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Role of C - reactive protein, Serum Ferritin and D-Dimer in Covid Cases:

Systematic Review & Meta Analysis

Dr. Kondabolu Sai Kiran1, Dr. Kakarlapudi Yasitha2, Dr. Sowkhya Panakala3,Natasha Pitcairn4,Dr. Rahul VC Tiwari5, Dr. Mudita Sharma6, Dr. Heena Tiwari7.

1MBBS, Andhra Medical College, Dr. NTR Univerity of Health sciences, Visakhapatnam , Andhra pradesh, INDIA. [email protected]

2 MBBS, ANDHRA MEDICAL COLLEGE, Dr. NTR Univerity of Health sciences, Visakhapatnam , Andhra pradesh, INDIA. [email protected]

3MBBS, Andhra medical college, Dr.NTR University of Health sciences, Visakhapatnam, Andhra Pradesh, India. [email protected]

4Third Year MBBS Student,School of Medicine, Ross University, New York, NY.

[email protected]

5OMFS, FOGS, PhD Scholar, Dept of OMFS, Narsinbhai Patel Dental College and Hospital, Sankalchand Patel University, Visnagar, Gujarat,384315. [email protected]

6MDS, Consultant Oral & Maxillofacial Pathologist, Tonk ENT Dental & General Hospital, B-61, Sahkar Marg near ICICI Bank, Jaipur. [email protected]

7BDS, PGDHHM, MPH Student, Parul Univeristy, Limda, Waghodia, Vadodara, Gujrat, [email protected]

Corresponding Author:Dr. Heena Tiwari, BDS, PGDHHM, MPH Student, Parul Univeristy, Limda, Waghodia, Vadodara, Gujrat, [email protected]

ABSTRACT:

Introduction: Patients severely ill with coronavirus disease-2019 (COVID-19) showed hyperinflammation, and the associated biomarkers may be beneficial for risk stratification.

We investigated the association between several biomarkers, including serum C-reactive protein (CRP), D-dimer, serum ferritin, and the COVID-19 severity.

Methods: We conducted an online search for the COVID patients with the included lab reports and severity. The outcome of interest for this study was the composite poor outcome, which comprises mortality, acute respiratory distress syndrome, need for care in an intensive care unit, and severe COVID-19.

Results: A total of 5351 patients were pooled from 25 studies. Elevated CRP, D-dimer, ferritin was associated with an increased composite poor outcome, with an association of the mortality and the severity at various levels.

Conclusion: CRP, D-dimer, and ferritin were associated with a poor outcome in COVID-19.

Keywords: C-reactive protein (CRP), D-dimer, and Serum ferritin, and COVID-19 severity.

INTRODUCTION

Coronavirus disease-2019 is a pandemic that has claimed multiple lives.1 In few they progress to severe pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, and coma, death.2 The progress of the disease is unpredictable as to who will have mild and who will progress to severe illness. Comorbidities and laboratory markers have been suggested for risk stratification.3–6 There is enough evidence that in critically ill patients, there are features of hyperinflammation, which consist of incresed serum C-reactive protein (CRP), D-dimer, and hyperferritinemia. These observations suggest a possibly important role

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of a cytokine storm in COVID-19 pathophysiology.7-10Laboratory biomarkers to foretell the severity of COVID-19 are vital in a pandemic, because resource allocation must be prudently planned, especially in the situation of respiratory support readiness. In the current study, we directed a systematic review and meta-analysis to investigate the association between various biomarkers, including serum CRP, D-dimer, and serum ferritin, and the severity of COVID- 19.

MATERIALS AND METHODS

We conducted the search for the data from the online sources like the “EMBASE”,

“Pubmed”, “Scopus” “Medline” and other sources. The study was conducted by two reviewers independently. The PRISMA guidelines were followed. The articles were collected from January 2020 to February 2021. The search words are COVID, COVID19, SARS, CoV2, PANDEMIC, CRP, D-dimer, and serum ferritin. The animal studies, population data, epidemiology, reviews were excluded along with the inconclusive diagnosis, other languages than can’t be translated to English. We included those studies with adult patients with COVID-19 with data for serum CRP, D-dimer, and serum ferritin and reported the data based on the presence or absence of clinically validated definitions of mortality, severe COVID-19, ARDS, and intensive care unit (ICU) care.The heterogeneity of the analysis was studied using Cochran Q-statistic and I2 statistic with P<0.05 for Q-statistic, I2 ≥50% as significant.

Total participants, year of study, study type, clinical features, comorbidities, number of the patients were noted for all the studies. Table 1 Based on the WHO criteria meta regression was performed for the factors that may impact the severity.12-14 statistical analysis was done keeping the p value<0.05.

RESULTS

In the study 25 articles with 5350 patients were finalized from 313 records. Figure 1

Raised CRP and outcome

This meta-analysis of 13 studies showed that an elevated serum CRP was associated with an increased composite poor outcome [RR 1.84 (1.45, 2.33), p < 0.001; I2: 96%, p <

0.001] (Figure 2(a)).15–22,25–28,31 Subgroup analysis showed that an elevated CRP was associated with an increased risk of severe COVID-19 [RR 1.41 (1.14, 1.74), p = 0.002; I2:

93%, p < 0.001], need for ICU care [RR 1.96 (1.40, 2.74), p < 0.001], but not mortality [RR 2.95 (0.90, 9.68), p = 0.07; I2: 99%, p < 0.001].

Raised D-dimer and outcome

The meta-analysis of 11 studies showed that an elevated D-dimer was associated with an increase in composite poor outcome [RR 2.93 (2.14, 4.01), p < 0.001; I2: 77%, p < 0.001]

(Figure 3(a)).16–23,25– 27,31 Subgroup analysis showed that an elevated D-dimer was associated with increased mortality [RR 4.15 (2.43, 7.08), p < 0.001; I2: 83%, p = 0.01], severe COVID-19 [RR 2.42 (1.72, 3.40), p < 0.001; I2: 58%, p = 0.05], but not the need for ICU care [RR 0.94 (0.43, 2.07), p = 0.88]. By removing the Hu et al. study, 18 sensitivity analysis reduced heterogeneity for severe COVID-19 [RR 2.77 (2.06, 3.73), p < 0.001; I2:

19%, p = 0.30].

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1.15), p< 0.0001; I2: 76%] (Figure 4) in 10 stud- ies.10,23,24,27–33 Subgroup analysis results demon- strated that ferritin level was higher in non-survivors (mortality) [SMD 0.96 (0.78,1.13), p < 0.00001; I2: 0%, p = 0.41] and patients with severe COVID-19 [SMD 0.97 (0.43, 1.50), p < 0.004; I2: 82%, p = 0.001].

Meta-regression

Meta-regression analysis demonstrated that the association between an elevated CRP, D- dimer, serum ferritin level, and the composite poor outcome was not significantly affected by gender, age, hypertension, cardiovascular disease, diabetes, and COPD (p > 0.05).

Publication bias

The funnel-plot was qualitatively asymmetrical for D-dimer, PCT, CRP, and ferritin.

Regression- based Egger’s test depicted no indication of small- study effects for D-dimer (p = 0.073) and ferritin (p = 0.372) on the composite poor outcome. There was indication of small- study effects in the association between PCT (p = 0.003), CRP (p < 0.001), and a composite poor outcome.

Figure 1. Study flow diagram.

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TABLE 1- Comparison of the studies.

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Figure 2. Elevated CRP and composite poor outcome. (a) Patients with a composite poor outcome comprising mortality, ARDS, need for ICU care, and severe COVID-19 have an elevated serum CRP. (b) SROC (summary receiver operating characteristic.)analysis (with prediction and confidence contours) of an elevated CRP and a composite poor outcome.

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Figure 3. Elevated D-dimer and composite poor outcome. (a) Patients with a composite poor outcome comprising mortality, ARDS, need for ICU care, and severe COVID-19 have an elevated serum PCT. (b) SROC analysis (with prediction and confidence contours) of elevated D-dimer and a composite poor outcome.

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Figure 4. Higher serum ferritin and a composite poor outcome. Patients with a composite poor outcome comprising mortality, ARDS, need for ICU care, and severe COVID-19 have a higher serum ferritin level.

Discussion

This meta-analysis showed that elevated serum CRP, D-dimer, and serum ferritin levels were related with an augmented composite poor outcome that includes mortality, severe COVID- 19, ARDS, and the need for ICU care in patients with COVID-19. The effect estimate was not significantly modified by age, gender, cardiovascular disease, diabetes, and COPD.

In the systemic hyperinflammation phase of COVID-19 projected by Siddiqi and Mehra,35 there is a significant elevation of inflammatory cytokines and biomarkers, such as interleukin (IL)-2, IL-6, IL-7, granulocyte-colony stimulating factor, tumor necrosis factorβ, CRP, ferritin, and D-dimer. This stage has the most severe manifestation of the cytokine storm, in which extreme hyperinflammation may cause to cardiopulmonary collapse and multi-organ failure.CRP is an acute phase inflammatory protein manufactured by the liver that may be raised in several conditions, such as inflammation, cardiovascular disease, and infection. In the present study of 13 articles, an elevated CRP was concomitant with severe COVID-19, the need for ICU care, but not with death. Though there is no general agreement on a cutoff point to determining the severity of COVID-19, the majority of the studies used a ⩾10 mg/L limit. In present study, the cutoff values of serum CRP varied widely, with the lowest and highest values being >3 mg/L and >100 mg/L. These findings mirrored the paramount need for pursuing the optimal serum CRP cutoff value for COVID-19 prediction. The time period for serum CRP measurement was critical in light of the timely manner of serum CRP increment, which culminates 72 h after the initial insults.37,41 Despite its value in predicting a poor outcome in COVID-19, it should be noted that various aspects could affect serum CRP levels, including age, gender, smoking status, weight, lipid levels, BP, and liver health.37 These factors should be taken into account while interpreting the serum CRP level. Also, current research has shown that serum CRP level could also be used in checking the

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progression and improvement of patients with COVID-19.43In our study, we also found that an elevated D-dimer was linked with an increased composite poor outcome, particularly mortality and severe COVID-19. These findings support the hypothesis that SARS-CoV-2 may induce the dysfunction of the hemostatic system, leading to a hypercoagulable state, a condition which we commonly encounter in sepsis. In the absence of contraindications, a prophylactic dose of an anticoagulant is suggested for all hospitalized patients with COVID- 19.Accompanied by other biomarkers included in this study, we also found that a higher serum ferritin level was independently associated with ARDS, mortality, and severe COVID- 19. This suggests a presence of secondary hemophagocytic lymphohistiocytosis (sHLH) in COVID-19.7 sHLH is a condition of hyperinflammation described by a cytokine storm causing fatal multi-organ failure. This situation is most commonly triggered by viral infections, which might lead to a hypothesis of SARS-CoV-2 inducing this hyperinflammatory syndrome. The limitations of this systematic review and meta- analysis is the publication bias, non-peer-reviewed studies, and type of the retrospective studies.

Conclusion

This meta-analysis showed that an elevated serum CRP, PCT, D-dimer, and serum ferritin were associated with a composite poor outcome in patients with COVID-19.

References

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