Virtual reality exercise to help COVID patients with refractory breathlessness

Background: Immersive virtual reality (iVR)-based digital therapeutics (DTx) are gaining clinical attention in the field of pain management. Based on known analogy between chronic pain and dyspnea, we investigated the effects of visual respiratory feedback in iVR, on refractory breathlessness in patients recovering from severe COVID-19 pneumonia. Methods: We performed a controlled, randomized, single-blind, cross-over clinical study to evaluate an iVR-based intervention to alleviate refractory breathlessness in patients recovering from COVID-19 pneumonia. The single-site study was conducted at the university hospital of Geneva, Switzerland. Patients reported refractory breathlessness (≥5 on a 10-point dyspnea scale) and had a MoCA score of ≥24. Cross-over groups were randomly assigned, concealed from the referring clinician. Participants received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched avatar in iVR. Prior to the first exposure and following both experimental conditions, patients completed questionnaires. Breathing patterns were captured continuously. The COVVR clinical study is registered with ClinicalTrials.gov (NCT04844567) and is now closed. Findings: Study enrollment was open between November 2020 and April 2021. A total of 26 patients (27% women; age: mean=57, SD±12) were enrolled; 14 patients were randomly assigned to the ″synchronous/asynchronous″ sequence, 12 to the ″asynchronous/synchronous″ sequence. Data was available for all except two (7.7%) of 26 patients. The mean rating of breathing comfort was 0.1 at baseline, 0.8±1.8 for asynchronous, and 1.3±1.4 synchronous feedback (estimated difference of 0.5 (95%CI 0.05 to 1.04; p<0.05) between iVR conditions). Of all patients, 91.2% were satisfied with the intervention (1.8±1.6, t=5.201, p<0.0001, 95%CI 1.173 to inf) and 66.7% perceived it as beneficial for their breathing (0.7±1.9, t=1.806, p<0.05, 95%CI 0.036 to inf). No adverse events were reported. Interpretation: Based on these findings, we propose that our iVR-based DTx is a feasible and safe neuro-rehabilitation tool that improves breathing comfort in patients recovering from severe COVID-19 infection. More research is needed to generalize this tool in other groups of patients suffering from refractory breathlessness.

Overexpression of HAP4 in glucose-derepressed yeast cells reveals respiratory control of glucose-regulated genes

A link between control of respiration and glucose repression in yeast is reported. The HAP4 gene was overexpressed in a Δmig1 deletion background, generating a mutant in which respiratory function is stimulated and glucose repression is diminished. Although this combination does not result in derepression of genes encoding proteins involved in respiratory function, it nevertheless generates resistance against 2-deoxyglucose and hence contributes to more derepressed growth characteristics. Unexpectedly, overexpression of HAP4 in the Δmig1 deletion strain causes strong repression of several target genes of the Mig1p repressor. Repression is not restricted to glucose growth conditions and does not require the glucose repressors Mig2p or Hxk2p. It was observed that expression of the SUC2 gene is transiently repressed after glucose is added to respiratory-growing Δmig1 cells. Additional overexpression of HAP4 prevents release from this novel repressed state. The data presented show that respiratory function controls transcription of genes required for the metabolism of alternative sugars. This respiratory feedback control is suggested to regulate the feed into glycolysis in derepressed conditions.