key: cord-0327762-28wn23nl
authors: Steinbeis, F.; Thibeault, C.; Doellinger, F.; Ring, R. M.; Mittermaier, M.; Ruwwe-Gloesenkamp, C.; Alius, F.; Knape, P.; Meyer, H.-J.; Lippert, L. J.; Helbig, E. T.; Grund, D.; Temmesfeld-Wollbrueck, B.; Suttorp, N.; Sander, L. E.; Kurth, F.; Penzkofer, T.; Witzenrath, M.; Zoller, T.
title: Severity of respiratory failure and computed chest tomography in acute COVID-19 correlates with pulmonary function and respiratory symptoms after infection with SARS-CoV-2: an observational longitudinal study over 12 months
date: 2021-08-11
journal: nan
DOI: 10.1101/2021.08.11.21261883
sha: b10237a9b122887dc703e092265053e91f59095e
doc_id: 327762
cord_uid: 28wn23nl

Background Prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse. Research question: With this study, we aim to investigate pulmonary outcome following SARS-CoV-2 infection including pulmonary function, computed chest tomography, respiratory symptoms and quality of life over 12 months. Study design and Methods 180 patients after acute COVID-19 were enrolled into a single-centre, prospective observational study and examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate objective and subjective respiratory limitations. Patients were stratified according to acute COVID-19 disease severity. Results Of 180 patients enrolled, 42/180 were not hospitalized during acute SARS-CoV-2 infection, 29/180 were hospitalized without need for oxygen, 43/180 with need for low-flow and 24/180 with high-flow oxygen, 26/180 required invasive mechanical ventilation and 16/180 were treated with ECMO. After acute COVID-19, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity after the acute phase and improved over 12 months except for those requiring ECMO treatment. Patients with milder disease showed a predominant reduction of ventilated area instead of simple restriction. The CT score of lung involvement in the acute phase increased significantly with COVID-19 severity and was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with mild initially disease. Interpretation Severity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection. Patients with mild vs. severe disease show different patterns of lung involvement and symptom resolution.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) causes acute viral respiratory tract infections including pneumonia. After initial infection with SARS-CoV-2 in the upper respiratory tract, viral replication continues in lower airways and alveolar epithelial cells 37 , leading to a hyper-inflammatory immune response causing alveolar damage and vascular leakage 30, 38 . Chronic lung injury was observed in 25-63% patients three months post-acute COVID-19 21, 32 . Known pathomechanisms of chronic lung injury and fibrosis such as a TGF-beta dominated adaptive immune response 6 , fibroblast activation 11 , alveolar epithelial cell death and distortion of the basal lamina leading to alveolar collapse induration 26 17, 14, 28 . First data of the early post-acute COVID -19 phase revealed that up to four months post infection, COVID-19 patients show a pattern of pulmonary restriction and abnormal carbon monoxide diffusion capacity in lung function testing 3, 16, 22, 25, 40, 13, 21, 32 . Similar results were seen for month 6 and 12 after symptom onset in a Chinese prospective cohort study 15, 39 .

So far, prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 are sparse, particularly no data from European patients are available. Further, disease severity is commonly classified according to WHO groups into mild/moderate and severe and critical. With this prospective study, we aim to provide highresolution data on pulmonary function, symptom burden, patient reported outcomes and radiological characteristics of SARS-CoV-2 infection in more detail. We stratified patients into six severity categories and observed them over a period of 12 months. Moreover, this study aims to describe different patterns of pulmonary injury and their relation to subjective limitations in hospitalized and non-hospitalized patients with COVID-19.

the "ATS/ERS Task Force: Standardisation of Lung Function Testing" as TLC <5 th percentile of the lower limit of normal (LLN) and FEV1/FVC < LLN 20 . Complex restriction was defined according to Clay et al. as difference between ppv TLC and FVC >10% 4 . No further breakdown into severity grades was performed for categorical analysis.

Chest computed Tomography (CT):

CT-scans were performed on the basis of clinical guideline recommendations. If available, the first CT scan performed within 30 days after symptom onset was used for analysis. Chest-CT scans were reviewed by two senior thoracic radiologists. All images were reviewed blinded to the patient's clinical characteristics and disease severity. Pulmonary involvement during the acute phase was assessed using a visual score ranging from 0 (no involvement) to 5 (>75% involvement) for each lung lobe as described in more detail by Pan et al. 27 .

Symptom assessment and health related quality of life A standardized list of 43 symptoms was evaluated at each study visit at baseline and during follow-up in a patient interview (Table S3) . To capture overall impact on health, daily life and wellbeing in patients, the St. George's Respiratory Questionnaire (SGRQ) was measured 7 . A total score of 25 or higher, as suggested by the Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, was used as threshold for limitations in health and wellbeing.

Descriptive statistics was used to calculate median, inter-quartile range (IQR), mean and standard deviations (SD). Difference in continuous variables between three or more groups were analysed by one-way ANOVA or Kruskal-Wallis test. Fischer's exact test (for sample size <5 per group) or Chi-square test were used for analysis of categorical variables. The correlation between lung function and patient reported outcomes from SGRQ was calculated using Pearson correlation coefficients with a two-sided 95% confidence interval. Logistic regression was performed to assess association of clinical variables, radiological findings and patient reported outcomes with pulmonary restriction and reduced DLCO in post-acute COVID-19. For univariate and multivariate analysis of risk factors for pulmonary restriction and diffusion capacity, patient characteristics and comorbidities recorded at the study inclusion visit were used and for pulmonary function and SGRQ, the lowest values observed during follow-up was . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint used. Variables were adjusted for confounders as determined by clinical evidence (age, BMI) 12 or due to a significant relationship in univariate testing (i.e. gender, disease severity). Statistical significance was assumed for p<0.05. The level of significance is marked with asterisks; * for p < 0.05; ** p < 0.01; *** p < 0.001 and **** p < 0. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. ;  Body plethysmography, carbon monoxide diffusion capacity and respiratory muscle strength 55/180 (32%) study participants showed pulmonary restriction and 104/180 (61%) showed reduced carbon monoxide diffusion capacity (DLCO) (lowest value at any point of time during follow-up). Pulmonary restriction and impairment of DLCO was significantly associated with increasing severity of lung failure expressed as the level of respiratory support during the acute phase of SARS-CoV-2 infection (Table 1 ). In contrast, complex restriction, as defined by Clay et al. 4 , was not associated with severity of respiratory failure during acute SARS-CoV-2 infection, but was slightly more common among patients with mild disease.

Significant differences in restrictive ventilation patterns were seen between groups of different disease severity during acute COVID-19. (Figure 1 , Table s1 ). Median (IQR) of TLC and FVC was significantly lower in patients with higher level of respiratory support during acute COVID-19.

This difference persisted until 12-months after acute COVID-19.

Likewise, impaired DLCO was associated with disease severity. Significant differences were seen in patients stratified by level of respiratory support as a proxy of acute COVID-19 severity ( Figure 1 ). With regard to KCO (DLCO /VA, Krogh-Index), a different pattern was observed; significant differences were only seen at either month 3 or 6 post SARS-CoV-2 infection and differences between severity were less pronounced ( Figure 1 ).

There was no association between pulmonary obstruction and disease severity after acute COVID-19 (Table 1) . Reduced FEV1 was attributable to concurrent reduced FVC ( Figure s1a ).

Although there were individual cases with reduced airway occlusion pressure (P0.1) and inspiratory muscle strength (Pimax), no statistically significant differences regarding P0.1 and Pimax were seen between severity groups. (Figure s1b ).

Patients with pathological pulmonary function in the early post-acute phase (defined as TLC/FVC/DLCO < Lower Limit of Normal (LLN) at first follow-up) showed improvement up to month 12 for pulmonary restriction or reduced DLCO ( Figure 2 ). When all patients were analysed over time, median TLC, FVC, DLCO and KCO increased up to month 6, with no further improvement seen between month 6 and 12 ( Figure s2 , Table s1 ). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint In general, significant correlations with total SGRQ score were observed for FVC (p<0.0001), DLCO (p<0.001) and KCO (p<0.0001) but not for TLC (p=0.091) (Table 2, Figure s5 ). The contribution of SGRQ sub-scores for symptoms, activity and impact are shown in Table 2 .

Univariate logistic regression showed an association of pulmonary restriction and reduced DLCO with disease severity, gender, SGRQ outcome (score>25), Charlson Comorbidity Index and cardiovascular disease ( Table 3 ). The odds of restriction were 1.7 (95% CI 1.37-2.15, p=0.0001) times higher for every single increment in disease severity category (i.e. from LFO to HFO) and 1.8 (1.19-2.74, p=0.01) for every 5 points increase in CT-score. For reduced DLCO, logistic regression showed no significant association with initial pulmonary involvement (p=0.11), but for disease severity (OR 1.49, 95% CI 1.20-1.84; p<0.0001). Effect sizes were also adjusted for age, sex, BMI and disease severity (Table 3) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint Discussion:

In this study of COVID-19 survivors, we longitudinally analysed pulmonary function, respiratory symptoms and health related quality of life and studied CT chest morphology at acute phase of 180 patients during 12 months after SARS-CoV-2 infection. We identified demographic characteristics, clinical indicators and comorbidities that increase the risk and severity of pulmonary injury. The detailed data on pulmonary function presented gives first insight into different patterns of pulmonary impairment according to clinical severity in the acute phase and its sequelae up to 12 months post SARS-CoV-2 infection.

Reduced FVC, TLC and DLCO were associated with severe and critical COVID-19 in the literature, representing patients with LFO, HFO, IMV and ECMO in our cohort 12, 15, 39 . This study demonstrates that the degree of pulmonary functional impairment correlates with clinical severity during acute COVID-19 and that these differences in pulmonary function were still apparent after 12 months of follow-up.

Pulmonary restriction was associated with the degree of lung parenchymal involvement seen on CT scans during acute COVID-19, reflecting inflammation and fibrotic transformation It could be argued that pulmonary restriction after acute COVID-19 is caused by ventilatorinduced lung injury (VILI), a common observation in ARDS patients 31, 34 including subsequent pulmonary restriction and reduced DLCO 24, 35 . In this study however, there was no obvious difference in FVC, TLC and DLCO at all follow-up visits between patients who needed mechanical ventilation and those who received high-flow oxygen therapy. Although more data is needed to confirm this hypothesis, our data indicate that post COVID-19 pulmonary restriction is probably not caused by VILI, but rather by consequences of viral infection. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint Two different types of restriction were discernible in this study population: the pattern of simple pulmonary restriction was more frequently observed in patients with higher initial disease severity, whereas complex pulmonary restriction was seen predominantly in patients with less severe COVID-19. Complex restriction, according to the definition by Clay et al. 4 The symptom cluster including fatigue, dyspnoea and cognitive deficits as described for the early convalescent phase 23 persisted over 12 months of follow-up in our study population.

Respiratory health related quality of life as captured by total SGRQ improved over time, but . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint with a relevant proportion of patients remaining above the threshold value of 25 one year after acute COVID-19. TLC however did not correlate with SGRQ score, likely due to the high proportion of patients with complex restriction and preserved TLC.

Limitations of this study were the availability of data from a single centre at this point of time, and the reduced number of patients available in the first and the last 12 month follow-up visit, particularly in the group of patients after invasive mechanical ventilation and ECMO treatment.

By summarizing the results from pulmonary function tests with assessment of respiratory symptoms and the evolution of findings over time, we hypothesize that two main patterns of pulmonary involvement are discernible after COVID-19: in patients with severe disease and particularly those with respiratory failure requiring ECMO treatment, a pattern of interstitial lung involvement characterized by simple restriction and reduction of diffusion capacity predominates. This pattern has potential for functional and subjective improvement over time during the first year of follow-up. In patients with mild to moderate initial disease however, a disease pattern characterized by a loss of ventilated area and symptom persistence over one year after follow-up predominates. Particularly for the latter pattern, potential underlying mechanisms are unknown, and these patterns of pulmonary injury will need to be confirmed and further characterized in larger and multi-centric studies.

In conclusion, this study demonstrated the relevance of initial disease severity and results of thoracic CT for pulmonary functional impairment and respiratory symptoms in the first year after SARS-CoV-2 infection in hospitalized patients. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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The copyright holder for this this version posted August 11, 2021 Table 3 : Association of demographic characteristics, clinical indicators and comorbidities with pulmonary restriction and impaired DLCO post-acute COVID-19. Univariate analysis revealed male gender, disease severity, SGRQ score >25, Charlson Comorbidity Index and cardiovascular disease to be associated with pulmonary restriction and reduced DLCO. A relationship between CT-chest score was only seen for patients developing restriction. In multivariable analysis, adjustment for age, BMI, gender and disease severity showed SGRQ outcome over the threshold of 25 to be associated with both pulmonary restriction and impaired DLCO. Patient characteristics and comorbidities were collected at study inclusion. Worst SGRQ outcome independent of follow-up was used for univariate and multivariate analysis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint Median total SGRQ is higher after HFO, IMV and ECMO treatment and decreases until month 12, whereas for LFO, NOH and NOO is remains constant over time.

. CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted August 11, 2021. ; https://doi.org/10.1101/2021.08.11.21261883 doi: medRxiv preprint

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We thank the Pa-COVID-19 study group with Stefan Hippenstiel, Pinkus Tober-Lau, Sascha S. 

Author contributions: F.S. and T.Z. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. F.S., T.Z. and M.W. developed the study design, performed data analysis and interpretation and wrote the manuscript. F.D. and T.P. performed data analysis and interpretation of radiological data. C.T., C.R.G., F.A., P.K.,