Persisting exercise ventilatory inefficiency in subjects recovering from COVID-19. Longitudinal Data Analysis 34 Months Post-Discharge Running title: Persisting Exercise Ventilatory Inefficiency in post-COVID Subjects

doi:10.21203/rs.3.rs-3928238/v1

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Persisting exercise ventilatory inefficiency in subjects recovering from COVID-19. Longitudinal Data Analysis 34 Months Post-Discharge Running title: Persisting Exercise Ventilatory Inefficiency in post-COVID Subjects

https://doi.org/10.21203/rs.3.rs-3928238/v1

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Background

SARS-CoV-2 infection has raised concerns about long-term health repercussions. Exercise ventilatory inefficiency (EVin) has emerged as a notable long-termi sequela, potentially impacting respiratory and cardiovascular health. This study aims to assess the long-term presence of EVin after 34 months and its association with cardiorespiratory health in post-COVID patients.

Methods

In a longitudinal study on 32 selected post-COVID subjects, we performed two cardiopulmonary exercise tests (CPETs) at 6 months (T0) and 34 months (T1) after hospital discharge. The study sought to explore the long-term persistence of EVin and its correlation with respiratory and cardiovascular responses during exercise. Measurements included also V̇O_2peak end-tidal pressure of CO₂ (PET_CO2) levels, oxygen uptake efficiency slope (OUES) and other cardiorespiratory parameters, with statistical significance set at p<0.05. The presence of EVin at both T0 and T1 defines a persisting EVin (pEVin).

Results

Out of the cohort, five subjects (16%) have pEVin at 34 months. Subjects with pEVin, compared to those with ventilatory efficiency (Evef) have lower values of PET_CO2 throughout exercise, showing hyperventilation. Evef subjects demonstrated selective improvements in DL_CO and oxygen pulse, suggesting recovery in cardiorespiratory function over time. In contrast, those with pEvin did not exhibit these improvements. Notably, significant correlations were found between hyperventilation (measured by PET_CO2), oxygen pulse and OUES, indicating the potential prognostic value of OUES and Evin in post-COVID follow-ups.

Conclusions

The study highlights the clinical importance of long-term follow-up for post-COVID patients, as a significant group exhibit persistent EVin, which correlates with altered and potentially unfavorable cardiovascular responses to exercise. These findings advocate for the continued investigation into the long-term health impacts of COVID-19, especially regarding persistent ventilatory inefficiencies and their implications on patient health outcomes.

COVID-19

Cardiopulmonary exercise test

Exercise ventilatory inefficiency

Hyperventilation

End-tidal pressure of CO2

Oxygen pulse.

Post-COVID condition refers to a range of symptoms and clinical findings that persist following the acute phase of SARS-CoV-2 infection [1]. In these patients, the cardiopulmonary exercise test (CPET) has highlighted a reduction of maximal exercise capacity and oxygen uptake (V̇O_2peak) and has been helpful to elucidate the underlying pathophysiological mechanisms leading to exercise intolerance and unexplained perceived dyspnea [1, 2]. CPET has demonstrated that exercise hyperventilation and ventilatory inefficiency (Evin) are a contributor to numerous disabling signs and symptoms in post-COVID patients, such as persisting breathlessness and long-lasting exercise intolerance [3, 4].

Exercise ventilation efficiency is assessed by examining how minute ventilation (V̇E) correlates with the amount of carbon dioxide produced (V̇CO₂). This relationship is quantified using three metrics: the slope of V̇E against V̇CO₂ (V̇E/V̇CO_2slope), the lowest value observed (nadir) for this ratio, and the carbon dioxide ventilatory equivalent at the first ventilatory threshold (V̇E/V̇CO₂ at θL) [5]. These metrics are well-established for evaluating mismatches in ventilation and pulmonary perfusion during exercise in patients with heart and lung conditions [6]. High values of V̇E/V̇CO₂ relationship commonly indicate EVin, which is a condition of breathing dysfunction related to excessive ventilation [5].

Ventilatory inefficiency is a global indicator of cardiorespiratory response to exercise and a well-recognized prognostic marker in chronic patients second only to V̇O_{2peak [}7]. As pointed out by Weatherald et al, EVin is also an hallmark of pulmonary vascular disease, such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension where it is an excellent prognostic marker [8].

Understanding the pathophysiological origins of EVin is essential to comprehending the exercise response in post-COVID syndrome. A significant number of evidence indicate that a subset of asymptomatic COVID-19 survivors exhibit EVin, with prevalences reported at 29% and 17% at 6 and 12 months post-discharge, respectively [9–11]. Compared to those without exercise ventilatory inefficiency, those with ventilatory efficiency (Evef), post-COVID patients with Evin show lower values of end-tidal pressure of CO₂ (PET_CO2) throughout exercise and display hypocapnia and respiratory alkalosis, which may correlate with an impairment in diffusing capacity (DL_CO) [3, 4, 11, 12].

Moreover, evidence at 12 months following severe COVID-19 infections indicate that numerous patients, despite achieving normal V̇O_2peak levels, exhibit signs of Evin, notably linked to signs of underlying pulmonary microvascular disease and increased dead space ventilation [13]. Such vascular complications are believed to stem from endothelial dysfunction and a hypercoagulable state, both of which are acute sequelae of the systemic inflammatory response to SARS-CoV-2 infection [13].

In addition to V̇O_2peak and V̇_E/V̇_CO2 relationship, impairments of the respiratory and cardiovascular response to exercise, could be also evaluated through the oxygen pulse (O₂ pulse), and aerobic efficiency, which are also a common parameters to assess the cardiovascular risk in certain populations [14, 15]. O₂ pulse is the ratio between oxygen uptake and heart rate (HR): it reflects the amount of oxygen extracted by the tissue per heartbeat and could be used in some clinical population as a non-invasive estimator of stroke volume, or peripheral oxygen utilization [7].

Despite these parameters are less strong indicators for evaluating overall survival in general population, some recent long-term longitudinal studies show that low O₂ pulse at peak and oxygen uptake efficiency slope (OUES) values have been associated with increased cardiovascular and all-cause mortality in certain population [14–16] These data need to be further confirmed by other similar longitudinal studies: however some evidence show that Post-COVID patients has a reduced aerobic capacity and O₂ pulse independent from V̇O_2peak levels [17]. While this data could not be interpreted in terms of long-term implication, they could be a subclinical signs of altered cardiovascular response due to the infection in these patients [18].

The enduring clinical significance of EVin and the cardiovascular response to exercise in post-COVID patients remains an area of ongoing investigation [13, 19]. The persistence of these conditions after 1 year following hospital discharge underscores the need for pathophysiological investigations and sustained longitudinal studies.

Our study aims to explore the persistence of EVin in Post-COVID patients and to unravel its potential long-term repercussions on respiratory and cardiovascular health.

Our first hypothesis is that EVin may persist chronically after COVID-19 infection. Evidence suggests that it could be a sign of acute SARS-CoV-2 infection and a subclinical impairment of exercise response which involve both the cardiovascular and the respiratory systems and this leads to our second hypothesis. We also hypothesized that EVin is a sign of a broader dysfunction in the cardiorespiratory response, which may also correlate with signs of an increased cardiovascular risk.

We evaluated the resting and exercise ventilatory and cardiovascular responses in a cohort of selected post-COVID patients at 34 months from hospitalization. In this evaluation, we compared the data with a previous evaluation performed 6 months after discharge.

Selection of patients

Data were collected from the RESPICOVID initiative, a prospective observational study conducted at the Respiratory Medicine Unit of the University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona (Italy), involving patients hospitalized for COVID-19 pneumonia during the first two waves of the pandemic emergency in Italy. A dedicated outpatient clinic has been organized, and all subjects discharged were considered. The present longitudinal analysis with repeated measures has been designed to evaluate the long-term persistence of ventilatory inefficiency in subjects enrolled in the RESPICOVID-2 study [10]. Only subjects who performed both CPETs (at T0 and T1) were considered. Figure 1 shows the study flow diagram.

To better define the EVin and cardiovascular response to exercise, we excluded any potential physiological or pathological variable influencing exercise adaptations [6]. We have then excluded subjects meeting the following criteria: a) age exceeding 65 years; b) concurrent presence of respiratory and non-respiratory chronic diseases, respiratory failure, or need for long-term oxygen therapy; c) a body mass index (BMI) ≥ 35 kg/m²; and d) an inability to perform a CPET with a peak respiratory exchange ratio (RER) < 1.05 (to exclude poor motivation). Among chronic diseases, only stable arterial hypertension was accepted.

Measurements

All measures were prospectively collected beginning in July 2020, approximately 6 months after the subjects’ discharge (T0), and repeated until March 2023, 34 months after the discharge (T1). Only subjects with both CPET measures (T0 and T1) were considered for the analysis. Preliminary data about measures performed at T0 have been reported previously [10]. The local Ethics Committee approved the study protocol (no. 2785CESC), which was performed according to the Good Clinical Practice recommendations and the requirements of the Declaration of Helsinki. Written informed consent was obtained from all subjects.

Lung function

Lung function procedures were performed according to international recommendations [20–22]. A flow-sensing spirometer connected to a computer for data analysis (Jaeger MasterScreen PFT System) was used to measure lung function. Forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁), and total lung capacity (TLC) were recorded. FEV₁/FVC ratio was taken as the index of airflow obstruction. The single-breath method measured the diffusion capacity for carbon monoxide (DL_CO). FEV₁, FVC, TLC, and DL_CO were expressed as percentages of the predicted values [21, 22].

Cardiopulmonary exercise test

According to the ATS/ACCP Statement, for the CPET measures, we used a cycle ergometer (E100, Cosmed Srl, Rome, Italy) with a ramp protocol of 10 to 25 watts increment every minute and based on the predicted peak power output, to achieve an exercise time between 8–12 minutes [23]. Patient were monitored 3 minutes before the ramp protocol (rest phase) and 5 minutes after (cool down phase). Subjects were asked to avoid caffeine, alcohol, cigarettes, and strenuous exercise 24 hours before the day of testing and avoid eating for the 2 hours before the test. Subjects suspended β-blockers before testing but could take their current antihypertensive therapies. During the test, subjects were asked to maintain a pedal frequency of 65 per minute and were continuously monitored [23]. Subjects were continuously monitored with a 12-lead electrocardiogram (ECG) and a pulse oximeter; blood pressure was measured every two minutes. Stopping criteria consisted of symptoms, such as unsustainable perceived dyspnoea or leg fatigue, chest pain, a significant ST-segment depression at ECG, or a drop in systolic blood pressure or oxygen saturation ≤ 84% [23]. Cardio-respiratory measures were sampled continuously with a breath-by-breath method using a gas analysis system (Quark CPET, Cosmed Srl, Rome, Italy). Oxygen uptake was expressed in mL/kg/min and as a percentage of predicted. The ventilatory response during exercise was through the relationship of V̇_E against V̇_CO2 obtained every 10 seconds, excluding data above the respiratory compensation point (RCP). We gathered data of V̇_E/V̇_{CO2 slope} and Y-intercept (V̇_E/V̇_{CO2 intercept}) values obtained from the regression function. V̇_E/V̇_CO2 was also been evaluated at nadir (V̇_E/V̇_{CO2 nadir}) and the first ventilatory threshold (V̇_E/V̇_CO2 at θ_L) [7].

For the definition of the EVin, we used the regression equation of V̇_E/ V̇_{CO2 slope} for healthy subjects, considering three standard deviations as the upper limit [5]. Then, we considered subjects having a lower range of V̇_E/V̇_{CO2 slope} (EVef) and subjects with over the upper limit of V̇_E/V̇_{CO2 slope} (EVin). Subjects having EVin at T0 and T1 were defined as persisting ventilatory inefficiency subjects (pEVin).

The end-tidal pressure of CO₂ (PET_CO2, in mmHg) was measured as the mean of PET_CO2 during the 3-minute rest period and the last 20 seconds of the test and was recorded at any time during CPET (at rest, at θ_L, at the respiratory compensation point - RCP, and at peak of exercise).

The cardiovascular response to exercise was expressed by HR, O₂ pulse, OUES, oxygen uptake and workload relationship (V̇_O2/W_slope) and HR after 1 minute of recovery (heart rate recovery, HRR). O₂ pulse was calculated by dividing instantaneous V̇O₂ by HR [7]. The OUES describes the relationship between V̇_O2 and V̇_E during incremental exercise, via a log transformation of V̇_E, and was expressed in L/min as the gradient of the linear relationship of log₁₀ V̇_E to V̇_O2 [24]. V̇_O2/W_slope was calculated as the slope of oxygen uptake as a function of Watts [7, 24]. OUES thus represents the absolute rate of increase in oxygen uptake per 10-fold increase in minute ventilation. HRR in bpm was defined as the reduction in the HR from the peak exercise level to the rate 1 min after the end of exercise [25]

At the end of the exercise, dyspnoea and leg fatigue were measured by a Borg 6–20 rate perceived exertion (RPE) scale [26]. Perceived peak dyspnoea and fatigue data have been described as RPE and peak workload ratio. We considered a test as maximal if subjects had a plateau of the V̇O₂ for more than 20 seconds, a Respiratory Exchange Ratio (RER) > 1.15, and a Borg RPE score > 18 [23].

Self-Reported Questionnaire

The modified Medical Research Council (mMRC) questionnaire was administered to measure perceived breathlessness, with a range from 0 (shortness of breath with strenuous exercise) to 4 (too breathless to leave the house) [27].

Statistical analysis

A preliminary Shapiro-Wilk test was performed. Data are reported as percentages for categorical variables, as mean (SD) or median [IQR-interquartile range] for continuous variables with a normal or non-normal distribution, respectively. Categorical variables were compared using the Chi-square test or the Fisher exact test, while the independent t-test or the non-parametric Mann-Whitney test assessed continuous variables. Relationships between variables were assessed using Pearson’s correlation coefficient (r).

All analyses were performed using IBM SPSS, version 17.0 (IBM Corp., Armonk, NY, USA), with p-values of < 0.05 considered statistically significant.

We evaluated the same thirty-two post-COVID subjects at T0 (median time from discharge 184 days) and T1 (median 1015 days). At T0, of 32 subjects, 8 had EVin (25%), while at T1 5 subjects (16%) had a pEVin. Subjects with pEVin, in comparison to subjects with EVef, had significantly higher values of a baseline of V̇E/V̇CO_{2 slope}, V̇_E/V̇_{CO2 nadir}, and V̇E/V̇CO₂ at θ_L with lower values of V̇E/V̇CO_{2 intercept}. No other variables, including those related to COVID-19 hospitalization, differed between subjects with pEVin and subjects with EVef. Baseline variables were reported in Table 1.

Table 1

General, functional and CPET-related baseline variables.
Variables	All subjects (N = 32)	Subjects with EVef (N = 27)	Subjects with pEVin (N = 5)	p-value
Age, y	55.2 [9]	55 [5.5]	58 [13.1]	0.550
Male, n (%)	24 (75)	20 (74)	4 (80)	> 0.999
Current or former smokers, n (%)	18 (56)	15 (56)	3 (60)	> 0.999
Arterial hypertension^*, n (%)	10 (31)	9 (33)	1 (20)	> 0.999
BMI, kg/m²	26.8 ± 3.3	26.7 ± 3.4	27.3 ± 3.2	0.734
FEV₁, % predicted	115.7 ± 13.9	114.2 ± 13.8	126.2 ± 9.9	0.107
FVC, % predicted	119 [21]	117.5 [19]	124.5 [18]	0.376
FEV₁/FVC, %	79.3 ± 5.8	78.8 ± 5.9	82.3 ± 5.4	0.279
TLC, % predicted	102.7 ± 11.9	103 ± 11.8	100.5 ± 13.2	0.697
DL_CO, % predicted	92.6 ± 13.4	92.7 ± 13	91.7 ± 17.5	0.897
PaO₂, mmHg	101.9 ± 11.8	103 ± 11.7	96.4 ± 12	0.261
PaCO₂, mmHg	38.7 ± 3.1	38.5 ± 3.2	39.6 ± 3	0.482
6MWT, total distance walked meters	587.8 ± 84.3	592.4 ± 82.3	562.8 ± 101	0.480
mMRC, score	1 [0]	1 [0]	1 [1]	0.880
Workload, watts	166.6 ± 50.8	169.9 ± 52.1	148.8 ± 43.4	0.401
V̇_O2 at peak, ml	2114.9 ± 548.3	2143.6 ± 561.7	1960.2 ± 493.7	0.501
V̇_O2 at peak, ml/kg/min	26.2 ± 5.2	27 ± 5.7	24.7 ± 7.2	0.427
V̇_O2 at peak, % predicted	98.7 ± 15	100 ± 15.8	91.6 ± 6.1	0.255
V̇_O2/W_slope	9.71 ± 1.31	9.81 ± 1.23	9.18 ± 1.75	0.330
V̇_E/V̇_{CO2 slope}	28 ± 4	26.9 ± 3.3	33.9 ± 1.6	< 0.001
V̇_E/V̇_{CO2 nadir}	26.8 ± 2.6	26.2 ± 2.2	30.5 ± 2	< 0.001
V̇_E/V̇_CO2 at θ_L	28.1 ± 2.7	27.6 ± 2.5	31 ± 1.7	0.008
V̇_E/V̇_{CO2 intercept}	2.79 ± 3.6	3.35 ± 3.4	-0.24 ± 3.6	0.042
V̇_E at rest, L/min	15.9 ± 5.9	15.6 ± 5.8	17.6 ± 7.2	0.489
V̇_E at peak, L/min	85 [40.2]	84.1 [36.6]	101.3 [38.6]	0.159
RR change^§, breath/min	19 ± 7	18.5 ± 7.3	22.2 ± 4.1	0.282
O₂ pulse at peak, mL/bpm	13.5 ± 3	13.5 ± 3.2	12.6 ± 2.3	0.579
OUES, L/min	1.09 ± 0.22	1.11 ± 0.21	0.98 ± 0.20	0.242
HR_max	156.7 ± 14.3	157.3 ± 14.2	153.6 ± 13.9	0.593
HRR, beats/minute	23.8 ± 6.3	24.4 ± 6.3	20.6 ± 6	0.227
HR/V̇_O2 slope, L⁻¹	50.1 [33.8]	50.1 [31.8]	77.5 [56]	0.361
Perceived peak dyspnea^#	17 [4]	17 [4]	17 [3.5]	0.525
Perceived peak fatigue^#	18 [2]	18 [2]	18 [3]	> 0.999
Variables related to COVID-19 hospitalisation
Length of hospital stay, days	6 [5]	6.1 [5]	6 [11]	0.677
Needing of oxygen therapy, n (%)	22 (68)	18 (67)	4 (80)	> 0.999
Needing of ventilatory support, n (%)	13 (41)	11 (41)	2 (40)	> 0.999
Needing of ICU admission, n (%)	5 (16)	3 (11)	2 (40)	0.163
PaO₂/FiO₂ at admission (n = 16)	305.9 ± 102.2	305.7 ± 107.2	307.9 ± 84.2	0.986
PaO₂/FiO₂ < 300, n (%)	9 (53)	8 (53)	1 (50)	> 0.999
PaCO₂ at admission (n = 16)	34.2 ± 5.6	34.1 ± 4.9	35 ± 12.7	0.940
Data are shown as the number of subjects (%), means ± SD or medians [IQR-interquartile range]. In bold are reported significant values.
^*Subjects with arterial hypertension were treated with ACE inhibitors (N = 6, 19%), β-blockers (N = 4, 12%), and Ca²⁺ antagonist (N = 3, 9%); ^§Calculated as value at peak less value at rest; ^#Described as a Borg 6–20 perceived exertion rate score.

Abbreviations: EVef defines exercise ventilatory efficiency; pEVin, persisting exercise ventilatory inefficiency; BMI body mass index; FEV₁, forced expiratory volume at 1^st second; FVC, forced vital capacity; TLC, total lung capacity; DL_CO, diffusion capacity for carbon monoxide; PaO₂, partial arterial oxygen pressure; PaCO₂, partial pressure of arterial carbon dioxide; 6MWT, six-minute walking test; mMRC, modified Medical Research Council dyspnea score; V̇_O2, oxygen uptake; V̇_E/V̇_{CO2 slope}, the slope of V̇_E to carbon dioxide output-V̇_CO2 ratio; θ_L, the first ventilatory threshold; V̇_E/V̇_{CO2 intercept}, point of intercept of V̇_E to carbon dioxide output-V̇_CO2 ratio; V̇_E, minute ventilation; RR, respiratory rate; OUES, oxygen uptake efficiency slope; HRR, heart rate recovery; ICU, intensive care unit.

In all subjects, comparing T1 vs T0 (Table 2), there was an increment of BMI, DL_CO % predicted, V̇_O2 at peak % predicted, and O₂ pulse at peak, with a reduction of FEV₁ and FVC (both % predicted), V̇E/V̇CO₂ at θ_L and V̇_E at rest. In EVef, selective changes between T1 and T0 were evident in the following variables: BMI, DL_CO % predicted, O₂ pulse at peak, V̇_E/V̇_CO2 at θ_L and V̇_E at rest. No selective changes were evident in subjects with pEVin.

Table 2

CPET-related differences between T0 and T1.
	All subjects (N = 32)			Subjects with EVef (N = 27)			Subjects with pEVin (N = 5)
Variables	T0	T1	p-value	Mean difference (T1-T0)	95% CI	p-value	Mean difference (T1-T0)	95% CI	p-value
BMI, kg/m²	26.8 ± 3.3	27.6 ± 3.6	< 0.001	0.97	0.43 to 1.53	< 0.001	0.20	-0.34 to 0.74	0.368
FEV₁, % predicted	115.7 ± 13.9	113.1 ± 12.3	0.023	-2.2	-4.4 to 0.04	0.054	-5.5	-19.8 to 8.8	0.311
FVC, % predicted	119 [21]	115 [11]	0.010	-0.37	-8.3 to 7.6	0.925	-4	-13.9 to 5.9	0.289
FEV₁/FVC, %	79.3 ± 5.8	79.2 ± 4.9	0.910	0.2	-1.1 to 1.5	0.774	-1.8	-3.8 to 0.25	0.069
TLC, % predicted	102.7 ± 11.9	101.7 ± 10.8	0.413	-1.2	-3.7 to 1.1	0.292	1.2	-12.3 to 14.8	0.789
DL_CO, % predicted	92.6 ± 13.4	97.2 ± 12.1	0.004	5.2	2.1 to 8.4	0.002	1.7	-18.1 to 21.7	0.798
mMRC, score	1 [0]	1 [0]	0.705	0	-1.9 to 1.9	> 0.999	0.2	0.3 to 0.7	0.374
Workload, watts	166.6 ± 50.8	164.4 ± 44.9	0.462	-3.5	-10.6 to 3.6	0.327	4.4	-5-5 to 14.3	0.285
V̇_O2 at peak, ml	2114.9 ± 548.3	2188.2 ± 545.2	0.068	76.3	-16.3 to 168.9	0.102	56.8	-91.9 to 205.5	0.349
V̇_O2 at peak, ml/kg/min	26.2 ± 5.2	26.7 ± 5.9	0.333	-0.61	-1.8 to 0.5	0.287	0.24	-1.69 to 2.17	0.748
V̇_O2 at peak, % predicted	98.7 ± 15	101.9 ± 13	0.032	2.88	-0.54 to 6.3	0.095	5	-0.4 to 10.4	0.062
V̇_O2/W_slope	9.71 ± 1.31	10.34 ± 1.42	0.033	0.50	-0.15 to 1.15	0.128	1.27	0.20 to 2.34	0.030
V̇_E/V̇_{CO2 slope}	28 ± 4	27.8 ± 3.9	0.756	-0.36	-1.77 to 1.04	0.598	0.78	-1.8 to 3.4	0.451
V̇_E/V̇_{CO2 nadir}	26.8 ± 2.6	26.3 ± 3.1	0.161	-0.51	-1.36 to 0.33	0.224	-0.52	-2.27 to 1.24	0.458
V̇_E/V̇_CO2 at θ_L	28.1 ± 2.7	27.2 ± 3	0.028	-1.06	-1.94 to -0.18	0.020	0.04	-2.37 to 2.45	0.966
V̇_E/V̇_{CO2 intercept}	2.79 ± 3.6	3.26 ± 3.8	0.520	0.54	-1.1 to 2.2	0.514	0.06	-3.9 to 4	0.968
V̇_E at rest, L/min	15.9 ± 5.9	12.4 ± 2.8	0.002	-3.3	-0.98 to -5.7	0.007	-4.3	-11.9 to 3.3	0.191
V̇_E at peak, L/min	86.3 [42.8]	88.7 [39.6]	0.695	0.62	-4.90 to 6.15	0.818	-0.88	-18.4 to 16.7	0.896
RR change^§, breath/min	19 ± 7	18.6 ± 4.9	0.688	0.42	-1.6 to 2.5	0.680	-4.94	-13.9 to 4.08	0.203
O₂ pulse at peak, mL/bpm	13.5 ± 3	14.2 ± 3.5	0.031	0.80	-0.09 to 1.5	0.027	0.04	-1.46 to 1.54	0.943
OUES, L/min	1.09 ± 0.22	1.12 ± 0.24	0.186	0.03	-0.02 to 0.08	0.264	0.03	-0.04 to 0.11	0.331
HR_max	156.7 ± 14.3	155.2 ± 13.5	0.397	-2.7	-6.4 to 1.01	0.147	5	-8.6 to 18.6	0.365
HRR, beats/minute	23.8 ± 6.3	25.5 ± 6.7	0.192	1.59	-1.32 to 4.5	0.272	2.2	-6 to 10.4	0.500
Perceived peak dyspnea^#	17 [4]	17 [4]	0.182	-0.25	-1.4 to 0.8	0.640	0.2	-1.4 to 1.8	0.749
Perceived peak fatigue^#	18 [2]	18 [2.75]	0.212	0.18	-0.6 to 1.03	0.658	0.01	-1.2 to 1.2	> 0.999
Data are shown as the number of subjects (%), means ± SD or medians [IQR-interquartile range]. The difference between T1 and T0 are expressed as mean and confidence intervals at 95%. In bold are reported significant values.
^§Calculated as value at peak less value at rest; ^#Described as a Borg 6–20 perceived exertion rate score and peak workload ratio.

Abbreviations: EVef defines exercise ventilatory efficiency; pEVin, persisting exercise ventilatory inefficiency; BMI body mass index; FEV₁, forced expiratory volume at 1^st second; FVC, forced vital capacity; TLC, total lung capacity; DL_CO, diffusion capacity for carbon monoxide; mMRC, modified Medical Research Council dyspnea score; V̇_O2, oxygen uptake; V̇_E/V̇_{CO2 slope}, the slope of V̇_E to carbon dioxide output-V̇_CO2 ratio; θ_L, the first ventilatory threshold; V̇_E/V̇_{CO2 intercept}, point of intercept of V̇_E to carbon dioxide output-V̇_CO2 ratio; V̇_E, minute ventilation; RR, respiratory rate; OUES, oxygen uptake efficiency slope; HRR, heart rate recovery.

PET_CO2 was significantly lower in patients with EVin than EVef at any time point of the exercise (at rest, at θ_L, at RCP and peak) at T1, while at T0 were different at rest, at RCP, and peak (Fig. 2).

At T1, PET_CO2 at rest (r 0.366; p = 0.039 and r 0.353; p = 0.048), such as at θ_L (r 0.532; p = 0.002 and r 0.586; p < 0.001), at RCP (r 0.514; p = 0.004 and r 0.565; p = 0.001), and peak (r 0.427; p = 0.015 and r 0.480; p = 0.005) were significantly and respectively correlated with O₂ pulse at peak and OUES (Table 3).

Table 3

Correlations among variables of ventilatory inefficiency (V̇_E/V̇_{CO2 slope}), hyperventilation (PET_CO2) and cardiovascular response to exercise (OUES, O₂ pulse at peak), all evaluated at T1.
	PET_CO2 at rest	PET_CO2 at θ_L	PET_CO2 at RCP	PET_CO2 at peak	O₂ pulse at peak	OUES
V̇_E/V̇_{CO2 slope}	r -0.395 p = 0.025	r -0.723 p < 0.001	r -0.801 p < 0.001	r -0.579 p = 0.001	r -0.271 p = 0.134	r -0.339 p = 0.057
PET_CO2 at rest	-	r 0.535 p = 0.002	r 0.432 p = 0.019	r 0.574 p = 0.001	r 0.366 p = 0.039	r 0.353 p = 0.048
PET_CO2 at θ_L	-	-	r 0.941 p < 0.001	r 0.821 p < 0.001	r 0.532 p = 0.002	r 0.586 p < 0.001
PET_CO2 at RCP	-	-	-	r 0.815 p < 0.001	r 0.514 p = 0.004	r 0.565 p = 0.001
PET_CO2 at peak	-	-	-	--	r 0.427 p = 0.015	r 0.480 p = 0.005
O₂ pulse at peak	-	-	-	-	-	r 0.939 p < 0.001
OUES	-	-	-	-	-	-
In bold are reported significant values.

Our study starts from the hypothesis that EVin may be a persistent ventilo-perfusory alteration after COVID-19. In a selected cohort of Post-COVID patients, at almost three years of follow-up, we demonstrated that a pEVin may be present in 16% of subjects. These subjects have the phenomenon of hyperventilation, documented by lower levels of PET_CO2. The patient cohort, comprising individuals with both EVef and EVin, exhibited consistently normal maximal exercise capacity, as well as normal levels of FEV₁, FVC, TLC at both 6 months (T0) and 34 months after discharge (T1). This persistent exercise hyperventilation correlate with to an exacerbated cardiovascular response to exercise, which was the second hypothesis of this study.

Ventilatory Inefficiency and Hyperventilation

A reduction in maximal exercise capacity and V̇_O2peak has been reported as the main CPET feature of symptomatic post-COVID patients [1]. However, some of the asymptomatic post-COVID patients, despite maintaining preserved lung functionality, maximal exercise capacity and V̇O_2peak, exhibit EVin [10, 11]. Research has indicated that exercise ventilatory inefficiency may be a significant feature also in apparently healthy COVID-19 survivors: however, its clinical role has not yet been fully elucidated [19].

In healthy subjects, EVin is uncommon and anthropometric variables may influence it. Usually, higher V̇E/V̇CO_2slope than the normal range is an indicator of EVin [6, 28].EVin in cardiopulmonary chronic conditions may be caused mainly by two reasons: 1) An altered arterial partial carbon dioxide pressure (PaCO₂) set-point and chemosensitivity (usually a consequence of chronic hypoxemia), and 2) an abnormally high dead space fraction during exercise caused by a ventilatory-perfusion mismatch, which could involve the ventilation, or the pulmonary perfusion [8, 28].

Hyperventilation is a frequent manifestation of subjects recovering from COVID-19, and it is frequently associated with ventilatory inefficiency; both have been reported as a possible mechanism of persisting disabling signs and symptoms limiting exercise capacity due to an increase in the cost of ventilation [3, 4, 29]. The exact cause of this hyperventilation remains unknown. As a consequence of infection, an imbalance in the ventilatory control has been hypothesized as a cause of the hyperventilation in post-COVID subjects, related to either heightened activation of activator systems (including automatic and cortical ventilatory control, peripheral afferents, and sensory cortex) or suppression of inhibitory systems (endorphins) [3]. In COVID-19 survivors, there is also a close relationship between hypocapnia resulting from resting hyperventilation and residual DL_CO, which are the most common functional abnormality in the early convalescence phase [12, 30]. Compared with non-severe cases, patients with severe COVID-19 had a higher impairment in DL_CO, which likely indicates a restrictive pattern, and a decrease in TLC [30]. Although the ventilatory response was unrelated to disease severity, higher values of V̇_E/V̇_{CO2 slope} have been found in a follow-up of seven months as a negative predictor in a cohort of patients developing pulmonary fibrosis [31]. We now report a close association between hyperventilation at each phase of the exercise and the EVin as a permanent and distinctive sign of a proportion of asymptomatic survivors (Fig. 2). This phenomenon is probably related to a perpetual altered PaCO₂ set-point and chemosensitivity, or to an alteration of the ventilatory-perfusion mismatch, in which a residual lung function impairment in DL_CO may play a significant role [6, 12, 28].In our data, we confirm the role of DL_CO and the excess ventilation by the selective improvement after 34 months in EVef subjects only (Table 2).

In line with the assessments made in a shorter period after one year of discharge, the EVin prevalence in our survivors (16%) is similar to that described by Ingul CB and colleagues (17%), with similar considerations about hyperventilation (PET_CO2) [11]. Of note, Ingul CB and colleagues found a close relationship between the perceived dyspnea and EVin: this relationship is not confirmed in our asymptomatic patients cohort, in which the level of dyspnea is very low (median mMRC 1) [11]. While perceived dyspnea is typically multifaceted in nature, our methodology, which involved the selection of subjects without comorbidities and variables that might affect the ventilatory efficiency—like a subject's weight—could have impacted these findings [6, 32]. For instance, Ingul's study included a cohort with 29% obese patients, in contrast to our study, which comprised only three out of 32 subjects (approximately 9%) being obese (data not shown) [11]. Persistent viral presence, long-term inflammation, microclots, and hypoxia may contribute to developing symptoms in obese subjects [33]. Moreover, obesity, related to the alteration of mechanical lung function, may affect the subject’s dyspnoea perception a priori [34].

Cardiovascular response to exercise in patient with pEVin

COVID patients are at risk for cardiovascular disease during acute phase of the infection [18]. Due to the damage of pulmonary endothelium and microclots during the disease, we cannot exclude long-term cardiovascular complications in these patients. EVin is a well-recognized hallmark of pulmonary vascular disease and increased dead-space ventilation [28]. Despite normal V̇O_2peak levels in subject recovered from severe COVID after one year of follow-up, dead space ventilation correlate with D-Dimer plasma concentrations during hospital stay [13]. At six months of discharge, higher values of V̇_E/V̇_{CO2 slope} have been linked to diminished HRR, suggesting that post-COVID subjectswith EVin may have a cardiac autonomic dysfunction, a general predictor of mortality in adults without heart disease history [10, 25]. Moreover, studies evaluating the hemodynamic response during exercise confirm that normotensive post-COVID patients present a significantly higher blood pressure response in the post-exercise recovery of the CPET, with an achieved lower O₂ pulse at peak than controls without a history of COVID-19 [17]. O₂ pulse may have non-specific interpretation and attention should be paid when discussing this variable alone. However, recent data show that low levels of O₂ pulse during exercise may be related to an increase in cardiovascular and all-cause mortality in some population [14]. This leads speculating reduced O₂ pulse peak values in COVID-19 recovered subjects could be a significant measure of health outcome. Low O₂ pulse at peak is a consequence of a reduced V̇O_2peak during short-term follow-up. Already at 6 months of follow-up up to a year after hospital discharge for COVID-19, O₂ pulse and V̇O_2peak increased significantly [1, 10]. In our longer follow-up, we document a significant global improvement of the O₂ pulse from 6 to 34 months, despite no significant increase in VO_2peak. It should be noted that the increase was mainly in EVef patients, speculating that subjects with pEVin still have a potential impairment in cardiovascular response, or oxygen tissue utilization (Table 2). Moreover, we demonstrate a significant correlation between the O₂ pulse at peak and PET_CO2 (Table 3).

Similarly to O₂ pulse, OUES values represent an individual's cardiorespiratory reserve and indicate how effectively oxygen is extracted and utilized by the body [24]. The prognostic potential of OUES has been examined in some clinical populations, such as patients with heart failure and very recently, the determination of OUES on healthy males has proved its prediction in all-cause mortality [16, 35]. Our data about the correlation between the hyperventilation and OUES, similarly for O₂ pulse, define this variable as potentially prognostic for COVID survivors.

Data about the exercise training on parameters of cardiovascular response in patients with chronic obstructive pulmonary disease (COPD) report OUES - but also O₂ pulse - as susceptible to changes, as a sign of an enhancement of ventilatory function upon exercise [36]. In the context of post-COVID patients, although in a single survivor patient from critical COVID-19 illness, and the data requires scientific confirmation, home-based exercise training has been demonstrated to produce a remarkable increment not only of V̇_O2 peak but also of the OUES, with a consensual reduction in V̇_E/V̇_CO2 and exertional dyspnea [37].

Our study’s strength is related to evaluating the EVin for a very long time from COVID-19 discharge (pEVin). Although we report a small number of patients (an explicit limitation), this was related to a selective approach excluding patients having a condition potentially influencing the exercise ventilation assessment. We included a healthy population with a normal exercise capacity and pulmonary function tests. This may also be considered a study strength because we excluded any potential cause of ventilatory inefficiency. Finally, we lack same-time data concerning the structural pulmonary (by thorax computed tomography scan) and cardiac (by echocardiography) damage. There is a possibility that these data could have confirmed a coexistent organic residual alteration.

In conclusion, our longitudinal data analysis on COVID-19 survivors, performed at 34 months from discharge, confirms the persistence of exercise ventilatory inefficiency in 16% of subjects. These subjects exhibit a hyperventilation status that correlates closely with an altered and unfavorable cardiovascular response to exercise. These observations underscore the importance of prolonged follow-up studies in individuals recovering from COVID-19.

Ethics approval and consent to participate

Written consent was obtained before the first visit and the protocol was approved by the local ethics committee, Comitato etico per la Sperimentazione Clinica (CESC). The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Clinical trial registration number: 2785CESC.

Consent for publication

All patients gave informed consent.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors report no relationships that could be construed as a conflict of interest.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author contribution

Substantial contributions to the conception or design of the study and the acquisition, analysis, or interpretation of data: GD, GS, GF, NR, NB, MB, MF, MV, LDC, CC, BG, EC. Drafting the study or revising it critically for important intellectual content: GD, GS, GF, NR, NB, MB, MF, MV, LDC, CC, BG, EC. Final approval of the version to be published: GD, GS, GF, NR, NB, MB, MF, MV, LDC, CC, BG, EC

Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: GD, GS, GF, NR, NB, MB, MF, MV, LDC, CC, BG, EC.

All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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Persisting exercise ventilatory inefficiency in subjects recovering from COVID-19. Longitudinal Data Analysis 34 Months Post-Discharge Running title: Persisting Exercise Ventilatory Inefficiency in post-COVID Subjects

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Abstract

Figures

Introduction

Methods

Selection of patients

Measurements

Lung function

Cardiopulmonary exercise test

Self-Reported Questionnaire

Statistical analysis

Results

Discussion

Ventilatory Inefficiency and Hyperventilation

Cardiovascular response to exercise in patient with pEVin

Declarations

References

Additional Declarations

Status:

Version 1