The normal distribution of the hypoxic ventilatory response and methodological impacts: a meta-analysis and computational investigation.

The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental conditions. In the final analysis, 72 datasets reported mean HVR values and 60 datasets provided raw HVR datasets. Of the 60 datasets reporting raw HVR values, 35 (58.3%) were at least moderately positively skewed (skew > 0.5), and 21 (35%) were significantly positively skewed (skew > 1), indicating that lower HVR values are common. The skewness of HVR distributions does not appear to be an artifact of methodology or the unit with which the HVR is reported. Further analysis demonstrated that the use of step-down hypoxia versus progressive hypoxia methods did not have a significant impact on average HVR values, but that isocapnic protocols produced higher HVRs than poikilocapnic protocols. This work provides a reference for expected HVR values and illustrates substantial inter-individual variation in this key reflex. Finally, the prevalence of low HVRs in the general population provides insight into our understanding of blunted HVRs in high-altitude adapted groups. KEY POINTS: The hypoxic ventilatory response (HVR) plays a crucial role in determining an individual's predisposition to hypoxia-related pathologies. There is notable variability in HVR sensitivity across individuals as well as significant population-level differences. We report that the normal distribution of the HVR is positively skewed, with a significant prevalence of low HVR values amongst the general healthy population. We also find no significant impact of the experimental protocol used to induce hypoxia, although HVR is greater with isocapnic versus poikilocapnic methods. These results provide insight into the normal distribution of the HVR, which could be useful in clinical decisions of diseases related to hypoxaemia. Additionally, the low HVR values found within the general population provide insight into the genetic adaptations found in populations residing in high altitudes.

Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA).

Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.