24-Month assessment of respiratory function in patients hospitalized for severe Sars-Cov-2 pneumonia: a follow-up study

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Data may be preliminary. 13 January 2025 V1 Latest version Share on 24-Month assessment of respiratory function in patients hospitalized for severe Sars-Cov-2 pneumonia: a follow-up study Authors : Pini Laura 0000-0001-6563-4942 [email protected] , Guerini Michele , Giordani Jordan , Guido Levi 0000-0002-7163-2270 , Latronico Nicola , Piva Simone , Peli Elena , … Show All … , Benoni Roberto , Pini Alessandro , Abou Daher Amir , Piras Stefano , El Masri Yehia , Visca Dina , Caminati Marco 0009-0009-1134-059X , Senna Gianenrico , Muiesan Maria Lorenza , and Tantucci Claudio Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.173678404.46907713/v1 263 views 190 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Long COVID significantly impacts various body systems, particularly the respiratory system. This study aimed to analyze the lung ventilatory function and diffusion capacity of patients with severe SARS-CoV-2 pneumonia at different time points during a 24-month follow-up course. Methods: Ventilatory function and lung diffusion capacity of the lung were assessed 6, 12, 18, and 24 months after hospital discharge. Patients underwent spirometry and lung volume measurements. Ventilatory parameters and DLCO and KCO normalization were defined as achieving values > 80% predicted. Results: A total of 222 patients admitted to the Intensive Care Unit (ICU) of the ASST - Spedali Civili di Brescia, Brescia, Italy, who survived severe SARS-CoV-2 pneumonia were enrolled. Among the 172 patients who completed the study, 140 (85.59%) achieved normalization of ventilatory parameters and DLCO and KCO. The median time to recovery was 4.5 months, and the hazard ratio (HR) reduced by 2% as each year of age increased. The median time to normalize ventilatory parameters (VC, FVC, FEV 1 , Tiffeneau index, TLC, and KCO) was 1.5 months, while the median time to VA normalization was 4.5 months. Male gender reduces the normalization odds of the Tiffeneau index and Alveolar Volume (VA). The median time to DLCO normalization was 9 months, with HR reduced by 3.1% as each year of age increased and augmented by 226% in obese subjects. Conclusions: 24 months after hospital discharge, 19% of patients had persistent ventilatory and/or diffusive defects. Our study documented that male sex, age, and obesity impact the normalization odds of ventilatory function and diffusive capacity of the lung. These findings underline the chronic nature of lung damage following severe COVID-19 pneumonia and the need for long-term follow-ups . 24-Month assessment of respiratory function in patients hospitalized for severe Sars-Cov-2 pneumonia: a follow-up study Pini Laura 1,2 , Guerini Michele 1 , Giordani Jordan 1 , Levi Guido 3 , Latronico Nicola 4,5 , Piva Simone 4,5 , Peli Elena 4 , Benoni Roberto 6 , Pini Alessandro 7 , Abou Daher Amir 1 , Piras Stefano 1 , El Masri Yehia 1 , Visca Dina 8,9 , Caminati Marco 10,11 , Senna Gianenrico 10,11 , Muiesan Maria Lorenza 1,12 & Tantucci Claudio 1 . 1. Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy 2. Respiratory Physiopathology Unit, ASST – Spedali Civili di Brescia, Brescia, Italy 3. Pulmonology Department, ASST – Spedali Civili di Brescia, Brescia, Italy 4. Department of Anesthesia, Critical Care and Emergency, ASST Spedali Civili University Hospital, Brescia, Italy. 5. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 6. Department of Diagnostics and Public Health, University of Verona, Verona, Italy. 7. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy 8. Department of Medicine and Surgery, University of Insubria, Varese, Italy 9. Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy. 10. Department of Medicine, University of Verona, Verona, Italy. 11. Allergy Unit and Asthma Center, Verona Integrated University Hospital, Verona, Italy. 12. Internal Medicine Unit, ASST Spedali Civili di Brescia, Brescia, Italy. Corresponding Author: Prof. Laura Pini Department of Clinical and Experimental Sciences University of Brescia Respiratory Physiopathology Unit ASST - Spedali Civili di Brescia Piazzale Spedali Civili 1, Brescia, Italy [email protected] Tel: +39 030 399 6263 Abstract word count: 278 Manuscript word count: 2540 ABSTRACT Background: Long COVID significantly impacts various body systems, particularly the respiratory system. This study aimed to analyze the lung ventilatory function and diffusion capacity of patients with severe SARS-CoV-2 pneumonia at different time points during a 24-month follow-up course. Methods: Ventilatory function and lung diffusion capacity of the lung were assessed 6, 12, 18, and 24 months after hospital discharge. Patients underwent spirometry and lung volume measurements. Ventilatory parameters and DLCO and KCO normalization were defined as achieving values > 80% predicted. Results: A total of 222 patients admitted to the Intensive Care Unit (ICU) of the ASST - Spedali Civili di Brescia, Brescia, Italy, who survived severe SARS-CoV-2 pneumonia were enrolled. Among the 172 patients who completed the study, 140 (85.59%) achieved normalization of ventilatory parameters and DLCO and KCO. The median time to recovery was 4.5 months, and the hazard ratio (HR) reduced by 2% as each year of age increased. The median time to normalize ventilatory parameters (VC, FVC, FEV 1 , Tiffeneau index, TLC, and KCO) was 1.5 months, while the median time to VA normalization was 4.5 months. Male gender reduces the normalization odds of the Tiffeneau index and Alveolar Volume (VA). The median time to DLCO normalization was 9 months, with HR reduced by 3.1% as each year of age increased and augmented by 226% in obese subjects. Conclusions: 24 months after hospital discharge, 19% of patients had persistent ventilatory and/or diffusive defects. Our study documented that male sex, age, and obesity impact the normalization odds of ventilatory function and diffusive capacity of the lung. These findings underline the chronic nature of lung damage following severe COVID-19 pneumonia and the need for long-term follow-ups. KEY WORDS SARS-CoV-2 – Pulmonary function test – DLCO – Lung Volumes – Restrictive defect INTRODUCTION Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), emerged as a significant health concern following the global COVID-19 pandemic. This condition is characterized by persistent symptoms or new-onset complications continuing for weeks or months after the initial acute phase of COVID-19 infection. While the full spectrum of long-term effects is still being investigated, current evidence suggests that COVID-19 has lasting impacts on various body symptoms, with the respiratory system particularly vulnerable. The respiratory manifestations of long COVID are various and can range from mild to severe. Common symptoms include persistent cough, shortness of breath, chest pain, and reduced exercise tolerance. These symptoms can significantly impact daily activities and quality of life, increasing healthcare utilization and economic burden [1-3]. Pathophysiological mechanisms underlying the respiratory effects of Long COVID are complex and multifaceted. One proposed mechanism involves direct viral-induced lung damage, resulting in fibrosis and reduced lung function. Also, the hyperinflammatory state associated with severe COVID-19 may lead to persistent inflammation and immune dysregulation, contributing to ongoing respiratory symptoms. Vascular complications, including microthrombi formation and endothelial dysfunction, may also play a role in the long-term respiratory sequelae of COVID-19. Imaging studies revealed persistent abnormalities in the lungs of long COVID patients, even in those who experienced mild acute illness. These abnormalities include ground-glass opacities, consolidations, and fibrotic changes. Pulmonary function tests often demonstrate reduced lung diffusion capacity for carbon monoxide (DLCO) and restrictive ventilatory patterns, leading to impaired gas exchange and decreased lung volumes [4-9]. The long-term prognosis for patients with respiratory manifestations of long COVID remains uncertain. While some individuals experience gradual improvement over time, others struggle with persistent symptoms for extended periods. This outcome variability highlights the need for personalized patient care and long-term follow-up approaches. Management strategies for respiratory symptoms in Long COVID are evolving as our understanding of the condition grows. Current approaches often include pulmonary rehabilitation programs, breathing exercises, and symptomatic management. The implications of long COVID for public health are significant. Long-term respiratory complications following COVID-19 infection underline the importance of prevention strategies, including vaccination and public health measures to reduce transmission [10-11]. Additionally, healthcare systems must prepare for the ongoing care needs of long COVID patients, which may consume resources and require specialized multidisciplinary teams. Research efforts continue to better understand the natural history of long COVID, identify risk factors for persistent symptoms, and develop targeted interventions. Large-scale longitudinal studies are crucial to elucidate the long-term trajectory of respiratory function in affected individuals and to tailor evidence-based treatments[12-13]. This paper aims to analyze the long-term effects of SARS-CoV-2 pneumonia on ventilatory function and lung diffusion capacity at different time points during a 24-month follow-up course. MATERIALS AND METHODS Subjects and measurements Ventilatory function and diffusion capacity of the lung of a selected population admitted to the Intensive Care Unit (ICU) of the ASST – Spedali Civili di Brescia, Brescia, Italy, and survived severe SARS-CoV-2 pneumonia has been analyzed at 6, 12, 18, and 24 months after hospital discharge. Enrolled patients had to meet the following criteria: age over 18, a laboratory-confirmed SARS-COV2 infection documented through real-time reverse transcription-polymerase chain reaction (RT-PCR), pulmonary involvement diagnosed with clinical evaluation and chest X-ray or HRCT imaging, and critical disease state with the need for noninvasive (NIV) and/or orotracheal intubation (IOT) mechanical ventilation. Patients who could not perform spirometry and those with a history of known obstructive, restrictive, or mixed ventilatory defects caused by previous respiratory diseases were excluded from the study. A physical examination and complete pulmonary function test with maximal flow-volume curve, lung volumes, and Lung Diffusion Capacity for Carbon Monoxide (DLCO) measurements were performed for each patient. Recorded parameters were slow and forced vital capacity (VC and FVC), forced expiratory volume at the first second of maximal expiration (FEV1), and FEV1/VC % ratio. Lung volumes were measured through the inert gas dilution technique using the Helium closed-circuit multi-breaths method, including functional residual capacity (FRC) residual volume (RV) and total lung capacity (TLC), while DLCO along with alveolar volume (VA) and coefficient transfer for CO (KCO) through single breath technique (BIOMEDIN Instruments, Padua, Italy). DLCO and KCO have been adjusted for patients’ hemoglobin levels. Subjects who achieved FEV1/VC % ratio > LLN, values of Total Lung Capacity (TLC) > 80% pred. and DLCO > 80% pred. during follow-ups were considered as normalized and exited the study. In the presence of FEV1/VC % ratio > LLN, values of Total Lung Capacity (TLC) < 80% pred. and DLCO < 80% pred. were chosen to identify the presence of restrictive ventilatory defect and/or lung diffusion capacity reduction, respectively and were followed until normalization or otherwise until the follow-up end at 24 months. Patients who stopped attending visits were considered lost to follow-up. Data were described according to the pulmonary function test results, and a dedicated database, reporting demographic data, BMI, and relative percentages of the predicted values for respiratory function parameters such as TLC, Alveolar Volume (VA), KCO, and DLCO was designed. The study was performed in accordance with the Helsinki Declaration and approved by the Ethics Committee of the University of Brescia’s Department of Clinical and Experimental Science (DSCS) Ethics Committee. All participants signed written informed consent upon enrolling. Data were expressed as mean ± standard deviation (SD), and categorical variables were recorded as frequencies and percentages. Where applicable, demographic data of the recruited population were analyzed with the Student’s t-test for continuous variables and Fischer’s exact test for categorical variables. The Kaplan-Meier model examined the median time to normalization of respiratory function. The association between the normalization of spirometry parameters and demographic characteristics of the recruited population was studied by semi-parametric Cox regression analysis. This model estimates the effect of independent variables on the risk of an event at a given time using a time-based risk function. The Hazard Ratio (HR) derived from this analysis is an index that measures the effect of predictor variables on the risk of an event. An HR > 1 indicates that an increase in the predictor variable is associated with an increase in the risk of the event. An HR < 1 indicates that an increase in the predictor variable is associated with a decrease in the risk of the event. A HR = 1 indicates that the predictor variable does not affect the risk of the event. Survival analysis was performed considering fixed timepoint data in which hospitalization is the starting point (t0), the last follow-up corresponds to the right limit of the interval (tR), and the previous follow-up point corresponds to the left limit of the interval (tL). Statistical significance was assessed for p-values < 0.05. All analyses were performed with R software (version 4.4.0) [14]. RESULTS The study was conducted from March 2020 to April 2023. 222 patients discharged from the ICU department of the ASST - Spedali Civili di Brescia for severe SARS-CoV-2 pneumonia were enrolled during the study period. Enrolled patients underwent sequential follow-up evaluations at 6, 12, 18, and 24 months. 172 patients (77%) completed the study, while 51 (23%) were lost during follow-up. Among the patients who completed the follow-up series, 140 (63%) achieved normalization of respiratory function and pulmonary diffusion parameters, while 32 (14%) showed persistent ventilatory and/or diffusive deficit (Figure 1). The demographics of the population recruited in the study are presented in Table 1. A significantly higher percentage of male subjects (71.62%) than female subjects (28.38%) has been documented (p < 0.001). The mean age of the population is 61.34 years, while the mean weight and height are 85.5 kg and 1.68 m, respectively, with a mean BMI of 30.1. The male population has significantly higher mean values for weight and height than females. Analyzing the timing of normalization of both ventilatory function parameters and lung diffusing capacity, a median time of 4.5 months (95% CI=1.5-NA) has been documented. This finding is influenced by age as the Hazard Ratio of normalization decreases by 2% as each year increases (HR=0.98, 95% CI=0.97-0.99, p=0.047) (Figure 2). The analysis of individual respiratory function parameters revealed a median normalization time of 1.5 months for VC, FVC, FEV 1 , Tiffeneau index, TLC, and KCO regardless of the influence of demographic factors such as gender, age, and BMI, with the only exceptions of the Tiffeneau index in which the Hazard Ratio indicates a 42.4% reduced odds of normalization in male subjects (HR=0.576, 95% CI=0.388-0.857, p=0.006) and KCO in which the Hazard Ratio indicates a 116% increased odds of normalization in obese subjects (HR=2.16, 95% CI=1.24-3.77, p=0.007). The median time to VA normalization was 4.5 months (95% CI=1.5-NA), a result influenced, again, by male sex, in which the Hazard Ratio indicates 40.1% reduced odds of normalization (HR=0.599, 95% CI=0.388-0.857, p=0.006). Finally, the median time to DLCO recovery was 9.0 months (95% CI=1.5-NA), a result influenced by age and BMI. The Hazard Ratio indicates a reduced odds of normalization of 3.1% as each year increases (HR=0.969, 95% CI=0.949-0.988, p=0.002) and, in contrast, 226% increased odds of normalization in obese subjects (HR=3.26, 95% CI=0.709-3.14, p=0.003). DISCUSSION The results characterized the recovery timing of the main respiratory parameters, including lung diffusing capacity, and identified the main demographic factors capable of increasing or decreasing the odds of normalization over time in patients who suffered from severe SARS-CoV-2-related pneumonia. The normalization timing analysis of respiratory function shows that 24 months after hospital discharge, about 19% of the recruited population had persistent ventilatory (mainly restrictive) and/or diffusive deficits. Currently, only two studies in the literature evaluated the sequelae of SARS-CoV-2 infection on respiratory function at least 24 months after hospital discharge, and both corroborate what has been documented in our work, especially regarding the diffusive defect persistence. Faverio et al. conducted a two-year follow-up and found that several subjects had persistent diffusing capacity (DLCO) impairment associated with restrictive lung patterns. Specifically, 49% of the population had DLCO values < 80% pred. [15]. Similarly, the study by Han et al. evaluated lung function and radiological findings in post-COVID-19 hospitalized patients three years after discharge. The results indicated that many participants had significant lung function abnormalities, including reduced DLCO and persistent radiological changes, such as ground-glass opacities and reticular patterns on chest imaging [16]. These data underline the chronic nature of lung damage following severe SARS-CoV-2 pneumonia and the need to set up long-term follow-ups. It is known from the literature that various factors, including age, sex, and obesity, influence the recovery of respiratory function in patients with severe forms of SARS-CoV-2 pneumonia. Each factor significantly determines the recovery time of ventilatory function and lung diffusing capacity [17-20]. Our study showed how the normalization odds for ventilatory function and diffusing capacity of the lung, particularly DLCO, progressively decrease by 2% as each year of age rises. This finding is consistent with what is known in the literature, where age has been reported to be a recovery time determinant after SARS-CoV-2 pneumonia. The elderly population is generally more susceptible to severe respiratory infections and shows prolonged recovery time due to age-related physiological changes, including decreased lung function and altered immune responses. Aging is also associated with increased susceptibility to acute lung injury and chronic pulmonary sequelae after viral pneumonia [21-22]. Also, the elderly population had more severe disease manifestations, resulting in longer recovery periods [23]. Another factor that can reduce the odds of normalization of the main respiratory function parameters, particularly the Alveolar Volume (VA), is male gender. Again, the literature confirms what we have documented. Male patients tend to have longer recovery times than females. This disparity may be attributed to differences in immune responses, with women often showing a more robust immune response to viral infections [24]. In addition, the presence of comorbidities, which are more prevalent in the male sex, can further complicate recovery [25]. Finally, it should also be considered how the impact of the immune response is influenced by genetic and hormonal factors [26]. Another demographic factor that can affect the normalization odds is obesity. Our study documented how obesity increases the odds of normalization of lung diffusing capacity parameters, particularly DLCO and KCO. In this case, what we documented is not unanimously confirmed in the literature. In fact, obese patients often experience slower DLCO recovery than non-obese ones. This phenomenon could be attributed to several obesity-related factors, such as increased susceptibility to developing a fibrotic lung pattern, chronic pro-inflammatory status, excessive oxidative stress, impaired immunity, and cytokine signaling deregulation [27]. Also, several studies identified obesity as a prognostic factor that can increase the risk of developing long-term pulmonary complications that may further delay the DLCO normalization after Sars-CoV-2 infection [28-29]. In contrast, our findings, showing a faster normalization of the respiratory function in relation to obesity, may be explained by the fact that our recruited population, both men and women, showed a high basal mean BMI. This issue may have reduced population heterogeneity, thus influencing our respiratory function and lung diffusion normalization assessments related to obesity status. Another aspect that needs to be considered is that obese subjects have a higher tendency to develop collateral microcirculation [30]. This could influence the alveolar-capillary membrane gas exchanges, which in subjects with severe forms of SARS-CoV-2 pneumonia are impaired due to microthrombi formation, by increasing pulmonary capillary blood volume (Vc) as shown in studies on DLNO/DLCO ratios [31-32]. Also, it is fundamental to recall that obese subjects, especially those with low comorbidities, have higher baseline DLCO values than non-obese, likely due to greater KCO over time because of increasing Vc. [33-34]. For this reason, the decrease in lung diffusion capacity caused by SARS-CoV-2 pneumonia might find partial mitigation due to constitutively higher DLCO and KCO values. Therefore, obese subjects, while taking longer to return to their baseline lung diffusion values, may still achieve normalized (> 80% pred.) DLCO and KCO values in a shorter amount of time than non-obese subjects. This possibility is further supported by our analysis of median normalization times where, although DLCO showed a median normalization time of 9 months, its major determinants (KCO and VA) had shorter normalization times (4.5 and 1.5 months, respectively). Therefore, it would be advisable to investigate this aspect further to tailor dedicated clinical recovery protocols for this type of patient. CONCLUSIONS This study provides valuable insights into the long-term effects of SARS-CoV-2 pneumonia on ventilatory function and lung diffusion capacity. The findings suggest that a significant proportion of patients, particularly those with severe disease, experience persistent ventilatory and diffusive impairments up to 24 months after hospital discharge. Age, sex, and obesity were identified as key demographic factors influencing the odds of normalization of ventilatory function and diffusing capacity of the lung. While age and male gender were found to decrease the normalization odds, obesity seems to increase them for parameters like DLCO and KCO. To the best of our knowledge, this is one of the few follow-up studies conducted on patients who survived SARS-CoV-2 pneumonia that evaluates a two-year time window and specifically the only one focusing exclusively on severe forms that required prolonged ICU stays with the need for ventilatory support. The present findings suggest the importance of long-term follow-up and personalized care for patients with severe SARS-CoV-2 pneumonia and the need for further research to better understand the mechanisms that promote or delay their respiratory function recovery and tailor targeted interventions. ACKNOWLEDGMENTS Study Design: LP and CT Data Collection: MG, SP, EP, and AAD Data Analysis: RB, JG, GL Results interpretation: MG, JG and CT First Draft: JG and CT Manuscript revision: All Authors Manuscript approval upon submission: All Authors Conflict Of Interests The authors declare no conflict of interest in this work. Data Sharing Statement The data supporting the findings of this study are available from the corresponding author upon reasonable request. REFERENCES 1. Koc, H. C., Xiao, J., Liu, W., Li, Y., & Chen, G. (2022). Long COVID and its Management. International journal of biological sciences, 18(12), 4768–4780. 2. Scholkmann, F., & May, C. A. (2023). COVID-19, post-acute COVID-19 syndrome (PACS, ”long COVID”) and post-COVID-19 vaccination syndrome (PCVS, ”post-COVIDvac-syndrome”): Similarities and differences. Pathology, research and practice, 246, 154497. 3. Lechner-Scott, J., Levy, M., Hawkes, C., Yeh, A., & Giovannoni, G. (2021). Long COVID or post COVID-19 syndrome. Multiple sclerosis and related disorders, 55, 103268. 4. Turner, S., Khan, M. A., Putrino, D., Woodcock, A., Kell, D. B., & Pretorius, E. (2023). Long COVID: pathophysiological factors and abnormalities of coagulation. Trends in endocrinology and metabolism: TEM, 34(6), 321–344. 5. Constantinescu-Bercu, A., Lobiuc, A., Căliman-Sturdza, O. A., Oiţă, R. C., Iavorschi, M., Pavăl, N. E., Șoldănescu, I., Dimian, M., & Covasa, M. (2023). Long COVID: Molecular Mechanisms and Detection Techniques. International journal of molecular sciences, 25(1), 408. 6. Orzes, N., Pini, L., Levi, G., Uccelli, S., Cettolo, F., & Tantucci, C. (2021). A prospective evaluation of lung function at three and six months in patients with previous SARS-COV-2 pneumonia. Respiratory medicine, 186, 106541. 7. Pini, L., Montori, R., Giordani, J., Guerini, M., Orzes, N., Ciarfaglia, M., Arici, M., Cappelli, C., Piva, S., Latronico, N., Muiesan, M. L., & Tantucci, C. (2023). Assessment of respiratory function and exercise tolerance at 4-6 months after COVID-19 infection in patients with pneumonia of different severity. Internal medicine journal, 53(2), 202–208. 8. Azim, A., Pini, L., Khakwani, Z., Kumar, S., & Howarth, P. (2021). Severe acute respiratory syndrome coronavirus 2 infection in those on mepolizumab therapy. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology, 126(4), 438–440. 9. Latronico, N., Peli, E., Calza, S., Rodella, F., Novelli, M. P., Cella, A., Marshall, J., Needham, D. M., Rasulo, F. A., Piva, S., & LOTO Investigators (2022). Physical, cognitive and mental health outcomes in 1-year survivors of COVID-19-associated ARDS. Thorax, 77(3), 300–303. 10. Chuang, H. J., Lin, C. W., Hsiao, M. Y., Wang, T. G., & Liang, H. W. (2024). Long COVID and rehabilitation. Journal of the Formosan Medical Association = Taiwan yi zhi, 123 Suppl 1, S61–S69. 11. Besnier, F., Bérubé, B., Malo, J., Gagnon, C., Grégoire, C. A., Juneau, M., Simard, F., L’Allier, P., Nigam, A., Iglésies-Grau, J., Vincent, T., Talamonti, D., Dupuy, E. G., Mohammadi, H., Gayda, M., & Bherer, L. (2022). Cardiopulmonary Rehabilitation in Long-COVID-19 Patients with Persistent Breathlessness and Fatigue: The COVID-Rehab Study. International journal of environmental research and public health, 19(7), 4133. 12. Pye, A., Roberts, S. R., Blennerhassett, A., Iqbal, H., Beenstock, J., & Iqbal, Z. (2023). A public health approach to estimating the need for long COVID services. Journal of public health (Oxford, England), 45(1), 169–175. 13. The Lancet Respiratory Medicine (2023). Long COVID: confronting a growing public health crisis. The Lancet. Respiratory medicine, 11(8), 663. 14. R Core Team (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 15. Faverio, P., Paciocco, G., Tassistro, E., Rebora, P., Rossi, E., Monzani, A., Tundo, M., Milano, C., Messa, M., Marocchi, R., Pesci, A., Foti, G., Squillace, N., Cogliandro, V., Lettino, M., Strepparava, M. G., Bellelli, G., Ferrarese, C., Valsecchi, M. G., Bonfanti, P., … STORM Long-COVID Team (2024). Two-year cardio-pulmonary follow-up after severe COVID-19: a prospective study. Internal and emergency medicine, 19(1), 183–190. 16. Han, X., Chen, L., Guo, L., Wu, L., Alwalid, O., Liu, J., Zheng, Y., Chen, L., Wu, W., Li, H., Luo, Q., Zhao, H., Zhang, L., Bai, Y., Sun, B., Sun, T., Gui, Y., Nie, T., Chen, L., Yang, F., … Zheng, C. (2024). Long-term radiological and pulmonary function abnormalities at 3 years after COVID-19 hospitalization: a longitudinal cohort study. The European respiratory journal, 64(1), 2301612. 17. Voinsky, I., Baristaite, G., & Gurwitz, D. (2020). Effects of age and sex on recovery from COVID-19: Analysis of 5769 Israeli patients. The Journal of infection, 81(2), e102–e103. 18. PHOSP-COVID Collaborative Group (2022). Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. The Lancet. Respiratory medicine, 10(8), 761–775. 19. Oelsner, E. C., Sun, Y., Balte, P. P., Allen, N. B., Andrews, H., Carson, A., Cole, S. A., Coresh, J., Couper, D., Cushman, M., Daviglus, M., Demmer, R. T., Elkind, M. S. V., Gallo, L. C., Gutierrez, J. D., Howard, V. J., Isasi, C. R., Judd, S. E., Kanaya, A. M., Kandula, N. R., … Post, W. S. (2024). Epidemiologic Features of Recovery From SARS-CoV-2 Infection. JAMA network open, 7(6), e2417440. 20. Galindo-Oseguera, E., Pinto-Almazán, R., Arellano-Ramírez, A., Gasca-López, G. A., Ocharan-Hernández, M. E., Calzada-Mendoza, C. C., Castillo-Cruz, J., & Martínez-Herrera, E. (2023). Mortality and Survival Factors in Patients with Moderate and Severe Pneumonia Due to COVID-19. Healthcare (Basel, Switzerland), 11(7), 932. 21. Goplen, N. P., Wu, Y., Son, Y. M., Li, C., Wang, Z., Cheon, I. S., Jiang, L., Zhu, B., Ayasoufi, K., Chini, E. N., Johnson, A. J., Vassallo, R., Limper, A. H., Zhang, N., & Sun, J. (2020). Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia. Science immunology, 5(53), eabc4557. 22. Morales-Nebreda, L., Helmin, K. A., Torres Acosta, M. A., Markov, N. S., Hu, J. Y., Joudi, A. M., Piseaux-Aillon, R., Abdala-Valencia, H., Politanska, Y., & Singer, B. D. (2021). Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia. JCI insight, 6(6), e141690. 23. McQuattie-Pimentel, A. C., Ren, Z., Joshi, N., Watanabe, S., Stoeger, T., Chi, M., Lu, Z., Sichizya, L., Aillon, R. P., Chen, C. I., Soberanes, S., Chen, Z., Reyfman, P. A., Walter, J. M., Anekalla, K. R., Davis, J. M., Helmin, K. A., Runyan, C. E., Abdala-Valencia, H., Nam, K., … Budinger, G. R. S. (2021). The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging. The Journal of clinical investigation, 131(4), e140299. 24. Gualtieri, P., Marchetti, M., Renzo, L. D., De Santis, G. L., Palma, R., Colica, C., Frank, G., De Lorenzo, A., & Di Lorenzo, N. (2022). Impact of COVID-19 on the Destiny of Bariatric Patients. Nutrients, 15(1), 163. 25. Wu, Z. H., Tang, Y., & Cheng, Q. (2021). Diabetes increases the mortality of patients with COVID-19: a meta-analysis. Acta diabetologica, 58(2), 139–144. 26. Roux, H. M., Marouf, A., Dutrieux, J., Charmeteau-De Muylder, B., Figueiredo-Morgado, S., Avettand-Fenoel, V., Cuvelier, P., Naudin, C., Bouaziz, F., Geri, G., Couëdel-Courteille, A., Squara, P., Marullo, S., & Cheynier, R. (2023). Genetically determined thymic function affects strength and duration of immune response in COVID patients with pneumonia. Science advances, 9(38), eadh7969. 27. Briand, F., Sencio, V., Robil, C., Heumel, S., Deruyter, L., Machelart, A., Barthelemy, J., Bogard, G., Hoffmann, E., Infanti, F., Domenig, O., Chabrat, A., Richard, V., Prévot, V., Nogueiras, R., Wolowczuk, I., Pinet, F., Sulpice, T., & Trottein, F. (2022). Diet-Induced Obesity and NASH Impair Disease Recovery in SARS-CoV-2-Infected Golden Hamsters. Viruses, 14(9), 2067. 28. de Roos, M. P., Siegerink, S., Dijkstra, N. G., Broekman, B. F., Brinkman, K., Jonkman, N. H., & Bresser, P. (2022). Pulmonary function and Quality of Life in a prospective cohort of (non-) hospitalized COVID-19 pneumonia survivors up to six months. Chronic respiratory disease, 19, 14799731221114271. ?? 29. Sonnweber, T., Sahanic, S., Pizzini, A., Luger, A., Schwabl, C., Sonnweber, B., Kurz, K., Koppelstätter, S., Haschka, D., Petzer, V., Boehm, A., Aichner, M., Tymoszuk, P., Lener, D., Theurl, M., Lorsbach-Köhler, A., Tancevski, A., Schapfl, A., Schaber, M., Hilbe, R., … Tancevski, I. (2021). Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial. The European respiratory journal, 57(4), 2003481. ?? 30. Rutkowski, J. M., Davis, K. E., & Scherer, P. E. (2009). Mechanisms of obesity and related pathologies: the macro- and microcirculation of adipose tissue. The FEBS journal, 276(20), 5738–5746. 31. Imeri, G., Conti, C., Caroli, A., Arrigoni, A., Bonaffini, P., Sironi, S., Novelli, L., Raimondi, F., Chiodini, G., Vargiu, S., & Di Marco, F. (2024). Gas exchange abnormalities in Long COVID are driven by the alteration of the vascular component. Multidisciplinary respiratory medicine, 19(1), 938. 32. Seccombe, L. M., Heath, D., Farah, C. S., Di Michiel, J. R., Veitch, E. M., & Peters, M. J. (2023). Mechanisms of gas transfer impairment utilizing nitric oxide following severe COVID-19 pneumonitis. Physiological reports, 11(7), e15660. 33. Saydain, G., Beck, K. C., Decker, P. A., Cowl, C. T., & Scanlon, P. D. (2004). Clinical significance of elevated diffusing capacity. Chest, 125(2), 446–452. 34. Holley, A. B., Carbone, T., Holtzclaw, A. W., Huprikar, N. A., Wagner, R., & Morris, M. J. (2023). Obesity-related Changes in Diffusing Capacity and Transfer Coefficient of the Lung for Carbon Monoxide and Resulting Patterns of Abnormality across Reference Equations. Annals of the American Thoracic Society, 20(7), 969–975. FIGURE LEGENDS Figure 1: Characterization over time of the patient outcomes under the follow-up cycle at 6, 12, 18, and 24 months. Figure 2: Kaplan–Meier curves for recovery odds analysis with interval-censoring data analysis. The median time to recovery was 4.5 months (95%CI 1.5-NA). The recovery hazard ratio was lower as age increased (HR=0.98, 95% CI=0.97-0.99, p=0.046). 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Keywords dlco lung volumes pulmonary function test restrictive defect sars-cov-2 Authors Affiliations Pini Laura 0000-0001-6563-4942 [email protected] Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author Guerini Michele Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author Giordani Jordan Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author Guido Levi 0000-0002-7163-2270 Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia View all articles by this author Latronico Nicola Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia View all articles by this author Piva Simone Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia View all articles by this author Peli Elena Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia View all articles by this author Benoni Roberto Universita degli Studi di Verona Dipartimento di Diagnostica e Sanita Pubblica View all articles by this author Pini Alessandro Universita degli Studi di Firenze Dipartimento di Medicina Sperimentale e Clinica View all articles by this author Abou Daher Amir Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author Piras Stefano Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author El Masri Yehia Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author Visca Dina Universita degli Studi dell'Insubria Dipartimento di Medicina e Chirurgia View all articles by this author Caminati Marco 0009-0009-1134-059X Universita degli Studi di Verona Dipartimento di Medicina View all articles by this author Senna Gianenrico Universita degli Studi di Verona Dipartimento di Medicina View all articles by this author Muiesan Maria Lorenza Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author Tantucci Claudio Universita degli Studi di Brescia Dipartimento di Scienze Cliniche e Sperimentali View all articles by this author Metrics & Citations Metrics Article Usage 263 views 190 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Pini Laura, Guerini Michele, Giordani Jordan, et al. 24-Month assessment of respiratory function in patients hospitalized for severe Sars-Cov-2 pneumonia: a follow-up study. 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