key: cord-264220-xfptlkuc
authors: Tan, Chaochao; Huang, Ying; Shi, Fengxia; Tan, Kui; Ma, Qionghui; Chen, Yong; Jiang, Xixin; Li, Xiaosong
title: C‐reactive protein correlates with computed tomographic findings and predicts severe COVID‐19 early
date: 2020-04-25
journal: J Med Virol
DOI: 10.1002/jmv.25871
sha: 
doc_id: 264220
cord_uid: xfptlkuc

COVID‐19 has developed into a worldwide pandemic; early identification of severe illness is critical for controlling it and improving the prognosis of patients with limited medical resources. The present study aimed to analyze the characteristics of severe COVID‐19 and identify biomarkers for differential diagnosis and prognosis prediction. In total, 27 consecutive patients with COVID‐19 and 75 patients with flu were retrospectively enrolled. Clinical parameters were collected from electronic medical records. The disease course was divided into four stages: initial, progression, peak, and recovery stages, according to computed tomography (CT) progress. to mild COVID‐19, the lymphocytes in the severe COVID‐19 progressively decreased at the progression and the peak stages, but rebound in the recovery stage. The levels of C‐reactive protein (CRP) in the severe group at the initial and progression stages were higher than those in the mild group. Correlation analysis showed that CRP (R = .62; P < .01), erythrocyte sedimentation rate (R = .55; P < .01) and granulocyte/lymphocyte ratio (R = .49; P < .01) were positively associated with the CT severity scores. In contrast, the number of lymphocytes (R = −.37; P < .01) was negatively correlated with the CT severity scores. The receiver‐operating characteristic analysis demonstrated that area under the curve of CRP on the first visit for predicting severe COVID‐19 was 0.87 (95% CI 0.10–1.00) at 20.42 mg/L cut‐off, with sensitivity and specificity 83% and 91%, respectively. CRP in severe COVID‐19 patients increased significantly at the initial stage, before CT findings. Importantly, CRP, which was associated with disease development, predicted early severe COVID‐19.

Since the SARS-COVID-2 outbreak in China, a large number of cases have also been reported worldwide and the disease has become a global epidemic. Although the majority of patients show mild symptoms, COVID-19 causes mass casualty and poses great challenges to the global healthcare system. 1, 2 Early diagnosis of serious illness is critical to early classification and improvement of patients' prognosis. Additionally, the early identification of patients who will become severely ill could facilitate the allocation of the limited Abbreviations: AUC, area under the receiver-operating curve; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; NLR, granulocyte/lymphocyte ratio; ROC, receiver operating characteristic; WBC, white blood cell. medical resources to patients in need of aggressive treatment.

Therefore, further research is urgently needed on early diagnosis and prognosis. In addition, due to the similarity in the early stages of COVID-19 with the flu, it is not easy to distinguish between them, especially in the winter and spring. Any misdiagnosis will have disastrous consequences in controlling the epidemic. Changes in the number of lymphocytes, C-reactive protein (CRP), and erythrocyte sedimentation rates (ESR) have been previously reported in COVID-19 patients, but little is known about their correlation with disease severity. 3, 4 Therefore, it is necessary to determine the clinical laboratory biomarkers that will allow early and differential diagnosis of SARS-COV-2 infection and predict the severity of the disease. In this study, we aimed to compare clinical laboratory biomarkers between SARS-COV-2 and influenza infection, and also between mild and severe COVID-19 patients, to explore the most useful prognostic factors for early, accurate, and individualized assessment of COVID-19 patients. 

The exposure history, demographic data, clinical symptoms, comorbidities, laboratory findings, chest computed tomographic (CT) scans and clinical outcomes were collected. The radiographic scores for COVID-19 patients were blindly evaluated by two radiologist doctors. CT scores were recorded following previous research with some modifications. 6 In particular, 5 scores were assigned according to visual assessment of the involvement of each of the five lung lobes independently: 0 point, no involvement; 1 point, less than 5% involvement; 2 points, 25% involvement; 3 points, 26%-49% involvement; 4 points, 50% to 75% involvement; 5 points, more than 75% involvement ( Figure 1 ). The total CT score was the sum of the scores of the individual lobes ranging from 

Twenty-seven patients infected by SARS-COV-2 were retrospectively enrolled in our study. As shown in Table 1 , 11 (41%) patients had visited Wuhan, 12 (44%) patients had close contact with COVID-19 patients, and 4 patients (15%) denied any obvious history of exposure. There were two patients (7.4%) with no symptoms of pneumonia and six patients (22%) with severe symptoms. The average age of patients was 48.89 ± 18.47. The most common symptoms were fever (88%), cough (44%), and fatigue (33%). Twenty-six patients infected by SARS-COV-2 have been discharged from the hospital, and the remaining ones were still in the hospital. Meanwhile, 75 patients infected by influenza were retrospectively enrolled in our study. Compared to the SARS-COV-2 group, there were higher levels of WBC and granulocytes in influenza patients. There was no difference in the levels of lymphocytes and other biomarkers between the two groups (Table 1 ).

According to CT findings of previous research, COVID-19 patients can be categorized into four stages: initial stage, progression stage, peak stage, and recovery stage. In general, patients had a CT scan at an interval of 3 to 5 days. The median time was 3 days (Figure 2A, B) . Interestingly, these results also showed that compared with the mild group, the lymphocyte number progressively decreased at the progression stage and the peak stage, but increased in the recovery stage ( Figure 2C ). Moreover, the NLR showed changing trends similar to the lymphocyte numbers, which became significantly higher in the severe group at the recovery stage ( Figure 2D ). The CRP in the severe group at the progression stage was higher than that in the mild group but was decreased although with no statistically significant differences at the peak and recovery stages ( Figure 2E ). There were significant increases in the CT scores of the severe group at all four stages ( Figure 2F ). Also, there were significant differences in the ESR between the two groups at the early stage; however, no significant differences were observed at the three later stages ( Figure 2G ).

At present, CT is the main method to evaluate disease severity.

Correlation analysis showed that CRP (R = .62; P < .01), ESR (R = .55; P < .01), and NLR (R = .49; P < .01) were all positively correlated with the CT scores. Moreover, our results showed that the lymphocyte number (R = −.37; P < .01) was negatively associated with the CT scores, and not significantly correlated with CT scores (R = .14; P = .15) ( Figure 3 ). Our results suggest that a significant increase in CRP is a signal of lung deterioration and progression. Three patients in our study confirmed this point. Figure 4 ). ROC analysis also demonstrated at a cut-off value of 20.42 mg/L, the sensitivity, specificity, positive prediction value (PPV) and negative prediction value (NPV) of CRP were 83%, 91%, 71%, and 95%, respectively. At a cut-off value of 19.50 mm/h, the sensitivity, specificity, PPV, and NPV of ESR were 83%, 81%, 56%, and 94%, respectively. Furthermore, ROC analysis also showed that the AUC of CRP to predict disease severity was higher than CT scores, which demonstrated the excellent predictive power for the severity of COVID-19 patients ( Table 2) . we found that CRP increased significantly at the initial stage, further increased at the progression and peak stage l, but recovered dramatically at the recovery stage. Interestingly, we found that CRP increased significantly at the initial stage in severe COVID-19

patients; while still no significant difference in the CT scores were found between the severe and mild groups. Furthermore, ROC further confirmed that CRP was an early biomarker for predicting the severity of COVID-19 with good performance.

In the present cohort of COVID-19 pneumonia, we followed up the patients from the first visit throughout the hospitalization. Their ages ranged from 12 to 84 years. The patients had no history of tumors, severe kidney and liver disease and other serious blood diseases. To match the COVID-19 characteristics, patients with flu were screened under the same conditions and enrolled. Although flu is more common in young people compared with COVID-19 patients, previous research has suggested that both the WBC and granulocyte numbers did not significantly differ with age. 7 The present study showed that patients with flu had higher WBC, granulocyte, and NLR, Most of the previous studies identified and analyzed the data of patients after hospitalization; 3,12,13 however, this usually takes 1 or 2 days from the first visit to admission because of nucleic acid diagnosis.

Therefore, to predict the severity of COVID-19 as early as possible, we analyzed the laboratory data of patients' first visit. ROC analysis demonstrated that AUC of CRP for predicting severe COVID-19 was 0.87 (95% CI, 0.10-1.00), with sensitivity and specificity 83% and 91% at a cut-off value of 20.42 mg/L.

The present study is not devoid of limitations. First, only 27 COVID-19 patients were included. Although the small sample size may have resulted in biases, we collected data from multiple stages in the process of disease, which may help to increase the reliability of conclusions. Second, some biomarkers such as renal function and myocardial enzymes were not available in every stage during hospitalization.

In conclusion, we found that patients with flu had higher WBC, granulocyte and granulocyte/lymphocyte ratio, compared with COVID-19 patients. Moreover, CRP and ESR increased significantly at the early stage in severe COVID-19 patients, before identification of any change by the CT scores. Importantly, CRP was associated with disease development and showed good performance in predicting severity in an early stage of COVID-19.

This study was funded by the Novel Coronavirus Pneumonia Emergency Project of the Hunan Provincial Science and Technology Department (2020SK3018).

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The authors declare that there are no conflict of interests.

CT, YW, FS, and QM were involved in the paper drafting, data acquisition, and analysis; KT, XJ, and YC were responsible for data collection and data analysis; XL involved in the research design and revision of the manuscript.

https://orcid.org/0000-0001-8369-667X Xiaosong Li http://orcid.org/0000-0002-2522-4524