Hematology

D-Dimer as a potential biomarker for disease severity in COVID-19

a b s t r a c t

Introduction: This study seeks to determine the utility of D-dimer levels as a biomarker in determining disease severity and prognosis in COVID-19.

Methods: Clinical, imaging and laboratory data of 120 patients whose COVID-19 diagnosis based on RT-PCR were evaluated retrospectively. Clinically, the severity of COVID-19 was classified as noncomplicated or mild or severe pneumonia. Radiologically, the area of affected lungs compatible with viral pneumonia in each patient’s com- puted tomography was classified as either 0-30% or >= 31% of the total lung area. The D-dimer values and labora- tory data of patients with COVID-19 were compared with inpatient status, duration of hospitalization, and lung involvement during treatment and follow-up. To assess the predictive value of D-dimer, receiver operating char- acteristic (ROC) analysis was conducted.

Results: D-dimer elevation (> 243 ng/ml) was detected in 63.3% (76/120) of the patients. The mean D-dimer value was calculated as 3144.50 +- 1709.4 ng/ml (1643-8548) for inpatients with severe pneumonia in the inten- sive care unit. D-Dimer values showed positive correlations with age, duration of stay, lung involvement, fibrin- ogen, Neutrophil count, neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR). When the threshold D-dimer value was 370 ng/ml in the ROC analysis, this value was calculated to have 77% specificity and 74% sensitivity for lung involvement in patients with COVID-19.

Conclusion: D-Dimer levels in patients with COVID-19 correlate with outcome, but further studies are needed to see how useful they are in determining prognosis.

(C) 2020

  1. Introduction

The World Health Organization officially named the novel coronavi- rus pneumonia (NCP) coronavirus disease 2019 (COVID-19) [1]. The first COVID-19 case in Turkey was detected on March 11, 2020 [2]. The clinical findings of COVID-19 are generally reported as high fever, weakness, Muscle pain, dry cough and shortness of breath [2,3]. Lab markers can vary, with lymphopenia and thrombocytopenia observed in severe cases [3,4]. The diagnosis of 2019-novel coronavirus can be made by reverse-transcriptase polymerase-chain reaction (RT-PCR). computed tomography findings include peripheral ground glass densities in which multilobar, lower lobes and posterior segments are retained and sometimes accompanied by subsegment patchy consolida- tions [5]. Coagulopathy is present in COVID-19, and 81% of nonsurviving patients have been reported to have D-dimer levels higher than 1 ng/ml.

* Corresponding author at: Department of Emergency Medicine, Pamukkale University Hospital, Pamukkale University of Medical Sciences, 20070 Kinikli/Denizli, TR, Turkey.

E-mail address: [email protected] (A. Yilmaz).

[4,6]. In patients with severe community-acquired pneumonia and chronic obstructive pulmonary disease (COPD), the D-dimer level is reported to be high, functioning as a Prognostic biomarker [7,8]. This study seeks to determine the utility of D-dimer levels as a bio- marker in determining disease severity and prognosis in COVID-19.

  1. Methods
    1. Study group

Our study was approved by the institutional ethics committee of Pamukkale University. COVID-19 patients were assessed retrospectively after their diagnosis was confirmed by RT-PCR in the emergency depart- ment (ED) of Pamukkale University, which was the primary center des- ignated for the treatment of COVID-19 patients in Denizli between March 15 and April 30, 2020. The diagnosis and treatment of these pa- tients were performed in line with the Novel Coronavirus Pneumonia Diagnosis and treatment guidelines (Apr 14. Ed.) published by the Na- tional Health Commission of Turkey [9]. Those with oncological,

https://doi.org/10.1016/j.ajem.2020.12.023

0735-6757/(C) 2020

hematological, chronic liver and kidney diseases, pregnancy or surgery or trauma in the last 4 weeks were excluded from the study. A standard- ized abstraction tool was created for data collection of demographic

Table 1

Clinical classification of COVID-19 patients included in the study

Non-complication group Mild group Severe group

characteristics, comorbidities, imaging, and the results of the laboratory tests of the enrolled patients. All the above-stated data were gathered from an electronic medical records network utilized by our institutional system. We contacted 5 participants and their physicians to fill out the missing values required for the study; thus, no data were missing during the study. The interrater reliability rate was not calculated since this clinical trial was a single-blind study. Data on demographic characteris- tics, comorbidities, imaging, and results of the laboratory tests of en- rolled patients were collected from an electronic medical records network used by our institution’s system. The charts were reviewed and analyzed by a radiologist and three emergency medicine doctors. Before starting this study, an extensive study plan was constructed. No preliminary trials were required. Demographic, clinical, imaging, and laboratory data of 120 patients aged between 18 and 99 (71 males, 49 females, median 45 years, mean 48.61 +- 19.22 years) whose COVID-

19 diagnosis was validated by the rt-PCR test were evaluated retrospectively.

    1. Laboratory data analysis

Peripheral blood sampling was performed for COVID-19 patients’ complete blood count and biochemical and coagulation parameters. White blood cell count and neutrophil, lymphocyte, monocyte and

      1. patients reported symptoms such as fever, muscle / joint pain, cough, sore throat and nasal congestion without respiratory distress, tachypnea or

SPO2 < 93%,

      1. patients without comorbidities such as cardiovascular diseases, type 2 diabetes mellitus, hypertension, cancer, chronic lung diseases or other immunosuppressive conditions or under

50 years of age

      1. patients with normal chest radiography or thoracic tomography.

2.5. Statistics

  1. patients reported symptoms such as fever, muscle / joint pain, cough, sore throat and nasal congestion, with a respiratory rate < 30 / minute, SpO2 level above 90% in the room air.
  2. patients with signs of pneumonia on chest radiography or thoracic tomography.
  3. patients reported symptoms such as fever, muscle / joint pain, cough, sore throat and nasal congestion, respiratory distress, tachypnea (>=30 / minute) or SpO2 level in room air is below 90%
  4. patients with signs of pneumonia on chest radiography or thoracic tomography or patient with acute organ dysfunction.

platelet counts in the complete blood count were recorded for the study. In the biochemical analysis of patients, D-dimer values were recorded with coagulation parameters. The type of D-dimer utilized is D-dimer units (DDU), and the D-dimer level was tested through an immunoturbidimetric assay within the reference range of 0-243 ng/ml in our clinical laboratory. These laboratory data were compared with the inpatient status during the treatment and follow-up periods and with inpatient department and length of stay if hospitalization was required.

    1. Imaging

The computerized tomography scanners were a 16-slice helical CT scanner (Brilliance; Philips Medical Systems, Cleveland, OH, USA) and a 2-slice helical CT scanner (GE Brivo, Milwaukee, USA), both of which were operated only for COVID-19 patients during the pandemic period by taking the required disinfection and isolation measures. CT examina- tions were carried out between the patient and the shooting technician without resorting to intravenous contrast media by following social dis- tance and isolation measures. CT images of all the patients were evaluated on the workstation in mediastinal (WW: 350, WL: 50) and parenchymal (WW: -600, WL: 1600) window settings by a board-certified radiologist. CT examination was performed in all COVID-19 patients by following the isolation rules. For the subjects in whom D-dimer elevation was detected in the absence of typical clinical signs of pulmonary embolism (PE), venous Doppler ultrasound examination was performed to investi- gate Deep vein thrombosis , frequently found in the etiology of D-dimer elevation. When PE was suspected, a contrast-enhanced CT angi- ography scan was performed following the CT scan. Doppler ultrasound was preferred only for patients with High clinical suspicion of PE/DVT.

Clinically, the severity of COVID-19 was classified as noncomplicated or mild or severe pneumonia under the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidelines (4th Ed.) by the National Health Commission of Turkey (Table 1) [9]. Radiologically, the area of affected lungs consistent with viral pneumonia in each patient’s first chest CT after admission was measured and classified into 0-30% (common type) or >= 30% (severe-critical type) of the total lung area [10].

Continuous data with a normal distribution and homogeneity of var- iance are expressed as the mean +- SD and were compared by indepen- dent samples t-tests. Categorical variables are expressed as numbers (percentages) and were compared by chi-square tests. To assess the predictive value of D-dimer, receiver operating characteristic (ROC) analysis was conducted with calculations of the area under the ROC curve (AUC), sensitivity, and specificity. The statistical analyses were run in SPSS 21 for Windows (Chicago, IL), and a p value less than 0.05 was considered statistically significant.

  1. Results

A total of 120 subjects diagnosed with COVID-19 between March 15 and April 30, 2020 were classified clinically and radiologically. A total of 67.5% of the patients were afflicted with at least one comorbid condi- tion, including hypertension (31.7%), type 2 diabetes mellitus (15%), coronary artery disease (12.5%), and chronic kidney injury (8.3%). Seventy-three patients (60.8%) were hospitalized and followed-up in the COVID-19 service, while 18 patients (15%) were hospitalized in the intensive care unit. The average length of hospital stay was 9.09 (2-35) days. Twenty-nine patients were followed-up at home through contact tracing by recommending compliance with isolation conditions (Table 2).

Table 2

Study group descriptive features

N

%

Gender

Female

49

40,8

Male

71

59,2

Inpatient Groups

0-5 Days

26

28,6

6-10 Days

39

42,9

11 Days and more

26

28,6

Inpatient Department

No

29

24,2

Service

73

60,8

ICU

18

15,0

CT Scan

Performed

15

12,5

Unperformed

105

87,5

Involvement Group

Under 30%

74

70,5

Over 30%

31

29,5

N = Number of patient, CT = Computerized Tomography, ICU=Intensive care unit.

The patients were clinically divided into three groups: noncompli- cated, mild and severe pneumonia. Of 120 patients included in the study, 24.2% (29/120) were identified as noncomplicated, 60.8% (73/120) as mild, and 15% (18/120) as severe. D-Dimer elevation (> 243 ng/ml) was detected in 63.3% (76/120) of the patients, and this rate tended to increase as their clinical condition worsened. The mean D-dimer value was calculated as 3144.50 +- 1709.4 ng/ml (1643-8548) for inpatients with severe pneumonia in the intensive care unit. Furthermore, thorax CT results were obtained from 105 pa- tients included in the study. Accordingly, 70.5% (74/105) of the patients suffered lung involvement <30%, while 29.5% (31/105) had lung in- volvement >30%. In the patients with severe lung involvement, there were significant differences between D-dimer, fibrinogen, neutrophil, and lymphocyte levels compared with those with mild or no involve- ment. Similarly, significant differences were observed between the patients in the intensive care unit and those without intensive care unit hospitalization in terms of D-dimer, fibrinogen, neutrophil, and lymphocyte levels. Lung involvement and length of hospital stay were significantly higher in older patients than in their younger counterparts (Table 3) (Figs. 1-3).

Yes

Mean +- SD

63.89 +- 16.18

8.47 +- 5.11

p

Med (min – max)

44 (18-100)

1 (0-11)

Med (min – max)

64.5 (37-87)

8 (0-20)

0.0001? ?

0.0001? ?

265 (39-1596)

324.5 (173-1008)

5.42 (2.43-12.18)

1.63 (0.51-4.27)

245 (145-426)

3144.5 +- 1709.4

508.29 +- 189.54

10.72 +- 5.97

1.21 +- 0.59

237.17 +- 73.82

2706 (1643-8548)

503.5 (167-906)

9.29 (5.25-27.87)

1.17 (0.45-2.47)

246.5 (112-365)

0.0001??

0.048? ?

0.0001? ?

0.007? ?

0.337 ?

D-Dimer values were concluded to be positively correlated with age, length of stay, lung involvement, fibrinogen, and neutrophil count but negatively correlated with lymphocyte count (Table 4).

When the threshold D-dimer value was set as 370 ng/ml in the ROC analysis, this value for any lung involvement was calculated to have a specificity of 77% and a sensitivity of 74% in COVID-19 patients. When the threshold D-dimer value was 370 ng/ml, the area under the ROC curve (Az) was 0.813 (95% confidence interval, 0.722-0.904) (Fig. 4). The positive likelihood ratio was 3.2, and the negative likelihood ratio was 0.34.

ICU

No

Mean +- SD

45.91 +- 18.51

2.56 +- 3.43

0.0001? ?

0.0001? ?

0.0001? ?

0.035 ?

0.061 ?

0.0001? ?

0.265 ?

340.71 +- 258.55

410.18 +- 214.49

5.94 +- 2.24

1.69 +- 0.74

252.13 +- 58.09

  1. Discussion

p

This is a single-center, retrospective study focusing on cases who presented to a tertiary hospital and were diagnosed with SARS-CoV-2 by means of RT-PCR. This cohort study seeks to determine the utility of D-dimer levels as a biomarker in determining disease severity and prognosis in COVID-19. In hemostasis, the formation of fibrin clots in re- sponse to vascular damage from the coagulation system is balanced by the breakdown of coagulation by the fibrinolytic system. D-Dimer is a fi- brin degradation product resulting from the sequential cleavage of the fibrinogen formed in the coagulation system by the fibrinolytic system.

Over 30% Mean +- SD

60.29 +- 18.91

11.97 +- 7.47

Med (min – max)

43 (21-85)

6.5 (3-21)

Med (min – max)

62 (23-100)

10.5 (2-35)

237 (39-2714)

298 (173-1008)

5.57 (2.46-12.18)

1.73 (0.51-3.88)

244 (145-384)

1636.1 +- 1932.22

479.17 +- 175.78

7.95 +- 5.15

1.21 +- 0.54

239.13 +- 66.18

732 (66-8548)

458.5 (167-906)

6.23 (2.43-27.87)

1.14 (0.45-2.67)

250 (112-356)

ICU=Intensive care unit.

* p < 0.05 statistically significant; ?: Inpendent samples t-test; ?: Mann Whitney U test.

Image of Fig. 1

Fig. 1. Box plot chart showing the D-dimer value relationship according to patient hospitalization.

Table 3

Relation of lung involvement and ICU hospitalization with other variables

Lung involvement

Under 30% Mean +- SD

45.26 +- 17.48

7.26 +- 3.53

Age

Length of stay Lung involvement D-dimer Fibrinogen Neutrophil Lymphocyte Platelet

378.2 +- 453.62

401.97 +- 223.04

6 +- 2.25

1.75 +- 0.71

253.18 +- 54.88

Image of Fig. 2

Fig. 2. Box plot chart showing the D-dimer value relationship by length of hospital stay.

Image of Fig. 3

Fig. 3. Box plot chart showing the D-dimer value relationship with lung involvement in CT.

It is generally involved in the diagnostic algorithm of thrombosis and thrombosis-conditioned pathologies (DVT, PE, to name a few). How- ever, D-dimer elevation can be observed physiologically or pathologi- cally, as in Malignant diseases, Chronic liver diseases, postoperative conditions, pregnancy and inflammation and infection conditions. Our study revealed that D-dimer elevation was common among patients di- agnosed with COVID-19 and associated with disease severity.

Even though PE/DVT was not diagnosed in our patients, D-dimer el- evation was observed in 61.7%. D-Dimer was not previously considered a biomarker in viral or Bacterial pneumonia. D-Dimer has recently been reported to be elevated in patients diagnosed with COVID-19, and there

are many studies that suggest correlations with D-dimer elevation and disease severity. Examining 41 COVID-19 patients clinically and through laboratory tests, Huang et al. reported that those with severe conditions had D-dimer values 5 times higher than those of the other patients [11]. In another study with 183 COVID-19 patients, Tang et al. concluded that the D-dimer level was approximately 3.5 times higher in patients with severe conditions than in their nonsevere counterparts [12]. In a retro- spective study by Yao et al. analyzing the clinical and radiological find- ings of 248 COVID-19 patients in a hospital in Wuhan, they reported that D-dimer levels were significantly higher in patients with severe conditions than in other patients [13]. In another study, Yu et al. con- cluded that D-dimer levels were significantly elevated in 57 patients with confirmed COVID-19 pneumonia and in 46 patients with con- firmed community-acquired bacterial pneumonia (CAP) and that D-dimer was elevated to higher levels in COVID-19 patients [14].

As far as the aforementioned studies are concerned, the D-dimer levels of patients with severe conditions were reported to be signifi- cantly higher than those of mild and moderate patients. Given the most recent data in the literature, D-dimer values are frequently in- creased in 36-43% of COVID-19 patients [15]. In our study, we observed clinically and radiologically that patients with more extensive pneumo- nia manifested higher D-dimer levels than those without or with less extensive pneumonia. Our results suggest that D-dimer levels may as- sist in assessing severity and morbidity in the COVID-19 pandemic.

Pathological features of COVID-19 include alveolar damage, desqua- mation of pneumocytes, hyaline membrane formation, pulmonary edema and interstitial mononuclear inflammatory leaks. Disorders in the hemostasis cascade coupled with increased inflammatory load and hyperfibrinolysis lead to elevated D-dimer levels and greater lung in- volvement [16,17]. Patients with high D-dimer levels have longer hospi- talizations in intensive care units and lengths of hospital stay [6].

In COVID-19, lymphocytes are decreased and neutrophils are in- creased among patients who suffer from severe symptoms clinically and radiologically and manifest lung findings due to increased serum cytokines and chemokines [18,19].

Qu et al. suggested that age and Platelet levels of COVID-19 inpa- tients correlated positively with the length of hospital stay but nega- tively with lymphocyte levels [20]. Patients with severe pneumonia who were in the intensive care unit had D-dimer levels that were twice those of other patients.

In the report by Aggarwal et al., 16 patients with a definitive diagno- sis of COVID-19 were included. The clinical and Laboratory features of these patients were examined. In their study, which did not analyze D-dimer values, chest CT was performed in 44% of the patients (7 pa- tients), and multifocal ground-glass opacity was observed in all of them. In our study, chest CT was performed in 87.5% (105/120) of the patients, and only 29.5% (31/105) of them manifested lung involvement above 30%. This can be explained by the general condition of most pa- tients included in the study of Aggarwal et al., who needED intensive care units and mechanical ventilation [21].

    1. Limitations

We realize that several limitations might have influenced the results obtained in our study. First, since this is a retrospective study, the results and clinical follow-ups were accessed from the hospital registration

Table 4

Correlation between D-dimer and variables

Age

Length of stay

Lung involvement

Fibrinogen

Neutrophil

Lymphocyte

D-dimer

R

0.422??

0.254?

0.416??

0.407??

0.481??

-0.535??

p

0.000

0.015

0.000

0.002

0.000

0.000

*p < 0.05; **p < 0.01 statistically significant; spearman correlation Coefficient.

Image of Fig. 4

Fig. 4. The D-dimer value for lung involvement was 370, and the area under the ROC curve (Az) was 0.813 (95% confidence interval, 0.722-0.904).

system without seeing the patients; thus, additional laboratory examina- tions could not be conducted. Second, only the clinically suspected pa- tients among the study population were taken into consideration for PE/ DVT. Third, the follow-up of our patients’ CT findings could not be re- peated in terms of radiation exposure. Fourth, data on the intubation sta- tus of the patients, their health status after discharge, and their survival status could not be obtained. Fifth, a single reviewer abstracted the data. Sixth, this study utilized early generation CT scanners, rather than later generation CT scanning technology. Finally, the findings presented in this study were obtained only from a limited number of patients present- ing to the ED.

  1. Conclusion

Our findings suggest that the severity of COVID-19 pneumonia is closely associated with D-dimer levels, which tended to increase as the clinical or radiological conditions of patients with COVID-19 wors- ened. We are of the opinion that D-dimer levels in patients with COVID-19 correlate with outcome, but further studies are needed to see how useful they are in determining prognosis.

Author contribution statement

1-Study concept and design: M.O. and A.Y. 2-Acquisition of data: M.O., A.Y., A.O., M.S., and R.B. 3-Analysis and interpretation of data: H.S., A.Y., and V.C. 4-Drafting of the manuscript: M.O. and A.Y. 5-Critical revision of the manuscript for important intellectual content: M.O., A.Y., A.O., M.S., and R.B. 6-Statistical analysis: H.S., A.Y. and V.C. 7-Administrative, technical and material support: A.O., M.S., and R.B. 8-Study supervision: M.O., A.Y., and V.C.

Compliance with ethical standards

Pamukkale University Faculty of Medicine Ethics Committee was ap- proved for the study.

Declaration of Competing Interest

The authors declare that they have no conflicts of interest and no grants or funds were received in this study.

References

  1. WHO. WHO Director-General’s remarks at the media briefing on 2019-nCoV on 11 February 2020. https://www.who.int/dg/speeches/detail/who-director-general-s- remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 (WHO, 11 Feb- ruary 2020).
  2. Turkish Government. Ministry of Health. Available from: https://covid19.saglik.gov. tr/; 2020.
  3. Ei Azhar, Hui DSC, Memish ZA, Drosten C, Zumla A. The Middle East respiratory syn- drome (MERS). Infect Dis Clin North Am. 2019;33:891-905.
  4. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical char- acteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a de- scriptive study. Lancet. 2020;395:507-13.
  5. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease. (COVID-19): a systematic review of imaging findings in 919 patients. AJR Am J Roentgenol. 2019;2020:1-7.
  6. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mor- tality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-62.
  7. Querol-Ribelles JM, Tenias JM, Grau E, Querol-Borras JM, Climent JL, Gomez E, et al. Plasma d-dimer levels correlate with outcomes in patients with community- acquired pneumonia. Chest. 2004;126:1087-92.
  8. Snijders D, Schoorl M, Schoorl M, Bartels PC, van der Werf TS, Boersma WG. D-dimer levels in assessing severity and clinical outcome in patients with community- acquired pneumonia. A secondary analysis of a randomised clinical trial. Eur J Intern Med. 2012;23:436-41.
  9. COVID-19. (Sars-Cov-2 ENFEKSIYONU) Rehberi. 14 April 2020. Available from. https://covid19bilgi.saglik.gov.tr/depo/rehberler/COVID-19_Rehberi.pdf.
  10. 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.
  11. Chinese society of Radiology. Chinese Medical Association Radiology Branch. Radio- logical diagnosis of novel coronavirus pneumonia: expert recommendations from Chinese society of radiology. Chin J Radiol. 2020;54:279-85.
  12. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844-7.
  13. Yao Y, Cao J, Wang Q, Liu K, Luo Z, Yu K, et al. D-dimer as a biomarker for disease se- verity and mortality in COVID-19 patients: a case control study. Critical Care & Emer- gency Medicine; 2020. https://doi.org/10.21203/rs.3.rs-20850/v1.
  14. Yu B, Li X, Chen J, Ouyang M, Zhang H, Zhao X, et al. Evaluation of variation in D- dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis. Journal of thrombosis and thrombolysis. J Thromb Thrombolysis. 2020:1-10 Avail- able from https://doi.org/10.1007/s11239-020-02171-y.
  15. Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med. 2020. https://doi.org/10.1515/cclm-2020-0198.
  16. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420-2.
  17. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39:529-39.
  18. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020;7:91.96.:91-6 ciaa248.
  19. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospi- talized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020. https://doi.org/10.1001/jama.2020.1585.
  20. Qu R, Ling Y, Zhang YH, et al. Platelet-to-lymphocyte ratio is associated with progno- sis in patients with coronavirus disease-19. J Med Virol. 2020. https://doi.org/10. 1002/jmv.25767.
  21. Aggarwal S, Garcia-Telles N, Aggarwal G, Lavie C, Lippi G, Henry BM. Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States. Diagnosis. 2020;7: 91-6.