Six-Month Follow-up Chest CT findings after Severe COVID-19

Pneumonia

Manuscript type: Original Research

Authors: Xiaoyu Han1,2*, MD,PhD, Yanqing Fan3*, MD, Osamah Alwalid 1,2
, MD, PhD, Na

Li1,2, MD, Xi Jia1,2, MD, Mei Yuan1,2, MD, Yumin Li1,2, MD, PhD, Yukun Cao1,2, MD, Jin Gu1,2,

MD, PhD, Hanping Wu4, MD, PhD, Heshui Shi1,2, MD, PhD.

s
Addresses:

1. Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University

2.
es
of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, The

People’s Republic of China

Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, The People’s
pr
Republic of China

3. Department of Radiology, Wuhan Jinyintan hospital, No.1 Yintan Road, Dongxihu

District, Wuhan City, Hubei Province 430022, The People’s Republic of China

4. Department of Radiology, Michigan Medicine, University of Michigan, Michigan, The

United States of America.

In

Email:

Xiaoyu Han: xiaoyuhan1123@163.com

Yanqing Fan: 1024932023@qq.com

Osamah Alwalid: dr.osamah_alwalid@yahoo.com

Na Li- 1196335711@qq.com

Xi Jia- 63380648@qq.com

This copy is for personal use only. To order printed copies, contact reprints@rsna.org
 Mei yuan- 549954114@qq.com

Yukun Cao – 804423372@qq.com

Jin Gu – gujin-ll@163.com

Hanping Wu: netwhp@gmail.com

Heshui Shi: heshuishi@hust.edu.cn

Corresponding Author:

s
Heshui Shi: heshuishi@hust.edu.cn

* Xiaoyu Han and Yanqing Fan contributed equally to this work.

Acknowledgements

es
We would like to thank all colleagues for helping us during the current study and all the selfless

volunteers who participated in the study. We highly appreciate Dr. Hongwei Jiang, PhD
pr
(Epidemiology & Biostatistics, Huazhong University of Science and Technology) for his

assistance in statistical analysis. We also very grateful to many members of the frontline

medical staff for their selfless dedication and heroic dedication in the face of this outbreak,

despite the potential threat to their own lives and the lives of their families.

Disclosures of Conflicts of Interest

In

None declare.

Funding

This study was supported by the National Natural Science Foundation of China (grant

numbers: 82071921), Zhejiang University special scientific research fund for COVID-19

prevention and control, and the Fundamental Research Funds for the Central

Universities(2020kfyXGYJ019).

2
 Availability of data and material

The datasets used and/or analyzed during the current study are available from the

corresponding author on reasonable request.

Ethics approval and consent to participate

This study had ethics approval of the Ethics Commission of Wuhan Jin Yin-tan Hospital and

Wuhan Union Hospital. All participants remained anonymous, and written informed content

s
was acquired.

Consent for publication

Not applicable

Competing interests
es
The authors declare no competing non-financial/financial interests.
pr
See also the editorial by Wells, Devaraj, and Desai.
In

3
 Summary

This prospective longitudinal study found that approximately one-third of participants showed

chest CT findings with pulmonary fibrosis-like changes within 6 months after recovery from

severe COVID-19 pneumonia.

Key Results

s
1. Approximately one third of participants (40/114, 35%) recovered from severe COVID-19

developed lung fibrotic-like changes within 6 months of disease onset.

es
2. Older age (>50 years old), acute respiratory distress syndrome and higher baseline CT lung

involvement score (≥18 out of a possible score of 25) were associated with lung fibrotic-

like changes.
pr
3. Twenty-seven of 104(26%) patients had an abnormal DLCO at 6-month follow up, which

more frequently occurred in patients with lung fibrotic-like changes than in patients without

fibrotic-like changes.
In

4
 Abstract

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.

s
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

es
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
pr
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.
In

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

5
 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,

s
non-invasive mechanical ventilation and higher initial chest CT score.

es
pr
In

6
 Introduction

Coronavirus Disease 2019 (COVID-19) 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

s
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).

es
Chest CT plays a crucial role in the diagnosis and follow-up of patients with COVID-19

pneumonia. Numerous studies have documented radiographic changes in the acute course of

COVID-19, which range from mild to severe cases (4-7). Recent publications (8,9) have found
pr
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 (11-13). However, little is

In

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.

Methods

Study design and participants

7
 This prospective study obtained ethical approval from the Ethics Commission of Wuhan Jin

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

s
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

es
(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
pr
“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
In

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 follow-

up 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 DLCO

8
 divided by the alveolar volume (DLCO/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 DLCO was < 80% of the predicted

value.

CT image acquisition and interpretation

The initial CT examinations were performed in the supine position using one of two CT

s
scanners: SOMATOM Definition AS+ or SOMATOM Perspective (Siemens Healthineers,

Forchheim, Germany). Non-contrast Chest CTs were performed with the acquisition from the

es
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).
pr
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).

In

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,

9
 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

s
consensus resolved any disagreement. For each severe pneumonia patient, the predominant CT

patterns according to the Fleischner Society glossary (19) were enumerated as follows: ground-

es
glass 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
pr
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%-
In

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).

Statistical analysis

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

10
 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

s
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

es
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
pr
coefficient. Statistical significance was considered at a p value < .05 (two-tailed).

Results

Demographics and patients’ characteristics

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
In

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), compared with group 2, patients in group
11
 1 were significantly older (60±12 years vs 51±11 years, p=.003), had a higher heart rate at

admission (HR, 96±16 bpm vs 87±12 bpm, p=.03) and greater incidence of acute respiratory

distress syndrome (ARDS, 63% vs 8.1%, p<.001) and other comorbidities (73% vs 41%,

p=.01), particularly chronic pulmonary disease (28% vs 6.8%, p=.02). The hospital stay was

longer for patients in group 1 than patients in group 2 (27 days [IQR, 26] vs 15 days [IQR, 8]),

p<.001. Regarding treatment, patients in group 1 were more likely to receive

s
glucocorticosteroids (53% vs 20%, p=.01) and non-invasive mechanical ventilation (45% vs

8.1%, p<.001) than patients in group 2.

es
Comparison of peak laboratory findings

After correction for multiple comparisons (Table 2), the laboratory findings showed

significantly higher peak levels of hypersensitive C-reactive protein (hsCRP, 80 mg/L [IQR,
pr
124] vs 26 mg/L [IQR, 76], p=.03) and D-dimer (8.7 mg/L [IQR, 33] vs 1.0 mg/L [IQR, 1.5],

p<.001) in group 1 than in group 2.

Comparison of initial CT findings and scores

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
In

median total CT score was 15 [IQR, 9]. After correction for multiple comparisons (Table 3),

patients in group 1 had significantly higher scores for total lesions (20 [IQR, 5.5] vs 13[IQR,

7], p<.001), GGO (16 [IQR, 10] vs 10 [IQR, 8], p=.02) than patients in group 2. Thickening of

the adjacent pleura (55% vs 24%, p=.02, Figure 2) was more common in group 1.

Factors associated with lung fibrotic-like changes

The multivariable analysis identified an age>50 years (OR:8.5, 95% CI: 1.9-38 p=.01),

12
 HR>100bpm at admission (OR: 5.6, 95% CI: 1.1-29, p=.04), hospital stay ≥ 17 days (OR:5.5,

95% CI: 1.5-21, p=.01), ARDS (OR:13, 95% CI: 3.3-55, p<.001), noninvasive 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 scans as independent predictors of lung fibrotic-like changes (Table 4).

Scores for fibrotic-like changes

According to the Spearman’s correlation analysis (Table E1 [Appendix E1]), the score for

s
fibrotic-like changes was correlated with age (r=0.32, p<.001), HR at admission (r=0.24,

p=0.01), hospital stay (r=0.49, p<.001), ARDS (r=0.57, p<.001), peak hsCRP level (r=0.37,

es
p<.001), peak D-dimer level (r=0.59, p<.001), noninvasive mechanical ventilation (r=0.49,

p<.001), total CT score (r=0.47, p<.001), and CT score for GGO (r=0.38, p<.001). Compared

with the initial CT, a significant increase in the CT score for fibrotic-like changes (median, 0;
pr
range, 0-4; [IQR, 0] vs median, 0; range, 0-18; [IQR,4], p<.001) was observed in all patients

on 6 months follow-up CT (Table E2 [Appendix E1]). In addition, the median score for fibrotic-

like changes in patients in group 1 on 6 months follow-up CT was 6; range, 2-18; [IQR, 5].

Comparison of CT findings and scores between initial and follow-up scans

Significant decrease in the CT scores for total lesions (p<.001), GGO (p<.001), and
In

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).

Time points of occurrence of fibrotic-like changes or complete resolution

13
 In group 1, of 40 patients who exhibited lung fibrotic-like changes, 2/40 (5%) showed the

fibrotic-like changes on initial CT scans, 17/37 (46%) patients who presented for follow up

showed fibrotic-like changes at 3 months, and 22/40 (55%) showed these changes at 6 months

of follow-up. In group 2, of 43 (58%) patients who demonstrated complete resolution of CT

abnormalities, 20/43 (47%) patients who presented for follow up showed resolution at 3

months, and the remaining 23/43 (53%) showed resolution at the 6-month follow-up (Table E3

s
[Appendix E1]).

Follow-up findings

es
At the six-month follow-up (Table E4 [Appendix E1]), 7/114 (6.1%) of patients were still

complaining of dry cough; 11/114 (10%) had expectoration and 16/114 (14%) experienced

slight exertion dyspnea. Patients in group 1 with lung fibrotic-like changes more commonly
pr
experienced dry cough (p=.03) than patients in group 2. Of the 104 patients who underwent

PFT, 27 (26%) presented with abnormal pulmonary diffusion (DLCO＜80% predicted), with

patients in group 1 more frequently presenting diffusion abnormalities than patients in group 2

(50% vs 13%, p＜.001).

Discussion
In

In our study, 40/114 (35%) of patients who recovered from severe COVID-19 pneumonia

developed lung fibrotic-like changes within 6 months in whom most of the fibrotic-like changes

(55%, 22/40) presented on 6 months follow up CT. Using multivariable analysis, we found that

age > 50 years (odds ratio [OR]: 8.5, 95% CI: 1.9-38 p=.01), heart rate > 100 bpm at admission

(HR, 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 ARDS (OR: 13, 95% CI: 3.3-55, p < .001), non-invasive mechanical

14
 ventilation (OR:6.3, 95% CI: 1.3-30, p=.02) and a total chest CT score ≥ 18 (OR: 4.2, 95% CI:

1.2-14, p=.02) on the initial CT scans were independent predictors of the subsequent

development of lung fibrotic-like changes after six-months of follow-up.

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

s
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

es
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
pr
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

In

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

15
 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.

s
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

es
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
pr
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) reported an

increased extension of the GGO or consolidation and a decreased density on follow up CT

of COVID-19 pneumonia, which may indicate the gradual regression of the inflammation and
In

re-expansion of the alveoli. GGO in the acute phase of COVID-19 pneumonia may represent

the inflammatory infiltrates, edema or hemorrhaging (2, 3). Moreover, increased D-dimer

levels in the acute phase was associated with pulmonary embolism in COVID-19 patients,

which might also account for GGO appearance on the chest CT (29, 30), however, CT

pulmonary angiography was not routinely performed in our patients to clarify this point. The

pathophysiology underlying GGO in the convalescent phase of COVID-19 pneumonia and the

16
 correlation with fibrosis is worthy of further investigation.

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 fibrotic-

like 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

s
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

es
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
pr
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
In

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.

17
 References

1. World Health Organization. Coronavirus disease 2019 (COVID-19) Situation report.

https://covid19.who.int/. (Accessed 19 November 2020)
2. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai
C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang F-S. Pathological findings of COVID-19
associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine
2020;8(4):420-422. doi: 10.1016/s2213-2600(20)30076-x
3. Liu J, Zheng X, Tong Q, Li W, Wang B, Sutter K, Trilling M, Lu M, Dittmer U, Yang D.
Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human
pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol
2020;92(5):491-494. doi: 10.1002/jmv.25709

s
4. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, Fan Y, Zheng C. Radiological findings from
81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. The Lancet
Infectious Diseases 2020;20(4):425-434. doi: 10.1016/s1473-3099(20)30086-4

es
5. Pan F, Ye T, Sun P, Gui S, Liang B, Li L, Zheng D, Wang J, Hesketh RL, Yang L, Zheng C.
Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019
(COVID-19). Radiology 2020;295(3):715-721. doi: 10.1148/radiol.2020200370
6. Bandirali M, Sconfienza LM, Serra R, Brembilla R, Albano D, Pregliasco FE, Messina C.
Chest Radiograph Findings in Asymptomatic and Minimally Symptomatic Quarantined
Patients in Codogno, Italy during COVID-19 Pandemic. Radiology 2020;295(3):E7. doi:
10.1148/radiol.2020201102
7. Xu YH, Dong JH, An WM, Lv XY, Yin XP, Zhang JZ, Dong L, Ma X, Zhang HJ, Gao BL.
pr
Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused
by SARS-CoV-2. J Infect 2020;80(4):394-400. doi: 10.1016/j.jinf.2020.02.017
8. Han X, Cao Y, Jiang N, Chen Y, Alwalid O, Zhang X, Gu J, Dai M, Liu J, Zhu W, Zheng C,
Shi H. Novel Coronavirus Pneumonia (COVID-19) Progression Course in 17 Discharged
Patients: Comparison of Clinical and Thin-Section CT Features During Recovery. Clinical
infectious diseases : an official publication of the Infectious Diseases Society of America 2020.
doi: 10.1093/cid/ciaa271
9. Wang Y, Dong C, Hu Y, Li C, Ren Q, Zhang X, Shi H, Zhou M. Temporal Changes of CT
Findings in 90 Patients with COVID-19 Pneumonia: A Longitudinal Study. Radiology
2020:200843. doi: 10.1148/radiol.2020200843
In

10. Liu D, Zhang W, Pan F, Li L, Yang L, Zheng D, Wang J, Liang B. The pulmonary sequalae
in discharged patients with COVID-19: a short-term observational study. Respir Res
2020;21(1):125. doi: 10.1186/s12931-020-01385-1
11. Zhang P, Li J, Liu H, Han N, Ju J, Kou Y, Chen L, Jiang M, Pan F, Zheng Y, Gao Z, Jiang
B. Long-term bone and lung consequences associated with hospital-acquired severe acute
respiratory syndrome: a 15-year follow-up from a prospective cohort study. Bone research
2020;8:8. doi: 10.1038/s41413-020-0084-5
12. Antonio GE, Wong KT, Hui DS, Wu A, Lee N, Yuen EH, Leung CB, Rainer TH, Cameron
P, Chung SS, Sung JJ, Ahuja AT. Thin-section CT in patients with severe acute respiratory
syndrome following hospital discharge: preliminary experience. Radiology 2003;228(3):810-
815. doi: 10.1148/radiol.2283030726

18
 13. Das KM, Lee EY, Singh R, Enani MA, Al Dossari K, Van Gorkom K, Larsson SG, Langer
RD. Follow-up chest radiographic findings in patients with MERS-CoV after recovery. The
Indian journal of radiology & imaging 2017;27(3):342-349. doi: 10.4103/ijri.IJRI_469_16
14. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu
T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G,
Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China. The Lancet 2020. doi: https://doi.org/10.1016/S0140-
6736(20)30183-5
15. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia Ja, Yu
T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet
2020;395(10223):507-513. doi: https://doi.org/10.1016/S0140-6736(20)30211-7

s
16. World Health Organization. Clinical management of severe acute respiratory infection when
novel coronavirus (nCoV) infection is suspected: interim guidance.
https://www.who.int/docs/default-source/coronaviruse/clinical-management-of-novel-cov.pdf

edition)

es
Published on January 12, 2020.
17. General Office of National Health Committee. Notice on the issuance of a program for the
diagnosis and treatment of novel coronavirus (2019-nCoV) infected pneumonia (trial sixth

2020.2.18.http://www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc
2.shtml (Accessed 19 November 2020)
18. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E,
Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA
pr
2012;307(23):2526-2533. doi: 10.1001/jama.2012.5669
19. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner
Society: Glossary of Terms for Thoracic Imaging. Radiology 2008;246(3):697-722. doi:
10.1148/radiol.2462070712
20. Westcott JL, Cole SR. Traction bronchiectasis in end-stage pulmonary fibrosis. Radiology
1986;161(3):665-669. doi: 10.1148/radiology.161.3.3786716
21. Chang Y-C, Yu C-J, Chang S-C, Galvin JR, Liu H-M, Hsiao C-H, Kuo P-H, Chen K-Y,
Franks TJ, Huang K-M, Yang P-C. Pulmonary Sequelae in Convalescent Patients after Severe
Acute Respiratory Syndrome: Evaluation with Thin-Section CT. Radiology 2005;236(3):1067-
1075. doi: 10.1148/radiol.2363040958
In

22. Francone M, Iafrate F, Masci GM, Coco S, Cilia F, Manganaro L, Panebianco V, Andreoli
C, Colaiacomo MC, Zingaropoli MA, Ciardi MR, Mastroianni CM, Pugliese F, Alessandri F,
Turriziani O, Ricci P, Catalano C. Chest CT score in COVID-19 patients: correlation with
disease severity and short-term prognosis. Eur Radiol 2020. doi: 10.1007/s00330-020-07033-y
23. Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K. Persistent
elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and
IL-6 levels are consistent and efficient predictors of outcome over time. Chest
1995;107(4):1062-1073. doi: 10.1378/chest.107.4.1062
24. Desai SR, Wells AU, Rubens MB, Evans TW, Hansell DM. Acute respiratory distress
syndrome: CT abnormalities at long-term follow-up. Radiology 1999;210(1):29-35. doi:
10.1148/radiology.210.1.r99ja2629

19
 25. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role
for antifibrotic therapy. The Lancet Respiratory medicine 2020. doi: 10.1016/s2213-
2600(20)30225-3
26. Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H,
Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum
L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F. High risk of thrombosis in patients with
severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive care medicine
2020;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x
27. Kazerooni EA, Martinez FJ, Flint A, Jamadar DA, Gross BH, Spizarny DL, Cascade PN,
Whyte RI, Lynch JP, 3rd, Toews G. Thin-section CT obtained at 10-mm increments versus
limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with
pathologic scoring. AJR Am J Roentgenol 1997;169(4):977-983. doi:

s
10.2214/ajr.169.4.9308447
28. Pan Y, Guan H, Zhou S, Wang Y, Li Q, Zhu T, Hu Q, Xia L. Initial CT findings and temporal
changes in patients with the novel coronavirus pneumonia (2019-nCoV): a study of 63 patients

es
in Wuhan, China. Eur Radiol 2020;30(6):3306-3309. doi: 10.1007/s00330-020-06731-x
29. Oudkerk M, Büller HR, Kuijpers D, van Es N, Oudkerk SF, McLoud TC, Gommers D, van
Dissel J, Ten Cate H, van Beek EJ. Diagnosis, Prevention, and Treatment of Thromboembolic
Complications in COVID-19: Report of the National Institute for Public Health of the
Netherlands. Radiology 2020:201629. doi: 10.1148/radiol.2020201629
30. Thoma P, Rondelet B, Mélot C, Tack D, Naeije R, Gevenois PA. Acute pulmonary
embolism: relationships between ground-glass opacification at thin-section CT and
hemodynamics in pigs. Radiology 2009;250(3):721-729. doi: 10.1148/radiol.2503081134
pr
31. Wu X, Kim GH, Salisbury ML, Barber D, Bartholmai BJ, Brown KK, Conoscenti CS, De
Backer J, Flaherty KR, Gruden JF, Hoffman EA, Humphries SM, Jacob J, Maher TM, Raghu
G, Richeldi L, Ross BD, Schlenker-Herceg R, Sverzellati N, Wells AU, Martinez FJ, Lynch
DA, Goldin J, Walsh SLF. Computed Tomographic Biomarkers in Idiopathic Pulmonary
Fibrosis. The Future of Quantitative Analysis. American journal of respiratory and critical care
medicine 2019;199(1):12-21. doi: 10.1164/rccm.201803-0444PP
In

20
 Figures

s
es
pr
In

Figure 1: Participant flow diagram.

21
 s
Figure 2: Chest follow-up CT findings of COVID-19 pneumonia: (a) traction bronchiectasis;

(b) parenchymal bands; (c) honeycombing; (d, e) thickening of the adjacent pleura.

es
pr
In

22
 s
es
pr
Figure 3: Serial CT scans of a 46-year-old woman with severe COVID-19 pneumonia. (a-c)

The scan obtained on day 32 after symptom onset showed multiple ground-glass opacities

(GGOs) and interstitial thickening with mild cylindrical traction bronchiectasis involving the

middle lobe and lower lobe of the right lung. (d-f) The scan obtained on day 198 showed partial
In

absorption of the abnormalities, reduced extension, traction bronchiectasis (thin arrows) and

localized “honeycombing” (thick arrow) in the subpleural region of the right middle lobe.

23
 s
Figure 4: Serial CT scans of a 63-year-old man with emphysema and severe COVID-19

pneumonia. (a) The axial CT scan obtained on day 27 after onset of symptoms showed multiple

es
ground-glass opacities (GGO) in the subpleural right lung. (b) The scan obtained on day 72

showed obvious absorption of the abnormalities. (c) The scan obtained on day 164 showed

complete resolution.
pr
In

24
 s
es
Figure 5: Serial CT scans of a 57-year-old man with severe COVID-19 pneumonia. (a, b)

Axial and coronal thin-section CT scans obtained on day 9 after the onset of symptoms showed

extensive ground-glass opacities (GGO) and interstitial thickening bilaterally. (c, d) Scans
pr
obtained on day 46 showed evolution to a mixed pattern of ground-glass opacities and

consolidation with almost the same extent of lesions. (e, f) Scans obtained on day 159 showed

a marked decrease in the density of GGO, with a slightly increased extension of the GGO

(“tinted” sign or “melting sugar” sign, which defined as an imaging appearance of increased

extension of the GGO or consolidation and decreased density).

In

25
 Figure 6: Serial CT scans of a 52-year-old man with severe COVID-19 pneumonia. (a) The

axial thin-section CT scan obtained on day 8 after symptom onset showed multiple ground-

s
glass opacities (GGOs) bilaterally, with a slight traction of the right interlobar pleural (arrow).

(b, c) Scans obtained on days 79 and 149, respectively, showed continuous absorption of

es
previous opacifications, with the progression of interlobar pleural traction.
pr
In

26
 Appendix E1

s
es
Figure E1: Serial CT scan of a non-smoking 32-year-old woman with severe COVID-19

pneumonia and secondary bacterial infection. (a-c) Axial and sagittal thin-section CT scans

obtained on day 40 after the onset of symptoms showed multiple ground-glass opacities and
pr
consolidations that were predominately located in the anterior region of the left upper lobe and

right middle lobe. The lesions in the left upper lobe showed cystic changes (arrows). (d-f) Scans

at the same level obtained on day 182 showed obvious absorption of previous opacifications.

Marked architectural distortion and pulmonary atelectasis were observed in the anterior region

of the left upper lobe and right middle lobe, with bronchiectasis of some subsegmental bronchi
In

and emphysema within areas of atelectasis.

31
 Table E1: Correlation Coefficient for Fibrotic-like Changes Scores on Follow-up
CT Scans
CT scores of Fibrotic-like changes
Characteristics Spearman’s 95% CI P value
correlation coefficient
Age, years 0.324 0.149-0.479 <.001
Sex 0.036 -0.149-0.218 .71
Heart rate (bpm) 0.235 0.052-0.403 .01
Any comorbidities 0.300 0.122-0.459 .001
Chronic pulmonary disease 0.348 0.168-0.505 <.001
Duration of hospital stay 0.492 0.338-0.620 <.001
ARDS 0.570 0.432-0.683 <.001
Non-invasive mechanical
0.485 0.331-0.614 <.001
ventilation
Glucocorticosteroids use 0.335 0.159-0.491 <.001

s
Hyper-sensitive C-reactive
0.369 0.175-0.535 <.001
protein (mg/L)
D-dimer (mg/L) 0.586 0.407-0.722 <.001
Thickening of the adjacent
pleura
CT score of total lesions
CT score of GGO

es 0.300
0.469
0.377
0.123-0.459
0.312-0.601
0.208-0.525
.001
<.001
<.001
All data were analyzed using spearman correlation. HR, heart rate; ARDS, Acute respiratory distress
syndrome; GGO, ground-glass opacities.
pr
In

32
 Table E2: Comparison of CT Findings and Scores between Two Serial
Examinations in Convalescent Severe COVID-19 Patients
Characteristics Initial CT scans Follow-up CT scans P value
(n=114) (n=114)
Lung involvement ＜.001
Normal 0/114 (0) 25/114 (22%)
Unilateral 1/114(0.88%) 5/114 (4.4%)
Bilateral 73/114 (64%) 44/114 (39%)
Predominant CT pattern ＜.001
Normal 0/114 (0) 25/114 (22%)
GGO 44/114 (39%) 24/114 (21%)
Consolidation 17/114 (15%) 3/114 (2.6%)
Reticulation 13/114 (11%) 22/114 (19%)
Presence of nodule or mass 2/114 (1.8%) 19/114 (17%) ＜.001

s
Pleural effusion 7/114 (6.1%) 0/114 (0) .01
Emphysema 2/114 (1.8%) 2/114 (1.8%) .99
Thickening of the adjacent 27/114 (24%) 37/114 (32%) .10
pleura

Honeycombing
Pulmonary atelectasis
Bronchiectasis
CT score
Total lesions
GGO
Consolidation
Reticulation
fibrotic-like changes
es
Interlobar pleural traction 9/114 (7.9%)
2/114 (1.8%)
4/114 (3.5%)
8/114 (7.0%)

15(9)
10
5
(10)
(8)
5 (7)
0 (0)
19/114 (17%)
3/114 (2.6%)
13/114 (11%)
27/114 (24%)

3(8)
2(8)
0(0)
2(5)
0 (4)
.04
1.0
.02
＜.001

＜.001
＜.001
＜.001
.19
<.001
pr
Data are presented as medians (interquartile ranges) or n/N (%). p values comparing initial CT scans and
follow-up CT scans are from χ², Fisher’s exact test, independent-samples T test or Mann-Whitney U
test. GGO, ground-glass opacities.
In

33
 Table E3: Time Points of Presence of Fibrosis or Complete Resolution
Time interval from onset Group 1 Group 2
of symptoms (months) Fibrotic-like lung Complete radiological Residual GGO or interstitial
abnormalities (n=40) resolution(n=43) thickening(n=31)
At initial CT scan 2/40(5%) 0/43(0%) 31/31(100%)
At 3-month CT follow up* 17/37(46%) 20/34(59%) 12/12 (100%)
At 6-month CT follow up 22/40(55%) 23/43(53%) 31/31 (100%)
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.

s
es
pr
In

34
 Table E4: Comparison of Clinical Characteristics and
Pulmonary Function between Groups after 6-month Follow up

Characteristics All Group1 (n=40) Group 2(n=74) P value

patients(n=114)
Symptoms
Dry cough 7/114 (6.1%) 5/40(13%) 2/74(2.7%) .03
Expectoration 11/114 (10%) 5/40 (13%) 6/74 (8.1%) .42
Slight exertional dyspnea 16/114 (14%) 9/40 (23%) 7/74 (9.5%) .05
Maximum temperature (℃) 36.3 (0.5) 36.3 (0.5) 36.3 (0.6) .58
Heart rate (bpm) 81±12 82±12 81±12 .66
Oxygen saturation on 99±1 98±2 99±1 .11
room air(%)

s
Pulmonary Function
VC max% 106±16 101±18 109±15 .01
FVC% 108±17 102±18 111±15 .01
FEV1%
DLCO
＜80% for predicted
DLCO/VA

es
105±17
92±19
27/104 (26%)
97±17
102.7±19
82±19
18/36(50%)
94±18
106±16
98±17
9/68 (13%)
99±17
Data are presented as means±SD, medians (interquartile ranges) or n/N (%). p values comparing
patients with lung fibrotic changes (group 1) and patients without lung fibrotic changes (group 2)are
from χ², Fisher’s exact test, independent-samples T test or Mann-Whitney U test. VCmax,
maximum vital capacity; DLCO, carbon monoxide diffusion capacity; FVC, forced vital capacity;
.29
＜.001
＜.001
.15
pr
FEV1, forced expiratory volume in 1s; diffusion capacity of the lung for carbon monoxide; DLCO/VA,
DLCO divided by the alveolar volume.
In

35