Four-year respiratory consequences of COVID-19 related pneumonia: a longitudinal cohort study

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Methods This study was conducted between March 2020 and June 2020 at University Hospital Doctor Josep Trueta (Girona, Spain). We assessed the patient’s dyspnoea and performed, pulmonary function tests, a high-resolution CT (HRCT), a 6-minute walking test, a blood test, and the Saint George’s respiratory questionnaire 3 months after discharge. At the 6-month, 1-year, and 4-year follow-up, we repeated all tests except for pulmonary function, 6-min walking test, and HRCT, which were only performed if abnormal findings had been previously detected. Results Out of the 94 patients enrolled, 73% were male, the median age was 62.9 years, and most were non-smokers (58%). When comparing data 3 months and 4 years after discharge, the percentage of patients presenting dyspnoea ≥ 2 decreased (19.5% vs 7.9%), the quality-of-life total score improved (22.8% vs 18.1%), diffusing capacity for carbon monoxide improved (75.9% vs 81.4%), the 6-min walking test distance was enhanced (368.0 m vs 436.6 m), ground glass opacities findings waned (56.6% vs 0.8%), and traction bronchiectasis increased (2.7% vs 9.2%). Age was the only parameter that exhibited significant differences between patients with and without pulmonary fibrotic-like changes. Conclusion Most patients, 4 years after discharge, improved their pulmonary function, exercise capacity, clinical condition, and quality of life. Although pulmonary fibrotic-like changes were observed during the follow-ups, its disparity with clinical-functional improvement pointed to non-progressive and non-clinically relevant lung scars. COVID-19 coronavirus disease long-term sequelae pneumonia pulmonary fibrosis pulmonary function Figures Figure 1 Figure 2 Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) declared COVID-19 a global pandemic in March 2020 after realising the high infectivity and virulence of SARS-CoV-2. As of November 2024, this virus has caused more than 777 million confirmed cases and over 7 million deaths worldwide [1]. On 3 May 2023, The WHO developed the COVID-19 Strategic Preparedness and Response Plan for 2023–2025 that emphasises the significance of continuing the monitoring of patients who have overcome the COVID condition [2, 3]. Although several prospective studies have investigated the long-term respiratory consequences after COVID-19 [4–9], these findings have considerably fluctuated by factors such as patient population, disease severity, and evaluation standards, among others. In addition, only limited long-term data is available on developing these respiratory consequences. To date, the most extended follow-up study spans 3 years after discharge from two hospitals in China [9]. In that study, patients with residual lung changes on computed tomography (CT) after COVID-19 hospitalisation exhibited improvements in respiratory outcomes. However, more than one-third continued to have lung abnormalities on CT, which were associated with symptoms and abnormal pulmonary function. During the first wave of the COVID-19 pandemic, about 10–20% of COVID-19 patients developed severe pneumonia, and 20–25% required non-invasive respiratory support therapies (NIRT) [10]. Recently, our group reported the respiratory sequelae up to 12 months after discharge in COVID-19 patients with severe pneumonia requiring NIRT [4]. Although dyspnoea, quality of life, pulmonary function, and exercise capacity improved, fibrotic-like changes during the follow-up were observed in CT. Longitudinal studies are needed to raise awareness of the evolution of lung abnormalities, especially in COVID-19 survivors with a severe initial disease. Therefore, this study aimed to describe, 4 years after discharge, the respiratory consequences of COVID-19 patients with severe pneumonia requiring NIRT and to assess the progression and impact of those changes in the referred patients. Methods Study design We carried out an observational, prospective, single-centre study at the Respiratory Department of the University Hospital Doctor Josep Trueta, Girona, Spain. We collected data from all patients discharged from our department between March 2020 and June 2020 who had severe pneumonia, requiring NIRT, caused by COVID-19 (laboratory-confirmed). We performed the 4-year follow-up up to June 2024. We report our findings in accordance with the STROBE guidelines. Patients The inclusion and exclusion criteria of patients has been described elsewhere [4]. Briefly, we included data from adult patients diagnosed of severe pneumonia caused by SARS-CoV-2 (confirmed by PCR) and who had required NIRT (high-flow nasal cannula, continuous positive airway pressure, or non-invasive ventilation). We excluded data from patients who declined to participate. This cohort included the patients previously participating in a 1-year follow-up study [4]. Procedures We collected the patients’ characteristics and comorbidities from their medical records. We evaluated dyspnoea according to the modified Medical Research Council scale [11]. We also conducted a Saint George’s respiratory questionnaire (SGRQ) [12], pulmonary function tests, a blood test to retrieve the lymphocyte count, a chest high-resolution CT (HRCT), and a 6-min walking test. We performed the pulmonary function tests and the 6-min walking test according to the ATS/ERS guidelines [13] in the Lung Function Laboratory of our Hospital using the Master Screen PFT (Jagger, Germany). We performed the chest HRCT in the supine position during end-inspiration with a multislice CT scanner. Images were reconstructed at 1 mm slice thickness, with 1 mm increment, 512 mm×512 mm. A pulmonologist and a radiologist with clinical experience in chest imaging reviewed separately the CT features. We described the main CT patterns in agreement with the terms defined by the Fleischner Society and peer-reviewed literature on viral pneumonia [14, 15]. CT images were examined for the presence of reticular pattern (curvilinear opacity, coarse linear, or fine subpleural reticulation), parenchymal pattern (ground-glass opacities [GGO] or consolidation), and fibrotic pattern (honeycombing, architectural distortion, or traction bronchiectasis or bronchiolectasis) [15]. We evaluated dyspnoea and performed the SGRQ and the blood test 3 months, 6 months, 1 year, and 4 years after discharge. We performed pulmonary function tests, the 6-min walking test, and the HRCT only in those patients who had shown significant abnormal findings in that specific test at the previous evaluation. Abnormal findings were defined as a diffusing capacity for carbon monoxide (DLCO) or forced vital capacity (FVC) < 80% for pulmonary function tests and a distance walked inferior to the reference described in the Enright criteria [16] for the 6-minute walking test. We also considered relevant any abnormal finding in the chest HRCT and reassessed it in the next evaluation. We treated all patients presenting significant GGO at any follow-up time with prednisone. The GGO in CT images was quantified with a modified, previously published method [9]. Briefly, we divided each lung into three zones: upper (above the carina), middle, and lower (below the inferior pulmonary vein). If more than one zone out of the six defined for both lungs showed signs of GGO, we considered it significant GGO involvement. The initial prednisone regimen was 30 mg/day for 15 days and was gradually tapered between one to two months to 5 mg/day, a dose that was to be maintained until the next follow-up. Then, if a non-significant GGO was achieved, according to an improvement seen in the CT by the clinician, the treatment was interrupted. Statistical analysis Categorical variables were described as absolute numbers and percentages and quantitative variables as mean and standard deviation (SD). We used the Fisher's Exact test to compare categorical variables and the Welch's t-test to compare numerical variables. We used a multivariate logistic model to estimate the adjusted odd ratio (OR) of developing fibrotic-like changes. The candidate variables for adjustment were all available basal variables. We built the final model using the set of variables that maximised the Bayesian Information Criterion. During the follow-up, to account for repeated measures and missing values, we compared periods by fitting linear mixed-effect models using all patients available at baseline. For categorical variables, we present estimations in percentage together with their standard error. We used the likelihood ratio test to assess differences between periods. For quantitative variables, we present estimations with the standard error. We considered the F-test based on the Kenward-Roger approach to compare periods. We did not replace nor inferred missing values. We carried out all analyses using R (version 4.0.3). Results Baseline characteristics A total of 96 patients were screened, but two declined to participate. Therefore, 94 patients were enrolled in the study. Five of them died and 33 dropped out during the follow-up, and 56 patients completed the 4-year follow-up (Figure 1). Most study participants were male (69, 73%), the mean age was 62.9 years (SD: 13.2), and the mean body mass index was 29.81 kg/m 2 (SD: 5.23). Most patients were non-smokers (54, 57%), and the most common comorbidities were hypertension (45, 48%) and dyslipidaemia (32, 34%). The median length of hospital stay was 22 days (range: 3-87), and 46 patients (49%) were admitted to the intensive care unit (Table 1). Respiratory consequences of COVID-19 Three months after discharge, 19.5% of patients presented dyspnoea ≥ 2, whereas at the 4-year follow-up, that number decreased to 7.9% (p=0.045). The mean number of lymphocytes remained stable throughout the 4 years. Lactate dehydrogenase, ferritin, and C-reactive protein could not be measured at the 4-year follow-up, although their evolution up to 1-year has been previously described.[4] Quality-of-life parameters improved between the 3-month and 4-year follow-up, but only the symptoms score (35 . 66% vs 26 . 75%, p=0 . 003) and total score (22 . 77% vs 18 . 15%, p=0 . 012) differences were statistically significant (Table 2). The results of pulmonary function tests showed that most parameters remained within normality and stable between the 3-month and 4-year follow-ups. Only DLCO, which was below normal values 3 months after discharge (75.91%), improved at the 4-year visit (81 . 43%), although not significantly (p=0.294). The mean distance walked increased significantly between the 3-month (368.03 m) and the 4-year follow-ups (436 . 63 m, p=0 . 001). Oxygen saturation parameters remained stable and within normal limits throughout the follow-up (Table 3). The HRCT performed 3 months after discharge showed pathological signs in 97.9% of our cohort, while they were only detected in 9.1% of patients at the 4-year visit (p<0.001). The most common feature found at the 3-month visit was GGO (53.9%), and the least common—apart from consolidation and honeycomb that were not detected at some visits—was traction bronchiectasis (2.7%). At the 4-year follow-up, several observations previously detected showed a significant reduction, such as GGO (53.9% vs 0.9%, p<0.001), fine subpleural reticular (34.9% vs 5.4, p=0.016), coarse linear or curvilinear opacities (12.7% vs 0.3%, p=0.005), and architectural distortion (19.1% vs 0.6%, p=0.010). The percentage of patients with traction bronchiectasis increased progressively at each follow-up from the 3-month (2.7%) to the 4-year visit (9.2%), but differences were not statistically significant (p=0.136) (Table 3). Nonetheless, traction bronchiectasis present 3 months after hospital discharge remained unchanged during the rest of the follow-up (Fig 2). In the HRCT performed 4 years after discharge, 11.5% of patients presented signs of fibrotic-like changes, while 88.5% did not (Supplementary Table S1). When analysing separately the baseline characteristics of patients with and without fibrotic-like changes, the only statistically significant differences were found in age (univariate analysis, OR: 1.058; 95% confidence interval [CI]: 1.007-1.113; multivariate analysis, OR: 1.870; 95% CI: 1.079-3.577) (Table 4). Discussion To the best of our knowledge, this is the first study to evaluate the 4-year follow-up and changes over time in respiratory consequences after discharge in COVID-19 patients with severe pneumonia. Most symptoms and clinical variables improved between the 3-month and 4-year follow-up, including dyspnoea, quality of life, pulmonary function results, and walking distance. Similarly, the majority of pathological signs observed in HRCT waned over time, especially GGO, but traction bronchiectasis increased progressively. Age was the only risk factor found for developing fibrotic-like changes. Most patients showed pathological HRCT scan changes 3 months after hospital discharge, and GGO was found in more than half of them. GGO is the most common radiological feature in COVID-19 [4, 17] and other viral pneumoniae [18] around that lapse of time after discharge. In our cohort, a significant and progressive reduction in the percentage of patients with GGO was observed over time until nearly none showed it at the 4-year follow-up. Likewise, the percentage of patients with reticular patterns also decreased significantly during this period. Other follow-up post-COVID pneumonia reports have also shown a sharp decrease in GGO and reticular abnormalities over time [4, 7, 9]. Some studies have even suggested that these changes after COVID-19 pneumonia would gradually disappear completely [10, 17, 19]. Architectural distortion has been shown to be related to fibrosis [15]. In our study, architectural distortion improved progressively and significantly 4 years after the patients’ discharge, indicating that this feature caused by severe COVID-19 pneumonia could also be reversible. On the contrary, traction bronchiectasis showed a non-significant increasing trend. Although this alteration may also be reversible in some cases, long-term persistence in our study suggested a certain irreversible fibrotic-like change [18]. Only age was found to be a risk factor for developing fibrotic-like changes in our study. This finding was in line with that of other follow-up studies where age was identified as a potential predictor of these abnormalities [20–22]. Although DLCO has already been reported as the most frequent and persistent change after COVID-19 pneumonia [5, 23, 24], long-term follow-up studies [7, 9] showed normalisation of DLCO for most patients, which was in agreement with our findings. Dyspnoea, quality of life, and exercise capacity also improved between the 3-month and 4-year follow-up. Therefore, the clinical-functional improvement was in opposition to the development of fibrotic-like changes. In addition, the lack of differences in dyspnoea, quality of life, and pulmonary function at 4-year follow-up between patients with or without fibrotic-like changes could also indicate that these radiological signs were non-active scars rather than a feature of classical interstitial lung disease (ILD) or progressive pulmonary fibrosis [25]. In fact, traction bronchiectasis was an isolated and non-progressive radiological fibrotic-like change in our patients during the follow-up, and honeycombing, a reliable fibrosis sign in ILD, was not found, as in other series [23, 26]. Consequently, as other groups have considered, the term post-COVID-ILD appears to be inappropriate for most patients’ fibrotic-like changes after COVID-19 pneumonia [15, 27, 28]. Worsening or exacerbation of pre-existing ILD may have been the cause of uncommon cases of progressive fibrosis or cases of ILD associated with post-COVID-19 [29, 30]. Moreover, in severe cases, as those included in our study, acute respiratory distress syndrome and ventilator-induced lung injury may also have been the cause of residual lung abnormalities [18]. Differences in patient population, study design, and treatment, among others, could account for variations in the observed outcomes with previously reported data. For instance, our study included all discharged patients with COVID-19 pneumonia requiring NIRT, whereas other studies only included patients with lung abnormalities at discharge [7, 9]. Moreover, dyspnoea, lung function, and quality-of-life alterations at long follow-up times might also be due to other non-lung physical alterations, such as skeletal, cardiac, and respiratory muscle deconditioning [18]. Even radiological changes at long follow-up times could be provoked by sequelae of other non-ILD lung entities, such as pulmonary infarcts, considering that pulmonary embolism is not infrequent in severe post-COVID-19 patients [31]. Although the design of our study did not allow us to infer the effect of corticosteroids, this therapy was initiated in patients presenting significant GGO following an internal multidisciplinary protocol. Despite the fact that no placebo-controlled trials on the use of steroids in these cases have been undertaken [31], GGO, lymphocytic bronchoalveolar lavage, and organising pneumonia—the most frequent radiologic, cytological, and pathological abnormalities in post-COVID pneumonia—have been reported to improve with corticosteroids [32–34]. Notwithstanding the abovementioned, our study presented some limitations that should also be considered. First, our cohort was relatively small and was limited to patients discharged from hospital with a certain severity. Second, some patients with no symptoms refused some explorations during the follow-up. Third, we analysed associations without adjusting for multiple comparisons, which can increase the risk of type I errors. Fourth, this was a single-centre study, and no radiological and functional baseline data on study participants was available. In addition, although the proportion of patients with comorbidities was considered in our analysis, these were self-reported and might have resulted in underestimations. Conclusion Fibrotic-like changes were observed by HRCT four years after discharge in COVID-19 patients with severe pneumonia who had required NIRT. However, the disparity between the development of those radiological findings and the clinical-functional improvement pointed out more towards remanent scars or sequelae than to classical or progressive ILD. Our results add important information about the long-term consequences of patients having required NIRT, a substantial part of COVID-19 patients with severe pneumonia. Abbreviations COVID-19 coronavirus disease 2019 CI confidence interval CT computed tomography DLCO diffusing capacity for carbon monoxide FVC forced vital capacity GGO ground glass opacities HRCT high-resolution computed tomography ILD interstitial lung disease NIRT non-invasive respiratory support therapies OR odd ratio SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 SD standard deviation SGRQ Saint George’s respiratory questionnaire WHO World Health Organization Declarations Acknowledgements The authors would like to thank Matías Rey-Carrizo, PhD at BCN Medical Writing for revising the manuscript. The author M. Comas-Cufí is a Serra Húnter Fellow. Authors’ contribution All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: S.E., G.S., M.B. and R.O. Analysis and interpretation of the data: S.E., G.S., S.B., JC.C., V.P., M.C., M.B. and R.O. Statistical analysis: M.C. Drafting of the manuscript: S.E, G.S, M.C, M.B. and R.O. Critical revision of the manuscript for important intellectual content: S.E., G.S., S.B., JC.C.,V.P., M.C., M.B. and R.O. Funding No funding was received for this study. Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request and with permission of Dr. Josep Trueta University Hospital of Girona. Ethics approval and consent to participate We drafted the study according to the Declaration of Helsinki [35]. The study was approved by Clinical Research Ethics Committee of Girona (CEIm, code: 2023.060), Spain. We anonymised personal patient’s information to ensure data confidentiality and obtained written informed consent from all study participants. Clinical trial number: not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interest. Artificial intelligence involvement The authors declare that they have not used any type of generative artificial intelligence for the writing of this manuscript, nor for the creation of images, graphics, tables, or their corresponding captions. References World Health Organization. COVID-19 epidemiological update – 24 December 2024. Coronavirus disease (COVID-19) Epidemiological Updates and Monthly Operational Updates. 2024. https://www.who.int/publications/m/item/covid-19-epidemiological-update---24-december-2024. Accessed 6 Feb 2025. World Health Organization. From emergency response to long-term COVID-19 disease management: sustaining gains made during the COVID-19 pandemic. 2023. Burki T. WHO ends the COVID-19 public health emergency. Lancet Respir Med. 2023;11:P588. Eizaguirre S, Sabater G, Belda S, Calderón JC, Pineda V, Comas-Cufí M, et al. Long-term respiratory consequences of COVID-19 related pneumonia: a cohort study. BMC Pulm Med. 2023;23:439. Watanabe A, So M, Iwagami M, Fukunaga K, Takagi H, Kabata H, et al. One-year follow-up CT findings in COVID-19 patients: A systematic review and meta-analysis. Respirology. 2022;27:605–16. Stewart I, Jacob J, George PM, Molyneaux PL, Porter JC, Allen RJ, et al. Residual Lung Abnormalities after COVID-19 Hospitalization. Interim Analysis of the UKILD Post-COVID-19 Study. Am J Respir Crit Care Med. 2023;207:693–703. Han X, Chen L, Fan Y, Alwalid O, Jia X, Zheng Y, et al. Longitudinal Assessment of Chest CT Findings and Pulmonary Function after COVID-19 Infection. Radiology. 2023;307:e222888. Huang L, Li X, Gu X, Zhang H, Ren LL, Guo L, et al. Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study. Lancet Respir Med. 2022;10:863–76. Han X, Chen L, Guo L, Wu L, Alwalid O, Liu J, et al. Long-term radiological and pulmonary function abnormalities at 3 years after COVID-19 hospitalisation: A longitudinal cohort study. Eur Respir J. 2024;64:2301612. Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, et al. Six-Month Follow-up Chest CT findings after Severe COVID-19 Pneumonia. Radiology. 2021;299:E177–86. Munari AB, Gulart AA, Dos Santos K, Venâncio RS, Karloh M, Mayer AF. Modified medical research council dyspnea scale in gold classification better reflects physical activities of daily living. Respir Care. 2018;63:77–85. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85 Supplement B:25–31. Stanojevic S, Kaminsky DA, Miller MR, Thompson B, Aliverti A, Barjaktarevic I, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J. 2022;60:2101499. Hu Q, Guan H, Sun Z, Huang L, Chen C, Ai T, et al. Early CT features and temporal lung changes in COVID-19 pneumonia in Wuhan, China. Eur J Radiol. 2020;128:109017. Solomon JJ, Heyman B, Ko JP, Condos R, Lynch DA. CT of Post-Acute Lung Complications of COVID-19. Radiology. 2021;301:E383–95. Singh SJ, Puhan MA, Andrianopoulos V, Hernandes NA, Mitchell KE, Hill CJ, et al. An official systematic review of the European Respiratory Society/American Thoracic Society: Measurement properties of field walking tests in chronic respiratory disease. Eur Respir J. 2014;44:1447–78. Wu X, Liu X, Zhou Y, Yu H, Li R, Zhan Q, et al. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study. Lancet Respir Med. 2021;9:747–54. Murphy MC, Little BP. Chronic Pulmonary Manifestations of COVID-19 Infection: Imaging Evaluation. Radiology. 2023;307:e222379. Liu D, Zhang W, Pan F, Li L, Yang L, Wang J, et al. The Pulmonary Sequalae in Discharged Patients With COVID-19: A Short-term Observational Study. Respir Res. 2020;21:125. Caruso D, Guido G, Zerunian M, Polidori T, Lucertini E, Pucciarelli F, et al. Post-acute sequelae of COVID-19 pneumonia: Six-month chest CT follow-up. Radiology. 2021;301:E396–405. Zhao Y, Shang Y, Song W, Li Q, Xie H, Xu Q, et al. Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. EClinicalMedicine. 2020;25:100463. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. Faverio P, Luppi F, Rebora P, Andrea GD, Stainer A, Busnelli S, et al. One‑year pulmonary impairment after severe COVID‑19: a prospective, multicenter follow‑up study. Respir Res. 2022;26:65. Lee JH, Yim JJ, Park J. Pulmonary function and chest computed tomography abnormalities 6–12 months after recovery from COVID‑19: a systematic review and meta‑analysis. Respir Res. 2022;23:233. Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet. 2022;400:P769-786. Pan F, Ye T, Sun P, Gui S, Liang B, Li L, et al. Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19). Radiology. 2020;295:715–21. Konopka KE, Perry W, Huang T, Farver CF, Myers JL. Usual interstitial pneumonia is the most common fi nding in surgical lung biopsies from patients with persistent interstitial lung disease following infection with SARS-CoV-2. EClinicalMedicine. 2021;42:101209. Fonseca M, Summer R, Roman J. Acute Exacerbation of Interstitial Lung Disease as a Sequela of COVID-19 Pneumonia. Am J Med Sci. 2021;361:126–9. Wells AU, Devaraj A, Desai SR. Interstitial Lung Disease after COVID-19 Infection: A Catalog of Uncertainties. Radiology. 2021;299:E216–8. Kanne JP, Little BP, Schulte JJ, Haramati A, Haramati LB. Long-term Lung Abnormalities Associated with COVID-19 Pneumonia. Radiology. 2023;306:e221806. Singh SJ, Baldwin MM, Daynes E, Evans RA, Greening NJ, Jenkins RG, et al. Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation. Lancet Respir Med. 2023;11:709–25. Roberton BJ, Hansell DM. Organizing pneumonia: a kaleidoscope of concepts and morphologies. Eur Radiol. 2011;21:2244–54. Myall KJ, Mukherjee B, Castanheira AM, Lam JL, Benedetti G, Mak SM, et al. Persistent Post–COVID-19. Interstitial Lung Disease An Observational Study of Corticosteroid Treatment. Ann Am Thorac Soc. 2021;18:799–806. Paiva Simoes J, Alves Ferreira AR, Martins Almeida P, Trigueiros F, Braz A, Rodrigues Inácio J, et al. Respiratory Medicine Case Reports Organizing pneumonia and COVID-19: A report of two cases. Respir Med Case Reports. 2021;32:101359. World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310:2191–4. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable.docx TABLES.docx Cite Share Download PDF Status: Published Journal Publication published 02 Jul, 2025 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 07 Apr, 2025 Reviews received at journal 02 Apr, 2025 Reviews received at journal 31 Mar, 2025 Reviewers agreed at journal 24 Mar, 2025 Reviewers agreed at journal 21 Mar, 2025 Reviewers invited by journal 21 Mar, 2025 Editor assigned by journal 21 Mar, 2025 Editor invited by journal 19 Mar, 2025 Submission checks completed at journal 18 Mar, 2025 First submitted to journal 18 Mar, 2025 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. 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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-6142626","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":433295167,"identity":"45ed4d27-c8ba-46ac-8b75-1f81608045a8","order_by":0,"name":"Saioa Eizaguirre","email":"","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":false,"prefix":"","firstName":"Saioa","middleName":"","lastName":"Eizaguirre","suffix":""},{"id":433295168,"identity":"c1c7f224-9ece-4fb2-9721-4e11517bef66","order_by":1,"name":"Gladis Sabater","email":"","orcid":"","institution":"Hospital Universitari de Girona 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Orriols","email":"data:image/png;base64,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","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":true,"prefix":"","firstName":"Ramon","middleName":"","lastName":"Orriols","suffix":""}],"badges":[],"createdAt":"2025-03-03 04:53:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6142626/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6142626/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-025-03772-0","type":"published","date":"2025-07-02T15:58:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79325920,"identity":"4a089a4e-f01c-487f-984d-6fc3dd81e8af","added_by":"auto","created_at":"2025-03-27 05:31:16","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54027,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart describing patient recruitment\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6142626/v1/97a6e719a25b59d93d7475b4.jpg"},{"id":79326794,"identity":"ee5b68f7-e137-473f-8390-87060755b564","added_by":"auto","created_at":"2025-03-27 05:39:16","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":113836,"visible":true,"origin":"","legend":"\u003cp\u003eComputed tomography (CT) images of two patients in 2020 and 2024 showing traction bronchiectasis after COVID-19 hospitalisation. \u003cstrong\u003ea)\u003c/strong\u003e CT scan of a 79 years old male 3 months after discharge, \u003cstrong\u003eb)\u003c/strong\u003e CT scan of the same patient at the 4-year follow-up, \u003cstrong\u003ec)\u003c/strong\u003e CT scan of a 88 years old male 3 months after discharge, \u003cstrong\u003ed)\u003c/strong\u003e CT scan of the same patient at the 4-year follow-up\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6142626/v1/3513f47122823fc4dd2a87d5.jpg"},{"id":86179824,"identity":"09f0fca4-7dda-4964-9360-134bae4ac2b9","added_by":"auto","created_at":"2025-07-07 16:19:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":707985,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6142626/v1/3b2a5bf0-07d4-4d8e-967a-4d200136ebe5.pdf"},{"id":79325924,"identity":"bfebc341-bd03-4e73-8996-a98c0befd634","added_by":"auto","created_at":"2025-03-27 05:31:16","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18802,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-6142626/v1/d86519a7639f134bcc6a6c9d.docx"},{"id":79326795,"identity":"bc92b99f-064a-4cdd-9011-dc6dd8eadf2b","added_by":"auto","created_at":"2025-03-27 05:39:16","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":26250,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES.docx","url":"https://assets-eu.researchsquare.com/files/rs-6142626/v1/7f19a5502d4ed1c80c577389.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Four-year respiratory consequences of COVID-19 related pneumonia: a longitudinal cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) declared COVID-19 a global pandemic in March 2020 after realising the high infectivity and virulence of SARS-CoV-2. As of November 2024, this virus has caused more than 777\u0026nbsp;million confirmed cases and over 7\u0026nbsp;million deaths worldwide [1]. On 3 May 2023, The WHO developed the COVID-19 Strategic Preparedness and Response Plan for 2023\u0026ndash;2025 that emphasises the significance of continuing the monitoring of patients who have overcome the COVID condition [2, 3].\u003c/p\u003e \u003cp\u003eAlthough several prospective studies have investigated the long-term respiratory consequences after COVID-19 [4\u0026ndash;9], these findings have considerably fluctuated by factors such as patient population, disease severity, and evaluation standards, among others. In addition, only limited long-term data is available on developing these respiratory consequences. To date, the most extended follow-up study spans 3 years after discharge from two hospitals in China [9]. In that study, patients with residual lung changes on computed tomography (CT) after COVID-19 hospitalisation exhibited improvements in respiratory outcomes. However, more than one-third continued to have lung abnormalities on CT, which were associated with symptoms and abnormal pulmonary function.\u003c/p\u003e \u003cp\u003eDuring the first wave of the COVID-19 pandemic, about 10\u0026ndash;20% of COVID-19 patients developed severe pneumonia, and 20\u0026ndash;25% required non-invasive respiratory support therapies (NIRT) [10]. Recently, our group reported the respiratory sequelae up to 12 months after discharge in COVID-19 patients with severe pneumonia requiring NIRT [4]. Although dyspnoea, quality of life, pulmonary function, and exercise capacity improved, fibrotic-like changes during the follow-up were observed in CT. Longitudinal studies are needed to raise awareness of the evolution of lung abnormalities, especially in COVID-19 survivors with a severe initial disease.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to describe, 4 years after discharge, the respiratory consequences of COVID-19 patients with severe pneumonia requiring NIRT and to assess the progression and impact of those changes in the referred patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eWe carried out an observational, prospective, single-centre study at the Respiratory Department of the University Hospital Doctor Josep Trueta, Girona, Spain. We collected data from all patients discharged from our department between March 2020 and June 2020 who had severe pneumonia, requiring NIRT, caused by COVID-19 (laboratory-confirmed). We performed the 4-year follow-up up to June 2024. We report our findings in accordance with the STROBE guidelines.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003eThe inclusion and exclusion criteria of patients has been described elsewhere [4]. Briefly, we included data from adult patients diagnosed of severe pneumonia caused by SARS-CoV-2 (confirmed by PCR) and who had required NIRT (high-flow nasal cannula, continuous positive airway pressure, or non-invasive ventilation). We excluded data from patients who declined to participate. This cohort included the patients previously participating in a 1-year follow-up study [4].\u003c/p\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003eWe collected the patients\u0026rsquo; characteristics and comorbidities from their medical records. We evaluated dyspnoea according to the modified Medical Research Council scale [11]. We also conducted a Saint George\u0026rsquo;s respiratory questionnaire (SGRQ) [12], pulmonary function tests, a blood test to retrieve the lymphocyte count, a chest high-resolution CT (HRCT), and a 6-min walking test. We performed the pulmonary function tests and the 6-min walking test according to the ATS/ERS guidelines [13] in the Lung Function Laboratory of our Hospital using the Master Screen PFT (Jagger, Germany). We performed the chest HRCT in the supine position during end-inspiration with a multislice CT scanner. Images were reconstructed at 1 mm slice thickness, with 1 mm increment, 512 mm\u0026times;512 mm. A pulmonologist and a radiologist with clinical experience in chest imaging reviewed separately the CT features. We described the main CT patterns in agreement with the terms defined by the Fleischner Society and peer-reviewed literature on viral pneumonia [14, 15]. CT images were examined for the presence of reticular pattern (curvilinear opacity, coarse linear, or fine subpleural reticulation), parenchymal pattern (ground-glass opacities [GGO] or consolidation), and fibrotic pattern (honeycombing, architectural distortion, or traction bronchiectasis or bronchiolectasis) [15].\u003c/p\u003e \u003cp\u003eWe evaluated dyspnoea and performed the SGRQ and the blood test 3 months, 6 months, 1 year, and 4 years after discharge. We performed pulmonary function tests, the 6-min walking test, and the HRCT only in those patients who had shown significant abnormal findings in that specific test at the previous evaluation. Abnormal findings were defined as a diffusing capacity for carbon monoxide (DLCO) or forced vital capacity (FVC)\u0026thinsp;\u0026lt;\u0026thinsp;80% for pulmonary function tests and a distance walked inferior to the reference described in the Enright criteria [16] for the 6-minute walking test. We also considered relevant any abnormal finding in the chest HRCT and reassessed it in the next evaluation.\u003c/p\u003e \u003cp\u003eWe treated all patients presenting significant GGO at any follow-up time with prednisone. The GGO in CT images was quantified with a modified, previously published method [9]. Briefly, we divided each lung into three zones: upper (above the carina), middle, and lower (below the inferior pulmonary vein). If more than one zone out of the six defined for both lungs showed signs of GGO, we considered it significant GGO involvement. The initial prednisone regimen was 30 mg/day for 15 days and was gradually tapered between one to two months to 5 mg/day, a dose that was to be maintained until the next follow-up. Then, if a non-significant GGO was achieved, according to an improvement seen in the CT by the clinician, the treatment was interrupted.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were described as absolute numbers and percentages and quantitative variables as mean and standard deviation (SD). We used the Fisher's Exact test to compare categorical variables and the Welch's t-test to compare numerical variables. We used a multivariate logistic model to estimate the adjusted odd ratio (OR) of developing fibrotic-like changes. The candidate variables for adjustment were all available basal variables. We built the final model using the set of variables that maximised the Bayesian Information Criterion. During the follow-up, to account for repeated measures and missing values, we compared periods by fitting linear mixed-effect models using all patients available at baseline. For categorical variables, we present estimations in percentage together with their standard error. We used the likelihood ratio test to assess differences between periods. For quantitative variables, we present estimations with the standard error. We considered the F-test based on the Kenward-Roger approach to compare periods. We did not replace nor inferred missing values. We carried out all analyses using R (version 4.0.3).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 96 patients were screened, but two declined to participate. Therefore, 94 patients were enrolled in the study. Five of them died and 33 dropped out during the follow-up, and 56 patients completed the 4-year follow-up (Figure 1). Most study participants were male (69, 73%), the mean age was 62.9 years (SD: 13.2), and the mean body mass index was 29.81 kg/m\u003csup\u003e2\u003c/sup\u003e (SD: 5.23). Most patients were non-smokers (54, 57%), and the most common comorbidities were hypertension (45, 48%) and dyslipidaemia (32, 34%). The median length of hospital stay was 22 days (range: 3-87), and 46 patients (49%) were admitted to the intensive care unit (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRespiratory consequences of COVID-19\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree months after discharge, 19.5% of patients presented dyspnoea \u0026ge; 2, whereas at the 4-year follow-up, that number decreased to 7.9% (p=0.045). The mean number of lymphocytes remained stable throughout the 4 years. Lactate dehydrogenase, ferritin, and C-reactive protein could not be measured at the 4-year follow-up, although their evolution up to 1-year has been previously described.[4] Quality-of-life parameters improved between the 3-month and 4-year follow-up, but only the symptoms score (35\u003cem\u003e.\u003c/em\u003e66% vs 26\u003cem\u003e.\u003c/em\u003e75%, p=0\u003cem\u003e.\u003c/em\u003e003) and total score (22\u003cem\u003e.\u003c/em\u003e77% vs 18\u003cem\u003e.\u003c/em\u003e15%, p=0\u003cem\u003e.\u003c/em\u003e012) differences were statistically significant (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe results of pulmonary function tests showed that most parameters remained within normality and stable between the 3-month and 4-year follow-ups. Only DLCO, which was below normal values 3 months after discharge (75.91%), improved at the 4-year visit (81\u003cem\u003e.\u003c/em\u003e43%), although not significantly (p=0.294). The mean distance walked increased significantly between the 3-month (368.03 m) and the 4-year follow-ups (436\u003cem\u003e.\u003c/em\u003e63 m, p=0\u003cem\u003e.\u003c/em\u003e001). Oxygen saturation parameters remained stable and within normal limits throughout the follow-up (Table 3).\u003c/p\u003e\n\u003cp\u003eThe HRCT performed 3 months after discharge showed pathological signs in 97.9% of our cohort, while they were only detected in 9.1% of patients at the 4-year visit (p\u0026lt;0.001). The most common feature found at the 3-month visit was GGO (53.9%), and the least common\u0026mdash;apart from consolidation and honeycomb that were not detected at some visits\u0026mdash;was traction bronchiectasis (2.7%). At the 4-year follow-up, several observations previously detected showed a significant reduction, such as GGO (53.9% vs 0.9%, p\u0026lt;0.001), fine subpleural reticular (34.9% vs 5.4, p=0.016), coarse linear or curvilinear opacities (12.7% vs 0.3%, p=0.005), and architectural distortion (19.1% vs 0.6%, p=0.010). The percentage of patients with traction bronchiectasis increased progressively at each follow-up from the 3-month (2.7%) to the 4-year visit (9.2%), but differences were not statistically significant (p=0.136) (Table 3). Nonetheless, traction bronchiectasis present 3 months after hospital discharge remained unchanged during the rest of the follow-up (Fig 2).\u003c/p\u003e\n\u003cp\u003eIn the HRCT performed 4 years after discharge, 11.5% of patients presented signs of fibrotic-like changes, while 88.5% did not (Supplementary Table S1). When analysing separately the baseline characteristics of patients with and without fibrotic-like changes, the only statistically significant differences were found in age (univariate analysis, OR: 1.058; 95% confidence interval [CI]: 1.007-1.113; multivariate analysis, OR: 1.870; 95% CI: 1.079-3.577) (Table 4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first study to evaluate the 4-year follow-up and changes over time in respiratory consequences after discharge in COVID-19 patients with severe pneumonia. Most symptoms and clinical variables improved between the 3-month and 4-year follow-up, including dyspnoea, quality of life, pulmonary function results, and walking distance. Similarly, the majority of pathological signs observed in HRCT waned over time, especially GGO, but traction bronchiectasis increased progressively. Age was the only risk factor found for developing fibrotic-like changes.\u003c/p\u003e \u003cp\u003eMost patients showed pathological HRCT scan changes 3 months after hospital discharge, and GGO was found in more than half of them. GGO is the most common radiological feature in COVID-19 [4, 17] and other viral pneumoniae [18] around that lapse of time after discharge. In our cohort, a significant and progressive reduction in the percentage of patients with GGO was observed over time until nearly none showed it at the 4-year follow-up. Likewise, the percentage of patients with reticular patterns also decreased significantly during this period. Other follow-up post-COVID pneumonia reports have also shown a sharp decrease in GGO and reticular abnormalities over time [4, 7, 9]. Some studies have even suggested that these changes after COVID-19 pneumonia would gradually disappear completely [10, 17, 19]. Architectural distortion has been shown to be related to fibrosis [15]. In our study, architectural distortion improved progressively and significantly 4 years after the patients\u0026rsquo; discharge, indicating that this feature caused by severe COVID-19 pneumonia could also be reversible. On the contrary, traction bronchiectasis showed a non-significant increasing trend. Although this alteration may also be reversible in some cases, long-term persistence in our study suggested a certain irreversible fibrotic-like change [18]. Only age was found to be a risk factor for developing fibrotic-like changes in our study. This finding was in line with that of other follow-up studies where age was identified as a potential predictor of these abnormalities [20\u0026ndash;22].\u003c/p\u003e \u003cp\u003eAlthough DLCO has already been reported as the most frequent and persistent change after COVID-19 pneumonia [5, 23, 24], long-term follow-up studies [7, 9] showed normalisation of DLCO for most patients, which was in agreement with our findings. Dyspnoea, quality of life, and exercise capacity also improved between the 3-month and 4-year follow-up. Therefore, the clinical-functional improvement was in opposition to the development of fibrotic-like changes. In addition, the lack of differences in dyspnoea, quality of life, and pulmonary function at 4-year follow-up between patients with or without fibrotic-like changes could also indicate that these radiological signs were non-active scars rather than a feature of classical interstitial lung disease (ILD) or progressive pulmonary fibrosis [25]. In fact, traction bronchiectasis was an isolated and non-progressive radiological fibrotic-like change in our patients during the follow-up, and honeycombing, a reliable fibrosis sign in ILD, was not found, as in other series [23, 26]. Consequently, as other groups have considered, the term post-COVID-ILD appears to be inappropriate for most patients\u0026rsquo; fibrotic-like changes after COVID-19 pneumonia [15, 27, 28]. Worsening or exacerbation of pre-existing ILD may have been the cause of uncommon cases of progressive fibrosis or cases of ILD associated with post-COVID-19 [29, 30]. Moreover, in severe cases, as those included in our study, acute respiratory distress syndrome and ventilator-induced lung injury may also have been the cause of residual lung abnormalities [18].\u003c/p\u003e \u003cp\u003eDifferences in patient population, study design, and treatment, among others, could account for variations in the observed outcomes with previously reported data. For instance, our study included all discharged patients with COVID-19 pneumonia requiring NIRT, whereas other studies only included patients with lung abnormalities at discharge [7, 9]. Moreover, dyspnoea, lung function, and quality-of-life alterations at long follow-up times might also be due to other non-lung physical alterations, such as skeletal, cardiac, and respiratory muscle deconditioning [18]. Even radiological changes at long follow-up times could be provoked by sequelae of other non-ILD lung entities, such as pulmonary infarcts, considering that pulmonary embolism is not infrequent in severe post-COVID-19 patients [31]. Although the design of our study did not allow us to infer the effect of corticosteroids, this therapy was initiated in patients presenting significant GGO following an internal multidisciplinary protocol. Despite the fact that no placebo-controlled trials on the use of steroids in these cases have been undertaken [31], GGO, lymphocytic bronchoalveolar lavage, and organising pneumonia\u0026mdash;the most frequent radiologic, cytological, and pathological abnormalities in post-COVID pneumonia\u0026mdash;have been reported to improve with corticosteroids [32\u0026ndash;34].\u003c/p\u003e \u003cp\u003eNotwithstanding the abovementioned, our study presented some limitations that should also be considered. First, our cohort was relatively small and was limited to patients discharged from hospital with a certain severity. Second, some patients with no symptoms refused some explorations during the follow-up. Third, we analysed associations without adjusting for multiple comparisons, which can increase the risk of type I errors. Fourth, this was a single-centre study, and no radiological and functional baseline data on study participants was available. In addition, although the proportion of patients with comorbidities was considered in our analysis, these were self-reported and might have resulted in underestimations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFibrotic-like changes were observed by HRCT four years after discharge in COVID-19 patients with severe pneumonia who had required NIRT. However, the disparity between the development of those radiological findings and the clinical-functional improvement pointed out more towards remanent scars or sequelae than to classical or progressive ILD. Our results add important information about the long-term consequences of patients having required NIRT, a substantial part of COVID-19 patients with severe pneumonia.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOVID-19\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecoronavirus disease 2019\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDLCO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediffusing capacity for carbon monoxide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFVC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eforced vital capacity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGGO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eground glass opacities\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh-resolution computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eILD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterstitial lung disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNIRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-invasive respiratory support therapies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodd ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSARS-CoV-2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esevere acute respiratory syndrome coronavirus 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSGRQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSaint George\u0026rsquo;s respiratory questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWorld Health Organization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Mat\u0026iacute;as Rey-Carrizo, PhD at BCN Medical Writing for revising the manuscript. The author M. Comas-Cuf\u0026iacute; is a Serra H\u0026uacute;nter Fellow.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: S.E., G.S., M.B. and R.O. Analysis and interpretation of the data: S.E., G.S., S.B., JC.C., V.P., M.C., M.B. and R.O. Statistical analysis: M.C. Drafting of the manuscript: S.E, G.S, M.C, M.B. and R.O. Critical revision of the manuscript for important intellectual content: S.E., G.S., S.B., JC.C.,V.P., M.C., M.B. and R.O.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request and with permission of Dr. Josep Trueta University Hospital of Girona.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe drafted the study according to the Declaration of Helsinki [35]. The study was approved by Clinical Research Ethics Committee of Girona (CEIm, code: 2023.060), Spain. We anonymised personal patient\u0026rsquo;s information to ensure data confidentiality and obtained written informed consent from all study participants. Clinical trial number: not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eArtificial intelligence involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have not used any type of generative artificial intelligence for the writing of this manuscript, nor for the creation of images, graphics, tables, or their corresponding captions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld Health Organization. COVID-19 epidemiological update \u0026ndash; 24 December 2024. Coronavirus disease (COVID-19) Epidemiological Updates and Monthly Operational Updates. 2024. https://www.who.int/publications/m/item/covid-19-epidemiological-update---24-december-2024. Accessed 6 Feb 2025.\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. From emergency response to long-term COVID-19 disease management: sustaining gains made during the COVID-19 pandemic. 2023.\u003c/li\u003e\n\u003cli\u003eBurki T. WHO ends the COVID-19 public health emergency. Lancet Respir Med. 2023;11:P588.\u003c/li\u003e\n\u003cli\u003eEizaguirre S, Sabater G, Belda S, Calder\u0026oacute;n JC, Pineda V, Comas-Cuf\u0026iacute; M, et al. Long-term respiratory consequences of COVID-19 related pneumonia: a cohort study. BMC Pulm Med. 2023;23:439.\u003c/li\u003e\n\u003cli\u003eWatanabe A, So M, Iwagami M, Fukunaga K, Takagi H, Kabata H, et al. One-year follow-up CT findings in COVID-19 patients: A systematic review and meta-analysis. Respirology. 2022;27:605\u0026ndash;16.\u003c/li\u003e\n\u003cli\u003eStewart I, Jacob J, George PM, Molyneaux PL, Porter JC, Allen RJ, et al. Residual Lung Abnormalities after COVID-19 Hospitalization. Interim Analysis of the UKILD Post-COVID-19 Study. Am J Respir Crit Care Med. 2023;207:693\u0026ndash;703.\u003c/li\u003e\n\u003cli\u003eHan X, Chen L, Fan Y, Alwalid O, Jia X, Zheng Y, et al. Longitudinal Assessment of Chest CT Findings and Pulmonary Function after COVID-19 Infection. Radiology. 2023;307:e222888.\u003c/li\u003e\n\u003cli\u003eHuang L, Li X, Gu X, Zhang H, Ren LL, Guo L, et al. Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study. Lancet Respir Med. 2022;10:863\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eHan X, Chen L, Guo L, Wu L, Alwalid O, Liu J, et al. Long-term radiological and pulmonary function abnormalities at 3 years after COVID-19 hospitalisation: A longitudinal cohort study. Eur Respir J. 2024;64:2301612.\u003c/li\u003e\n\u003cli\u003eHan X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, et al. Six-Month Follow-up Chest CT findings after Severe COVID-19 Pneumonia. Radiology. 2021;299:E177\u0026ndash;86.\u003c/li\u003e\n\u003cli\u003eMunari AB, Gulart AA, Dos Santos K, Ven\u0026acirc;ncio RS, Karloh M, Mayer AF. Modified medical research council dyspnea scale in gold classification better reflects physical activities of daily living. Respir Care. 2018;63:77\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eJones PW, Quirk FH, Baveystock CM. The St George\u0026rsquo;s Respiratory Questionnaire. Respir Med. 1991;85 Supplement B:25\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eStanojevic S, Kaminsky DA, Miller MR, Thompson B, Aliverti A, Barjaktarevic I, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J. 2022;60:2101499.\u003c/li\u003e\n\u003cli\u003eHu Q, Guan H, Sun Z, Huang L, Chen C, Ai T, et al. Early CT features and temporal lung changes in COVID-19 pneumonia in Wuhan, China. Eur J Radiol. 2020;128:109017.\u003c/li\u003e\n\u003cli\u003eSolomon JJ, Heyman B, Ko JP, Condos R, Lynch DA. CT of Post-Acute Lung Complications of COVID-19. Radiology. 2021;301:E383\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eSingh SJ, Puhan MA, Andrianopoulos V, Hernandes NA, Mitchell KE, Hill CJ, et al. An official systematic review of the European Respiratory Society/American Thoracic Society: Measurement properties of field walking tests in chronic respiratory disease. Eur Respir J. 2014;44:1447\u0026ndash;78.\u003c/li\u003e\n\u003cli\u003eWu X, Liu X, Zhou Y, Yu H, Li R, Zhan Q, et al. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study. Lancet Respir Med. 2021;9:747\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eMurphy MC, Little BP. Chronic Pulmonary Manifestations of COVID-19 Infection: Imaging Evaluation. Radiology. 2023;307:e222379.\u003c/li\u003e\n\u003cli\u003eLiu D, Zhang W, Pan F, Li L, Yang L, Wang J, et al. The Pulmonary Sequalae in Discharged Patients With COVID-19: A Short-term Observational Study. Respir Res. 2020;21:125.\u003c/li\u003e\n\u003cli\u003eCaruso D, Guido G, Zerunian M, Polidori T, Lucertini E, Pucciarelli F, et al. Post-acute sequelae of COVID-19 pneumonia: Six-month chest CT follow-up. Radiology. 2021;301:E396\u0026ndash;405.\u003c/li\u003e\n\u003cli\u003eZhao Y, Shang Y, Song W, Li Q, Xie H, Xu Q, et al. Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. EClinicalMedicine. 2020;25:100463.\u003c/li\u003e\n\u003cli\u003eHuang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497\u0026ndash;506.\u003c/li\u003e\n\u003cli\u003eFaverio P, Luppi F, Rebora P, Andrea GD, Stainer A, Busnelli S, et al. One‑year pulmonary impairment after severe COVID‑19: a prospective, multicenter follow‑up study. Respir Res. 2022;26:65.\u003c/li\u003e\n\u003cli\u003eLee JH, Yim JJ, Park J. Pulmonary function and chest computed tomography abnormalities 6\u0026ndash;12 months after recovery from COVID‑19: a systematic review and meta‑analysis. Respir Res. 2022;23:233.\u003c/li\u003e\n\u003cli\u003eWijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet. 2022;400:P769-786.\u003c/li\u003e\n\u003cli\u003ePan F, Ye T, Sun P, Gui S, Liang B, Li L, et al. Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19). Radiology. 2020;295:715\u0026ndash;21.\u003c/li\u003e\n\u003cli\u003eKonopka KE, Perry W, Huang T, Farver CF, Myers JL. Usual interstitial pneumonia is the most common fi nding in surgical lung biopsies from patients with persistent interstitial lung disease following infection with SARS-CoV-2. EClinicalMedicine. 2021;42:101209.\u003c/li\u003e\n\u003cli\u003eFonseca M, Summer R, Roman J. Acute Exacerbation of Interstitial Lung Disease as a Sequela of COVID-19 Pneumonia. Am J Med Sci. 2021;361:126\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eWells AU, Devaraj A, Desai SR. Interstitial Lung Disease after COVID-19 Infection: A Catalog of Uncertainties. Radiology. 2021;299:E216\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eKanne JP, Little BP, Schulte JJ, Haramati A, Haramati LB. Long-term Lung Abnormalities Associated with COVID-19 Pneumonia. Radiology. 2023;306:e221806.\u003c/li\u003e\n\u003cli\u003eSingh SJ, Baldwin MM, Daynes E, Evans RA, Greening NJ, Jenkins RG, et al. Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation. Lancet Respir Med. 2023;11:709\u0026ndash;25.\u003c/li\u003e\n\u003cli\u003eRoberton BJ, Hansell DM. Organizing pneumonia: a kaleidoscope of concepts and morphologies. Eur Radiol. 2011;21:2244\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eMyall KJ, Mukherjee B, Castanheira AM, Lam JL, Benedetti G, Mak SM, et al. Persistent Post\u0026ndash;COVID-19. Interstitial Lung Disease An Observational Study of Corticosteroid Treatment. Ann Am Thorac Soc. 2021;18:799\u0026ndash;806.\u003c/li\u003e\n\u003cli\u003ePaiva Simoes J, Alves Ferreira AR, Martins Almeida P, Trigueiros F, Braz A, Rodrigues In\u0026aacute;cio J, et al. Respiratory Medicine Case Reports Organizing pneumonia and COVID-19: A report of two cases. Respir Med Case Reports. 2021;32:101359.\u003c/li\u003e\n\u003cli\u003eWorld Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310:2191\u0026ndash;4.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, coronavirus disease, long-term sequelae, pneumonia, pulmonary fibrosis, pulmonary function","lastPublishedDoi":"10.21203/rs.3.rs-6142626/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6142626/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eWe aimed to describe respiratory sequelae up to 4 years after discharge in COVID-19 patients with severe pneumonia having required non-invasive respiratory support therapies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study was conducted between March 2020 and June 2020 at University Hospital Doctor Josep Trueta (Girona, Spain). We assessed the patient\u0026rsquo;s dyspnoea and performed, pulmonary function tests, a high-resolution CT (HRCT), a 6-minute walking test, a blood test, and the Saint George\u0026rsquo;s respiratory questionnaire 3 months after discharge. At the 6-month, 1-year, and 4-year follow-up, we repeated all tests except for pulmonary function, 6-min walking test, and HRCT, which were only performed if abnormal findings had been previously detected.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOut of the 94 patients enrolled, 73% were male, the median age was 62.9 years, and most were non-smokers (58%). When comparing data 3 months and 4 years after discharge, the percentage of patients presenting dyspnoea\u0026thinsp;\u0026ge;\u0026thinsp;2 decreased (19.5% vs 7.9%), the quality-of-life total score improved (22.8% vs 18.1%), diffusing capacity for carbon monoxide improved (75.9% vs 81.4%), the 6-min walking test distance was enhanced (368.0 m vs 436.6 m), ground glass opacities findings waned (56.6% vs 0.8%), and traction bronchiectasis increased (2.7% vs 9.2%). Age was the only parameter that exhibited significant differences between patients with and without pulmonary fibrotic-like changes.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eMost patients, 4 years after discharge, improved their pulmonary function, exercise capacity, clinical condition, and quality of life. Although pulmonary fibrotic-like changes were observed during the follow-ups, its disparity with clinical-functional improvement pointed to non-progressive and non-clinically relevant lung scars.\u003c/p\u003e","manuscriptTitle":"Four-year respiratory consequences of COVID-19 related pneumonia: a longitudinal cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 05:31:11","doi":"10.21203/rs.3.rs-6142626/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-07T10:56:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-02T18:53:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-31T11:40:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326183543981109352627836250248857358902","date":"2025-03-24T15:42:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"40723158310236259849151617850947863546","date":"2025-03-21T09:49:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-21T07:40:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-21T07:04:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-19T07:00:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-18T11:53:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-03-18T11:52:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fecfec53-c2e9-4952-8cff-abba02ea8bf2","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T16:11:52+00:00","versionOfRecord":{"articleIdentity":"rs-6142626","link":"https://doi.org/10.1186/s12890-025-03772-0","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2025-07-02 15:58:14","publishedOnDateReadable":"July 2nd, 2025"},"versionCreatedAt":"2025-03-27 05:31:11","video":"","vorDoi":"10.1186/s12890-025-03772-0","vorDoiUrl":"https://doi.org/10.1186/s12890-025-03772-0","workflowStages":[]},"version":"v1","identity":"rs-6142626","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6142626","identity":"rs-6142626","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}