Ischemic stroke in patients that recover from COVID-19: Comparisons to historical stroke prior to COVID-19 or stroke in patients with active COVID-19 infection.

BACKGROUND AND
PURPOSE: Understanding the relationship of COVID-19 to stroke is important. We compare characteristics of pre-pandemic historical stroke (Pre-C), cases in acute COVID infection (Active-C) and in patients who have recovered from COVID-19 infection (Post-C).
METHODS: We interrogated the Qatar stroke database for all stroke admissions between Jan 2019 and Feb 2020 (Pre-C) to Active-C (Feb2020-Feb2021) and Post-C to determine how COVID-19 affected ischemic stroke sub-types, clinical course, and outcomes prior to, during and post-pandemic peak. We used the modified Rankin Scale (mRS) to measure outcome at 90-days (mRS 0-2 good recovery and mRS 3-6 as poor recovery). For the current analysis, we compared the clinical features and prognosis in patients with confirmed acute ischemic stroke.
RESULTS: There were 1413 cases admitted (pre-pandemic: 1324, stroke in COVID-19: 46 and recovered COVID-19 stroke: 43). Patients with Active-C were significantly younger, had more severe symptoms, fever on presentation, more ICU admissions and poor stroke recovery at discharge when compared to Pre-C and Post-C. Large vessel disease and cardioembolic disease was significantly more frequent in Active-C compared to PRE-C or post-C.
CONCLUSIONS: Stroke in Post-C has characteristics similar to Pre-C with no evidence of lasting effects of the virus on the short-term. However, Active-C is a more serious disease and tends to be more severe and have a poor prognosis.

Introduction

The number of COVID-19 cases worldwide exceeded 430,000,000 as of February 24, 2022 with most patients recovering from the infection [1]. COVID-19 may affect the cardiovascular system and increases the risk of venous thrombosis and pulmonary embolism [2], myocardial injury [3] and stroke [4, 5]. Acute stroke has been reported in 0.5–2.5% of active COVID-19 and tends to be more severe with a higher mortality [4]. Stroke in active COVID-19 tends to be severe and caries a higher rate of mortality [4-7]. To our knowledge, there are no studies that have compared the stroke phenotype in patients that recover from COVID-19 infection to stroke in patients with no previous history of stroke or when stroke occurs following a complete recovery from the infection.

We have previously published on acute stroke in COVID-19 pandemic from Qatar [7, 8]. Our previous research compared the rates of stroke admissions prior to the pandemic and during the pandemic. There was a significant increase in patients with severe stroke and there were fewer patients admitted with diagnosis of ‘stroke mimic’ during the first phase of the COVID-19 pandemic. Our main objective for the current research was to compare the clinical presentation, severity and type of stroke, and prognosis in strokes that were admitted to our hospital prior to the COVID-19 pandemic (Pre-C), stroke in patients with active COVID-19 infection (Active-C) and the development of stroke in subjects who had full clinical recovery from COVID-19 (Post-C).

Methods

The Qatar Stroke Database prospectively collects information on most acute stroke (98%) admitted in Qatar to the Hamad General Hospital (HGH) since February 2013 as previously published [9, 10]. The Institutional Review Board, Hamad Medical Corporation at the Medical Research Centre (MRC-01-20-489) approved the study. Data will be made available on request.

All acute stroke patients admitted to HGH between January-2019 to February-2020 were evaluated for the study (Pre-C) and served as the reference comparator for the COVID-19 cases. The patients who developed stroke while they had active COVID-19 positive were admitted to the hospital between February 2020 (when the first cases of COVID-19 were reported in Qatar) and February 2021. The active-C cases all had active viral disease at the time of the stroke and the Post-C patients had all recovered from the viral illness at the time of the stroke. All patients in the Post-C group had a confirmation of the diagnosis of COVID-19 infection with rt-PCR testing. All patients in post-C group were tested for COVID-19 had fully recovered from the viral infection and no patients displayed symptoms associated with long-COVID. The clinical information including risk factors, investigations, clinical presentation, and course during hospitalization were recorded. The severity of symptoms at admission (NIHSS score), clinical diagnosis as defined by the TOAST classification [11] and Bamford classification [12], and the length of stay in hospital are also recorded. The modified Rankin Scale (mRS) pre-admission, at discharge, and at 90-day follow-up are also documented.

Patient and public involvement

Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research.

Statistical analysis

Descriptive statistics in the form of mean and standard deviations for continuous variables and frequency with percentages for categorical variables were performed. One-way ANOVAs with post hoc (Bonferroni) analyses were performed to see significant mean level differences for all continuous variables according to Pre-COVID, Active COVID and Post -COVID stroke groups. Chi-Square tests with standardized residuals were calculated to see association with categorical variables and the groups. Multivariate logistic regression analysis was performed to see associated risk factors to 90 days poor outcome. Adjusted odds ratio (OR) with 95% C.I. and P values were presented. P value less than equal to 0.05 (two tailed) was considered statistically significant level. SPSS 28.0 statistical package was used for the analysis.

Results

There were 1413 patients [age; 54.2 ± 12.9 male 1156/1413 (81.8%) female 257/1413 (18.2%)] admitted to HGH during the study period and available for analysis. Of the 1413 stroke patients, there were 1324 patients admitted without COVID-19 in the 14 months prior to the pandemic (Pre-C), 46 cases with active COVID-19 infection (Active-C) and 43 COVID-19-recovered cases (Post-C) as shown in the Table 1.

Table 1

Demographic and clinical characteristics of patients with recovered COVID-19, active COVID-19, and pre-pandemic stroke patients.

Characteristics or Investigations	Total Stroke Cases (n = 1413)	Pre-COVID Stroke (n = 1324)	Active-COVID Stroke (n = 46)	Post-COVID Stroke (n = 43)	P Value
Age, Mean, years	54.2 ±12.9	54.3 ±12.9	51.3 ±10.2	54.4 ±14.3	0.31
Sex—Male	1156 (81.8)	1077 (81.3)	44 (95.7)	35 (81.4)	0.05
Female	257 (18.2)	247 (18.7)	2 (4.3)	8 (18.6)
Risk factors
Hypertension	1033 (73.1)	986 (74.5)	21 (45.7)	26 (60.5)	<0.001
Diabetes	775 (54.8)	732 (55.3)	19 (41.3)	24 (55.8)	0.17
Dyslipidemia	770 (54.5)	754 (56.9)	3 (6.5)	13 (30.2)	<0.001
Atrial Fibrillation on Admission	75 (5.3)	70 (5.3)	0	5 (6.7)	0.05
Active Smoking	456 (32.3)	439 (33.2)	8 (17.4)	9 (20.9)	0.02
Prior Stroke	171 (12.1)	163 (12.3)	4 (8.7)	4 (9.3)	0.001
Coronary Artery Disease	183 (13.0)	174 (13.1)	4 (8.7)	5 (11.6)	0.65
BMI on admission (mean)	27.8 ±5.1	27.9 ±5.1	26.2 ±4.0	26.5 ±4.4	0.01
Fever on Admission	24 (1.7)	7 (0.5)	13 (28.3)	4 (9.3)	<0.001
NIHSS on admission (mean)	5.1 ±6.1	4.8 ±5.9	10.8 ±8.6	6.1 ±7.4	<0.001
NIHSS Severity
Mild (NIHSS 0–4)	939 (66.5)	898 (67.8)	14 (30.4)	27 (62.8)	<0.001
Moderate (NIHSS 5–10)	270 (19.1)	248 (18.7)	14 (30.4)	8 (18.6)
Severe (NIHSS >10)	204 (14.4)	178 (13.4)	18 (39.1)	8 (18.6)
IV Thrombolysis given	146 (10.3)	140 (10.6)	4 (8.7)	2 (4.7)	0.42
Thrombectomy done	74 (5.2)	70 (5.3)	1 (2.2)	3 (7.0)	0.57
ICU Admission	85 (6.0)	64 (4.8)	15 (32.6)	6 (14.0)	<0.001
Intubated during Admission	73 (5.2)	61 (4.6)	9 (19.6)	3 (7.0)	<0.001
TOAST Classification
Small Vessel Disease	622 (44.0)	605 (45.7)	5 (10.9)	12 (27.9)	<0.001
Large Vessel Disease	231 (16.3)	210 (15.9)	13 (28.3)	8 (18.6)
Cardioembolic	359 (25.4)	329 (24.8)	16 (34.8)	14 (32.6)
Stroke of Determined Origin	86 (6.1)	75 (5.7)	6 (13.0)	5 (11.6)
Stroke of Undetermined Origin	115 (8.1)	105 (7.9)	6 (13.0)	4 (9.3)
Prognosis at Discharge
Good (mRS 0–2)	829 (58.7)	791 (59.7)	11 (23.9)	27 (62.8)	<0.001
Poor (mRS 3–6)	584 (41.3)	533 (40.3)	35 (76.1)	16 (37.2)
Prognosis at 90-Days (n = 1088)
Good (mRS 0–2)	721 (66.3)	671 (67.2)	18 (39.1)	32 (74.4)	<0.001
Poor (mRS 3–6)	367 (33.7)	328 (32.8)	28 (60.9)	11 (25.6)
Mortality at Discharge	19 (1.3)	18 (1.4)	1 (2.2)	0	0.66
Mortality at 90-Days (n = 1088)	49 (4.5)	42 (4.2)	5 (10.9)	2 (4.7)	0.10
Characteristics or Investigations	Total Stroke Cases (n = 1413)	Pre-COVID Stroke (n = 1324)	Active-COVID Stroke (n = 46)	Post-COVID Stroke (n = 43)	P Value
Heart rate	81.8 ±14.9	81.6 ±14.9	84.8 ±13.8	84.7 ±13.7	0.16
Systolic Blood Pressure	155.8 ±30.5	156.4 ±30.6	147.6 ±33.3	146.7 ±22.5	0.02
Diastolic Blood Pressure	90.6 ±19.2	90.6 ±19.3	88.6 ±20.1	92.5 ±15.3	0.63
Platelet Counts	270.3 ±78.5	268.7 ±75.3	302.6 ±123.9	285.5 ±101.1	0.007
HbA1c on Admission	7.6 ±4.8	7.5 ±4.9	7.9 ±2.5	7.7 ±2.4	0.87
Length of Stay	6.3 ±10.1	5.3 ±5.5	29.1 ±31.0	11.5 ±29.1	<0.001

There was no significant difference in the age of the three groups. The higher percentage of males reflects the demographics of Qatar with a predominantly male expatriate population as have been previously reported [9, 10]. The mean duration of time between recovery from COVID-19 infection and stroke was 126.9±75.9 days (median 124 days). Small vessel disease (SVD) is the most common type of stroke in the Qatari and expatriate population, likely due to the high prevalence of poorly controlled hypertension and diabetes as has been previously documented [10]. SVD was significantly lower in active-C (10.9%) compared to 45.7% in pre-C and 27.9% in post-C (p<0.001). The active-C group was associated with an increase in the percentage of large vessel and embolic stroke as shown in the Table 1.

The active-C patients were more likely to have higher NIHSS on admission and significantly more patients had cortical strokes. The admission NIHSS was 10.8± 8.6 in active-C, compared to 4.8± 5.9 in the pre-C and 6.1±7.4 in post-C patients (p <0.001). Active COVID-19 patients were more likely to be febrile (28.3% versus pre-C (0.5%) and post-C (9.3%). Patients with active COVID-19 and stroke were more likely to have admissions to the ICU (active-C: 32.6%, pre-C: 4.8% and post-C: 14%; p<0.001), more frequently required intubation (active-C:19.6%, pre-C: 4.61% and post-C: 7%; p<0.001) and had longer length of hospitalization [LOC] (active-C: 29.1±31.0, pre-C: 5.3±5.5 and post-C: 11.5±29.1 days, P<0.001). One Way ANOVA with Bonferroni post-hoc analysis was performed to see statistical significance of mean differences between the groups of NIHSS on admission and length of stay. On Post-hoc analysis of NIHSS on admission, active-C patients score was significantly higher than the pre-C patients, whereas there was no statistical difference between pre-C and post-C patients NIHSS score on admission, (p<0.001). On Post-hoc analysis of length of stay, active-C and post-C patient’s duration of stay was significantly prolonged when compared to the pre-C patients (p<0.001).

Patients with stroke following recovery from COVID-19 (post-C) had a clinical profile very similar to pre-C patients. These patients had all fully recovered from the acute infection, and none had any symptoms suggestive of profiles of COVID-19 long-haulers. They had milder neurological disease on admission, and similar mRS at discharge (mRS [0-2] active-C: 23.9%, pre-C: 59.7% and post-C: 62.8% P <0.001). They were, however, more likely to be febrile on admission compared to pre-C. Recovering COVID-19 stroke patients with fever had similar clinical course and prognosis to patients without fever (poor outcome [mRS 3–6] 20.0 vs 21.6%, p = 0.93) and all febrile recovering stroke patients had no evidence of active COVID-19 infection.

Patients in whom acute stroke occurred during active COVID-19 infection had slower recovery during hospitalization and at 90-days follow-up when compared to pre-C or post-C patient as shown in Fig 1. At 90-day follow up, good recovery (mRS 0–2) was seen in 39.1% in active-C patients compared to 67.2% in pre-C and 74.4% in post-C subjects (P <0.001).

Fig 1

Showing outcome of patients with active COVID-19 infection have significantly fewer patients who improved to a mRS of 0–2 at the 90-days follow-up compared to patients who never had the viral infection or who fully recovered from the infection.

Adjusting age and sex in the multivariate logistic regression analysis, NIHSS score on admission (adjusted OR: 1.23, 95% C.I.: 1.20–1.26, p = 0.001) and febrile on admission (adjusted OR: 3.65, 95% C.I. 1.36–9.83, p = 0.01), were found to be associated with poor outcome at 90 days (Table 2 and Fig 2). There was no statistical association for BMI, prior hypertension, ICU admission and intubated during admission. The regression model was able to discriminate 83% accurately for the 90 days poor outcome.

Table 2

Multivariate analysis of the variables associated with 90-day poor outcome in all three groups.

VARIABLE	ODDS RATIO	95% CI		P Value
		LOWER	UPPER
Age	1.06	1.04	1.07	<0.001
Sex	0.55	0.37	0.81	0.002
BMI	1.00	0.97	1.03	0.86
Prior Hypertension	1.14	0.75	1.73	0.53
Prior Dyslipidemia	1.42	1.03	1.96	0.04
Prior Stroke	1.08	0.69	1.68	0.72
Febrile on Admission	6.02	1.69	21.38	0.006
NIHSS score on Admission	1.19	1.15	1.23	<0.001
ICU Admission	1.17	0.56	2.49	0.69
Systolic Blood Pressure	1.0	0.99	1.01	0.85
Platelet count	1.00	0.99	1.00	0.17

Fig 2

ROC CURVE- To predict accuracy of 90-day poor outcome from the model.

Discussion

Patients with active COVID-19 related stroke had severe stroke and were also more likely to be febrile, requiring intubation and ICU admissions, and longer hospital stay. The most important new observation from our study relates to the stroke in patients with full recovery following COVID-19 infection. These patients had a rt-PCR confirmed diagnosis of COVID-19 infection and the stroke occurred following weeks to months of complete recovery of the viral infection. The overall pattern of stroke in this group was similar to and the profile and clinical course of patients with stroke prior to the pandemic. The stroke was likely related to the underlying vascular risk factors and not due to possible long-term sequala of the COVID-19 infection although we cannot be entirely certain of any potential relationship.

It is important to note that all patients in the post-C group had fully recovered from the viral infection and none had symptoms commonly associated with COVID-19 long-haulers. When comparing to the 1324 patients who had a stroke prior to the COVID-19 pandemic, the post-C had identical presentation, risk factors, clinical course, and prognosis. It is also interesting that once the patients recovered, the types of stroke as defined by the TOAST criteria [11] were very similar to what we had observed over in patients in the 14 months prior to COVID-19 pandemic.

Our study suggests that COVID-19 did not contribute to the etiology of stroke once the patient recovers. There are however several factors related to COVID-19 that may increase the risk of stroke in patients who have recovered and these needs attention [13, 14]. Potential mechanisms include continued endothelial injury [13], cardioembolism and potential paradoxical embolism via a PFO [15] or arterial dissection [16]. While the recovery is complete following COVID-19 in most patients, the “long-haulers” may have a prolonged inflammatory and prothrombotic state and therefore at a high risk for complications [17]. COVID-19 infection results in injury to the arterial endothelium, resulting in a prothrombotic state [13]. The prothrombotic state may persist and increase the risk of stroke. Cardiac muscle injury and heart failure seen with COVID-19 [15] may potentially contribute to embolic stroke in some cases. Cardioembolism was the final diagnosis in 14% of our patients with stroke following recovery from COVID-19 which is lower than the 25% seen in pre-COVID-19 cases and therefore likely did not contribute to the post-COVID-19 cases. Similarly, there were no cases of arterial dissection in the post-COVID-19 group.

There are strengths to our study. The Qatar Stroke Database is very robust and has prospectively recorded stroke trends in the country for more than 7 years. While the prospective data collection had shown a steady increase in admission rates over several years, the dramatic decline during over three months as the number of COVID-19 cases is very striking [8]. This is similar to multiple observations from around the world as noted in a recent meta-analysis from our group [18]. Our study shows that active COVID-19 positive stroke patients were more likely to be sicker, had more cortical involvement and had prolonged LOC and fewer frequency of good recovery at discharge. We also showed that patients who suffer a stroke following recovery from COVID-19 has similar characteristics to pre-COVID-19 cases.

The study has some limitations. A change over three months is brief and may not be sufficient to completely understand COVID-19-related changes. We noted higher rates of fever in the post-COVID patients. Although we are confident that none of the patients had active COVID-19, we cannot rule this out with certainty, nor can we rule out the possibility that this group of patients were on a higher risk for other infections. We did not document the relationship between the severity of COVID-19 and stroke. We also do not have enough long-term follow-up data at present on the patients seen during the pandemic to adequately document the changes in outcomes.

In summary, we present a comparison study on stroke subtypes prior to the pandemic to COVID-19 positive cases, and stroke in patients who recovered from the illness. Our data in 43 patients who had recovered from COVID-19 is reassuring in indicating no short-term effects of the illness.

19 Oct 2021

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Reviewer 1:

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. The authors made all data underlying the findings in their manuscript fully available without restriction. However there are some issues about the language and grammar.

to authors: in the abstract the period of the study is between Jan 2020 and Feb 2021, while in the methods section in the manuscript you did not mention that only you mention that patients between January-2019 to February-2020 were evaluated for the study (PPS) and served as the reference comparator for the COVID-19 cases. # At the end of introduction (We also evaluated the characteristics of stroke in post-COVID-19 stroke to no history of COVID-19 infection) please consider revising language. # At results :male/female 2404 (73.7%)/4860 (26.3%)] please correct number. Why did not you exclude the stroke mimic patients from the clinical characteristics and risk factors studied? it would differ in the percentage of each studied parameter. # in discussion: (None of our patients had symptoms associated with long haulers and as best as best as we can determine) please correct. # (This is similar to our recent meta-analysis of multiple observations from around the world (ADD our recent meta-analysis) please put the reference.

#( A change over three months is brief and may not be sufficient to completely understand COVID-19-related changes)this statement is not clear what do you mean by it?

Reviewer 2:

The timing of the manuscript is perfect given the ongoing pandemic. This study has provided new knowledge on stroke patients who have recovered from COVID-19. This is in addition to the already published data on acute stroke with acute Covid-19 infection.

However, there are a few minor comments

1) The authors should provide the population the HGH provides stroke services to since the hospital admits 95% of strokes in Qatar.

2) Statistics:

a) For consistency, p value should be added to “more frequently required intubation (CS:31.3%, PPS: 5.1% and RCS: 3.2%)” similar to the ICU admissions.

b) P value for NIHSS, ICU admission and other three-group comparisons (p. 16-18 of PDF) – a single p value is reported, presumably reflecting the ANOVA; the post-hoc Bonferroni p values should also be reported, at least in supplementary

3) The authors should remove or edit the comment “ ADD our recent meta-analysis” in the sentence “This is similar to our recent meta-analysis of multiple observations from around the world (ADD our recent meta-analysis) ( page 19 of PDF)

Reviewer 3:

The objective of this article was to compare characteristics and outcomes among acute stroke patients prior to the COVID-19 pandemic, stroke patients during active COVID-19 infection, and stroke patients after recovering from COVID-19. I appreciate the authors' revision of the manuscript. I believe this is an interesting article that would be of interest to the journals’ readers, but a number of improvements are still needed:

ABSTRACT

1. Some of the terminology should be more specific/clarified in the results section. For example: (1) What specific outcome do you mean by “poor stroke recovery”?, (2) “Large vessel disease and cardioembolic disease was significantly higher…”. Do you mean these were significantly more common?, (3) “There was a significant decline in stroke mimics…” Do you mean stroke mimics were less common, and if so, compared to which groups?

2. Methods: You mention that you included stroke cases between January 2020 and Feb 2021. However, in the full methods section, you stated that you included stroke patients admitted to HGH starting from January 2019. Please clarify

INTRODUCTION

1. “The number of COVID-19 worldwide…”. You should specify that this is the number of COVID-19 cases

2. While I appreciate the added detail in the introduction, make sure that everything is relevant to your study and it is clear why it is relevant for the reader. For example, what is the relevance of your prior publications that stroke occurs at a young age and acute stroke in COVID-19 pandemic from Qatar?

3. It doesn’t appear that the main objective was to evaluate the RISK of stroke (ie, the risk of having a stroke among all individuals in the source population who recovered from COVID-19- there is no quantification of this anywhere). Be careful with terminology.

METHODS

1. How did you define RCS patients? This should be clearly stated, because you need to define your main exposure group. Was it acute stroke within a specific number of days of recovering from COVID-19 infection? Would someone who had a stroke 1 year after recovering from COVID-19 be considered in the same group as individuals who had a stroke 1 month after recovering?

2. Statistical analysis: In your multivariate logistic regression model, did you also include a variable for the category of stroke (COVID-19 stroke, pre-COVID-19 stroke, recovered stroke)? Or was this model only run on patients with recovered stroke?

RESULTS

1. Under “demographic characteristics in the three groups”, the second and third sentences do not belong in the results section and should be moved to the discussion (interpretation of results should be limited to the discussion section only)

2. Same for the discussion about stroke mimics (“The details and possible reasons for the decrease in the percentage of stroke-mimics…”.. “Small vessel disease (SVD)…”)

TABLE

1. Table 1- Should clarify that BMI is mean +/- standard deviation

Finally, please review the article thoroughly for typos.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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5. Review Comments to the Author

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Reviewer #1: The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. The authors made all data underlying the findings in their manuscript fully available without restriction. However there are some issues about the language and grammar.

to authors: in the abstract the period of the study is between Jan 2020 and Feb 2021, while in the methods section in the manuscript you did not mention that only you mention that patients between January-2019 to February-2020 were

evaluated for the study (PPS) and served as the reference comparator for the COVID-19 cases. # At the end of introduction (We also evaluated the characteristics of stroke in post-COVID-19 stroke to no history of COVID-19 infection) please consider revising language. # At results :male/female 2404 (73.7%)/4860 (26.3%)] please correct number. Why did not you exclude the stroke mimic patients from the clinical characteristics and risk factors studied? it would differ in the percentage of each studied parameter. # in discussion: (None of our patients had symptoms associated with long haulers and as best as best as we can determine) please correct. # (This is similar to our recent meta-analysis of multiple observations from around the world (ADD our recent meta-analysis) please put the reference.

#( A change over three months is brief and may not be sufficient to completely understand COVID-19-related changes)this statement is not clear what do you mean by it?

Reviewer #2: The timing of the manuscript is perfect given the ongoing pandemic. This study has provided new knowledge on stroke patients who have recovered from COVID-19. This is in addition to the already published data on acute stroke with acute Covid-19 infection.

However, there are a few minor comments

1) The authors should provide the population the HGH provides stroke services to since the hospital admits 95% of strokes in Qatar.

2) Statistics:

a) For consistency, p value should be added to “more frequently required intubation (CS:31.3%, PPS: 5.1% and RCS: 3.2%)” similar to the ICU admissions.

b) P value for NIHSS, ICU admission and other three-group comparisons (p. 16-18 of PDF) – a single p value is reported, presumably reflecting the ANOVA; the post-hoc Bonferroni p values should also be reported, at least in supplementary

3) The authors should remove or edit the comment “ ADD our recent meta-analysis” in the sentence “This is similar to our recent meta-analysis of multiple observations from around the world (ADD our recent meta-analysis) ( page 19 of PDF)

Reviewer #3: The objective of this article was to compare characteristics and outcomes among acute stroke patients prior to the COVID-19 pandemic, stroke patients during active COVID-19 infection, and stroke patients after recovering from COVID-19. I appreciate the authors' revision of the manuscript. I believe this is an interesting article that would be of interest to the journals’ readers, but a number of improvements are still needed:

ABSTRACT

1. Some of the terminology should be more specific/clarified in the results section. For example: (1) What specific outcome do you mean by “poor stroke recovery”?, (2) “Large vessel disease and cardioembolic disease was significantly higher…”. Do you mean these were significantly more common?, (3) “There was a significant decline in stroke mimics…” Do you mean stroke mimics were less common, and if so, compared to which groups?

2. Methods: You mention that you included stroke cases between January 2020 and Feb 2021. However, in the full methods section, you stated that you included stroke patients admitted to HGH starting from January 2019. Please clarify

INTRODUCTION

1. “The number of COVID-19 worldwide…”. You should specify that this is the number of COVID-19 cases

2. While I appreciate the added detail in the introduction, make sure that everything is relevant to your study and it is clear why it is relevant for the reader. For example, what is the relevance of your prior publications that stroke occurs at a young age and acute stroke in COVID-19 pandemic from Qatar?

3. It doesn’t appear that the main objective was to evaluate the RISK of stroke (ie, the risk of having a stroke among all individuals in the source population who recovered from COVID-19- there is no quantification of this anywhere). Be careful with terminology.

METHODS

1. How did you define RCS patients? This should be clearly stated, because you need to define your main exposure group. Was it acute stroke within a specific number of days of recovering from COVID-19 infection? Would someone who had a stroke 1 year after recovering from COVID-19 be considered in the same group as individuals who had a stroke 1 month after recovering?

2. Statistical analysis: In your multivariate logistic regression model, did you also include a variable for the category of stroke (COVID-19 stroke, pre-COVID-19 stroke, recovered stroke)? Or was this model only run on patients with recovered stroke?

RESULTS

1. Under “demographic characteristics in the three groups”, the second and third sentences do not belong in the results section and should be moved to the discussion (interpretation of results should be limited to the discussion section only)

2. Same for the discussion about stroke mimics (“The details and possible reasons for the decrease in the percentage of stroke-mimics…”.. “Small vessel disease (SVD)…”)

TABLE

1. Table 1- Should clarify that BMI is mean +/- standard deviation

Finally, please review the article thoroughly for typos.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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16 Mar 2022

Reviewer 1:

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. The authors made all data underlying the findings in their manuscript fully available without restriction. However there are some issues about the language and grammar.

to authors: in the abstract the period of the study is between Jan 2020 and Feb 2021, while in the methods section in the manuscript you did not mention that only you mention that patients between January-2019 to February-2020 were evaluated for the study (PPS) and served as the reference comparator for the COVID-19 cases. # At the end of introduction (We also evaluated the characteristics of stroke in post-COVID-19 stroke to no history of COVID-19 infection) please consider revising language. # At results: male/female 2404 (73.7%)/4860 (26.3%)] please correct number. Why did not you exclude the stroke mimic patients from the clinical characteristics and risk factors studied? it would differ in the percentage of each studied parameter. # in discussion: (None of our patients had symptoms associated with long haulers and as best as best as we can determine) please correct. # (This is similar to our recent meta-analysis of multiple observations from around the world (ADD our recent meta-analysis) please put the reference. #(A change over three months is brief and may not be sufficient to completely understand COVID-19-related changes)this statement is not clear what do you mean by it?

Response: We thank the reviewer for the comments. We have corrected the time period and have removed the “stroke mimics” and done a complete re-analysis of the data for the revised manuscript. We have revised the abstract to reflect the changes. Additional changes in the “Introduction” and “Discussion” section will, we hope, improve the quality of the research.

Reviewer 2:

The timing of the manuscript is perfect given the ongoing pandemic. This study has provided new knowledge on stroke patients who have recovered from COVID-19. This is in addition to the already published data on acute stroke with acute Covid-19 infection.

However, there are a few minor comments

1) The authors should provide the population the HGH provides stroke services to since the hospital admits 95% of strokes in Qatar.

We have added information in the “Methods” section on the catchment area of HGH.

2) Statistics:

a) For consistency, p value should be added to “more frequently required intubation (CS:31.3%, PPS: 5.1% and RCS: 3.2%)” similar to the ICU admissions.

We apologize for this error. This was a typing error. We have added the p values to the above-mentioned variables.

b) P value for NIHSS, ICU admission and other three-group comparisons (p. 16-18 of PDF) – a single p value is reported, presumably reflecting the ANOVA; the post-hoc Bonferroni p values should also be reported, at least in supplementary

We thank the reviewer for the comment. The post-hoc Bonferroni analysis for the continuous variables are added to the results section

We apologize for this error. We have added the p values to the

3) The authors should remove or edit the comment “ ADD our recent meta-analysis” in the sentence “This is similar to our recent meta-analysis of multiple observations from around the world (ADD our recent meta-analysis) ( page 19 of PDF)

We apologize for the error. The correct manuscript/reference has been added

Reviewer 3:

The objective of this article was to compare characteristics and outcomes among acute stroke patients prior to the COVID-19 pandemic, stroke patients during active COVID-19 infection, and stroke patients after recovering from COVID-19. I appreciate the authors' revision of the manuscript. I believe this is an interesting article that would be of interest to the journals’ readers, but a number of improvements are still needed:

ABSTRACT

1. Some of the terminology should be more specific/clarified in the results section. For example: (1) What specific outcome do you mean by “poor stroke recovery”?, (2) “Large vessel disease and cardioembolic disease was significantly higher…”. Do you mean these were significantly more common?, (3) “There was a significant decline in stroke mimics…” Do you mean stroke mimics were less common, and if so, compared to which groups?

2. Methods: You mention that you included stroke cases between January 2020 and Feb 2021. However, in the full methods section, you stated that you included stroke patients admitted to HGH starting from January 2019. Please clarify

As noted in our response to reviewer 1, we have completely revised the abstract.

INTRODUCTION

1. “The number of COVID-19 worldwide…”. You should specify that this is the number of COVID-19 cases

2. While I appreciate the added detail in the introduction, make sure that everything is relevant to your study and it is clear why it is relevant for the reader. For example, what is the relevance of your prior publications that stroke occurs at a young age and acute stroke in COVID-19 pandemic from Qatar?

3. It doesn’t appear that the main objective was to evaluate the RISK of stroke (ie, the risk of having a stroke among all individuals in the source population who recovered from COVID-19- there is no quantification of this anywhere). Be careful with terminology.

We thank the reviewer for the comments. We have revised the “Introduction” section to make it more focused

METHODS

1. How did you define RCS patients? This should be clearly stated, because you need to define your main exposure group. Was it acute stroke within a specific number of days of recovering from COVID-19 infection? Would someone who had a stroke 1 year after recovering from COVID-19 be considered in the same group as individuals who had a stroke 1 month after recovering?

2. Statistical analysis: In your multivariate logistic regression model, did you also include a variable for the category of stroke (COVID-19 stroke, pre-COVID-19 stroke, recovered stroke)? Or was this model only run on patients with recovered stroke?

We thank the reviewer for the useful suggestion and we have made corrections accordingly

RESULTS

1. Under “demographic characteristics in the three groups”, the second and third sentences do not belong in the results section and should be moved to the discussion (interpretation of results should be limited to the discussion section only)

2. Same for the discussion about stroke mimics (“The details and possible reasons for the decrease in the percentage of stroke-mimics…”.. “Small vessel disease (SVD)…”)

We thank the reviewer for the comments and we have made appropriate changes

TABLE

1. Table 1- Should clarify that BMI is mean +/- standard deviation

We have changed it as suggested by the reviewer

Finally, please review the article thoroughly for typos.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Submitted filename: PLOS response to reviewers-March 02.docx

Click here for additional data file.

21 Apr 2022

28 Apr 2022

We are thankful for the additional comments from reviewer #1. We have corrected the errors in the abstract and the discussion section (track changes).

We have also explained the questions raised about the strokes subtypes. We appreciated the thoughtful comments.

Submitted filename: Response to the reviewers comments.docx

Click here for additional data file.

10 Jun 2022

Ischemic stroke in patients that recover from COVID-19: Comparisons to historical stroke prior to COVID-19 or stroke in patients with active COVID-19 infection

PONE-D-21-32603R2

Dear Dr. Shuaib,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Farzad Taghizadeh-Hesary

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: the manuscript is technically sound, and do the data support the conclusions. The authors have adequately addressed comments raised in a previous round of review and the manuscript is now acceptable for publication. The manuscript is presented in an intelligible fashion and written in standard English. The authors made all data underlying the findings in their manuscript fully available.

Reviewer #3: Thank you for addressing the reviewer comments. I believe this will make a valuable contribution to the research field.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

**********

14 Jun 2022

PONE-D-21-32603R2

Ischemic stroke in patients that recover from COVID-19: Comparisons to historical stroke prior to COVID-19 or stroke in patients with active COVID-19 infection

Dear Dr. Shuaib:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Farzad Taghizadeh-Hesary

Academic Editor

PLOS ONE