key: cord-0764580-9kfdkwb7 authors: Clavario, P.; De Marzo, V.; Lotti, R.; Barbara, C.; Porcile, A.; Russo, C.; Beccaria, F.; Bonavia, M.; Bottaro, L. C.; Caltabellotta, M.; Chioni, F.; Santangelo, M.; Hautala, A.; Ameri, P.; Canepa, M.; Porto, I. title: Assessment of functional capacity with cardiopulmonary exercise testing in non-severe COVID-19 patients at three months follow-up date: 2020-11-16 journal: nan DOI: 10.1101/2020.11.15.20231985 sha: eccc2d5bff49d4d8e32704afd7f210ad69516a6e doc_id: 764580 cord_uid: 9kfdkwb7 Introduction Long-term effects of Coronavirus Disease of 2019 (COVID-19) and their sustainability in a large number of patients are of the utmost relevance. We aimed to determine: 1)functional capacity of non-severe COVID-19 survivors by cardiopulmonary exercise testing (CPET); 2)those characteristics associated with worse CPET performance. Methods We prospectively enrolled the first 150 consecutive subjects with laboratory-confirmed COVID-19 infection discharged alive from March to April 2020 at Azienda Sanitaria Locale (ASL)3, Genoa, Italy. At 3-month from hospital discharge, complete clinical evaluation, trans-thoracic echocardiography, cardiopulmonary exercise testing (CPET), pulmonary function test (PFT), and dominant leg extension (DLE) maximal strength evaluation were performed. Results Excluding severe and incomplete/missing cases, 110 patients were analyzed. Median percent predicted peak oxygen uptake (%pVO2) was 90.9(79.2-109.0)%. Thirty-eight(34.5%) patients had %pVO2 below, whereas 72(65.5%) above the 85% predicted value (indicating normality). Median PFT parameters were within normal limits. Eight(21.1%) patients had a mainly respiratory, 9(23.7%) a mainly cardiac, 3(7.9%) a mixed-cardiopulmonary, and 18(47.4%) a non-cardiopulmonary limitation of exercise. Eighty-one(73.6%) patients experimented at least one symptom, without relationship with %pVO2 (p>0.05). Multivariate linear regression analysis showed age ({beta}=0.46, p=0.020), percent weight loss ({beta}=-0.77, p=0.029), active smoke status ({beta}=-7.07, p=0.019), length of hospital stay ({beta}=-0.20, p=0.042), and DLE maximal strength ({beta}=1.65, p=0.039) independently associated with %pVO2. Conclusions Half of non-severe COVID-19 survivors show functional capacity limitation mainly explained by muscular impairment, albeit cardiopulmonary causes are possible. These findings call for future research to identify patients at higher risk of long-term effects, that may benefit from careful surveillance and targeted rehabilitation. PFT parameters were within normal limits. Eight(21.1%) patients had a mainly respiratory, 9(23.7%) a mainly cardiac, 3(7.9%) a mixedcardiopulmonary, and 18(47.4%) a non-cardiopulmonary limitation of exercise. Eighty-one(73.6%) patients experimented at least one symptom, without relationship with %pVO2 (p>0.05). Multivariate linear regression analysis showed age (β=0.46, p=0.020), percent weight loss (β=-0.77, p=0.029), active smoke status (β=-7.07, p=0.019), length of hospital stay (β=-0.20, p=0.042), and DLE maximal strength (β=1.65, p=0.039) independently associated with %pVO2. Half of non-severe COVID-19 survivors show functional capacity limitation mainly explained by muscular impairment, albeit cardiopulmonary causes are possible. These findings call for future research to identify patients at higher risk of long-term effects, that may benefit from careful surveillance and targeted rehabilitation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint To date, the Coronavirus Disease of 2019 (COVID-19) pandemic accounts for more than 50 million confirmed cases and up to 1 million deaths worldwide [1] . Whereas handling the initial phase has been challenging for health systems, the sheer number of cases raises alarm about the sustainability of even minor sequelae after hospital discharge. COVID-19 is a mainly respiratory disease, but cardiovascular (CV) alterations are also associated with worse prognosis [2] . For the chronic phase, the main concerns are the development of pulmonary interstitial disease and/or a lingering CV involvement, as hypothesized by a recent CV magnetic resonance study [3] and potentially explained by the Severe Acute Respiratory Syndrome-Coronavirus type 2 (SARS-CoV2)-associated endothelitis [4] . How to intercept, assess, and treat this large number of patients with potential long-term consequences of COVID-19 remains uncertain, with the hypothesized rehabilitative effort mainly focused on the post-intensive care patients [5, 6] . It should be noted, however, that among the 20,000+ COVID-19 patients hospitalized in Italy and discharged alive, those classified as clinically severe or critical represent less than 20% [7] . Conversely, despite data from the 2003 SARS outbreak highlighting long-term exercise capacity reduction even in absence of cardiac or pulmonary abnormalities[8], data on long-term functional COVID-19 effects in less clinically complex patients are lacking. Aims of our study were: 1) to evaluate pulmonary, cardiac, and functional capacity of non-severe COVID-19 survivors by performing cardio-pulmonary exercise testing (CPET); 2) to identify those baseline and clinical characteristics associated to worse performance at CPET. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint We included the first 150 consecutive subjects undergoing post-COVID-19 evaluation at the Outpatient Cardiac Rehabilitation center of Genoa, Italy. The local healthcare authority (Azienda Sanitaria Locale, ASL 3 Genovese) set up a structured follow-up program for all patients with a history of Reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection admitted to COVID-19 wards from 1 st of March 2020 to date (recruitment is still ongoing). For the purpose of the study, we included in analysis all non-severe patients, excluding those requiring mechanical ventilation and intensive care. At 3 months from hospital discharge, all patients received complete clinical evaluation, transthoracic echocardiography (TTE), CPET, pulmonary function test (PFT), and dominant leg extension (DLE) maximal strength evaluation. All patients signed an informed consent. Study protocol and informed consent conform to the Declaration of Helsinki and were approved by the Ethics Committee of the Liguria Region (n° 430/2020CER). All procedures and protocols are described in detail in online-only material. Categorical variables are presented as frequencies and percentages and were compared by chisquare test or Fisher's exact test. Continuous variables are reported as mean and standard deviation (SD) or median and interquartile range (IQR) according to their distribution. Normally distributed variables were compared by means of unpaired Student's t test. Non-normally distributed variables were compared with the U Mann-Whitney non-parametric test. The main outcome measure was percent predicted peak VO2 (%pVO2). Patients were categorized according to the value of %pVO2 below or above 85%. Multivariate linear regression model was used to estimate the beta coefficients with 95% confidence interval (CI) of %pVO2. The model was adjusted for time from hospital discharge to CPET and all clinically meaningful covariates with p <0.10 in univariate analysis. All analyses were performed with R environment 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) and packages tableone, finalfit, and ggplot2. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint Of the first 150 evaluated patients, we excluded 24 (16.0%) who had needed invasive ventilation, 7 (4.7%) for missing data, and 9 (6.0%) as they were unable to perform CPET. The final population included 110 patients. Table 1 depicts the characteristics of the study patients. Forty-five (40.9%) patients were female, median age was 61.7 (53.5-69.2) years, median body mass index (BMI) at CPET evaluation was 26.8 (23.9-30.5) kg/m 2 , median weight at hospital admission was 82.0 (70.0-95.0) kg, whereas median weight at CPET evaluation was 77.0 (67.0 89.8) kg with median percent weight loss of 9.4 (6.0-12.9) %. Forty-five (40.9%) patients were active smokers. The reason for maximal CPET interruption was exhaustion/leg fatigue for 109 (94.5%), dyspnea for At PFT, median forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusing capacity of lungs for carbon monoxide (DLCO) were within normal limits; however, 2 (1.8%) patients had mild and 2 (1.8%) moderate impairment of FEV1, 1 moderate impairment of FEV1, 5 (4.5%) mild and 2 (1.8%) impairment of FVC, and 9 (8.2%) mild, 6 (5.5%) moderate and 2 (1.8%) severe DLCO impairment. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint At multivariate linear regression analysis adjusted for time from hospital discharge to CPET, age (β=0.46, p=0.020), percent weight loss (β=-0.77, p=0.029), active smoke status (β=-7.07, p=0.019), length of hospital stay (β=-0.20, p=0.042), and DLE maximal strength (β=1.65, p=0.039) ( Figure 1 ) were independently associated with %pVO2 ( Table 2) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint 7 Our study has the following main findings: 1) 1/3 rd of non-severe COVID-19 survivors had a significant alteration both in exercise capacity and %pVO2 at 3 months after hospital discharge; 2) in about half of patients with abnormal %pVO2, this was due to abnormal peripheral oxygen extraction, most likely to some degree of muscle impairment, as DLE maximal strength was independently associated with peak oxygen consumption; 3) more than 2/3 rd (74.3%) of patients experimented at least one disabling symptom at 3 months after hospital discharge, although there was no relationship between symptoms and worst %pVO2. To our knowledge, for the first time we assessed clinical status and exercise capacity of COVID-19 patients performing complete CPET evaluation after hospital discharge. Regarding the first point, our results are reminiscent of Ong et al., who found a 41% prevalence in reduced %pVO2 among 44 SARS 3-month survivors[8], albeit they also included 10/44 (22.7%) patients that had required invasive ventilation. The abnormal %pVO2 was accompanied by an early anaerobic threshold, translating into a significant impairment in daily activities. On note, abnormal physical function and performance in COVID-19 survivors have been preliminarily described by Belli et al. [9] using 1-min sit-to-stand test and Short Physical performance Battery, without the more objective CPET evaluation. Due to the ongoing and accelerating COVID-19 worldwide pandemic, these observations raise important concerns for health systems, as we proved that a substantial number of non-severe COVID-19 patients still had objective exercise impairment several months after hospital discharge. As for the second point, it is noteworthy that a cardiopulmonary cause determining the exercise capacity and %pVO2 reduction could only be found in about half of patients. Interestingly, DLE maximal strength was independently associated with peak oxygen consumption suggesting that muscle impairment should be responsible for the residual cases, probably due to bed rest and subsequently muscular deconditioning, but also with a potential role for corticosteroid We also highlight the role of hospital stay, that appeared longer among patients with abnormal %pVO2, probably for both the forced confinement during the acute phase and the need for aggressive medical care in COVID-19. Regarding this, our data can again only be compared with . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint 8 Belli et al. [9] , which found no association between physical performance and length of hospital stay, but without measuring objective CPET-derived parameters. We believe that the most important of our findings is the relationship between %pVO2 and maximal strength of the lower limb muscles, maintained even after accounting for cardiopulmonary variables, for length of hospitalization, and for percent weight loss. In our opinion this reduces the likelihood that bed rest, exercise deprivation and loss of muscle mass alone could cause this degree of impairment, raising the possibility of a direct effect of SARS-CoV2 at the muscle level. We only mention the possibility of mitochondrial dysfunction[12], as several ongoing research projects are exploring its role on the pathogenesis of COVID-19 acute phase [13] [14] [15] . As for the third point, we demonstrate that almost 3/4 ths of patients experienced at least one disabling symptom 3 months after hospital discharge, without any relationship with exercise capacity. Several studies have already investigated the residual symptoms burden of patients recovering from COVID-19, observing different rates between out-patients (about 35% in Tenforde et al.) [16] and patients who had needed hospitalization (87% in the study by Carfì et al.) [6] . We report relatively high rates of disabling symptoms (50% dyspnea, 49.1% fatigue). Halpin et al. In conclusion, it has been known for many years that most critically ill patients face long-lasting functional impairment after discharge [10] ; what is mostly worrying about our data is that we found severe mid-term consequences of COVID-19 in a non-ICU population. This observation supports the need for targeted management of these patients also during the acute phase (e.g. applying appropriate nutrition and early mobilization plans). Moreover, as there was no relationship with %pVO2, symptoms alone should not guide the post-acute management of COVID-19 patients: more objective techniques, such as CPET, should probably be used to rapidly intercept and assess the exercise impairment and, perhaps, to decide whether to start a physical rehabilitation program. Our study has important limitations. Firstly, all patients came from an area of the city of Genoa. Secondly, the functional capacity evaluation was conducted three months after hospital discharge, with the patients unsupervised in the meantime and no data available about the baseline condition prior to COVID-19. Moreover, no direct structural evaluation at the muscle level was performed. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.15.20231985 doi: medRxiv preprint Potential Effects of Coronaviruses on the Cardiovascular System: A Review Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19) COVID-19 and pulmonary rehabilitation: preparing for phase three Persistent Symptoms in Patients After Acute COVID-19 The Role of Genetic Sex and Mitochondria in Response to COVID-19 Infection COVID-19, Mitochondria, and Interferon Mitochondria and microbiota dysfunction in COVID-19 pathogenesis Feldstein LR, Investigators IVYN, Team CC-R, Investigators IVYN Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network -United States Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation None.