key: cord-0869254-7elp2kqi
authors: Sonnweber, Thomas; Sahanic, Sabina; Pizzini, Alex; Luger, Anna; Schwabl, Christoph; Sonnweber, Bettina; Kurz, Katharina; Koppelstätter, Sabine; Haschka, David; Petzer, Verena; Boehm, Anna; Aichner, Magdalena; Tymoszuk, Piotr; Lener, Daniela; Theurl, Markus; Lorsbach-Köhler, Almut; Tancevski, Amra; Schapfl, Anna; Schaber, Marc; Hilbe, Richard; Nairz, Manfred; Puchner, Bernhard; Hüttenberger, Doris; Tschurtschenthaler, Christoph; Aßhoff, Malte; Peer, Andreas; Hartig, Frank; Bellmann, Romuald; Joannidis, Michael; Gollmann-Tepeköylü, Can; Holfeld, Johannes; Feuchtner, Gudrun; Egger, Alexander; Hoermann, Gregor; Schroll, Andrea; Fritsche, Gernot; Wildner, Sophie; Bellmann-Weiler, Rosa; Kirchmair, Rudolf; Helbok, Raimund; Prosch, Helmut; Rieder, Dietmar; Trajanoski, Zlatko; Kronenberg, Florian; Wöll, Ewald; Weiss, Günter; Widmann, Gerlig; Löffler-Ragg, Judith; Tancevski, Ivan
title: Cardiopulmonary recovery after COVID-19 – an observational prospective multi-center trial
date: 2020-12-10
journal: Eur Respir J
DOI: 10.1183/13993003.03481-2020
sha: 33ffa8f8b65281dac2a070070e7ea3266eccbb94
doc_id: 869254
cord_uid: 7elp2kqi

BACKGROUND: After the 2002/2003 SARS outbreak, 30% of survivors exhibited persisting structural pulmonary abnormalities. The long-term pulmonary sequelae of coronavirus disease 2019 (COVID-19) are yet unknown, and comprehensive clinical follow-up data are lacking. METHODS: In this prospective, multicentre, observational study, we systematically evaluated the cardiopulmonary damage in subjects recovering from COVID-19 at 60 and 100 days after confirmed diagnosis. We conducted a detailed questionnaire, clinical examination, laboratory testing, lung function analysis, echocardiography, and thoracic low-dose computed tomography (CT). RESULTS: Data from 145 COVID-19 patients were evaluated, and 41% of all subjects exhibited persistent symptoms 100 days after COVID-19 onset, with dyspnea being most frequent (36%). Accordingly, patients still displayed an impaired lung function, with a reduced diffusing capacity in 21% of the cohort being the most prominent finding. Cardiac impairment, including a reduced left ventricular function or signs of pulmonary hypertension, was only present in a minority of subjects. CT scans unveiled persisting lung pathologies in 63% of patients, mainly consisting of bilateral ground-glass opacities and/or reticulation in the lower lung lobes, without radiological signs of pulmonary fibrosis. Sequential follow-up evaluations at 60 and 100 days after COVID-19 onset demonstrated a vast improvement of both, symptoms and CT abnormalities over time. CONCLUSION: A relevant percentage of post-COVID-19 patients presented with persisting symptoms and lung function impairment along with pulmonary abnormalities more than 100 days after the diagnosis of COVID-19. However, our results indicate a significant improvement in symptoms and cardiopulmonary status over time.

shares clinical and mechanistic characteristics with the severe acute respiratory syndrome (SARS) in 2002/2003 including ACE2-dependent cellular entry and interleukin-6 (IL6) driven hyper-inflammation, potentially leading to imbalanced immune responses and acute respiratory distress syndrome (ARDS) [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] . In different studies evaluating SARS survivors months after infection, fibrotic features, including abnormal scoring of airspace opacity and reticular shadowing, were observed in up to 36% of the patients [2, 14, 15] . A one-year followup study on 97 recovering SARS patients in Hong Kong showed that 27.8% of survivors presented with decreased lung function and signs of pulmonary fibrosis compared to a normal population, which was confirmed by another follow-up study [2, 14, 16] . Moreover, the phylogenetically related Middle East respiratory syndrome-coronavirus (MERS-CoV) was shown to induce pulmonary fibrosis in up to 33% of patients [17] . As SARS-CoV-2 shares high homology with SARS-CoV-1, and to a lesser extent with MERS-CoV, it is thus conceivable that survivors of COVID-19 may also develop pulmonary fibrosis [7] . With worldwide over 27 million confirmed cases by today, and on average 20% of patients with a moderate-to-severe course of the infection often needing hospitalization, the development of fibrosing lung disease after clearance of infection could become an enormous health concern [1] .

We thus designed a prospective, multicentre, observational study, the Development of interstitial lung disease (ILD) in patients with severe SARS-CoV-2 infection (CovILD) study, aimed at systematically evaluating the persisting cardiopulmonary damage of COVID-19 patients 60 days and 100 days after COVID-19 onset.

Enrollment of the CovILD study began on April 29, 2020 ( Fig S1) . The trial site is located at the Department of Internal Medicine II, Medical University of Innsbruck (Austria), with two additional participating medical centers in Zams and Münster (Austria), which are tertiary care centers (Innsbruck, Zams) and an acute rehabilitation facility (Münster) all located in Tyrol, the first major COVID-19 hotspot in Austria. Diagnosis of COVID-19 was confirmed if a typical clinical presentation (according to current WHO guidelines) along with a positive RT-PCR SARS-CoV-2 test obtained from a nasopharyngeal or oropharyngeal swab were present [18] . Eligibility included the necessity of hospitalization (either on a normal ward or intensive care unit (ICU)) or outpatient care with persisting symptoms. A total of 190 patients were screened for study participation and 145 individuals were included in the final study. Reasons for non-participation were mainly logistic (e.g. tourists who left the country, and individuals who lived too far away from the study center in Innsbruck to attend regular follow-up, N=27) or rejection of study participation (N=18).

We herein present a follow-up evaluation performed 60 days (63 ± 23 (mean ± SD); visit 1) and 100 days (103 ± 21); visit 2) after diagnosis of COVID-19. Of note, in Tyrol the healthcare system was never overloaded at the local peak of the pandemic, thus, all patients received supportive care according to the standard of care at the trial site hospitals and no selection bias due to triage methods was apparent. The trial protocol was approved by the institutional review board at Innsbruck Medical University (EK Nr: 1103/2020) and was registered at ClinicalTrials.gov (registration number: NCT04416100). Informed consent was obtained from each patient.

During the follow-up visits, the following examinations were performed: clinical examination, medical history, a questionnaire about typical COVID-19 symptoms including cardiorespiratory, gastrointestinal, and neurological symptoms during the disease and at follow-up, the Modified British Medical Research Council (mMRC) dyspnea score, a standardized performance status score, lung function testing including spirometry, body plethysmography, diffusion capacity for carbon monoxide (DLCO) adjusted for hemoglobin, capillary blood gas analysis, trans-thoracic echocardiography, standard laboratory examinations and a low-dose computed tomography (CT) scan of the chest.

All serological markers were determined on fully automated random access instruments: Creactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), N-terminal pro natriuretic peptide (NT-proBNP), and serum ferritin were determined on a Roche Cobas 8000 analyzer and D-dimer on a Siemens BCS-XP instrument using the Siemens D-Dimer Innovance® reagent.

CT scans were acquired without ECG gating on a 128 slice multidetector CT with a 128 x 0.6 mm collimation and spiral pitch factor of 1.1 (SOMATOM Definition Flash, Siemens Healthineers, Erlangen, Germany). Scans were obtained in craniocaudal direction without iodine contrast agent and in low-dose setting (100 kVp tube potential). If patients had a clinical suspicion for pulmonary embolism (PE), additional contrast CTs were conducted. Axial reconstructions were performed with a slice thickness of 1 mm. CT images were evaluated for the presence of ground-glass opacities (GGO), consolidations, bronchiectasis, and reticulations as defined by the glossary of terms of the Fleischner society [19] . When present, the distribution of the findings was graded according to their distribution (unilateral/bilateral, involved lobes).

Overall, pulmonary findings were graded for every lobe using the following CT severity score: 0none, 1-minimal (subtle GGO), 2-mild (several GGO, subtle reticulation), 3-moderate (multiple GGO, reticulation, small consolidation), 4-severe (extensive GGO, consolidation, reticulation with distortion), and 5-massive (massive findings, parenchymal destructions). The maximum score was 25 (i.e. maximum score 5 per lobe). This score was used because the BSTI (British Society of Thoracic Imaging) COVID-19 classifies only the extent of abnormality < 25%, 26-50%, 51-75%, and >75%, and the BSTI Post-COVID-19 CT Report Codes do not discriminate between "Improving" (PCVCT1 -No significant fibrosis or concerning features) from "fibrosis" (PCVCT3 -fibrosis ± inflammatory change present (inflammation > fibrosis/fibrosis > inflammation/fibrosis without inflammation)). In addition, we did not have a pre-COVID-19 baseline and an acute phase COVID-19 CT scan in most patients.

prototype for the detection and quantification of abnormalities consistent with pneumonia was used to calculate the percentage of opacity and percentage of high opacity, indicating percentages of GGO and consolidation, respectively.

Statistical analyses were performed with statistical analysis software package (IBM SPSS 

In total, 145 patients with a confirmed diagnosis of COVID-19 participated in the CovILD study, and 133 subjects were available also for the second follow-up. The mean time from the diagnosis of COVID-19, as defined by positive SARS-COV2 PCR testing, to follow-up was 63 days (SD ± 23) for visit 1 and 103 days (SD ± 21) for visit 2. The study cohort consisted of 55% male individuals, aged 50 to 70 years (Table 1) . Sixty-one-percent of COVID-19 patients were overweight or obese (BMI>25 or >30, respectively). Most individuals had preexisting comorbidities (77%) with cardiovascular and metabolic diseases being the most frequent ( Table   1 ). The majority of study participants (75%) were hospitalized during the acute phase of COVID-19, half of the hospitalized patients required oxygen supply, and 22% of all subjects were admitted to the ICU due to the necessity of non-invasive or invasive mechanical ventilation as determined by the treating physicians. Patients who were admitted to the ICU had more comorbidities such as cardiovascular disease, arterial hypertension, diabetes mellitus, hypercholesterolemia, chronic kidney disease, or immune-deficiency as compared to subjects without the necessity of ICU treatment (Table S1 ). Additionally, higher age and male gender were related to a more severe course of acute COVID-19.

At the second follow-up visit, a relevant number of patients still reported an impaired performance status and persisting symptoms including dyspnea (36%), night sweat (24%), sleep disorders (22%), or hyposmia/anosmia (19%), but with decreasing frequency compared to the acute phase of COVID-19 and the first follow-up visit ( Figure 1 ). Notably, severe symptoms, such as a severely impaired performance status (as assessed by a standardized questionnaire) or severe dyspnea (mMRC 3-4) were only found in 2% and 4% of all study participants at second follow-up, respectively. Overall, a marked and continuous improvement of all assessed symptoms (namely impairment of performance status, dyspnea, cough, fever, diarrhea or vomiting, night sweat, hyposmia/anosmia, and sleep disorders) from disease onset to follow-up at visits 1 and 2 was observed ( Figure 1 ).

At follow-up visit 1 and visit 2, trans-thoracic echocardiography unveiled a high rate of diastolic dysfunction (60% and 55% of all subjects, respectively). Signs of pulmonary hypertension as well as a pericardial effusion were detected only in a smaller portion of the cohort (Table S2) .

Whereas the frequency of diastolic dysfunction, signs of pulmonary hypertension, and LVEF impairment did not significantly change from follow-up visit 1 to 2, the number of patients with pericardial effusion diminished over time (p=0.039).

An impaired lung function, reflected by reduced static and/or dynamic lung volumes, or impaired DLCO, was present in 42% and 36% of individuals at visit 1 and visit 2, respectively ( Table 2 ).

In detail, 100 days after diagnosis of COVID-19 a reduction in FVC and/or FEV 1 was found in 22%, a reduced TLC in 11%, and an impaired DLCO in 21% of all individuals. Additionally, hypoxia, as reflected by a reduced pO2 assessed with capillary blood gas analysis (pO2 <75mmHg), was still present in 37% of all subjects, and these patients demonstrated mild (80%, pO2 <75-65mmHg) or moderate (20%, pO2 <65-55mmHg) hypoxia at rest. Notably, dynamic lung volumes and DLCO significantly increased over time. As compared to follow-up visit 1 there was a moderate but significant improvement of most of these parameters over time ( Table   2 ).

At visit 2, mild elevations in inflammatory markers such as CRP (12%), IL-6 (6%), or PCT (9%) were still present in a smaller portion of the cohort (also refer to Table S2 ). Accordingly, biomarkers associated with COVID-19 disease severity, such as D-dimer, NT-proBNP, and serum ferritin were still elevated in 27%, 23%, and 17% of COVID-19 patients at second followup, respectively.

CT imaging revealed radiological lung abnormalities typical for COVID-19 in 77% of patients at visit 1 and in 63% of individuals at visit 2 (Figure 2 A) . The main findings were GGOs, consolidation, and reticulation. Bronchial dilation was found in a small portion of the cohort (representative CT scans are depicted in Figure 3 ). In 75% of patients, pulmonary involvement was found bilateral, with the lower lobes most prominently affected (Table S4) . Notably, by the time of visit 2, consolidations and bronchial dilations almost completely resolved, and the mean extent of GGOs significantly decreased. Contrary, reticulations only gradually improved from visit 1 to 2 ( Figure 2A ). In eight patients, who presented with a clinical suspicion of an incidental PE (e.g. deteriorating dyspnea despite resolution of radiological lung findings, tachycardia, significant hypoxia, or lack of D-dimer decrease/D-dimer increase), additional contrast agent CT was performed, and one incidental PE was detected.

Radiological assessment of the severity of COVID-19 related lung pathologies was performed on CT scans using both an automated software-based analysis with Syngo.via CT Pneumonia Analysis Software as well as an evaluation by two independent radiologists. Importantly, the software-based pneumonia quantification and the severity scoring by two radiologists demonstrated a high correlation (correlation coefficient ρ=0.893, p<0.001). The pulmonary CT severity score unveiled a moderate structural involvement in most patients at the first follow-up, which significantly improved over time (Figure 2 Finally, we analyzed the impact of demographic and clinical factors on the persistence of symptoms, patient performance status, and CT findings at follow-up with a series of fixed-effect ordinary and generalized linear models ( Figure S2 , S3, and S4). These analyses revealed that the severity of acute COVID-19 (as reflected by the need for medical treatment), age, gender, and preexisting diseases such as cardiovascular diseases, pulmonary diseases, diabetes mellitus type 2, and malignancy were related to patient recovery. Despite that, a striking improvement of the CT severity score was found in patients of all COVID-19 severity groups, including subjects who needed mechanical ventilation at an ICU ( Figure 5 ).

The ongoing pandemic considerably increases the demand for healthcare and raises concerns on physiological and radiological disease outcome in COVID-19 patients needing hospitalization or even treatment in the ICU [20] . Accordingly, early lung function analysis of patients with COVID-19 at the time of discharge from hospital revealed a high rate of abnormalities indicative of potential interstitial lung disease. Moreover, a retrospective study 30 days after discharge had shown a reduced diffusion capacity as the central finding in 26% of post-acute COVID-19 patients [21, 22] . To our knowledge, this prospective study represents the first three-month cardiopulmonary follow-up analysis of patients with confirmed COVID-19 including critical cases. The majority of patients enrolled in the CovILD study were previously hospitalized, male and displayed co-morbidities, which have been identified as risk factors for a severe course of COVID-19 [23] [24] [25] [26] . Importantly, 21% of patients were admitted to the ICU, comparable to the ICU admission rates of 26% to 33% previously published for COVID-19 patients [1, 25] .

During post-acute care, patients reported a high rate of persisting dyspnea, and one-third of COVID-19 patients displayed an impaired lung function, with a reduced diffusing capacity being the most prominent finding even more than 100 days after COVID-19 diagnosis. This is in accordance with observations in 110 SARS survivors three and six months after infection [14] . In line, long-term SARS studies revealed disturbed gas exchange as the most relevant residual finding ranging from 15.5% to 57.2% of patients [2, 14, 27] . Furthermore, several studies on ARDS survivors have shown that their pulmonary function generally returns to normal or near to normal within 6 to 12 months, and predominantly DLCO may remain abnormal in patients at one

year after recovery [28, 29] . Although, a relevant portion of our cohort presented with persisting cardiopulmonary impairment at follow-up, as evidenced by echocardiography or lung function testing, we observed a gradual improvement over time.

The major CT findings of patients affected by COVID-19 were previously shown to include GGO and consolidation with bilateral involvement and peripheral and diffuse distribution [30] .

Importantly, this study reveals that more than 100 days after disease onset, two-thirds of patients had residual radiological changes, predominantly including residual GGO combined with reticulation. Since most patients had no CT scan before or during hospitalization, preexisting lung injury cannot be completely ruled out for the sub-group of patients with moderate to severe findings present at follow-up.

In line with our findings, CT abnormalities with low mean severity were also detected in 75.4% of SARS survivors six months after admission to the hospital [15] . From a clinical perspective, it is important to note that the high prevalence of persisting radiological abnormalities in our cohort was not well reflected by pulmonary function testing. Data on the inferiority of pulmonary function testing in the screening for ILD in a population at high risk for progressive disease support these findings [31] . To date, it remains unclear, if such subclinical structural changes justify the routine repetitive use of CT imaging in follow-up care after COVID-19 pneumonia. For example, follow up-studies in ARDS survivors including chest CT have shown that persistent radiographic abnormalities were of little clinical relevance [32] . In addition, a 15-years follow-up study of 71 patients with moderate to severe SARS showed that the rate of interstitial abnormalities remarkably declined within the first two years of recovery to only 4.6% of patients [27] . In line, our imaging findings demonstrate high reversibility of COVID-19 associated cardiopulmonary damage, and no clear signs of progressive ILD have been identified so far.

Finally, we have to acknowledge limitations of the presented study. First, the CovILD trial was initiated during the onset of the COVID-19 epidemic in Austria, thus pre-existing co-morbidities were assessed retrospectively, and cardiopulmonary evaluation prior COVID-19 was only available in a small portion of the cohort. Thus, we cannot fully evaluate the impact of potentially pre-existing cardiopulmonary impairment on the findings presented herein. Secondly, according to the ethics approval we used low dose CT without contrast agent to assess radiological pulmonary impairment. Whereas this strategy reduces the cumulative radiation dose and precludes contrast agent related complications, it is also associated with limitations. Although the image quality of low-dose CT was found sufficient, some very subtle fibrotic changes may be recognized as (non-fibrotic) reticulations due to the lower image quality. However, even in regular dose CT, clear discrimination between residual inflammation and early fibrosis is extremely difficult, especially in patients with a clear overall improvement. Additionally, as we did not routinely use contrast agent, we did not screen the cohort for occult PE, and additional contrast CTs were only indicated in case of clinical suspicion of PE.

In summary, we describe significant residual clinical, functional, and CT-morphological changes in the majority of COVID-19 patients, which dramatically improved within the observation period of three months. We conclude that follow-up care should be considered for patients with persisting clinical symptoms after COVID-19 which may include serial measures of lung function, echocardiography, and CT scans of the chest. (17) Chronic kidney disease 10 (7) Chronic liver disease 8 (6) Malignancy 17 (12) Immunodeficiency ‡ 9 (6) Hospitalizedno. (C) CT severity scoring by radiologists at COVID-19 onset, 60 days, and 100 days after COVID-19 diagnosis. The severity score was calculated via CT evaluation by two independent radiologists who qualitatively graded lung impairment for each lobe separately (grade 0-5, with 0 for no involvement and 5 for massive involvement). A total score was achieved by summation of grades for all five lobes (maximum: 25 points).

(B-C) bars indicate mean; whiskers depict one standard error (SE). N acute =23, N V1 =145, N V2 =135. Data are depicted as mean ± SD. Wilcoxon signed-rank tests were applied to assess time-dependent changes. The first follow-up took place 60 days after COVID-19 diagnosis; the second follow-up was performed 100 days after COVID-19 diagnosis.

Blood samples were available from 145 patients at the first follow-up and 134 patients at the second follow-up. The first follow-up took place 60 days after COVID-19 diagnosis; the second follow-up was performed 100 days after COVID-19 diagnosis. CT scans of the lung were available from 145 patients at the first follow-up and 135 patients at the second follow-up.

Data transformation and statistical analysis were done with R programming suite version 3.6.3

with the tidyverse package bundle [1] . Statistical significance of differences of the investigated parameters between the study visits was assessed by mixed-effect linear modeling (fixed effect: study visit, random effect: study participant, R package lmer) and p values of the study visit effect estimates were presented (β ≠ 0; two-tailed T-test for ordinary mixed-effect models, Wald Z test for generalized mixed-effect linear models) [2] . For normally distributed continuous parameters, canonical mixed-effect linear regression was applied. For CT severity score, mixedeffect generalized linear models with log link function and assumed Poisson distribution of residuals were used. Binary parameters were modeled with mixed-effect logistic regression (logit link function, assumed binomial distribution of residuals). In modeling tasks investigating the baseline difference in parameters between patients with various history of acute COVID-19 severity (according to the need for medical treatment), the patient severity group term was included, where the patient severity groups were defined as follows: (1) outpatients (n = 36), (2) hospitalized subjects without oxygen therapy or ICU stay (n = 37), (3) hospitalized participants with oxygen therapy but without ICU stay (n = 40) and (4) ICU patients (n = 32).

To identify demographic and clinical factors impacting the persistence of symptoms and radiological lung findings at visit 1 and visit 2 a series of fixed-effect ordinary and generalized linear models were created for the key investigated parameters (change of performance status: ordinary linear model; impaired performance, presence of persistent symptoms and presence of CT abnormalities: logistic regression; CT severity score: generalized linear model with log link function and assumed Poisson distribution of residuals). The dependent binary variables of the models were patient treatment group, sex, age ≥ 65 years, obesity, smoking history, presence of cardiovascular diseases, hypertension, pulmonary diseases, hypercholesterolemia, type 2

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sex, age ≥ 65 years, obesity, smoking history, presence of cardiovascular diseases, hypertension, pulmonary diseases, hypercholesterolemia, type 2 diabetes, and malignancy. Significant coefficients of the optimized models

Visit 1 = 60 days and visit 2 = 100 days after diagnosis of COVID-19

The raw full models were optimized by an initial automated removal of non-relevant terms using the stepAIC function of MASS package, followed by manual stepwise elimination of non

Significant coefficients of the optimized models (β for ordinary linear models, exp β for generalized linear models/logistic regression) were presented as bar plots with whiskers representing the 95% confidence interval and p values (β ≠ 0; two-tailed T-test for ordinary linear models

Supplementary References

Welcome to the Tidyverse

Modern Applied Statistics with S

Statistics: An Introduction using R

A Coefficient of Determination for Generalized Linear Models

Elegant Graphics for Data Analysis

We acknowledge the dedication, commitment, and sacrifice of the staff, providers, and personnel in our institutions through the COVID-19 crisis and the suffering and loss of our patients as well as in their families and our community. 

The authors declare no conflict of interest related to this study.