganciclovir prophylaxis yielded more ventilator-free days (VFDs) in CMV-seropositive adults with either sepsis or trauma and respiratory failure, including in the sepsis subgroup.

The primary outcome analyzed in the phase 3 study, initially VFDs as in the phase 2 study, was revised to RFDs in December 2021, after considering the effect of the COVID-19 epidemic.

CMV reactivation in plasma was significantly lower in the ganciclovir group at day 28, and there were no significant differences in the adverse events (AEs) between the ganciclovir and placebo groups.

Dr. Stapleton said they have not found a biological explanation for the higher mortality in the ganciclovir group. She added that the question of ganciclovir prophylaxis remains unresolved, and the data do not support routine ganciclovir prophylaxis of CMV reactivation in critically ill adults without an underlying immunosuppressive condition.

Azithromycin in Preschoolers with Severe Wheezing Episodes Diagnosed at the Emergency Department (AZ-SWED)

Wheezing in young children is very common, especially in the preschool years, explained Fernando D. Martinez, MD, Regents’ Professor, Swift-McNear Professor of Pediatrics, and director of the Asthma & Airway Disease Research Center at the University of Arizona.

“There are 50,000 hospitalizations of children in the first four years of life each year for this condition,” he said.

The AZ-SWED, randomized, placebo-controlled, precision medicine study sought to answer whether a five-day course of azithromycin could decrease the severity of wheezing episodes in children 18 to <60 months, presenting to the emergency department with severe wheezing. The study strived to address this question in children with or without H. influenza, M. catarrhalis, or S. pneumoniae positivity in baseline nasopharyngeal samples.

Azithromycin did not decrease the severity of wheezing illness, regardless of the presence or absence of these bacterial species.

Based on the AZ-SWED findings, Dr. Martinez said, “To those who provide guidelines for treatment of children, we propose emphatically that children should not be treated with antibiotics [for wheezing illness]” if there are no underlying causes to consider such treatment.

Progression in Tumor Size and Stage Following Intensive Strategies for the Evaluation of Patients with Small Pulmonary Nodules

The current standard of care (SoC) for monitoring small pulmonary nodules, periodic surveillance with chest computed tomography, was not non-inferior to more intensive surveillance, regarding the primary outcome of progression in tumor sizes >20 mm at the time of lung cancer diagnosis.

The findings from the large, cluster-randomized, pragmatic Watch the Spot clinical trial were shared by Michael K. Gould, MD, MS, professor of health systems science at the Kaiser Permanente Bernard J. Tyson School of Medicine.

Notably, among the 16,845 patients in the more intensive surveillance arm and 17,841 patients in the SoC less intensive arm, only 504 (1.5 percent) patients were diagnosed with lung cancer within 27 months of nodule identification.

“We were looking to validate the current SoC, and we were unable to do it [in this study],” Dr. Gould concluded. He added that the high frequency (nearly 30 percent) of progression to stage III/IV disease at the time of lung cancer diagnosis in patients without mediastinal involvement, regardless of the intensity of surveillance, however, was “dramatic and unexpected.”

A Phase 3 Trial of Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis

In patients with idiopathic pulmonary fibrosis (IPF), treatment with nerandomilast, an orally administered preferential inhibitor of phosphodiesterase 4B, resulted in a smaller decline in forced vital capacity (FVC), compared with placebo, over 52 weeks.

These encouraging results were shared by Marlies S. Wijsenbeek, MD, PhD, a pulmonary physician at Erasmus Medical Center.

“These results are a major step forward after a decade of failed phase 3 studies,” Dr. Wijsenbeek said. “We now have a positive trial that is important for the treatment of IPF.”

While nintedanib and pirfenidone are approved for treating patients with IPF and slow lung function decline, disease progression does not cease, and patients often discontinue these treatments due to AEs.

Both the 9- and 18-mg doses of nerandomilast decreased the loss of lung function, compared to placebo, regardless of background therapy. Although neither dose of nerandomilast improved mortality, there were numerically fewer deaths in the nerandomilast (18 mg) group, compared to placebo.

In patients who received both nerandomilast and pirfenidone, the plasma concentration of nerandomilast was lower; therefore, findings in the subgroup receiving both drugs need to be interpreted cautiously, Dr. Wijsenbeek noted.