The Role of initial and follow-up C-reactive protein titer in COVID-19 pneumonia: A single-center study of 1000 cases in a tertiary care setting in India

Shital Patil; Ganesh Narwade; Uttareshvar Dhumal

doi:10.4103/jalh.jalh_20_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 3 | Issue : 1 | Page : 17-24

The Role of initial and follow-up C-reactive protein titer in COVID-19 pneumonia: A single-center study of 1000 cases in a tertiary care setting in India

Shital Patil¹, Ganesh Narwade¹, Uttareshvar Dhumal²
¹ Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
² Department of Radiodiagnosis, MIMSR Medical College, Latur, Maharashtra, India

Date of Submission	21-Jun-2022
Date of Acceptance	01-Aug-2022
Date of Web Publication	27-Dec-2022

Correspondence Address:
Prof. Shital Patil
Department if Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jalh.jalh_20_22

Abstract

Introduction: Robust data of C-reactive protein (CRP) are available in bacterial infection, and it can be utilized in this coronavirus disease 2019 (COVID-2019) pneumonia pandemic for initial assessment before planning of treatment in indoor setting compared to other inflammatory markers and computerized tomography (CT) severity. Methods: A prospective, observational, 12-week-follow-up study, included 1000 COVID-19 cases confirmed with real-time reverse transcription-polymerase chain reaction; all cases were assessed with lung involvement documented and categorized on high-resolution computerized tomography (HRCT) thorax, oxygen saturation, and inflammatory marker as CRP at entry point and follow-up. Age, gender, comorbidity, use of bilevel positive airway pressure/noninvasive ventilation (BiPAP/NIV), and outcome as with or without lung fibrosis as per CT severity were key observations. Statistical analysis is performed using Chi-square test. Results: The HRCT severity score at entry point has significant correlation with CRP titer [P < 0.00001]. CRP titer has significant association with duration of illness (P < 0.00001). Comorbidities has significant association with CRP titer (P < 0.00001). CRP titer has significant association with oxygen saturation at entry point (P < 0.00001). BiPAP/NIV requirement during hospitalization has significant association with CRP titer (P < 0.00001). Timing of BiPAP/NIV requirement has significant association with CRP titer (P < 0.00001). Follow-up CRP titer during hospitalization compared to entry point normal and abnormal CRP has significant association in post-COVID lung fibrosis (P < 0.00001). Conclusions: CRP has documented a very crucial role in COVID-19 pneumonia in predicting severity of illness, progression of illness, and sequential CRP titers that will help assessing response to treatment during hospitalization and analyzing post-COVID lung fibrosis.

Keywords: Coronavirus disease 2019 pneumonia, C-reactive protein, inflammatory marker, oxygen saturation

How to cite this article:
Patil S, Narwade G, Dhumal U. The Role of initial and follow-up C-reactive protein titer in COVID-19 pneumonia: A single-center study of 1000 cases in a tertiary care setting in India. J Adv Lung Health 2023;3:17-24

How to cite this URL:
Patil S, Narwade G, Dhumal U. The Role of initial and follow-up C-reactive protein titer in COVID-19 pneumonia: A single-center study of 1000 cases in a tertiary care setting in India. J Adv Lung Health [serial online] 2023 [cited 2023 Jun 10];3:17-24. Available from: https://www.jalh.org//text.asp?2023/3/1/17/365489

Introduction

The current pandemic of coronavirus disease 2019 (COVID-2019) caused by severe acute respiratory syndrome-corona virus-2, originally emerged from China, has documented 274,628,461 confirmed cases and 5,358,978 deaths globally, and 34,752,164 confirmed cases and 478,007 deaths in India.^[1] The current practical guidelines stating recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management in COVID-19 disease have been developed by the International Federation of Clinical Chemistry and Laboratory Medicine Task Force.^[2],[3]

The laboratory of Oswald Avery first documented "C-reactive protein (CRP)" as inflammatory protein released in serum of patients with acute infections and later on labeled as "acute phase reactant". Robust data are available regarding its role in infections, inflammatory, ischemic, and traumatic tissue injuries and malignancy, while the advent of sensitive quantitative immunoassays in the 1970s greatly enhanced its clinical utility. In 1974, Kaplan and Volanakis^[4] and Siegel et al.^[5] reported "proinflammatory" role of CRP.

COVID-19 pneumonia is a heterogeneous disease with variable effect on lung parenchyma, airways, and vasculature, leading to long-term effects on lung functions, which occurred as resultant pathophysiological effects of immune activation pathway and direct virus-induced lung damage. In COVID-19 pneumonia, pathophysiology constitutes different pathways such as immune activation, inflammatory, thrombogenic, and direct viral affection to lungs and extrapulmonary tissues.^[6],[7] CRP can be used as marker of inflammation in COVID-19 pneumonia.^[8] Robust data of CRP is available as an inflammatory marker in analysing infective diseases, non-infective conditions, surgical, postoperative, and inflammatory conditions such as rheumatoid arthritis, gout, and venous thromboembolism.^{[9],[10],[11],[12]} Data of CRP in severe H1N1 viral pneumonia are available,^[13] and a number of recent series have reported an association between CRP and COVID-19 disease severity.^{[8],[14],[15],[16],[17],[18],[19]}

In the present study, we have utilized CRP as a basic marker in laboratory panel workup in all COVID patients and analyzed it as a core marker during the follow-up in all admitted patients to assess response to therapy and predictor of post-COVID fibrosis as dismal outcome of this pandemic of pneumonia in a tertiary care setting.

Methods

Ethical approval

This study was approved by the Institutional Review Board (IRB)/Ethics Committee at Venkatesh Hospital and Critical Care Center, Latur, India, and MIMSR Medical College, Latur, India (Approval number: VCC/30–2020–2021; Approval date July 10, 2020).

Data source

A prospective, observational, 12-week-follow-up study, conducted from July 2020 to May 2021, in MIMSR Medical College, Latur, and Venkatesh Hospital, Latur, India, included 1000 COVID-19 cases confirmed with real-time reverse transcription-polymerase chain reaction (RT-PCR), to find out the role of CRP in predicting severity of illness, assessing response to therapy, and outcome as post-COVID fibrosis in diagnosed COVID-19 pneumonia cases admitted in critical care unit. In total, 1000 cases were enrolled in the study after the IRB approval and written informed consent of all included cases was taken at the respective center of study in Venkatesh Hospital and MIMSR Medical College, Latur.

Inclusion criteria

COVID-19 patients, confirmed with RT-PCR, above the age of 18 years, hospitalized in the study centers, including those with comorbidities, and irrespective of severity and oxygen saturation were included in the study.

Exclusion criteria

Those not willing to give consent, not able to perform CRP, not willing to remain in the follow-up, cases who died during hospitalization, or before 12 weeks of discharge from hospital were excluded.

All study cases were undergone the following assessment after enrollment in present study

The COVID-19 RT-PCR test was performed on nasopharyngeal samples collected with all standard institutional infection control policies. If the first RT-PCR test results were negative and radiological features were clearly documenting pneumonia, then we have repeated RT-PCR test on nasopharyngeal samples and finally enrolled all cases with positive COVID-19 RT-PCR test. High-resolution computerized tomography (HRCT) thorax used to assess the severity of lung involvement as per COVID-19 Reporting and Data System (CO-RADS)^[20] and categorized as mild, if score <7, moderated, if score 8–15, and severe if score >15 or 15–25. Clinical assessment, routine biochemistry, and haematological workup done in all study cases. Viral inflammatory markers such as CRP, ferritin, lactate dehydrogenase, and interleukin-6 (IL-6) were done in all cases as a protocol. Entry point CRP titer was utilized as an assessment tool for the severity of illness with clinical parameters. If CRP analysis was normal at the entry point, then the CRP titer was repeated on the day of discharge from the hospital, or done during hospitalization, if the clinical course deteriorates. If CRP analysis was abnormal at the entry point, we repeated on every 72 h as the follow-up to assess severity, progression of illness, and also titer utilized to assess response to medical treatment. Follow-up HRCT thorax was done after 12 weeks of discharge from the hospital for analysis of post-COVID lung fibrosis in selected cases with abnormal CRP titer at discharge and required bilevel positive airway pressure/noninvasive ventilation (BiPAP/NIV) during hospitalization and cases required oxygen supplementation at home [Figure 1].

Figure 1: Flow of the study

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Study design

Prospective, Observational, 12-weeks follow up study.

Interpretation of results

Negative: value up to 6 mg/L
Positive: value above 6 mg/L
Significant: four-fold raised CRP vale, i.e., >24 mg/L
Highly significant: sixteen-fold raised values, i.e., 96 mg/L
Follow-up significance: values raised or decreased in two-to-four-fold change.

Statistical analysis

The statistical analysis was performed using Chi-square test in R-3.4 is available as a Free Software under the terms of the (Free Software Foundation's GNU General Public License in source code form, Vienna, Austria). Significant values of Chi-square were seen from the probability table for different degrees of freedom required. P value was considered significant, if it was below 0.05, and highly significant, in case if it was < 0.001.

Results: Covariates

In the present study, 1000 COVID-19 pneumonia cases were confirmed by COVID-19 RT-PCR; males were 650/1000 and females were 350/1000; age >50 were 600 cases and age <50 were 400 cases. Significant association in CRP and COVID-19 pneumonia has been documented with variables such as age, gender, diabetes mellitus, ischemic heart disease (IHD), hypertension, chronic obstructive pulmonary disease (COPD), and obesity (P < 0.00001) [Table 1].

Table 1: Other variables and C-reactive protein titer in coronavirus disease 2019 pneumonia cases (n=1000)

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Results: Core observations

The HRCT severity score at entry point with CRP titer has significant correlation in COVID-19 pneumonia cases (P < 0.00001) [Table 2]. CRP titer has significant association with duration of illness (DOI) (P < 0.00001) [Table 3]. CRP titer has significant association with oxygen saturation (P < 0.00001) [Table 4]. BiPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with CRP titer (P < 0.00001) [Table 5]. Timing of BiPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with CRP titer (P < 0.00001) [Table 6]. Follow-up CRP titer during hospitalization compared to entry point abnormal CRP has a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 7]. Follow-up CRP titer during hospitalization as compared to entry point normal CRP has a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 8].

Table 2: Correlation of computed tomography severity (at entry point) and C-reactive protein in coronavirus disease 2019 cases (n=1000)

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Table 3: Duration of illness at entry point during hospitalization and C-reactive protein titer in coronavirus disease 2019 pneumonia cases (n=1000)

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Table 4: Oxygen saturation at entry point and C-reactive protein titer in coronavirus disease 2019 pneumonia cases (n=1000)

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Table 5: Correlation of bilevel positive airway pressure use with C-reactive protein titer in coronavirus disease 2019 pneumonia cases (n=1000)

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Table 6: Bilevel positive airway pressure/noninvasive ventilation initiation time at entry point and C-reactive protein titer coronavirus disease 2019 pneumonia cases (n=600)

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Table 7: Abnormal C-reactive protein titer at entry point (n=680) and follow-up and its correlation with post-COVID lung fibrosis

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Table 8: Normal C-reactive protein titer (n=320) at entry point and follow-up and its correlation with post-COVID lung fibrosis

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Discussion

In the present study, the computerized tomography (CT) severity score at entry point with CRP titer has significant correlation in COVID-19 pneumonia cases (P < 0.00001). We have documented CT severity as the best visual marker of COVID-19 pneumonia severity, which can be correlated with inflammatory marker CRP. Various authors have documented similar observation in their studies.^{[21],[22],[23],[24],[25],[26],[27],[28]} The best "visual marker" of severity of illness is CT thorax, and we have documented CRP as a stronger inflammatory marker associated with it. Numerous authors have documented similar observations.^{[29],[30],[31]} We have documented the use of CRP and CT severity in triaging the cases at the entry point and proper use of interventions in indoor setting according to "clinical, radiological, and inflammatory marker panel" in our institute. Huang C et al.^[31] observed a similar role in their study.

In the present study, CRP titer has a significant association with DOI in COVID-19 pneumonia cases (P < 0.00001). We have also documented that the proportionate number of cases with DOI <7 days and many cases with DOI >15 days were having normal CRP titer, while pneumonia cases between 7 and 14 days of illness were having abnormal or raised CRP titer. Rational for this observation is not known, maybe inflammatory response pattern is different, and we have correlated CRP pattern with other inflammatory markers like IL-6 and D-dimer and documented that these two markers raised parallel to CRP. Our findings are collaborating with studies by various authors.^{[32],[33],[34]} Raised CRP after the 2^nd week of illness may indicate worsening of COVID-19 pneumonia or possible secondary bacterial infection (confirmed with procalcitonin in selected cases), which will help clinician to formulate antibiotics policy accordingly and indirectly guiding in management of these cases by assessing follow-up titers.

In the present study, BiPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with CRP titer (P < 0.00001). We have documented higher CRP titers in cases requiring ventilatory support than requiring high-flow nasal cannula or just oxygen supplementation; thus, it will help in predicting severity timely to and also help in analyzing disease severity. Authors^{[17],[35],[36],[37]} have documented similar observation in their studies and mentioned role CRP as "biomarker of severity" of COVID-19 pneumonia.

In the present study, CRP titer has a significant association with oxygen saturation in COVID-19 pneumonia cases (P < 0.00001). Various authors^{[15],[18],[38],[39]} have documented similar to our observation in their studies, mentioned that hypoxia and infection are the best triggers of inflammation, and synergistic effects of both lead to a significant rise in CRP titer, which indicates advanced disease.

In the present study, timing of BiPAP/NIV requirement during the course of COVID-19 pneumonia in critical care setting has a significant association with CRP titer (P < 0.00001) similar to our observation that has been documented in various studies, i.e., the positive correlation of CRP with ventilatory requirement and underlying pathophysiology of acute respiratory distress syndrome in these cases, and timely CRP titer analysis helped in predicting "timings of ventilatory support" requirement.^{[19],[40],[41],[42],[43],[44],[45]}

In the present study, follow-up CRP titer during hospitalization compared to entry point abnormal CRP has a significant association in post-COVID lung fibrosis (P < 0.00001). Rational for similar observation is exaggerated inflammatory response due to advanced lung inflammation and necrosis resulting in overproduction of inflammatory cytokines linked to elevated titers of CRP in severe patients with COVID-19. Cytokines has "double-edged sword effect," i.e., cytokines have a protective role in controlling infection; while in hyperactive state, cytokines will cause exaggerated lung inflammation, lung parenchymal damage, and resultant lung fibrosis, and the possible explanation for this is significantly raised CRP in cases with lung fibrosis than without lung fibrosis. Liu et al.^[45] observed similar findings in their study.

In the present study, follow-up CRP titer during hospitalization compared to entry point normal CRP has significant association in post-COVID lung fibrosis (P < 0.00001). We have documented the progression of illness in a few cases presented with nonsevere illness, which were picked up by the follow-up CRP titer; hence, we recommend follow-up titer as it has a crucial role in analyzing progression and preventing worsening in these cases. Importantly, these cases have documented post-COVID lung fibrosis than those with normal follow-up titers. Yan LA et al.,^[46] in their retrospective analysis in Wuhan, China, documented similar findings.

In the present study, the age of patient, i.e., <50 years and >50 years, has a significant association in COVID-19 cases with normal and abnormal CRP titer (P < 0.00001). we have also documented that gender of included cases has a significant association in COVID-19 cases with normal and abnormal CRP titer (P < 0.010. Authors^{[47],[48],[49]} have documented similar findings in their studies. In the present study, comorbidity as diabetes mellitus, COPD, hypertension, IHD, and obesity has a significant association in COVID-19 cases with normal and abnormal CRP titer (P < 0.00001). Numerous authors^{[18],[50],[51],[52],[53],[54],[55],[56],[57],[58]} have documented similar observations in their studies.

Limitations of the study

Our study is having enough sample size and analyzed the role of CRP at entry point and follow-up during 12-week-period, and association with pos—COVID-19 lung fibrosis is documented. The first limitation is confounding factors, leading to abnormal CRP titer rheumatological disorders such as rheumatoid arthritis, cancer, and trauma were not done during the entire duration of 12 weeks and its effect on COVID-19 severity parameters were not possible. The second limitation is an association of CRP titer with other modes of intensive care treatments as high-flow nasal cannula and invasive mechanical ventilatory support are not assessed differently, and cases predominantly on BiPAP/NIV were considered ventilatory support, probably because the majority of COVID-19 cases receiving high-flow nasal cannula were shifted to BiPAP/NIV and/or mechanical ventilation in intensive care units.

Conclusions

CRP is an easily available, sensitive, reliable, cost-effective, and universally acceptable inflammatory marker in COVID-19 pneumonia. CRP has a very crucial role in COVID-19 pneumonia in predicting the severity of illness, especially "follow-up titers" have a significant role in step-up or step-down interventions in critical care settings. Correlating CRP with variables such as DOI, oxygenation status, and timing of BiPAP/NIV has an important role in predicting outcomes.

CRP titer has a significant association in predicting the progression of pneumonia, and we have documented that the proportionate number of COVID-19 cases with mild variety on CT thorax with normal initial CRP has progressed to a critical course. We have also documented that serial or follow-up CRP titers have played a crucial role along with other inflammatory markers. We have observed rising CRP titers, especially in the 2^nd week of illness, which indicate nosocomial bacterial infection and guided in targeting antibiotic treatment accordingly. CRP follow-up titer can help in predicting the progression of COVID pneumonia and assessing the risk of post-COVID lung fibrosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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