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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 36  |  Issue : 1  |  Page : 6-10

C-reactive protein and its association with COVID-19: A preliminary study during the first wave of pandemic in a tertiary care hospital in North-East India


1 Department of Microbiology, Regional Institute of Medical Sciences, Imphal, Manipur, India
2 Department of Medicine, Regional Institute of Medical Sciences, Imphal, Manipur, India

Date of Submission20-Aug-2021
Date of Acceptance10-Nov-2021
Date of Web Publication02-Sep-2022

Correspondence Address:
Dr. Khuraijam Ranjana Devi
Department of Microbiology, Regional Institute of Medical Sciences, Imphal, Manipur
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jms.jms_108_21

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  Abstract 


Background: COVID-19 is the third serious Coronavirus outbreak after severe acute respiratory syndrome (2002–2003) and Middle East respiratory syndrome (2012). There is an increasing need for a credible marker to triage patients and for telescoping the prognosis of COVID-19 more so in resource-constrained settings. COVID-19 patients were found to have a significant increase of C-reactive protein (CRP) levels (20–50 mg/L). Severe COVID-19 patients were noted to have up to 86% elevated CRP. 10-fold higher CRP was found in patients who died from COVID-19 than the recovered cases.
Objectives: To demonstrate the association of CRP levels with COVID-19 infected patients and to assess the findings in accordance with different variables.
Materials and Methods: Thirty-three nonconsecutive COVID-19 tested positive patients whose blood samples were sent for CRP testing were included for a retrospective study conducted between August 2020 and February 2021.
Results: This study revealed elevation in CRP levels in patients belonging to severe cases (median = 46.71 mg/L) followed by moderate (median = 21.61 mg/L) and mild cases (median = 8.572 mg/L). Patients with comorbidities were noted to have higher median CRP (37.86 mg/L) compared to those without comorbidities (median = 20.3 mg/L). This study also detected increased CRP levels (median = 43.732 mg/L) in morbid cases compared to recovered cases (median = 20.3 mg/L).
Conclusion: In a hospital with limited resources, this study successfully demonstrated the significant role of CRP in COVID-19 outcome elucidating the importance of CRP levels when used for triaging patients and monitoring disease progression.

Keywords: Biomarkers, c reactive protein, COVID-19


How to cite this article:
Devi YB, Presanambika H, Kongbrailatpam B, Singh KB, Chongtham D, Devi KR. C-reactive protein and its association with COVID-19: A preliminary study during the first wave of pandemic in a tertiary care hospital in North-East India. J Med Soc 2022;36:6-10

How to cite this URL:
Devi YB, Presanambika H, Kongbrailatpam B, Singh KB, Chongtham D, Devi KR. C-reactive protein and its association with COVID-19: A preliminary study during the first wave of pandemic in a tertiary care hospital in North-East India. J Med Soc [serial online] 2022 [cited 2022 Sep 30];36:6-10. Available from: https://www.jmedsoc.org/text.asp?2022/36/1/6/355572




  Introduction Top


COVID-19 is the most serious outbreak the world has encountered after severe acute respiratory syndrome (SARS) in 2002–2003 and Middle East respiratory syndrome in 2012. On January 30, 2020, the World Health Organisation (WHO) announced the outbreak as a public health emergency of international concern, and on March 11, 2020, the WHO declared COVID-19 as a pandemic. This pandemic has taken a global toll with 156,805,325 infected cases worldwide and 3,272,273 deaths as of May 7, 2021.[1],[2],[3] It is caused by SARS-COV-2 virus that belongs to the genera betacoronavirus of the family Coronaviridae. The family Coronaviridae includes 4 genera namely alphacoronavirus, betacoronavirus, gammacoronavirus and deltacoronavirus. Five members of this family namely 29E, OC43, NL63, HKU1, and SARS-COV2 are known to infect humans.[4] It is the largest known single-stranded enveloped RNA virus (31 kb) encoding for 9860 aminoacids. It has an incubation period of 5–6 days (may range up to 14 days) during which the patients will be asymptomatic but highly contagious.

The earliest response for any viral infection is the activation of innate immune system. SARS-COV2 virus binds to Toll-like receptor which leads to activation of interleukin (IL)-6. IL-6 triggers inflammation by stimulating the production of acute-phase reactants. Acute phase reactants are proteins whose plasma concentrations increase (positive acute-phase reactants) or decrease (negative acute phase reactants) in response to inflammation. C-reactive protein (CRP) is an important positive acute phase reactant whose level increases within 6–9 h of inflammation and when the stimuli end, the level decreases exponentially over 18–20 h. CRP interacts with complement factor C1q which leads to the activation of complement pathways. As a result of activation of complement pathways, a large number of cytokines are released leading to cytokine storm which acts as the key pathogenic feature of SARS-COV2 infection.[5],[6],[7],[8],[9]

While human strains of Coronavirus are associated with about 15%–30% of cases of common cold, SARS-CoV-2 presents with varying degrees of severity ranging from flu-like symptoms to death.[4] The complications and seriousness of COVID-19 are due to the cytokine storm which includes acute respiratory distress syndrome, acute respiratory failure, sepsis, and disseminated intravascular coagulation.

Various diagnostic biomarkers including CRP, aspartate aminotransferase, high sensitive cardiac troponin, D-dimer, lactate dehydrogenase have been found to be associated with COVID-19 infection.

This study was done in an effort to demonstrate the distinct association of CRP levels with COVID-19-infected patients and to analyze the findings in accordance with different variables such as age, gender, severity, co-morbidities and outcome.


  Materials and Methods Top


This is a single center, retrospective study done in the Department of Microbiology and Department of Medicine, Regional Institute of Medical Sciences Hospital, Imphal, between August 2020 and February 2021. Patients who were tested COVID 19 positive by Reverse transcriptase-polymerase chain reaction or by TRUNAT and whose samples were tested for CRP were included in this study.

Following standard precautions for COVID 19, a total of 33 nonconsecutive samples were tested in Serology section of Microbiology Department. Centrifugation was avoided as a precaution to prevent aerosol generation but allowed to stand at room temperature for 30–40 min. Quantitative measurement of CRP was done using Merilyzer Proviso (using Proviso CRP Kit by Meril Diagnostics). CRP-turbilatex is a quantitative latex-based turbidimetric test for the measurement of CRP in human serum. Latex particles coated with specific anti-human CRP are agglutinated when mixed with samples containing CRP. The agglutination causes an absorbance change dependent on the CRP contents of the patient samples that can be quantified by comparison from a calibrator of known CRP concentration. Concentration is automatically calculated by reference to a calibration curve stored in the instrument. 6 mg/L was used as reference value. Samples with CRP levels >6 mg/L were reported as positive.

Relevant clinical history and personal details were collected from the record section of the hospital through proper channel. The presenting symptoms of COVID-19 infection, presence of co-morbidities, initial blood workup, the progression of the disease, and outcome of the infection in the study group were recorded and analyzed. Further review and data analysis such as percentage, median were done using SPSS (Statistical Package for Social Sciences) software version 21 (IBM Corp. Armonk, NY, USA).


  Results Top


For analysis, patients were grouped into seven age categories as given in [Table 1].
Table 1: Age group categorization

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C-reactive protein and age

The CRP of different age groups categorized into different groups is shown in [Figure 1].
Figure 1: C-reactive protein and its association with age

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C-reactive protein and gender

In this study, males (n = 20) predominated females (n = 13). However, the median CRP of females was noted to be higher (24 mg/L) than males (median CRP 20.81 mg/L).

C-reactive protein and severity

Clinical classification of the patients was made based on the National Clinical Management Protocol: COVID-19-MoHFW.[10] 36.4% (n = 12) belonged to mild category, 33.3% (n = 11) belonged to moderate and 30.3% (n = 10) belonged to severe category as given in [Table 2].
Table 2: MoHFW classification of severity

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Out of the 12 mild cases, 50% (n = 6) had elevated CRP. The median CRP of the mild cases was 8.57 mg/L (0.25–77.027). 90.9% (n = 10) and 100% (n = 10) of the moderate and severe cases had elevated CRP. The median CRP of the moderate and severe cases were 21.61 mg/L (0.47–59.4 mg/L) and 46.71 mg/L (24–111.48 mg/L), respectively [Figure 2].
Figure 2: C-reactive protein and its association with severity and co-morbidities

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C-reactive protein and Comorbidities

Eight patients out of 33 (3 mild cases, 1 moderate, and 4 severe cases) had comorbidities such as diabetes (n = 4), hypertension (n = 4), pulmonary tuberculosis (PTB) (n = 1), and pancreatitis (n = 1). Of these, 2 patients had both diabetes and hypertension. Two patients with diabetes had fatal outcome. The CRP of the patients with comorbidities ranged from 14.93 to 111.48 mg/L (Median = 37.86 mg/L), whereas the CRP of the patients without comorbidities ranged from 0.25 to 96 mg/L (Median = 20.3 mg/L) [Figure 2].

Patients with diabetes mellitus and PTB were noted to have lesser elevation in CRP compared to other counterparts as shown in [Figure 3].
Figure 3: Comparison of C-reactive protein levels of patients with diabetes, pulmonary tuberculosis and other co-morbidities

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Mortality

Mortality was noted only among severe cases. The mortality recorded was 40%, 2 patients each from the age group of 51 to 60 years and >60 years. The CRP of the morbid cases varied between 42.05 and 48.95 mg/L (Median = 43.732 mg/L). CRP of the nonmorbid cases varied between 0.25 and 111.48 mg/L (Median = 20.3). Lymphopenia and neutrophilia were observed in 83.33% and 100% of mild and moderate cases. 90% (n = 9) of the severe cases had neutrophilia, 80% (n = 8) had lymphopenia.


  Discussion Top


SARS-CoV-2 was first described in December 2019. It then spread rapidly to 215 countries making it a global pandemic. India reported its first case of COVID 19 pandemic on January 30, 2020. Slowly but steadily, it spread to various states and union territories of the country including Manipur, a small state in North-East India. Manipur reported its first case on March 24, 2020, making Manipur the first state to report a case of COVID 19 in all of North East India. It was quickly followed by the detection of a second positive case in Assam on March 31, 2020.

COVID-19, still a challenge to clinicians and researchers, demands a very accurate timely diagnosis to prevent any future complications and case mortality. Although various blood tests are being performed for COVID-19 patients, significant changes are noted in differential leukocyte count and CRP levels.

In this study, we studied the association of CRP as a diagnostic marker for COVID-19 with different variables such as severity, age, comorbidities, and mortality. Of the 33 cases in this study, 78.8% (n = 29) showed CRP levels above the reference range. The elevated levels of CRP are attributed to the increased production of inflammatory cytokines which are activated by the immune system in response to the virus. They can also cause tissue destruction on hyperactivation.

In a study conducted by Chen et al. done to estimate the use of CRP as a marker in assessing the severity of COVID-19, a positive correlation was found with CRP and increasing severity of the disease. Moderate and severe infections were shown to have higher CRP levels compared to mild infection (95% confidence interval, P < 0.001).[2] Similar findings have also been noted in studies conducted by Mardani et al., Velavan and Meyer, Wang in COVID-19 infected patients.[11],[12],[13] Similar findings were seen in our study with higher levels of CRP (24–111.48 mg/L) seen in the severe cases followed by the moderate (0.47–59.4 mg/L) and mild cases (0.25–77.027 mg/L), suggesting that higher inflammatory response is noted in severe COVID-19 patients than moderate and mild patients.

In a meta-analysis done by Sahu et al., they illustrated higher levels of CRP in patients who died of COVID-19 infection than the survivors (P = 0.000, the standard deviation in means = 1.371).[14] This study also noted that the patients who died of COVID-19 infection had a higher elevation in CRP levels (median 43.73 mg/L) than the recovered patients (median 22.51 mg/L). Therefore, the extent of the disease is found to be directly linked with the CRP concentration.

This study detected lymphopenia in 87.9% (n = 29) cases and neutrophilia in 90.9% (n = 30) cases. This is in concordance with a study conducted by Li et al. in China where they illustrated a decrease in lymphocyte count and increase in neutrophil count in COVID-19 infected cases compared to infection-free controls.[15] This implies the activity of CD8+ and CD4+ T lymphocytes in eliminating the virus from the body. White blood cell count can be used to identify patients requiring attention and intervention even before severe symptoms set in.[5]

In our study, patients with comorbidities were found to have higher CRP levels (Median = 37.86 mg/L) than the recovered patients (Median = 20.3 mg/L). This is owing to the presence of pro-inflammatory state leading to activation of innate immune cells in patients with metabolic disorders. This study noted that patients with diabetes mellitus as a comorbidity recorded lesser elevation in CRP compared to the patients with other comorbidities. This may be attributed to the low immune function due to the weakening of macrophage and lymphocyte function in diabetes. One patient with PTB was also noted to have lesser elevation in CRP compared to other complications due to the invasion and multiplication of tubercle bacilli in macrophages diminishing the immune response.[16]

Hence, our study proposes the prognostic value of CRP concentration in such a way that increased level is associated with amplified progression of disease. Consequently, CRP levels can be supplemented for triaging the patients in addition to the presently followed guidelines.

Limitation of the study

The limitation of our study is the relatively small sample size leading to lesser approximation compared to other similar studies. This could be minimized by expanding it into a larger observational study. D-dimer and serum ferritin levels could not be included in our study as detection of these tests were not available in the institute during the initial days of the pandemic although they are now available for the benefit of COVID 19 patients.


  Conclusion Top


Based on the findings of this study, we confirm a positive correlation between serum CRP levels with the progression of the disease with/without the presence of comorbidities. CRP levels could be used to assist clinicians for optimized triaging and for prioritizing patients who require radiological assistance and also to monitor the disease progression. However, validation by larger observational studies is required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Available from: https://www.worldmeters.info/coronavirus. [Last accessed on 2021 May 07].  Back to cited text no. 1
    
2.
Chen W, Zheng KI, Liu S, Yan Z, Xu C, Qiao Z. Plasma CRP level is positively associated with the severity of COVID-19. Ann Clin Microbiol Antimicrob 2020;19:18.  Back to cited text no. 2
    
3.
Channappanavar R, Perlman S. Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39:529-39.  Back to cited text no. 3
    
4.
Mesel-Lemoine M, Millet J, Vidalain PO, Law H, Vabret A, Lorin V, et al. A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes. J Virol 2012;86:7577-87.  Back to cited text no. 4
    
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Tjendra Y, Al Mana AF, Espejo AP, Akgun Y, Millan NC, Gomez-Fernandez C, et al. Predicting disease severity and outcome in COVID-19 patients: A review of multiple biomarkers. Arch Pathol Lab Med 2020;144:1465-74.  Back to cited text no. 5
    
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Jesenak M, Brndiarova M, Urbancikova I, Rennerova Z, Vojtkova J, Bobcakova A, et al. Immune parameters and COVID-19 infection – Associations with clinical severity and disease prognosis. Front Cell Infect Microbiol 2020;10:364.  Back to cited text no. 6
    
7.
Gulhar R, Jialal I. Physiology, acute phase reactants. Updated 2021 Apr 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK519570/.[Last accessed on 2021 Mar 03].  Back to cited text no. 7
    
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Sadeghi-Haddad-Zavareh M, Bayani M, Shokri M, Ebrahimpour S, Babazadeh A, Mehraeen R, et al. C-reactive protein as a prognostic indicator in COVID-19 patients. Interdiscip Perspect Infect Dis 2021;2021:1-5.  Back to cited text no. 8
    
9.
Ali N. Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19. J Med Virol 2020;92:2409-11.  Back to cited text no. 9
    
10.
National Clinical Management Protocol: COVID-19 – MoHFW. Available from: https://www.mohfw.gov.in. [Last accessed on 2021 Mar 02].  Back to cited text no. 10
    
11.
Mardani R, Ahmadi Vasmehjani A, Zali F, Gholami A, Mousavi Nasab SD, Kaghazian H, et al. Laboratory parameters in detection of COVID-19 patients with positive RT-PCR; a diagnostic accuracy study. Arch Acad Emerg Med 2020;8:e43.  Back to cited text no. 11
    
12.
Velavan TP, Meyer CG. Mild versus severe COVID-19: Laboratory markers. Int J Infect Dis 2020;95:304-7.  Back to cited text no. 12
    
13.
Wang L. C-reactive protein levels in the early stage of COVID-19. Med Mal Infect 2020;50:332-4.  Back to cited text no. 13
    
14.
Sahu BR, Kampa RK, Padhi A, Panda AK. C-reactive protein: A promising biomarker for poor prognosis in COVID-19 infection. Clin Chim Acta 2020;509:91-4.  Back to cited text no. 14
    
15.
Li Q, Ding X, Xia G, Chen HG, Chen F, Geng Z, et al. Eosinopenia and elevated C-reactive protein facilitate triage of COVID-19 patients in fever clinic: A retrospective case-control study. EClinicalMedicine 2020;23:100375.  Back to cited text no. 15
    
16.
Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis. Int J Infect Dis 2020;94:91-5.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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