• Users Online: 369
  • Print this page
  • Email this page

ORIGINAL ARTICLE Table of Contents  
Ahead of print publication
Role of prognostic markers as a predictor of mortality and short-term prognosis in COVID-19


1 Department of Emergency Medicine, Travancore Medical College, Kollam, Kerala, India
2 Department of Community Medicine, Travancore Medical College, Kollam, Kerala, India

Click here for correspondence address and email

Date of Submission25-Apr-2022
Date of Decision29-Aug-2022
Date of Acceptance01-Sep-2022
Date of Web Publication06-Oct-2022
 

  Abstract 


Introduction: As the world is slowly out of its second wave wrecked by the Delta strain, the world population is now struck once again with a new strain of COVID-19. As the outbreak is spreading, prognostic markers such as C-reactive protein (CRP), D-dimer, and ferritin levels can help the physician in predicting clinical outcomes at an early stage. Materials and Methods: Our study made an analysis of patients presented to the emergency medicine department with positive COVID antigen or reverse transcriptase–polymerase chain reaction (RT-PCR) results. Patient demographic data, clinical profile, and values of D-dimer, CRP, and serum ferritin were obtained. All the patients were subjected to standard treatment according to COVID protocol. Results: Our study population was comprised of 312 patients. Among them, 162 (51.9%) were male, and 150 (48.1%) were female. Our study found that among 45 patients, who had expired, 38 (84.4%) patients had elevated D-dimer values, 45 (100%) patients had elevated CRP values, and 41 (91.1%) patients had elevated ferritin values. P =001, which is statistically significant. Conclusion: Our study found that values of prognostic markers such as D-dimer, CRP, and serum ferritin at the time of presentation can be used as a predictor of mortality and risk stratification and predict the probable need for prolonged hospital and intensive care unit stay. These values also correlate well with the disease severity of the patients. They can also be used to predict the probable need for respiratory support during the course of a stay in the hospital.

Keywords: COVID-19, C-reactive protein, D-dimer, ferritin, hospital stay, intensive care unit stay, mortality, prognosis


How to cite this URL:
Jayachandran AK, Nelson V, Thaiba F, Shajahan ME. Role of prognostic markers as a predictor of mortality and short-term prognosis in COVID-19. Apollo Med [Epub ahead of print] [cited 2022 Nov 28]. Available from: https://apollomedicine.org/preprintarticle.asp?id=357995





  Introduction Top


The pandemic created by coronavirus started in December 2019 and is still spreading rapidly across the world. The world is facing a fresh wave of COVID-19 infections by a new strain of coronavirus designated B.1.1.529, named Omicron.[1]

During a pandemic situation, risk stratification of patients from E. D. itself can help in the appropriate allocation of limited resources. D-dimer is a degradation product of cross-linked fibrin, indicating increased thrombin generation and fibrin dissolution by plasmin. High D-dimer levels are common in infectious and inflammatory diseases.[2] Serum ferritin is an iron-storage protein with the primary role of regulating cellular oxygen metabolism. Ferritin is composed of two different subunits, H and L. Previous studies have suggested that H-ferritin acts as an immune modulatory molecule with both proinflammatory and immunosuppressive functions. Elevated ferritin levels are indicative of a strong inflammatory reaction.[3] C-reactive protein (CRP) is a type of protein produced by the liver that serves as an early marker of infection and inflammation.[4]

As the outbreak is spreading once again rapidly across the world, with limited or no lockdown restrictions, the already strained health sector is starring at new emerging variants of COVID-19. In developing nations where resources are limited, prognostic markers such as CRP, D-dimer, and ferritin levels can help the physician in predicting clinical outcomes at an early stage. We would like to assess the use of these prognostic markers in predicting clinical outcomes and mortality using values at the time of presentation. We also want to determine whether prognostic markers can also predict the probable need for intensive care unit (ICU) care and respiratory support like oxygen, noninvasive ventilation (NIV), or mechanical ventilation (MV), which can help the physician to allocate limited resources judiciously.


  Materials and Methods Top


Study design, study population, and duration

A cross-sectional study was done on patients presented to the Emergency Medicine Department at Travancore Medical College Hospital between May 1, 2021, and June 30, 2021.

Inclusion and exclusion criteria

Patients presenting to the emergency medicine department

  • With symptoms consistent with COVID-19 and a positive COVID antigen or reverse transcriptase–polymerase chain reaction (RT-PCR) result
  • Age ≥18 years were included in the study.


Patients with ages <18 years and pregnant females were excluded from the study.

Methodology

After obtaining clearance from the Institutional Ethical Committee (IEC No: 71/21), our study made an analysis of patients presented to the emergency medicine department with positive COVID antigen or RT-PCR results. Patient demographic data, clinical profile, and values of D-dimer, CRP, and serum ferritin were obtained. All the patients were subjected to standard treatment according to COVID protocol.

D-dimer and serum ferritin were analyzed with the VIDAS ELFA method, and CRP was analyzed by the turbidimetric method. D-dimer <500 ng/ml was considered normal. Normal values of serum ferritin were defined as 20–322 and 10–291 ng/ml in males and females, respectively. CRP normal value was defined <6 mg/l.

Statistical analysis

Data were analyzed using SPSS software version 16.0 (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc). Descriptive statistics such as mean, frequency, and percentages were calculated. The Chi-square test was used to find the statistical significance. P < 0.05 was considered statistically significant. The mean values of D-dimer, CRP, and serum ferritin were calculated.


  Results Top


Our study population comprised 312 patients. Among them, 162 (51.9%) were male, and 150 (48.1%) were female [Table 1].
Table 1: Sociodemographic profile of the patients

Click here to view


Clinical profile

At the time of presentation, 43 (13.8%) patients were categorized among Category A, followed by 87 (27.9%) among Category B and 182 (58.3%) among Category C [Table 2].
Table 2: Clinical profile of the patients

Click here to view


Category A was defined as patients with mild upper respiratory tract symptoms and or fever without shortness of breath or hypoxia. Category B patients had a moderate disease with R.R. ≥24/min or SpO2 90 to ≤93% on room air. Category C patients had a severe disease with R.R. >30/min or SpO2 <90% on room air.

Among our study population, 154 (49.4%) had diabetes mellitus, 141 (45.2%) had hypertension, 30 (9.6%) had coronary artery disease, 17 (5.4%) had chronic kidney disease, and 8 (2.6%) had chronic liver disease [Figure 1]. One hundred and ten (35.36%) patients required oxygen, 54 (17.3%) patients required NIV, and 14 (4.5%) patients required MV at the time of presentation. Forty-five (14.4%) among 312 patients expired in our study population [Table 2].
Figure 1: Comorbidities

Click here to view


Prognostic markers and prognosis

Ten (23.25%) patients among Category A, 37 (42.52%) among Category B, and 124 (67.39%) among Category C had elevated D-dimer values. Of 171 patients with elevated D-dimer, 29 (17%), 92 (53.8%), and 50 (29.2%) patients required <5, 5–10, and >10 days of hospital stay, respectively [Table 3]; P = 0.001, which was statistically significant. Of 171 patients with elevated D-dimer, 106 (62%), 58 (33.9%), and 7 (4.1%) patients required <5, 5–14, and >14 days of ICU stay, respectively [Table 3]; P = 0.001, which was statistically significant. Of 171 patients with elevated D-dimer values, 71 (41.52%) patients required oxygen support, 46 (26.9%) required NIV, and 13 (7.6%) patients required MV at the time of presentation [Table 3]. Our study found that the P value for the relationship of oxygen requirement, NIV, or MV at the time of admission in patients with elevated D-dimer values was 0.001, 0.01, and 0.001, respectively, which was statistically significant.
Table 3: Prognostic markers in COVID-19

Click here to view


Nineteen (7.9%) patients among Category A, 52 (21.8%) among Category B, and 168 (70.3%) among Category C had elevated CR P values. Of 239 patients with elevated CRP, 35 (14.6%), 138 (57.7%), and 66 (27.6%) patients required <5, 5–10, and >10 days of hospital stay, respectively [Table 3]; P = 0.001, which was statistically significant. Of 73 patients with elevated CRP, 157 (65.7%), 74 (31.0%), and 8 (3.3%) patients required <5, 5–14, and >14 days of ICU stay, respectively [Table 3]; P = 0.001, which was statistically significant. Of 239 patients with elevated CRP values, 98 (41%) patients required oxygen support, 53 (22.2%) required NIV, and 14 (5.9%) patients required MV at the time of presentation [Table 3]. Our study found that values of CRP had a significant relationship with the requirement of oxygen requirement, NIV, or MV at the time of admission; P = 0.011, 0.001, and 0.034, respectively, which was statistically significant.

Ten (4.8%) patients among Category A, 42 (20.1%) among Category B, and 157 (75.1%) among Category C had elevated serum ferritin values. Of 209 patients with elevated serum ferritin, 33 (15.8%%), 116 (55.5%), and 60 (28.7%) patients required <5, 5–10, and >10 days of hospital stay, respectively [Table 3]; P = 0.001, which was statistically significant. Of 209 patients with elevated serum ferritin, 134 (64.1%), 68 (32.5%), and 7 (3.3%) patients required <5, 5–14, and >14 days of ICU stay, respectively [Table 3]; P = 0.001, which was statistically significant. Of 209 patients with elevated serum ferritin values, 92 (44%) patients required oxygen support, 50 (23.9%) required NIV, and 14 (6.7%) patients required MV at the time of presentation [Table 3]. Our study found that the P value for the relationship between oxygen requirement and NIV at the time of admission in patients with elevated serum ferritin values was 0.001 and 0.001, respectively, which was statistically significant. The P value for the relationship between serum ferritin and MV was 0.007, which was not statistically significant [Table 3].

Our study also found that mean values of prognostic markers were significantly elevated in patients requiring hospital stay >10 days, 1578.51 ng/ml, 39.21 mg/l, and 694.01 ng/ml for D-dimer, CRP, and serum ferritin, respectively. Further, our study also found that the mean values of prognostic markers were significantly elevated in patients requiring ICU stay >14 days, 2389.38 ng/ml, 47.87 mg/l, and 694.01 ng/ml for D-dimer, CRP, and serum ferritin, respectively [Table 4].
Table 4: Mean values

Click here to view


Prognostic markers and mortality

Our study found that among 45 patients, who had expired, 38 (84.4%) patients had elevated D-dimer values, 45 (100%) patients had elevated CRP Values, and 41 (91.1%) patients had elevated ferritin values [Table 5]. Our study could prove that elevated prognostic markers such as CRP, D-dimer, and serum ferritin had a significant relationship in predicting mortality; P = 0.001, which was statistically significant [Table 5].
Table 5: Prognostic markers and mortality

Click here to view


Further, our study also found that the mean value of D-dimer at the time of presentation among survived patients was 1021.12 ng/ml, whereas among the expired group was 2379.62 ng/ml. Similarly, the mean value of CRP at the time of presentation among survived patients was 30.93 mg/l, whereas among the expired group was 79.09 mg/l, and the mean value of serum ferritin at the time of presentation among survived patients was 454.49 ng/ml, whereas among the expired group was 812.91 ng/ml [Table 4].


  Discussion Top


Few studies have shown that elevated D-dimer is associated with adverse outcomes.[5],[6],[7] Elevated D-dimer indicates a hypercoagulable state, which can be attributed to (1) an aggressive proinflammatory response and insufficient control of the anti-inflammatory response. It can induce dysfunction of endothelial cells, resulting in excess thrombin generation;[5],[8] (2) hypoxia can stimulate thrombosis through increasing blood viscosity and also through a hypoxia-induced transcription factor-dependent signaling pathway;[5],[9] (3) other risk factors such as advanced age, long-term bed rest, and invasive treatment also lead to a hypercoagulable state;[5],[10] and (4) some patients also develop sepsis-induced coagulopathy or disseminated intravascular coagulation.[8]

From our study, we could prove that 38 (84.4%) expired patients had elevated D-dimer values, and the mean value of expired patients was 2379.62 ng/ml, whereas among survived patients was 1021.12 ng/ml. This is similar to a study done by Zhang et al., whose study also predicted that in-hospital mortality was significantly higher in patients with D-dimer ≥2.0 μg/ml than in those who had D-dimer <2.0 μg/ml on admission.[5] Zang et al. also suggested that D-dimer values of 2.0 μg/ml on admission might be the optimum cutoff to predict in-hospital mortality for COVID-19. Similarly, Qeadan et al. suggested the optimal cutoff of D-dimer (2.1 mg/L) for in-hospital mortality and 2.0 mg/L for invasive ventilator dependence.[6]

CRP is a nonspecific acute phase protein produced by hepatocytes and elevated in acute infection or inflammation. Secretions begin 4–10 h after an inflammatory insult and peak at 48 h, with a short half-life of 19 h.[11] Elevated CRP levels are also seen in COVID-19 infection and can be useful in triaging and prognostication. In our study, CRP was elevated in all 45 patients who had expired, and their mean value was 79.09 mg/l. A study done by Stringer et al. suggested that CRP ≥40 mg/l on admission to the hospital should be considered a reliable indicator of disease severity and increased risk of death.[12] Similarly, Chen et al. found that the level of plasma CRP positively correlates well with the severity of COVID-19 pneumonia, and CRP can be used as an early indicator for severe illness and help the physician to stratify patients for ICU transfer.[13]

Serum ferritin is also another inflammatory marker which elevates during COVID-19 infection. Our study found that 41 (91.1%) expired patients had elevated serum ferritin with mean values of 812.91 ng/ml. A study done by Para et al. concluded that high ferritin levels should be considered critically ill.[14] Patients with ferritin values >3000 ng/ml appeared to have an inflammatory activation with elevated CRP and D-dimer values.[14] Qeadan et al. also suggested that serum ferritin values of 714 ng/ml on admission might be the optimum cutoff to predict in-hospital mortality for COVID-19. Similarly, Qeadan et al. have also suggested that the optimal cutoff of 502 ng/ml for invasive ventilator dependence.[6]

Our study also found that patients with elevated D-dimer, CRP, or serum ferritin required prolonged ICU and hospital stay. Patients with elevated values were positively associated with a higher requirement for respiratory support [Table 3].


  Conclusion Top


Our study found that values of prognostic markers such as D-dimer, CRP, and serum ferritin at the time of presentation can be used as a predictor of mortality. Further, our study also found that values of D-dimer, CRP, and serum ferritin at the time of presentation can be used in risk stratification and predict the probable need for prolonged hospital and ICU Stay. These values also correlate well with the disease severity of the patients. They can also be used to predict the probable need for respiratory support during the course of a stay in the hospital.

Limitation

Our study was done retrospectively in a single center with limited patients. Ours has been a tertiary care center; most of the patients had severe disease at the time of presentation itself.

Acknowledgment

The authors acknowledge the support from Sony Simon, Department of Community Medicine, Travancore Medical College, Kollam, for his support in statistical analysis.

Conflicts of interest

There are no conflicts of interest.

Patient consent/ethical committee approval

Patient consent was obtained from all patients. The Institutional Ethical Committee Approval was obtained on August 3, 2020-IEC No: 71/21.

Funding

Nil.

Authors' contribution statement

  • Dr. Ajith Kumar J: conception of the idea, drafting of the article, critical revision of the article, and final approval of the version to be published
  • Dr. Vincy Nelson: Critical revision of the article and final approval of the version to be published
  • Dr. Thaiba F: Drafting the article, data collection, critical revision of the article, and final approval of the version to be published
  • Dr. Mohammad Easa Shajahan: Drafting the article, data collection, critical revision of the article, and final approval of the version to be published.




 
  References Top

1.
Update on Omicron. WHO. Available from: https://www.who.int/news/item/28-11-2021-update-on-omicron. [Last accessed on 2021 Nov 28].  Back to cited text no. 1
    
2.
Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus disease 2019. Crit Care Med 2020;48:1358-64.  Back to cited text no. 2
    
3.
Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol 2017;29:401-9.  Back to cited text no. 3
    
4.
Marnell L, Mold C, Du Clos TW. C-reactive protein: Ligands, receptors and role in inflammation. Clin Immunol 2005;117:104-11.  Back to cited text no. 4
    
5.
Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z,et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost 2020;18:1324-9.  Back to cited text no. 5
    
6.
Qeadan F, Tingey B, Gu LY, Packard AH, Erdei E, Saeed AI. Prognostic Values of Serum Ferritin and D-Dimer Trajectory in Patients with COVID-19. Viruses 2021;13:419. doi: 10.3390/v13030419. PMID: 33807920; PMCID: PMC7998367.  Back to cited text no. 6
    
7.
Halaby R, Popma CJ, Cohen A, Chi G, Zacarkim MR, Romero G,et al. D-Dimer elevation and adverse outcomes. J Thromb Thrombolysis 2015;39:55-9. doi: 10.1007/s11239-014-1101-6. PMID: 25006010; PMCID: PMC4300425.  Back to cited text no. 7
    
8.
Levi M, van der Poll T. Coagulation and sepsis. Thromb Res 2017;149:38-44. doi: 10.1016/j.thromres.2016.11.007. Epub 2016 Nov 19. PMID: 27886531.  Back to cited text no. 8
    
9.
Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res 2019;181:77-83. doi: 10.1016/j.thromres.2019.07.013. Epub 2019 Jul 15. PMID: 31376606.  Back to cited text no. 9
    
10.
Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M,et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010;8:2450-7. doi: 10.1111/j.1538-7836.2010.04044.x. PMID: 20738765.  Back to cited text no. 10
    
11.
Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003;111:1805-12.  Back to cited text no. 11
    
12.
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.  Back to cited text no. 12
    
13.
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. 13
    
14.
Para O, Caruso L, Pestelli G, Tangianu F, Carrara D, Maddaluni L, et al. Ferritin as prognostic marker in COVID-19: The FerVid study. Postgrad Med 2022;134:58-63.  Back to cited text no. 14
    

Top
Correspondence Address:
Ajith Kumar Jayachandran,
Department of Emergency Medicine, Travancore Medical College, Thattamala, Kollam - 691 020, Kerala
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_68_22



    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
  Search
 
   Ahead Of Print
  
 Article in PDF
     Search Pubmed for
 
    -  Jayachandran AK
    -  Nelson V
    -  Thaiba F
    -  Shajahan ME


Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed252    
    PDF Downloaded2    

Recommend this journal