key: cord-0697109-k4bo0rbe authors: Lerum, Tøri Vigeland; Aaløkken, Trond Mogens; Brønstad, Eivind; Aarli, Bernt; Ikdahl, Eirik; Lund, Kristine Marie Aarberg; Durheim, Michael T.; Rodriguez, Jezabel Rivero; Meltzer, Carin; Tonby, Kristian; Stavem, Knut; Skjønsberg, Ole Henning; Ashraf, Haseem; Einvik, Gunnar title: Dyspnoea, lung function and CT findings three months after hospital admission for COVID-19 date: 2020-12-10 journal: Eur Respir J DOI: 10.1183/13993003.03448-2020 sha: ee8cf0878d1a1468a81bb9167c16aebc89c38bf3 doc_id: 697109 cord_uid: k4bo0rbe The long-term pulmonary outcomes of coronavirus disease 2019 (COVID-19) are unknown. We aimed to describe self-reported dyspnoea, quality of life, pulmonary function, and chest CT findings three months following hospital admission for COVID-19. We hypothesised outcomes to be inferior for patients admitted to intensive care units (ICU), compared with non-ICU patients. Discharged COVID-19-patients from six Norwegian hospitals were consecutively enrolled in a prospective cohort study. The current report describes the first 103 participants, including 15 ICU patients. Modified Medical Research Council dyspnoea scale (mMRC), EuroQol Group's Questionnaire, spirometry, diffusion capacity (DL(CO)), six-minute walk test, pulse oximetry, and low-dose CT scan were performed three months after discharge. mMRC was >0 in 54% and >1 in 19% of the participants. The median (25th–75th percentile) forced vital capacity and forced expiratory volume in one second were 94% (76, 121) and 92% (84, 106) of predicted, respectively. DL(CO) was below the lower limit of normal in 24%. Ground-glass opacities (GGO) with >10% distribution in ≥1 of 4 pulmonary zones were present in 25%, while 19% had parenchymal bands on chest CT. ICU survivors had similar dyspnoea scores and pulmonary function as non-ICU patients, but higher prevalence of GGO (adjusted odds ratio [95% confidence interval] 4.2 [1.1, 15.6]) and performance in lower usual activities. Three months after admission for COVID-19, one fourth of the participants had chest CT opacities and reduced diffusion capacity. Admission to ICU was associated with pathological CT findings. This was not reflected in increased dyspnoea or impaired lung function. The lower airways and lungs are the primary targets for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The majority of patients requiring hospital admission for coronavirus disease 2019 (COVID- 19) have respiratory symptoms such as cough and dyspnoea, in addition to signs of impaired lung function with varying degrees of hypoxemia [1] . These symptoms are associated with widespread ground-glass opacities (GGO) on chest computed tomography (CT) scans and chest x-rays [2, 3] . Approximately 15-30 % percent of hospital admitted COVID-19 patients develop severe respiratory failure and acute respiratory distress syndrome (ARDS), which necessitate admission to intensive care units (ICU) and possibly mechanical ventilation [1, 4, 5] . According to the World Health Organization (WHO) the fatality rate from COVID-19 is 1-10 %, depending on age and underlying comorbidities [6] . As the COVID-19 pandemic represents a new disease, the long-term pulmonary outcomes in survivors of COVID-19 are unknown. Evidence from other coronavirus pneumonias, such as SARS and Middle East Respiratory Syndrome (MERS), suggests that impaired lung function and parenchymal opacities persist only in a minority of patients not having required mechanical ventilation [7] . In patients developing ARDS, however, as many as 11-45 % have impaired lung function and persistent infiltrates on x-ray after 10-12 months [8] . In order to identify and manage potential long-term sequelae of COVID-19, more research on the natural course of the disease is warranted [9] . Early reports of survivors following hospital admission for COVID -19 show reduced diffusion capacity, total lung capacity, exercise capacity, or abnormal chest CT scan in almost 50% after 1 month [10] . In the current study, we assessed patient-reported dyspnoea, lung function, quality of life (QoL), and parenchymal opacities in chest CT scans three months after hospital admission for COVID-19 in a prospective, consecutive Norwegian cohort of patients with or without ICU treatment. Patient-reported outcomes and lung function after hospital admission for COVID-19 (PROLUN) is a multicentre prospective cohort study performed in six major hospitals in Norway. The study was approved by the Regional Ethics Committee for South-Eastern Norway (no. 125384), by data protection officers at each participating centre, and registered to ClinicalTrials.gov (NCT04535154). Patients aged above 18 years who had been admitted for >8 hours with a discharge diagnosis (International Statistical Classification of Diseases and Related Health Problems 10) of U07.1 (COVID-19, virus identified), U07.2 (COVID-19, virus unidentified) or J12.x (viral pneumonia, in combination with positive SARS-CoV-2 identification in nasopharyngeal swab) were considered for eligibility. Exclusion criteria included living outside the hospitals' catchment areas, inability to provide informed consent, or participation in the WHO trial Solidarity. Eligible patients were invited by mail about six weeks after hospital discharge. Informed consent was obtained by return of a written signed consent form or through a secure digital consent form (Services for Sensitive Data, TSD, University of Oslo). One telephone reminder was performed for non-respondents. In accordance with the study protocol, an interim report of the first 100 participants was planned. This number was achieved on June 24, 2020. The current study thus comprises all participants who had attended the three-month follow-up visit by June 24, 2020 (n=103). Participants returned to the respective hospitals' outpatient clinics for a three-month follow-up visit. The median (25 th -75 th percentile) time between the hospital admission and the three-month visit was 83 (73-90) days, 82 days (73-90) in the non-ICU, and 85 days (81-90) in the ICU-group (p=0.090). The criteria for admission to ICU were similar across centres; inability to maintain a satisfactory pulse oximetric saturation (SpO 2 ) through O 2 -supplementation by nasal cannula or non-rebreather mask. In addition, the participants were assessed by an anaesthesiologist before transfer to ICU. Self-reported dyspnoea: the modified Medical Research Council dyspnea scale (mMRC), range 0-4, was used [11, 12] . This measure was not administered for the first 18 participants, or at St. Olav Hospital. However, for these participants we performed additional analyses with the last value carried forward from self-reported mMRC four to six weeks prior to the visit. QoL: the EuroQol Group's EQ-5D-5L questionnaire [13] was used to measure healthrelated QoL. It contains five items scored on an ordinal scale from 1 (no problems) to 5 (unable/extreme problems). This questionnaire was administered by mail or web-link four to six weeks prior to the visit. Scores were available for 88 (89%) of the participants. EQ-5D index values were prepared using the crosswalk method with UK weights [14] . Pulmonary function tests: Spirometry was conducted to measure the forced vital capacity (FVC) and the forced expiratory volume in one second (FEV 1 ) (Jaeger, Höechberg, Germany and CareFusion, Yorba Linda, CA, USA). The ratio of FEV 1 /FVC was calculated. Diffusion capacity of the lungs for carbon monoxide (DL CO ) and alveolar ventilation (VA) were measured, and DL CO /VA (KCO) was calculated. All procedures were executed according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines [15, 16] . The Global Lung Function Initiative Network (GLI) reference values were used to calculate the percentage of predicted values, the lower limit of normal (LLN), and z-scores [17, 18] . A sixminute walk test (6MWT) was performed according to ATS/ERS, with baseline SpO 2 measured by pulse oximetry on index fingers [19] . Chest CT: low-dose, thin-section CT images were obtained in supine and prone position, during breath-holding and deep inspiration. The same CT protocol, adjusted for the different CTscanners employed, was used for all examinations. The tube current settings were adjusted to each patient's weight, with low dose references at 120 kVp, high pitch, and shortest possible rotation time. For evaluation of lung parenchyma, we applied thin reconstructed slice thickness (0.9-1.25mm), with a high-spatial-frequency kernel, and a softer kernel with thicker (2-3 mm) slices for mediastinal evaluation. Two experienced thoracic radiologists independently reviewed all images, blinded to the participants' clinical history. The degree of consensus was high. The presence, extent, and distribution of interstitial findings were registered using nomenclature recommended by the Fleischner Society [20] . For the purpose of the current analysis, GGO, and parenchymal bands were assessed. Findings were registered in four separate apico-basal zones of the lungs using anatomic landmarks in the mediastinum [21] . Other clinical variables: baseline demographic characteristics (sex, age, height, weight, history of smoking), body mass index (BMI), comorbidities (diabetes or hypertension), and data from the COVID-19 hospital admissions were obtained from the electronic patient records. Clinical variables indicating the severity of COVID-19 were: use of oxygen, admission to ICU, use of mechanical ventilation, the maximal level of C-reactive protein (CRP), and D-dimer. All collected data was stored in TSD, designed for storing and post processing sensitive data in compliance with the Norwegian "Personal Data Act" and "Health Research Act". For continuous data, median and 25 th -75 th percentiles were reported in descriptive statistics. Group comparison was performed with Mann-Whitney U-tests or chi-square tests, as appropriate. For lung function variables the predicted value was calculated, reporting LLN and zscore. Descriptive analyses of the cohort were considered important for this interim report. We also tested the hypothesis that participants admitted to the ICU would have more dyspnoea, lower lung function, lower QoL, and more pathological CT findings, than participants not admitted to the ICU. The main outcome measures were (1) mMRC ≥1, (2) DL CO 10% GGO in at least one lung zone, and (4) the presence of parenchymal bands. Secondary outcomes were 6MWTdistance, SpO 2 , EQ-5D-5L-scores and EQ-5D index. The association between COVID-19 severity indices and main outcomes were assessed by univariate logistic regression analyses. The association between ICU admission, predefined as the major indicator of COVID-19 severity, and the main outcomes were adjusted by multivariable analysis. Due to a limited number of participants, only a few independent variables were allowed: age and sex, except for DL CO