ORIGINAL ARTICLE
Year : 2022 | Volume
: 5 | Issue : 3 | Page : 106--112
Role of C-Reactive protein in COVID-19 pneumonia as “A jack of all trades is a master of none!”: A single-center experience of 2000 cases
Shital Patil1, Shubhangi Khule2, Deepak Patil3, Sham Toshniwal4,
1 Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
2 Department of Pathology, MIMSR Medical College, Latur, Maharashtra, India
3 Department of Internal Medicine, MIMSR Medical College, Latur, Maharashtra, India
4 Department of Internal Medicine, NIMS Medical College, Jaipur, Rajasthan, India
Correspondence Address:
Prof. Shital Patil
Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
India
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-19) pneumonia pandemic for initial assessment and planning of treatment in indoor setting in association with high-resolution computed tomography (HRCT) severity. Methods: A prospective, observational, 12-week follow-up study included 2000 COVID-19 cases confirmed with reverse transcription–polymerase chain reaction (RT-PCR). All cases were assessed with lung involvement documented and categorized on HRCT thorax, oxygen saturation, CRP at entry point, and follow-up. Protocolised recordings of age, gender, comorbidity, and bilevel-positive airway pressure (BIPAP)/non-invasive ventilation (NIV) use were done. Final radiological outcome as with or without lung fibrosis as per follow-up computed tomography in accordance to entry point severity were analysed. Clinical and final outcomes were recorded as per requirement of interventions in indoor units. Statistical analysis was done by Chi-square test. Results: HRCT severity score at entry point has a significant correlation with CRP titer (P < 0.00001). CRP titer has a significant association with duration of illness (P < 0.00001). Comorbidities have a significant association with CRP titer (P < 0.00001). CRP titer has a significant association with oxygen saturation (P < 0.00001). BIPAP/NIV requirement during hospitalization has a significant association with CRP titer (P < 0.00001). Timing of BIPAP/NIV requirement has a significant association with CRP titer (P < 0.00001). Follow-up CRP titer during hospitalization as compared to entry point (initial) normal and abnormal CRP has a 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 at entry point and progression of illness during course of hospitalization. Role of CRP as “a jack of all trades is a master of none” in COVID-19 pneumonia is a real misnomer due to its major impact on guiding step-up and step-down interventions in critical care units. CRP is considered a 'game changer' inflammatory molecule during the entire course of COVID-19 assessment. Role of CRP as an inflammatory marker “oftentimes better than a master of one” in comparison to other available markers interleukin-6, ferritin, and lactate dehydrogenase due to easy availability and cost-effectiveness.
How to cite this article:
Patil S, Khule S, Patil D, Toshniwal S. Role of C-Reactive protein in COVID-19 pneumonia as “A jack of all trades is a master of none!”: A single-center experience of 2000 cases.J Assoc Pulmonologist Tamilnadu 2022;5:106-112
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How to cite this URL:
Patil S, Khule S, Patil D, Toshniwal S. Role of C-Reactive protein in COVID-19 pneumonia as “A jack of all trades is a master of none!”: A single-center experience of 2000 cases. J Assoc Pulmonologist Tamilnadu [serial online] 2022 [cited 2023 May 29 ];5:106-112
Available from: https://www.japt.in//text.asp?2022/5/3/106/370810 |
Full Text
Introduction
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus-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] 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 an 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 the “pro-inflammatory” 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 pathway, inflammatory pathway, thrombogenic pathway and direct virus induced cytotoxic effects in pulmonary and extrapulmonary tissues.[6],[7] CRP can be used as a marker of inflammation in COVID-19 pneumonia.[8] CRP can be used as an inflammatory marker and help in analysing infectious and non-infective causes conditions resulting in rise in titer. Non-infective conditions resulting into rise in CRP titer are inflammatory conditions such as rheumatoid, gout; post-surgical or postoperative cases 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 as a core marker during 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 tertiary care setting.
Methods
Ethical approval
This study was approved by the Institutional Review Board/Ethics Committee at Venkatesh Hospital and Critical Care Center, Latur, India, and MIMSR Medical College, Latur, India (Approval number: VCC/52-2020-2021; Approval date: August 20, 2020).
Data source
A prospective, observational, 12-week follow-up study, conducted during July 2020 to May 2021, in MIMSR Medical College, Latur, and Venkatesh Hospital, Latur, India, included 2000 COVID-19 cases confirmed with reverse transcription–polymerase chain reaction (RT-PCR), to find out the role of CRP in predicting the severity of illness and assessing response to therapy and outcome as post-COVID fibrosis in diagnosed COVID-19 pneumonia cases admitted in critical care unit. Total 2000 cases were enrolled in the study after IRB approval, and written informed consent of all included cases was taken at respective centers of study in Venkatesh Hospital and MIMSR Medical College, Latur [Figure 1].{Figure 1}
Inclusion criteria
COVID-19 patients, confirmed with RT-PCR, above the age of 18 years, hospitalized in the study centers, including those with comorbidities irrespective of severity and oxygen saturation were included in the study.
Exclusion criteria
Those not willing to give consent, not able to perform CRP, and not willing to remain in follow-up and cases that died during hospitalization or before 12 weeks of discharge from hospital were excluded.
All study cases were undergone protocolised assessment after enrolment in study
COVID 19 RT PCR test was performed on nasopharyngeal samples collected with all standard institutional infection control policies. If the first sample test results were negative and radiological features clearly documenting pneumonia then we have repeated the RT PCR test. Finally, we have enrolled COVID 19 RT PCR positive cases in our study. High resolution computed tomography (HRCT) thorax was done to assess the severity of lung involvement as per COVID 19 Reporting and Data System.[20] Radiological categorization was done as mild if score <7, moderated if score 8–15, and severe if score ><7, moderate if score 8-15 and severe if score 16–25. Clinical assessment, routine biochemistry analysis and haematological workup with viral inflammatory markers such as CRP, ferritin, lactate dehydrogenase (LDH), and interleukin 6 (IL 6) titers done in all cases. Entry point CRP titer was utilized as an assessment tool of severity of illness with clinical parameters. If CRP analysis was normal at entry point, then CRP titer was repeated on the day of discharge from hospital or done during hospitalization if clinical course deteriorates. If CRP analysis was abnormal at entry point, we repeated it every 72 h as 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 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].
Study design
Methodology of CRP titer assessment: ImmunoturbidimetryNormal values: Normal values up to 6 mg/LInterpretation of results:
Negative: value up to 6 mg/LPositive: value above 6 mg/LSignificant: four-fold raised CRP value, i.e., >24 mg/LHighly significant: sixteen-fold raised values, i.e., 96 mg/LFollow-up significance: values raised or decreased in two-to-four-fold change.
Statistical analysis
The statistical analysis was done by using Chi-square test in R-3.4 software. Significant values of χ2 were seen from 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, 2000 COVID-19 pneumonia cases confirmed by COVID-19 RT-PCR, males were 1300/2000 and females were 700/2000, age >50 were 1200 cases, and age <50 were 800 cases. A 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}
Core observations
HRCT severity score at entry point with CRP titer has a significant correlation in COVID-19 pneumonia cases (P < 0.00001) [Table 2]. CRP titer has a significant association with duration of illness (DOI) (P < 0.00001) [Table 3]. CRP titer has a significant association with oxygen saturation (P < 0.00001) [Table 4]. BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has a 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 a significant association with CRP titer (P < 0.00001) [Table 6]. Follow-up CRP titer during hospitalization as 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}{Table 3}{Table 4}{Table 5}{Table 6}{Table 7}{Table 8}
Discussion
In the present study, computed tomography (CT) severity score at entry point with CRP titer has a 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 observations in their studies.[21],[22],[23],[24],[25],[26],[27],[28] 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 usefulness of CRP and CT severity in triaging the cases at entry point and guided for proper use of interventions in indoor care settings according to the “clinical, radiological, and inflammatory marker panel.” Herold T et al.[32] 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 a 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. Rationality for this observation is not known, maybe the inflammatory response pattern is different, and we have correlated CRP pattern with other inflammatory markers such as IL-6 and D-dimer and documented that these two markers raised parallel to CRP. Our findings are collaborating with studies by various authors.[17],[32],[33] Raised CRP after the 2nd week of illness may indicate worsening of COVID-19 pneumonia or possible secondary bacterial infection (confirmed with procalcitonin in selected cases) which will help the 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 a 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 and help in analyzing disease severity. Liu et al.,[34] Qin et al.,[35] Sahu et al.,[36] and Deng et al.[37] have documented similar observations in their studies and mentioned the role of CRP as a “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). Xie et al.,[38] Chen et al.,[39] Gao et al.,[15] and Guan et al.[18] have documented similar observations in their studies. Authors have mentioned that hypoxia and infection are the best triggers of inflammation resulting in a significant rise in CRP titer which is a marker of advanced disease.
In the present study, timing of BIPAP/NIV requirement during the course of COVID-19 pneumonia in critical care settings has a significant association with CRP titer. (P < 0.00001) Numerous studies by authors Wu C et al,[19] Bilaloglu S et al,[40] Volanakis JE et al,[41] Vanderschueren S et al,[42] Landry A et al,[43] Goyal P et al[44] & Liu D et al[45] have documented positive correlation of CRP titer with ventilatory support requirement. Authors have observed rising titers and four-fold raised titers indicate underlying acute respiratory distress syndrome in these cases. Authors have concluded that timely CRP titer analysis helped in predicting “timings of ventilatory support” requirement.
In the present study, follow-up CRP titer during hospitalization as compared to entry point abnormal CRP has a significant association in post-COVID lung fibrosis (P < 0.00001). Rationale for similar observation is an 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 have a “double-edge sword effect,” i.e., cytokines have a protective role in controlling infection, while in hyperactive state, cytokines will cause exaggerated lung inflammation and lung parenchymal damage and resultant lung fibrosis and 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 as compared to entry point normal CRP has a significant association in post-COVID lung fibrosis (P < 0.00001). We have documented the crucial role of serial CRP titer in assessing progression of pneumonia in cases presenting with nonsevere illness. In the present study, few cases with mild illness progressed to critical courses and were easily picked up by doing sequential CRP titer. Importantly, these cases have documented post-COVID lung fibrosis than those with normal follow-up titers. Yan et al.[46] in their retrospective analysis in Wuhan, China, documented similar findings.
In the present study, the age of patients, 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 the gender of included cases has a significant association in COVID-19 cases with normal and abnormal CRP titer (P < 0.010). Zhu et al.,[47] Wang et al.,[48] and Ahnach et al.[49] have documented similar findings in their study. In the present study, comorbidities such as diabetes mellitus, COPD, hypertension, IHD, and obesity have a significant association in COVID-19 cases with normal and abnormal CRP titer (P < 0.00001). Numerous studies by authors Guan WJ et al,[18] Fang L et al,[50] Yang J et al,[51] Yang X et al,[52] Arokiasamy P et al,[53] Shi Y et al,[54] Mo P et al,[55] Patel AB et al,[56] Dietz W et al[57] and CDC guidelines on COVID-19[58] mentioned similar findings as in our study.
Limitations of study
Our study is having enough sample size and analyzing the role of CRP at entry point and follow-up during the 12-week period and association with post-COVID-19 lung fibrosis is documented. The first limitation is confounding factors leading to abnormal CRP titers such as rheumatological disorders, cancer, and trauma were not evaluated during the entire duration of 12 weeks. Hence the effect of these confounding factors on CRP titer & its effect on final outcome in COVID-19 pneumonia is not possible. The second limitation is an association of CRP titer on requirement of other modes of ventilation such as high flow nasal canula and invasive mechanical ventilation is not assessed individually. In present study, we have considered BIPAP/NIV as primary mode ventilatory support because majority of COVID 19 cases receiving high flow nasal cannula were shifted to BIPAP/NIV and or mechanical ventilation & vice versa 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. Sequential or “follow up CRP 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 outcome.
CRP titer has a significant association in predicting the progression of pneumonia, and we have documented that a proportionate number of COVID-19 cases with mild variety on CT thorax with normal initial CRP have progressed to 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 2nd week of illness indicating nosocomial bacterial infection, and guided in targeting antibiotic treatment accordingly. CRP follow-up titers can help in predicting the progression of COVID pneumonia and assessing the risk of post-COVID lung fibrosis.
Hence, the role of CRP in COVID-19 pneumonia as “a jack of all trades is a master of none” is a real misnomer but “oftentimes better than a master of one” in comparison to other available inflammatory markers IL-6, ferritin, and LDH due to easy availability and cost-effectiveness.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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