Daily Respiratory Research Analysis

BACKGROUND: Diaphragm dysfunction impedes weaning from mechanical ventilation. Transvenous diaphragm neurostimulation can increase diaphragm strength but its impact on patient outcomes is uncertain. METHODS: This international, multicenter, open-label, randomized clinical trial (RESCUE-3) included adult patients requiring mechanical ventilation for ≥96 hours who met readiness-to-wean criteria and failed ≥2 weaning attempts. Patients were randomized to twice-daily transvenous diaphragm neurostimulation (Treatment) or standard of care (Control). The primary outcome was successful weaning at Day 30. Secondary outcomes included duration of ventilation to Day 30 and mortality at Day 30. The pre-specified primary analysis utilized a Bayesian approach with borrowing of prior information from a previous phase II randomized trial, downweighted to account for possible differences in trials. RESULTS: Due to slow enrolment and financial considerations, the trial was halted at the first interim analysis after 200 patients were randomized. Overall, 216 patients were randomized in the modified intent-to-treat population (Treatment, 102; Control 114). At Day 30, 71 (70%) Treatment patients and 69 (61%) Control patients were successfully weaned (adjusted hazard ratio 1.34, 95% credible interval 1.01-1.78, posterior probability of superiority, 97.9%). Treatment reduced the duration of ventilation (adjusted difference -2.5 days, 95% credible interval -5.0 to 0.1, posterior probability of superiority, 97.1%). Serious adverse events were reported in 36% of Treatment patients and 24% of Control patients; 9.8% of Treatment patients and 10.5% of Control patients died (adjusted hazard ratio 0.74, 95% credible interval 0.37-1.46, posterior probability of superiority 80.6%). CONCLUSION: Although the trial was stopped early due to slow enrollment, transvenous diaphragm neurostimulation showed a high probability of potential benefit for weaning success but with a possible increase in serious adverse events. 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/). Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03783884.

BACKGROUND: Low-complexity automated nucleic acid amplification tests (LC-aNAATs) are molecular assays widely used to diagnose tuberculosis disease in children. The lateral flow urine lipoarabinomannan assay (LF-LAM) is recommended for use amongst children with HIV. Previous systematic reviews have assessed the diagnostic accuracy of LC-aNAATs and LF-LAM separately in children, but in clinical practice the tests may be used concurrently, i.e. in 'parallel'. OBJECTIVES: To compare the diagnostic accuracy of the parallel use of LC-aNAAT on respiratory and stool specimens in children, and with LF-LAM on urine amongst children with HIV, versus each assay alone for detecting pulmonary tuberculosis disease. SEARCH METHODS: We searched MEDLINE, Embase, Science Citation Index-Expanded, Conference Proceedings Citation Index - Science, Biosis Previews, the Cochrane Central Register of Controlled Trials, Scopus, WHO (World Health Organization) Global Index Medicus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry up to 3 November 2023. There was a WHO public call for data on the accuracy of LC-aNAAT and LF-LAM for children until December 2023. SELECTION CRITERIA: We included studies that enroled children under 10 years of age with presumptive pulmonary tuberculosis, and provided data to assess the accuracy of parallel testing and at least one of the component tests, against a microbiological reference standard (MRS) based on culture or composite reference standard (CRS) that included clinical diagnosis. DATA COLLECTION AND ANALYSIS: We extracted data using a standardised form and assessed study quality using QUADAS-2 and QUADAS-C tools. We performed bivariate random-effects meta-analysis using a Bayesian approach to estimate sensitivity and specificity and absolute differences between index tests. Diagnostic accuracy estimates were calculated primarily against the MRS and secondarily against the CRS. We used GRADE to assess the certainty of the evidence on comparative accuracy. MAIN RESULTS: We included 14 studies to assess parallel testing in children with and without HIV. In addition, six of the 14 studies were included to evaluate LC-aNAATs with LF-LAM amongst children with HIV. Other than a high risk of bias with the CRS due to the potential incorporation of index results in clinical diagnoses, studies generally had low risk of bias across QUADAS-2 and QUADAS-C domains. Parallel use of respiratory and stool LC-aNAATs Children without HIV or HIV status unknown We included eight studies (2145 participants, tuberculosis prevalence 8.1% (173/2145)) for assessment against the MRS. Parallel use of LC-aNAAT on respiratory samples and stool had an estimated pooled sensitivity of 79.9% (95% credible interval (CrI) 67.9 to 89.8) and an estimated pooled specificity of 93.4% (95% CrI 87.2 to 97.0). Compared to LC-aNAAT on respiratory samples alone, parallel testing had 7.1 (95% CrI 3.2 to 13.4) percentage points higher sensitivity and -1.7 (95% CrI -3.8 to -0.6) percentage point change in specificity (both low-certainty evidence). Compared to LC-aNAAT on stool alone, parallel testing had 22.1 (95% CrI 13.7 to 32.7) percentage points higher sensitivity (moderate-certainty evidence) and a -4.1 (95% CrI -8.0 to -1.7) percentage point difference in specificity (low-certainty evidence). Children with HIV Against the MRS (seven studies, 697 participants, tuberculosis prevalence 6.3% (44/697)), parallel use of LC-aNAAT on respiratory samples and stool had an estimated pooled sensitivity of 70.2% (95% CrI 51.1 to 84.7) and specificity of 95.4% (95% CrI 91.7 to 97.8). Compared to LC-aNAAT on respiratory samples alone, parallel testing had 4.0 (95% CrI 0.6 to 12.9) percentage points higher sensitivity (moderate-certainty evidence) and -1.9 (95% CrI -3.9 to -0.7) percentage point difference in specificity (moderate-certainty evidence). Compared to LC-aNAAT on stool alone, parallel testing had 8.5 (95% CrI 2.4 to 20.9) percentage points higher sensitivity and -1.4 (95% CrI -3.3 to -0.4) percentage point difference in specificity (both moderate-certainty evidence). Composite reference standard The parallel use of respiratory and stool LC-aNAATs had lower sensitivity than the CRS in children with and without HIV, with smaller differences compared to using each component test alone (very low-certainty evidence for children without HIV; low-certainty evidence for children with HIV). The specificity of parallel testing was similar between MRS and CRS. Parallel use of respiratory and stool LC-aNAATs and LF-LAM amongst children with HIV We included six studies for the evaluation of diagnostic accuracy against the MRS (653 participants, tuberculosis prevalence 6.6% (43/653)). Parallel use of LC-aNAAT on respiratory and stool samples and LF-LAM had an estimated pooled sensitivity of 77.6% (95% CrI 60.0 to 89.6) and an estimated pooled specificity of 83.9% (95% CrI 73.9 to 90.4). Compared to LC-aNAAT on respiratory and stool samples, parallel testing had 6.9 (95% CrI 1.5 to 20.1) percentage points higher sensitivity (low-certainty evidence) and a -10.2 (95% CrI -19.6 to -4.9) percentage point difference in specificity (moderate-certainty evidence). Composite reference standard Against the CRS (six studies, 674 participants, tuberculosis prevalence 42.4% (286/674)), parallel use of LC-aNAAT on respiratory and stool samples and LF-LAM had a pooled sensitivity of 30.0% (95% CrI 13.2 to 54.8) and specificity of 83.3% (95% CrI 69.8 to 90.2). Compared to LC-aNAAT on respiratory and stool samples, parallel testing had 11.5 (95% CrI 3.8 to 26.7) percentage points higher sensitivity (very low-certainty evidence) and -10.1 (95% CrI -21.6 to -4.9) percentage point difference in specificity (low-certainty evidence). AUTHORS' CONCLUSIONS: Using LC-aNAAT with both respiratory and stool samples may increase the sensitivity of diagnostic testing for tuberculosis in children, including those with HIV, and the addition of LF-LAM for children with HIV may further increase sensitivity, although at the cost of reduced specificity. Stool and urine testing is non-invasive and may complement testing respiratory samples to increase tuberculosis case detection in children. The benefits of parallel testing may be greater in settings with high tuberculosis prevalence, while there may be a larger proportion of false-positive results and greater risk of overtreatment in areas of low tuberculosis prevalence. FUNDING: Liverpool School of Tropical Medicine, Foreign, Commonwealth and Development Office (FCDO) WHO, TB Prevention, Diagnosis, Treatment, Care & Innovation (PCI), Global TB Programme REGISTRATION: Protocol available via https://doi.org/10.1002/14651858.CD016071, version published 13 May 2024.

IMPORTANCE: In 2023, new immunization strategies became available for preventing respiratory syncytial virus (RSV) hospitalizations in infants and older adults. Modeling studies to understand the population-level impact of their use are important for public health planning. OBJECTIVE: To estimate the number of hospitalizations averted in 2023 to 2024 due to new RSV immunization strategies and provide scenario projections for future seasons. DESIGN, SETTING, AND PARTICIPANTS: This decision analytical model examined RSV hospitalizations in King County, Washington, from October 7, 2023, through April 26, 2025. The population of King County was disaggregated into infants younger than 6 months, infants aged 6 to 11 months, children aged 1 to 4 years, children/adults aged 5 to 59 years, adults aged 60 to 74 years, and adults aged 75 years or older. EXPOSURES: Respiratory syncytial virus vaccination for adults aged 60 years or older, maternal RSV vaccination, and long-acting monoclonal antibodies (nirsevimab) for infants younger than 8 months. MAIN OUTCOMES AND MEASURES: The proportion of RSV hospitalizations averted in adults aged 60 years or older and infants younger than 1 year were estimated using an RSV transmission model calibrated to RSV hospitalizations. RESULTS: The RSV transmission model simulated the population of King County, which includes approximately 2.3 million individuals, with 23 700 infants younger than 1 year and 446 500 adults aged 60 years or older. During the 2023 to 2024 RSV season, 21.2% of adults aged 60 to 74 years, 32.7% of adults aged 75 years or older, and 33.0% of infants were protected through active or passive immunization. A total of 125 (95% projection interval [PI], 77-192) RSV hospitalizations were averted, with most of the benefit observed in infants younger than 6 months (28.6% [95% PI, 26.9%-30.5%] reduction from baseline) and adults aged 75 years or older (14.8% [95% PI, 14.3%-15.5%] reduction from baseline). For the 2024 to 2025 season, optimistic scenarios of high immunization coverage (50% in older adults and 80% in infants) projected reductions of 29.8% (95% PI, 29.1%-30.8%) in adults aged 75 years or older and 68.8% (95% PI, 66.0%-71.7%) in infants younger than 6 months compared with a counterfactual scenario with no immunizations. Targeting infants eligible for catch-up doses of nirsevimab early in the season increased the proportion of RSV hospitalizations averted in infants aged 6 to 11 months from 31.7% (95% PI, 29.4%-33.9%) to 40.4% (95% PI, 39.0%-42.1%). If vaccine protection in adults aged 75 years or older waned by 50% in the second year after immunization, the proportion of RSV hospitalizations averted was projected to decrease to 22.2% (95% PI, 21.7%-23.0%). CONCLUSIONS AND RELEVANCE: In this decision analytical model of RSV immunizations, the results suggest a modest reduction in RSV-diagnosed hospitalizations during the 2023 to 2024 season due to limited availability of immunization products, particularly for infants. A higher uptake earlier in the season may lead to substantial reductions in RSV hospitalizations in the 2024 to 2025 season.