key: cord-0800864-39bhy6s3
authors: Han, Xiaoyu; Fan, Yanqing; Alwalid, Osamah; Li, Na; Jia, Xi; Yuan, Mei; Li, Yumin; Cao, Yukun; Gu, Jin; Wu, Hanping; Shi, Heshui
title: Six-Month Follow-up Chest CT findings after Severe COVID-19 Pneumonia
date: 2021-01-26
journal: Radiology
DOI: 10.1148/radiol.2021203153
sha: 43ccc3cff2fba2735e6708083810118271f02101
doc_id: 800864
cord_uid: 39bhy6s3

BACKGROUND: Little is known about the long-term lung radiographic changes in convalescent COVID-19 patients, especially the severe cases. PURPOSE: To prospectively assess pulmonary sequelae and explore the risk factors for lung fibrotic-like changes on six-month follow-up chest CT of survivors of severe COVID-19 pneumonia. MATERIALS AND METHODS: 114 patients (80[70%] men; mean age, 54±12 years) were studied prospectively. Initial and follow-up CT scans were obtained on 17±11 days and 175±20 days respectively after symptom onset. Lung changes (opacification, consolidation, reticulation, and fibrotic-like changes) and CT extent scores (score per lobe, 0-5; maximum score, 25) were recorded. Patients were divided into two groups: group#1 presence and group#2 absence of CT evidence of fibrotic-like changes (traction bronchiectasis, parenchymal bands, and/or honeycombing) based on their six-month follow-up CT. Between-group differences were assessed by Fisher’s exact test, two-sample t-test or Mann-Whitney U test. Multiple logistic regression analyses were performed to identify the independent predictive factors of fibrotic-like changes. RESULTS: On follow-up CT, evidence of fibrotic-like changes was observed in 40/114 (35%) of patients (group#1), while the remaining 74/114 (65%) patients (group#2) showed either complete radiological resolution (43/114, 38%) or residual ground-glass opacification or interstitial thickening (31/114, 27%). Multivariable analysis identified age >50 years (odds ratio [OR]:8.5, 95%CI:1.9-38, p=.01), heart rate >100bpm at admission (OR:5.6, 95%CI:1.1-29, p=.04), duration of in-hospital stay ≥17 days (OR:5.5, 95%CI:1.5-21, p=.01), and acute respiratory distress syndrome (OR:13, 95%CI:3.3-55, p<.001), non-invasive mechanical ventilation (OR:6.3, 95%CI:1.3-30, p=.02) and total CT score ≥18 (OR:4.2, 95%CI:1.2-14, p=.02) on initial CT as independent predictors for lung fibrotic-like changes at 6 months. CONCLUSIONS: Six-month follow-up CT showed lung fibrotic-like changes in more than one-third of patients who survived severe COVID-19 pneumonia. These changes were associated with an older age, acute respiratory distress syndrome, longer in-hospital stays, tachycardia, non-invasive mechanical ventilation and higher initial chest CT score. See also the editorial by Wells, Devaraj, and Desai.

Coronavirus Disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. By November 19, 2020 , this disease has been found in more than 200 countries with 55,659,785 confirmed cases and has caused 1,338,769 deaths (1) . Pathological studies (2, 3) have shown that COVID-19 causes injuries in multiple organs and tissues with extensive pulmonary involvement which is similar to the pathology found in other coronavirus infections (i.e. severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome infection (MERS-CoV).

Chest CT plays a crucial role in the diagnosis and follow-up of patients with pneumonia. Numerous studies have documented radiographic changes in the acute course of COVID-19, which range from mild to severe cases (4) (5) (6) (7) . Recent publications (8, 9) have found that approximately 94% of hospitalized patients have persistent lung parenchymal findings on their discharge CT scans at. In addition, Liu et al (10) reported that lung opacities in 53.0% of mild COVID-19 cases resolved with no adverse sequelae within 3 weeks after discharge. Data from previous coronavirus infections (SARS-CoV and MERS-CoV) suggested that there may be substantial fibrotic consequences following COVID-19 patients (11) (12) (13) . However, little is known about the long-term lung changes after COVID-19 infection. The purpose of this study was to evaluate pulmonary changes on six-month follow-up Chest CT scans and to explore the risk factors for lung fibrotic-like changes in patients who recovered from severe COVID-19 pneumonia.

I n p r e s s 8 

Yin-tan Hospital and Wuhan Union Hospital. All participants remained anonymous, and written informed content was acquired. This trial was registered with the Chinese Clinical Trial Registry, ChiCTR2000038609.

We prospectively enrolled 114 severe COVID-19 patients who had been discharged from the hospital after treatment for COVID-19 as inpatients between December 25, 2019 and February 20, 2020 at our institutions (Wuhan Jin Yin-tan Hospital, n= 69; Wuhan Union Hospital, n=45, Figure 1 ).Throat swab samples were collected for confirmation of SARS-CoV-2 by RT-PCR (Sansure Biotech Inc., Changsha, China) as previously described (14, 15) . The World Health

Organization's (WHO) interim guidance diagnostic criteria for adults with severe COVID-19 pneumonia were used (16) . The discharge criteria were based on the sixth edition of the "Pneumonia Diagnosis and Treatment Plan for New Coronavirus Infection" in China (17) .

The medical records of each participant were reviewed by one of four physicians (YML, XYH, NL, and XJ, with 7, 5, 4 and 3 years of experience in thoracic radiology, respectively). Age, sex, underlying comorbidities, onset of symptoms, peak acute phase laboratory results and the treatments received by individual patients were recorded. The durations from the onset of disease to hospital admission and chest CT scan were reviewed. The Berlin definition of acute respiratory distress syndrome (ARDS) was used. (18) .

The initial CT scans of each participant were done at admission. Within 1 week of the followup CT scans, 104 patients underwent standard pulmonary function testing (PFT) for maximum vital capacity (VCmax%), forced expiratory volume in 1s (FEV1%), forced vital capacity (FVC%), diffusion capacity of the lung for carbon monoxide (DLCO), and DL CO I n p r e s s 9 divided by the alveolar volume (DL CO /VA) measured in a single breath test. The results were compared with age-and sex-matched control subjects and reported as percentages of predicted values. Pulmonary diffusion was regarded as abnormal when DL CO was < 80% of the predicted value.

The initial CT examinations were performed in the supine position using one of two CT scanners: SOMATOM Definition AS+ or SOMATOM Perspective (Siemens Healthineers, Forchheim, Germany). Non-contrast Chest CTs were performed with the acquisition from the thoracic inlet to the diaphragm. The following parameters were used: detector collimation widths of 64×0.6 mm or 128×0.6 mm; and a tube voltage of 120 kV. The tube current was regulated by an automatic exposure control system (CARE Dose 4D; Siemens Healthineers).

Images of 62/114 (54%) patients were reconstructed with a slice thickness of 5mm and an interval of 5 mm. Images in 52/114 (46%) patients were reconstructed with a slice thickness of 1mm and an interval of 1mm. Images were reconstructed with a pulmonary B70F kernel and a mediastinal B30f kernel (SOMATOM Definition AS+), or pulmonary B80s kernel and a mediastinal B30s kernel (SOMATOM Perspective).

All 114 patients underwent follow-up CT examinations using the same scanners as the initial CT scans. Images of all patients were reconstructed with a slice thickness of 1mm and an interval of 1 mm. Prior to the prospectively planned 6-month follow up scan, 83 of 114 patients (73%) had CT scans at 3 months after symptom onset to monitor the evolution of their lung disease.

All CT images were reviewed in random order by three senior cardiothoracic radiologists (HSS, I n p r e s s 10 YQF, and JG, with 31, 13 and 10 years of experience in thoracic radiology, respectively) who were not aware of any clinical and laboratory findings or patient outcomes. The readers independently assessed the CT features using axial and multiplanar reconstructed images. The mediastinal window (center, 50; width, 350) and lung window (center, -600; width, 1200) were obtained from the picture archiving and communication system (Vue PACS, version 11.3.5.8902, Carestream Health, Canada). After independent evaluation, discussion and consensus resolved any disagreement. For each severe pneumonia patient, the predominant CT patterns according to the Fleischner Society glossary (19) were enumerated as follows: groundglass opacities (GGO), consolidation, reticulation, emphysema, thickening of the adjacent pleura, pleural effusion, presence of nodules or masses, honeycombing, bronchiectasis and interlobar pleural traction (retraction of the interlobar pleura toward the lesions). The CT evidence of fibrotic-like changes was defined as the presence of traction bronchiectasis, parenchymal bands (12, 20) , and/or honeycombing (19) (Figure 2 ).

To quantify the extent of pulmonary abnormalities (total lesions, GGO, consolidation, reticulation and fibrotic-like changes), a semiquantitative CT score (21) was assigned on the basis of the area involved in each of the five lung lobes: 0, no involvement; 1, < 5% 2, 5%-25%; 3, 26%-49%; 4, 50%-75%; and 5, >75%. The total CT severity score was calculated by summing the individual lobar scores (possible scores range from 0 to 25).

The analyses were performed using SAS software (SAS, version 9.4, SAS Institute, Cary, NC, USA). The Kolmogorov-Smirnov test was used to assess the normality of continuous data.

Normally and non-normally distributed data, and categorical variables are presented as the I n p r e s s 11 means (SD) and the medians (IQR), and numbers (%), respectively. Between-group differences in categorical variables were assessed using by Fisher's exact test, and continuous variables with normally and non-normally distributed data were assessed using the two-sample t-test or Mann-Whitney U test, respectively. P-values for multiple univariate testing on acute phase data were adjusted by using the Benjamini and Hochberg method. A cutoff CT score value of 18 was selected as suggested by a recent investigation (22) , which indicated that chest CT score ≥ 18 was correlated with the disease severity and increased mortality risk in patients with COVID-19 pneumonia. Multiple logistic regression analyses were performed to identify the independent predictive factors of fibrotic-like changes. The final model was determined using stepwise logistic regression, with significance level for selection set at p=.05. Factors associated with the CT score of fibrotic-like changes were analyzed by calculating the Spearman's correlation coefficient. Statistical significance was considered at a p value < .05 (two-tailed).

One hundred fourteen patients (80 men, 34 women; mean age, 54±12 years; age range, 24-82 years) were included ( Table 1 ). The initial and follow-up scans were obtained on 17±11 days and 175 ±20 days after disease onset, respectively. Evidence of fibrotic-like changes was observed in 40/114 (35%) patients (group 1) on follow-up CT scans (Figure 3 ), of which the proportion of patients with de novo fibrotic abnormalities was 38/40 (95%). The remaining 74/114 (65%) patients (group 2) showed either complete radiological resolution (43/114, 38%, Figure 4 ), or residual GGO or interstitial thickening (31/114, 27%, Figure 5 ).

After correction for multiple comparisons (Table 1) 

After correction for multiple comparisons (Table 2) 

The initial CT scans were obtained on 17±11 days after the onset of symptoms, with no difference between the two groups (19±11 days vs 16±11 days, p=1.00, Table 3 ). The overall median total CT score was 15 [IQR, 9] . After correction for multiple comparisons ( Figure 2 ) was more common in group 1.

The multivariable analysis identified an age>50 years (OR: 8 p=.02) on initial CT scans as independent predictors of lung fibrotic-like changes ( Table 4) .

According to the Spearman's correlation analysis ( 

Significant decrease in the CT scores for total lesions (p<.001), GGO (p<.001), and consolidation (p<.001) were observed in all patients (Table E2 [Appendix E1]). Compared with the initial CT scans, the incidence rate of nodules or masses (17% vs 1.8%, p<.001), interlobar pleural traction (17% vs 7.9%, p=.04, Figure 6 ), pulmonary atelectasis (11% vs 3.5%, p=.02, Figure E1 [Appendix E1]) and bronchiectasis (24% vs 7.0%, p＜.001) were significantly higher in the follow-up scans, while pleural effusion was completely resorbed (0 vs 6.1%, p=.01). (Table E3 [Appendix E1]).

At the six-month follow-up (Table E4 [ Patients with lung fibrotic-like changes showed a higher incidence of ARDS (63%,25/40), which was also a predictor of fibrotic-like changes. Previous studies (23, 24) demonstrated that a substantial proportion of patients who survive ARDS may develop progressive fibrotic-like changes on CT scans. Nevertheless, it remains uncertain whether the fibrotic-like changes observed in this study represent true fibrotic lung disease (e.g. at pathology or on longer term follow-up CT). Whether or not these fibrotic-like changes, found at 6 months, reflect permanent change in the lung remains to be investigated. Additionally, the high frequency of non-invasive mechanical ventilation is another risk factor for the development of fibrotic-like changes at 6 months in our study. Based on previously published data (24), mechanical ventilation was strongly related to fibrotic-like changes observed after ARDS. Likewise, the lung fibrotic-like changes in our patients may also be associated with ventilator-induced lung injury. The laboratory results also demonstrated higher D-dimer and hsCRP levels in patients with pulmonary fibrotic-like changes. Emerging evidence of coagulopathy and an over exuberant inflammatory response has been reported in severe COVID-19 patients (25, 26) , which are associated with disease severity and may also lead to greater damage to the pulmonary parenchyma.

We found that a higher CT score (≥18) on the initial CT was an independent prognostic factor for the presence of fibrotic-like changes on the 6 months follow up exam. According to a previous study on idiopathic pulmonary fibrosis (27) , CT score was correlated with the degree I n p r e s s 16 of pulmonary fibrosis in pathological specimens. Moreover, a recent publication revealed an association between a CT score of ≥ 18 was associated with an increased mortality risk in COVID-19 patients (22) . Therefore, a greater extent of lung injury in the acute phase may be associated with a higher mortality rate and more severe pulmonary sequelae in survivors. In addition, the correlations of scores for fibrotic-like changes with the aforementioned risk factors were also confirmed in our study.

At the six-month follow-up, a few patients still complained of ongoing respiratory symptoms, and 26% of patients had pulmonary diffusion abnormalities, which more frequently occurred in patients with fibrotic-like changes. Thus, both structural and functional lung impairments may simultaneously occur in patients who survive severe COVID-19 pneumonia.

On the follow-up CT, significant decreases in CT scores for total lesions, GGO and consolidation were observed compared with the initial CT. Although the predominant CT pattern on follow up CT was still GGO, but the densities were visually decreased, which might follow the "tinted" sign (10) or "melting sugar" sign (28) . Two studies (10, 28) Our study has several limitations. First, sample size was small and only 6 months of follow up.

Patients with fibrotic-like changes require longer follow-up to determine whether the fibroticlike changes are permanent, progressive or reversible. Second, the extent of lung fibrotic-like changes was not quantified by a computer-based analysis as described in previous study (31) .

However, we have supplied the semi-quantitative scores for the fibrotic-like changes, which were shown to be correlated with the degree of pulmonary fibrosis in pathological specimens.

Third, the inter and intra reader comparison of CT grading was not performed. Fourth, the years of smoking was not evaluated in the present study. Fifth, 62/114 (54.4%) patients had a slice thickness of 5 mm in the initial scan, in which case subtle findings may be occult or overlooked.

However, all follow up CT scans were performed with thin slices of 1 mm to assess the lung abnormalities. Finally, the lack of a histological correlation is a limitation. Further studies are warranted to explore whether fibrotic-like changes on CT scans represent true pathological fibrosis.

In summary, follow-up CT scans obtained within 6 months of disease onset showed lung fibrotic-like changes in more than one third of patients who survived severe COVID-19 pneumonia. These patients were older and had more severe disease during the acute phase.

However, the long-term lung sequelae of these CT findings are still largely unknown. This report serves as a basis for new prospective large-scale long-term investigations analyzing these high-risk patients. Data are presented as n/N (%). Group 1, patients with lung fibrotic-like changes; Group 2, patients without lung fibrotic-like changes. GGO, ground-glass opacification. * 83 CT scans were available at 3-month after symptoms onset. 

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