The Impact of COVID-19 on the Response to Hypoxia

Abstract

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.

Introduction

Over the past several decades, there has been an increasing interest in traveling to high altitude for work, sports, or leisure activities. However, exposure to hypoxic environment can be hazardous for the human body. The physiological responses to high-altitude hypoxia are difficult to predict, highly individualized, and depend on several factors such as genetics, sex, age, background fitness, and perceived exertion (Luks et al., 2017). Some external factors are also implicated, such as the ascent profile, sleep altitude differences, or physical effort (Luks et al., 2017). Maladaptive response to this extreme environment can put one at risk of developing severe high-altitude illness (SHAI) (Richalet et al., 2012; Song et al., 2016). The daily altitude gain, acute mountain sickness history, and maximum altitude reached, all influence the occurrence of sickness (Waeber et al., 2015).

Identifying people at risk before exposure to high altitude may be beneficial through proposed adaption of their ascent profile or preventive therapeutics. Individual tolerance to hypoxia and susceptibility to developing an inadequate response to hypoxia and subsequent SHAI symptoms can now be evaluated and predicted by the validated SHAI score, shown to be stable over time (Richalet and Lhuissier, 2015). This score can be calculated by means of the Richalet Test (Canouï-Poitrine et al., 2014; Richalet et al., 2021; Richalet et al., 2012), developed in France where it is commonly used during mountain medicine consultations. During these consultations, subjects perform a hypoxic cardiopulmonary exercise test and answer questionnaires on clinical and environmental items to obtain the objective physiological measurements needed to compute the SHAI score (Canouï-Poitrine et al., 2014; Richalet et al., 2021).

Since the beginning of 2020, the world has been caught up in the coronavirus disease 2019 (COVID-19) pandemic with 516 million cases worldwide (according to the World Health Organization [WHO]). The viral culprit, SARS-CoV-2, induces clinical manifestations generally involving more than one organ, and most typically the respiratory, cardiovascular, and neurological systems. Symptoms have been demonstrated to persist for weeks and even months, resulting in long-term consequences. Viral-induced injury to the lung frequently results in hypoxemia, the long-term persistence of which may be linked to reduced physiological adaptation to hypoxia (Mao et al., 2020). Studies on the (long term) course of a SARS-CoV-2 infection have been published and international guidelines have been written and are being continuously updated (Siemieniuk et al., 2020).

Travel to high-altitude destinations have resumed since restrictions imposed during the COVID-19 pandemic have been lifted, and mountain medicine is confronted by the recent issue of the potential effect of COVID-19 on the physiological adaptation during an ascent to high altitude. A reduction in arterial oxygen partial pressure is common in subjects when exposed to high altitude (Millet et al., 2021). Alterations of the response to hypoxia have been observed after infection by SARS-CoV-2, a virus with potential to significantly damage the nervous system, and to affect cardiorespiratory functions (Mao et al., 2020). One hypothesis is that COVID-19 patients have an impaired response to hypoxia when compared with their response before illness. Consistent with Moore and Moore's “two hit model” (Moore and Moore, 1995) of critical illness initiation, COVID-19 may negatively impact the response to hypoxia. Conversely, reports of high prevalence of dyspnea in COVID-19 patients up to 3 months after infection, would indicate a more “positive” influence on the neurological control of breathing (Carfì et al., 2020; Goërtz et al., 2020).

In such cases, COVID-19 infection-induced changes in the carotid bodies may lead to an altered response to impaired oxygenation (Villadiego et al., 2020). In other words, a “sensitization” in subjects having suffered from COVID-19 could result in an increased hypoxic response (Richalet and Lhuissier, 2015).

To our knowledge, no controlled trial to date has studied the effect of COVID-19 on the control of breathing and response to hypoxia, in particular, the subsequent implications of such an effect on exposure to high altitude. In this study, we aimed to increase our understanding of the potential long-term effects of COVID-19 on the cardiorespiratory response to hypoxia. To this end we asked a cohort of participants who had previously undertaken the Richalet test before the COVID-19 pandemic, to retake the test. Results of those who had tested positive to COVID-19 between the first and second Richalet tests were compared with those of the control group having stayed free of COVID-19.

Materials and Methods

Subjects

This multicenter study was approved by the « Comité de Protection des Personnes Sud-Est I (CPP 2021-016) » and registered at ClinicalTrials.org. All participants provided written informed consent before participation. Eight centers from the multiSHAI study (Richalet et al., 2021) network participated in our study. Among the candidates consulted between 2015 and 2020 in these centers, 68 adult participants were recruited by email. Candidates were asked to participate on a voluntary basis and were informed that participation would entail a retaking of the altitude consultation with a hypoxia exercise test. Participants were asked if they had tested positive to COVID-19 during the 24 months before inclusion, regardless of wave, with polymerase chain reaction, serology, or chest computed tomography (CT) scan. Provided that they had an oxygen saturation of SpO2 > 95% in ambient air and presented no significant persisting symptoms of COVID-19 on the day of the experiment, these candidates could then be included in the study in either the control or COVID+ group.

Exclusion criteria were history of neuromuscular, metabolic, or renal pathologies; psychiatric or behavioral disorders; inability to participate in accordance with sections L1121-5 to L1121-8 of the Public Health regulations (Code de la Santé Publique); guardianship or curatorship; lack of health insurance; refusal to participate; infection by a pathogen other than SARS-CoV-2; and age below 18 years.

Design

All 68 included participants, divided into those having tested positive to COVID-19 (COVID+ group) and those having stayed free of COVID-19 (control group), were evaluated by way of a field questionnaire on relevant medical history, current medication use and/or treatments, risk factors (smoking, alcohol use), physical exercise, mountaineering habits, and sociodemographic and anthropometric details (age, sex, weight, height, body mass index). Participants in the COVID+ group were also asked to fill in a questionnaire on details concerning the disease (suffered symptoms and illness duration, eventual treatments and/or hospitalization and complications). Severity of illness was classed as severe in participants reporting having needed hospitalization.

The participants then performed the “Richalet” hypoxia exercise test (Richalet et al., 2021), under the same conditions as used in the test performed before the pandemic (same center, same operator, same protocol). Briefly, this test was performed on an ergocycle and consisted of four consecutive exercise phases: phase RN (rest in normoxia), phase RH (rest in hypoxia), phase exercise in hypoxia (EH), and phase exercise in normoxia (EN). Heart rate (HR in bpm), minute ventilation (VE in l/min), and pulse oximetric O₂ saturation (SpO₂ in %) were measured continuously throughout the test.

Every phase lasted on average 4 minutes and the decision to move to the next phase depended on the three main parameters (cardiac frequency, respiratory rate, and SpO2) reaching a stable state for 30 seconds. The test started with a load of 40 W, which was maintained for 1 minute, after which it was increased until reaching a load inducing 40%–50% of the heart rate reserve. This individually calculated target for the load corresponds to a window within which variables of the hypoxia response remain stable. The same final load individually attained in the first test performed before the pandemic was used in the second test.

From these variables, were calculated the three main physiological parameters of the Richalet test allowing the evaluation of the individual tolerance to hypoxia: desaturation induced by hypoxia at exercise (ΔSpE), hypoxic cardiac response at exercise (HCR_e), and hypoxic ventilatory response at exercise (HVR_e), considered to represent the indirect measurements of the chemosensitivity and response to hypoxia (Richalet et al., 2021): $H V R_{e} = (V e_{E H} - V e_{E N}) \times \frac{100}{(S p_{E N} - S p {O_{2}}_{E H})} \times \frac{1}{b o d y w e i g h t}$ $H C R e = \frac{H R_{E H} - H R_{E N}}{S p {O_{2}}_{E N} - S p {O_{2}}_{E H}}$

Δ S p O_{2} = S p_{E N} - S p_{E H}

With Ve in l/min, $Δ S p O_{2}$ in %, body weight in kg and HR in beats/min and consequently HVR_e in l/min/kg and HCR_e in beats/min/%.

Finally, the SHAI score was calculated for each participant by means of the three main outcomes of the hypoxia exercise test and the additional altitude mountain consultation questionnaire (Richalet et al., 2012, 2021).

Data analyses

Data in individual hospital centers were collected from participants' medical charts and pseudonymized according to the Referencing Method MR01, as recommended by the “Commission Nationale de l'Informatique et des Libertés.” They were then sent to the French mountain medicine training and research institute (Institut de Formation et de Recherche en Médecine de Montagne; IFREMMONT) in Chamonix Mont-Blanc to be collected in a structured electronic data collection system. To determine the extent to which having suffered from COVID-19 impacts an individual's response to hypoxia, analyses were performed on the four primary outcomes of the study: the three main physiological parameters of the Richalet test and the computed SHAI score. Results obtained by the COVID+ group in the period preceding the COVID-19 pandemic from 2015 to 2019 (PRE) were compared with those obtained post-COVID-19 infection (POST), as well as with those obtained in the control group over the same period.

Statistical methods

Data are expressed as mean (±standard deviation) or median [1st-3rd interquartile] for quantitative variables and as percentages and numbers for qualitative variables. The Shapiro–Wilk test was used to assess normality. Characteristics of participants were analyzed with a T-test for quantitative data or with a Chi-square test for qualitative data.

A first analysis was performed to investigate the effect of having suffered from COVID-19 on an individual's response to hypoxia. Within each group, intraindividual evolution of parameters between PRE and POST was analyzed using the nonparametric paired Wilcoxon test. Due to the non-normal distribution, for each participant, all physiological parameters were expressed as the difference between POST and PRE data. Analyses of differences between groups (control and COVID+ groups) were then performed using nonparametric Kruskal–Wallis test.

A second analysis was performed to evaluate the change in participants' profile with regard to their SHAI risk score after having suffered from COVID-19. For this, we used Chi-square test between Control and COVID+ groups on the normalized SHAI scores (“At risk” corresponding to a worsening of the status, “No risk” corresponding to an improvement in status or “No difference”).

Statistical analyses were performed using SPSS software version 25.0 (IBM, New York). For all analyses, a p < 0.05 was considered statistically significant. Reporting of the present Coronaltitude study was done according to the “STrengthening the Reporting of OBservational studies in Epidemiology” (STROBE) guidelines.

Results

Demographic and clinical characteristics

Of the thousands of tests performed over the studied period, 641 had been done in exactly the same setting and by the same operator as those to be performed in our study and thus represented the group of potential candidates to whom we sent invitations. Of these, we included 68 participants for analysis, with 36 in the COVID+ group. Table 1 summarizes the demographic and clinical characteristics of participants as a function of time point, PRE and POST pandemic. Only the “snoring” characteristic significantly differed between groups (at PRE p = 0.017, at POST p = 0.031). We observed lifestyle modifications between the PRE and POST tests for four participants: one in the control group had stopped smoking and three of the COVID+ group had begun regular endurance training. However, their HVR_e and HCR_e values remained within the average of their own group and therefore did not seem to influence the analyses.

Table 1.

Demographic and Clinical Characteristics of Participants at Time Points PRE and POST

General characteristics	Control group		COVID+ group		p-value between groups
General characteristics	PRE	POST	PRE	POST	At PRE	At POST
Demographic information
Number of participants	32		36		—	—
Age (years)	47.4 (11.5)	49.8 (11.8)	46.1 (14.1)	48.4 (14.1)	0.681	0.648
Female gender	14 (44%)		18 (50%)		—	—
Duration between tests (years)	2.42 (0.83)		2.47 (1.0)		0.830
Clinical
Weight (kg)	71.7 (13.1)	71.8 (13.7)	71.0 (13.1)	70.7 (13.0)	0.830	0.743
BMI (kg/m²)	23.5 (3.0)	23.6 (3.5)	24.3 (2.9)	24.3 (2.8)	0.263	0.353
HRrest (beats/min)	67.5 (10.0)	67.3 (10.2)	68.2 (11.3)	68.2 (11.2)	0.799	0.735
SBP_rest (mmHg)	123.6 (11.4)	123.2 (8.8)	124.4 (14.0)	125.8 (14.1)	0.790	0.384
DBP_rest (mmHg)	74.4 (7.2)	74.9 (8.4)	74.7 (10.6)	78.1 (9.4)	0.890	0.142
Comorbidities
Systemic hypertension	4 (13%)	4 (13%)	2 (6%)	3 (8%)	0.314	0.573
Coronary diseases	3 (9%)	3 (9%)	3 (8%)	5 (14%)	0.880	0.564
Hypercholesterolemia	1 (3%)	2 (6%)	1 (3%)	1 (3%)	0.933	0.486
Asthma	2 (6%)	2 (6%)	2 (6%)	3 (8%)	0.903	0.743
Bronchopulmonary diseases	2 (6%)	2 (6%)	1 (3%)	1 (3%)	0.486	0.486
Migraine	5 (16%)	5 (16%)	3 (8%)	3 (8%)	0.352	0.352
Smoking	0 (0%)	0 (0%)	2 (6%)	1 (3%)	0.176	0.342
Sleep apnea syndrome	1 (3%)	1 (3%)	0 (0%)	0 (0%)	0.285	0.285
Snoring	3 (9%)	3 (9%)	12 (33%)^a	11 (31%)^a	0.017	0.031
Regular endurance training	10 (31%)	9 (30%)	10 (28%)	13 (36%)	0.754	0.482
SHAI history
Severe AMS	2 (6%)	2 (6%)	1 (3%)	2 (6%)	0.486	0.903
HAPE	0 (0%)	0 (0%)	1 (3%)	1 (3%)	0.342	0.342
HACE	0 (0%)	0 (0%)	0 (0%)	0 (0%)	—	—

Categorical variable values are shown as the number of participants with corresponding percentages n (%), and continuous variable values are shown as means (SDs).

A t-test or a Chi-square test were performed.

Different from Control group.

AMS, acute mountain sickness; BMI, body mass index; DBP, diastolic blood pressure; HACE, high-altitude cerebral edema; HAPE, high-altitude pulmonary edema; HRrest, heart rate at rest; SBP, systolic blood pressure; SD, standard deviation; SHAI, severe high-altitude illness.

Clinical findings of the COVID participants

Of our 36 COVID+ participants, we retrieved clinical COVID information for 33 of them (Table 2). None of the participants presented symptoms on the day of the test or had been hospitalized for severe complications.

Table 2.

Clinical Findings of the COVID+ Participants

Variable	n	%
Female gender	17	52
Diagnosis
PCR confirmed	31	94
Serologically confirmed	9	27
CT scan	1	3
Dyspnea	10	30
Fever >38°C	15	45
Anosmia and/or ageusia	20	61
Fatigue	28	85
Coughing	11	33
Headache	8	24
Duration between 1st symptoms and test (day)	214 (128)^a	46-515^b

Variables are summarized as the number of participants and corresponding percentages.

This value is showed as a mean (SDs) of all COVID+ patients.

These values are the corresponding min and max value. n = 33.

CT scan, computed tomography scan; PCR, polymerase chain reaction.

Outcomes of the Richalet test

Analyses of our four specific outcomes showed no significant difference between COVID+ and control groups (Table 3). For each group, we then performed the same analyses between PRE and POST values. We observed a significant increase in time for Sp_EN, VE_EH, and VE_EN variables in the COVID+ group (p = 0.025, p = 0.012, and p = 0.038, respectively), all possibly pointing to a higher ventilatory response following COVID-19. We also observed a significant increase for Sp_EH and decrease for VE_RN variables in the control group (p = 0.041 and p = 0.001, respectively).

Table 3.

Outcomes of the Richalet Test

Variable	Control group n = 32			COVID+ group n = 36			p-value COVID+ vs. Control
Variable	PRE	POST	POST–PRE	PRE	POST	POST–PRE	POST–PRE
VE_RN (l/min)	11.5 [9.0/13.8]	10.0 [8.5/12.1]^a	−1.0 [−2.5/0.0]	10.6 [8.0/12.5]	11.0 [8.8/12.9]	−0.4 [−2.0/2.5]	0.072
VE_RH (l/min)	13.0 [11.0/15.6]	12.0 [10.5/16.0]	0.0 [−2.2/1.3]	15.0 [10.3/18.2]	13.0 [11.3/15.5]	−0.9 [−4.0/2.0]	0.815
VE_EH (l/min)	39.0 [35.5/44.1]	37.0 [32.5/43.0]	−0.8 [−4.6/1.6]	36.7 [32.5/43.7]	40.5 [34.4/47.5]^a	1.9 [−1.0/5.8]^b	0.003
VE_EN (l/min)	30.5 [26.0/35.0]	27.0 [23.0/35.3]	−1.3 [−3.6/1.0]	28.0 [25.0/30.5]	29.3 [25.1/33.0]^a	2.1 [−1.8/4.0]^b	0.007
HR_RN (bpm)	71 [65/76]	68 [63/74]	−1.0 [−4.5/3.0]	68 [61/78]	67 [62/79]	0.0 [−5.0/4.0]	0.701
HR_RH (bpm)	83 [75/89]	79 [74/85]	−0.5 [−6.0/2.0]	85 [71/95]	81 [69/90]	−2.5 [−11.0/3.5]	0.721
HR_EH (bpm)	120 [116/127]	119 [111/127]	−0.5 [−8.0/2.5]	123 [114/131]	124 [113/135]	−1.5 [−7.0/4.0]	0.868
HR_EN (bpm)	103 [97/111]	100 [93/110]	−2.0 [−7.5/5.0]	105 [99/111]	106 [94/115]	−1.5 [−6.0/3.0]	0.806
Sp_RN (%)	99 [98/100]	99 [99/99]	0.0 [0.0/0.0]	98 [98/99]	99 [99/99]	0.0 [0.0/1.0]	0.305
Sp_RH (%)	93 [89/95]	94 [90/96]	0.0 [−1.0/3.0]	90 [87/93]	91 [86/95]	−1.0 [−2.0/2.0]	0.091
Sp_EH (%)	77 [74/78]	78 [74/80]^a	2.0 [−1.0/2.5]	76 [73/81]	78 [72/81]	0.0 [−2.0/2.5]	0.258
Sp_EN (%)	99 [97/99]	99 [98/99]	0.0 [0.0/0.0]	98 [97/99]	99 [98/99]^a	1.0 [0.0/1.0]	0.178
ΔSpR (%)	6.5 [4.0/10.5]	5.5 [3.0/9.0]	0.0 [−3.0/1.0]	8.0 [5.0/11.0]	8.0 [5.0/12.5]	1.0 [−2.0/3.0]	0.070
ΔSpE (%)	22.0 [20.5/25.0]	21.0 [19.0/23.5]	−2.0 [−2.5/1.0]	21.5 [17.0/26.0]	21.0 [17.0/26.0]	0.0 [−2.5/3.0]	0.166
HVR_e (l/min/kg)	0.63 [0.41/0.76]	0.64 [0.44/0.79]	0.01 [−0.10/0.11]	0.62 [0.44/0.86]	0.62 [0.45/1.04]	0.11 [−0.09/0.26]	0.113
HCR_e (bpm/%)	0.81 [0.56/0.90]	0.87 [0.72/1.00]	0.09 [−0.11/0.21]	0.86 [0.68/1.02]	0.80 [0.63/1.03]	−0.06 [−0.16/0.19]	0.439
SHAI score	4.0 [2.5/5.8]	4.0 [2.8/5.3]	0.0 [−1.0/0.3]	3.5 [2.8/5.3]	3.5 [1.8/5.0]	−0.8 [−2.0/0.5]	0.398
VE_EH/VO_2EH^c	28.9 [27.8/31.7]	29.5 [28.3/30.9]	0.2 [−1.7/1.2]	31.0 [28.4/32.8]	34.2 [30.6/38.1]^a	0.7 [−1.1/2.3]^b	0.019

Variables are summarized as median [1st/3d quartiles].

p-value <0.05 is considered statistically significant.

Different from PRE. n = 68.

Different from Control group.

n = 31 (COVID+: 15; Control: 16).

ΔSpE, Sp_EN–Sp_EH; ΔSpR, Sp_RN–Sp_RH; HCRe, hypoxic cardiac response at exercise; HR, heart rate; HVRe, hypoxic ventilatory response at exercise; Sp, transcutaneous pulse O₂ saturation; VE, ventilation; VO₂, oxygen consumption.

Analyzing the delta of the VE/oxygen consumption (VO₂) parameter (Table 3) revealed a significant difference between groups only during the EH phase from PRE to POST (p = 0.019) mainly supported by significant differences in VE_EH/VO_2EH at POST between the groups (p = 0.040) and between PRE and POST specifically for the COVID+ group (control: p = 0.856, COVID+: p = 0.017). The analysis of each parameter independently (VE_EH and VO_2EH) showed a significant increase for the delta of VE_EH between PRE and POST in the COVID+ group (n = 31, p = 0.049), but not of the VO₂ delta (n = 31, p = 0.104). These results appear to highlight the parameter likely modifying the ventilatory response to hypoxia.

Changes to SHAI risk profile

Table 4 shows changes in the risk profile between PRE and POST pandemic Richalet tests for participants with or without COVID history. We observed no significant differences due to COVID infection (p-value = 0.970).

Table 4.

Descriptive Changes of “Risk Status” at the Richalet Test

	Control group (n = 32)		COVID+ group (n = 36)		p
	n	%	n	%	p
No change	28	88%	31	86%	0.970
Change to “no risk”	3	9%	4	11%
Change to “at risk”	1	3%	1	3%

Number with corresponding percentage. Profile change to “no risk” corresponding to an improvement of the status. Profile change to “at risk” corresponding to a worsening of the status. A p-value of a Chi-square test.

Discussion

In the present study, we used the Richalet test to examine for the first time the extent to which having suffered from COVID-19 impacts an individual's response to hypoxia. We observed no significant effect of COVID-19 on the main performance outcomes of the Richalet test, namely HVR_e, HCR_e, and the SHAI score. Furthermore, we confirmed the stability and validity of the SHAI score over time by demonstrating no significant change between PRE- and POST-pandemic performances within the control group.

Interestingly, we observed a significant increase in VE at exercise both in normoxia and hypoxia in the COVID+ group compared with the control group that remained significant when normalizing VE for VO2 during hypoxic exercise. The significant increase in VE in normoxia was no longer significant when normalized between groups for VO2. This result suggests a COVID-19-induced enhancement of VE (Table 3). Noteworthy is that this significant increase in VE was not accompanied by significantly better HVR_e or lower SHAI risk score over time in the COVID+ group compared with the control group. Nonetheless, although not significant, the results of the primary outcome variables (ΔSpE, HVR_e, SHAI score) (Table 3) seem to point to a positive influence of COVID-19 on response to hypoxia. This study is the first to demonstrate a positive link between having suffered from COVID-19 and the ventilatory response to hypoxia. More specifically, by means of the Richalet test, we have demonstrated an increase in ventilatory response to hypoxia from PRE to POST pandemic in individuals who tested positive for COVID-19, particularly notable during exercise.

This could have consequences on an individual's hypoxic response to and acclimatization at high altitude, and possibly even lead to their inappropriate physiological response to hypoxia. Concordantly, the same interaction between COVID-19 and hyperventilation at exercise in normoxia has been observed in other studies where it was referred to as inappropriate exercise hyperventilation (Wirth and Scheibenbogen, 2022). The exact mechanism behind this phenomenon is, as of yet, unknown. It has, however, been theorized that inappropriate exercise hyperventilation might be related to a modification of central ventilatory control as part of the aftermath of a pulmonary infection (Motiejunaite et al., 2021).

Hypoxia and subsequent arterial PO₂ changes are mainly detected by the carotid bodies, from where the hypoxic ventilatory response is initiated (Fukushi et al., 2021). Tobin et al. (2020) have ascribed the difference in hypoxia sensitivity among individuals to a difference in threshold of arterial oxygen partial pressure required to activate the carotid bodies. One reasonable hypothesis could therefore be that COVID-19 infection leads to an alteration in the ability of carotid bodies to detect arterial PO₂.

Indeed, both sensitization and desensitization of the carotid bodies in the aftermath of COVID-19 infection, are currently incriminated and debated in relevant literature. Machado and Paton (2021) suggested COVID-19 infection-induced sensitivity changes in the carotid bodies with a subsequent impact on the regulatory control of respiratory and autonomic systems. Contrarily to the desensitization that can be observed in patients with “silent hypoxemia,” an alteration in oxygen sensing in the carotid bodies could go both ways (Simonson et al., 2021; Swenson et al., 2021). In some patients, overcoming the hypoxic challenge provoked by COVID-19 infection might have been linked to the carotid bodies becoming sensitized, which could lead to a “hyperactive” autonomic and respiratory response.

Multiple theories have been proposed to account for the pathophysiological mechanisms behind the sensitization of the peripheral chemoreceptors to impaired oxygenation. Regarding the occurrence of anosmia and ageusia in COVID-19 patients and the implied neuroinvasive potential of SARS-CoV-2, some authors (Porzionato et al., 2020; Villadiego et al., 2020) have hypothesized that a direct invasion of the glomus cells in carotid bodies could be behind changes in intrinsic chemoreception and chemosensitivity. In favor of this argument, the carotid body parenchyma has high expression levels of ACE2, the receptor to which SARS-CoV2 adheres and invades human cells (Machado and Paton, 2021).

Collectively, this study using the Richalet test has presented interesting new findings on the impact of COVID-19 on the response to hypoxia. While the predictive aspect of this test is still under discussion in the literature (Bärtsch and Swenson, 2013; Richalet et al., 2013), our use of a longitudinal approach with objective parameters together with the recent validation of the test predictability in a multicentric study (Richalet et al., 2021) help mitigate this limitation. Three main limitations of this work should however be noted: First, the small size of our sample of participants disallows any firm conclusions to be drawn from the results. Second, we did not objectively address the duration between the end of symptoms and the test. Being subjective as based on each patient's declaration and not on a medical observation, these data could not be appropriately used. Patients with significant persisting symptoms of COVID-19 were not, however, included in the study. Third, it was not possible to obtain sufficient VE/VCO2 data from the centers involved in the study, so these data are missing.

This is an important limitation, as we can only speculate on an increase in VE/VCO2 during hypoxic exercise following COVID-19 (concomitant to the observed increase for VE/VO2). Elevated VE/VCO2 could indeed be related to persistent increased dead space VE and/or pulmonary hypertension in a COVID+ group of patients. Finally, the clinical findings represented in the COVID+ group of our study were not representative of the grand variety found in COVID-19 cases worldwide. All reported cases among our participants remained on the mild-to-moderate side of the illness spectrum, with no declared severe complications or hospitalization and with fast-to-normal recovery rates. Therefore, since only mild COVID-19 cases have been tested with regard to subsequent tolerance to hypoxia after illness, the results and interpretations cannot be generalized and only compared with corresponding cases of the world population. Our work should incite future studies to extend the present findings by testing more severe cases of COVID-19 to formulate thorough recommendations for individuals having suffered from COVID-19 and subsequently planning a stay at high altitude.

Conclusion

The take-home message of this study is that individuals having suffered from mild to moderate COVID-19 seem to have an increased ventilatory response to exercise both in hypoxia and normoxia. However, having suffered from COVID-19 does not seem to affect an individual's predicted risk of developing SHAI. Future research is needed to determine the actual impact on the risk of developing an inappropriate hypoxic response when acclimatizing or during an ascent to high altitude in patients having suffered from COVID-19. All points discussed in this study must be considered bearing in mind the novelty of the COVID-19 pandemic, and their confirmation by future research is desired.

Footnotes

Acknowledgment

The authors warmly thank Mr. John Warren for his help reviewing the English.

Authors' Contributions

F.L-J., A.L., P.Z., G.D., and Y.S. contributed to the design of the study. The data were acquired and collated by P.R., S.D., J-M.B., A.F., F.P., C.P., M.P., T.T., J-P.R., and A.L. and analyzed by A.L., C.P., F.L-J., and Y.S. The article was drafted and revised critically for important intellectual content by all authors (A.L., P.C., Y.S., C.T., P.R., P.Z., G.D., S.D., J-M.B., A.F., F.P., C.P., M.P., T.T., J-P.R., F.L-J.). The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Patient Involvement

Patients were informed about the study design and all participants provided written informed consent before participation.

Data Sharing Statement

All data relevant to the study are included in the article. Pseudonymized data could be made available on reasonable request addressed to the corresponding author.

Author Disclosure Statement

The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation, and do not constitute endorsement by the ACSM. The author(s) declare having no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding Information

This work was funded by the “Institut de Formation et de Recherche en Médecine de Montagne” (IFREMMONT).

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