Daily Respiratory Research Analysis

RATIONALE: Guidelines recommend amikacin liposome inhalation suspension (ALIS) for refractory Mycobacterium avium complex lung disease (MACLD) treatment, alongside other antibiotics. Efficacy of ALIS on microbiological endpoints and patient-reported outcomes (PROs) in the newly diagnosed MACLD population is unknown. OBJECTIVES: ARISE aimed to validate Quality of Life-Bronchiectasis Respiratory Domain (QOL-B RD) and Patient-Reported Outcomes Measurement Information System Short Form v1.0-Fatigue 7a (PROMIS F SF-7a) in patients treated for new/recurrent MACLD. We present treatment outcome results, including microbiological endpoints, PROs, and safety. METHODS: Adults with noncavitary MACLD were randomized 1:1 to ALIS (590 mg) or empty liposome control (comparator), plus azithromycin (250 mg) and ethambutol (15 mg/kg) once daily for 6 months, then 1 month off treatment. RESULTS: Of 99 patients, most had Mycobacterium intracellulare (43.4%) and/or M avium (32.3%) infections. Culture conversion with ALIS was achieved by 80.6% by month 6 (comparator, 63.9%) and 78.8% by month 7 (comparator, 47.1%; nominal P = .0010). Among patients achieving culture conversion by month 6, first negative culture defining conversion occurred at month 1 for 74.3% with ALIS (comparator, 46.7%). Mean QOL-B RD score through month 7 improved with ALIS versus plateauing with comparator after month 3; both arms showed improved PROMIS F SF-7a without between-arm difference. Positive correlations between culture conversion and improved QOL-B RD score were observed with ALIS. No ALIS-related serious adverse events or deaths were reported. CONCLUSIONS: More patients with newly diagnosed MACLD receiving 6 months of ALIS alongside a macrolide-based regimen achieved culture conversion by month 6 and month 7 numerically more rapidly versus comparator. No new safety signals were identified.Clinical trial registered with www.clinicaltrials.gov (NCT04677543).

Sustained and functional antibody responses to respiratory pathogens through vaccination is critical for global public health. The development and deployment of mRNA vaccines during the coronavirus disease 2019 (COVID-19) pandemic was a landmark achievement in modern medicine and ushered in a new age of vaccine innovation. The mRNA-based vaccines elicited strong antibody responses, both neutralizing and extra-neutralizing, against the viral Spike protein. The antibody levels waned with time since vaccination, and that coupled with the antigenic drift of the virus prompted updates to the mRNA vaccine composition and evaluation of other mRNA modalities. Self-amplifying mRNA (sa-mRNA) vaccines such as ARCT-154 can prolong antigen production and durability of humoral immune response post-immunization, and can thus be administered at a lower dose. How this translates into the overall humoral architecture compared to that shaped by conventional mRNA vaccinations, however, is unclear. Here, we analyze serum-based antibody responses in a subset of participants from a recent Phase III trial comparing neutralizing immune responses elicited by ARCT-154 and mRNA BNT162B2 as a post-hoc research. All participants had received three doses of mRNA COVID-19 vaccines and were randomized to receive a booster dose of ARCT-154 or BNT162B2. Primary outcomes of this research were to quantify waning responses against ancestral/wild type SARS-CoV-2 Spike (WT Spike) and a panel of diverse SARS-CoV-2 variant Spikes. Through a systems serology approach, we identified that the sa-mRNA vaccine ARCT-154 elicited a unique antibody response compared to BNT162B2 defined by a sustained, activating profile to the vaccine-encoded Spike protein and a broad spectrum of drifted Spikes. Notably, potently activating FcγRIIIA-binding antibodies showed a sustained stimulation in the ARCT-154-treatment arm, and this translated to an enhanced natural killer (NK) cell activation. The NK-activation through ARCT-154 was present for both target WT Spike and the antigenically drifted BA.5 Spike, which was the predominant form of SARS-CoV-2 during the observation period. Our results support a model whereby prolonged antigen expression and presentation moves immune profiles towards activating phenotypes with broad antigenic coverage.

RATIONALE: Greater ambient air temperatures may have implications for respiratory health. While prior research has primarily examined the associations of air temperature with lung health in the general population, individuals with chronic obstructive pulmonary disease (COPD) may be particularly susceptible. This study aims to assess the associations between air temperature and pulmonary function, as well as biomarkers of inflammation and oxidative stress, in this potentially susceptible population. METHODS: We conducted a study of 166 participants with COPD (either a former or no history of smoking) from eastern Massachusetts, United States, who completed up to 4 visits over 12 months at the VA Boston Healthcare System between 2012 and 2017, yielding 620 observations. Daily mean temperature exposures, at a spatial resolution of 4 × 4 km, were assigned to geocoded home addresses. We used generalized additive mixed models to investigate associations of short-term temperature exposures at 0- to 1-day, 2- to 6-day, 0- to 6-day, and 0- to 13-day moving averages with repeated lung function measurements, blood biomarkers of systemic inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin 6, soluble vascular cell adhesion molecule 1), and urinary biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine, malondialdehyde), adjusting for confounders (eg, air conditioner usage and season). We performed mediation analyses to determine if temperature-lung function relationships were mediated by inflammatory or oxidative stress pathways. RESULTS: The population was 97.0% male, mean (SD) age = 72.8 (8.4) years, mean (SD) percent predicted forced expiratory volume in 1 second (FEV1%) = 66.2 (21.8), and mean (SD) temperature = 10.2 °C (10.4 °C). Higher temperature exposures at all moving averages were associated with lower FEV1. For example, per 5 °C increase in temperature at lags of 0 to 1 and 0 to 13 days, FEV1 decreased by (mL, 95% CI) 12.06 (-23.14 to -0.98) and 16.24 (-29.23 to -3.25), respectively. Similarly, higher temperature exposures were associated with lower forced expiratory volume in 1 second/forced vital capacity. There were positive associations between higher temperature across all moving averages and higher hsCRP. For instance, a 5 °C increase in temperature at lags of 0 to 1 days and 0 to 13 days was associated with percent increases in hsCRP of 6.37 (95% CI, 1.05-11.97) and 9.40 (95% CI, 3.02-16.16), respectively. hsCRP did not mediate the temperature-lung function relationship. Associations were similar, adjusting for indoor and outdoor air pollution. No associations were observed with forced vital capacity or other inflammatory or oxidative stress biomarkers. CONCLUSION: Short-term exposures to higher air temperatures were associated with lower lung function and higher hsCRP concentrations among individuals with COPD, suggesting that rising air temperature may be an important determinant of health in this susceptible group.