key: cord-0916945-cd65x9sx
authors: Anastasio, Fabio; Barbuto, Sarah; Scarnecchia, Elisa; Cosma, Paolo; Fugagnoli, Alessandro; Rossi, Giulio; Parravicini, Mirco; Parravicini, Pierpaolo
title: Medium-term impact of COVID-19 on pulmonary function, functional capacity and quality of life
date: 2021-02-11
journal: Eur Respir J
DOI: 10.1183/13993003.04015-2020
sha: 8109419804c8bf94dab9adc261970b7661626a02
doc_id: 916945
cord_uid: cd65x9sx

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide determining a dramatic impact on the healthcare system. Aim of this study is to evaluate mid-term clinical impact of COVID-19 on respiratory function. METHODS: 379 patients were evaluated 4 months after SARS-COV-2 diagnosis. Patients were divided in two groups based on the presence of pneumonia during COVID. Clinical conditions, quality of life, symptomatology, 6-min walking test, pulmonary function test with spirometry and diffusing capacity of carbon monoxide were analysed. Data were compared to clinical evolution during COVID (development of acute respiratory distress syndrome [ARDS], needing of invasive mechanical ventilation [IMV], partial oxygen saturation/ fraction of inspired oxygen [SpO(2)/FiO(2)] ratio and pneumonia severity index [PSI]). RESULTS: After a median of 135 days, 260 (68.6%) of 379 patients referred almost one symptom. Patients who developed pneumonia during COVID-19 showed lower SpO(2) at rest (p<0.001), SpO(2) during 6-min walking test (p<0.001), total lung capacity (p<0.001), airway occlusion pressure after 0.1 s [P0.1] (p=0.02), P0.1/maximal inspiratory pressure [MIP] ratio (p=0.005) and higher Borg category-ratio scale (p=0.006) and modified Medical Research Council breathlessness scale (p=0.003), compared to patients without pneumonia. SpO(2)/FiO(2) ratio and PSI during SARS-COV-2 pneumonia were directly associated with mid-term alteration of partial oxygen saturation at rest (p<0.001), SpO(2) during 6-min walking test (p<0.001), residual volume (p<0.001), total lung capacity (respectively p<0.001 and p=0.003) and forced vital capacity (respectively p=0.004, p=0.03). CONCLUSION: Lung damage during COVID-19 correlates to the reduction of pulmonary function after 4 months from acute infection.

The respiratory system is subjected to major involvement during COVID-19 also due to the hyperactive host immune response and the inflammatory organ injury, but there are no evidences about organ dysfunction at mid and long term. In previous experiences with Coronavirus lung involvement of SARS and MERS, radiologic abnormalities, impairment of pulmonary function and reduced exercise capacity improved over time but may be persistent in some for months or even years [1] [2] [3] . Evidence about pulmonary function tests, after discharge, among COVID-19 patients is currently limited to little retrospective studies with small samples showing, in severe COVID-19, a reduction of forced vital capacity (FVC), diffusing capacity or transfer factor of the lung for carbon monoxide (D LCO ), total lung capacity (TLC), 6-minutes walking test (6MWT) and impairment in respiratory muscle strength with necessity of respiratory rehabilitation [4] [5] [6] [7] .

The aim of our study (Respiratory Sequelae on is to evaluate the respiratory function 4 months after diagnosis in patients surviving to SARS-COV-2 infection and the difference between patients with or without initial lung involvement. The second outpatient visit will be completed in 12 months after diagnosis.

Patients between 18 and 80 years old with COVID-19 diagnosis were recruited. Patients were evaluated at the time of diagnosis and then after a median of 4 months for respiratory function with an outpatient visit. Inclusion criterion was COVID-19 diagnosis by Polymerase Chain Reaction (PCR) on pharyngeal swab or on alveolar-bronchial washing in case of double negative swab. Exclusion criterion was previous diagnosis of pulmonary disease, excluding asthma. Data on COVID-19 evolution were collected retrospectively, developing of ARDS, needing of IMV, SpO 2 /FiO 2 ratio, pneumonia severity index (PSI), steroid therapy, pulmonary embolism (PE) and worst blood tests (creactive protein [CRP] , procalcitonin [PCT] , ferritin, d-dimer, troponin I Hs, neutrophil/lymphocytes [N/L] ratio and lactate dehydrogenase [LDH] ) were acquired at the time of diagnosis.

ARDS was diagnosed according to the "Berlin definition": timing of worsening of the respiratory symptoms, diffuse bilateral pneumonia at chest imaging and PaO 2 /FiO 2 ≤ 300mmHg with PEEP ≥ 5cm H 2 O [10] . Patients with ARDS well-controlled by NIV or HFNO were not submitted at ICU for the lack of beds [11] . The use of NIV or HFNO were not evaluated for the heterogeneity of treatments and lack of full data. 

Outpatient pulmonary function tests were performed using MasterScreen Body (Jaeger, Wurzburg, Germany) and were performed by technicians at the pulmonary function laboratory. Forced expiratory volume in the first second (FEV1), FVC, FEV1/FVC ratio, TLC, residual volume (RV), RV/TLC, D LCO /alveolar volume (VA), maximal ventilatory ventilation (MVV), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), the airway occlusion pressure 0.1 second after the beginning of inspiration (P0.1), the airway occlusion pressure in relation to maximal inspiratory drive (P0.1/MIP), specific airway resistance (SR), peak expiratory flow (PEF) and Maximum Expiratory Flows at different lung volume levels (MEF75, 50, 25) were included in the analysis. For each patient, parameters were expressed as percentage (%) of a theoretical value calculated by Global Lung Function 2012 equations [8] .

Six-minute walking test 6-MWT was performed on room air under the supervision of a respiratory therapists in the pulmonary rehabilitation department according to American Thoracic Society guidelines [9] . BlueNight Oximeter (Sleepinnov Technology SAS, Moirans, France) pulse oximeter was used for recordings. Borg category-ratio scale (CR10) and self-reported intensity of exertion on the Borg rating of perceived exertion (RPE) were collected before and after 6MWT.

Patients were divided in two groups according to the presence of radiological signs of pneumonia during COVID-19 acuteness to assess the difference of pulmonary function, 6MWT and health variables at mid-term. Therefore, variables were analysed by the presence/absence of acute respiratory distress syndrome (ARDS), needing of invasive mechanical ventilation (IMV), SpO 2 /FiO 2 ratio and PSI.

At the health check, participants were requested to self-complete an Italian version of the 12-item short form survey (SF-12) and IPAQ. The SF12 includes eight subscales: physical functioning, role (physical), bodily pain, general health, vitality, social functioning, role (emotional) and mental health. These were summarized into two scales: a physical component score (PCS) and a mental component score (MCS), in accordance with the guidelines for the SF12 instrument [12] . Both scores ranged between 0 and 100, with a higher score indicating better health.

To evaluate the level of physical activity (PA), the IPAQ was used. Patients answered questions regarding activities carried out during a week, at work, at home, means of transport and leisure. Patients were then classified according to the level of PA. In the high-intensity group, those who practiced vigorous activity at least 3 days a week (or combinations equivalent to 3000 Metabolic Equivalents [MET-minutes/week]) were considered; moderate intensity for 3 or more days a week of vigorous intensity activity for at least 20 minutes (or combinations equivalent to 600 METminutes/week); and low intensity those that did not correspond to any of the other categories cited [13] .

Continuous variables were expressed as median and Inter-Quartile Range (IQR) and the categorical variables were presented as absolute value and percentage. Differences between groups were assessed by median test and Kruskal-Wallis test. Chi-square statistics were used to assess differences between categorical variables. Pearson's correlation coefficient and Cox regression were used to study relations between variables. Statistical analysis was carried out by SPSS V.26 statistical software package (SPSS for Windows V26, SPSS Inc., Chicago, IL, USA) and a p-value of 0.05 or less was considered statistically significant.

Ethical approval for the "Cardio-Respiratory Sequelae on COVID-19" Study was granted by the Ethics Committee of Brianza on 06 August 2020. Written informed consent were obtained from all subjects.

From 01 March 2020 to 01 June 2020, 1464 cases of SARS-COV-2 positivity were detected at our Hospital. Five-hundred and ninety-four patients were hospitalized, 64 of them were admitted to ICU and supported by invasive mechanical ventilation. Among the total sample 150 patients died. A total of 379 random selected patients were evaluated after a median of 135 days (IQR 102-175) after the onset of symptoms of COVID-19. The age ranged between 20-80yo, median 56 (IQR 49-63). Onehundred seventy-four patients (45.9%) were male. Median BMI was 25.2 (IQR 22.6-28.7). Preexisting comorbidities are reported in Table 1 . Twenty-five (6.6%) patients were active smoker, 128 (33.8%) patients were ex-smokers, At the out-patient clinical follow-up, 211 (69.9%) patients referred almost one symptom. Exertional dyspnoea (42.7%), weakness (29.8%), joint and muscular pain (13.7%), thoracic pain (11.9%), anosmia and ageusia (10.3%) and depression (8.2%) were the most reported symptoms at evaluation (Table 1) . Sixty (15.8%)patients had mMRC ≥ 2. A clear difference was found between referred dyspnoea and mMRC.

Among 379 evaluated patients, 222 had developed pneumonia. Among these 222 patients, 143 (64.4%) were hospitalized at our COVID Department and 135 (60.8%) required oxygen supplementation. ARDS occurred in 61 (27.5%) patients and 34 (15.3%) of them were admitted to intensive care unit (ICU) for invasive mechanical ventilation. Seven (3.2%) patients showed pulmonary embolism during COVID acuteness. During hospitalization, steroid was administrated in 42 (18.9%) patients with pneumonia and 8 (5.1%) patients without pneumonia. Table 2 shows laboratory and clinical parameters of pneumonia patients.

Differences in general characteristics between patients with pneumonia during COVID-19 and patients without it are showed in Table 1 . Patients with respiratory failure during COVID-19 acuteness were older (p<0.001), male (p<0.001), with higher BMI (p<0.001) and had a greater prevalence of obesity (p<0.001), hypertension (p<0.001), CVD (p=0.007), diabetes (p=0.003), CKD (p=0.01) and actual smoker (p<0.001).

Regarding mid-term vital parameters, respiratory tests and 6MWT (Table 3) , patients who developed pneumonia during COVID-19 showed higher SBP (p=0.002) and DBP (p=0.002), CR10 (p=0.006), mMRC (p=0.003), CR10 after 6MWT (p=0.04), PEF (p=0.009) and MEF75 (p=0.02) and lower SpO 2 at rest (p<0.001), SpO 2 during 6MWT (p<0.001), P0.1 (p=0.02), P0.1/MIP (p=0.005) and TLC (p<0.001). Paradoxically, patients without pneumonia involvement showed higher SR (p=0.03), RV (p<0.001) and lower MIP (p=0.02). Repeating the same analysis excluding obese patients, the results didn't change.

In the pneumonia group, patients who reported exertional dyspnoea, showed reduction of 6MWT (%) distance (86 [74-93] vs 90 [79-103], p=0.05) without any other difference in pulmonary function.

Evaluating pulmonary involvement in patients with pneumonia, patients who developed ARDS showed higher SBP (p=0.05) and DBP (p=0.02) and lower SpO 2 during 6MWT (p=0.004), FVC (p=0.004) and TLC (p<0.001). Interestingly, patients without ARDS showed higher SR (p<0.001), RV (p<0.001), TLC (p<0.001) and RV/TLC (p=0.05).

Patients who required IMV, compared to patients with pneumonia who didn't required IMV, showed lower 6MWT distance (p=0.006), SpO 2 during 6MWT (p=0.002), DLCO/VA (p=0.05), TLC (p<0.001), FVC (p=0.004). SR (p<0.001), RV (p<0.001) and RV/TLC (p=0.05) was higher in patients who not required IMV. SpO 2 /FiO 2 ratio and PSI during Sars-COV-2 infection were an important expression of lung damage according to radiological findings. Table 4 shows the correlating SpO 2 /FiO 2 ratio and PSI during Sars-COV-2 with the principal parameters investigated during the mid-term outpatient visit. Patients with pneumonia that showed a greater reduction of SpO 2 /FiO 2 ratio during Sars-COV-2 acute infection exhibited lower SpO 2 at rest (p<0.001), SpO 2 during 6MWT (p<0.001), MEP (p=0.01), RV (p<0.001), TLC (p<0.001) and FVC (p=0.004). Correlation between SpO 2 /FiO 2 ratio and SpO 2 at rest (p<0.001) and during 6MWT (p<0.001) was higher in non-ARDS patients. In patients with ARDS, SpO 2 /FiO 2 ratio correlates positively with SpO 2 at rest (p=0.05), MMRc (p=0.04), 6MWT distance (p=0.02), P0.1/MIP (p=0.04) and DLCO/VA (p=0.02) and inversely with MVV (p=0.02) (Figure 1) . Similarly, PSI correlates inversely with SpO 2 at rest (p<0.001) and during 6MWT (p<0.001), HR during 6MWT (p<0.001), RV (p<0.001), TLC (p=0.003) and FVC (p=0.03).

Selecting patients with pneumonia during COVID, steroid therapy was administered to 42 (18.9%) patients, 14 (23.0%) with ARDS and 28 (17.4%) without it. Steroid therapy, also corrected for SpO 2 /FiO 2 ratio, PSI, ARDS development or IMV need, was positively correlated with MMRc (p=0.05) and P0.1/MIP (p=0.01, β=0.170) and inversely with RV (p=0.02, β=-0.181), TLC (p=0.01, β=-0.197), FEV1 (p=0.01, β=-0.226), FVC (p=0.02, β=-0.211).

Evaluating all parameters by the time after diagnosis, Figure 2 shows the directly correlation between days from diagnosis and DLCO/VA (p<0.001) and 6MWT distance (p=0.004).

Median PCS12 was 45.8 (IQR 37.9-50.9), median MCS12 was 50.9 (IQR 40.9-57.2). IPAQ questionnaire showed a good prevalence of active patients: 81.7% of subjects declared to do adequate amount of physical activities.

There was no significant correlation between PCS12, MCS12 or IPAQ and lung function, development of pneumonia, ARDS, IMV, SpO 2 /FiO 2 ratio or PSI.

In previous experiences with Coronavirus lung involvement of SARS and MERS, radiologic abnormalities, impairment of pulmonary functions and reduced exercise capacity improved over time but may be persistent in some for months or even years [1] [2] [3] .

Evidence about pulmonary function tests, after discharge, among COVID-19 patients is currently limited to little retrospective studies with small samples: a reduction of FVC after 6 week from discharge on 13 patients [4] , reduction of D LCO , TLC, 6MWT in severe COVID-19 compared to nonsevere COVID-19 at 30 days and impairment in respiratory muscle strength in more than half of the subjects [5] and reduction of TLC, FEV1, FVC, D LCO and small airway function at 3 months in a small number of patients were reported [7] . In all studies, a reduction of D LCO was denoted but not in D LCO /VA, this finding was related to the reduction of alveolar volume without residual interstitial abnormalities or pulmonary vascular abnormalities [14] .

The proposed pathogenic mechanism assumes an initial damage induced by COVID-19, similar to the one induced by SARS, due to a microvascular injury with initial interstitial thickening with clear lungs on radiology exams along with a profound hypoxaemia [15, 16] , followed by the development of alveolar damages inducing a gradual loss of the alveolar spaces [16] . The decreased alveolar volume may be explained by temporary changes in mechanical properties of the chest wall and respiratory muscles after critical illness and are supposed to encompass a possible long lasting pulmonary parenchymal dysfunction post-COVID-19 [17] .

Our study is, at our knowledge, the first with a large sample on this argument. Our results show a reduction of respiratory functions and exercise capacity secondary to SARS-COV-2 pneumonia, mostly in patients who developed ARDS during the acute phase. The severity of pneumonia, assessed with the development of ARDS, the needing of IMV, the worst SpO 2 /FiO 2 ratio and PSI during COVID-19 acuteness, seems to be associated with the reduction of D LCO /VA and secondarily with the reduction of SpO 2 at rest and during the 6MWT, but also impacting on 6MWT distance, HR during 6MWT, MEP, TLC, RV and FVC. Effect on DLCO/VA and 6MWT distance appear to decrease over time. Interestingly, patients without pneumonia compared to patients with pneumonia during COVID-19 showed a more increased SR and RV, but with comparable RV/TLC, describing a possible involvement of lower airway instead of lung parenchyma. Respiratory muscle weakness, as reflected by decreased MIP and MEP, could be due to different factors, such as a myopathy caused by the virus in respiratory muscles, especially in the diaphragm, or could be a possible effect of limited physical activity secondary to the lock down. In IMV patients, the decreased MEP could be explained by the combination of curarization, corticosteroids and lack of spontaneous respiratory movements for several days. P0.1 and P0.1/MIP were significant decreased in pneumonia patients, describing a possible neural drive impairment in these patients. These results appear to be independent from the different prevalence of obesity in the two groups.

The correlation between steroid treatment and dyspnoea scale and some respiratory functional values appear to be independent from pneumonia severity and could reflect the contribute of steroid to viral myopathy through several mechanisms, such as altered electrical excitability of muscle fibres, loss of thick filaments and inhibition of protein synthesis [18] [19] [20] , even if MIP and MEP didn't prove this relation.

Evaluating HRQoL, a reduction of physical health was referred instead a normal mental health was reported despite the long period of isolation and extreme uncertainty during the COVID-19 could have created psychological and mood disturbances.

In conclusion, the reduction of respiratory functions and exercise capacity observed after COVID were more pronounced in patients who developed ARDS or require IMV. In these patients, in order to obtain a rapid restoration of normal functional parameters, respiratory rehabilitation and gradual physical activity seem to be effective tools, as showed in randomized trial on 6-week respiratory rehabilitation, after discharge, that showed improvement in respiratory function (FEV1, TLC, FEV1/FVC, 6MWT and D LCO ), quality of life and anxiety of older patients [6] .

According to these results, patients without pneumonia and without symptoms didn't need any evaluation. DLCO, 6MWT and plethysmography could be avoided in patients without pneumonia, performing only spirometry with bronchodilator responsiveness testing and recommending early resumption of physical activity. On the contrary, in patients who developed ARDS, DLCO, 6MWT and complete spirometry could uncover presence of residual pulmonary and functional impairment, with the need of respiratory rehabilitation and gradual physical activity.

There are several limitations to this study. Firstly, the lack of pulmonary function tests before COVID-19 infection. Secondly, we assessed inspiratory and expiratory muscle strength with mouth pressure, but low values might result from technical difficulties. The functional disability appears out of proportion to the degree of lung function impairment and may be due to additional factors such as muscle deconditioning and steroid myopathy. Lastly, the lack of correlation between pulmonary function and radiological signs.

Our study will provide another prospective evaluation after 12 months to better understand the respiratory long term sequelae of SARS-COV-2 disease. Long term follow-up studies are needed to better understand the impact of SARS-COV-2 on human pathophysiology.

Patients with a worst lung involvement during SARS-COV-2 infection showed impaired pulmonary function test parameters and 6MWT SpO 2 values 4 months after the acuteness. Clinical and instrumental long-term check on these patients is advisable, enabling a respiratory rehabilitation course aimed at respirational recovery. 

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SpO 2 partial Oxygen Saturation, FiO 2 Fraction of Inspired Oxygen, PSI Pneumonia Severity Index, CRP C-reactive protein

DBP Diastolic Blood Pressure, CR10 Borg Category-Ratio scale, RPE Rate of Perceived Exertion, mMRC modified Medical Research Council, 6MWT 6-Minute Walking Test, MVV Maximal Ventilatory Ventilation, MIP Maximal Inspiratory Pressure, MEP Maximal Expiratory Pressure, P0.1 airway occlusion Pressure after 0.1s, D LCO Lung Capacity for Carbon Monoxide, VA Alveolar volume, SR Specific airway Resistance, RV Residual Volume, TLC Total Lung Capacity, FEV1 Forced Expiratory Volume in the first second, FVC Forced Vital Capacity, PEF Peak Expiratory Flow, MEF Maximum Expiratory Flows at different lung volume levels

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