The Impact of COVID-19 on the Response to Hypoxia.

Louis, Alexandre, Charlotte Pröpper, Yann Savina, Corentin Tanne, Guy Duperrex, Paul Robach, Pascal Zellner, Stéphane Doutreleau, Jean-Michel Boulet, Alain Frey, Fabien Pillard, Cristina Pistea, Mathias Poussel, Thomas Thuet, Jean-Paul Richalet, and François Lecoq-Jammes. The impact of COVID-19 on the response to hypoxia. High Alt Med Biol. 24:321-328, 2023. Background: Severe high-altitude illness (SHAI) and coronavirus disease 2019 (COVID-19), while differing in most aspects of pathophysiology, both involve respiratory capacity. We examined the long-term impact of COVID-19 on response to hypoxia in individuals free of symptoms but having tested positive during the pandemic. The need for recommendations for such individuals planning a stay at high altitude are discussed. Methods: This multicenter study recruited participants from the multiSHAI cohort, all of whom had previously undergone a hypoxic exercise test. These participants were classified into two groups depending on whether they had since suffered mild-to-moderate COVID-19 (COVID+) or not (Control) and then asked to retake the test. Primary outcomes were: desaturation induced by hypoxia at exercise (ΔSpE), hypoxic cardiac response at exercise, hypoxic ventilatory response at exercise, and SHAI risk score. Results: A total of 68 participants retook the test, 36 classified in the COVID+ group. Analyses of primary outcomes showed no significant differences between groups. However, the COVID+ group showed significantly increased ventilation (VE) parameters during both hypoxic (p = 0.003) and normoxic exercise (p = 0.007). However, only the VE/oxygen consumption relationship during hypoxic exercise was significantly different. Conclusion: This study demonstrates no negative impact of COVID-19 on response to hypoxia as evaluated by the Richalet test. Clinical Trial Registration: NTC number: NCT05167357.

Reduced Flow-Mediated Dilatation Is Not Related to COVID-19 Severity Three Months after Hospitalization for SARS-CoV-2 Infection.

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide, with more than two million deaths. Evidence indicates the critical role of the vascular endothelium in its pathophysiology but, like potential changes in functional vasodilation, the vascular effect of SARS-CoV-2 at a given distance from the acute infection is largely unknown. We assessed brachial artery flow-mediated dilatation (FMD) in 27 COVID-19 patients needing conventional or intensive care unit hospitalization, three months after SARS-CoV-2 infection diagnosis and in nine age- and sex- matched control subjects. Interestingly, the FMD was lower in COVID-19 patients as compared to controls (8.2 (7.2-8.9) vs. 10.3 (9.1-11.7)); p = 0.002, and half of the hospitalized COVID-19 survivors presented with a reduced FMD < 8% at three months of COVID-19 onset. Impaired FMD was not associated with severe or critical SARS-CoV-2 infection, reflected by ICU hospitalization, total hospitalization duration, or severity of lung damage. In conclusion, reduced FMD is often observed even three months after hospitalization for SARS-CoV-2 infection, but such alteration predominantly appears to not be related to COVID-19 severity. Longer and larger follow-up studies will help to clarify the potential prognosis value of FMD among COVID-19 patients, as well as to further determine the mechanisms involved.

New Insights into the Implication of Mitochondrial Dysfunction in Tissue, Peripheral Blood Mononuclear Cells, and Platelets during Lung Diseases.

Lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, or idiopathic pulmonary fibrosis are major causes of morbidity and mortality. Complex, their physiopathology is multifactorial and includes lung mitochondrial dysfunction and enhanced reactive oxygen species (ROS) release, which deserves increased attention. Further, and importantly, circulating blood cells (peripheral blood mononuclear cells-(PBMCs) and platelets) likely participate in these systemic diseases. This review presents the data published so far and shows that circulating blood cells mitochondrial oxidative capacity are likely to be reduced in chronic obstructive pulmonary disease (COPD), but enhanced in asthma and pulmonary arterial hypertension in a context of increased oxidative stress. Besides such PBMCs or platelets bioenergetics modifications, mitochondrial DNA (mtDNA) changes have also been observed in patients. These new insights open exciting challenges to determine their role as biomarkers or potential guide to a new therapeutic approach in lung diseases.

Pulmonary hemodynamics responses to hypoxia and/or CO2 inhalation during moderate exercise in humans.

In this study, we hypothesized that adding CO2 to an inhaled hypoxic gas mixture will limit the rise of pulmonary artery pressure (PAP) induced by a moderate exercise. Eight 20-year-old males performed four constant-load exercise tests on cycle at 40% of maximal oxygen consumption in four conditions: ambient air, normobaric hypoxia (12.5% O2), inhaled CO2 (4.5% CO2), and combination of hypoxia and inhaled CO2. Doppler echocardiography was used to measure systolic (s)PAP, cardiac output (CO). Total pulmonary resistance (TPR) was calculated. Arterialized blood pH was 7.40 at exercise in ambient and hypoxia conditions, whereas CO2 inhalation and combined conditions showed acidosis. sPAP increases from rest in ambient air to exercise ranged as follows: ambient + 110%, CO2 inhalation + 135%, combined + 184%, hypoxia + 217% (p < 0.001). CO was higher when inhaling O2-poor gas mixtures with or without CO2 (~ 17 L min-1) than in the other conditions (~ 14 L min-1, p < 0.001). Exercise induced a significant decrease in TPR in the four conditions (p < 0.05) but less marked in hypoxia (- 19% of the resting value in ambient air) than in ambient (- 33%) and in both CO2 inhalation and combined condition (- 29%). We conclude that (1) acute CO2 inhalation did not significantly modify pulmonary hemodynamics during moderate exercise. (2) CO2 adjunction to hypoxic gas mixture did not modify CO, despite a higher CaO2 in combined condition than in hypoxia. (3) TPR was lower in combined than in hypoxia condition, limiting sPAP increase in combined condition.

Ability of pulmonary function decline to predict death in amyotrophic lateral sclerosis patients.

OBJECTIVES: Objectives were to evaluate the relative risk of death associated with lung function decline in patients with amyotrophic lateral sclerosis (ALS), and to examine the ability of ALS patients to perform volitional pulmonary function tests (PFTs). METHODS: The PFTs of 256 consecutive patients referred to the Strasbourg University Hospital ALS Centre over an eight-year period were reviewed. Slow vital capacity (VC), maximal inspiratory and expiratory pressures (MIP, MEP), sniff nasal inspiratory pressure (SNIP), and peak cough flow (PCF) were performed at diagnosis and then every four months. The instantaneous risk of death associated with PFTs deterioration was calculated using time-dependent covariate Cox models. The changes of each PFT over time were examined and compared. RESULTS: A total of 985 acceptable PFT sessions were recorded. The risk of death was significantly associated with the decline in pulmonary function, regardless of the PFT parameter and its expression. When VC, MIP/SNIP and MEP (% of predicted) decreased by 10%, or PCF decreased by 50 L/min, the risk of death was multiplied by 1.31 (95% CI 1.21-1.41), 1.48 (1.32-1.66), 1.54 (1.32-1.79), and 1.32 (1.19-1.75), respectively. MIP, SNIP and MEP were decreased earlier in the course of disease and plunged deeper than VC within months before death, but were more affected by learning effect. CONCLUSIONS: This study provides tools to calculate the increase in risk of death from a PFT decline. At an individual level, since each test showed some flaws, the use of a combination of PFTs for ALS respiratory monitoring is recommended.

Cardio-respiratory responses to hypoxia combined with CO2 inhalation during maximal exercise.

We measured the effects of adding CO2 to an inhaled hypoxic gas mixture on cardio-respiratory parameters during maximal exercise. Eight young males performed four incremental maximal exercise tests on cycle under ambient air, hypoxia (FIO2 0.125), inhaled CO2 (FICO2 0.045), and combination of hypoxia and inhaled CO2. The highest ventilation (VE) and VE/CO2 output were recorded in CO2 inhalation and combined treatments. Arterial O2 partial pressure was higher in combined than in hypoxia treatment, but the difference between the treatments narrowed from rest to end-exercise, at least partly because the magnitude of the increase in VE (%) at exercise was smaller in combined treatment than in hypoxia. Arterial O2 content was higher in combined treatment than in hypoxia at rest, but no more at maximal exercise. Cardiac output was higher and O2 extraction lower when breathing O2-poor gas mixtures than under the two other treatments. For a given oxygen consumption, hypoxia and combined treatment showed similar cardiac output and O2 extraction.

Maximal aerobic capacity in ageing subjects: actual measurements versus predicted values.

We evaluated the impact of selection of reference values on the categorisation of measured maximal oxygen consumption (V'O2peak) as "normal" or "abnormal" in an ageing population. We compared measured V'O2peak with predicted values and the lower limit of normal (LLN) calculated with five equations. 99 (58 males and 41 females) disease-free subjects aged ≥70 years completed an incremental maximal exercise test on a cycle ergometer. Mean V'O2peak was 1.88 L·min-1 in men and 1.26 L·min-1 in women. V'O2peak ranged from 89% to 108% of predicted in men, and from 88% to 164% of predicted in women, depending on the reference equation used. The proportion of subjects below the LLN ranged from 5% to 14% in men and 0-22% in women, depending on the reference equation. The LLN was lacking in one study, and was unsuitable for women in another. Most LLNs ranged between 53% and 73% of predicted. Therefore, choosing an 80% cut-off leads to overestimation of the proportion of "abnormal" subjects. To conclude, the proportion of subjects aged ≥70 years with a "low" V'O2peak differs markedly according to the chosen reference equations. In clinical practice, it is still relevant to test a sample of healthy volunteers and select the reference equations that better characterise this sample.

Cryopreservation with dimethyl sulfoxide prevents accurate analysis of skinned skeletal muscle fibers mitochondrial respiration.

Impact of cryopreservation protocols on skeletal muscle mitochondrial respiration remains controversial. We showed that oxygen consumption with main mitochondrial substrates in rat skeletal muscles was higher in fresh samples than in cryopreserved samples and that this difference was not fixed but grow significantly with respiration rates with wide fluctuations around the mean difference. Very close results were observed whatever the muscle type and the substrate used. Importantly, the deleterious effects of ischemia-reperfusion observed on fresh samples vanished when cryopreserved samples were studied. These data demonstrate that this technic should probably be performed only extemporaneously.

Exercise-induced second-degree atrioventricular block in endurance athletes.

Training induces volume- and time-dependent morphological and functional changes in the heart. Heart rhythm disorders, such as atrial arrhythmia (including atrial fibrillation and atrial flutter), are a well-established consequence of such long-term endurance practice. Although resting bradycardia and first-degree atrioventricular persist in veteran athletes, a higher conduction system impairment has never been reported neither at rest nor during exercise. We report here two cases of Type II second-degree atrioventricular block occurring during exercise in middle-age well-trained athletes. Because animal and human studies suggest that a progressive myocardial fibrosis could explain such phenomenon, long-term training could also have consequences on the conduction pathways.

Impact of 3D conformal radiotherapy on lung function of patients with lung cancer: a prospective study.

BACKGROUND: The development of three-dimensional conformal radiotherapy (3D-RT) has enabled the restriction of the dose to normal lung, limiting radiation-induced lung injury. OBJECTIVES: This study was designed to describe the time course of lung function until 7.5 months after 3D-RT in patients with lung cancer, and assess the relationship between lung function changes and dose-volume histogram (DVH) analysis or computed tomography scan changes. Radiation doses were optimized according to recent guidelines. METHODS: Sixty-five lung cancer patients treated with 3D-RT agreed to participate in this prospective, hospital-based study. Lung volumes, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) were measured before radiotherapy (RT), 10 weeks, 4 and 7.5 months after the beginning of 3D-RT. RESULTS: Eleven lung cancer patients (17%) developed grade 2-3 respiratory symptoms after RT. At 7.5 months, vital capacity (VC) was 96 ± 2%, total lung capacity (TLC) 95 ± 2%, FEV1 93 ± 2% and DLCO 90 ± 2% of the initial value. Only 15% of patients showed pulmonary function reduction > 20%. Patients with FEV1 or DLCO < 60% before RT did not show significant changes after RT. There were weak correlations between reduction of VC, TLC, FEV1 or DLCO and radiation dosimetric parameters and between reduction of VC or FEV1 and radiation-induced pneumonitis images. CONCLUSIONS: In lung cancer, the reduction of lung function within 7.5 months after 3D-RT was small and correlated, albeit weakly, with DVH parameters. Patients with initially impaired lung function showed tiny changes in spirometry and DLCO values.

Asthma as a cause of persistent dyspnea in treated myasthenia gravis patients.

AIMS: The aim of this study was to evaluate the proportion of patients with treated myasthenia gravis (MG) who present with dyspnea not related to MG. METHODS: We analyzed the files of 63 consecutive adult patients with treated MG and persistent dyspnea who had been referred to our Pulmonary Function Test (PFT) Department between 2000 and 2010. RESULTS: We observed that asthma was the first cause of MG-unrelated dyspnea in MG patients, with 9 patients (14%) presenting with asthma-related PFT abnormalities. Six patients had asthma for several years before developing MG, and 3 patients (4%) developed asthma a few months after MG was diagnosed, suggesting a non-coincidental association between the two conditions. In all 3 cases, asthma appeared in elderly patients with severe late-onset AchR-Ab- positive MG, treated with pyridostigmine and corticosteroids and/or intravenous immunoglobulins. In all 3 patients, ß(2)-adrenergic agonist treatment allowed only partial control of dyspnea. In one case, respiratory symptoms were alleviated when pyridostigmine dosage was reduced. CONCLUSIONS: Patients with treated MG and persistent dyspnea should be investigated for asthma using PFT before being diagnosed with refractory MG. If asthma is diagnosed, a bronchodilator treatment should be instituted and a reduction in pyridostigmine dosage should be proposed.