Respiratory Medicine

Relationship of platelet counts, platelet volumes, and Curb-65 scores in the prognosis of COVID-19 patients

a b s t r a c t

Objectives: This study investigated the relationship between 28-day mortality in patients with COVID-19 pneu- monia and the CURB-65 score, platelet count (PLT), Mean platelet volume , and MPV/PLT ratio (MPR). Methods: A total of 247 patients with COVID-19 pneumonia who presented to the emergency department be- tween March 15, 2020 and May 15, 2020 were retrospectively analyzed. The age, gender, clinical presentation, history of chronic disease, thoracic computed tomography findings, MPV, PLT, MPR, CURB-65 scores, and 28- day mortality of patients were recorded.

Results: The patients had a mean age of 51 years (IQR: 39-63 years) and 55.5% were females. The most common symptom was cough (30.4% of patients). The most common comorbidity was hypertension (13.4%), 49.8% of the cases showed intermediate involvement, and 7.7% of patients died within the first 28 days. The mean MPV was

9.71 +- 1.15, the mean PLT was 226.68 +- 83.82, and the mean MPR was 0.056 +- 0.12. There were significant cor- relations of 28-day mortality with the CURB-65 score, MPV, and MPR levels (p = 0.000, p = 0.034, and p = 0.034, respectively). No significant correlation was found between the PLT count and 28-day mortality (p = 0.105). Conclusions: In addition to the CURB-65 score, MPV and MPR values can be used to predict 28-day mortality in patients with COVID-19 pneumonia.

(C) 2021

  1. Introduction

COVID-19 was declared as a pandemic by the World Health Organi- zation (WHO) [1]. The main presenting symptoms of COVID-19 are fever, cough and shortness of breath [2]. The clinical course and causa- tive microorganisms are different between COVID-19 pneumonia and community-acquired pneumonia . COVID-19 pneumonia has a viral origin and can rapidly cause acute respiratory distress syndrome.

Although Polymerase chain reaction is the standard diagnostic test for COVID-19, laboratory findings are important for confirming the diagnosis. Since COVID-19 is a dynamic disease that can lead to unex- pected outcomes, laboratory findings are critical to assess the progres- sion of COVID-19 and guide Treatment interventions [3]. As such, it may be helpful that parameters checked upon admission have predic- tive value for COVID-19 Disease progression and mortality.

* Corresponding author at: Emergency Medicine Specialist, University of Health Sciences Turkey, Bursa Yuksek Ihtisas Training and Research Hospital, Emergency Department, Turkey

E-mail address: [email protected] (Y. Isler).

1 Postal address: Yuksek Ihtisas Training and Research Hospital, Emergency Department, Mimar Sinan Mah. Emniyet Cad. Polis Okulu Karsisi Yildirim, Bursa, Turkey.

During the progression of COVID-19, some Blood parameters have been reported to decrease significantly, while others increase signifi- cantly [4]. The laboratory abnormalities predominantly found included hypoalbuminemia, elevated inflammatory markers, such as C reactive protein, lactate dehydrogenase, and erythrocyte sedimentation rate, among others. The frequency of lymphopenia found suggests that COVID-19 might act on lymphocytes, especially T lymphocytes, as does SARS-CoV, may be including.

Gorelik et al. demonstrated that the increase in mean platelet vol- ume (MPV) strongly predicts in-hospital and long-term mortality [5]. Golcuk et al. also found that MPV is valuable for predicting mortality and disease severity at admission in patients with CAP [6]. COVID-19 pneumonia differs from CAP in terms of its features, but MPV remains a useful prognostic indicator for critically ill COVID-19 patients [7]. However, some studies showed a negative correlation between the MPV and platelet count (PLT) in severe COVID-19 patients [8].

It has also been reported that the combination of MPV and PLT may be clinically more significant than either parameter individually [8,9]. Inexpensive, accessible, and widely used laboratory tests of the severity of COVID-19 are important. MPV and PLT counts are widely and rou- tinely used in clinical practice. The CURB-65 score can also be easily cal- culated in the emergency department. To our knowledge, there are no studies investigating the diagnostic value of the CURB-65 score, PLT, or

https://doi.org/10.1016/j.ajem.2021.11.010

0735-6757/(C) 2021

MPV/PLT ratio (MPR) for COVID-19-associated mortality. Therefore, this study investigated whether the CURB-65 score, PLT count, MPV, and MPR are associated with 28-day mortality in COVID-19 pneumonia.

  1. Material and methods

A retrospective analysis of 7.138 patients who presented to the emergency department of the Bursa Yuksek Ihtisas Training and Re- search Hospital between March 15, 2020 and May 15, 2020 was con- ducted. Of these patients, 5.517 with a negative PCR, and 1.621 with a positive PCR but no evidence of COVID-19 pneumonia were excluded from the study. Accordingly, a total of 247 patients were included. Ap- proval was obtained from the ethics committee of the hospital during the planning stage of the study (2011-KAEK-25 2020/05-20).

Patient information was gathered from the hospital automation sys- tem and patient files. The assessment of the patients and files were made by 2 emergency medicine specialists and 2 emergency medical as- sistants who completed 2 years of training.

State chart abstractors were trained in chart abstraction prior to data collection, and the abstractors were not aware of the Study objectives. The abstractors used the hospital information management system to obtain data, which were collected on data abstraction forms. Abstractor performance was monitored. However, interobserver reliability was not assessed.The study was carried out in accordance with the principles of the Declaration of Helsinki. All data pertaining to the study were ob- tained from electronic hospital records. (Hospital Information Manage- ment System).

The sampling method was described as retrospective study. Age, gender, clinical presentation, chronic disease history, computerize to- mography (CT) findings, and 28-day mortality were recorded. COVID- 19 pneumonia imaging findings of patients with CT were evaluated by the radiologist according to the Expert Consensus Statement on the Reporting of COVID-19-Related Chest CT Findings of the North American Society of Radiology [10].

MPV, PLT and MPR were calculated according to hemogram exami- nations performed during the first evaluation in the emergency depart- ment. CURB 65 was calculated the patients age, vital signs (respiratory rate and blood pressure), biochemistry analysis (blood urea nitrogen) and confusion. Missing data were excluded. The final diagnosis and hos- pitalization information were recorded, and the 28-day mortality rate was calculated.

Inclusion and exclusion criterias: Patients over 18 years of age and with a positive PCR, and evidence of

COVID-19 pneumonia were included the study.

Patients under 18 years of age, and those who were pregnant, had a negative PCR result, or had no signs of pneumonia on CT data were excluded from the study.

    1. Statistical analysis

Data were analyzed using SPSS 22.0 software for Windows (SPSS Inc., Chicago, IL, USA). Descriptive statistics are expressed as means +- standard deviation or median values, while categorical variables are expressed as numbers and percentages (%). The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of the data. The Mann-Whitney U and Kruskal-Wallis tests were used to evaluate significant differences in continuous numerical variables between the groups, because the assumptions of parametric tests were not met. spearman correlation analysis was used to investigate the relationships of the CURB-65 score with the other parameters. The Chi-square test and Fisher’s exact test were used to determine the relationships of cat- egorical variables. Variables considered useful for predicting mortality were included in a logistic regression model using the “enter” method. A Receiver operating characteristic curve analysis was performed to determine the diagnostic value of the MPR value for predicting

Table 1

Clinical and demographic data of the patients.

n

%

Gender Female

137

55.5

Male

110

44.5

Fever No

181

73.3

Yes

66

26.7

No

172

69.6

Cough Yes

75

30.4

Sore throat No

234

94.7

Yes

13

5.3

Diarrhea No

232

93.9

Yes

15

6.1

Weakness No

233

94.3

Yes

14

5.7

Dyspnoea No

221

89.5

Yes

26

10.5

Loss of smell-taste No

219

88.7

Yes

28

11.3

Joint pain No

206

83.4

Yes

41

16.6

Comorbidities No

173

70

Yes

74

30

HT No

214

86.6

Yes

33

13.4

DM No

224

90.7

Yes

23

9.3

COPD /ASTHMA No

227

91.9

Yes

20

8.1

No

236

95.5

CAD Yes

11

4.5

Malignancy Yok

241

97.6

Var

6

2.4

Atypical

29

11.7

Pneumonia Intermediate

123

49.8

Typical

95

38.5

Yes

19

7.7

28-day mortality No

228

92.3

Total

247

100

HT: Hypertension, DM: Diabetes Mellitus, COPD: Chronic Obstructive Pulmonary Disease, CAD: Coronary Artery Disease.

28-day mortality. A p-value < 0.05 was considered statistically signifi- cant. The 95% confidence intervals (CIs) were also calculated.

  1. Results

A total of 247 patients with positive PCR results for COVID-19 were included in the study. The median patient age was 51 years (IQR: 39-63). There were 137 (55.5%) females in the study. Cough was the most common symptom (n = 75, 30.4%). Of the 247 patients, 74 (30%) had comorbidities, among which hypertension (HT) was the most common (n = 33, 13.4%). CT revealed intermediate involvement in 123 (49.8%) of patients with pneumonia. While 15 patients (6.1%) died within the first 14 days, 19 (7.7%) died within the first 28 days. Pa- tients vital signs, clinical and demographic data are shown in Tables 1 and 2.

The average MPV of patients was 9.71 +- 1.15 fL, the mean platelet level was 226.68 +- 83.82 uL, and the mean MPR was 0.056 +- 0.12 fL/uL. The Mann-Whitney U test was performed to investigate whether there were relationships among the CURB-65 score, MPV, PLT, and

Table 2

Age, clinical and laboratory data.

Age, Median (IQR 25-75) 51 (36-93)

Respiration Rate, Median (IQR 25-75) 16 (14-20) Temperature, Mean +- Standard Deviation 36.05 +- 0.74 Diastolic Blood Pressure, Median (IQR 25-75) 106(90-122) Systolic Blood Pressure, Median (IQR 25-75) 154 (136-158) SPO2 Mean +- Standard Deviation 92.52 +- 5.65

SPO2: Oxygen saturation.

Table 3

28-day mortality analysis of variables.

28-day mortality

n

Median (IQR: 25-75)

p value

CURB-65

No

228

0 (0-1.0)

<0.001?

Yes

19

5.0(4.0-5.0)

Total 247 0 (0-1.0)

MPV No 228 9.50 (8.33-10.30 <0.05?

Yes 19 10.10(9.30-11.20)

Total 247 9.50(8.90-10.30)

Platelet No 228 211,500(174250-262,000) >0.05?

Yes 19 192,000(124000-262,000)

Total 247 208,000(172000-262,000)

MPR No 228 0.45 (0.35-0.57) <0.05?

Yes 19 0.61(0.39-0.87)

Total 247 0.46(0.35-0.58)

* Mann Whitney U test, MPV:Mean Platelet Volume, MPR:Mean Platelet Volume/ Platelet Count Ratio.

Table 4

Logistic regression analysis of variables.

Variables B

S.E.

Wald

df

Sig.

Exp(B)

95% C.I.for

EXP(B)

Lower

Upper

Gender -0.768

0.508

2.283

1

0.131

0.464

0.171

1.256

Comorbidity -1.756

0.518

11.466

1

0.001

0.173

0.063

0.477

Constant -1.199

0.367

10.699

1

0.001

0.301

MPR levels in patients who died within 28 days. The CURB-65 score, MPV, and MPR were significantly different between patients who died within 28 days and those who did not (p = 0.000, p = 0.034, and p = 0.034, respectively) [Table 3].

In a logistic regression analysis, the presence of a comorbidity was a significant predictor of 28-day mortality (Exp beta = 0.173; (95% CI

0.063-0.473, p = 0.001) [Table 4]. No significant correlation was found between the CURB-65 score and MPR (p > 0.05) according to the Spearman’s rho test.

The CURB-65 score, MPV, PLT, and MPR did not differ by the type of pneumonia (p > 0.05) according to the Kruskal-Wallis test.

In the ROC curve analysis to identify predictors of 28-day mortality, the area under the curve (AUC) for the CURB-65 score was 0.988 (95% CI 0.966-1.000, p < 0.001) while that for the MPR was 0.647 (95% CI

0.496-0.797, p < 0.05) [Fig. 1].

When the cutoff value of the CURB-65 score for 28-day mortality was 2.5, it had a sensitivity of 94.7% and specificity of 95.7%. When the cutoff value was 3.5, the score had a sensitivity of 94.7% and specificity of 100.0%. A cutoff value of the MPR for 28-day mortality of 0.042 had a sensitivity of 73.7% and specificity of 42.1%. When the cutoff value was 0.048, the sensitivity was 52.6% and the specificity was 52.6% [Table 5].

The Chi-square test and Fisher’s exact test showed significant associ- ations of HT, diabetes mellitus, and chronic renal failure with 28-day mortality (p < 0.05, p < 0.05, and p < 0.05, respectively) [Table 6].

  1. Discussion

Since coronavirus disease 2019 (COVID-19), a life-threatening infec- tious disease sustained by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2), is frequently complicated by thrombotic episodes, both venous and arterial [11]. We provide here an updated analysis of current scientific literature data exploring the association between CURB-65 score, PLT count, MPV, and MPR and 28-day mortality rate in patients with COVID-19.

The clinical symptoms of COVID-19 usually include fever, weakness, and dry cough [12]. Similar to other investigations, we found that the most common symptoms were cough and intermediate involvement [13].

Image of Fig. 1

Fig. 1. Area under curve values of mean platelet volume/platelet ratio to prediction mortality.

Table 5

ROC analysis according to CURB-65 and MPR at the diagnosis of mortality.

secondary to COVID-19 increased mortality by 1.76 times. In addition to lung capacity, the MPV value could be used as an auxiliary marker

AUC(95% CI) p Risk

Fact

Cut off

Sensitivity

%

Specificity

%

for predicting mortality in COVID-19 patients [20]. An increase in MPV is also related to worse prognoses in patients with chronic inflamma-

28-day mortality

0.988

(0.966-1.000)

0.647

(0.496-0.797)

0.000 CURB65 2.5 94.7 95.2

3.5 94.7 100.0

0.034 MPR 0.042 73.7 42.1

0.048 52.6 52.6

0.060 47.4 81.1

tory disease, severe pneumonia, and septic shock [21]. In patients with severe CAP, an increase in MPV after hospitalization was found to pre- dict mortality [22]. In this study, the MPV value was a significant predic- tor of 28-day mortality in COVID-19 pneumonia patients.

In patients with CAP, mortality increases as the CURB-65 score in- creases [23]. In this study, we evaluated the correlation between the

Prior reports show comorbidities (HT, DM, COPD/Astma, CAD, Malignancy) were detected in 32% [14] of the elderly patients with COVID-19, and 26% [13] of those with underlying chronic diseases who died due to COVID-19 pneumonia.

We observed a 30% rate of comorbidities; hypertension was de- tected in 13.4% of patients, and thus represents an important risk factor for 28-day mortality caused by COVID-19 pneumonia. The presence of a comorbidity (HT, DM, COPD/Astma, CAD, Malignancy) was also an inde- pendent risk factor. However, while advanced age was an important risk factor for mortality in other studies, it was not an independent risk factor in this study [13].

platelet activation in viral pneumonia may cause lung damage by stimulating the respiratory inflammatory response [15]. The tendency toward temporarily lower PLT in patients with COVID-19 may indicate worsening of the thrombotic state, where a lower PLT is associated with increased mortality [16]. In a study conducted in Wuhan, China, thrombocytopenia on presentation to hospital in patients with COVID- 19 was associated with a 4.24-fold increase in the risk of mortality [17]. Some studies found associations of thrombocytopenia with the sever- ity of COVID-19 and associated mortality. It has been reported that as the PLT decreases, the mortality rate increases [18]. We did not find any rela- tionship between PLT and mortality. Similarly, other studies have re-

ported normal PLT in many patients at the time of hospitalization [19].

A decrease in the PLT increases MPV. Guclu et al. found that a 1-unit increase in MPV between the first and third days of hospitalization

Table 6

Relationship between comorbidities and 28-day mortality.

28-day mortality

Total

p value

No

Yes

HT

No

n

201

13

214

<0.05#

%

88.2%

68.4%

86.6%

Yes

n

27

6

33

%

11.8%

31.6%

13.4%

DM

No

n

211

13

224

<0.05#

%

92.5%

68.4%

90.7%

Yes

n

17

6

23

%

7.5%

31.6%

9.3%

COPD /ASTHMA

No

n

210

17

227

>0.05#

%

92.1%

89.5%

91.9%

Yes

n

18

2

20

%

7.9%

10.5%

8.1%

CAD

No

n

219

17

236

>0.05?

%

96.1%

89.5%

95.5%

Yes

n

9

2

11

%

3.9%

10.5%

4.5%

CRF

No

n

226

17

243

<0.05?

%

99.1%

89.5%

98.4%

Yes

n

2

2

4

%

0.9%

10.5%

1.6%

Malignancy

No

n

224

17

241

>0.05?

%

98.2%

89.5%

97.6%

Yes

n

4

2

6

%

1.8%

10.5%

2.4%

Total

n

228

19

247

%

92.3%

7.7%

100.0%

# Chi-square test.

* Fisher’s Exact test, HT: Hypertension, DM: Diabetes Mellitus, CRF: Chronic Renal Failure COPD: Chronic Obstructive Pulmonary Disease, CAD: Coronary Artery Disease.

MPV and CURB-65 score. We also examined whether the accuracy of predictions of 28-day mortality in COVID-19 pneumonia patients could be improved by combining the MPV and CURB-65 score. Similar to studies of CAP patients, our results confirmed that the CURB-65 score is an independent predictor of mortality in patients with COVID- 19 pneumonia [24].

The pathophysiological mechanism underlying the association of the MPR with COVID-19 prognosis is unclear but may involve the following. First, under Inflammatory conditions, platelet production increases due to the increased thrombopoietin synthesis mediated by cytokines [25]. Second, the MPV reflects the metabolism, proliferation, and platelet production of megakaryocytes in the bone marrow [26]. Poor prognosis in patients with a low PLT count and high MPV may be associated with an increased risk of oxidative stress, thrombosis, and apoptosis in active platelets [27]. In many diseases, an increase in MPR is associated with an unfavorable prognosis, such as post-ischemic stroke, pneumonia, sepsis, critical illness, febrile epilepsy, and malignant tumors [28].

In severe COVID-19 patients, the MPV is negatively correlated with the PLT. Therefore, the use of the MPR is highly recommended as an in- dicator of Platelet function [29]. Ranias et al. showed that an increase in the MPR in pneumonia patients with ischemic stroke can predict 30-day mortality [30]. In our study, we also found that an increase in MPR predicted a poor prognosis, and mortality, in patients with COVID-19 pneumonia.

  1. Conclusion

We determined that CURB-65 score, PLT count, MPV and MPR may be associated with 28-day mortality in COVID-19 pneumonia patients.

Declarations

Ethical committee approval was obtained from Yuksek Ihtisas Edu- cation and Research Hospital Ethical committee during the study plan- ning phase.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interest

There is no financial and non-financial competing interest. There is no conflict of interest between authors.

Acknowledgment

We would like to thank Melih Yuksel for his contribution.

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