Daily Respiratory Research Analysis

BACKGROUND: The World Health Organization recommends evaluation of all household contacts (HHC) of index tuberculosis (TB) patients for TB disease (TBD) and TB infection (TBI). Tests to identify TBI and TBD are preferred but can be skipped in persons living with HIV and children <5 years. There is equipoise on the need for these tests in other HHC. METHODS: We conducted a superiority, open label cluster-randomized trial in Benin and Brazil to compare three strategies to evaluate HHC aged 5-50 of persons newly diagnosed with drug susceptible pulmonary TBD: Standard: tuberculin skin testing (TST) for TBI and if positive, chest X-ray (CXR) to rule out TBD; rapid molecular test (RMT): same as Standard, except CXR replaced by an RMT; and No-TST: CXR for all but no TST. Randomization was computer-generated and stratified by country, in blocks of variable length. The primary outcome was TB preventive therapy (TPT) initiation among HHC considered eligible (positive TST, if done, and no evidence of TBD on CXR or RMT). Secondary outcomes were: completion of investigations to detect TBI and TBD, detection of TBD, TPT completion, severe adverse events, and societal costs. RESULTS: Among 1,589 participating HHC enrolled from 29 January 2020, to 30 November 2022, 474 were randomized to the standard, 583 to the RMT, and 532 to the no-TST strategies; all were included in the analyses. Of 848 HHC considered eligible for TPT, 802 (94.6%) initiated TPT, with no difference between strategies (95%, 94%, and 95% for the standard, RMT, and no-TST strategies, respectively). Of the secondary outcomes, protocol-mandated investigations to detect TBI and exclude possible TBD were completed for 93.4% overall, with slight differences between arms (93%, 95%, and 93% for the standard, RMT, and no-TST strategies, respectively). Adverse events resulting in discontinuation of TPT occurred in 3 (0.4%) participants in total (with 1, 0, and 2 events among participants in the Standard, RMT, and no-TST arms, respectively). The proportion completing TPT was similar with Standard and RMT strategies but was 13% lower (95% confidence interval: 3% to 23% lower) with the No-TST strategy. Societal costs per HHC completing investigations were $61 ($56-$65) with the standard strategy, compared to $52 ($49-$55) with the RMT strategy and $74 ($72-$77) with the no-TST strategy. CONCLUSION: This randomized trial provides high-quality evidence that TST followed by selected use of CXR or an RMT to exclude disease can achieve high rates of TPT initiation at reasonable costs. A limitation of the trial is the potential study effect, which may have affected adherence by providers and HHCs. RMT could replace CXR in the management of HHC in resource limited settings. REGISTRATION: clinicaltrials.gov NCT04528823.

RATIONALE: Viral lung infections are a major cause of morbidity and mortality worldwide. Despite significant advances in vaccines and antivirals, there remains a tremendous need for broadly applicable treatments that can be utilized across viral infections. Prior to infecting epithelial cells, viruses interact with the epithelial glycocalyx, which contains high molecular weight hyaluronan (HMWHA), a glycosaminoglycan that has beneficial effects in lung injury. OBJECTIVE: To determine the role of HMWHA in viral pneumonia. METHODS: We infected mice with Influenza or SARS-Cov2 and treated with prophylactic or therapeutic doses of HMWHA or saline control. We performed in vitro experiments of infection with viruses of respiratory and non-respiratory human and animal cells and evaluated the effect of HMWHA on infection. We analyzed existing databases for expression of hyaluronan and the transcription factor E2F1. Finally, we performed a clinical trial with HMWHA in patients with severe COVID-19 Measurements and Main Results: Exogenously applied HMWHA improved survival in SARS-CoV2 and influenza infection in mice, by ameliorating inflammation via the inhibition of E2F1. In a clinical study, inhaled HMWHA improved outcomes in patients with severe COVID-19. Furthermore, airway epithelia naturally express HMWHA, which is induced during viral infection and prevents infection via macromolecular crowding of viruses. CONCLUSIONS: Our data provide a mechanistic justification for the use of HMWHA as a broadly effective prophylactic and therapeutic agent in viral airway infection. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

IMPORTANCE: Infectious outbreaks of respiratory viruses within long-term care facilities (LTCFs) for older adults are associated with high rates of hospitalization and death. Despite evidence that airborne transmission contributes substantially to the spread of respiratory viruses within residential care for older adults, this mode of transmission has been largely unaddressed by existing infection control practices. OBJECTIVE: To determine whether germicidal UV (GUV) appliances reduce acute respiratory infection (ARI) incidence in LTCFs. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, 2-arm, double-crossover, cluster randomized clinical trial assessed the effectiveness of GUV appliances in common spaces on the incidence of ARIs in 4 LTCFs in metropolitan and regional South Australia. LTCFs were divided into 2 equally sized zones (mean [SD] size, 44 [9] beds per zone). Within each LTCF, zones were randomized to active GUV appliances (intervention) or inactive (control) for 6 weeks, which was followed by a 2-week washout, crossover, and a further 2-week washout. Seven consecutive cycles were performed during the 110-week study period from August 31, 2021, to November 13, 2023. Data were analyzed from January 18, 2024, to December 4, 2024. INTERVENTION: Continuous GUV appliance activity within common (non-resident room) areas for 6 weeks. MAIN OUTCOME AND MEASURES: The primary outcome was the incidence rate of ARIs (per zone per cycle). A secondary analysis of long-term trends was performed based on infections per week. RESULTS: Eight assessed zones across 4 LTCFs represented a total of 211 952 bed-days. Of 596 ARIs recorded across all zones, 475 (79.7%) occurred during intervention or control periods. The incidence rate in the control arm was 4.17 infections per zone per cycle (95% CI, 2.43-5.91), compared with 3.81 infections per zone per cycle (95% CI, 2.21-5.41) in the intervention arm (incidence rate ratio, 0.91; 95% CI, 0.77-1.09; P = .33). A posteriori secondary analysis with time-series autoregressive modeling showed that the control group recorded 2.61 ARIs per week (95% CI, 2.51-2.70) compared with 2.29 ARIs per week (95% CI, 2.06-2.51) in the intervention group (mean difference, 0.32; 95% CI, 0.10-0.54; P = .004). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that GUV light appliances in common areas of LTCFs did not reduce the incidence rate of ARIs per zone per cycle but did modestly reduce the total numbers of ARIs by the study conclusion. GUV appliances might be considered to support existing infection prevention and control practices in these settings. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registration: ACTRN12621000567820.