Degree of COVID-19 Severity and Mortality in Stroke: Correlation of Clinical and Laboratory Parameters

doi:10.21203/rs.3.rs-3435345/v1

Background

Stroke is one of the neurological manifestations of COVID-19. Acute stroke patients with COVID-19 had a significant morbidity and mortality. The clinical and laboratory data of these patients were investigated to determine the key factors in predicting mortality.

Method

This retrospective case-control study was conducted at Dr. Sardjito General Hospital Yogyakarta, Indonesia using data from July 2020 - August 2021. All acute stroke patients with confirmed COVID-19 were included. Patients’ medical records were used to collect the clinical and laboratory data. For baseline characteristics, univariate tests were used, followed by bivariate and multivariate analyses to determine significant predictors of mortality.

Result

We included a total of 72 subjects, consisting of 65 (90.28%) subjects with ischemic stroke and 7 (9.72%) with hemorrhagic stroke. The overall mortality rate was 58.3%, which consisted of 50% ischemic and 8.3% hemorrhagic stroke cases. Lowered Glasgow Coma Scale (GCS), loss of consciousness, generalized seizures, worsened modified Ranking Scale (mRS), history of dyslipidemia, worsened clinical severity of COVID-19 infection, respiratory distress, higher neutrophil count, C-Reactive Protein levels (> 41mg/dl), Blood Urea Nitrogen (> 29.05mg/dl), and Random Blood Glucose level (> 111.5mg/dl) at admission were all significantly associated with mortality (p < 0.05). Cox regression analysis revealed a 17.535 higher risk of mortality in individuals with severe COVID-19 (p = 0.032). Higher mRS scores more than doubled the probability of mortality (p = 0.001).

Conclusion

The poorer functional status assessed by mRS and the greater degree of COVID-19 on admission should be carefully identified since they may increase the risk of mortality in stroke patients with COVID-19.

COVID-19

mortality

stroke

predictors

mRS

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, a.k.a. Coronavirus Disease 2019 (COVID-19) has become a major health problem since the end of 2019 with over 750 million confirmed cumulative cases and about 1% total deaths recorded globally.¹ Since the World Health Organization (WHO) declared that COVID-19 is no longer a public health emergency of international concern in May 2023, advancements in disease treatment and global transmission prevention, including vaccination programs, have made it possible to reach the end of COVID-19 pandemic era.² The WHO emphasized the decrease in COVID-19 fatalities, hospitalizations, and intensive care admissions, as well as the increase in population immunity against SARS-CoV-2 on this occasion. However, COVID-19 awareness should still be considered imperative because several surges of cases were reported and new variants identified in various locations, such as the increase of COVID-19 cases in Western Pacific areas at the end of year 2022 despite the low number of cases in other parts of the world.¹

Neurological manifestations, such as encephalitis, encephalopathy, and stroke were found in 36.4% of COVID-19 patients with involvement of central nervous system symptoms.³ The incidence of stroke among COVID-19 patients was reported up to 3.4% in the Philippines with ischemic stroke being the most prevalent type.⁴ COVID-19 increases the risk of ischemic stroke 7.8 times in the first three days after respiratory distress.⁵ The pathophysiology of stroke in COVID-19 is related to viral affinity towards the Angiotensin Converting Enzyme (ACE-2) receptors, which directly causes brain neuron damage⁶, activation on the immune system in the form of cytokine storms, which increases the incidence of inflammation⁷, a combination of hypercoagulability and endothelial dysfunction⁸, and hypoxemia due to respiratory distress.⁹

Death is more common in acute stroke patients with COVID-19.^4,5 In individuals with COVID-19, the risk of mortality doubles with the occurence of acute ischemic stroke.⁵ COVID-19 patients with stroke tended to have poor outcomes due to limited admission to intensive care facilities and use of ventilators.^4,10 Although it is uncommon, the mortality rate of hemorrhagic stroke patients with COVID-19 infection was also double compared to those without hemorrhagic stroke.¹¹ Mortality in stroke patients with COVID-19 is further associated with older age, dyspnea, smoking, kidney disease, hypertension, malignancy, diabetes mellitus (DM), and lung disease.^4,10 Several laboratory markers from previous studies have become predictors of COVID-19 mortality, such as increased D-dimer, decreased platelet count, decreased hemoglobin concentration, increased creatinine, increased Interleukin-6 (IL-6), and elevated cardiac troponin-I.¹² Other predictors are albumin, total bilirubin, Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT), nitrogen urea (p-ES), C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin levels.¹² This study examined the clinical and laboratory parameters to predict mortality factors in acute stroke patients with COVID-19.

Research Subject

This retrospective case-control study used medical record data at the Dr. Sardjito General Hospital in Yogyakarta, Indonesia from July 2020 – August 2021. All acute stroke patients with the evidence from non-contrast head computerized tomography (CT) scan imaging and confirmed COVID-19 from polymerase chain reaction (PCR) of SARS-Cov-2 from nasal swab sampling, age > 18 years with complete medical records covering all clinical and laboratory parameters were included in this study. The exclusion criteria were patients with incomplete data.

Research variables

The patients’ demographic information, medical history, clinical features, degree of COVID-19, laboratory results upon admission, and mortality outcome were all obtained. Data on the patient's medical history included history of previous stroke, hypertension, diabetes mellitus, dyslipidemia, and renal insufficiency. Clinical data collected included systolic and diastolic blood pressure, level of consciousness, motor deficits, aphasia, cranial nerves paresis, focal seizures, generalized seizures, any incidence of respiratory failure, and the patient's functional status with Activity Daily Living (ADL) score:; Instrumental Activity of Daily Living (IADL), Barthel Index, modified Rankin Scale (mRS), degree of neurological deficit at admission according to the National Institutes of Health Stroke Scale (NIHSS) score, as well as the patients’ severity of COVID-19. COVID-19 severity was classified as mild, moderate, or severe based on the categorization of medical records by internal medicine specialists in accordance with the 3rd edition of the 2020 COVID-19 Management Guidelines in Indonesia.¹³ Laboratory data included routine blood analysis at admission (hemoglobin, erythrocytes, leukocytes, neutrophils, lymphocytes, neutrophil-to-lymphocyte ratio (NLR), monocytes, eosinophils, basophils, and platelets), random blood glucose (RBG) level, coagulation factors: plasma prothrombin time (PPT), activated partial thromboplastin time (APTT), internationalized normalized ratio (INR), and D-dimer), markers of tissue damage (CRP, LDH); renal function biomarkers: blood urea nitrogen (BUN) and creatinine; and electrolytes (sodium, potassium, and chloride). Stroke type was determined based on the description non-contrast head computerized tomography (CT) scan.

Statistical analysis

Statistical analysis was performed using SPSS version 23 (IBM Corp., Armonk, NY). The univariate descriptive analysis assessed the characteristics and demographics of the research subjects. The bivariate analysis compared clinical and laboratory characteristics between patients who died (deceased group) with those who survived (surviving group) at hospital release. Shapiro-Wilk analysis was used to determine the distribution of numerical data. Independent T-tests were used for data with normal distribution, while Mann-Whitney tests were used for non-normal distributions. Data were considered significant when p < 0.05. Regression analysis was conducted to assess the most influential variables in the mortality of stroke patients with COVID-19. Determination of the hazard ratio was done by Cox-regression tests with the dependent variables as mortality and length of stay, using the backward system. The significant variables were assessed in a Kaplan-Meier model to show survival analysis. The interval variables were transformed into categorical variables by measuring the cut-off point with a receiver operating characteristic (ROC) curve and J Youden Index.

The demographic and clinical characteristics of the study subjects are listed in Table 1. A total of 72 subjects were included in the study. The respondents’ mean age was 62.33 ± 12.28 years, with more males than females. The majority of stroke incidences were first-time occurrences. Almost all of the patients had an ischemic stroke (90.3%). Hypertension was the most prevalent comorbidity from the history of previous diseases (63.9%). Prior history of diabetes mellitus (DM), heart disease, dyslipidemia, and renal insufficiency were reported in <50% of subjects. The average blood pressure indicated systolic hypertension, defined by systolic above 140 mmHg with diastolic values below 90 mmHg. The median of quantitative GCS value was 15, with a 5-point interquartile range, equivalent to compos mentis to soporous state. There were 33 subjects (45.8%) who experienced a decrease in consciousness (GCS<15). The majority of subjects had motor deficits (72.2%) and cranial nerve paresis (51.4%), while only a few suffered aphasia, focal seizures, or generalized seizures. The patient's functional status on admission based on ADL, IADL, Barthel Index, and mRS scores showed high dependence. The classification of neurological deficits based on the NIHSS score revealed a moderate average of neurological deficits. More than half of the patients (52.8%) had severe COVID-19. The percentages of patients’ who experienced severe respiratory failure and death were 56.9% and 58.3%, respectively. Tables 2 and 3 show the comparison of the clinical and laboratory characteristics between the surviving and deceased groups of COVID-19 stroke patients. Essential laboratory characteristics showed increased total leukocytes, neutrophil lymphocyte ratio (NLR), coagulation factors, markers of tissue damage, decreased kidney function marked by increased blood urea nitrogen (BUN) and creatinine, impaired renal function, and liver damage indicated by increased SGOT and SGPT.

Table 1. Demographic, Clinical, and Laboratory Characteristic of Subjects

Characteristics	Proportion (%)	Mean ± SD/Median (IQR)
Age (years)		62.33 ± 12.28
Gender - Man - Woman	43 (59.7%) 29 (40.3%)
Episode Stroke - New Strokes - Recurrent Strokes	51 (70.8%) 21 (29.2%)
Stroke Type - Ischemic Stroke / IS - Hemorrhagic Stroke / HS	65 (90.3%) 7 (9.7%)
History of Hypertension	46 (63.9%)
History of DM	32 (44.4%)
History of Cardiac Disease	16 (22.2%)
History of Dyslipidemia	13 (18.1%)
History of Renal Insufficiency	19 (26.4%)
Systolic (mmHg)		141. 04 ± 28.63
Diastolic (mmHg)		83.51 ± 17.73
Quantitative GCS (score)		15 (5)
Loss of Consciousness	33 (45.8%)
Motor Deficit	52 (72.2%)
Aphasia	18 (25%)
Cranial Nerve Paresis	37 (51.4%)
Focal Seizures	2 (2.8%)
Generalized Seizures	6 (8.3%)
ADL (score)		18 (8)
IADL (score)		14 (4)
NIHSS (score)		11.5 (12)
Barthel Index (score)		40 (50)
mRS on Admission (score)		5 (2)
Severity of COVID-19 - Mild - Moderate - Severe	6 (8.3%) 28 (38.9%) 38 (52.8%)
Hemoglobin (g/dl)		13.5 (3.7)
Erythrocyte (10⁶/µL)		4.61 ± 1.09
Leukocytes (10³/µL)		10.05 (5.35)
Neutrophils (%)		82.3 (10.6)
Lymphocytes (%)		10.7 (8.4)
NLR		7.69 (7.51)
Monocytes (%)		6.2 (4.7)
Eosinophils (%)		0 (0.5)
Basophils (%)		0.1 (0.1)
Platelets (10³/µL)		263.81 ± 122.09
PPT (seconds)		15.85 (3)
APTT (seconds)		35.65 (12.8)
INR		1.17 (0.23)
D-Dimer (ng/mL)		1182.5 (3177)
CRP (mg/dl)		92.5 (115)
LDH (U/L)		317.5 (213)
Albumin (g/dL)		3.27 ± 30.50
BUN (mg/dL)		23.4 (35.1)
Creatinin (mg/dL)		1.31 (1.01)
RBG (mg/dl)		135 (186)
Sodium		136.5 (7)
Potassium		4.31 ± 0.88
Chloride		102 (7)
SGOT (U/L)		42.5 (42)
SGPT (U/L)		26.5 (28)
Respiratory Distress	41 (56.9%)
Length Of Stay (LOS)		5.5 (7)
Mortality - Survive - Dead	30 (41.7%) 42 (58.3%)

ADL: Activity Daily Living; IADL: Instrumental Activity of Daily Living; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Ranking Scale; DM: Diabetes Mellitus NLR: Neutrophil Lymphocyte Ratio; PPT: Plasma Prothrombin Time; APTT: Activated Partial Thromboplastin Time; INR: International Normalized Ratio; CRP: C-reactive protein; LDH: Lactate Dehydrogenase; BUN: Blood Urea Nitrogen; RBG: Random Blood Glucose; SGOT: Serum Glutamic Oxaloacetic Transaminase; SGPT: Serum Glutamic Pyruvic Transaminase

Table 2 showed no significant differences in age, sex, or stroke episodes between COVID-19 stroke patients who survived and those who died (p>0.05). Subjects in the deceased group had a history of dyslipidemia, lower diastolic blood pressure, lower quantitative GCS, decreased consciousness, and generalized seizures (p<0.05). Functional status and more severe neurologic deficits on admission were found in deceased subjects (p<0.05). More severe degrees of COVID-19 and more cases of respiratory failure were experienced in subjects in the dead group (p<0.05).

Table 2. Clinical Characteristics of the Survive vs Dead Subjects

Characteristics	Survive (n = 30)	Dead (n = 42)	p-value
Age (years)^a	59.6 ± 13.4	64.29 ± 11.02	0.109
Gender^b - Man - Woman	17 (39.5%) 13(44.8%)	26 (60.5%) 16 (55.2%)	0.419
Episode Stroke^b - New Strokes - Recurrent Strokes	20 (66.7%) 10 (33.3%)	31 (73.8%) 11 (26.2%)	0.432
Stroke Type^b -Ischemic Stroke / IS - Hemorrhagic Stroke / SH	29 (6.7%) 1 (3.3%)	36 (85.7%) 6 (14.3%)	0.125
Systolic (mmHg)^a	144.2 ±25.2	138.7 ± 30.9	0.428
Diastolic (mmHg)^a	88.6 ± 18.1	79.8 ± 16.8	0.039*
Quantitative GCS^c(score)	15 (2)	12.5 (6)	0.008*
Loss of Consciousness^b	8 (26.7%)	25 (59.5%)	0.006*
Motor Deficit^b	25 (83.3%)	27 (64.3%)	0.075
Aphasia^b	7 (23.3%)	11 (26.2%)	0.783
Cranial Nerve Paresis^b	15 (50%)	22 (52.4%)	0.843
Focal Seizures^b	1 (3.3%)	1 (2.4%)	0.808
Generalized seizures^b	5 (16.7%)	1 (2.4%)	0.031*
ADL^c (score)	11 (10)	18 (2)	0.002*
IADL^c (score)	10.5 (6)	14 (2)	0.003*
NIHSS^c(score)	6 (7)	17 (12)	<0.001*
Barthel Index^c(score)	52.5 (56)	25 (30)	0.024*
mRS at Admission^c(score)	4 (2)	5 (1)	0.001*
History of Hypertension^b	20 (66.7%)	26 (61.9%)	0.678
History of DM^b	10 (33.3%)	22 (52.4%)	0.109
History of Cardiac Disease^b	6 (20%)	10 (23.8%)	0.701
History of Dyslipidemia^b	9 (30%)	4 (9.5%)	0.026*
History of Renal Insufficiency^b	6 (20%)	13 (31%)	0.299
Severity of COVID-19^c - Mild - Moderate - Severe	5 (16.7%) 17(56.7%) 8 (26.7%)	1 (2.4%) 11 (26.2%) 30 (71.4%)	0.001*
Respiratory Distress^b	1 (3.3%)	40 (95.2%)	<0.001*
Length Of Stay (LOS)^c	7.5 (3)	3 (8)	0.012*

*p value<0.05 was considered significant, ^aUnpaired T-test, ^bChi’s Square, ^cMann-Whitney test

ADL: Activity Daily Living; IADL: Instrumental Activity of Daily Living; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Ranking Scale; DM: Diabetes Mellitus; IS: Ischemic Stroke; HS: Hemorrhagic Stroke

Table 3 revealed significantly higher neutrophils, whereas monocytes and eosinophils were much lower in deceased subjects. BUN, CRP, and RBG levels were higher in the deceased group than in the survivors (p<0.05).

Table 3. Laboratory Characteristics of the Survive vs Dead Subjects

Characteristics	Survive (n = 30)	Dead (n = 42)	p-value
Hemoglobin^a (g/dl)	13.35 (2.9)	13.85 (4.8)	0.205
Erythrocyte^b (10⁶/µL)	4.53 ± 0.73	4.68 ± 1.3	0.163
Leukocytes^a (10³/µL)	9.89 (6.07)	10.14 (5.04)	0.991
Neutrophils^a (%)	79 (20.9)	83.8 (7.6)	0.018*
Lymphocytes^a (%)	10.9 (15.4)	10 (7.3)	0.299
NLR^a	7.26 (8.88)	8.53 (7.68)	0.213
Monocytes^a (%)	7.6 (5.3)	5.25 (3.5)	0.008*
Eosinophils^a (%)	0.1 (1.1)	0 (0.1)	0.047*
Basophils^a (%)	0.1 (0.1)	0.1 (0.2)	0.149
Platelets^b (10³/µL)	296.20±108.15	240.68±127.38	0.068
PPT^a (seconds)	15.95 (3.9)	15.8 (2.6)	0.727
APTT^a (seconds)	39.55 (14.3)	34.85 (10.9)	0.057
INR^a	1.16 (0.33)	1.2 (0.26)	0.526
D-Dimer^a (ng/mL)	952.5 (2355)	1585 (3590)	0.320
CRP^a (mg/dl)	48 (139)	119 (101)	0.028*
LDH^a (U/L)	311 (223)	342 (227)	0.293
Albumin^b (g/dL)	3.20±0.67	3.32±0.56	0.387
BUN^a (mg/dL)	18.85 (24.7)	34.25 (39.4)	0.009*
Creatinin^a (mg/dL)	1.19 (0.9)	1.39 (1.29)	0.105
RBG^a (mg/dl)	127 (122)	158.5 (242)	0.032*
Sodium^a	137 (7)	136 (9)	0.626
Potassium^b	4.07±0.87	4.46±0.87	0.065
Chloride^a	101.5 (6)	102 (9)	0.552
SGOT^a (U/L)	39.5 (39)	44.5 (42)	0.203
SGPT^a (U/L)	25.5 (29)	28 (32)	0.740

*p value<0.05 was considered significant, ^aMann Whitney test, ^bUnpaired T-test

NLR: Neutrophil Lymphocyte Ratio; PPT: Plasma Prothrombin Time; APTT: Activated Partial Thromboplastin Time; INR: International Normalized Ratio; CRP: C-Reactive Protein; LDH: Lactate Dehydrogenase; BUN: Blood Urea Nitrogen; RBG: Random Blood Glucose; SGOT: Serum Glutamic Oxaloacetic Transaminase; SGPT: Serum Glutamic Pyruvic Transaminase

Based on the important clinical and laboratory criteria from the bivariate analysis, the clinically valuable and significant variables (p<0.25) were assessed using the hazard ratio (HR) analysis by the Cox regression method with the backward system, as shown in Table4.

Table 4. Hazard Ratio Analysis

Variable	Hazard Ratio	CI 95% (upper-lower)	p-value^a
mRS	2.020	1.346 – 3.029	0.001*
Monocytes	1.138	1.023 – 1.266	0.018*
BUN	1.002	1.001 – 1.003	0.033*
Mild COVID-19 Degree	Reference	Reference	Reference
Moderate COVID-19 Degree	9.654	0.0702 – 132.693	0.090
Severe COVID-19 Degree	17.535	1.275 – 241.094	0.032*

*p value<0.05 was considered significant, ^acox-regression analysis with mortality and length of stay (LOS) as dependent variable, input analysis using backward system.

mRS: modified Ranking Scale; BUN: Blood Urea Nitrogen; COVID-19 : Corona Virus Disease 2019

Regression analysis showed that individuals with severe COVID-19 had a 17-fold greater risk of death (HR: 17.535; 95% CI: 1.275 – 241.094; p=0.032). An increment in the mRS score also doubled the risk of mortality (HR: 2.020; 95% CI: 1.346 – 3.029; p=0.001). On the other hand, a low monocyte count (HR: 1.138; p=0.018) and a high BUN rate upon admission (HR: 1.002; p=0.033) were both poor predictors.

Significant predictors in the HR model were presented in a Kaplan-Meier curve (Figure 1) to indicate the survival rate. The mid-survival times for the stroke-COVID-19 patients, respectively, were expected survival until 15 days for moderate degree and 5 days for severe degree of COVID-19 infection. Furthermore, the mRS could significantly predict mortality when it was >4.5. Half of the patients with mRS below 4.5 were expected to survive until 15 days, whereas those with mRS >4.5 were only expected until 5 days. As a result, the patients’ 15-day survival probability of the population with mild degree of infection (80.95%) and mRS <4.5 (69.7%) was significantly higher (p<0.05) than severe degree (26.7%) and mRS >4.5 (25.6%).

According to our findings, the mortality rate of patients with confirmed stroke and COVID-19 was 58.3% (Table 1). This conclusion is consistent with prior studies on COVID-19 stroke patients who had a higher fatality rate than those who did not have stroke, both hemorrhagic and ischemic stroke.^4,5,12 Dyspnea, smoking, cardiovascular problems, kidney and liver diseases, hypertension, diabetes, and malignancy were all significantly related with elevated mortality rates in COVID-19.¹⁴

The prevalence was higher in elderly patients. According to our demographic data, the average age of the population was 62.33 ± 12.28 years old. Based on data from the Centers for Disease Control and Prevention, the risk of mortality from COVID-19 increased 90 times at the age of 65–74 years and 220 times at the age of 75–84 years compared to the age of 18–29 years. ¹⁵ Age > 65 years was also significantly associated with an increased infection fatality rate of SARS-CoV-2 infected patients in 45 countries.¹⁵ Longer duration of comorbidities and inadequate compensation for organ function resulted in greater patient mortality.¹⁶ Furthermore, our study found that male patients were more prevalent than females. Differences in ACE-2 protein expression in the lungs are regulated by sex hormone modulators including anti-androgen and anti-estrogen, which indirectly influence the incidence of COVID-19 infection.¹⁷ Sex disparities can also be attributed to male smoking prevalence. Nicotine has direct effects on the ACE-2 receptors, which bind to the COVID virus and induce lung tissue and neuronal damage.¹⁷

Our data revealed no link between a history of hypertension, higher systolic blood pressure, and mortality outcome in COVID-19 stroke patients. Uncontrolled blood pressure was not significantly associated with 30-day mortality or hospitalization incidence in COVID-19 patients with hypertension, according to one recent research.¹⁸ On the contrary, a history of hypertension with mean elevated blood pressure showed that systolic hypertension was related with a substantially greater risk of mortality and an increased incidence of intensive care unit (ICU) admission in patients with COVID-19.^4,19

In COVID-19 stroke patients, a decrease of consciousness, as well as focal and general neurological deficits were found to increase the risk of mortality. Previous studies identified the GCS score as a risk factor for predicting mortality and allowing rapid risk stratification for SARS-CoV-2 infected stroke patients in tertiary care hospitals in low-middle-income countries where laboratory findings may be unavailable during crisis.²⁰ Furthermore, any neurological co-morbidities were shown to have a direct significant association with stroke in patients with COVID-19, which increased mortality and ICU hospitalizations.⁴

The degree of COVID-19 (HR: 17.53; p = 0.032) and incidence of respiratory failure (p < 0.001) were shown to have a significant association with mortality in this study. A more severe level of COVID-19 may cause cytokine cascades, exaggerated inflammatory responses, coagulation dysfunction, and organ destructions, worsening the prognosis of COVID-19 stroke patients. Most patients with severe COVID-19 are dyspneic or hypoxemic one week after onset, with serious lung damage causing gas exchange to not be properly performed.⁹

Functional status and stroke severity at the time of admission were significantly associated with short and long-term prognosis in stroke, particularly following acute stroke treatments.^21,22 The mRS is a popular tool for assessing functional status. It is often assessed on admission as well as 3 months or one year following stroke onset to measure the difference in patient’s functional state.^22,23,24 In acute stroke patients with COVID-19, an increment in mRS score doubled the risk of mortality (Table 4). This finding was consistent with the recent study conducted by Al Qawasmeh et al. in 2022, which reported COVID-19 increased stroke severity and in-hospital mortality but it was not linked with the development of the unfavorable outcomes assessed using mRS > 2 was considered as unfavorable outcomes) after 3 months in the patients who survived acute stroke and COVID-19.²⁴ Because of its ease of use, mRS is increasingly being used in daily practice to assess the functional status or functional outcome in stroke patients. Even pre-stroke mRS is considered to be accurate for prognostics in acute stroke patients.²²

Both the worsening COVID-19 degree (HR: 17.53) and higher mRS (HR:2.02) were significantly (p < 0.05) associated with the mortality of stroke-COVID-19 patients, reducing the expected mid-survival time threefold. The shown results (Fig. 1) were aligned with another recent study²⁵, which showed higher odds ratio (HR: 2.51) and lower survival rate from 60-day mortality in ischemic stroke patients with COVID-19, compared to the ischemic stroke group alone. Despite the similar results, the observed mortality and functional outcomes in this study were more severe compared to the previous study. These results varied due to different patient management and clinical guidelines which were still being developed during the pandemic era from both conducted studies.

As shown in Table 3, the increase in infection markers, kidney function markers, and blood glucose levels were significantly different between the surviving and deceased groups of acute stroke patients with COVID-19. An increased CRP level was significantly associated with an increased risk of thrombosis, whereas increased LDH indicated the presence of tissue damage, which was observed in COVID-19 patients.^26,27 Neutrophils, lymphocytes, and inflammatory mediators are linked to anti-atherosclerotic vascular damage. Activated neutrophils can secrete a variety of proteolytic enzymes that promote endothelium and basement membrane breakdown, enhancing the instability of the atherosclerotic plaque.²⁸ In contrast to our findings, the NLR was previously identified as a potential inflammatory biomarker.²⁹

The laboratory parameters’ predictors with the highest ratio were a low monocyte count (HR: 1.138; p = 0.018) and a high BUN rate at admission (HR: 1.002; p = 0.033). Circulating pro-inflammatory stimuli in COVID-19 patients trigger the activation of blood monocytes by inducing tissue factor expression. Tissue factors expressed by activated monocytes, monocyte-derived microvesicles, and endothelial cells activate coagulation pathways, resulting in fibrin deposition and blood coagulation.³⁰ Several etiologies could cause high BUN values in stroke patients with COVID-19. Involvement of ACE-2 in the kidneys, which is nearly 100 times higher than in respiratory organs, deposition of viral antigen immune complexes, specific immunological effector mechanisms, and virus-induced cytokines or mediators have a direct effect on damage to kidney tissue, as well as an indirect effect via hypoxia, shock, and rhabdomyolysis.³¹

The observed coagulation blood markers showed insignificant association in predicting mortality of stroke patients with COVID-19. The population in this study consisted of 90.3% ischemic stroke patients, which was caused by the progression of a hypercoagulability state, either due to thrombotic events or embolism³². COVID-19 infection itself has been highly associated with increased risk for thrombosis and rising of D-dimer levels, which leads to worsening outcomes of the patients³³. Whether the infection cascade causes the hypercoagulability state, following the thrombotic events of stroke, or the coagulation event in stroke causes the similar state, worsened by COVID infection, should be further studied in a wider population in normal, stroke, COVID-19, and stroke-COVID-19 patients, prospectively.

In this study, the deceased group had considerable hyperglycemia compared to the surviving group, although there was no significant difference between the groups who had previously been diagnosed with DM (Tables 1 and 2). Moreover, there was no significant association found between the random blood glucose level and mortality in stroke patients with COVID-19. These results imply that stress from hyperglycemia may modify immunological and inflammatory responses, resulting in a deleterious clinical outcome in stroke patients with and without DM.³⁴

The patients’ therapy for COVID-19 may have differed due to the dynamic national treatment guidelines for COVID-19 during the study period, which was one of our study’s limitations. Furthermore, this was a single-center study done at Dr. Sardjito General Hospital, a tertiary referral hospital that may have received a higher proportion of severe COVID-19 patients with complex comorbidities.

In conclusion, clinical features and laboratory results on admission in COVID-19 stroke patients are important to predict mortality. The worse functional status assessed by mRS, as well as the higher degree of severity of COVID-19, may increase the risk of mortality in stroke patients with COVID-19. Lower monocyte count and increased BUN levels were the key laboratory results in predicting mortality.

COVID-19

Corona Virus Disease 2019

GCS

Glasgow Coma Scale

mRS

modified Ranking Scale

WHO

World Health Organization

SARS-Cov-2

Severe Acute Respiratory Syndrome Coronavirus 2

ACE-2

Angiotensin Converting Enzyme

DM

Diabetes Mellitus

IL-6

Interleukin-6

SGOT

Serum Glutamic Oxaloacetic Transaminase

SGPT

Serum Glutamic Pyruvic Transaminase

p-ES

nitrogen urea

CRP

C-reactive protein

LDH

Lactate Dehydrogenase

CT

computerized tomography

PCR

polymerase chain reaction

SARS-Cov-2

Severe Acute Respiratory Syndrome Coronavirus 2

ROC

receiver operating characteristic

ADL

Activity Daily Living

IADL

Instrumental Activity of Daily Living

NIHSS

National Institutes of Health Stroke Scale

NLR

Neutrophil Lymphocyte Ratio

BUN

Blood Urea Nitrogen

PPT

Plasma Prothrombin Time

APTT

Activated Partial Thromboplastin Time

INR

International Normalized Ratio

BUN

Blood Urea Nitrogen

RBG

Random Blood Glucose

PPT

plasma prothrombin time

APTT

activated partial thromboplastin time

INR

internationalized normalized ratio

IS

Ischemic Stroke

HS

Hemorrhagic Stroke

LOS

Length of Stay

HR

Hazard Ratio

Ethics Approval and Consent to Participate

The research already had ethical approval from Medical Ethic Committee Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada No. KE/FK/0288/EC in accordance with the Declaration of Helsinki. The data collection was conducted without collecting any subject’s private data, i.e.; fullname, full address, and full medical record number. This study generated intial and specific code number to identify each subject.

Consent for Publication

Not applicable.

Availability of Data and Materials

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

Competing Interests

The authors declare that they have no competing interests.

Funding

The authors report no source of funding for this research.

Author’s Contributions

AG: Coordinating Research Conduction, Conceptualization, Investigation, Writing – original draft. YCBNS: Conceptualization, Methodology, Data Manager and Analysis, Writing – original draft. TRS: Conceptualization, Methodology, Investigator. AM: Methodology, Investigator, Writing – original draft. RANAS: Data Administrator, Investigator. DBN: Data Administration, Review & Editing of Manuscript. MAR: Conceptualization, Supervision, Resources, Methodology, Review & Editing of Manuscript IS: Supervision, Resources, Methodology, Review & Editing of Manuscript.

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No competing interests reported.

Degree of COVID-19 Severity and Mortality in Stroke: Correlation of Clinical and Laboratory Parameters

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Journal Publication

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Abstract

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BACKGROUND

METHODS

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Statistical analysis

RESULTS

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Status:

Journal Publication

Version 1