Pulmonary Function and Radiologic Features in Survivors of Critical COVID-19
2021; Elsevier BV; Volume: 160; Issue: 1 Linguagem: Inglês
10.1016/j.chest.2021.02.062
ISSN1931-3543
AutoresJessica González, Iván D. Benítez, Paola Carmona, Sally Santisteve, Aída Monge, Anna Moncusí‐Moix, Clara Gort‐Paniello, Lucía Pinilla, Amara Carratalá, María Zuil, Ricard Ferrer, Adrián Ceccato, Laia Fernández‐Barat, Ana Motos, Jordi Riera, Rosario Menéndez, Darío García-Gasulla, Óscar Peñuelas, Jesús F. Bermejo-Martín, Gonzalo Labarca, Jesús Caballero, Gerard Torres, David de Gonzalo‐Calvo, Antoni Torres, Ferrán Barbé, Rosario Amaya Villar, José M. Añón, Carme Barberà, José Barberán, Aaron Blandino Ortíz, Elena Bustamante-Munguira, Jesús Caballero, Cristina Carbajales, Nieves Carbonell, Mercedes Catalán-González, Cristóbal Galbán‐Malagón, Victor Daniel Gumucio, María del Carmen de la Torre, Emili Dı́az, Ángel Estella, Elena Gallego, J.L. García Garmendia, José Garnacho‐Montero, José M. Gómez, Arturo Huerta, Ruth Noemí Jorge García, Ana Loza-Vázquez, Judith Marín‐Corral, Amalia Martínez de la Gándara, Ignacio Martínez Varela, Juan López Messa, Guillermo M. Albaiceta, Mariana Andrea Novo, Yhivian Peñasco, Juan Carlos Pozo-Laderas, Pilar Martí, Ferran Roche‐Campo, Ángel Sánchez-Miralles, Susana Sancho Chinesta, Lorenzo Socías, Jordi Solé‐Violán, Fernando Suárez-Sipmann, Luis Tamayo Lomas, Josep Trenado,
Tópico(s)Long-Term Effects of COVID-19
ResumoBackgroundMore than 20% of hospitalized patients with COVID-19 demonstrate ARDS requiring ICU admission. The long-term respiratory sequelae in such patients remain unclear.Research QuestionWhat are the major long-term pulmonary sequelae in critical patients who survive COVID-19?Study Design and MethodsConsecutive patients with COVID-19 requiring ICU admission were recruited and evaluated 3 months after hospitalization discharge. The follow-up comprised symptom and quality of life, anxiety and depression questionnaires, pulmonary function tests, exercise test (6-min walking test [6MWT]), and chest CT imaging.ResultsOne hundred twenty-five patients admitted to the ICU with ARDS secondary to COVID-19 were recruited between March and June 2020. At the 3-month follow-up, 62 patients were available for pulmonary evaluation. The most frequent symptoms were dyspnea (46.7%) and cough (34.4%). Eighty-two percent of patients showed a lung diffusing capacity of less than 80%. The median distance in the 6MWT was 400 m (interquartile range, 362-440 m). CT scans showed abnormal results in 70.2% of patients, demonstrating reticular lesions in 49.1% and fibrotic patterns in 21.1%. Patients with more severe alterations on chest CT scan showed worse pulmonary function and presented more degrees of desaturation in the 6MWT. Factors associated with the severity of lung damage on chest CT scan were age and length of invasive mechanical ventilation during the ICU stay.InterpretationThree months after hospital discharge, pulmonary structural abnormalities and functional impairment are highly prevalent in patients with ARDS secondary to COVID-19 who required an ICU stay. Pulmonary evaluation should be considered for all critical COVID-19 survivors 3 months after discharge. More than 20% of hospitalized patients with COVID-19 demonstrate ARDS requiring ICU admission. The long-term respiratory sequelae in such patients remain unclear. What are the major long-term pulmonary sequelae in critical patients who survive COVID-19? Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated 3 months after hospitalization discharge. The follow-up comprised symptom and quality of life, anxiety and depression questionnaires, pulmonary function tests, exercise test (6-min walking test [6MWT]), and chest CT imaging. One hundred twenty-five patients admitted to the ICU with ARDS secondary to COVID-19 were recruited between March and June 2020. At the 3-month follow-up, 62 patients were available for pulmonary evaluation. The most frequent symptoms were dyspnea (46.7%) and cough (34.4%). Eighty-two percent of patients showed a lung diffusing capacity of less than 80%. The median distance in the 6MWT was 400 m (interquartile range, 362-440 m). CT scans showed abnormal results in 70.2% of patients, demonstrating reticular lesions in 49.1% and fibrotic patterns in 21.1%. Patients with more severe alterations on chest CT scan showed worse pulmonary function and presented more degrees of desaturation in the 6MWT. Factors associated with the severity of lung damage on chest CT scan were age and length of invasive mechanical ventilation during the ICU stay. Three months after hospital discharge, pulmonary structural abnormalities and functional impairment are highly prevalent in patients with ARDS secondary to COVID-19 who required an ICU stay. Pulmonary evaluation should be considered for all critical COVID-19 survivors 3 months after discharge. FOR EDITORIAL COMMENT, SEE PAGE 15In December 2019, SARS-CoV-21Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;22;395(10224):565-574.Google Scholar was identified as the cause of COVID-19. Through person-to-person transmission,2Li Q. Guan X. Wu P. et al.Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.N Engl J Med. 2020; 382: 1199-1207Crossref PubMed Scopus (10590) Google Scholar it spread rapidly across China3Toit A Du Outbreak of a novel coronavirus.Nat Rev Microbiol. 2020; 18: 123Crossref PubMed Scopus (205) Google Scholar and many other countries,4Holshue M.L. DeBolt C. Lindquist S. et al.First case of 2019 novel coronavirus in the United States.N Engl J Med. 2020; 382: 929-936Crossref PubMed Scopus (4257) Google Scholar causing a global pandemic and a public health emergency of international concern.5Sohrabi C. Alsafi Z. O'Neill N. et al.World Health Organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19).Int J Surg. 2020; 76: 71-76Crossref PubMed Scopus (3432) Google Scholar By October 3, 2020, there were 34,680,199 confirmed cases, including 1,029,525 deaths globally. FOR EDITORIAL COMMENT, SEE PAGE 15 SARS-CoV-2 infection has a wide range of clinical presentations, with the majority of patients having mild disease with a favorable prognosis.6Cascella M. Rajnik M. Aleem A. Dulebohn S.C. Di Napoli R. Features, evaluation, and treatment of coronavirus (COVID-19).in: StatPearls [Internet]. StatPearls Publishing, 2021Google Scholar However, for a significant proportion of hospitalized patients (20%-67%), SARS-CoV-2 may cause severe illness with rapid disease progression resulting in ARDS.7Wang D. Hu B. Hu C. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16038) Google Scholar,8Yang X. Yu Y. 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This syndrome is defined as "new or worsening impairment in physical, cognitive or mental status arising after critical illness and persisting beyond discharge from the acute care setting."10Rawal G. Yadav S. Kumar R. Post-intensive care syndrome: an overview.J Transl Intern Med. 2017; 5: 90-92Crossref PubMed Google Scholar After ARDS, regardless of its origin, patients frequently show several functional impairments across biopsychosocial domains.11Herridge M.S. Moss M. Hough C.L. et al.Recovery and outcomes after the acute respiratory distress syndrome (ARDS) in patients and their family caregivers.Intensive Care Med. 2016; 42: 725-738Crossref PubMed Scopus (278) Google Scholar Similarly, lung damage, impaired lung function, and psychological impairment are common and can last for months or even years in patients who have recovered from other types of coronavirus pneumonia, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).12Ahmed H. Patel K. Greenwood D.C. et al.Long-term clinical outcomes in survivors of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus outbreaks after hospitalisation or ICU admission: a systematic review and meta-analysis.J Rehabil Med. 2020; 52: jrm00063PubMed Google Scholar,13Chan K.S. Zheng J.P. Mok Y.W. et al.SARS: prognosis, outcome and sequelae.Respirology. 2003; 8: S36-S40Crossref PubMed Scopus (182) Google Scholar In follow-up studies of these patients lasting 0.3 to 2 years,14Hui D.S. Joynt G.M. Wong K.T. et al.Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors.Thorax. 2005; 60: 401-409Crossref PubMed Scopus (354) Google Scholar,15Ngai J.C. Ko F.W. Ng S.S. To K.W. Tong M. Hui D.S. The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status.Respirology. 2010; 15: 543-550Crossref PubMed Scopus (345) Google Scholar impaired lung diffusing capacity for carbon monoxide (Dlco), defective total lung capacity (TLC), and poor 6-min walking test (6MWT) outcomes were the most common lung function abnormalities. Moreover, approximately one-third of SARS and MERS survivors may have psychological dysfunction, such as depression and anxiety, beyond 6 months.12Ahmed H. Patel K. Greenwood D.C. et al.Long-term clinical outcomes in survivors of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus outbreaks after hospitalisation or ICU admission: a systematic review and meta-analysis.J Rehabil Med. 2020; 52: jrm00063PubMed Google Scholar Regarding SARS-CoV-2, recent research has demonstrated that nearly half of discharged patients show residual abnormalities on chest CT scan.16Huang Y. Tan C. Wu J. et al.Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase.Respir Res. 2020; 21: 163Crossref PubMed Scopus (336) Google Scholar,17Li K. Fang Y. Li W. et al.CT image visual quantitative evaluation and clinical classification of coronavirus disease (COVID-19).Eur Radiol. 2020; 30: 4407-4416Crossref PubMed Scopus (482) Google Scholar Moreover, these studies showed that in early convalescence (1 month after discharge), approximately three-quarters of patients with COVID-19 demonstrated pulmonary function impairment, represented most frequently again by declines in Dlco.16Huang Y. Tan C. Wu J. et al.Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase.Respir Res. 2020; 21: 163Crossref PubMed Scopus (336) Google Scholar A recent study of patients with noncritical disease18Zhao Y.M. Shang Y.M. Song W.B. et al.Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.EClinicalMedicine. 2020; 25: 100463Abstract Full Text Full Text PDF PubMed Scopus (570) Google Scholar demonstrated that a considerable proportion of COVID-19 survivors showed radiologic (70%) and pulmonary function (25%) abnormalities 3 months after discharge. Although short-term radiologic and pulmonary function outcomes have been reported16Huang Y. Tan C. Wu J. et al.Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase.Respir Res. 2020; 21: 163Crossref PubMed Scopus (336) Google Scholar,19Mo X. Jian W. Su Z. et al.Abnormal pulmonary function in COVID-19 patients at time of hospital discharge.Eur Respir J. 2020; 55: 2001217Crossref PubMed Scopus (517) Google Scholar in patients with noncritical disease, little is known about the outcomes of patients with critical COVID-19 3 months after discharge. Furthermore, ARDS resulting from COVID-19 shows a unique phenotype20Gattinoni L. Coppola S. Cressoni M. et al.COVID-19 does not lead to a "typical" acute respiratory distress syndrome.Am J Respir Crit Care Med. 2020; 201 (1299-1300)Crossref Scopus (957) Google Scholar,21Filbin MR, Mehta A, Schneider AM, et al. Plasma proteomics reveals tissue-specific cell death and mediators of cell-cell interactions in severe COVID-19 patients. bioRxiv [Preprint]. 2020 Nov 3:2020.11.02.365536.Google Scholar that requires different management strategies for ARDS in the acute phase22Marini J.J. Gattinoni L. Management of COVID-19 respiratory distress.JAMA. 2020; 323: 2329-2330Crossref PubMed Scopus (733) Google Scholar,23Bain W. Yang H. Shah F.A. et al.COVID-19 versus non-COVID ARDS: comparison of demographics, physiologic parameters, inflammatory biomarkers and clinical outcomes [published online ahead of print February 5, 2021].Ann Am Thorac Soc. 2021; https://doi.org/10.1513/AnnalsATS.202008-1026OCCrossref PubMed Scopus (82) Google Scholar and a more exhaustive and close short-term follow-up,24van Gassel RJJ Bels J.L.M. Raafs A. et al.High prevalence of pulmonary sequelae at 3 months after hospital discharge in mechanically ventilated survivors of COVID-19.Am J Respir Crit Care Med. 2021; 203: 371-374Crossref PubMed Scopus (84) Google Scholar including respiratory, mental health, and quality of life assessment. Herein, we report the first descriptive observational cohort of recruited patients with COVID-19 who underwent an ICU stay. Participants were followed up 3 after months hospital discharge and underwent an evaluation of symptoms (involving the Short-Form Health Survey [SF-12] and Hospital Anxiety and Depression Scale [HADS]) and characterization of pulmonary function, including lung volume (TLC and residual volume), Dlco assessments, and 6MWT assessment. Moreover, we performed chest CT scan. The study was approved by the Medical Ethics Committee of Hospital Universitary Arnau de Vilanova (Identifier: CEIC/2273). Informed consent was acquired for most patients by using emergency consent mechanisms in accordance with the ethics approval guidelines for the study. This was a descriptive observational study performed to include all patients who experienced a critical care admission resulting from COVID-19 in Hospital Universitari Arnau de Vilanova and Hospital Universitari Santa Maria in Lleida, Spain, between March and June 2020. The study is a subset of the ongoing multicenter study Centro de Investigación Biomédica En Red Enfermedades Respiratorias Unidad de Cuidados Intensivos COVID (ClinicalTrials.gov Identifier: NCT04457505). The main objective was to determine the risk of and prognostic factors for critical illness in patients with COVID-19, as well as the impact of COVID-19 on respiratory and cardiovascular function within the first year of follow-up. All patients showed positive results for SARS-CoV-2, were older than 18 years, met the Berlin definition of ARDS,25Ranieri V.M. Rubenfeld G.D. Thompson B.T. et al.Acute respiratory distress syndrome: the Berlin definition.JAMA. 2012; 307: 2526-2533Crossref PubMed Scopus (7584) Google Scholar and had undergone an ICU stay. Patients were unable to follow-up if they were transferred to another hospital during ICU hospitalization or later, if they were receiving palliative care, or if they had a severe mental disability that made it impossible to carry out pulmonary function tests after discharge. Patient sociodemographic and comorbidity data were obtained. Clinical, vital, ventilatory, and laboratory parameters were recorded at ICU admission. The latter included general blood tests with acute markers of inflammation, such as D-dimer, ferritin, C-reactive protein, procalcitonin, lactate dehydrogenase, and fibrinogen. In addition to the baseline records, we collected data such as length of stay and the need for and duration of invasive and noninvasive mechanical ventilation, including high-flow nasal canula and prone positioning, during the ICU stay. General and respiratory symptoms, including anosmia, ageusia, fever, dry and wet cough, wheeze, dyspnea measured by the modified Medical Research Council, asthenia, and muscular fatigue, were assessed in the consultation. To complete the clinical evaluation, answers to the SF-12 and the HADS questionnaire were self-reported by all patients. The SF-12 is a well-known health-related quality-of-life questionnaire consisting of 12 questions that measure eight health domains to assess physical and mental health. These eight multi-item variables include general health, physical functioning, role physical, body pain, vitality, social functioning, role emotional, and mental health. This questionnaire has been validated in healthy populations and in patients with several chronic diseases and conditions.26Mols F. Pelle A.J. Kupper N. Normative data of the SF-12 health survey with validation using postmyocardial infarction patients in the Dutch population.Qual Life Res. 2009; 18: 403-414Crossref PubMed Scopus (149) Google Scholar,27Cheak-Zamora N.C. Wyrwich K.W. McBride T.D. Reliability and validity of the SF-12v2 in the medical expenditure panel survey.Qual Life Res. 2009; 18: 727-735Crossref PubMed Scopus (262) Google Scholar The SF-12 was scored according to the normative standards established by Ware et al28Ware J.E. Kosinski M. Keller S.D. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity.Med Care. 1996; 34: 220-233Crossref PubMed Scopus (13449) Google Scholar such that persons with a normal health-related quality of life would have an average SF-12 score of 50, with an SD of 10. This scoring system can be used to assess the degree of well-being and functional status of people older than 14 years, identifying positive and negative physical health and mental health states, through the analysis of eight dimensions. Scores of < 50 indicate a poor health-related quality of life, whereas scores of > 50 indicate a good health-related quality of life. Its use to evaluate the functional status after hospitalization in patients who survived ARDS has been validated.29Biehl M. Kashyap R. Ahmed A.H. et al.Six-month quality-of-life and functional status of acute respiratory distress syndrome survivors compared to patients at risk: a population-based study.Crit Care. 2015; 19: 356Crossref PubMed Scopus (34) Google Scholar The HADS is a 14-item self-report screening scale that was developed originally to indicate the possible presence of anxiety and depression states in medical nonpsychiatric outpatient clinic settings.30Zigmond A.S. Snaith R.P. The Hospital Anxiety and Depression Scale.Acta Psychiatr Scand. 1983; 67: 361-370Crossref PubMed Scopus (34059) Google Scholar The HADS assesses symptoms over the preceding week and consists of a seven-item anxiety subscale and a seven-item depression subscale. Each item on the questionnaire is scored as 0 to 3, with a maximum score of 21. A general cutoff of 8 of 21 is used to identify a possible case of anxiety or depression.31Bjelland I. Dahl A.A. Haug T.T. Neckelmann D. The validity of the Hospital Anxiety and Depression Scale: an updated literature review.J Psychosom Res. 2002; 52: 69-77Crossref PubMed Scopus (7422) Google Scholar Airway function (spirometry, lung volume, and diffusing capacity) was measured in all participants using a flow spirometer (MasterScreen; Jaeger) according to the guidelines of the American Thoracic Society.32Celli B.R. MacNee W. Agusti A. et al.Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.Eur Respir J. 2004; 23: 932-946Crossref PubMed Scopus (3614) Google Scholar Pulmonary parameters included TLC, FVC, residual volume, FEV1, FEV1 to FVC ratio, and Dlco. The results were expressed as a percentage of the predicted value according to the European Community Lung Health Survey.33Roca J. Burgos F. Sunyer J. et al.References values for forced spirometry.Eur Respir J. 1998; 11: 1354-1362Crossref PubMed Scopus (250) Google Scholar Additionally, spirometric postbronchodilation measurements were determined 15 min after inhalation of 400 μg of salbutamol. The 6MWT was performed according to the current American Thoracic Society guidelines.34Crapo R.O. Casaburi R. Coates A.L. et al.ATS statement: guidelines for the six-minute walk test.Am J Respir Crit Care Med. 2002; 166: 111-117Crossref PubMed Scopus (8776) Google Scholar Patients were scanned using a 16- and 64-slice multidetector CT scanner (Brilliance 16 and 64; Philips Healthcare) with the following scan parameters: 16 × 1.5-mm slice collimation, 0.75-s gantry rotation time, 120-kV tube voltage, and 3-mm section thickness with a 1.5-mm reconstruction interval. Images were acquired with patients in the supine position in the craniocaudal direction at end-inspiration. The resulting images were visualized with an image archiving and communication system with standard lung (level, –450 Hounsfield units [HU]; width, 1,600 HU) and mediastinal (level, 40 HU; width, 400 HU) windows. Chest CT imaging was not performed or was not available for five patients. All CT images were reviewed by a pulmonologist (J. G.) with experience in imaging who was blinded to the clinical data. CT images were evaluated as described previously17Li K. Fang Y. Li W. et al.CT image visual quantitative evaluation and clinical classification of coronavirus disease (COVID-19).Eur Radiol. 2020; 30: 4407-4416Crossref PubMed Scopus (482) Google Scholar for the presence of the following characteristics: (1) density: ground-glass opacities, mixed ground-glass opacities, or consolidation; (2) internal structures: air bronchogram, interlobular septal thickening, cavitation, pulmonary nodules; (3) number of lobes affected by ground-glass or consolidative opacities; (4) fibrotic or reticular lesions; (5) pleural effusion; (6) thoracic lymphadenopathy; and (7) underlying lung disease (TB, emphysema, or interstitial lung disease). Fibrotic pattern was defined according to the Fleischner Society glossary of terms for thoracic imaging: reticulation, architectural distortion, traction bronchiectasis, and honey combing.35Lynch D.A. Sverzellati N. Travis W.D. et al.Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper.Lancet Respir Med. 2018; 6: 138-153Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar Because of the nature and the atypical presentation of COVID-19, most frequently we saw these components separately, and the clinical image did not fit into a classic interstitial lung disease pattern. The coexistence of ground-glass opacities with a predominantly upper and sometimes bilateral, but usually asymmetrical (often unilateral), presentation without immediate subpleural sparing and the coexistence in some cases of pulmonary nodules does suggest a typical pattern of usual interstitial pneumonia or nonspecific interstitial pneumonia. For that reason, we used the term "fibrotic pattern." To quantify the severity of lung affectation, the total severity score (TSS) was assessed. Each of the five lung lobes was determined for the percentage of lobar involvement. After this, the severity of each lobe was classified as none (0%), minimal (1%-25%), mild (26%-50%), moderate (51%-75%), or severe (76%-100%), with a corresponding score of 0, 1, 2, 3, or 4, respectively. The TSS is calculated by summing the five lobe scores (range, 0-20).36Ooi G.C. Khong P.L. Müller N.L. et al.Severe acute respiratory syndrome: temporal lung changes at thin-section CT in 30 patients.Radiology. 2004; 230: 836-844Crossref PubMed Scopus (248) Google Scholar Descriptive statistics of the mean (SD) or median (interquartile range [IQR]) were estimated for quantitative variables with a normal or nonnormal distribution, respectively. The normality of the distribution was analyzed using the Shapiro-Wilk test. The absolute and relative frequencies were used for qualitative variables. To assess the pulmonary inflammation severity, the CT scan score was categorized by tertiles. Lung function parameters were compared according to pulmonary inflammation severity using the appropriate tests (analysis of variance or a nonparametric Kruskal-Wallis test for quantitative variables and Fisher exact test for qualitative variables). The P value for trend was computed from the Spearman rank correlation coefficient when the variable was continuous and from the χ 2 test for trend if the variable was categorical. Furthermore, we evaluated the associations among demographic data, clinical data, and ICU stay in patients with pulmonary inflammation measured by CT scan score at the 3-month follow-up. Selection of variables was carried out using a relaxed least absolute shrinkage and selection operator (LASSO) model.37Leisman D.E. Harhay M.O. Lederer D.J. et al.Development and reporting of prediction models.Crit Care Med. 2020; 48: 623-633Crossref PubMed Scopus (157) Google Scholar,38Hastie T. Tibshirani R. Tibshirani R.J. Extended comparisons of best subset selection, forward stepwise selection, and the lasso.Crit Care Med. 2020; 48: 623-633PubMed Google Scholar Five-fold cross-validation was carried out to determine the lambda parameter of the LASSO model.39Zhang Y. Yang Y. Cross-validation for selecting a model selection procedure.J Econom. 2015; 187.1: 95-112Crossref Scopus (241) Google Scholar Lambda was selected as the value that minimized the mean square error. A Spearman correlation test between the independent risk factors from the LASSO analysis and the rest of the variables was performed. To perform the LASSO analysis, missing values were replaced by the means of the nonmissing values. The same analysis was performed for the presence of lung lesions (reticular or fibrotic/no lesions) and type of lesion (reticular/fibrotic) among patients with lesions. R statistical software version 4.0.1 (R Foundation for Statistical Computing) was used for all the analyses. Figure 1 shows the flowchart of the study. One hundred twenty-five critically ill patients with ARDS resulting from COVID-19 were admitted during the study period. Thirty-six died during the ICU stay (28.8%), and 10 were transferred to other hospitals (only two patients were transferred to undergo extracorporeal membrane oxygenation). After hospital discharge, three patients were receiving palliative treatment or were severely disabled and one was undergoing follow-up in another center. Of the 75 eligible patients who completed the 3-month follow-up, 13 were unreachable or decided not to participate in follow-up. The latter did not differ in sociodemographic or clinical characteristics compared with the final cohort. A total of 62 patients completed the evaluation. The characteristics of the study population are displayed in Table 1. Briefly, they were predominantly middle-aged, overweight, and male. Most of them were former smokers. The prevalence of pre-existing hypertension, diabetes mellitus, chronic heart disease, asthma, and COPD was 37.1%, 14.5%, 9.7%, 4.8%, and 4.8%, respectively. The median ICU stay was 14.5 days (IQR, 7.0-25.8 days), and the median overall hospitalization was 26 days (IQR, 15-38.5 days). Thirty-nine survivors (62.9%) required invasive mechanical ventilation (IMV) for a median duration of 17.4 days (SD, 8.5 days). In seven patients, both IMV and noninvasive mechanical ventilation modes were used. During the ICU stay, prone positioning was needed in 35 of the patients (56.5%). All patients needed a high-flow nasal canula during the ICU stay. Patients mostly were treated with hydroxychloroquine (98.4%), corticosteroids (58.3%), tocilizumab (25.8%), and interferon-β (17.7%). Ninety percent of patients received methylprednisolone and 10% hydrocortisone with a median maximum dose of 500 mg (IQR, 300 mg). Lopinavir plus ritonavir was used in only two patients (3.23%). All patients received antibiotic treatment, and only one patient received antifungal treatment. Only two patients were readmitted after the hospital discharge, one because respiratory problems and the other for other causes.Table 1Demographic and Biological Characteristics of Patients Who Survived Critical COVID-19 Included in the Follow-upCharacteristicData (N = 62)Age, y60 (48-65)Sex Male46 (74.2) Female16 (25.8)BMI, kg/m228.2 (25.4-32.6)Smoking history Current3 (5.0) Former31 (51.7) Nonsmoker26 (43.3)Comorbidities Hypertension23 (37.1) Diabetes mellitus9 (14.5) Chronic heart disease6 (9.7) Asthma3 (4.8) COPD3 (4.8)ICU stay Length, d14.5 (7.0-25.8) Mechanical ventilationInvasive39 (62.9)Length, d17.4 ± 8.5Noninvasive30 (49.2)Length, d2 (1-4) Prone positioning35 (56.5)Length, h43.9 ± 30.7 Hydroxychloroquine61 (98.4) Interferon-β11 (17.7) Tocilizumab16 (25.8) Methylprednisolone35 (56.4)Maximum daily dose, mg500 (120-500) Antibiotics62 (100) APACHE13.5 ± 4.3 Worst Pao2 to Fio2 ratio126.0 (90.1-173.0) Worst Spo2 to Fio2 ratio172 (124-215)Laboratory data on ICU admission CRP, mg/dL182 (102-243) Hemoglobin, g/L13.2 ± 1.84 Platelet count, × 109/L224 (172-305) White blood count, × 109/L9.18. (5.99-10.40) Lymphocyte count, × 109/L0.80 (0.57-1.14) Urea nitrogen, mM/L29 (24-48) Creatinine, mg/dL0.8 (0.65-0.95) LDH, U/L836 ± 341 Ferritin, mg/dL602 (464-2112) D-dimer, mg/L430 (285-756)Data are presented as No. (%), mean ± SD, or median (interquartile range). No. of missing: smoking history, n = 2; BMI, n = 2; Pao2 to Fio2 ratio, n = 11; CRP, n = 2; LDH, n = 44; ferritin, n = 45; D-dimer, n = 14; and worst Pao2 to Fio2 ratio, n = 11. APACHE = Acute Physiology And Chronic Health Evaluation; CRP = C-reactive protein; LDH = lactate dehydrogenase. Open table in a new tab Data are presented as No. (%), mean ± SD, or median (interquartile range). No. of missing: smoking history, n = 2; BMI, n = 2; Pao2 to Fio2 ratio, n = 11; CRP, n = 2; LDH, n = 44; ferritin, n = 45; D-dimer, n = 14; and worst Pao2 to Fio2 ratio, n = 11. APACHE = Acute Physiology And Chronic Health Evaluation; CRP = C-reactive protein; LDH = lactate dehydrogenase. At the 3-month follow-up, the most common symptoms were dyspnea (46.7%), followed by muscular fatigue (29.5%) and wet and dry cough (18.0% and 16.4%, respectively) (Table 2). Only one patient experienced fever or anosmia after discharge, and none experienced wheeze, anosmia, or abdominal pain. Five patients were receiving supplemental oxygen after hospital discharge. Only one patient showed incidental pulmonary thromboembolism on chest CT scan after discharge.Table 2Symptoms and Quality-of-Life, Anxiety, and Depression Questionnaire Results at the 3-Month Follow-upVariableDataSymptoms Asym
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