Maximum chest CT score is associated with progression to severe illness in patients with COVID-19: a retrospective study from Wuhan, China

Worldwide, the Coronavirus Disease 2019 (COVID-19) pandemic, caused by infection with the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), has resulted (as of October 23, 2020) in 41,570,883 confirmed cases and 1,134,940 deaths [1]. As of that date, the rate of overall case-fatality across China was approximately 5.1%. Although relatively few deaths have been observed in patients with mild COVID-19, the rate of case fatality clearly is elevated among critically ill patients. Nevertheless, the nature of the factors influencing the prognosis of COVID-19 patients remains unclear [2, 3].

The onset of COVID-19 is associated with symptoms such as fever, cough, and myalgia. The case definition adopted in China and elsewhere includes further stratification of cases as mild, moderate, and severe/critical [4]. More than 80% of the laboratory-confirmed cases in China (including both non-pneumonia and pneumonia cases) were of the mild to moderate types [5]. A fifth of these cases progressed to a severe or critical stage, with the highest reported case fatality rate reaching 4.47% for patients in Wuhan diagnosed before March 2020 [6]. Most previous studies have focused only on the general epidemiological findings, clinical characteristics, and outcomes of patients with COVID-19 [3, 7, 8]. However, few studies (to our knowledge) have investigated clinical findings in patients who progress from moderate- to severe/critical-type symptoms.

In this study, we performed a comprehensive analysis of the clinical course and imaging findings of 243 hospitalized COVID-19 patients who initially presented with moderate-type symptoms. These patients were admitted to the isolation ward of the Central Hospital of Wuhan; this facility was one of the first hospitals in Wuhan to admit COVID-19 patients, and is located very close to a seafood market suspected as a source of the initial outbreak. We sought to identify risk factors associated with progression from moderate- to severe/critical-type symptoms in COVID-19 patients.

A total of 457 adult patients diagnosed with COVID-19 were admitted to our hospital from December 25, 2019, to February 16, 2020. Of these, 191 patients remained hospitalized, had diagnoses that were not confirmed by SARS-CoV-2 RNA detection, or had died by the time of our final follow-up; these cases were excluded from our analysis. We also excluded another 7 patients who were diagnosed with severe/critical-type symptoms on admission. An additional 16 patients were excluded because their medical records were not available. In total, 243 patients with confirmed COVID­19 pneumonia were enrolled in the analysis (Fig. 1). Forty patients progressed from having moderate symptoms to severe/critical symptoms during follow-up (Supplementary file). The mean age of these 243 patients was 47 years, with a range of 20 to 89 years. One hundred thirty-eight (56.8%) were female (Table 1). The patients who developed severe/critical symptoms were older (p < 0.001) and more likely male (p = 0.046) than patients with moderate-type symptoms. The most common symptoms at onset were fever (83.5%) and cough (63.8%), followed by weakness (45.7%) and sputum (28.8%). Chest tightness was more likely to occur in patients with severe/critical symptoms (42.5%) than in patients with (p = 0.002). Patients in the severe/critical-type symptom group had (compared to patients in the moderate-type group) significantly higher mean serum levels of D-dimer (2.1 ± 4 vs. 0.8 ± 1.6 mg/L; p < 0.001), C-reactive protein (3.6 ± 3.2 vs. 2 ± 3 mg/L; p = 0.038), α-hydroxybutyrate dehydrogenase (247 ± 352 vs. 142 ± 57 U/L; p < 0.001), lactate dehydrogenase (251 ± 119 vs. 185 ± 79 U/L; p = 0.002), creatine kinase, (273 ± 636 vs. 120 ± 172 U/L; p < 0.001), and creatinine (211 ± 449 vs. 67 ± 43 μmol/L; p < 0.001). The neutrophil-to-lymphocyte ratio (NLR) also was significantly higher in the severe/critical-type group than in the moderate-type group (10.6 ± 7.7 vs 3.7 ± 3.9; p < 0.001). Other laboratory findings did not differ significantly between the two groups. In comparison to patients in the moderate-type group, patients in the severe/critical-type group were more likely to have underlying hypertension (15, 37.5% vs. 30, 14.8%, respectively), chronic obstructive pulmonary disease (COPD) (5, 12.5% vs. 5, 2.5%), and chronic kidney disease (6, 15% vs. 4, 2%).

All patients had abnormal CT imaging features (Fig. 2). There were no significant differences in the initial CT scores between the moderate-type group and severe/critical-type group (p = 0.112). Compared to the moderate-type group, patients in the severe/critical-type group had significantly higher median maximum CT score (7, IQR 0–20, vs. 14, IQR 3–28, respectively; p < 0.001). There was no significant difference in the median time from onset of symptoms to hospitalization between the moderate-type group and the severe/critical-type group (p = 0.733). In comparison with patients in the moderate-type group, patients in the severe/critical-type group had longer hospital stays (22 days, IQR 18.5–28.5, vs. 18 days, IQR 13–24, respectively; p < 0.001) and a longer time from illness onset to high CT score (13 days, IQR 8–17.8, vs. 9 days, IQR 6–12; p < 0.001) (Fig. 3).

Using univariable analysis, the calculated odds of progression to the severe/critical-type symptoms was found to be higher in patients having any comorbidity, including hypertension and COPD. Age (≥60 years); sex (male); chest tightness; serum levels of D-dimer (≥1 mg/L), C-reactive protein (≥1 mg/L), α-hydroxybutyrate dehydrogenase (≥180 U/L), lactate dehydrogenase (≥250 U/L), creatine kinase (≥190 U/L), and creatinine (≥97 μmol/L); serum NLR; and highest CT score also were associated with disease progression. The length of the hospital stay and time from illness onset to the time of the highest CT score also were associated with disease progression. No collinearity was detected between variables. Next, we included these variables in the multivariable logistic regression analysis. We found that the combination of COPD (OR = 9.06, 95% CI [1.30–63.36]; p = 0.026) and a higher maximum CT score (OR = 1.39, 95% CI [1.21–1.60]; p < 0.001) were associated with disease progression (Table 2).

Using receiver operating characteristic curve (ROC) analysis, an optimal cutoff value of a maximum CT score of 11 with a sensitivity of 85.0% (95% CI: 70.2–94.3%) and specificity of 78.3% (95% CI: 72–83.8%) was shown to be predictive of disease progression (Fig. 4). The area under the ROC was 0.861 (95% CI: 0.811–0.902).

This retrospective study identified high CT scores and COPD as risk factors for deterioration in hospitalized patients with COVID-19 in Wuhan, China. Additionally, being older and male, having chest tightness, hypertension, and elevated serum levels of D-dimer, C-reactive protein, α-hydroxybutyrate dehydrogenase, lactate dehydrogenase, creatine kinase, creatinine, and serum NLR were associated with progression to severe or critical COVID-19 illness.

Recently, in a retrospective, multicenter cohort study of 191 patients, Zhou et al. demonstrated that older age is associated with mortality in hospitalized COVID-19 patients [12]. Other studies also have shown that older age (> 65 years) is associated with poorer clinical outcome in patients with COVID-19 [7, 13, 14]. The present study confirmed that more severely or critically ill patients were older (> 60 years) than patients with moderate-type COVID-19 symptoms. An age-dependent risk also has been seen in previous studies of severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) [14, 15]. However, in the current study, older age was not shown to be an independent predictor of deterioration in hospitalized patients with COVID-19. The difference between the present and previous studies may be due, in part, to the different outcomes being assesssed. The current study was aimed at the progress of moderate-type patients with COVID-19 who eventually recovered, rather than dying. Furthermore, we had a relatively small sample size for the severe/critical group.

Chest CT is the routine imaging modality for clinical diagnosis of patients with COVID-19 pneumonia in the Hubei Province. This technique may help in screening patients with suspected COVID-19 symptoms, especially those with a negative reverse transcription-polymerase chain reaction (RT-PCR) result at the early stages of the disease [16]. In order to comprehensively evaluate the CT features of COVID-19 pneumonia, a semi-quantitative scoring system has been developed to quantitatively estimate the severity of inflammation based on quantifying the extent of pulmonary abnormalities (including ground-glass opacities, consolidations, or other fuzzy interstitial opacities) [11]. Using this method, no significant difference in initial CT score was found between moderate-type and severe/critical-type groups in the present study. In contrast, a recent study showed that CT scores in severe/critical-type groups were significantly higher than those in the moderate-type groups [17]. This difference may reflect the fact that all of the patients with COVID-19 in the present study were of the moderate type initially. With the progression of COVID-19, there were significant differences in the highest CT scores between the moderate-type and severe/critical-type groups. Moreover, using multivariable analysis, the maximum CT score were found to be an important independent predictor of deterioration of patients who progressed from moderate-type symptoms to severe/critical-type symptoms. Furthermore, ROC analysis showed that an optimal cutoff value of a maximum CT score index of 11 (sensitivity of 85.0% and specificity of 78.3%) predicted deterioration. We hope that this maximum CT score index can be used to identify patients at earlier stages of COVID-19 who potentially may progress to severe/critical-type symptoms from moderate-type symptoms. Patients with this maximum CT score index then would receive more aggressive treatment and close monitoring. However, the efficacy of such an approach remains to be validated in multi-center and large-sample studies in the future.

Lung complications, especially pneumonia, are common in patients with COPD. According to a national cross-sectional study, the total number of patients with COPD in China approximates 100 million [18]. Most recent studies have shown no significant differences in COVID-19 severity between patients with and without COPD [2, 8, 19‐21]. In the current study, COPD was more common in the severe/critical-type group than in the moderate-type group, a finding that agrees with the results reported by Guan et al. [7]. In addition, COPD was found (in the present study) to be associated with the deterioration of patients with COVID-19. It should be noted that all studies to date, including the present work, have used small sample sizes of COVID-19 patients with COPD. The potential impact of COPD on the disease outcomes of patients with COVID-19 requires further observation and research.

Comorbidities have been shown to be associated with an increase in the risk of developing severe COVID-19. Recently published data suggested that neither type 2 diabetes mellitus nor hypertension are associated with the risk of developing severe COVID-19 [22]. A high incidence of COVID-19 was reported among colorectal cancer subjects and lung cancer patients [22]. Malignancy also was associated with a higher risk of severe COVID-19 [23]. Separately, COVID-19 patients with underlying liver disease were observed to have worse outcomes [24]. However, these comorbidities did not show statistical significance in our multivariable logistic regression analysis, presumably because of the relatively small sample size and few cases with complications.

Our study has some limitations. First, not all laboratory tests were done in all patients, including the measurement of levels of α-hydroxybutyrate dehydrogenase, lactate dehydrogenase, creatine kinase, procalcitonin and brain natriuretic peptide. Therefore, the roles of these parameters might be underestimated in predicting disease progression. In addition, we did not analyze the changes in laboratory findings in the process of the disease progression or patient recovery. Some of these results might also contribute to deterioration in some patients. Second, this was a retrospective study from a single center with a relatively small sample size and a certain selection bias, as some patients were transferred to other medical institutions by government decree. Thus, comparisons of clinical characteristics, laboratory findings, and imaging features may be skewed. In addition, chest CT score emerged as potentially associated with the risk for disease progression. However, there may have a risk of spurious association when multiple comparisons are made. Third, the semi-quantitative methods used for measuring COVID-19 pneumonia lesions may be somewhat subjective, and the time between the maximum chest CT score scan and the development of severe/critical illness was not analyzed as part of the present study. Last, infants, children and adolescents were not included in the present study; an effort should be made to include these groups in future studies.

Maximum CT score and COPD showed independent association with an increased risk of COVID-19 disease progression. A maximum CT score higher than 11 was associated with development of severe illness.