QUIRINO MEMORIAL MEDICAL CENTER

Center for Neurologic Science

Clinical Outcome of Patients with Concomitant Covid19 Infection

and Acute Stroke Admitted in QMMC

Lester de Pedro Dimzon, MD

Author

Lex Lycurgus N. Castillo, MD

Adviser

December, 2021

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I.RESEARCH TITLE

Clinical Outcome of Patients with Concomitant Covid19 Infection

and Acute Stroke Admitted in QMMC

II.PROPONENTS

NAME AND SIGNATURE

PROJECT LEADER ______Lester D. Dimzon, MD____

RESEARCH ADVISER _ Lex Lycurgus N. Castillo, MD__

RESEARCH STATISTICIAN ____________________________

COOPERATING AGENCY/ ____________________________

COMPANY(IF ANY)

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III. INTRODUCTION

Stroke is the second leading cause of death and a major cause of disability

worldwide. Its incidence is increasing because the population ages (1). In the

Philippines, there are limited data on the epidemiology of stroke, which is a problem

common to many countries in Southeast Asia (2). However, it is also the second leading

cause of death in the country with a prevalence of 0·9%; ischemic stroke comprises

70% while hemorrhagic stroke comprises 30% (3).

Presently the entire world is devastated by COVID 19 pandemic brought about

by SARS-CoV2 Virus and has been active well up to now before January of 2020 when

its pathogenic potential exploded full force in Wuhan (4). The first case in the

Philippines was identified on January 30, 2020 (5). A recent systematic review and

meta-analysis of 108,571 COVID-19 patients, in 1106 of whom ischemic or hemorrhagic

stroke occurred, yielded an overall pooled incidence of acute stroke in COVID-19

patients of 1.4% (6). According to the panel of the World Stroke Organization, the risk of

ischemic stroke during COVID-19 is around 5% and COVID-19-related hemorrhagic

strokes are far less common (7).

In a recently published Philippine CORONA STUDY done by Espiritu et al with

37 participating hospital, showed that the proportion of patients who had covid19 with

an acute stroke is approximately 3.37%, wherein 2.41% had cerebral infarction and

0.93% have hemorrhagic stroke (8).

The rate of thrombotic complications in patients with severe COVID-19-related

pneumonia admitted to an ICU was reported to be as high as 49%. COVID-19 has been

associated with several coagulation abnormalities such as elevated rates of D-dimer,

prothrombin time found to be modestly prolonged, and thrombocytopenia is

inconsistently associated with COVID-19 severity (9).

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 D-dimer represents the activation of coagulation and fibrinolysis systems. It is

usually used in clinical practice to exclude a diagnosis of deep vein thrombosis (DVT)

and pulmonary embolism (PE) and confirm diagnosis of disseminated intravascular

coagulation (7). Some researchers reported that increased D-dimer level independently

predicted poor outcome in patients with acute ischemic stroke (10). Elevated D-dimer

level has been identified as a useful predictor for mortality in patients with COVID-19

and several studies demonstrated its prognostic potential and optimal cutoff value (11).

Thus, this study will be conducted to determine the clinical outcome of patients

with concomitant covid19 infection with acute ischemic stroke or with intracerebral

hemorrhage admitted in QMMC.

IV. OBJECTIVES

General Objective

 To determine if there’s a significant difference in the clinical outcome of patients

with concomitant COVID19 infection and acute ischemic stroke or intracerebral

hemorrhage as compared to those who are covid19 negative stroke patients

admitted at Quirino Memorial Medical Center.

Specific Objectives

 To determine stroke type as to:

 Acute ischemic stroke

 Intracerabral hemorrhage

 To determine the stroke severity of the patient based on NIHSS Score upon

admission as to:

- Mild (NIHSS 1-4)

- Moderate (NIHSS 5-20)

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 - Severe (NIHSS 21 and above)

 To determine the clinical outcome of patients with concomitant COVID19

infection and acute ischemic stroke or intracerebral hemorrhage and those who

are covid19 negative stroke patients.

- Mortality Rate

 To determine if there is a significant difference the clinical outcome of patients

with concomitant COVID19 infection and acute ischemic stroke or intracerebral

hemorrhage to those who are covid19 negative stroke patients admitted at

Quirino Memorial Medical Center.

V. SIGNIFICANCE OF THE STUDY

The findings of this study may prove beneficial to the following:

Patients with concomitant COVID19 infection and acute ischemic stroke. The

results of the study may provide valuable information on identifying patients who are at

high risk for thrombosis. With the available data, prognosis of high-risk patients may be

improved by early initiation of antithrombotic prophylaxis both mechanical and

pharmacologic if without contraindications.

Patients with concomitant COVID19 infection and intracerebral hemorrhage. The

results of the study may provide valuable information on identifying patients who are at

high risk. With the available data, prognosis of high-risk patients may be improved by a

multispecialty approach including early referral to a neurosurgeon if with indication.

Clinicians. This study may help physicians in developing clinical guidelines or

pathways especially in the emergency room which includes D dimer as part of the initial

biomarkers to be requested for patients who has a concomitant COVID19 infection and

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acute ischemic stroke. This study may also guide physicians in identifying high risk

patients for thrombosis.

Government Institutions. The findings of this study may guide health policy maker

in crafting policies directed towards the provision of improved health care services

specifically in the prevention and early diagnostics or screening of patients who are at

risk or exposed. Policies directed also for the improvement of all our tertiary government

hospitals with brain specialty capability which provides quality but cost-effective care to

the patients.

Researchers. The results of this study may be used as baseline information or

support to researches on topics similar to what is currently undertaken. The information

provided may be used to support proposals related to the topic presently under study.

CONCEPTUAL FRAMEWORK

Independent Variables Dependent

Outcome
Variable
Stroke Type  Mortality rate

NIHSS Score

Figure 1. Interplay of variables

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REVIEW OF RELATED LITERATURE

In the rapidly evolving COVID-19 pandemic, many patients presenting with acute

ischemic stroke may be potentially infected with the SARS CoV-2 agent thus all stroke

patients in areas with high prevalence of community transmission should be considered

potential cases (9). In a recent systematic review and meta-analysis showed that the

overall pooled incidence of acute stroke in Covid19 patients is 1.4%. However, it is

STILL UNCERTAIN if What proportion of these strokes are related to COVID infection,

and what proportion are incidentally related only (6).

But in some studies, a characteristic pattern of stroke is seen in many COVID-19

patients. Most were younger and less likely to have hypertension and previous stroke

and usually a Large artery occlusion with a characteristic pattern of multiple arterial

territories which is reported in 43% of cases (6). But in a study done by Querishi et al

entitled Acute Ischemic Stroke and COVID-19, an Analysis of 27676 Patients. They

analyze 54 health care facilities using the Cerner deidentified COVID-19 dataset. They

found out that Patients with COVID-19 (compared with those without COVID-19) who

developed acute ischemic stroke were older, more likely to be Black, and had a higher

frequency of hypertension, diabetes, hyperlipidemia, atrial fibrillation, and congestive

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heart failure. They added that Acute ischemic stroke was infrequent in patients with

COVID-19 and usually occurs in the presence of other cardiovascular risk factors (12).

However, the Increasing overall proportion of patients with LVO is due to a decrease in

hospital referral of stroke patients with minor symptoms due social distancing and stay-

in-shelter recommendations (13). In another study, in covid19 patients with ischemic

stroke, 45% were cryptogenic stroke followed by cardioembolic in 22% (6). But the

surprisingly high proportion of cryptogenic strokes in these population was attributed to

the limited resources and time to complete a thorough investigation in such patients at

high risk of dying in a healthcare system under high pressure (13).

The high frequency of ischemic stroke in young subjects with COVID-19 and a

paucity of vascular risk factors raises the possibility that mechanisms peculiar to

COVID-19 may be responsible (14). In a study done by Tan et al, they stated that AIS

severity in COVID-19 patients are typically at least moderate (NIHSS score 19±8), with

a high prevalence (40.9%) of LVO and a high mortality rate (38.0%) was reported (1).

Yamakawa et al, added that Frequent cryptogenic stroke and elevated d-dimer level

support increased risk of thromboembolism in COVID-19 associated with high mortality

(3). Thus, COVID-19 patients with AIS present with greater D-dimer levels. Thresholds

for outcomes prognostication should be higher in this population (11).

Strokes in patients with COVID-19 may be due to usual causes such as

atherosclerosis, hypertension, and atrial fibrillation (14). But the mechanisms that

appears to be directly related to COVID-19 is multifactorial. In some patients they could

be related to conventional stroke mechanisms as previously mentioned with COVID-19

acting as a trigger. Others may be directly caused by COVID-19 infection through

specific pathophysiological mechanisms (6).

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 In fact, in a recently published review article last June 2021 from the European

Journal of neurology entitled Covid 19 and Ischemic Stroke. They enumerated 4

possible pathophysiological axes seem to be related to thromboembolism and stroke in

patients diagnosed with COVID-19: immune-mediated thrombosis and

hypercoagulopathy, alternative renin-angiotensin system (RAS) pathway, cardio

embolism and COVID-19–associated cardiopathy, and SARS CoV-2–mediated damage

of the neurovascular unit (13).

D-dimer is a soluble fibrin degradation product that results from ordered

breakdown of thrombi by the fibrinolytic system. Numerous studies have shown that D-

dimer serves as a valuable marker of activation of coagulation and fibrinolysis.

Consequently, D-dimer has been extensively investigated for the diagnosis of venous

thromboembolism (VTE) and is used routinely for this indication (15).

Before COVID19 pandemic, there were several studies correlating D dimer levels

and acute ischemic stroke. In a study done by Takeo et al., they concluded that a high

D-dimer level on admission could help predict unfavorable outcomes in patients with a

minor ischemic stroke with large vessel occlusion (4). In addition, Yuan et al., stated

that high D-dimer levels may be associated with the risks of total stroke and ischemic

stroke, but not with hemorrhagic stroke and a high D-dimer levels on admission may

predict adverse clinical outcomes, including all-cause mortality, 5-day recurrence, and

90-day poor functional outcomes, of patients with AIS or TIA (5).

In terms of coagulation dysfunction in COVID-19 patients, it insidiously drives

progression to severe illness and fatal outcome, and is characterized by elevated D-

dimer and thrombi in the veins and arteries. The high level of D-dimer in COVID-19 is

triggered by excessive clots and hypoxemia. In addition, D-dimer elevation is frequently

observed in COVID-19 patients with severe disease, and correlates significantly with

mortality (7).

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 Lee et al. reported that 20–55% of patients hospitalized with COVID-19 have

laboratory evidence of coagulopathy, with increased levels of D-dimer to above twice

normal, slight prolongation of prothrombin time (1–3 s above normal), mild

thrombocytopenia, and in late disease, decreased fibrinogen levels. A D-dimer level

above 4 times normal was associated with a 5-fold increase in the likelihood of critical

illness (14).

RESEARCH METHODOLOGY

STUDY DESIGN

This is an ambi-directional cohort study

STUDY POPULATION

A. Inclusion Criteria

 All service 19-year-old patients and above admitted with radiologically

diagnosed stroke (infarct/hemorrhage) using non-contrast cranial CT scan

or cranial magnetic resonance imaging (MRI) with or without a

concomitant laboratory confirmed COVID19 infection on RTPCR.

B. Exclusion Criteria

 Patients who are 18 years old and below

 Patients who are discharged against medical advice (DAMA) or

transferred to other institution during the study

The patients will be selected as per protocol based on the inclusion and

exclusion criteria.

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SETTING/LOCATION

The study will be conducted at Quirino Memorial Medical Center, Quezon City.

SAMPLE SIZE CALCULATION

All patients as described in the inclusion criteria will be included in the study

STUDY VARIABLES

In this study, the clinical outcome of patients with acute ischemic stroke or

intracerebral hemorrhage with or without a concomitant COVID19 infection will be

classified into two:

1. Survivor – A patient who met the inclusion criteria and was discharged alive.

2. Non-survivor – A patient who met the inclusion criteria and died as a direct

cause of both diseases.

DEFINITION OF TERMS

The National Institutes of Health Stroke Scale (NIHSS) - is a widely accepted,

clinically-validated measurement of stroke severity. The NIHSS score is defined as the

sum of 15 individually evaluated elements, and ranges from 0 to 42. Stroke severity

may be categorized as follows: no stroke symptoms, 0; minor stroke, 1–4; moderate

stroke, 5–15; moderate to severe stroke, 16–20; and severe stroke, 21–42 (16).

Disease Severity Classification of Patients with Probable or Confirmed COVID-

19:

A. Mild Disease 1. Symptomatic patients presenting with fever, cough, fatigue,

anorexia, myalgias; other non-specific symptoms such as sore throat, nasal congestion,

headache, diarrhea, nausea and vomiting; loss of smell (anosmia) or loss of taste

(ageusia) preceding the onset of respiratory symptoms with NO signs of pneumonia or

hypoxia.

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 B. Moderate Disease 1. Adolescent or adult with clinical signs of non-severe

pneumonia (e.g. fever, cough, dyspnea, respiratory rate (RR) = 21-30 breaths/minute,

peripheral capillary oxygen saturation (SpO2) >92% on room air) Child with clinical

signs of non-severe pneumonia (cough or difficulty breathing and fast breathing [ < 2

months: > 60; 2-11 months: > 50; 1-5 years: > 40] and/or chest indrawing).

C. Severe Disease I. Adolescent or adult with clinical signs of severe pneumonia

or severe acute respiratory infection as follows: fever, cough, dyspnea, RR>30

breaths/minute, severe respiratory distress or SpO2 < 92% on room air Child with

clinical Signs of pneumonia (cough or difficulty in breathing) plus at least one of the

following: a. Central cyanosis or SpO2 < 90%; severe respiratory distress (e.g. fast

breathing, grunting, very severe chest indrawing); general danger sign: inability to

breastfeed or drink, lethargy or unconsciousness, or convulsions. b. Fast breathing (in

breaths/min): < 2 months: > 60; 2-11 months: > 50; 1-5 years: > 40.

D. Critical Disease - Patients manifesting with acute respiratory distress

syndrome, sepsis and/or septic shock:

1. Acute Respiratory Distress Syndrome (ARDS) a. Patients with onset

within 1 week of known clinical insult (pneumonia) or new or worsening

respiratory symptoms, progressing infiltrates on chest X-ray or chest CT scan,

with respiratory failure not fully explained by cardiac failure or fluid overload

2. Sepsis a. Adults with life-threatening organ dysfunction caused by a

dysregulated host response to suspected or proven infection. Signs of organ

dysfunction include altered mental status, difficult or fast breathing, low oxygen

saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or

low blood pressure, skin mottling, or laboratory evidence of II. coagulopathy,

thrombocytopenia, acidosis, high lactate or hyperbilirubinemia b. Children with

suspected or proven infection and > 2 age-based systemic inflammatory

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 response syndrome criteria (abnormal temperature [> 38.5 °C or < 36 °C);

tachycardia for age or bradycardia for age if < 1 year; tachypnea for age or need

for mechanical ventilation; abnormal white blood cell counts for age or > 10%

bands), of which one must be abnormal temperature or white blood cell count.

3. Septic Shock a. Adults with persistent hypotension despite volume

resuscitation, requiring vasopressors to maintain MAP > 65 mmHg and serum

lactate level >2 mmol/L b. Children with any hypotension (SBP < Sth centile or >

2 SD below normal for age) or two or three of the following: altered mental status;

bradycardia or tachycardia (HR < 90 bpm or > 160 bpm in infants and heart rate

< 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or weak

pulse; fast breathing; mottled or cool skin or petechial or purpuric rash; high

lactate; reduced urine output; hyperthermia or hypothermia (17).

DATA COLLECTION PROCEDURES

This will be an ambi-directional analysis of charts of patients selected from

hospital records based on inclusion and exclusion criteria, admitted from April 1, 2020 to

September 31, 2021. Data of the selected patients will be collected from the medical

records by the researcher. A data collection form with be utilized and each patient will

have an identity code. General data, clinical, and radiographic findings and outcome of

patients noted in the medical record will be analyzed. Primary outcome will be assessed

as survivor and non-survivor.

All data gathered will be tabulated and reviewed by the researcher and a

statistician. The data sheets will be kept confidential by the researcher until all data

have been interpreted, after which they will be shredded after a year. No other person

has access to the documents, laboratories and other files of the study other than the

researchers, statistician and reviewers involved.

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TARGET TIME PERIOD

The study will be conducted from April 1, 2020 – September 31, 2021.

DATA PROCESSING AND ANALYSIS

The data obtained will be organized and coded. Raw data will be stored to

prevent loss. The data will be encoded and analyzed using the Statistical Package for

Social Sciences (SPSS) software. Interpretation of the analyzed data followed based

on the tables prepared.

For analysis of data, both descriptive and inferential analyses will be done, hence

descriptive and inferential statistics will be used. The risk ratio will also be determined.

Descriptive statistics will include frequency and percentage to present clinical

and demographic variables of the respondents. Frequencies, percentages and means

will be used particularly in the tabular presentation of clinical and demographic profile of

the patients.

For inferential analysis, non-parametric statistics will be used specifically Chi-

square test for goodness of fit. The level of significance was set at 95% confidence

interval.

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DUMMY TABLES

Table 1. Demographic Profile of Patients with Concomitant COVID19 infection and

Acute Ischemic Stroke

Outcome

Total Survivor Non-survivor

Demographic profile
f % f % f %

AGE

19-45 yo

Above 45 yo

Total

SEX

Male

Female

Total

Table 2. Clinical Profile and D-dimer Level of Patients with Concomitant COVID19

infection and Acute Ischemic Stroke

Outcome

Clinical Profile Total Survivor Non-survivor

f % f % f %

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 Stroke Type

Infarct

Hemorrhage

Stroke Severity

Mild

Moderate

Severe/Critical

Table 3. Demographic Profile of Patients and Outcome

df Chi-square Sig Decision

value

Age x outcome

Sex x outcome

Table 4. Clinical Profile of Patients and Outcome

Clinical profile df Chi-square Sig Decision

value

Stroke type x Outcome

COVID19 positive x

Outcome

Stroke severity x Outcome

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ETHICAL CONSIDERATIONS

The identity of the patients included in this study will be kept confidential and only

coded numbers instead of names will be used to assure anonymity of the source. All

data will be encoded in a secure laptop with password and only the researcher and

statistician have access to them. The data gathered will be saved during the entire

duration of data processing, writing of final paper until the final presentation of research.

Once the final research output has been presented and approved by the research

committee, all records and raw data will be destroyed after a year. The data contained

in the laptop will be deleted and all notes pertaining to the study will likewise be

discarded by shredding.

Significant data and results of this study may be presented to the medical

community, and may be used as baseline for future researches, and may be also cited

as reference for other related studies. The anonymity of participants will be kept with

utmost confidentiality when research is shared during presentation in scientific forum or

when submitted for publication. In all instances, strict confidentiality will be maintained,

and no information that will identify the patient as participant will be disclosed.

An informed consent is no longer required from the participants as the data

gathered are all part of the routine interview and examination of the patients on initial

consult and succeeding follow-up.

GANTT CHART FOR TIMETABLE OF ACTIVITIES

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Reserach Specific Expected Duration by month
phase Activities outcome
J F M A M J J A S O N D 2022

Making of the Finish it by                        

research 5-7
proposal months

(Introduction to
methodology,
then have it
checked and
approved by
Research and
Ethics
committee)

Phase 2: Data Once approved Finish it                        

collection by Ethics until
committee, December
  collection of 2021
data starts
(reviewing of
medical
records)

Phase 3 : Data entry, For 1-2                        

interpretation months
Data and analysis
interpretation (together with
and analysis the statistician)

Phase 4 : Finalizing the For 1-3                        

manuscript months
Final
Manuscript
writing

BUDGET

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 Expenditure/Item Amount in Peso

Materials and supplies 3000-4000

(bond papers, folders,

paper clips, etc)

Printing, photocopy, binding 3000-4000

of research proposal/final

manuscript

Statistician 5000-10000

Others 5000

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29096812.

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