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 <LLN, (3) >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 <LLN, in which current/previous smoking vs. never smoking was adjusted for. All statistical analyses were performed using Stata version 16.1 (StataCorp., College Station, TX, USA). A p-level <0.05 was considered statistically significant.

Demographic and clinical characteristics from the hospital admission are shown in Table 1 .

Several indices of COVID-19 severity were higher in participants admitted to ICU than in the non-ICU participants; length of stay, oxygen therapy, the maximum levels of CRP and D-dimer, and the prevalence of bilateral lung densities. However, the demographic variables (sex, age, body mass index, and smoking status) were comparable between the groups. Hypertension was less commonly observed in those admitted to ICU than in non-ICU participants. The median (25 th to 75 th percentile) time from symptom onset to admission were 7 (5-9) and 9 (6-11) days in ICU and non-ICU participants, respectively (p=0.125). prevalence of GGO was not significantly different between ICU and non-ICU participants, however, after adjustment for age and sex, the odds of having these pathological CT findings were significantly higher in participants admitted to ICU, compared to those not admitted to ICU (Table 3) . Parenchymal bands, indicating early progression to fibrosis, were found in one of five participants. With regard to parenchymal bands, an association with CRP and ventilator treatment was observed (p=0.018 and p=0.038, respectively) (Supplementary table 1 ). There was no difference between participants admitted to ICU and participants not admitted to ICU (Table   3) . The scores on the five EQ-5D-5L items are shown in Figure 1 . Participants admitted to ICU had a higher median score on usual activities than participants admitted to regular wards only, 4 (25-75 th percentile 2-4) vs 2 (1-2), respectively (p=0.014)). The median EQ-5D index scores (SD) were 0.61 (0.23) and 0.72 (0.19) for ICU and non-ICU patients, respectively (p=0.087).

In this three-month follow-up of a prospective cohort study of patients surviving hospital admission for COVID-19, approximately half of all participants had persistent dyspnoea on exertion, and one in four had reduced diffusion capacity for carbon monoxide. Persistent GGO on CT-scans were present in one fourth of the participants, while one in five had parenchymal bands. Participants admitted to ICU during hospital admission had higher prevalence of persistent CT abnormalities and reported more problems in usual activities, but similar lung function and self-reported dyspnoea to those not admitted to ICU.

The favourable spirometry outcomes observed in this cohort were accompanied by a low prevalence of reduced peripheral oxygen levels and reduced exercise capacity, as indicated by the 6MWT. In total, our results indicate that development of chronic respiratory failure after three months is not common in survivors of COVID-19 hospital admission, including survivors of ICU admission. The degree of self-reported dyspnoea three months after hospital admission was not associated with prior ICU stay, which we used as a marker of COVID-19 severity.

Dyspnoea is subjective and may be influenced by a number of other variables. The proportion of participants in our study with reduced diffusion capacity after three months was comparable to studies of SARS and MERS, and to other early reports in COVID-19 survivors [7, 10, 22, 23] .

Persistent opacities in at least 10% of one or more lung parenchyma zones, as assessed by CT, were present in approximately one in four participants after three months. Compared with reports after four weeks of follow-up in another cohort [10] , this finding suggests that COVID-19 related GGO may resolve without development of persistent fibrosis. However, some of these CT findings may persist and gradually develop into fibrotic changes, as reflected by the finding of parenchymal bands in one fifth of our study population [24] . In a retrospective study of COVID-19 patients eight weeks after hospital discharge, approximately 25 % showed signs of early fibrosis [22] . This is consistent with findings in our cohort. We found that age was associated with persistent GGO in our material, which is consistent with findings regarding community-acquired pneumonia [25] . In addition, explorative analyses find the inflammatory marker CRP to be associated with both persistent GGO and parenchymal bands. Interestingly, parenchymal bands were also associated with ventilator treatment. However, it is still unknown if the persistent pathological CT findings will progress to symptomatic pulmonary fibrosis over time or if various treatments for COVID-19 may influence the long-term outcome of parenchymal opacities.

We found CT abnormalities after three months to be more common in participants admitted to ICU. Yet, there were no differences in lung function or diffusion capacity, SpO2, or 6MWT distance between these participants and participants not admitted to ICU, in spite of ICUpatients having more bilateral lung opacities on chest x-ray and higher levels of markers of systemic inflammation during hospital admission. All patient-reported outcomes were also similar between groups, except that more participants admitted to ICU reported an impaired ability to perform usual activities. If replicated in additional studies, the association between showed that one in four had persistent ground-glass opacities, and one in five had parenchymal bands. ICU admission was associated with persistent CT-abnormalities and reduced ability to perform usual activities, but not with dyspnoea, impaired lung function or reduced functional capacity, three months after discharge from the hospital. Ingelheim to perform the current study.

GE conceived the study. 

The pulmonary and radiological departments at Akershus University Hospital have received unrestricted grants from Boehringer Ingelheim for funding of CT-scans and study coordinator in the current study.

The full protocol has been published on www.clinicaltrials.gov (NCT04535154). An anonymized data file will be shared through the website of the journal upon publication. The statement of the authors to each item on the STROBE checklist is available as supplementary material.

Legend Figure 1 . Distribution of EQ-5D-5L dimension scores for ICU (n=13) and non-ICU patients (n=75). 1=No problems, 2=Slight problems, 3=Moderate problems, 4=Severe problems, 5=Unable/Extreme problems. 

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Recommendation of low-dose CT in the detection and management of COVID-2019

Clinical and Chest Radiography Features Determine Patient Outcomes In Young and Middle Age Adults with COVID-19

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the

Risk Factors of Severe Disease and Efficacy of Treatment in Patients Infected with COVID-19: A Systematic Review, Meta-Analysis and Meta-Regression Analysis

Long-term clinical outcomes in survivors of severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus outbreaks after hospitalisation or ICU admission: A systematic review and meta-analysis

What's Next After ARDS: Long-Term Outcomes

COVID-19 interstitial pneumonia: monitoring the clinical course in survivors

Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase

The MRC breathlessness scale

The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population

Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)

Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets

ERS/ATS standards for single-breath carbon monoxide uptake in the lung

Standardization of Spirometry

Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations

Official ERS technical standards: Global Lung Function Initiative reference values for the carbon monoxide transfer factor for Caucasians

technical standard: field walking tests in chronic respiratory disease

Fleischner Society: glossary of terms for thoracic imaging

Diagnosis of biopsy verified usual interstitial pneumonia by computed tomography

First report on clinical and radiological features of COVID-19 pneumonitis in a Caucasian population: factors predicting fibrotic evolution

Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

Radiographic resolution of community-acquired pneumonia

OR, odds ratio; CI, confidential interval; mMRC, modified Medical Research Council dyspnoea scale

intensive care unit; CRP, C-reactive protein; DL CO , diffusion capacity of the lungs for carbon monoxide

LLN, lower limit of normal