Pulmonary function trajectories in COVID-19 survivors with- and without pre-existing respiratory disease at three and twelve months after hospital discharge

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Beijers, Roel van Zeeland, Vivian van Kampen-van den Boogaart, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3875380/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract A significant proportion of COVID-19 survivors still experience a reduced diffusion capacity three and twelve months after discharge. We aimed to compare pulmonary function trajectories between hospitalized COVID-19 patients with pre-existing respiratory disease (PRD) and patients without pre-existing respiratory disease (Non-PRD) at three and twelve months after hospital discharge. This single-centre retrospective cohort study included COVID-19 patients admitted to the VieCuriMedical Centre (Venlo, the Netherlands) between February and December 2020 that were invited to the outpatient clinic at three and twelve months after discharge. During this visit, pulmonary function tests were performed and impairments were based on lower limit of normal. Data of 239 patients were analysed (65% male, 66±10 years, and 26% with a history of respiratory disease). Three months after discharge, 49% and 64% of the Non-PRD patients (n=177) and PRD patients (n=62) had a low diffusion capacity, respectively. This improved over time in Non-PRD patients ( p =0.003), but not in PRD patients ( p =0.250). A low diffusion capacity was still observed in 34% and 57% of the Non-PRD and PRD group, respectively, twelve months after discharge. Pulmonary function impairments, mainly a reduced diffusion capacity, are observed among hospitalized COVID-19 patients with PRD and Non-PRD, at three and twelve months follow-up. Although diffusion capacity impairments restore over time in Non-PRD patients, poor recovery was observed among PRD patients. Health sciences/Diseases/Respiratory tract diseases Health sciences/Medical research/Epidemiology Figures Figure 1 Figure 2 Figure 3 Introduction Since the onset of the COVID-19 pandemic in December 2019, 772 million confirmed COVID-19 cases have been reported worldwide according to the World Health Organization (WHO) [ 1 ]. Within the Netherlands, 6.6 million cases have been confirmed until March 2023, from which around 9% of the people required hospitalization during the acute COVID-19 phase, thereby placing an immense burden on hospitals and health care systems [ 2 ]. Hospitalized COVID-19 patients most commonly presented symptoms such as fever, fatigue, cough, and dyspnoea, leading to the need of oxygen therapies and sometimes even admission to intensive care units (ICUs) during hospitalization [ 3 , 4 ]. While part of the patients recovers during the acute phase (within four weeks), half of the hospitalized COVID-19 patients still experience symptoms three months after the acute infection [ 5 ]. This feature of ongoing symptoms is often defined as long COVID or Post COVID-19 condition [ 5 ]. The most common persisting symptoms reported by COVID-19 survivors three months after discharge include fatigue, dyspnoea, and sleep- and memory problems [ 5 ]. Even one year after infection, one-third of the hospitalized COVID-19 patients is not feeling fully recovered and experiences symptoms such as fatigue, muscle weakness, poor sleep, memory- and concentration problems, and breathlessness [ 6 , 7 ], which largely impacts the health-related quality of life of these patients [ 8 ]. Some symptoms associated with the post COVID-19 condition have been found to be related to impairments in pulmonary function [ 8 , 9 ]. Long-term pulmonary function impairments mainly include a reduced diffusion capacity, which has been reported in up to 52–56% of the hospitalized COVID-19 patients three months after discharge [ 10 – 12 ]. A large prospective cohort study shows that even one year after discharge, persistent pulmonary function damage, i.e. abnormal diffusion capacity and declined total lung capacity (TLC), are reported in 39% and 42% of the COVID-19 survivors, respectively [ 13 ]. Although in the majority of the patients, these pulmonary function impairments improve over time, still one-third of the COVID-19 patients that were hospitalized during the acute phase of the infection have a reduced diffusion capacity one year later [ 14 ]. Acute disease severity, female gender, and the presence of co-morbidities including chronic respiratory disease, diabetes, and hypertension were associated with worse long-term pulmonary function outcomes in hospitalized COVID-19 patients [ 10 , 13 , 14 ]. Next to the changes in static lung volumes and gas exchange function, impairments in respiratory muscle function have been reported among hospitalized and non-hospitalized COVID-19 patients [ 15 – 17 ]. More specifically, a large retrospective study has revealed significant reductions in inspiratory muscle strength in non-hospitalized COVID-19 patients at three months follow-up [ 15 ]. Hereby, they also found a strong association between a decreased inspiratory muscle strength and a higher dyspnoea sensation [ 15 ]. Accordingly, in a cohort of hospitalized COVID-19 patients, 88% of the survivors experienced a reduced inspiratory muscle strength approximately five months after the acute infection [ 16 ]. These findings indicate respiratory muscle dysfunction in post COVID-19 patients, which may be attributed to impairments in respiratory muscle contractibility [ 18 ]. Especially in patients with already compromised respiratory muscle contractibility and decreased pulmonary function, as in chronic obstructive pulmonary disease (COPD) and asthma, it is important to monitor long-term changes in pulmonary function since they might be more susceptible for additional pulmonary impairments after a SARS-CoV-2 infection [ 18 , 19 ]. However, current data is lacking on the long-term pulmonary function changes in a large cohort of hospitalized COVID-19 patients that distinguishes between patients with- and without pre-existing respiratory disease. The aim of this study is therefore to compare pulmonary function trajectories between hospitalized COVID-19 patients with pre-existing respiratory disease (PRD) and patients without pre-existing respiratory disease (Non-PRD) at three and twelve months after hospital discharge. Methods Study design and population This single-centre retrospective cohort study included all COVID-19 patients admitted to the VieCuri Medical Centre in Venlo, the Netherlands, in the first (between February and June 2020) and second wave (between July and December 2020) of the COVID-19 pandemic. Patients were eligible for inclusion in this study if they were hospitalized with a confirmed SARS-CoV-2 infection based on positive reverse transcription polymerase chain reaction, visited the post COVID-19 aftercare program three and twelve months after hospital discharge, and were aged above 18 years. After hospital discharge, all patients were invited at the multidisciplinary COVID-19 aftercare program for evaluation by the departments of Internal Medicine and Pulmonology at three months follow-up. The aftercare program included amongst others of a pulmonary function test. Based on the clinical outcomes retrieved during the outpatient clinic visit at three months, patients were referred to a specialist if necessary. A standardized follow-up visit at twelve months was planned for patients that experienced symptoms at three months follow-up, while the twelve months follow-up visit was facultative for patients who did not experience symptoms anymore. In case patients did not visit the outpatient clinic, reasons for not visiting were retrieved from the electronic medical records. According to the medical ethics committee of Maastricht University Medical Centre+, the current study is beyond the scope of the Medical Research Involving Human Subjects Act (WMO) (2021–3059). Informed consent for all patients was waived due to the retrospective approach of the study and the exceptional circumstances related to the COVID-19 crisis in accordance with the national guidelines and European privacy law. Data collection Baseline and hospitalization characteristics were collected during the acute COVID-19 phase defined as the time between hospital admission and discharge. Pulmonary function tests were performed during the outpatient clinic visits at three and twelve months follow-up. A detailed description of data collection and pulmonary function assessment procedures are provided in the supplemental material (see Supplementary 1). Statistical analysis For comparison of patient characteristics and pulmonary function outcomes between the PRD and Non-PRD group, a Chi-Square test was calculated and an independent samples T-test or Mann-Whitney U-test as appropriate. To compare pulmonary function outcomes between three and twelve months, a paired samples T-test or a Wilcoxon sign rank test was used as appropriate. A McNemar test was performed to assess significant changes over time for dichotomous variables (under/above lower limit of normal (LLN)). Analyses were performed using IBM SPSS statistics, version 28. A p- value < 0.05 was considered statistically significant. Results Patient characteristics In total, 624 patients were hospitalized during the first and second wave at the VieCuri Medical Centre, of which 169 patients died before the three months follow-up assessment (see Fig. 1 ). Eventually, 347 out of the 387 patients who survived and could have attended the outpatient clinic (90%) had a three months follow-up assessment, with 332 patients also completing the pulmonary function assessment. Ninety-three patients did not complete the pulmonary function assessment at twelve months with the main reason that they felt fully recovered. Consequently, 239 patients had a pulmonary function assessment at three and twelve months, and were included for analyses in this study. The mean age of the study group was 66 years with the majority being male (65%) of whom 62 (26%) had PRD (see Table 1 ). The most frequently reported co-morbidities were hypertension (47%), obesity (31%), and diabetes (31%). Median length of hospital stay was 7 days (4–14) and 20% of the patients had been admitted to the ICU with a median stay of 12 days (5–34). Time between discharge and three and twelve months follow-up was 110 days (96–132) and 384 days (353–422), respectively. Of the 239 patients, 213 (89%) received nasal oxygen therapy during hospitalization. No differences were observed in patient and hospitalization characteristics between PRD and Non-PRD patients. Baseline characteristics of the 93 excluded patients compared to the 239 included patients are provided in the supplemental material (see Supplementary 2; Table S1 ). Table 1 Patient characteristics of the hospitalized COVID-19 patients with both three and twelve months pulmonary function assessment for the total group and stratified by PRD. Patient characteristics Total (n = 239) PRD patients (n = 62) Non-PRD patients (n = 177) p -value Waves First Second 159 (67) 80 (33) 39 (63) 23 (37) 120 (68) 57 (32) 0.482 Age in years 66 ± 10 68 ± 10 66 ± 10 0.199 Male 155 (65) 42 (68) 113 (64) 0.580 BMI in kg/m 2 28 ± 4.7 28 ± 3.9 29 ± 5.0 0.481 BMI categories 0.596 Normal weight (18.5–24.9 kg/m²) 53 (22) 15 (24) 38 (22) Overweight (25.0-29.9 kg/m²) 110 (47) 31 (50) 79 (45) Obese (≥ 30.0 kg/m²) 73 (31) 16 (26) 57 (33) Co-morbidities Hypertension 112 (47) 32 (52) 80 (45) 0.635 Type 2 diabetes 73 (31) 21 (34) 52 (29) 0.565 Obesity 73 (31) 16 (26) 57 (33) 0.428 Chronic cardiac disease 56 (23) 15 (24) 41 (23) 0.937 Chronic respiratory disease 62 (26) - - - Chronic kidney disease 24 (10) 6 (10) 18 (10) 0.992 Chronic neurologic disease 22 (9) 8 (13) 14 (8) 0.403 Rheumatologic disorder 29 (12) 7 (11) 22 (12) 0.936 Autoimmune disorder 27 (11) 6 (10) 21 (12) 0.525 Malignant neoplasma 21 (9) 7 (11) 14 (8) 0.681 CCI score a 3 (2–4) 4 (2–5) 3 (2–4) - Hospital stay Days from onset to admission a 8 (7–12) 8 (6–13) 8 (7–12) 0.825 Days from admission to discharge a 7 (4–14) 7 (4–13) 7 (5–14) 0.736 ICU admission 48 (20) 10 (16) 38 (22) 0.366 Length of ICU stay in days a 12 (5–34) 8 (4–26) 13 (9–37) 0.098 Days from discharge to three months FU a 110 (96–132) 104 (94–123) 111 (96–134) 0.096 Days from discharge to twelve months FU a 384 (353–422) 384 (360–416) 384 (352–426) 0.985 Oxygen treatments during hospital stay Nasal oxygen therapy 213 (89) 53 (86) 160 (90) 0.285 Non-invasive ventilation 10 (4) 2 (3) 8 (5) 0.785 Invasive ventilation 39 (16) 6 (10) 33 (19) 0.067 Table 1 legend : Data are shown as median ± SD or n (%) unless indicated otherwise. a Median (IQR). Abbreviations: BMI, body mass index; CCI, charlson co-morbidity index; FU, follow-up; ICU, intensive care unit; PRD, pre-existing respiratory disease. Pulmonary function outcomes at three months In the Non-PRD group, lowest percentage of predicted of 76% (64–89) was seen for diffusion capacity of the lungs (DLCO) (see Fig. 2 a). Median DLCO was also lowest in the PRD group (63% (56–87); see Fig. 2 b), and this was lower than the Non-PRD group ( p = 0.003). Most prevalent pulmonary function impairments were found for DLCO (49%), TLC (28%), RV (28%), and MEP (24%) in Non-PRD patients (see Fig. 2 a). In PRD patients, 64%, 14%, 17%, and 19% showed an impaired DLCO, TLC, RV, and MEP (see Fig. 2 b), respectively, which was not different compared to the Non-PRD patients ( p > 0.05). Pulmonary function changes between three and twelve months In PRD and Non-PRD patients with an impaired TLC at three months, increments over time were seen in TLC of 15% (11–32) and 4% (0–12) ( p = 0.009 and p < 0.001, respectively; see Fig. 3 a). The increment in TLC was larger in the PRD group than the Non-PRD group ( p = 0.034). In patients with a normal TLC at three months, no difference over time was observed in TLC in the PRD group (1% (-1-4); p = 0.108), while a small increase of TLC was observed in the Non-PRD group (3% (0–8); p < 0.001). An increase in DLCO of 13% (4–25) was seen in Non-PRD patients with an abnormal DLCO at three months ( p < 0.001; see Fig. 3 b). This was higher compared to the PRD patients with an impaired DLCO at three months ( p = 0.032), in which only small increments over time were observed (3% (-7-14); p = 0.088). Patients with a normal DLCO at three months showed increments over time in DLCO in the PRD and Non-PRD group (3% (-1-13); p = 0.041 and 4% (0–9); p = 0.006, respectively). Overall, DLCO percentage of predicted increased over time in the Non-PRD group ( p < 0.001), but still remained lowest at twelve months (81% (70–91); see Fig. 2 a). In the PRD group, median DLCO also increased over time to 65% (56–87) at twelve months ( p = 0.008; see Fig. 2 b), but was still lower than the Non-PRD group ( p = 0.002). Over time, DLCO and TLC impairments decreased to 34% and 19% in Non-PRD patients at twelve months, respectively ( p 0.05). In PRD patients, DLCO, TLC, RV, and MEP impairments were still present in 57%, 5%, 14%, and 24% at twelve months, respectively ( p > 0.05; see Fig. 2 b). DLCO impairments were higher in the PRD group compared to the Non-PRD group at twelve months ( p = 0.012), while TLC abnormalities were more frequently seen in Non-PRD patients than PRD patients ( p = 0.025). Discussion This study shows that pulmonary function abnormalities, mainly a reduced DLCO, are seen in two-third and half of the hospitalized COVID-19 patients with PRD and Non-PRD, respectively, three months after discharge. Over time, DLCO impairments decreased to one third in the Non-PRD group, whereas no changes were observed in the PRD group with still two-third of the patients experiencing a reduced DLCO twelve months after discharge. Results of the current study confirm previous research showing that DLCO abnormalities are the most frequently observed long-term pulmonary function impairment among hospitalized COVID-19 patients [ 8 ]. Although DLCO impairments mostly restore over time in Non-PRD patients [ 14 , 20 , 21 ], our cohort of PRD patients did not show improvements in DLCO abnormalities over time. These patients might already have an impaired DLCO caused by the pathological characteristics of their underlying disease including emphysema and pulmonary hypertension, which are known to negatively influence the diffusion capacity of the lungs [ 22 , 23 ]. Accordingly, in PRD patients with an abnormal DLCO at three months, only a small increase in DLCO (3%) was seen over time, while a larger improvement (13%) was noticed among Non-PRD patients. The exact pathophysiological mechanism behind these pulmonary function impairments post COVID-19 remains to be elucidated but prolonged systemic inflammation and (pulmonary) vascular damage have been proposed [ 24 , 25 ]. Furthermore, protracted inflammation caused by the SARS-CoV-2 infection along with the already pro-inflammatory state of the lungs as seen in COPD could potentially explain the poor recovery in PRD patients [ 23 ]. Reduced lung volumes are also frequently reported among post COVID-19 patients [ 8 ]. Accordingly, in our cohort of Non-PRD patients, 28% demonstrated a reduced TLC and RV three months after discharge, which was still present in 19% and 24%, respectively, twelve months after discharge, thereby indicating a restrictive pattern in COVID-19 survivors similar to other corona-virus induced-syndromes [ 26 ]. In contrast, a reduced TLC (5%) was less present in PRD patients at twelve months follow-up. This could be explained due to the fact that in obstructive pulmonary diseases such as COPD, increments in TLC are usually observed due to the loss of elastic recoil in the lungs, thereby reflecting hyperinflation, which subsequently results in less patients falling below LLN in the PRD group [ 27 ]. Respiratory muscle dysfunction might play a key role in the changed lung volumes among COVID-19 survivors. Several mechanisms have been hypothesized via which a SARS-CoV-2 infection may affect respiratory muscle performance such as by reducing respiratory muscle contractibility and by paralysis of the unilateral diaphragm [ 28 , 29 ]. We found that an impaired MEP was still noted in 24% and 21% of the PRD and Non-PRD patients at twelve months, respectively, which was not improved over time in both groups. Respiratory muscle weakness is also a main feature among patients with COPD and this is known to contribute to the high levels of dyspnoea in these patients [ 30 , 31 ]. Since it has become apparent that COVID-19 may cause damage to the respiratory muscles, this has also been proposed as one of the main factors leading to prolonged respiratory complications in post COVID-19 patients [ 28 ]. The poor recovery in pulmonary function impairments, especially in DLCO, is concerning in PRD patients, since it is known that DLCO impairments are associated with an increased all-cause mortality risk and decreased health-related quality of life in patients with COPD [ 32 , 33 ]. Zhang et al. (2022) was the first study to describe lung function trajectories in post COVID-19 patients up to two years after infection. They showed improvements in pulmonary function outcomes during the first year after infection, as in line with our results in Non-PRD patients, but an alarming declining trend was found during the second year [ 34 ]. This highlights the urgent need for longer-term follow-up measurements beyond one year to monitor the exact trajectory of pulmonary function patterns in post COVID-19 patients. This study has several limitations. First, the lack of data on pulmonary function outcomes before the SARS-CoV-2 infection makes it difficult to establish any causality. Secondly, we only included patients with three and twelve months follow-up data which has led to some overestimation of the pulmonary function impairments, since DLCO abnormalities were less present in PRD and non-PRD patients with only three months follow-up data (52% and 35%, respectively). Lastly, this study only selected hospitalized patients in the first and second wave of the pandemic, which makes the generalizability of our results less for the latter waves of the pandemic and for non-hospitalized post COVID-19 patients. However, the results give a reliable representation of the long-term pulmonary function outcomes in COVID-19 survivors from both general ward and ICU using real-world data from clinical practice, with the unique aspect of distinguishing between PRD and Non-PRD patients. This gave us the opportunity to acknowledge a highly vulnerable patient population. In conclusion, this study shows that pulmonary function impairments, mainly a reduced DLCO, are observed in PRD and Non-PRD hospitalized COVID-19 patients at three and twelve months follow-up. Although DLCO impairments restore over time in Non-PRD patients, poor recovery was noted among PRD patients. Future longitudinal studies with longer follow-up periods beyond one year are needed to unveil the precise pattern of respiratory complications in post COVID-19 patients with- and without PRD, which may subsequently contribute to personalized disease management in the future. Declarations Acknowledgements The authors would like to thank all clinical physicians of the COVID-19 outpatient clinic at the VieCuri Medical Centre for their time and effort. Author contributions D.G.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing; R.J.H.C.G.G.: Conceptualization, Investigation, Methodology, Supervision, Visualization, Writing – review & editing; R.V.Z.: Investigation, Resources, Writing – review & editing; V.V.K.V.D.B.: Investigation, Resources, Writing – review & editing; R.P.: Investigation, Methodology, Writing – review & editing; A.M.W.J.S.: Conceptualization, Investigation, Methodology, Supervision, Visualization, Writing – review & editing; J.P.V.D.B.: Conceptualization, Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing; F.H.M.V.O.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing – review & editing. Conflicts of interest All authors have no conflicts of interest related to this work. Data availability statement Datasets and scripts used in this study are available from the corresponding author upon request. Human ethics approval declaration According to the medical ethics committee of Maastricht University Medical Centre+, the current study is beyond the scope of the Medical Research Involving Human Subjects Act (WMO) (2021-3059). Informed consent for all patients was waived due to the retrospective approach of the study and the exceptional circumstances related to the COVID-19 crisis in accordance with Dutch AVG (GDPR) guidelines (Article 47). All methods were carried out according to the research guidelines and regulations of the VieCuri Medical Centre. Financial support This research was supported by the VieCuri Corona Foundation and Regio Noord-Limburg. These funding sources had no role in the study design, collection, analysis and interpretation of data, writing of the report, and in the decision to submit the article for publication. References WHO. 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Supplementary Files Paperpulmonaryfunction3and12monthsScientificReportssupplement.docx Cite Share Download PDF Status: Published Journal Publication published 17 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 20 Jun, 2024 Reviews received at journal 10 Jun, 2024 Reviewers agreed at journal 10 Jun, 2024 Reviews received at journal 01 May, 2024 Reviewers agreed at journal 15 Apr, 2024 Reviewers invited by journal 30 Jan, 2024 Editor assigned by journal 30 Jan, 2024 Editor invited by journal 23 Jan, 2024 Submission checks completed at journal 23 Jan, 2024 First submitted to journal 18 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3875380","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":268962484,"identity":"da661761-cf93-440e-9eb2-5385d7bdce63","order_by":0,"name":"Debbie Gach","email":"","orcid":"","institution":"NUTRIM, Institute for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Department of Respiratory Medicine, Maastricht","correspondingAuthor":false,"prefix":"","firstName":"Debbie","middleName":"","lastName":"Gach","suffix":""},{"id":268962485,"identity":"f16f3e48-bd3d-4a03-977b-3f25b43359d7","order_by":1,"name":"Rosanne J.H.C.G. Beijers","email":"","orcid":"","institution":"NUTRIM, Institute for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Department of Respiratory Medicine, Maastricht","correspondingAuthor":false,"prefix":"","firstName":"Rosanne","middleName":"J.H.C.G.","lastName":"Beijers","suffix":""},{"id":268962486,"identity":"e52a21a1-07d4-475d-9795-251a5fd46658","order_by":2,"name":"Roel van Zeeland","email":"","orcid":"","institution":"VieCuri Medical Centre, Department of Respiratory Medicine, Venlo","correspondingAuthor":false,"prefix":"","firstName":"Roel","middleName":"van","lastName":"Zeeland","suffix":""},{"id":268962487,"identity":"03f6c785-fb81-472a-81b8-5aab1238a677","order_by":3,"name":"Vivian van Kampen-van den Boogaart","email":"","orcid":"","institution":"VieCuri Medical Centre, Department of Respiratory Medicine, Venlo","correspondingAuthor":false,"prefix":"","firstName":"Vivian","middleName":"van Kampen-van den","lastName":"Boogaart","suffix":""},{"id":268962488,"identity":"d291b0d0-832b-4013-8d3d-8d16349152bd","order_by":4,"name":"Rein Posthuma","email":"","orcid":"","institution":"NUTRIM, Institute for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Department of Respiratory Medicine, Maastricht","correspondingAuthor":false,"prefix":"","firstName":"Rein","middleName":"","lastName":"Posthuma","suffix":""},{"id":268962489,"identity":"689ededd-319a-4692-8cdd-c28d18f7dbdd","order_by":5,"name":"Annemie M.W.J. Schols","email":"","orcid":"","institution":"NUTRIM, Institute for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Department of Respiratory Medicine, Maastricht","correspondingAuthor":false,"prefix":"","firstName":"Annemie","middleName":"M.W.J.","lastName":"Schols","suffix":""},{"id":268962490,"identity":"4f5358c9-9d2a-438d-9a29-32a201e58d8c","order_by":6,"name":"Joop P. van den Bergh","email":"","orcid":"","institution":"VieCuri Medical Centre, Department of Internal Medicine, Venlo","correspondingAuthor":false,"prefix":"","firstName":"Joop","middleName":"P. van den","lastName":"Bergh","suffix":""},{"id":268962491,"identity":"59e46ac5-8fd6-4b4a-a918-8ffbb34a9667","order_by":7,"name":"Frits H.M. van Osch","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYBAC9gYgwdhgw8AG5howMPAR0sJzAKwlDaGFjUgthxEihLVIJB/+8HPH+cQ+9uZn0hUFDHlEaElLk+w9czuxjeeYmeQZA4Ziglrsec6YMTO23TZmk8hhk2wwYEhsI2gLzxnjz4xt54zZ5N8Qq4W9x0Case2AHJsED9Fa2oB+aUuWY+NJM7ZsMJAgQgszMzDE2ux45NsPP7zZ8McmsZ+QFnQgQaqGUTAKRsEoGAXYAADbFDM16YwzwgAAAABJRU5ErkJggg==","orcid":"","institution":"VieCuri Medical Centre, Department of Clinical Epidemiology, Venlo","correspondingAuthor":true,"prefix":"","firstName":"Frits","middleName":"H.M. van","lastName":"Osch","suffix":""}],"badges":[],"createdAt":"2024-01-18 09:44:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3875380/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3875380/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-67314-0","type":"published","date":"2024-07-17T16:13:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50173441,"identity":"702152c8-6866-4108-b518-6925b6b8124a","added_by":"auto","created_at":"2024-01-25 16:00:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1779704,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the (included) study population.\u003c/p\u003e","description":"","filename":"Figure1Flowchartoftheincludedstudypopulation.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3875380/v1/47d790007881378ad6193995.jpg"},{"id":50173443,"identity":"2708daf9-e045-44c8-8773-c334345bb4fe","added_by":"auto","created_at":"2024-01-25 16:00:56","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2684711,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eab\u003c/strong\u003e. Pulmonary function of the hospitalized COVID-19 patients with both three and twelve months pulmonary function assessment and stratified by PRD.\u003c/p\u003e\n\u003cp\u003eData are shown as median (IQR) for continuous variables and n (%) for categorical variables. \u003csup\u003e*\u003c/sup\u003eIndicates a significant difference between three and twelve months follow-up,\u003cem\u003e p\u003c/em\u003e\u0026lt;0.05. Abbreviations: DLCO, diffusing capacity of the lungs for carbon monoxide; FEV\u003csub\u003e1\u003c/sub\u003e, forced expiratory volume in 1 second; FVC, forced vital capacity; MEP, maximum expiratory pressure; MIP, maximum inspiratory pressure; RV, residual volume; TLC, total lung capacity; VA, alveolar volume; VCmax, maximum vital capacity.\u003c/p\u003e","description":"","filename":"Figure2ABPulmonaryfunction.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3875380/v1/5ca683dfa14e56fbf9b20612.jpg"},{"id":50174330,"identity":"65f29418-da20-4da6-8281-106260a44fd4","added_by":"auto","created_at":"2024-01-25 16:08:56","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1401808,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eab\u003c/strong\u003e. Pulmonary function changes in TLC (A) and DLCO (B) of the hospitalized COVID-19 patients with both three and twelve months pulmonary function assessment and stratified by PRD as well as below/above LLN at three months follow-up.\u003c/p\u003e\n\u003cp\u003eData are shown as median (IQR). \u003csup\u003e*\u003c/sup\u003eIndicates a significant difference between the PRD and Non-PRD group,\u003cem\u003e p\u003c/em\u003e\u0026lt;0.05. \u003csup\u003e#\u003c/sup\u003eIndicates a significant difference between three and twelve months follow-up,\u003cem\u003e p\u003c/em\u003e\u0026lt;0.05. Abbreviations: DLCO, diffusing capacity of the lungs for carbon monoxide; LLN, lower limit of normal; PRD, pre-existing respiratory disease; TLC, total lung capacity.\u003c/p\u003e","description":"","filename":"Figure3ABPulmonaryfunctionchanges.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3875380/v1/8b9d24dbcb0586789e303bc7.jpg"},{"id":61595315,"identity":"2a347ca7-57b0-4bd7-a451-d01dd480c52b","added_by":"auto","created_at":"2024-08-01 17:22:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1793312,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3875380/v1/250317a8-9fb4-4d79-9723-44064e679248.pdf"},{"id":50173444,"identity":"5b6624bd-30ac-4eef-a57e-31f9f2622975","added_by":"auto","created_at":"2024-01-25 16:00:56","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":31032,"visible":true,"origin":"","legend":"","description":"","filename":"Paperpulmonaryfunction3and12monthsScientificReportssupplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-3875380/v1/761e652afe96335ebd7e36b8.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pulmonary function trajectories in COVID-19 survivors with- and without pre-existing respiratory disease at three and twelve months after hospital discharge","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince the onset of the COVID-19 pandemic in December 2019, 772\u0026nbsp;million confirmed COVID-19 cases have been reported worldwide according to the World Health Organization (WHO) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Within the Netherlands, 6.6\u0026nbsp;million cases have been confirmed until March 2023, from which around 9% of the people required hospitalization during the acute COVID-19 phase, thereby placing an immense burden on hospitals and health care systems [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hospitalized COVID-19 patients most commonly presented symptoms such as fever, fatigue, cough, and dyspnoea, leading to the need of oxygen therapies and sometimes even admission to intensive care units (ICUs) during hospitalization [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile part of the patients recovers during the acute phase (within four weeks), half of the hospitalized COVID-19 patients still experience symptoms three months after the acute infection [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This feature of ongoing symptoms is often defined as long COVID or Post COVID-19 condition [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The most common persisting symptoms reported by COVID-19 survivors three months after discharge include fatigue, dyspnoea, and sleep- and memory problems [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Even one year after infection, one-third of the hospitalized COVID-19 patients is not feeling fully recovered and experiences symptoms such as fatigue, muscle weakness, poor sleep, memory- and concentration problems, and breathlessness [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], which largely impacts the health-related quality of life of these patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome symptoms associated with the post COVID-19 condition have been found to be related to impairments in pulmonary function [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Long-term pulmonary function impairments mainly include a reduced diffusion capacity, which has been reported in up to 52\u0026ndash;56% of the hospitalized COVID-19 patients three months after discharge [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A large prospective cohort study shows that even one year after discharge, persistent pulmonary function damage, i.e. abnormal diffusion capacity and declined total lung capacity (TLC), are reported in 39% and 42% of the COVID-19 survivors, respectively [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although in the majority of the patients, these pulmonary function impairments improve over time, still one-third of the COVID-19 patients that were hospitalized during the acute phase of the infection have a reduced diffusion capacity one year later [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Acute disease severity, female gender, and the presence of co-morbidities including chronic respiratory disease, diabetes, and hypertension were associated with worse long-term pulmonary function outcomes in hospitalized COVID-19 patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Next to the changes in static lung volumes and gas exchange function, impairments in respiratory muscle function have been reported among hospitalized and non-hospitalized COVID-19 patients [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. More specifically, a large retrospective study has revealed significant reductions in inspiratory muscle strength in non-hospitalized COVID-19 patients at three months follow-up [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Hereby, they also found a strong association between a decreased inspiratory muscle strength and a higher dyspnoea sensation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Accordingly, in a cohort of hospitalized COVID-19 patients, 88% of the survivors experienced a reduced inspiratory muscle strength approximately five months after the acute infection [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These findings indicate respiratory muscle dysfunction in post COVID-19 patients, which may be attributed to impairments in respiratory muscle contractibility [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEspecially in patients with already compromised respiratory muscle contractibility and decreased pulmonary function, as in chronic obstructive pulmonary disease (COPD) and asthma, it is important to monitor long-term changes in pulmonary function since they might be more susceptible for additional pulmonary impairments after a SARS-CoV-2 infection [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, current data is lacking on the long-term pulmonary function changes in a large cohort of hospitalized COVID-19 patients that distinguishes between patients with- and without pre-existing respiratory disease. The aim of this study is therefore to compare pulmonary function trajectories between hospitalized COVID-19 patients with pre-existing respiratory disease (PRD) and patients without pre-existing respiratory disease (Non-PRD) at three and twelve months after hospital discharge.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eThis single-centre retrospective cohort study included all COVID-19 patients admitted to the VieCuri Medical Centre in Venlo, the Netherlands, in the first (between February and June 2020) and second wave (between July and December 2020) of the COVID-19 pandemic. Patients were eligible for inclusion in this study if they were hospitalized with a confirmed SARS-CoV-2 infection based on positive reverse transcription polymerase chain reaction, visited the post COVID-19 aftercare program three and twelve months after hospital discharge, and were aged above 18 years.\u003c/p\u003e \u003cp\u003eAfter hospital discharge, all patients were invited at the multidisciplinary COVID-19 aftercare program for evaluation by the departments of Internal Medicine and Pulmonology at three months follow-up. The aftercare program included amongst others of a pulmonary function test. Based on the clinical outcomes retrieved during the outpatient clinic visit at three months, patients were referred to a specialist if necessary. A standardized follow-up visit at twelve months was planned for patients that experienced symptoms at three months follow-up, while the twelve months follow-up visit was facultative for patients who did not experience symptoms anymore. In case patients did not visit the outpatient clinic, reasons for not visiting were retrieved from the electronic medical records.\u003c/p\u003e \u003cp\u003e According to the medical ethics committee of Maastricht University Medical Centre+, the current study is beyond the scope of the Medical Research Involving Human Subjects Act (WMO) (2021\u0026ndash;3059). Informed consent for all patients was waived due to the retrospective approach of the study and the exceptional circumstances related to the COVID-19 crisis in accordance with the national guidelines and European privacy law.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eBaseline and hospitalization characteristics were collected during the acute COVID-19 phase defined as the time between hospital admission and discharge. Pulmonary function tests were performed during the outpatient clinic visits at three and twelve months follow-up. A detailed description of data collection and pulmonary function assessment procedures are provided in the supplemental material (see Supplementary 1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor comparison of patient characteristics and pulmonary function outcomes between the PRD and Non-PRD group, a Chi-Square test was calculated and an independent samples T-test or Mann-Whitney U-test as appropriate. To compare pulmonary function outcomes between three and twelve months, a paired samples T-test or a Wilcoxon sign rank test was used as appropriate. A McNemar test was performed to assess significant changes over time for dichotomous variables (under/above lower limit of normal (LLN)). Analyses were performed using IBM SPSS statistics, version 28. A \u003cem\u003ep-\u003c/em\u003evalue\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eIn total, 624 patients were hospitalized during the first and second wave at the VieCuri Medical Centre, of which 169 patients died before the three months follow-up assessment (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Eventually, 347 out of the 387 patients who survived and could have attended the outpatient clinic (90%) had a three months follow-up assessment, with 332 patients also completing the pulmonary function assessment. Ninety-three patients did not complete the pulmonary function assessment at twelve months with the main reason that they felt fully recovered. Consequently, 239 patients had a pulmonary function assessment at three and twelve months, and were included for analyses in this study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe mean age of the study group was 66 years with the majority being male (65%) of whom 62 (26%) had PRD (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The most frequently reported co-morbidities were hypertension (47%), obesity (31%), and diabetes (31%). Median length of hospital stay was 7 days (4\u0026ndash;14) and 20% of the patients had been admitted to the ICU with a median stay of 12 days (5\u0026ndash;34). Time between discharge and three and twelve months follow-up was 110 days (96\u0026ndash;132) and 384 days (353\u0026ndash;422), respectively. Of the 239 patients, 213 (89%) received nasal oxygen therapy during hospitalization. No differences were observed in patient and hospitalization characteristics between PRD and Non-PRD patients. Baseline characteristics of the 93 excluded patients compared to the 239 included patients are provided in the supplemental material (see Supplementary 2; Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics of the hospitalized COVID-19 patients with both three and twelve months pulmonary function assessment for the total group and stratified by PRD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;239)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePRD\u003c/p\u003e \u003cp\u003epatients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-PRD patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;177)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWaves\u003c/p\u003e \u003cp\u003e\u003cem\u003eFirst\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eSecond\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159 (67)\u003c/p\u003e \u003cp\u003e80 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (63)\u003c/p\u003e \u003cp\u003e23 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e120 (68)\u003c/p\u003e \u003cp\u003e57 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.482\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge in years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e155 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e113 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.580\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI in kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.481\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI categories\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.596\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNormal weight (18.5\u0026ndash;24.9 kg/m\u0026sup2;)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOverweight (25.0-29.9 kg/m\u0026sup2;)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79 (45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eObese (\u0026ge;\u0026thinsp;30.0 kg/m\u0026sup2;)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCo-morbidities\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80 (45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType 2 diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.565\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.428\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic cardiac disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.937\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic respiratory disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e-\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.992\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic neurologic disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatologic disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.936\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAutoimmune disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.525\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignant neoplasma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.681\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCI score\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (2\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHospital stay\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays from onset to admission\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (7\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (6\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (7\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.825\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays from admission to discharge\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (4\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (4\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (5\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.736\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.366\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of ICU stay in days\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (5\u0026ndash;34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (4\u0026ndash;26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (9\u0026ndash;37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays from discharge to three months FU\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110 (96\u0026ndash;132)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104 (94\u0026ndash;123)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e111 (96\u0026ndash;134)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays from discharge to twelve months FU\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e384 (353\u0026ndash;422)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e384 (360\u0026ndash;416)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e384 (352\u0026ndash;426)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.985\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOxygen treatments during hospital stay\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNasal oxygen therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e213 (89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e160 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-invasive ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.785\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003elegend\u003c/b\u003e: Data are shown as median\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or n (%) unless indicated otherwise. \u003csup\u003ea\u003c/sup\u003eMedian (IQR). Abbreviations: BMI, body mass index; CCI, charlson co-morbidity index; FU, follow-up; ICU, intensive care unit; PRD, pre-existing respiratory disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePulmonary function outcomes at three months\u003c/h2\u003e \u003cp\u003eIn the Non-PRD group, lowest percentage of predicted of 76% (64\u0026ndash;89) was seen for diffusion capacity of the lungs (DLCO) (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Median DLCO was also lowest in the PRD group (63% (56\u0026ndash;87); see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb), and this was lower than the Non-PRD group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Most prevalent pulmonary function impairments were found for DLCO (49%), TLC (28%), RV (28%), and MEP (24%) in Non-PRD patients (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). In PRD patients, 64%, 14%, 17%, and 19% showed an impaired DLCO, TLC, RV, and MEP (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb), respectively, which was not different compared to the Non-PRD patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePulmonary function changes between three and twelve months\u003c/h2\u003e \u003cp\u003eIn PRD and Non-PRD patients with an impaired TLC at three months, increments over time were seen in TLC of 15% (11\u0026ndash;32) and 4% (0\u0026ndash;12) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively; see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). The increment in TLC was larger in the PRD group than the Non-PRD group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034). In patients with a normal TLC at three months, no difference over time was observed in TLC in the PRD group (1% (-1-4); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.108), while a small increase of TLC was observed in the Non-PRD group (3% (0\u0026ndash;8); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAn increase in DLCO of 13% (4\u0026ndash;25) was seen in Non-PRD patients with an abnormal DLCO at three months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). This was higher compared to the PRD patients with an impaired DLCO at three months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032), in which only small increments over time were observed (3% (-7-14); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.088). Patients with a normal DLCO at three months showed increments over time in DLCO in the PRD and Non-PRD group (3% (-1-13); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041 and 4% (0\u0026ndash;9); \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006, respectively).\u003c/p\u003e \u003cp\u003eOverall, DLCO percentage of predicted increased over time in the Non-PRD group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but still remained lowest at twelve months (81% (70\u0026ndash;91); see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). In the PRD group, median DLCO also increased over time to 65% (56\u0026ndash;87) at twelve months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008; see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb), but was still lower than the Non-PRD group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). Over time, DLCO and TLC impairments decreased to 34% and 19% in Non-PRD patients at twelve months, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). However, RV and MEP abnormalities were still observed in 24% and 21% at twelve months, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In PRD patients, DLCO, TLC, RV, and MEP impairments were still present in 57%, 5%, 14%, and 24% at twelve months, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05; see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). DLCO impairments were higher in the PRD group compared to the Non-PRD group at twelve months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012), while TLC abnormalities were more frequently seen in Non-PRD patients than PRD patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study shows that pulmonary function abnormalities, mainly a reduced DLCO, are seen in two-third and half of the hospitalized COVID-19 patients with PRD and Non-PRD, respectively, three months after discharge. Over time, DLCO impairments decreased to one third in the Non-PRD group, whereas no changes were observed in the PRD group with still two-third of the patients experiencing a reduced DLCO twelve months after discharge.\u003c/p\u003e \u003cp\u003eResults of the current study confirm previous research showing that DLCO abnormalities are the most frequently observed long-term pulmonary function impairment among hospitalized COVID-19 patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Although DLCO impairments mostly restore over time in Non-PRD patients [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], our cohort of PRD patients did not show improvements in DLCO abnormalities over time. These patients might already have an impaired DLCO caused by the pathological characteristics of their underlying disease including emphysema and pulmonary hypertension, which are known to negatively influence the diffusion capacity of the lungs [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Accordingly, in PRD patients with an abnormal DLCO at three months, only a small increase in DLCO (3%) was seen over time, while a larger improvement (13%) was noticed among Non-PRD patients. The exact pathophysiological mechanism behind these pulmonary function impairments post COVID-19 remains to be elucidated but prolonged systemic inflammation and (pulmonary) vascular damage have been proposed [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Furthermore, protracted inflammation caused by the SARS-CoV-2 infection along with the already pro-inflammatory state of the lungs as seen in COPD could potentially explain the poor recovery in PRD patients [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eReduced lung volumes are also frequently reported among post COVID-19 patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Accordingly, in our cohort of Non-PRD patients, 28% demonstrated a reduced TLC and RV three months after discharge, which was still present in 19% and 24%, respectively, twelve months after discharge, thereby indicating a restrictive pattern in COVID-19 survivors similar to other corona-virus induced-syndromes [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In contrast, a reduced TLC (5%) was less present in PRD patients at twelve months follow-up. This could be explained due to the fact that in obstructive pulmonary diseases such as COPD, increments in TLC are usually observed due to the loss of elastic recoil in the lungs, thereby reflecting hyperinflation, which subsequently results in less patients falling below LLN in the PRD group [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRespiratory muscle dysfunction might play a key role in the changed lung volumes among COVID-19 survivors. Several mechanisms have been hypothesized via which a SARS-CoV-2 infection may affect respiratory muscle performance such as by reducing respiratory muscle contractibility and by paralysis of the unilateral diaphragm [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. We found that an impaired MEP was still noted in 24% and 21% of the PRD and Non-PRD patients at twelve months, respectively, which was not improved over time in both groups. Respiratory muscle weakness is also a main feature among patients with COPD and this is known to contribute to the high levels of dyspnoea in these patients [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Since it has become apparent that COVID-19 may cause damage to the respiratory muscles, this has also been proposed as one of the main factors leading to prolonged respiratory complications in post COVID-19 patients [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe poor recovery in pulmonary function impairments, especially in DLCO, is concerning in PRD patients, since it is known that DLCO impairments are associated with an increased all-cause mortality risk and decreased health-related quality of life in patients with COPD [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Zhang et al. (2022) was the first study to describe lung function trajectories in post COVID-19 patients up to two years after infection. They showed improvements in pulmonary function outcomes during the first year after infection, as in line with our results in Non-PRD patients, but an alarming declining trend was found during the second year [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This highlights the urgent need for longer-term follow-up measurements beyond one year to monitor the exact trajectory of pulmonary function patterns in post COVID-19 patients.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the lack of data on pulmonary function outcomes before the SARS-CoV-2 infection makes it difficult to establish any causality. Secondly, we only included patients with three and twelve months follow-up data which has led to some overestimation of the pulmonary function impairments, since DLCO abnormalities were less present in PRD and non-PRD patients with only three months follow-up data (52% and 35%, respectively). Lastly, this study only selected hospitalized patients in the first and second wave of the pandemic, which makes the generalizability of our results less for the latter waves of the pandemic and for non-hospitalized post COVID-19 patients. However, the results give a reliable representation of the long-term pulmonary function outcomes in COVID-19 survivors from both general ward and ICU using real-world data from clinical practice, with the unique aspect of distinguishing between PRD and Non-PRD patients. This gave us the opportunity to acknowledge a highly vulnerable patient population.\u003c/p\u003e \u003cp\u003eIn conclusion, this study shows that pulmonary function impairments, mainly a reduced DLCO, are observed in PRD and Non-PRD hospitalized COVID-19 patients at three and twelve months follow-up. Although DLCO impairments restore over time in Non-PRD patients, poor recovery was noted among PRD patients. Future longitudinal studies with longer follow-up periods beyond one year are needed to unveil the precise pattern of respiratory complications in post COVID-19 patients with- and without PRD, which may subsequently contribute to personalized disease management in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all clinical physicians of the COVID-19 outpatient clinic at the VieCuri Medical Centre for their time and effort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eD.G.: \u003cem\u003eConceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eR.J.H.C.G.G.:\u0026nbsp;\u003cem\u003eConceptualization, Investigation, Methodology, Supervision, Visualization, Writing \u0026ndash; review \u0026amp; editing;\u003c/em\u003e R.V.Z.:\u003cbr\u003e\u003cem\u003eInvestigation, Resources, Writing \u0026ndash; review \u0026amp; editing;\u003c/em\u003e V.V.K.V.D.B.:\u0026nbsp;\u003cem\u003eInvestigation, Resources, Writing \u0026ndash; review \u0026amp; editing;\u003c/em\u003e R.P.:\u003cbr\u003e\u003cem\u003eInvestigation, Methodology, Writing \u0026ndash; review \u0026amp; editing;\u003c/em\u003e A.M.W.J.S.:\u003cbr\u003e\u003cem\u003eConceptualization, Investigation, Methodology, Supervision, Visualization, Writing \u0026ndash; review \u0026amp; editing;\u003c/em\u003e J.P.V.D.B.:\u003cbr\u003e\u003cem\u003eConceptualization, Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing \u0026ndash; review \u0026amp; editing;\u003c/em\u003e F.H.M.V.O.:\u003cbr\u003e\u003cem\u003eConceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing \u0026ndash; review \u0026amp; editing.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have no conflicts of interest related to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDatasets and scripts used in this study are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman ethics approval declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the medical ethics committee of Maastricht University Medical Centre+, the current study is beyond the scope of the Medical Research Involving Human Subjects Act (WMO) (2021-3059). Informed consent for all patients was waived due to the retrospective approach of the study and the exceptional circumstances related to the COVID-19 crisis in accordance with Dutch AVG (GDPR) guidelines (Article 47). All methods were carried out according to the research guidelines and regulations of the VieCuri Medical Centre.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the VieCuri Corona Foundation and Regio Noord-Limburg. These funding sources had no role in the study design, collection, analysis and interpretation of data, writing of the report, and in the decision to submit the article for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWHO. World Health Organization Coronavirus (COVID-19) Dashboard. https://data.who.int/dashboards/covid19/cases?n=c (2023).\u003c/li\u003e\n\u003cli\u003eRIVM. 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We aimed to compare pulmonary function trajectories between hospitalized COVID-19 patients with pre-existing respiratory disease (PRD) and patients without pre-existing respiratory disease (Non-PRD) at three and twelve months after hospital discharge. This single-centre retrospective cohort study included COVID-19 patients admitted to the VieCuriMedical Centre (Venlo, the Netherlands) between February and December 2020 that were invited to the outpatient clinic at three and twelve months after discharge. During this visit, pulmonary function tests were performed and impairments were based on lower limit of normal. Data of 239 patients were analysed (65% male, 66±10 years, and 26% with a history of respiratory disease). Three months after discharge, 49% and 64% of the Non-PRD patients (n=177) and PRD patients (n=62) had a low diffusion capacity, respectively. This improved over time in Non-PRD patients (\u003cem\u003ep\u003c/em\u003e=0.003), but not in PRD patients (\u003cem\u003ep\u003c/em\u003e=0.250). A low diffusion capacity was still observed in 34% and 57% of the Non-PRD and PRD group, respectively, twelve months after discharge. Pulmonary function impairments, mainly a reduced diffusion capacity, are observed among hospitalized COVID-19 patients with PRD and Non-PRD, at three and twelve months follow-up. Although diffusion capacity impairments restore over time in Non-PRD patients, poor recovery was observed among PRD patients.\u003c/p\u003e","manuscriptTitle":"Pulmonary function trajectories in COVID-19 survivors with- and without pre-existing respiratory disease at three and twelve months after hospital discharge","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-25 16:00:52","doi":"10.21203/rs.3.rs-3875380/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-20T08:51:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-10T20:57:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56820209916786083940816709076436812710","date":"2024-06-10T13:48:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-01T13:36:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"740bc4a4-a5f7-4717-8b01-7a754d28c32a","date":"2024-04-15T19:21:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-31T02:09:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-31T02:03:40+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-01-23T13:44:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-23T13:42:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-01-18T09:35:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7c68564e-7018-4c90-bd63-0c30ab0b644e","owner":[],"postedDate":"January 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28336491,"name":"Health sciences/Diseases/Respiratory tract diseases"},{"id":28336492,"name":"Health sciences/Medical research/Epidemiology"}],"tags":[],"updatedAt":"2024-08-01T16:21:45+00:00","versionOfRecord":{"articleIdentity":"rs-3875380","link":"https://doi.org/10.1038/s41598-024-67314-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-07-17 16:13:22","publishedOnDateReadable":"July 17th, 2024"},"versionCreatedAt":"2024-01-25 16:00:52","video":"","vorDoi":"10.1038/s41598-024-67314-0","vorDoiUrl":"https://doi.org/10.1038/s41598-024-67314-0","workflowStages":[]},"version":"v1","identity":"rs-3875380","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3875380","identity":"rs-3875380","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}