|Year : 2023 | Volume
| 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|
Prof. Shital Patil
Department if Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
Source of Support: None, Conflict of Interest: None
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. 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.,
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 and Siegel et al. 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., CRP can be used as marker of inflammation in COVID-19 pneumonia. 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.,,, Data of CRP in severe H1N1 viral pneumonia are available, and a number of recent series have reported an association between CRP and COVID-19 disease severity.,,,,,,
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|| |
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).
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.
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.
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) 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].
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.
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)|
Click here to view
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)|
Click here to view
|Table 3: Duration of illness at entry point during hospitalization and C-reactive protein titer in coronavirus disease 2019 pneumonia cases (n=1000)|
Click here to view
|Table 4: Oxygen saturation at entry point and C-reactive protein titer in coronavirus disease 2019 pneumonia cases (n=1000)|
Click here to view
|Table 5: Correlation of bilevel positive airway pressure use with C-reactive protein titer in coronavirus disease 2019 pneumonia cases (n=1000)|
Click here to view
|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)|
Click here to view
|Table 7: Abnormal C-reactive protein titer at entry point (n=680) and follow-up and its correlation with post-COVID lung fibrosis|
Click here to view
|Table 8: Normal C-reactive protein titer (n=320) at entry point and follow-up and its correlation with post-COVID lung fibrosis|
Click here to view
| 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.,,,,,,, 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.,, 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. 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.,, 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 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,,, 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,,, 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.,,,,,,
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. 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., 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,, 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,,,,,,,,, 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 2nd 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
Conflicts of interest
There are no conflicts of interest.
| References|| |
Abernethy TJ, Avery OT. The occurrence during acute infections of a protein not normally present in the blood: I. Distribution of the reactive protein in patients' sera and the effect of calcium on the flocculation reaction with c polysaccharide of pneumococcus. J Exp Med 1941;73:173-82.
Macleod CM, Avery OT. The occurrence during acute infections of a protein not normally present in the blood: II. Isolation and properties of the reactive protein. J Exp Med 1941;73:183-90.
Volanakis JE, Kaplan MH. Specificity of C-reactive protein for choline phosphate residues of pneumococcal C-polysaccharide. Proc Soc Exp Biol Med 1971;136:612-4.
Kaplan MH, Volanakis JE. Interaction of C-reactive protein complexes with the complement system. I. Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphingomyelin. J Immunol 1974;112:2135-47.
Siegel J, Rent R, Gewurz H. Interactions of C-reactive protein with the complement system. I. Protamine-induced consumption of complement in acute phase sera. J Exp Med 1974;140:631-47.
Pepys MB. C-reactive protein fifty years on. Lancet 1981;1:653-7.
Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003;111:1805-12.
Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell L, Chernyak Y, et al.
Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: Prospective cohort study. BMJ 2020;369:m1966.
Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 1930;52:561-71.
Morley JJ, Kushner I. Serum C-reactive protein levels in disease. Ann N Y Acad Sci 1982;389:406-18.
Murashima M, Nishimoto M, Kokubu M, Hamano T, Matsui M, Eriguchi M, et al.
Inflammation as a predictor of acute kidney injury and mediator of higher mortality after acute kidney injury in non-cardiac surgery. Sci Rep 2019;9:20260.
Folsom AR, Lutsey PL, Astor BC, Cushman M. C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thromb Haemost 2009;102:615-9.
Vasileva D, Badawi A. C-reactive protein as a biomarker of severe H1N1 influenza. Inflamm Res 2019;68:39-46.
Luo X, Zhou W, Yan X, Guo T, Wang B, Xia H, et al.
Prognostic value of C-reactive protein in patients with coronavirus 2019. Clin Infect Dis 2020;71:2174-9.
Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al.
Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 2020;92:791-6.
Liang W, Liang H, Ou L, Chen B, Chen A, Li C, et al.
Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. JAMA Intern Med 2020;180:1081-9.
Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y, et al.
Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol 2020;127:104370.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al.
Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.
Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al.
Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934-43.
Prokop M, van Everdingen W, van Rees Vellinga T, Quarles van Ufford H, Stöger L, Beenen L, et al.
CO-RADS: A categorical ct assessment scheme for patients suspected of having COVID-19-definition and evaluation. Radiology 2020;296:E97-104.
Tan C, Huang Y, Shi F, Tan K, Ma Q, Chen Y, et al.
C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol 2020;92:856-62.
Wu J, Wu X, Zeng W, Guo D, Fang Z, Chen L, et al.
Chest CT findings in patients with coronavirus disease 2019 and its relationship with clinical features. Invest Radiol 2020;55:257-61.
Sun D, Li X, Guo D, Wu L, Chen T, Fang Z, et al.
CT quantitative analysis and its relationship with clinical features for assessing the severity of patients with COVID-19. Korean J Radiol 2020;21:859-68.
Zhang B, Zhang J, Chen H, Chen L, Chen Q, Li M, et al.
Novel coronavirus disease 2019 (COVID-19): Relationship between chest CT scores and laboratory parameters. Eur J Nucl Med Mol Imaging 2020;47:2083-9.
Yilmaz A, Sabirli R, Seyit M, Ozen M, Oskay A, Cakmak V, et al.
Association between laboratory parameters and CT severity in patients infected with Covid-19: A retrospective, observational study. Am J Emerg Med 2021;42:110-4.
Warusevitane A, Karunatilake D, Sim J, Smith C, Roffe C. Early diagnosis of pneumonia in severe stroke: Clinical features and the diagnostic role of C-reactive protein. PLoS One 2016;11:e0150269.
Chalmers S, Khawaja A, Wieruszewski PM, Gajic O, Odeyemi Y. Diagnosis and treatment of acute pulmonary inflammation in critically ill patients: The role of inflammatory biomarkers. World J Crit Care Med 2019;8:59-71.
Matsumoto H, Kasai T, Sato A, Ishiwata S, Yatsu S, Shitara J, et al.
Association between C-reactive protein levels at hospital admission and long-term mortality in patients with acute decompensated heart failure. Heart Vessels 2019;34:1961-8.
Wang L. C-reactive protein levels in the early stage of COVID-19. Med Mal Infect 2020;50:332-4.
Lonsane A, Chopra RK, Jayamani M. Late breaking abstract – Correlation of CT severity score and inflammatory markers to predict the disease severity in COVID 19 patients. Eur Respir J 2021;58:PA819.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al.
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al.
Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol 2020;146:128-36.e4.
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846-8.
Stringer D, Braude P, Myint PK, Evans L, Collins JT, Verduri A, et al.
The role of C-reactive protein as a prognostic marker in COVID-19. Int J Epidemiol 2021;50:420-9.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al.
Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020;71:762-8.
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.
Deng Y, Liu W, Liu K, Fang YY, Shang J, Zhou L, et al.
Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: A retrospective study. Chin Med J (Engl) 2020;133:1261-7.
Xie J, Covassin N, Fan Z, Singh P, Gao W, Li G, et al.
Association between hypoxemia and mortality in patients with COVID-19. Mayo Clin Proc 2020;95:1138-47.
Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al.
Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ 2020;368:m1091.
Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA 2020;324:799-801.
Volanakis JE. Human C-reactive protein: Expression, structure, and function. Mol Immunol 2001;38:189-97.
Vanderschueren S, Deeren D, Knockaert DC, Bobbaers H, Bossuyt X, Peetermans W. Extremely elevated C-reactive protein. Eur J Intern Med 2006;17:430-3.
Landry A, Docherty P, Ouellette S, Cartier LJ. Causes and outcomes of markedly elevated C-reactive protein levels. Can Fam Physician 2017;63:e316-23.
Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, et al.
Clinical characteristics of covid-19 in New York City. N Engl J Med 2020;382:2372-4.
Liu D, Zhang W, Pan F, Li L, Yang L, Zheng D, et al.
The pulmonary sequalae in discharged patients with COVID-19: A short-term observational study. Respir Res 2020;21:125.
Yan L, Zhang HT, Goncalves J, Xiao Y, Wang M, Guo Y, et al
. An interpretable mortality prediction model for COVID-19 patients. Nat Mach Intell 2020;2:283-8.
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al.
A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al.
Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.
Ahnach M, Zbiri S, Nejjari S, Ousti F, Elkettani C. C-reactive protein as an early predictor of COVID-19 severity. J Med Biochem 2020;39:500-7.
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020;8:e21.
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.
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al.
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med 2020;8:475-81.
Arokiasamy P, Uttamacharya U, Jain K, Biritwum RB, Yawson AE, Wu F, et al.
The impact of multimorbidity on adult physical and mental health in low- and middle-income countries: What does the study on global ageing and adult health (SAGE) reveal? BMC Med 2015;13:178.
Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host susceptibility to severe COVID-19 and establishment of a host risk score: Findings of 487 cases outside Wuhan. Crit Care 2020;24:108.
Mo P, Xing Y, Xiao Y, Deng L, Zhao Q, Wang H, et al.
Clinical characteristics of refractory coronavirus disease 2019 in Wuhan, China. Clin Infect Dis 2021;73:e4208-13.
Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: What is the evidence? JAMA 2020;323:1769-70.
Dietz W, Santos-Burgoa C. Obesity and its implications for COVID-19 mortality. Obesity (Silver Spring) 2020;28:1005.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]