|Year : 2021 | Volume
| Issue : 3 | Page : 63-69
High sensitivity C reactive protein level is associated with prognosis in patients with severe coronavirus disease 19 pneumonia
Lei Zhang1, Bilian Yu2, Lizhen Yang3, Hong Zhang4, Guxiang Huang5, Liang Tang2, Min Xu6, Jienan Zhou7, Le Xiao7, Jianjun Tang2, Xianling Liu8, Chang Shu9, Xin Li10
1 Department of Vascular Surgery, Secondary Xiangya Hospital, Central South University; Vascular Diseases Institute, Changsha, Hunan, China
2 Department of cardiovascular medicine, Secondary Xiangya Hospital, Central South University, Changsha; Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
3 Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei; Respiratory intensive care unit, Secondary Xiangya Hospital, Central South University, Changsha, China
4 Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei; Department of Cardiac surgery, Secondary Xiangya Hospital, Central South University, Changsha, China
5 Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei; Department of Geratology, Secondary Xiangya Hospital, Central South University, Changsha, China
6 Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei; Intensive care unit, Secondary Xiangya Hospital, Central South University, Changsha, China
7 Department of Vascular Surgery, Secondary Xiangya Hospital, Central South University; Vascular Diseases Institute, Changsha, Hunan; Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
8 Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei; Department of Oncology, Secondary Xiangya Hospital, Central South University, Changsha, China
9 Department of Vascular Surgery, Secondary Xiangya Hospital, Central South University; Vascular Diseases Institute, Changsha, Hunan; State key laboratory of cardiovascular diseases, Central of vascular surgery, Fuwai Hospital, National Centre for Cardiovascular disease, Chinese academic of Medical Sciences and Peking Union Medical College, Beijing, China
10 Department of Vascular Surgery, Secondary Xiangya Hospital, Central South University; Vascular Diseases Institute, No.139 Renmin Road-Changsha -410011, Hunan; Anti-2019-nCov pneumonia medical support group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
|Date of Submission||11-May-2021|
|Date of Decision||29-May-2021|
|Date of Acceptance||30-May-2021|
|Date of Web Publication||21-Jul-2021|
Dr. Xin Li
Department of Vascular Surgery, Secondary Xiangya Hospital, Central South University, No.139 Renmin Road-Changsha-410011, Hunan, China. Vascular Diseases Institute, Central South University, Changsha, Hunan, China. Anti-2019-nCov Pneumonia Medical Support Group to Wuhan from Secondary Xiangya Hospital, Central South University at Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei
Source of Support: None, Conflict of Interest: None
OBJECTIVES: The objective of the study is to describe the association of high-sensitivity C-reactive protein (hsCRP) in patients with severe coronavirus disease-19 (COVID-19) pneumonia and determine the relationship between hsCRP, prognosis, and other factors.
METHODS: The hsCRP level and other clinical data of patients with severe COVID-19 pneumonia in Tongji Hospital were retrospectively reviewed. Unpaired t-test and Mann–Whitney test were used to compare difference in data between groups. Spearman analysis was used to analyze the correlation.
RESULTS: Fifty-seven patients (25 male [43.9%] and 32 female [56.1%]) were included, and their condition was monitored for 28 days. The baseline hsCRP level was 35.5 ± 81.9 mg/L, and the hsCRP level of 49 patients increased (86.0%). Moreover, 45 (78.9%) patients recovered to ordinary/mild COVID-19 pneumonia and 12 (21.1%) progressed to critical COVID-19 pneumonia or continued having severe pneumonia. In the recovered group, the hsCRP level decreased significantly (P = 0.0023). The hsCRP level in the deteriorated group was significantly higher than that of the recovered group (P = 0.0019 and P = 0.0004). ΔhsCRP was significantly correlated with time from onset (P = 0.0151), prognosis (P = 0.0151), ΔD-dimer level (P = 0.0320), Δwhite blood cell count (P = 0.0018), and Δneutrophil count (P = 0.0061).
CONCLUSIONS: Severe COVID-19 pneumonia is crucial to patient prognosis and manifests high hsCRP levels; decreased hsCRP level is associated with improved patient prognosis, but hsCRP level may not increase in patients with deteriorating conditions. Simultaneous increase in hsCRP and D-dimer levels may indicate risk for venous thromboembolism in COVID-19 patients.
Keywords: COVID-19 pneumonia, high sensitivity C-reactive protein, inflammation, prognosis
|How to cite this article:|
Zhang L, Yu B, Yang L, Zhang H, Huang G, Tang L, Xu M, Zhou J, Xiao L, Tang J, Liu X, Shu C, Li X. High sensitivity C reactive protein level is associated with prognosis in patients with severe coronavirus disease 19 pneumonia. Vasc Invest Ther 2021;4:63-9
|How to cite this URL:|
Zhang L, Yu B, Yang L, Zhang H, Huang G, Tang L, Xu M, Zhou J, Xiao L, Tang J, Liu X, Shu C, Li X. High sensitivity C reactive protein level is associated with prognosis in patients with severe coronavirus disease 19 pneumonia. Vasc Invest Ther [serial online] 2021 [cited 2021 Dec 8];4:63-9. Available from: https://www.vitonline.org/text.asp?2021/4/3/63/325190
| Introduction|| |
The novel coronavirus disease-19 (COVID-19) has become a worldwide public health event from the late 2019–2020. The causative agent was quickly identified as a kind of severe respiratory syndrome-like coronavirus. Until March 8, 2020, the estimated mortality rate of COVID-19 pneumonia was approximately 3.8% (3100/80,859 according to official real-time COVID-19 pneumonia data in China on March 8, 2020). COVID-19 pneumonia has been classified into four clinical types based on the Guidelines for the diagnosis and treatment of COVID-19 infection developed by the National Health Commission (Trial Version 5). (1) Mild: the patient has very mild symptoms, and no pneumonia is detected in computed tomography (CT). (2) Ordinary: the patient experiences fever and respiratory tract symptoms, and pneumonia is detected by CT. (3) Severe: the patient experiences respiratory distress (respiratory rate >30/min), with oxygen saturation ≤93% at rest and PaO2/FiO2 ≤300 mmHg. (4) Critical, the patient has respiratory failure that needs mechanical ventilation, shock, and combined multiorgan failure [Supplement Table 1]. Patients with severe COVID-19 pneumonia are in the “crucial phase” of determining prognosis. In these patients, systemic inflammation elicits high immune response, and levels of various cytokines factors are elevated. Some laboratory tests have been used to monitor progress of inflammation or bacterial infection such as erythrocyte sedimentation rate, C-reactive protein (CRP), procalcitonin (PCT), D-dimer, interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α). Some frontline physicians have already observed that the CRP level is elevated in COVID-19 patients. Except for the above laboratory factors, the high-sensitivity CRP (hsCRP) level is extremely elevated in most patients with severe COVID-19 pneumonia, and the level is also changed during the treatment period and may be related to some other factors. Therefore, we collected hsCRP and relative clinical data of COVID-19 patients to determine the relationship between hsCRP, prognosis, and other factors in this novel disease.
| Methods|| |
Clinical data of 57 consecutive patients with severe COVID-19 pneumonia admitted in B8 West Isolation Ward of Tongji Hospital, Wuhan, China, were collected and reviewed retrospectively. The study was approved by the Ethics Committee of Secondary Xiangya Hospital, Changsha, China.
The diagnosis of severe COVID-19 pneumonia was based on the World Health Organization Interim Guidance and Guidelines for the Diagnosis and Treatment of COVID-19 Infection by the National Health Commission (Trial Version 5). The patients were admitted in the isolation ward on February 10, 2020. The hsCRP level and other relative clinical data were collected from admission to March 8, 2020. Laboratory results of hsCRP and other items were collected upon admission and before discharge or when the patient's condition progressed to critical COVID-19 pneumonia.
Unpaired t-test and Mann–Whitney test were used to compare data between two groups. Correlation between the hsCRP value change at two-time points (ΔhsCRP) and patient factors (i.e., age, sex, comorbidities, symptoms, time from onset, and prognosis) were analyzed. Furthermore, the correlation between ΔhsCRP and some infection indicators or cytokine factors, such as D-dimer, PCT, white blood cells (WBC), neutrophils, lymph cells, monocytes, IL-2R, IL-6, and TNF-α, were also analyzed. The nonparametric Spearman correlation method was used in the correlation analysis. All statistical analysis and graphs were derived using GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA).
| Results|| |
A total of 57 patients were included in this study. There were 25 male (43.9%) and 32 female (56.1%) patients. The mean patient age was 62.8 ± 13.0 years. The average period from the first symptom onset to admission was 12.6 ± 8.0 days. The patients' epidemiological history, symptoms, and underlying diseases are shown in [Table 1]. Of the 57 patients, four (7.0%) died of respiratory failure and multiorgan failure.
|Table 1: Epidemiological and clinical characteristics of patients with severe novel coronavirus pneumonia|
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The mean hsCRP level at admission was 35.5 ± 81.9 mg/L, and hsCRP levels in 49 (86.0%) patients increased. Treatments include oxygen therapy, antivirus drugs, antibiotics if the patients also had bacterial infection, glucocorticoids for continuous fever, Chinese traditional herbal medicine, and other supportive treatments. All patients had severe COVID-19 pneumonia; after 4 weeks of treatment, 45 (78.9%) patients recovered to ordinary or mild COVID-19 pneumonia, and the condition of 12 (21.1%) patients deteriorated to critical COVID-19 pneumonia or remained having severe COVID-19 pneumonia. Patients were thus divided into two groups: the recovered group and deteriorated group. In the recovered group, the median baseline hsCRP level was 11.4. The hsCRP level at admission decreased significantly (P = 0.0023) before discharge. However, for the deteriorated group, the median baseline hsCRP was 62.2. No significant differences were observed between the hsCRP level at admission and deterioration time point (P = 0.6217). On admission and discharge/deterioration time points, the hsCRP level in the deteriorated group was significantly higher than that of the recovered group [P = 0.0019 and P = 0.0004, [Figure 1]. As regards other cytokine factors and infection markers, the D-dimer level (P < 0.0001), PCT level (P < 0.0001), WBC count (P < 0.0061), neutrophil count (P = 0.0003), lymph cell count (P < 0.0001), and monocyte count (P = 0.0252) were significantly different between the two groups [Table 2]. The difference in two hsCRP results (ΔhsCRP, interval 14–28 days) of each patient was analyzed to determine their correlation with other factors such as age, sex, comorbidities, symptoms, time from onset, and prognosis. Analysis result shows that ΔhsCRP had significant correlation with time from onset [r = 0.3204, 95% confidence interval (CI) 0.0574–0.5418, P = 0.0151] and prognosis (r = 0.3232, 95% CI 0.0605-0.5440, P = 0.0151) [Table 3] and [Figure 2]. Moreover, the correlation of ΔhsCRP with ΔD-dimer, ΔWBC count, Δneutrophil count, Δlymph cell count, Δmonocyte count, ΔIL-2R, ΔIL-6, and ΔTNF-α was also analyzed [Table 4] and [Figure 3]. A significant correlation was found between ΔhsCRP and ΔD-dimer levels (r = 0.2845, 95% CI 0.0179–0.5132, P = 0.0320), ΔWBC count (r = 0.4042, 95% CI 0.1529–0.6064, P = 0.0018), and Δneutrophil count (r = 0.3591, 95% CI 0.1009–0.5720, P = 0.0061). No significant correlation was found between ΔhsCRP and other biomarkers. We present a summary of the changes in hsCRP level in a typical recovered case and a deteriorated case and combined their clinical features to track their prognosis [Supplement Figure 1] and [Supplement Figure 2].
|Figure 1: Comparison of high-sensitivity C-reactive protein levels between the recovered group and deteriorated group. (a) In the recovered group, the high-sensitivity C-reactive protein level at discharge decreases significantly compared with the level at admission (n = 45, **P = 0.0023). (b) In the deteriorated group, the high-sensitivity C-reactive protein level did not show significant differences between admission and deterioration (n = 12, n.s P = 0.7192). (c) On admission, the high-sensitivity C-reactive protein level in the deteriorated group was significantly higher than those in the recovered group (n = 57, **P = 0.0019). Upon discharge or deterioration time point, the high-sensitivity C-reactive protein levels in the deteriorated group were significantly higher than those in the recovered group (n = 57, ***P = 0.0004)|
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|Figure 2: Correlation analysis using the Spearman method showed that Δhigh-sensitivity C-reactive protein (mg/L) is significantly correlated with time from onset (r = 0.3204, 95% confidence interval 0.0574–0.5418, P = 0.0151) and patients' prognosis (r = 0.3232, 95% confidence interval 0.0605–0.5440, P = 0.0142)|
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|Figure 3: Correlation analysis using the Spearman method showed that Δhigh-sensitivity C-reactive protein (mg/L) is significantly correlated with ΔD-dimer, ΔWBC count, and Δneutrophil cell count; however, it was not significantly correlated with ΔPCT, Δlymph cell count, Δmonocyte count, ΔIL-2R, ΔIL-6, and ΔTNF-α|
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|Table 2: Various indicators of inflammation, cytokine factor, and bacterial infection statistics between the recovered and deteriorated groups|
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|Table 3: Correlation analysis result of value change of high-sensitivity C-reactive protein and age, sex, comorbidities, symptoms, time from onset, and prognosis|
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|Table 4: Correlation analysis results of value change of high-sensitivity C-reactive protein and ΔD-dimer, value change of procalcitonin, change in white blood cell count, Δneutrophil cell count, Δlymph cell count, Δmonocyte count, value change in interleukin-2 receptor, value change in interleukin 6, and value change in tumor necrosis factor-α|
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| Discussion|| |
The COVID-19 outbreak started in late 2019; since then, the number of patients with COVID-19 increased rapidly in China during the Chinese Lunar New Year. At present, it has infected approximately 89,000 people worldwide. In its early stages, the number of cases doubled every 7.4 days. With a mean serial interval of 7.5 days, the basic reproductive number of cases was estimated at 2.2. Within 1 month of treating COVID-19 pneumonia, especially the severe and critical types, some frontline physicians concluded some key points of treatment. Since the antivirus drug for COVID-19 is not yet developed, supportive treatment is still the main method of treatment.
Many studies have reported that hsCRP level increases with higher risk of major adverse cardiovascular (CV) events and death., Several prospective epidemiological studies have shown that plasma level of hsCRP is a strong independent predictor of risk for myocardial infarction, stroke, peripheral arterial disease,, and vascular death among individuals without known CV disease. Moreover, hsCRP has been identified to elevate in hemodialysis patients with increased intimal-media thickness. hsCRP is an inflammatory marker that increases with acute infection or trauma, and it has been shown to predict overall mortality as well as CV event. Some large-scale studies have shown that hsCRP level is associated with mortality in a highly admixed population, independent of a large set of lifestyle, and clinical variables. Therefore, increase in hsCRP level in patients with severe COVID-19 pneumonia is not surprising due to the severe inflammation in this type. Does the elevation of hsCRP level associated with any other factors related for this novel disease? Is increased hsCRP level related to patients' prognosis? Will it correlate with other inflammatory markers?
In patients with severe COVID-19, the high-sensitivity C-reactive protein level increases with nonspecific viral infection or viral combined with bacterial infection
At the Tongji Hospital, we treated 57 patients with severe COVID-19 pneumonia, and their clinical data and laboratory results were collected and analyzed. We found that virus infection indicators or bacterial infection biomarkers are elevated separately. However, hsCRP was almost elevated extremely in every patient following admission. As regards laboratory results of patients with severe COVID-19 pneumonia, D-dimer and PCT levels and WBC and neutrophil counts increased in patients with concomitant bacterial infection (n = 12, 21% data not shown). Patients with viral pneumonia alone only showed decrease in lymph cell count or increase in cell cytokine factors. In this study, the hsCRP levels were elevated in both situations. The baseline hsCRP level at admission was elevated in 86% of the patients, and it appears that hsCRP is more nonspecific than other markers. It may be related to the sepsis caused by the virus. Sepsis is a severe clinical syndrome related to the host's response to infection. The severity of infections is due to an activation of an immune response cascade that will lead to an autoamplification of cytokine production, i.e. cytokine storm., Therefore, extreme elevation of hsCRP level in patients with severe COVID-19 pneumonia reflects the whole inflammation situation but does not predict the CV event risk. Even though the virus potentially cause cardiac injury,, other specific CV biomarkers such as troponin and electrocardiogram change should be considered.
High-sensitivity C-reactive protein level change may predict patients' prognosis and recovery
Our results showed that the hsCRP level of the recovered group decreased significantly (P = 0.0013) between admission and discharge. Moreover, the baseline hsCRP level in the recovered group is significantly lower than that of the deteriorated group upon admission (P = 0.0005). At 3 weeks later, the significant difference in hsCRP level between the recovered group and deteriorated group is unsurprising (P < 0.0001). Although hsCRP is usually used in predicting death risk in patients with CV disease, it can also be used to predict risk for all-cause death. Some studies compared the predictive performance of hsCRP ≥10 mg/L and <2 mg/L, and the hazard ratio for all-cause mortality was 2.49 (95% CI 2.19–2.84; P < 0.001), for CV mortality was 2.26 (95% CI 1.91–2.68; P < 0.001), and for non-CV mortality was 2.96 (95% CI 2.40–3.65; P < 0.001). The study also found that higher plasma hsCRP level was associated with high mortality independent of age, symptom severity, creatinine, and NT-proBNP. Furthermore, hsCRP combined with other biomarkers such as PCT is a better predictor of contrast-induced nephropathy after percutaneous coronary intervention than either hsCRP or PCT alone. As above, the hsCRP is definitely unspecific to any CV diseases. Any processes related to inflammation cause its elevation. However, it still has special value to predict prognosis in patients with severe COVID-19 pneumonia. The median baseline hsCRP in the recovered group was 3.7, which was lower than that of the deteriorated group at 23.1. For cases with extremely increasing hsCRP level, glucocorticoid treatment or immunotherapy (tocilizumab) may be helpful. If acute respiratory distress syndrome occurs, mechanical ventilation is needed to support respiration. Otherwise, the decreasing trend of hsCRP may indicate better result. In the present study, decrease in hsCRP level may be more significantly related to patients' recovery. However, the number of patients in the deteriorated group was small; we infer that significant differences may be more observed if a large sample was involved.
High-sensitivity C-reactive protein value change is correlated with time from onset and other biomarkers
In this study, the correlation analysis showed that hsCRP is also significantly correlated with time from onset, except with prognosis. The incubation period of the coronavirus is 1–14 days, but it is 3–7 days in most cases. The time duration from onset in our patients was 12.3 ± 8.0 days. This may explain that the patients already have severe inflammation. It may be likely the watershed of COVID-19 pneumonia. The hsCRP level may indicate that the patients are in the crucial phase of the disease. Persistently high hsCRP level may predict the patients' poor prognosis; however, the decrease in hsCRP level may predict recovery, as we previously stated.
Furthermore, in the correlation analysis of hsCRP and other blood biomarkers, we assessed the changes in the levels of hsCRP and other biomarkers. Levels of D-dimer and PCT, WBC count, neutrophil count (an indicator of bacterial infection), IL-2R, IL-6, TNF-α, lymph cell count, and monocyte count (an indicator of viral infection or inflammation) were included in the analysis. As a result, we find significant correlation between levels of hsCRP and D-dimer, WBC count, and neutrophil count. However, other biomarkers appeared to have no significant correlation with change in hsCRP level. Huang et al. reported elevation of IL-2 and TNF-α in patients admitted in the intensive care unit (ICU). However, our patients who have been transferred to the ICU also demonstrated increase in cytokine factors. In addition, their hsCRP level was elevated slightly. It is not very surprising that hsCRP is related to change in WBC and neutrophil cell counts; however, interestingly, the hsCRP and D-dimer have the same direction of change. There might be a nonspecific infection, or venous thrombosis embolism (VTE) risk is increasing because of the coincrease in hsCRP and D-dimer levels. This discovery may help frontline physicians to judge the patients' condition and adjust their treatment methods or be aware of the VTE risk in COVID-19 patients.
This study has some limitations. In this study, the observation period was not sufficient, as we only focused on the hsCRP change trend during hospitalization. In addition, hsCRP data were not the same due to differences in patients' conditions. Follow-up result was not collected following discharge. We may gather follow-up data in the future.
| Conclusions|| |
Although hsCRP is a nonspecific biomarker in the blood, its level change may predict prognosis in patients with severe COVID-19 pneumonia independently, especially in alleviated cases. Extreme elevation of hsCRP prognosis may occur after approximately 12 days since COVID-19 pneumonia onset. Monitoring hsCRP level may help physician judge the condition of patients with severe COVID-19 pneumonia and thereby prevent progression to critical pneumonia. In addition, simultaneous increase in hsCRP and D-dimer level may also imply elevated risk for VTE.
The authors sincerely appreciate all the members of the medical support group from Secondary Xiangya Hospital, Central South University, to Tongji Hospital in Wuhan, especially, in memory of doctors who devoted their life to fight COVID-19 in China. The authors are further grateful and sincerely appreciated all people who are still working to contain the disease. We shall see the dawn of this antivirus war in a not far away future.
Consent to publish
The consent to publish we obtained from participants was verbal. The verbal consent was obtained due to the contagious diseases; no hard copy can be kept after touched by patients. This verbal consent was approved by the ethics committee.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]