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      Respiratory and Psychophysical Sequelae Among Patients With COVID-19 Four Months After Hospital Discharge

      , MD, PhD , 1 , 2 , , MD 1 , 2 , , MD 2 , , MD, PhD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 2 , , MD, PhD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 2 , , MD, PhD 1 , 2 , , MD 2 , , MD 1 , 2 , , MD 1 , 2 , , MD, PhD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 2 , 1 , , MD, PhD 1 , 2 , , MD, PhD 1 , 2 , , MD 1 , 2 , , MD 1 , 2 , , MD 1 , 2

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          Key Points


          What respiratory, functional, and psychological sequalae are associated with recovery from coronavirus disease 2019 (COVID-19)?


          In this cohort study of 238 patients with COVID-19 hospitalized in an academic hospital in Northern Italy, more than half of participants had a significant reduction of diffusing lung capacity for carbon monoxide or measurable functional impairment and approximately one-fifth of patients had symptoms of posttraumatic stress 4 months after discharge.


          These findings suggest that despite virological recovery, a sizable proportion of patients with COVID-19 experienced respiratory, functional, or psychological sequelae months after hospital discharge.


          This cohort study examines prevalence and risk factors associated with lung function or physical impairment or posttraumatic stress symptoms among survivors of severe coronavirus disease 2019 (COVID-19).



          Although plenty of data exist regarding clinical manifestations, course, case fatality rate, and risk factors associated with mortality in severe coronavirus disease 2019 (COVID-19), long-term respiratory and functional sequelae in survivors of COVID-19 are unknown.


          To evaluate the prevalence of lung function anomalies, exercise function impairment, and psychological sequelae among patients hospitalized for COVID-19, 4 months after discharge.

          Design, Setting, and Participants

          This prospective cohort study at an academic hospital in Northern Italy was conducted among a consecutive series of patients aged 18 years and older (or their caregivers) who had received a confirmed diagnosis of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection severe enough to require hospital admission from March 1 to June 29, 2020. SARS-CoV-2 infection was confirmed via reverse transcription–polymerase chain reaction testing, bronchial swab, serological testing, or suggestive computed tomography results.


          Severe COVID-19 requiring hospitalization.

          Main Outcomes and Measures

          The primary outcome of the study was to describe the proportion of patients with a diffusing lung capacity for carbon monoxide (D lco ) less than 80% of expected value. Secondary outcomes included proportion of patients with severe lung function impairment (defined as D lco <60% expected value); proportion of patients with posttraumatic stress symptoms (measured using the Impact of Event Scale–Revised total score); proportion of patients with functional impairment (assessed using the Short Physical Performance Battery [SPPB] score and 2-minute walking test); and identification of factors associated with D lco reduction and psychological or functional sequelae.


          Among 767 patients hospitalized for severe COVID-19, 494 (64.4%) refused to participate, and 35 (4.6%) died during follow-up. A total of 238 patients (31.0%) (median [interquartile range] age, 61 [50-71] years; 142 [59.7%] men; median [interquartile range] comorbidities, 2 [1-3]) consented to participate to the study. Of these, 219 patients were able to complete both pulmonary function tests and D lco measurement. D lco was reduced to less than 80% of the estimated value in 113 patients (51.6%) and less than 60% in 34 patients (15.5%). The SPPB score was suggested limited mobility (score <11) in 53 patients (22.3%). Patients with SPPB scores within reference range underwent a 2-minute walk test, which was outside reference ranges of expected performance for age and sex in 75 patients (40.5%); thus, a total of 128 patients (53.8%) had functional impairment. Posttraumatic stress symptoms were reported in a total of 41 patients (17.2%).

          Conclusions and Relevance

          These findings suggest that at 4 months after discharge, respiratory, physical, and psychological sequelae were common among patients who had been hospitalized for COVID-19.

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          Most cited references 42

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          Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

          Summary Background In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding National Key R&D Program of China.
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            Pathological findings of COVID-19 associated with acute respiratory distress syndrome

             Zhe Xu,  Lei Shi,  Yijin Wang (2020)
            Since late December, 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV)1, 2 was reported in Wuhan, China, 2 which has subsequently affected 26 countries worldwide. In general, COVID-19 is an acute resolved disease but it can also be deadly, with a 2% case fatality rate. Severe disease onset might result in death due to massive alveolar damage and progressive respiratory failure.2, 3 As of Feb 15, about 66 580 cases have been confirmed and over 1524 deaths. However, no pathology has been reported due to barely accessible autopsy or biopsy.2, 3 Here, we investigated the pathological characteristics of a patient who died from severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by postmortem biopsies. This study is in accordance with regulations issued by the National Health Commission of China and the Helsinki Declaration. Our findings will facilitate understanding of the pathogenesis of COVID-19 and improve clinical strategies against the disease. A 50-year-old man was admitted to a fever clinic on Jan 21, 2020, with symptoms of fever, chills, cough, fatigue and shortness of breath. He reported a travel history to Wuhan Jan 8–12, and that he had initial symptoms of mild chills and dry cough on Jan 14 (day 1 of illness) but did not see a doctor and kept working until Jan 21 (figure 1 ). Chest x-ray showed multiple patchy shadows in both lungs (appendix p 2), and a throat swab sample was taken. On Jan 22 (day 9 of illness), the Beijing Centers for Disease Control (CDC) confirmed by reverse real-time PCR assay that the patient had COVID-19. Figure 1 Timeline of disease course according to days from initial presentation of illness and days from hospital admission, from Jan 8–27, 2020 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. He was immediately admitted to the isolation ward and received supplemental oxygen through a face mask. He was given interferon alfa-2b (5 million units twice daily, atomisation inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy, and moxifloxacin (0·4 g once daily, intravenously) to prevent secondary infection. Given the serious shortness of breath and hypoxaemia, methylprednisolone (80 mg twice daily, intravenously) was administered to attenuate lung inflammation. Laboratory tests results are listed in the appendix (p 4). After receiving medication, his body temperature reduced from 39·0 to 36·4 °C. However, his cough, dyspnoea, and fatigue did not improve. On day 12 of illness, after initial presentation, chest x-ray showed progressive infiltrate and diffuse gridding shadow in both lungs. He refused ventilator support in the intensive care unit repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula (HFNC) oxygen therapy (60% concentration, flow rate 40 L/min). On day 13 of illness, the patient's symptoms had still not improved, but oxygen saturation remained above 95%. In the afternoon of day 14 of illness, his hypoxaemia and shortness of breath worsened. Despite receiving HFNC oxygen therapy (100% concentration, flow rate 40 L/min), oxygen saturation values decreased to 60%, and the patient had sudden cardiac arrest. He was immediately given invasive ventilation, chest compression, and adrenaline injection. Unfortunately, the rescue was not successful, and he died at 18:31 (Beijing time). Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates (figure 2A, B ). The right lung showed evident desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified. Figure 2 Pathological manifestations of right (A) and left (B) lung tissue, liver tissue (C), and heart tissue (D) in a patient with severe pneumonia caused by SARS-CoV-2 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. The pathological features of COVID-19 greatly resemble those seen in SARS and Middle Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis and mild lobular and portal activity (figure 2C), indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue (figure 2D). Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient. X-ray images showed rapid progression of pneumonia and some differences between the left and right lung. In addition, the liver tissue showed moderate microvesicular steatosis and mild lobular activity, but there was no conclusive evidence to support SARS-CoV-2 infection or drug-induced liver injury as the cause. There were no obvious histological changes seen in heart tissue, suggesting that SARS-CoV-2 infection might not directly impair the heart. Although corticosteroid treatment is not routinely recommended to be used for SARS-CoV-2 pneumonia, 1 according to our pathological findings of pulmonary oedema and hyaline membrane formation, timely and appropriate use of corticosteroids together with ventilator support should be considered for the severe patients to prevent ARDS development. Lymphopenia is a common feature in the patients with COVID-19 and might be a critical factor associated with disease severity and mortality. 3 Our clinical and pathological findings in this severe case of COVID-19 can not only help to identify a cause of death, but also provide new insights into the pathogenesis of SARS-CoV-2-related pneumonia, which might help physicians to formulate a timely therapeutic strategy for similar severe patients and reduce mortality. This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on February 25, 2020
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              World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.


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                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                27 January 2021
                January 2021
                27 January 2021
                : 4
                : 1
                [1 ]Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
                [2 ]Azienda Ospedaliero–Universitaria Maggiore della Carità, Novara, Italy
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                Open Access: CC-BY License JAMA Network Open
                Corresponding Author: Mattia Bellan, MD, PhD, Università del Piemonte Orientale, via Solaroli 17, Novara (NO) 28100, Italy ( mattia.bellan@ 123456med.uniupo.it ).
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                Copyright 2021 Bellan M et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

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