Breath-Holding Physiology and Adverse Outcomes of COVID-19: A Prospective Validation Study

Rationale: In a recent prospective observational study, we demonstrated that gas exchange andchemoreflex deficits measured via breath-holding maneuvers (i.e. breath-hold induced desaturationand maximal breath-hold duration) were associated with incident adverse COVID-19 outcomes (i.e.respiratory failure and/or death). COVID-19 remains a major cause of respiratory failure, and simplemeans to identify risk of future deterioration are needed. Here we sought to validate our breath-holding prediction score in a prospective study of COVID-19 patients. We also assessed whetherbreath-holding measures were associated with increased pulmonary radiological severity via chestX-ray and CT. Methods: In a pragmatic validation study, hospitalized COVID-19 patients (N=110,three recruitment centers) performed breath-holds at admission to assess mean desaturation(greatest desaturation observed visually with oximetry following 20-s breath-holds) and maximalbreath-hold duration (via timing device) which were combined with covariates (baseline saturation,BMI, cardiovascular disease) to provide a published prediction score (Messineo et al 2021). Oddsratios for incident adverseCOVID-19 outcomes (composite of bi-level ventilatory support, ICUadmission, death) were described for patients with versus without elevated prediction scores (score>0). Regression analysis determined whether the prediction score was associated with pulmonarydeficits on X-ray (Borghesi-Maroldi score) and CT (3D-volumetric evaluation) scored by tworadiologists. Additional analysis examined associations with a previously-validated, biomarker-based COVID-19 prediction score (“4C-score”). Results: Elevated prediction score was associatedwith adverse COVID-19 outcomes (N=13/110), OR[95%CI]=5.17[1.34-20.03], P=0.015 (positivepredictive value=10/48, negative predictive values=59/62). Results were diminished in magnitudewith the absence of mean desaturation (OR=3.81[1.09-13.28]), but not of maximal breath-holdingduration (OR=5.41[1.40-20.93]). The continuous prediction score meaningfully discriminatedbetween individuals with versus without adverse outcomes (AUC=0.74, ROC). The prediction scorewas also linearly associated with radiological severity per increased X-ray scores(β[95%CI]=0.13[0.02-0.23] units per score, P=0.026, N=103) and CT scores (β=1.02[0.39-1.65],P=0.002, N=45); mean desaturation specifically was associated with CT scores (β=2.16[0.99-3.34]%lung involvement per Þsaturation) and borderline associated with X-ray scores (β=0.20[-0.005-0.41] points per Þsaturation; fully adjusted). Elevated 4C-scores (≥high-risk category) wereassociated with our prediction score (OR=1.34[1.17-1.54]), but had a weaker association withadverse outcomes (OR=1.79[0.52-6.22]). Conclusions: In a pragmatic prospective observationstudy, we confirmed that deficits in breath-holding physiology are predictive of adverse COVID-19outcomes. Elevated prediction score was associated with 5-fold odds of respiratory failure, andmore severe pulmonary deficits observed in chest imaging. Breath-holding physiology may haveutility for rapid identification of COVID-19 patients at elevated respiratory failure risk.