|Year : 2021 | Volume
| Issue : 2 | Page : 149-154
Role of d-dimer levels at admission in predicting outcome in coronavirus disease-2019 patients: A tertiary care center study from India
Jasdeep Singh1, Jasvinder Kaur Bhatia1, Sitaram Ghosh2, Brajesh Singh1
1 Department of Pathology, Command Hospital (EC), Kolkata, West Bengal, India
2 Department of Surgery, Command Hospital (EC), Kolkata, West Bengal, India
|Date of Submission||27-Nov-2020|
|Date of Decision||17-Dec-2020|
|Date of Acceptance||03-Jan-2021|
|Date of Web Publication||07-Oct-2021|
Col (Dr) Jasvinder Kaur Bhatia
Department of Pathology, Command Hospital (EC), Kolkata - 700 027, West Bengal
Source of Support: None, Conflict of Interest: None
Introduction: Worldwide pandemic spread of the novel coronavirus disease-2019 (COVID-19) has led to people being afflicted by COVID-19 with an ever-rising mortality leading to 1,079,029 deaths as on October 13, 2020 (covid19.who.int). Due to the rising incidence and mortality associated with COVID 19 in India with 7,175,880 confirmed cases and 109,856 deaths reported till October 13, 2020, it was imperative to have an early and effective predictor of clinical outcome to augment the present management of COVID 19 patients. Objective: The aim of the present retrospective study was to evaluate whether elevated D-dimer levels at admission in a reverse transcription-polymerase chain reaction (RT-PCR) confirmed COVID-19 patients could predict the severity of disease and outcome. Methods: D-dimer levels of patients with RT-PCR confirmed COVID-19 were retrospectively evaluated for patients admitted at this tertiary care hospital in India from March 28, 2020 to June 2, 2020. D-dimer levels on admission along with the clinicopathological profile of the patients were retrieved from the records held and intensive care unit (ICU) as well as death events were collected to calculate the optimum cutoff using the receiver operating characteristic curve. The subjects were divided into two groups and D-dimer levels between uncomplicated cases and those requiring ICU admission or died during the course of disease compared to assess the predictive value of D-dimer. Results: A total of 70 patients were included in this study admitted in this tertiary care hospital whose complete D-dimer records were available and retrieved retrospectively. Ten deaths occurred during hospitalization in the study period. Patients with mean D-dimer levels ≥4026.56 μg/ml (fibrinogen equivalent units [FEU]) had a higher incidence of morbidity and mortality as compared to those who with lower mean D-dimer levels of 1268.66 μg/dl (FEU) with P < 0.001. The optimum cutoff value of D-dimer to predict in-hospital ICU admission or mortality at our hospital was 857.9 μg/L (FEU) with a sensitivity of 93.3% and a specificity of 69.09% and a negative predictive value of 97.44%. Conclusion: A D-dimer level > 857.9 μg/L (FEU) at admission portends a worse outcome for COVID-19 patients.
Keywords: Coronavirus disease-2019, D-dimer, severe acute respiratory syndrome coronavirus 2
|How to cite this article:|
Singh J, Bhatia JK, Ghosh S, Singh B. Role of d-dimer levels at admission in predicting outcome in coronavirus disease-2019 patients: A tertiary care center study from India. J Mar Med Soc 2021;23:149-54
|How to cite this URL:|
Singh J, Bhatia JK, Ghosh S, Singh B. Role of d-dimer levels at admission in predicting outcome in coronavirus disease-2019 patients: A tertiary care center study from India. J Mar Med Soc [serial online] 2021 [cited 2021 Dec 9];23:149-54. Available from: https://www.marinemedicalsociety.in/text.asp?2021/23/2/149/327563
| Introduction|| |
The world is battling with nonabating coronavirus disease 2019 (COVID-19) pandemic, leading to high morbidity and mortality in more than 100 countries all around the world. The WHO declared the outbreak of the disease as a Public Health Emergency of International Concern on January 30, 2020. The disease is known to have originated in Wuhan, Hubei province, China in December 2019 and has left no border uncrossed leading to overwhelming the health-care services world over. As of October 13, 2020, 37,704,153 COVID-19 confirmed cases worldwide and 7,175,880 confirmed cases in India with 109,856 deaths reported.
The novel etiological agent of COVID-19 is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus bears homology to earlier epidemics of SARS and Middle East respiratory syndrome viruses in the Coronaviridae family. It is known to target the respiratory epithelium of the human host and enters the respiratory epithelial cells through the angiotensin-converting enzyme 2 receptor.
The varied manifestation of the illness ranges from asymptomatic, mild infection to severe acute respiratory tract infections in humans. The clinical presentation of the disease is also varied and may present as fever, cough, dyspnea, watery diarrhea, myalgia, severe lymphopenia, deranged coagulation markers, cardiac disease, and even sudden death. The disease is characterized by a variety of pathophysiological derangements which include pulmonary inflammation and microthrombosis, which may also spill over into the systemic circulation in the severe form of the disease. The associated hyper inflammation and coagulopathy are in turn associated with a wide derangement in D-dimer levels. D-dimer elevations were seen ranging from 36% to 43% of COVID-19 patients. Elevated D-dimer level is also considered to be one of the major risk factors for mortality in adult inpatients with COVID-19.
D-dimer heralds its origin from the lysis of cross-linked fibrin and reflects on activation of the coagulation pathway and then followed by fibrinolysis. Even though several studies have shown elevated D dimer levels to be associated with adverse outcomes in COVID 19, still the prognostic value and the optimal cutoff value for D dimer on admission to predict mortality are yet to be determined for the Indian population, as most of the data available are either Chinese from early studies, European or North America from the recently published studies. Even after the sludge of publications since the onset of the COVID-19 epidemic, there is still no consensus on cutoff levels or uniform use of the unit of D-dimer quantitative assay to predict the outcome of COVID-19 patients.
| Methods|| |
The study was a retrospective study conducted in a tertiary care hospital with COVID-19 designated beds and intensive care unit (ICU) facility located in Eastern India and an in-house, Indian Council of Medical Research (ICMR) approved polymerase chain reaction (PCR) based COVID-19 ribosomal nucleic acid (RNA) detection laboratory.
Data of all 120 sequentially admitted patients with RNA-PCR laboratory-confirmed COVID-19 between March 29, 2020 and June 1, 2020 were retrospectively screened and analyzed. The diagnosis of COVID-19 was done by RNA detection PCR of the SARS-CoV-2 at the ICMR-approved onsite pathology laboratory. A total of 70 admitted patients who had undergone quantitative baseline D-dimer level on admission and had a definite outcome in terms of favorable or adverse events were included in the study. The adverse events included patients requiring ICU admission and died during the hospital stay. The study was approved by the Institutional Ethics Committee and the requirement for informed consent was waived by the after due deliberation by the IEC vide 2020/IEC/Clinical trial/COVID/CHEC dated June 16, 2020.
All available clinical, laboratory, and outcome data were extracted from medical records held with the hospital. Results of laboratory investigations were taken into consideration from the database where blood samples were collected within 24 h of admission to perform routine laboratory tests, such as complete blood count conducted on EDTA samples, coagulation profile (prothrombin time, D-dimer, fibrinogen degradation products, activated partial thromboplastin time, and fibrinogen) on sodium citrate samples and serum biochemical tests were conducted in the in-house clinical hospital laboratory. Quantitative D-dimer levels were determined by VIDAS® D-Dimer Exclusion II TM VIDAS (Biomerieux SA, France) by two-step enzyme immunoassay sandwich method with fluorescent detection (ELFA) after calibration of the VIDAS equipment and simultaneous running of two inbuilt controls. The normal detection range of the test was from 45 ug/L, fibrinogen equivalent units (FEU) to 10,000 ug/L (FEU). The mean interday and mean intraday CV% were 4.5% and 3.5%, respectively. The normal clinical range of D-dimer in citrated plasma for out- patients at our coagulation laboratory was 45–500 ug/L (FEU). The D-dimer result was expressed in ug/ml (FEU), which is the SI unit as advocated by the International Society of Thrombosis and Hemostasis (ISTH). In all the test samples, citrated plasma was separated within the first hour and analysis was completed within 2 h after collection.
The data were compiled in an Excel sheet format. Continuous and categorical variables were presented as mean ± standard deviation or median as deemed appropriate. Categorical variables were presented as n (%). Event frequencies were compared with the Chi-square test. Other comparisons between the two groups were made with unpaired Student's t-test. The optimal D-dimer cutoff point was evaluated by the receiver operator characteristic (ROC) curve. A value of P < 0.05 was accepted as statistically significant. The statistical software package IBM®, SPSS® (version 22. Maryland, New York, US) was used for analysis.
| Results|| |
Data of the 70 eligible patients were included in the study from March 29, 2020 to June 1, 2020; the mean age of the patients was 45.2 years, ranging from 4 to 81 years. Seventeen patients were older than 65 years and 9 patients were female [Table 1]. The most common presentation was fever in 60% and 31% presented with pneumonia. About 17% of the patients with severe symptoms received therapy with antiinterleukin-6 (IL-6) inhibitor after IL-6 levels were done and 3% of patients received crossmatched convalescent patient plasma therapy [Table 1]. Listed in [Table 2] are the comorbidities of the recovered and adverse outcome group and [Table 3] reflects the laboratory results obtained on admission. There mean age of patients and underlying comorbidities were significantly higher in the adverse outcome group which required ICU admission or died after admission. A total of 15 adverse events were recorded including 10 all-cause deaths of these COVID-19 patients. There was a significant difference in mean D-dimer levels between the favorable (1268.66 μg/L, FEU) and adverse outcome groups (4026.56 μg/L, FEU) as represented in [Figure 1] with a significant P < 0.001.
|Table 1: Clinical and therapeutic profile of the patients included in the study (n=70)|
Click here to view
|Table 2: Comorbidity distribution in the uneventful recovery and the adverse outcome groups of coronavirus disease 2019 patients|
Click here to view
|Table 3: Comparative age and laboratory profile of coronavirus disease 2019 patients in the favorable and adverse outcome groups|
Click here to view
High D-dimer levels as a predictor of adverse outcome
The optimum cutoff value for D-dimer to predict adverse outcomes was 857.9 ug/L (FEU) using the ROC curve [Figure 2] with a sensitivity of 93.33% and a specificity of 69.09%. The area under the ROC curve for all adverse events was 0.84. According to the optimum cutoff value, 39 patients' D-dimer levels on admission were <857.9 μg/L (FEU), and 31 patients had D-dimer levels over 857.9 ug/L (FEU). Fourteen of the 15 patients with adverse outcomes had D-dimer levels greater than 857.9 μg/L (FEU). The sensitivity and specificity in predicting adverse events were 93.33% and 69.09%, respectively, which was significant [Table 4] and [Table 5].
|Table 4: Predictive value of D-dimer in coronavirus disease 2019 patients|
Click here to view
|Table 5: Significance of D-dimer in predicting adverse outcome in coronavirus disease 2019 patients|
Click here to view
|Figure 2: Receiver operator characteristic curve to calculate the predictive cutoff value of D-dimer in coronavirus disease-2019 patients|
Click here to view
High D-dimer levels as a predictor of mortality
A total of 10 deaths occurred during hospitalization of these 70 COVID-19 patients, all of them were observed among patients with D-dimer levels ≥857.9 μg/L (FEU) at the time of admission. The sensitivity and specificity of predicting the death of D-dimer at admission above 857.9 μg/L (FEU) were 100% and 65%, respectively [Table 4] and [Table 6].
|Table 6: Significance of D-dimer in predicting mortality of coronavirus disease 2019 patients|
Click here to view
| Discussion|| |
There are multiple hematological, coagulation, and inflammatory markers used to predict outcome in COVID-19. The decision of admission of the patient is based on the age of the patient, clinical status in terms of SpO2 levels, and concurrent comorbidities. Several laboratory parameters which are related to inflammation, myeloid activity, and coagulation are used to assess the disease severity and ensure the triaging of patients. D-dimer is one of these markers found to be significant even on the meta-analysis of various studies published but requires to be further analyzed in various geographical subgroups.
The main objective of this study was to establish the role of D-dimer at admission as a predictor of adverse outcome and mortality in our study population of COVID-19 patients and to determine an actionable cutoff value of D-dimer which could be used in the future on other COVID-19 patients for improving their outcomes. We were able to determine that D-dimer was an independent predictor of in-hospital death and ICU admissions for patients with COVID-19. This study provides a cutoff value of 857.9 ug/L (FEU) of D-dimer in SI units at baseline to identify those patients with COVID-19 who are likely to require ICU admission or have high mortality.
D-dimer elevation has been reported to be one of the most common laboratory findings noted in COVID-19 patients requiring hospitalization. Huang et al. showed that D-dimer levels median of 500 μg/L on admission were higher in patients who required critical care support than those who did not need it. Chen et al. also observed abnormal coagulation results, especially markedly elevated D-dimer in deaths due to COVID-19. Zhou et al. conducted a retrospective study involved 191 patients with COVID-19 and found that D-dimer levels >1000 μg/L on admission were associated with in-hospital death. In our study, the value of D-Dimer was lower as compared to the earlier studies as even asymptomatic patients who were COVID-19 positive were admitted and underwent complete evaluation.
However, these previous studies did not provide a well-evaluated cutoff for D-dimer and suffered from the lacunae of not using SI units, the methodology of testing for D-dimer, there was no clarity on the use of DDU or FEU which are SI units for quantitative analysis of D-dimer. These lacunas were also brought out by the mini-review of 26 D-dimer studies in COVID-19 by Favaloro and Thachil.
It is also well known that intermethodology variation in D-dimer testing cannot be standardized, but our results can surely contribute to harmonize the data of D-dimer in COVID-19 patients and benefit future management of these patients. The recent guidance issued by the ISTH on risk assessment and management of coagulopathy in COVID 19 has arbitrarily defined D dimer levels at admission as three four folds increase from baseline and does not provide an actionable cut-off value. This was due to the variability involved in testing methods and different SI units used by the various studies.
Elevated D-dimer levels in COVID-19 patients indicate a hypercoagulable state which may be attributed to aggressive inflammatory response associated with a dysregulated or limited anti-inflammatory response leading to impending cytokine storm. The inflammatory response causes endothelium activation resulting in excess thrombin generation with activation of the coagulation pathway and later the fibrinolytic pathway leading to D-dimer generation. The virus primarily affects the pulmonary vasculature leading to hypoxemia and induction of hypoxia-inducible transcription factor-dependent signaling pathway. The formation of microthrombi and the presence of megakaryocytes have also been confirmed on autopsy findings in the lungs of deceased COVID-19 patients. Any underlying comorbidity and superinfection may also induce sepsis-induced coagulopathy or disseminated intravascular coagulation in these patients.
In the current study, we determined a clear cutoff value 857.9 μg/L (FEU) which was established by ROC curve analysis, which amounts to a nearly two-fold increase for D-dimer from our routine laboratory normal range for adult patients. Notably, in our study, the 10 nonsurvivors with D-dimer ≥857.9 μg/L (FEU), 4 of whom had no severity symptoms or comorbidities on admission. Thus, patients who have raised D-dimer at baseline 857.9 μg/L (FEU) require admission to the hospital and close monitoring even in the absence of other severity symptoms.
The D-dimer evaluation which is due to the common link between inflammatory and coagulation pathways may lack specificity, but this limitation can be overcome by its sensitivity which was 100% in predicting mortality in our study and 93% in predicting ICU admissions, thus D-dimer can be used in predicting prognosis and outcome of COVID-19 patients. D-dimer also offers an opportunity as an important prognostic marker in a sea of biochemical and hematological parameters to predict the outcome of COVID-19 patients.
Limitation of the study
Our study has a limitation of a small sample size with a limited number of cases and may have selection bias because it was a single-center, retrospective study, even if it had sufficient power to detect the significant differences between favorable and adverse outcome groups.
Even with the above-mentioned limitations, it is still the first study from eastern India to establish a cutoff value of D-dimer using FEU, SI units to harmonize the data available on D-dimer values in COVID-19 patients in predicting the outcome of patients.
| Conclusion|| |
D-dimer on admission >857.9 μg/L (FEU) could effectively predict ICU admission and also mortality in our patients with COVID-19, which indicates D-dimer can be used as an early and a helpful marker to more closely monitor and provide early intervention in admitted patients of COVID-19. This will help in the on-going endeavor to reduce mortality in these patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Eurosurveillance Editorial Team. Note from the editors: World Health Organization declares novel coronavirus (2019-nCoV) sixth public health emergency of international concern. Euro Surveill. 2020 Feb;25(5):200131e. doi: 10.2807/1560-7917.ES.2020.25.5.200131e. Epub 2020 Jan 31. PMID: 32019636; PMCID: PMC7014669.
Mullen L, Potter C, Gostin LO, Cicero A, Nuzzo JB. An analysis of International Health Regulations Emergency Committees and Public Health Emergency of International Concern Designations. BMJ Glob Health. 2020 Jun;5(6):e002502. doi: 10.1136/bmjgh-2020-002502. PMID: 32546587; PMCID: PMC7299007.
WHO Coronavirus Disease (COVID-19) Dashboard. CEST; July 30, 2020. Available from: https://covid19.who.int/
. [Last accessed on 2020 Oct 13].
Helmy YA, Fawzy M, Elaswad A, Sobieh A, Kenney SP, Shehata AA, et al.
The COVID-19 pandemic: A Comprehensive review of taxonomy, genetics, epidemiology, diagnosis, treatment, and control. J Clin Med 2020;9:1225.
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-coV-2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Med 2020;46:586-90.
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.
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.
McGonagle D, O'Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol 2020;2:e437-e445.
Lippi G, Favaloro EJ. D-dimer is associated with severity of coronavirus disease 2019: A Pooled analysis. Thromb Haemost 2020;120:876-8.
Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, Zhang Z. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. Journal of Thrombosis and Haemostasis. 2020;18:1324-9.
Soomro AY, Guerchicoff A, Nichols DJ, Suleman J, Dangas GD. The current role and future prospects of D-dimer biomarker. Eur Heart J Cardiovasc Pharmacother 2016;2:175-84.
Mosesson MW. Terminology for macromolecular derivatives of crosslinked fibrin. On behalf of the subcommittee on fibrinogen of the scientific and standardization committee of the ISTH. Thromb Haemost 1995;73:725-6.
Paliogiannis P, Mangoni AA, Dettori P, Nasrallah GK, Pintus G, Zinellu A, et al.
D-dimer concentrations and COVID-19 severity: A Systematic review and meta-analysis. Front Public Health 2020;8:432.
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. Br Med J 2020;368:m1091.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al.
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.
Favaloro EJ, Thachil J. Reporting of D-dimer data in COVID-19: Some confusion and potential for misinformation. Clin Chem Lab Med 2020;58:1191-9.
Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: A Comment. J Thromb Haemost 2020;18:2060-63.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al.
COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.
Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al.
Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8.
Colantuoni A, Martini R, Caprari P, Ballestri M, Capecchi PL, Gnasso A, et al.
COVID-19 sepsis and microcirculation dysfunction. Front Physiol 2020;11:747.
Fox SE, Akmatbekov A, Harbert JL, Li G, Brown JQ, Vander Heide RS. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. The Lancet Respiratory Medicine. 2020 Jul 1;8(7):681-6.
Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al
. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020;18:1023-6.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]