key: cord-0768086-8uu8kl9v
authors: Liao, Jie‐lan; Chen, Yu; Huang, Chong‐quan; He, Gui‐qing; Du, Ji‐cheng; Chen, Que‐lu
title: Clinical differences in chest CT characteristics between the progression and remission stages of patients with COVID‐19 pneumonia
date: 2020-10-17
journal: Int J Clin Pract
DOI: 10.1111/ijcp.13760
sha: e05e4e7aa5a49f15b1805b61cfebfb134156b146
doc_id: 768086
cord_uid: 8uu8kl9v

INTRODUCTION: Computed tomography (CT) can be effective for the early screening and diagnosis of COVID‐19. This study aimed to investigate the distinctive CT characteristics of two stages of the disease (progression and remission). METHODS: We included all COVID‐19 patients admitted to Wenzhou Central Hospital from January to February, 2020. Patients underwent multiple chest CT scans at intervals of 3–10 days. CT features were recorded, such as the lesion lobe, distribution characteristics (subpleural, scattered, or diffused), shape of the lesion, maximum size of the lesion, lesion morphology (ground‐glass opacity, GGO), and consolidation features. When consolidation was positive, the boundary was identified to determine its clarity. RESULTS: The ratios of some representative features differed between the remission stage and the progression phase, such as round‐shape lesion (8.0% vs. 34.4%), GGO (65.0% vs. 87.5%), consolidation (62.0% vs. 31.3%), large cable sign (59.0% vs. 9.4%), and crazy‐paving sign (20.0% vs. 50.0%). Using these features, we pooled all the CT data (n = 132) and established a logistic regression model to predict the current development stage. The variables consolidation, boundary feature, large cable sign, and crazy‐paving sign were the most significant factors, based on a variable named ‘prediction of progression or remission’ (PPR) that we constructed. The ROC curve showed that PPR had an AUC of 0.882 (cutoff value = 0.66, sensitivity = 0.75, specificity = 0.875). CONCLUSION: CT characteristics, in particular, round shape, GGO, consolidation, large cable sign, and crazy‐paving sign, may increase the recognition of the intrapulmonary development of COVID‐19.

The highly infectious disease Coronavirus Disease 2019 has widely spread throughout the world since the beginning of 2020, and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since emerging in Wuhan, it has rapidly spread to other cities in China, and multiple countries beyond China. On February 28, 2020, the World Health Organization (WHO) declared COVID-19 a global public health emergency (World Health Organization 2020 COVID-19 situation report). As of March, 2020, approximately 800,000 individuals have had a positive diagnosis, and the number is still rising sharply. [24] [25] [26] Among the limited detection approaches, CT is effective for the early screening and diagnosis of COVID- 19 . CT features have be used to distinguish community acquired pneumonia and COVID-19 through artificial intelligence algorithms. 1 In addition, CT features may help to indicate severe/critical development, as the incidences of consolidation, linear opacities, crazy-paving pattern, and bronchial wall thickening in severe/critical patients were significantly higher than those in ordinary patients. 2 Previous studies have used the total severity score (TSS) according to CT visual quantitative evaluation for diagnosing severe/critical COVID-19, which provides a high area under the curve (AUC) value. 3 Overall, different factors are related to the onset and severity of COVID-19, which contribute to diagnosis and prognosis. 27, 28 However, very few studies have focused on the different stages of development of COVID-19, or have accurately distinguished between the progression stage and remission stage using CT data. In the present study, we analyzed the CT images from 107 COVID-19 cases, and examined the distinctive characteristics of both the progression and remission stages. Our findings provide a reference for assessing the clinical condition/stage of patients and will help in determining treatment strategies.

This article is protected by copyright. All rights reserved 2 | METHODS

This retrospective study included all COVID-19 patients admitted to our hospital from January 10, 2020 to February 20, 2020. Each patient provided informed consent at admission. The inclusion criteria were as follow: (1) Positive SARS-CoV-2 nucleic acid throat swab test, and a diagnosis consistent with the Diagnostic Standards for COVID-19 Pneumonia Diagnosis and Treatment Program (Trial Version 6). (2) A definite outcome (survival or death). (3) Clear blood routine test results. (4) Chest CT scans were undertaken and the appropriate features were acquired. Almost all patients underwent multiple chest CT scans during the treatment period, at intervals of 3-10 days. Specifically, 32 patients received two scans at two time points (the progression stage and the remission stage), and 100 patients had complete data from a scan at only one stage (the remission stage). Herein, the two stages were defined as follows. If the scan was performed within 3 days before the severity category worsened (from ordinary to severe, or from severe to critical) or the total chest lesion was significantly enlarged, this time point was regarded as the progression stage. If the scan was performed within 3 days before the severity category was alleviated (from mild to cured, from ordinary to mild, from severe to ordinary, or from critical to severe), this time point was regarded as the remission stage.

A GE OPTIMA 540 16-row multilayer spiral scanner ( ) was used for CT scanning. Patients underwent scanning in the supine position. The continuous scan range was from the apex to the bottom of the lung.

Scanning parameters were as follows: voltage, 120 kV; tube current, 200 mA; rotation speed, 27.5mm/turn; pitch, 1.375; and layer pace and layer thickness, 5 mm. Later, the routine algorithm for thin-layer reconstruction (layer thickness, 1.25 mm) was used to acquire the CT images. Subsequently, chest images were reviewed independently by two senior diagnostic radiologists (one with 15 years and the other with 32 years of experience). The radiologists were blinded to the pathological and clinical status of each patient.

When their opinions differed, agreement was reached through discussion.

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The lung window and mediastinum window were used to analyze the images, which were grouped according to the dynamic observation and the medical record. We recorded the following CT image characteristics: the lesion lobe, distribution characteristics (subpleural, scattered, or diffused), shape of the lesion (round, nodular, or irregular patches), maximum size of the lesion (< 3cm, ≥ 3cm and < 5cm, or ≥ 5cm), lesion morphology (ground-glass opacity [GGO] and consolidation features, and when consolidation was positive, the boundary was observed to distinguish whether it was clear), large cable sign (a clear large cable sign that usually appears in the late stages and also the similar linear opacities that are usually observed in the early stages; commonly, an early linear opacity can turn to a large cable sign after absorption; when this sign was positive, we further observed whether it was parallel to the pleura or bridged to the pleura. Figure 1C shows some typical large cable signs), crazy-paving sign, air bronchogram signs, septal thickening, pleural effusion, and mediastinal lymph node enlargement. Other important features are shown in Supplemental Figure 1.

SPSS software (version 25.0; ) was used for statistical analyses. Categorical data were compared using Fisher's exact test. Continuous data were described as mean ± standard and compared using the Mann Whitney test or Wilcoxon matched-pairs signed rank test. Logistic regression was used to predict the development stage. Receiver operating characteristic (ROC) curves were generated using SPSS to assess predictive power. All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant.

Together, we enrolled 107 cases, including 58 males and 49 females, with an average age of 44.9 ± 12.7

years. Other demographic characteristics are listed in Table 1 . Regarding severity levels, 89.7% were of the

This article is protected by copyright. All rights reserved ordinary type and 10.3% were in severe stages (severe or critical). Baseline symptoms and signs, and laboratory examination results of enrolled patients were as follows. For symptoms and signs (Table 2) , fever, dry cough, expectoration, diarrhea, throat pain, fatigue, and muscle aches were commonly seen signs.

For laboratory examination results, elevated C-reactive protein, lymphopenia, and leukopenia were significant phenotypes (Table 2) . After an average period of 22.7 days of treatment (22.7 ± 9.0 days, min = 5 days, max = 60 days), all patients were cured and no deaths occurred.

Among all enrolled patients, we found 32 cases with CT images indicating the progression and 100 cases with images indicating the remission stage. Some features were different between the two stages, including round-shape lesion (8.0% vs. 34.4%), GGO (65.0% vs. 87.5%), consolidation (62.0% vs. 31.3%), large cable sign (59.0% vs. 9.4%), and crazy-paving sign (20.0% vs. 50.0%) ( Table 3 ). Fisher's exact test was performed to analyze these features in the 32 cases with CT scans at two time points. Here, a negative result meant that there was no longer an association between remission and progression, namely that large changes occurred when patients entered the remission stage. Consistently, the round-shape lesion proportion, GGO ratio, consolidation ratio, large cable signs, and crazy-paving signs in the remission stage were no longer correlated with the progression stage (Table 4 ). In particular, consolidation does not necessarily mean a worsening of COVID-19 but can be an indicator of a sufficient immune reaction, as well as a sign of improvement. Finally, remission of crazy-paving sign (which disappeared in 11 individuals) was an obvious indicator of improvement. Some typical cases with consolidation and large cable sign changes are presented in Figure 1 , which consistently implied that consolidation and large cable signs are more frequently seen in the remission stage rather than in the progression stage.

Using the above associated factors, we pooled all the CT data (n = 132) into one dataset and established a model to predict the current developing stage (remission or progression). Using logistic (two-tailed) regression, we found the consolidation, boundary feature, large cable sign, and crazy-paving sign variables were the most significant factors distinguishing between progression and remission (Table 5 ). Next, we constructed a variable that we named 'prediction of progression or remission' (PPR) based on the above four parameters ( Table 6 ). The ROC curve showed that PPR had an AUC of 0.882 (cutoff value = 0.66, with a sensitivity of 0.75 and a specificity of 0.875) (Figure 2 ).

To date, this is the first report regarding unique CT features during progression and remission of COVID- 19 . We revealed that the characteristics of round shape, GGO, consolidation, large cable sign, and crazypaving sign significantly change between the progression and remission stages. Using four features (variable consolidation, boundary feature, large cable sign, and crazy-paving sign) can help to distinguish the development stage of COVID-19.

Using CT examinations, the occurrence, development, and prognosis of COVID-19 can be comprehensively understood. CT has advantages over histological examination in that it can evaluate the whole lungs. Histological examination may be prone to sampling errors due to sample being obtained from localized regions. Since its emergence, the CT imaging characteristics of COVID-19 have been studied by different research groups. Case reports have shown common trends during development, such as rapidly progressing peripheral consolidations and GGOs in both lungs. 4 In addition, patchy GGOs have been found in both adult and pediatric COVID-19 patients. 5 , Positive CT findings, including consolidation, greater total lung involvement, linear opacities, crazy-paving signs, and reversed halo signs, are usually more frequent a long time after the onset of symptoms. 6 After the accumulation of samples, typical manifestations of COVID-19 were reported. Early radiological investigations consistently reported that bilateral GGOs and consolidation with a peripheral and posterior lung distribution were regarded as a cardinal hallmark of Accepted Article . Up to 98% of cases have presented GGO as the most common imaging finding. 7 In Zhejiang province of China, it was reported that the imaging pattern of multifocal peripheral ground-glass or mixed opacity with predominance in the lower lung is highly indicative of COVID-19 in the first week of symptom onset. 8 In Korea, the observation of pure to mixed GGO lesions with a patchy to confluent or nodular shape is frequent. 9 Some indirect evidence shows that when compared with the initial CT features, a progressive process may exhibit opacities, consolidation, interstitial thickening, fibrous strips, and air bronchograms. 10 GGO with a peripheral distribution are the most widely reported manifestation of COVID-19. 11 In summary, early CT findings are generally patchy GGO with or without consolidation involving multiple lobes, mainly in the peripheral zone, accompanied by halo sign, vascular thickening, crazy-paving pattern, or air bronchogram sign. 12 However, very few studies have investigated the differences in CT between severity stages, and even fewer studies have reported on the features of progression and remission.

In contrast, several reports have described the typical trends of progression. A study published in Lancet Infectious Diseases described Wuhan patients grouped on the basis of the interval between symptom onset and the first CT scan. They showed a trend that as the disease developed, the prevalence of GGOs continued to decrease; meanwhile, consolidation and mixed patterns became more frequent. 13 In our study, the 32 progression cases were all included in the 100 remission cases, and as expected, they had some imaging features in common. Overall, the baseline imaging characteristics were as follow: multiple lesions, multiple lobe involvement, mostly subpleural distribution, lesions located in both lungs, irregular patches, air bronchogram, and septal thickening, which are largely consistent with published reports. [14] [15] [16] When the disease enters the remission stage, there are no changes in lobe involvement, the distribution of lesions, the maximum lesion size, and the shape of the lesion. However, some interesting changes warrant attention. In the remission stage, the frequency of GGO decreases and the frequency of consolidation significantly increases, especially consolidation with blurred boundary. Moreover, increased large cable sign and reduced crazy-paving sign were indicators of remission in our study. As previously suggested, consolidation and cable sign are common signs of viral pneumonia. 17, 18 Machine-learning studies have also suggested that consolidation is one of the most discriminative features of COVID-19. Theoretically,

This article is protected by copyright. All rights reserved consolidation may be associated with the coagulopathy status [29] [30] [31] in pneumonia. Some researchers believe that an increase in consolidation indicates disease progression, and the degree of lung consolidation and fibrosis is closely related to the severity of the patient's condition. 32 However, the present study is the first work indicating that consolidation is more closely associated with an improvement rather than worsening, and this feature is diverse in the two stages. In our study, the consolidation feature in progression generally showed nodular consolidation or reversed halo sign changes, while the consolidation in remission frequently showed an increased GGO density but reduced volume, and subsequently many consolidations of the GGO areas were dissipated or absorbed accompanied by large cable signs. This is consistent with the observation from Pan et al.'s work, 19 which shows that when the disease reaches the peak stage, consolidation usually becomes apparent, and then it enters the absorption phase followed by improvement.

In addition, Jin et al. claimed that there is a consolidation period after sufficient progression, and the consolidation volume decreases and enters the absorption period. 20 The dynamic observation of all patients showed no increase in consolidation volume. To date, most scholars believe that the consolidation change is an essential part of disease progression, and even a landmark of severe or critical stages. [21] [22] [23] However, in our study, we found that consolidation differed in the two stages; the remission stage had more frequent consolidation, and the boundary of consolidation in the remission stage was usually blurred, while that in the progression stage was much clearer. Moreover, the possible pathological mechanisms of consolidation in the two stages are different. Progressive consolidation includes the accumulation of a large amount of cell exudate in the alveolar cavity and vasodilation in the interstitial blood vessels, which cause edema in alveolar and interstitial vessels, and this aggravates symptoms. Remissive consolidation may include the fibrous exudation of the alveolar cavity and the resolution of capillary congestion in the alveoli wall.

Another finding of our study was that the large cable sign was positively correlated with remission, which suggests that large cable sign indicates the gradual absorption of the lesion and that the patient is recovering. Similar changes were also observed in the study by Bernheim et al., 22 but very few studies have drawn a conclusion about the implication to remission. Out of 53 large cable sign cases, 50 showed cable bridging the pleura, which may be due to the absorption speed in the edema-thickened interlobular septal being slower than in the exudative lesion. However, the definite mechanism requires further study.

This article is protected by copyright. All rights reserved Our study has some limitations. Based on a limited number of cases, we pooled the data of ordinary and severe patients together to form the progression and remission groups, which may have induced intra-group differences. Our future studies will examine features in different subgroups separately. In addition, the follow-up time of absorption was limited, and further recovery of lung function and CT remission features are unclear.

In conclusion, CT characteristics may strengthen the recognition of the intrapulmonary development of COVID-19 and help radiologists distinguish progression and remission phases more accurately over time.

In particular, these characteristics include round shape, GGO, consolidation, large cable sign, and crazypaving sign. Understanding different CT characteristics will help us to better determine the clinical condition and formulate reasonable treatment plans, potentially avoiding over-treatment. Figure S1 . Typical examples of important features.

The study was supported by the Major Project of Wenzhou Municipal Science and Technology Bureau (ZY202004), and Basic Public Welfare Research Project of Zhejiang Province (LGF20H010003).

JL collected data, drafted the initial manuscript, and reviewed and revised the manuscript. YC and CH collected data, and reviewed and revised the manuscript. GH reviewed and revised the manuscript. QC conceptualized and designed the study, collected data, carried out the analyses, critically reviewed the

This article is protected by copyright. All rights reserved manuscript for important intellectual content, and reviewed and revised the manuscript. JD carried out the analyses, critically reviewed the manuscript for important intellectual content, and reviewed and revised the manuscript.

The datasets generated and/or analyzed during the current study are available from the corresponding autho r on reasonable request.

Ji-cheng Du: https://orcid.org/0000-0002-7698-7556

Que-lu Chen: https://orcid.org/0000-0001-5624-0335 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

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