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. 2024 Oct 3;19(10):e0301313. doi: 10.1371/journal.pone.0301313

Deciphering changes in the incidence of hemorrhagic stroke and cerebral venous sinus thrombosis during the coronavirus disease 2019 pandemic: A nationwide time-series correlation study

Soo Hyeon Cho 1,#, Dong Kyu Kim 2,#, Min Cheol Song 3, Euiho Lee 4,5, Seoncheol Park 6,7, Darda Chung 8,*, Jongmok Ha 9,10,*
Editor: Sonu Bhaskar11
PMCID: PMC11449313  PMID: 39361618

Abstract

Introduction

Hemorrhagic stroke and cerebral venous sinus thrombosis (CVST) are associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. We aimed to investigate changes in the incidence of hemorrhagic stroke and CVST in South Korea before and during the coronavirus disease 2019 pandemic and the factors associated with these changes.

Materials and methods

We conducted a nationwide time-series study using population-based databases between 2007 and 2022. The real-world and forecasted incidences of acute non-traumatic subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and CVST during the pandemic period (2020–2022) were estimated and compared with the pre-pandemic period (2007–2019). The prevalence of conventional risk factors was measured using time-series data. Finally, a time-series correlation analysis was performed to examine the temporal association between conventional risk factors, SARS-CoV-2 infection, and SARS-CoV-2 vaccination.

Results

The incidence of hemorrhagic stroke (SAH and ICH) was lower during the pandemic than during the pre-pandemic period. This observed decrease was associated with a reduction in the prevalence of conventional risk factors but not with SARS-CoV-2 infection or vaccination. The incidence of CVST was higher during the pandemic than during the pre-pandemic period, which may be temporally related to SARS-CoV-2 vaccination (Pearson correlation coefficient [r] = 0.349, P = 0.031).

Conclusion

We report reassuring evidence of hemorrhagic stroke associated with SARS-CoV-2 infection and vaccination. However, awareness of CVST may be required for future vaccine rollouts and SARS-CoV-2 outbreaks.

1. Introduction

Various neurological complications have been associated with SARS-CoV-2 infection and vaccination, raising public health concerns [1, 2]. One of the controversial complications linked to these novel immune stimuli is hemorrhagic stroke and cerebral venous sinus thrombosis (CVST). These diseases are particularly relevant because they are major neurological conditions that can cause disabilities and societal burden [3].

Hemorrhagic stroke or intracranial hemorrhage can crudely be dichotomized into intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), each of which has overlapping causes (e.g., hypertension, usage of antithrombotic medication) and distinct etiologic risk factors (e.g., arteriovenous malformation for the former and intracranial aneurysm for the latter) [4]. Moreover, CVST is a venous thrombotic disorder that can cause seizures and venous strokes in young adults and is often associated with the use of oral contraceptives or conditions that provoke serum hypercoagulability [5].

Data-driven, self-controlled case series studies have identified an association between hemorrhagic stroke and SARS-CoV-2 vaccines. A study in England has reported an increased risk of ICH, 1–7 and 15–21 days after the first dose of BNT162b2 mRNA-based vaccine, and an increased risk of SAH following 0–14 days of SARS-CoV-2 infection [6]. Another study in Wales has reported an increased risk of hemorrhagic events at 8–14 days after the first dose of the BNT162b2 vaccine and 0–28 days after SARS-CoV-2 infection [7]. Furthermore, a Scottish study has identified increased hemorrhagic risks within 7–27 days of the first ChAdOx1-S/nCoV-19 vaccine dose and within 28 days of the first BNT162b2 vaccine dose [8].

Viral vector-based SARS-CoV-2 vaccination, especially ChAdOx1-S/nCoV-19 was associated with CVST, which can be generally explained through mechanisms of thrombosis with thrombocytopenia syndrome (TTS) [9–11]. A Scottish study has identified an increased risk of venous thromboembolism, 14–27 days and >28 days after the first dose of the ChAdOx1-S/nCoV-19 vaccine [8]. Another study in England has reported that the first dose of the ChAdOx1-S/nCoV-19 vaccine increased the risk of CVST by an incidence risk ratio of 4.01 within 8–14 days [12].

Although these studies provide sufficient evidence to suggest an association, none have validated these findings using a time-series study design, especially in the Korean population. Thus, this study aimed to investigate changes in the incidence of hemorrhagic stroke and CVST in South Korea before and during the coronavirus disease 2019 (COVID-19) pandemic. Furthermore, we explored the factors that could explain these changes.

2. Materials and methods

2.1. Study design and participants

This nationwide time-series correlation study used population-based data from the Health Insurance Review and Assessment Service (HIRA), National Health Insurance Service (NHIS), and Korea Disease Control and Prevention Agency (KDCA) databases over a period of 15.5 years (January 2007 to July 2022).

Patients with non-traumatic SAH, ICH, and CVST were screened using the International Classification of Diseases (ICD)-10 codes I60, I61, and I67.6, respectively, based on the HIRA research data (identifier: M20230314001). To ascertain the acuteness of onset and urgency of the condition, we screened patients who had visited the emergency room because of hemorrhagic stroke or CVST. This decision assumed that acute conditions were more feasible in explaining the temporal association with a risk factor than subacute or chronic cases, which are inclined to have a mixed etiologic nature. Moreover, we excluded patients who had been diagnosed with hemorrhagic stroke or CVST within 2 years to avoid recurrence and those who had been diagnosed with acute ischemic stroke (ICD-10 code: I63) within 30 days to avoid the inclusion of hemorrhagic transformation cases. The crude incidence rate (CIR) for each month was calculated using the monthly incidence of the target disease as the numerator and the monthly average population as the denominator [13].

2.2 Data collection: Patient-level data on risk factors

We collected patient-level data on diagnoses, sociodemographic characteristics, comorbidities, and medication history using HIRA claims data. These included primary diagnoses, subdiagnoses, medical services received, medical institutions visited, and healthcare costs, including co-payments.

The relevant comorbid risk factors per incident cases were collected for hemorrhagic stroke on hypertension (HTN; I10–I15, I67.4, O10–11, and O13–16), [14] atrial fibrillation (AF; I48), end-stage renal disease (ESRD; N18.5), liver cirrhosis (LC; K70.30, K70.31, K71.7, K74.60, K74.69, and K76.6), [15] Marfan syndrome (Q87.4), autosomal dominant polycystic kidney disease (ADPKD; Q61.2), Moyamoya disease (MMD; I67.5), intracranial aneurysm (IA; I67.1 and Q28.3), and arteriovenous malformation (AVM; Q28.2).

For CVST, a history of cancer (C00-C97), head trauma within 3 months (S02.0, S02.8, S02.9, S06, and S07), [16] sepsis within 3 months (A40.0-A41.9, R65.1, and R57.2), [17] and pregnancy-related outcomes within 3 months (O80–O84) were recorded. We also attained relevant medication history in hemorrhagic stroke and CVST as follows: antiplatelet agents (AP; aspirin, dipyridamole, triflusal, clopidogrel, ticagrelor, ticlopidine, prasugrel, cilostazol, sarpogrelate, and beraprost) and oral anticoagulants (OAC; warfarin, rivaroxaban, apixaban, edoxaban, dabigatran, enoxaparin, dalteparin, and nadroparin) for hemorrhagic stroke and hormonal agents (bazedoxifene acetate, estrogen, and tibolone) and oral contraceptives (ethinyl estradiol, drospirenone, and levonorgestrel) for CVST. The prevalence of risk factors and medication use in incident hemorrhagic stroke or CVST cases was calculated on a monthly basis.

2.3. Data collection: COVID-19 and vaccination data

Nationwide SARS-CoV-2 infection data from January 2020 to December 2022 were collected as monthly outbreak summaries from the KDCA database. Data on SARS-CoV-2 vaccination status from February 2021 to December 2022 were extracted from the NHIS database.

For vaccination data, the vaccination rate was specified for the following three different platforms to allow an in-depth analysis of the biological mechanism: mRNA-based (including BNT162b2 and mRNA-1273), viral vector-based (including ChAdOx1 nCoV-19 and Ad26.COV2.S), and recombinant protein vaccines (NVX-CoV2373).

2.4. Statistical analysis

In this study, total sex- and age-specific crude CIRs were calculated per 100,000 persons for the pre-pandemic (2007–2019) and pandemic (2020–2022) periods. The standardized morbidity ratio (SMR) was calculated as the ratio between the observed value during the pandemic and the pre-pandemic reference value [13, 18]. The 95% confidence interval (CI) for SMR was estimated using Byar’s approximation method [19].

Furthermore, the monthly prevalence of comorbid risk factors and medication history were estimated in patients with hemorrhagic stroke and CVST (cumulative risk factor or medication history count / incident hemorrhagic stroke or CVST cases). Prevalence data were compared between the pre-pandemic and pandemic periods. The traditional Wald method was used to examine the CI for the difference between proportions [20]. Finally, the weighted ranks of the risk factors were assessed considering the risk ratios collected from previous literature and used for crude comparisons between the pre-pandemic and pandemic periods [21–29].

For the time-series analysis, a polynomial regression model for hemorrhagic stroke and a simple regression model for CVST were selected to forecast the expected incidence and 95% CIs during the pandemic (2021–2022) period based on the baseline pre-pandemic (2007–2019) incidence. The best-fit forecast models were compared based on the Akaike information criterion (AIC) and Bayesian information criterion (BIC). Models with the lowest AIC and BIC values were selected for the study [30]. The odds ratio (OR) between the expected (forecasted) value and the observed value (number of hemorrhagic stroke and CVST cases) was used for comparison. The OR, excluding 1.0, was clinically significant at the 5% level.

The temporal association between hemorrhagic stroke/CVST and prevalent comorbid risk factors, medication history, SARS-CoV-2 infection, and SARS-CoV-2 vaccination was determined using Pearson’s correlation analysis of data collected during the pre-pandemic (2007–2019) and pandemic (2020–2022) periods. The degree of correlation followed a conventional paradigm (weak: 0.10 ≤ r < 0.30, moderate: 0.30 ≤ r < 0.50, and strong: r ≥ 0.50) [31].

2.5. Standard protocol approval, registration, and patient consent

The Institutional Review Board at Samsung Medical Center granted an exemption for review of this study because it involved the analysis of de-identified data already obtained through the epidemiological investigation, presented a minimal risk to the participants, and met the needs of current public health interests (identifier: SMC 2023-03-056). The need for consent was waived owing to the retrospective nature of this study, which used de-identified population data. All the experiments were conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology Reporting Guidelines.

3. Results

3.1. Summary of collected data for analysis

A total of 2,428,946 cases were collected for I60, and 5,906,398 cases were collected for I61. Among these, emergency cases were 156,783 cases for I60, 309,116 for I61, and 1,022 for I67.6. Altogether, 6,847 patients with stage I60 and 23,866 patients with stage I61 were excluded because they were diagnosed with stage I63 within 30 days. Moreover, 33,961, 34,323, and 75 cases of I60, I61, and I67.6, respectively, were excluded from the study owing to 2-year washout. Finally, 115,975 cases of I60, 250,927 cases of I61, and 947 cases of I67.6 were used for statistical analysis (Fig 1).

Fig 1. Flow diagram of study participants.

Fig 1

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3.2. Incidence of hemorrhagic stroke (SAH and ICH) and CVST in pre-pandemic (2007–2019) versus pandemic (2020–2022) period

For SAH, the pre-pandemic CIR was 0.61 per 100,000 persons, whereas the pandemic CIR was slightly lower at 0.55 per 100,000 persons (SMR: 0.90; 95% CI, 0.89–0.91). The same downward trend in the incidence was observed in both sexes during the pandemic. When stratified by age, significantly lower CIR was observed for individuals aged ≥30 years during the pandemic period.

For ICH, the pre-pandemic CIR was 1.32 per 100,000 persons, whereas during the pandemic period, CIR decreased to 1.21 per 100,000 persons (SMR: 0.91; 95% CI, 0.91–0.92). A similar trend was observed for the sex-specific CIR in patients with ICH. Lower CIRs were observed in all age groups during the pandemic.

For CVST, the pre-pandemic CIR was 0.004 per 100,000 persons, whereas during the pandemic period, the CIR increased to 0.009 per 100,000 persons (SMR: 2.312; 95% CI, 2.018–2.650). The same trend was observed for the sex-specific CIR. When broken down into age groups, a higher CIR was observed in the 10–79-year age group (Table 1).

Table 1. Sex-specific and age-specific crude cumulative incidence and rate ratio of hemorrhagic stroke and CVST during the pre-pandemic (2007–2019) and pandemic (2020–2022) periods.

Statistically significant results were bold typed.

2007–2019 (pre-pandemic) 2020–2022 (pandemic) pre-pandemic vs pandemic
N CIR N CIR SMR (95% CI)
SAH Total 97,958 0.61 18,017 0.55 0.9 (0.89–0.91)
Sex
Male 39,484 0.50 6,680 0.41 0.83 (0.81–0.85)
Female 58,474 0.73 11,337 0.68 0.94 (0.92–0.96)
Age
≤9 258 0.00 40 0.00 0.78 (0.56–1.08)
10~19 623 0.07 92 0.06 0.87 (0.70–1.08)
20~29 1,770 0.17 265 0.15 0.89 (0.78–1.01)
30~39 6,396 0.56 784 0.38 0.67 (0.62–0.72)
40~49 19,256 1.46 2,622 1.12 0.77 (0.74–0.80)
50~59 25,644 1.96 4,410 1.64 0.84 (0.81–0.87)
60~69 19,135 2.04 4,284 1.71 0.84 (0.81–0.86)
70~79 16,164 2.79 3,007 1.98 0.71 (0.68–0.74)
≥80 8,712 1.39 2,513 1.25 0.91 (0.87–0.95)
ICH Total 211,386 1.32 39,541 1.21 0.91(0.91–0.92)
Sex
Male 114,902 1.45 21,403 1.33 0.92(0.90–0.93)
Female 96,484 1.20 18,138 1.10 0.91(0.90–0.93)
Age
≤9 1,396 0.02 111 0.01 0.40(0.33–0.48)
10~19 1,946 0.23 225 0.16 0.68(0.59–0.78)
20~29 3,386 0.33 466 0.27 0.81(0.74–0.90)
30~39 8,950 0.79 1,291 0.62 0.79(0.75–0.84)
40~49 27,076 2.05 3,709 1.59 0.77(0.75–0.80)
50~59 46,006 3.51 7,424 2.77 0.79(0.77–0.81)
60~69 43,208 4.62 8,803 3.51 0.76(0.74–0.78)
70~79 47,448 8.20 8,488 5.59 0.68(0.67–0.70)
≥80 31,970 5.09 9,024 4.51 0.89(0.87–0.91)
CVST Total 643 0.004 304 0.009 2.31(2.02–2.65)
Sex
Male 340 0.004 169 0.010 2.45(2.03–2.94)
Female 303 0.004 135 0.008 2.17(1.77–2.65)
Age
≤9 12 0.000 2 0.000 0.83(0.22–3.24)
10~19 23 0.003 12 0.008 3.07(1.54–6.09)
20~29 93 0.009 54 0.031 3.44(2.46–4.80)
30~39 124 0.011 44 0.021 1.94(1.38–2.74)
40~49 125 0.009 51 0.022 2.31(1.67–3.19)
50~59 111 0.008 69 0.026 3.03(2.25–4.09)
60~69 82 0.009 41 0.016 1.87(1.28–2.71)
70~79 47 0.008 21 0.014 1.70(1.02–2.84)
≥80 26 0.004 10 0.005 1.21(0.59–2.47)
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Crude CIR was calculated per 100 000 population.

‡The standardized morbidity ratio was calculated as (2020–2022 mean CIR)/(2007–2019 mean CIR).

Abbreviations: N, absolute number of patients; CIR, cumulative incidence rate; SMR, standardized morbidity ratio; SAH, subarachnoid hemorrhage; ICH, intracerebral hemorrhage; CVST, cerebral venous sinus thrombosis.

3.3. Real-world incidence of hemorrhagic stroke and CVST during the pandemic (2007–2019) period versus forecasted estimate

When spread by months, the observed incidence of SAH was significantly lower than the expected incidence in March, October, and December 2020; August and October–December 2021; January–April and July 2022 (rate ratios: 0.80–0.88). The observed incidence of ICH was within the expected incidence in all pandemic months except for March 2020 and March 2022 (rate ratios: 0.88 and 0.84, respectively). For CVST, the observed incidence was significantly higher than the forecasted incidence for May–July and October 2021, and June 2022 (rate ratios: 1.66–2.16) (Fig 2, S1 File).

Fig 2. Real-world incidence of hemorrhagic stroke and cerebral venous sinus thrombosis from 2020 to 2022 versus estimated incidence projections based on 2007–2019 incidence data.

Fig 2

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The blue lines denote the observed incidence, green line the expected incidence, darker and lighter grey shades 80% and 95% CI of the predicted incidence, respectively. (a) subarachnoid hemorrhage (SAH). (b) intracerebral hemorrhage (ICH). (c) cerebral venous sinus thrombosis (CVST).

3.4. Comparing the prevalence of conventional risk factors of hemorrhagic stroke and CVST during pre-pandemic (2007–2019) and pandemic (2020–2022) periods

During the pandemic period, a significantly higher prevalence of AP or OAC therapy, HTN, ESRD, AF, LC, ADPKD, MMD, and IA was observed among incident patients with SAH than during the pre-pandemic period.

Moreover, a notably higher prevalence of AP or OAC therapy, HTN, ESRD, AF, LC, ADPKD, MMD, and IA was observed in patients with incident ICH during the pandemic period than during the pre-pandemic period. Conversely, a notably lower prevalence of AVM was observed in patients with incident ICH during the pandemic compared with the pre-pandemic prevalence.

Finally, there was no significant difference between the prevalence of contraceptive and hormonal therapy, sepsis within 3 months, and cancer within one year in incident CVST cases (Fig 3, S1 File).

Fig 3. Visualization of known risk factors for the prevalence of hemorrhagic stroke and cerebral venous sinus thrombosis (CVST) from the pre-pandemic (2007–2019) versus post-pandemic (2020–2022) period through a pyramid chart.

Fig 3

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Blue bars in the left indicate pre-pandemic prevalence of incident hemorrhagic stroke or CVST cases. Red bars in the right indicate pandemic prevalence of incident hemorrhagic stroke or CVST cases. The x-axis denotes prevalence metrics per 100,000 persons. (a) subarachnoid hemorrhage (SAH). (b) intracerebral hemorrhage (ICH). (c) cerebral venous sinus thrombosis (CVST). Abbreviations: HTN, hypertension; ESRD, end-stage renal disease; Afib, atrial fibrillation; LC, liver cirrhosis; ADPKD, autosomal dominant polycystic kidney disease; MMD, Moyamoya disease; AVM, arteriovenous malformation.

3.5. Time-series correlation analysis: Hemorrhagic stroke/CVST incidence, comorbid risk factor prevalence, SARS-CoV-2, SARS-CoV-2 vaccination

During the pre-pandemic period, prevalence of ESRD showed a mild negative temporal association (r = -0.151, P = 0.039) and intracranial aneurysm a mild positive temporal association (r = 0.222, P = 0.005) with SAH incidence. However, during the pandemic period, AP therapy and intracranial aneurysms showed a strong positive temporal association (r = 0.528 and r = 0.650; P = 0.007 and P < 0.001, respectively) with the incidence of SAH. Additionally, a moderately positive temporal association was found between SAH incidence and the prevalence of HTN, AF, and MMD (r = 0.422, 0.368, and 0.357; P = 0.048, 0.021, and 0.016, respectively) during the pandemic period.

During the pre-pandemic period, the prevalence of OAC therapy, ESRD, AF, LC, and MMD showed a mild-to-moderate negative association with ICH. However, the prevalence of AVM was moderately positively associated with the incidence of ICH (r = 0.305, P < 0.001). During the pandemic period, the prevalence of AP therapy and HTN demonstrated strong positive temporal associations with the incidence of ICH (r = 0.890 and 0.835, respectively; P < 0.001 for both).

Finally, during the pre-pandemic period, the prevalence of contraceptive and hormonal therapies demonstrated a mildly positive temporal association with CVST incidence (r = 0.281, P = 0.002). During the pandemic period, this association was no longer significant, and CVST incidence demonstrated a moderately positive temporal association with COVID-19 vaccination (r = 0.349, P = 0.031) (Table 2).

Table 2. Summary of time-series correlation analyses between hemorrhagic stroke & CVST and known risk factors during the pre-pandemic (2007–2019) and pandemic (2020–2022) periods.

Statistically significant results were bold typed.

2007–2019 (pre-pandemic) 2020–2022 (pandemic)
r p r p
SAH Antiplatelet therapy -0.055 0.500 0.528 0.007
Anticoagulant therapy 0.051 0.470 0.177 0.345
Hypertension -0.056 0.490 0.422 0.048
End-stage renal disease -0.151 0.039 -0.155 0.432
Atrial fibrillation 0.022 0.760 0.368 0.021
Liver cirrhosis -0.127 0.094 0.115 0.543
Marfan syndrome 0.061 0.432 0.064 0.394
ADPKD 0.006 0.927 -0.024 0.900
Moyamoya disease 0.071 0.408 0.357 0.016
Intracranial aneurysm 0.222 0.005 0.650 <0.001
Arteriovenous malformation 0.028 0.711 0.131 0.523
SARS-CoV-2 infection - - -0.393 0.058
SARS-CoV-2 vaccination - - -0.279 0.093
 mRNA-based - - -0.264 0.056
 Viral vector-based - - -0.134 0.478
 Recombinant protein - - -0.359 0.095
ICH Antiplatelet therapy -0.192 0.054 0.890 <0.001
Anticoagulant therapy -0.240 0.009 0.154 0.433
Hypertension -0.132 0.179 0.835 <0.001
End-stage renal disease -0.335 <0.001 0.176 0.346
Atrial fibrillation -0.246 0.011 0.438 0.052
Liver cirrhosis -0.190 0.017 0.389 0.089
Marfan syndrome 0.015 0.867 0.252 0.170
ADPKD -0.102 0.119 0.137 0.567
Moyamoya disease -0.177 0.028 0.072 0.656
Intracranial aneurysm -0.030 0.703 0.233 0.146
Arteriovenous malformation 0.305 <0.001 0.294 0.099
SARS-CoV-2 infection - - -0.179 0.111
SARS-CoV-2 vaccination - - -0.185 0.321
 mRNA-based - - -0.094 0.586
 Viral vector-based - - -0.315 0.191
 Recombinant protein - - -0.247 0.135
CVST Contraceptives and hormones ≤ 90d 0.281 0.002 0.047 0.699
Sepsis within ≤ 90d 0.026 0.329 - -
Trauma within ≤ 90d - - - -
Cancer within ≤ 1y 0.202 0.070 0.262 0.260
SARS-CoV-2 infection - - -0.311 0.256
SARS-CoV-2 vaccination - - 0.349 0.031
 mRNA-based - - 0.289 0.061
 Viral vector-based - - 0.297 0.247
 Recombinant protein - - -0.319 0.118
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Note: Statistical significance was set at P < 0.05.

Abbreviations: r, Pearson’s correlation coefficient; ADPKD, Autosomal Dominant Polycystic Kidney Disease; SAH, subarachnoid hemorrhage; ICH, intracerebral hemorrhage; CVST, cerebral venous sinus thrombosis

4. Discussion

In this study we analyzed the incidences of new-onset hemorrhagic stroke and CVST before and after the COVID-19 pandemic. The observed incidence of hemorrhagic stroke was lower than expected during the pandemic period in certain months, and this trend was associated with a decrease in the diagnosis of conventional risk factors. The observed incidence of CVST was higher than expected during the pandemic period, and this trend may have been temporally associated with SARS-CoV-2 vaccination.

The incidence of SAH and ICH was lower during the pandemic period than during the pre-pandemic period. Owing to the affinity of SARS-CoV-2 to angiotensin-converting enzyme 2 prevalent in cerebrovascular endothelium, [32] the association between SARS-CoV-2 and acute ischemic stroke has been implicated by several studies [33, 34]. However, the association between SARS-CoV-2 and hemorrhagic stroke has been unclear [35, 36]. Our result is in line with large population studies that have reported lower volume of hospitalization or incidence of SAH or ICH in patients during the pandemic [37, 38]. This finding may be partly associated with hospital avoidance and saturation of emergency medical services during the height of the pandemic; specifically, during the peak delta variant outbreak in September 2021 and Omicron variant outbreak in January 2022 in South Korea. In part, further investigations into excess sudden unexpected deaths or deaths of unknown cause during the pandemic period may support our findings regarding the aftermath of lower detection of subarachnoid hemorrhage (SAH), which could have been rapidly fatal if left untreated. Additionally, this finding can be attributed to a decrease in the number of minor stroke cases, which do not exceed the healthcare-seeking behavior threshold [39, 40].

Despite large-scale reports on the potential causative association between hemorrhagic stroke and mRNA-based SARS-CoV-2 vaccines, our study did not reveal any temporal associations between the two. Furthermore, despite the increased mean prevalence of conventional risk factors in incident hemorrhagic stroke cases during the pandemic (i.e., higher dependability on these risk factors), the prevalence decreased during the pandemic, resulting in a positive temporal association with the declining incidence of hemorrhagic stroke. By contrast, no significant temporal association was observed between hemorrhagic stroke incidence and SARS-CoV-2 infection or vaccination, indicating that the decreased incidence of hemorrhagic stroke during the pandemic was more attributable to the downward trend in the prevalence of conventional risk factors than to SARS-CoV-2 infection or vaccination. Alternatively, the decreased incidence of hemorrhagic stroke during the pandemic may have contributed to the lower discovery rate of important conventional risk factors in incident cases. Nevertheless, the decreased prevalence of certain conventional risk factors (i.e., HTN, AP therapy, and AF) is not confined to incident hemorrhagic stroke cases and represents a larger nationwide trend, including the general population, supporting the initial hypothesis [41–43].

When hemorrhagic stroke was categorized into SAH and ICH, the association between the prevalence of intracranial aneurysms and the decrease in SAH incidence increased from mild to strong during the pandemic, implying a stronger link. Several interpretations are possible. First, a notable portion of patients who experience SAH are often diagnosed with the culprit aneurysm only at the time of stroke diagnosis. Hence, this finding may indicate a decrease in the number of undiagnosed aneurysmal SAH during the pandemic. Alternatively, this finding may be a result of decreased diagnosis of unruptured incidental intracranial aneurysms owing to lower access to healthcare during the pandemic, leading to low SAH awareness and suboptimal health-seeking behavior, [44] especially in conjunction with the prevalence trends of AP therapy, HTN, AF, and MMD, which all demonstrated a downward trend and a significant positive temporal association with SAH incidence. When analyzed by weighted ranks of attribution, no significant change in ranks in the conventional risk factor domain was recognized before and after the pandemic, implying a lack of intragroup alterations and a stable contribution of different mechanisms in patients with SAH. This indicates a quantitative game, not a qualitative game.

For CVST, we identified an association between vector-based vaccines and increased incidence, in agreement with previous studies that utilize different research designs [12]. Viral vector-based vaccines have reported to be associated with TTS-related CVST [9]. However, in our study, when divided into vaccine platforms, all three mechanisms (mRNA-based, viral vector-based, and protein recombinant) demonstrated a positive temporal association with CVST incidence, although no significant association was observed. Case reports of CVST following mRNA-based vaccines have been recognized, [45, 46] implying the possibility of diverse biological mechanisms that may contribute to the development of CVST in vaccine recipients. Nevertheless, because of the limitations of our study, we believe that these findings should be interpreted with caution.

Our study has some limitations. First, observational time-series studies can only reveal possible temporal associations and not causation. Secondly, population-based data were not equally implicated for each individual, thus limiting the scope of interpretation. Third, we only included patients who visited the emergency medicine service, thereby limiting the number of patients evaluated in our study. However, this process likely ascertained the acute-onset patients who may have a higher chance of being linked to the risk factors. Furthermore, our list of conventional risk factors was not exhaustive, and other factors may have influenced the change in hemorrhagic stroke (e.g. smoking, diabetes, cerebral amyloid angiopathy, etc.) or CVST (e.g. vasculitis, prothrombotic hematological disorders, etc.) incidence. Regarding CVST, the number of reported events were relatively small compared to the overall variable count. Additionally, we have not yet examined post-vaccination period statistics, which could offer further insights into the contribution of vaccines to CVST. In future studies, we may address these limitations by expanding the scope of venous thrombotic disorders beyond CVST, relaxing the inclusion criteria to encompass urgent outpatient clinic visits, and incorporating data from the post-pandemic period.

In conclusion, we offer insights into deciphering the changes in hemorrhagic stroke and CVST incidence over the years amidst the pandemic and its association with various conventional risk factors, SARS-CoV-2 infection, and SARS-CoV-2 vaccines. We believe that our study facilitates the public’s understanding of a prevalent, notable cerebrovascular disease and provides reassuring evidence on the association between hemorrhagic stroke (SAH and ICH) and SARS-CoV-2 vaccines or infection, whereas reinforcing the already known association between SARS-CoV-2 vaccines and CVST for future vaccine rollout.

Supporting information

S1 File

(DOCX)

pone.0301313.s001.docx (145KB, docx)

Acknowledgments

The authors would like to acknowledge every frontline healthcare professional in the field who has strived to achieve the best patient outcomes during the tumultuous phase of the COVID-19 pandemic. We also thank Hyoseon Jeong for assistance with the pharmacological data search, which was crucial to our study.

Data Availability

De-idenitified data used for this study is available at National Health Insurance Sharing Service (https://nhiss.nhis.or.kr) or HIRA Healthcare Big-data Hub (https://opendata.hira.or.kr) for approved studies.

Funding Statement

The author(s) received no specific funding for this work.

References

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Decision Letter 0

Sonu Bhaskar

27 May 2024

PONE-D-24-10134Deciphering changes in the incidence of hemorrhagic stroke and cerebral venous sinus thrombosis during the coronavirus disease 2019 pandemic: a nationwide time-series correlation studyPLOS ONE

Dear Dr. Ha,

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Reviewer #1: Thank you for the article.

The results of this study are not much different than what we expected from literature and clinical experience.

There are of course confounding factors that plague all studies related to COVID studies including this one:

-The vaccines became available very quickly from a historical perspective. This makes interpretation of temporal associations between when the pandemic and vaccination difficult. This is especially important if there is delay in reporting.

-The study relies on reported risk factors. This seems to be dependent on bias of health care professionals. For instance, oral contraceptives as a risk factor for CVST seem to be exaggerated. Not surprising then, that women are more often imaged for CVST than men, and less often that scans show CVST.

-After becoming apparent that some vaccines are associated with ICH, they were withdrawn at least for younger populations in some European countries. How was that in Korea?

-Definition of pandemic period can be discussed. By spring-summer of 2021 the number of severe cases had dropped drastically and for practical purposes the pandemic was mostly a common cold being diagnosed in asymptomatic individuals.

The authors claim that the decrease in incidence of SAH might be related to less access to health care. While there is evidence for some conditions such as appendicitis in March-May 2020 in Europe, by June 2020 it was business as usual for us in Europe. In the case of appendicitis as an example there was increased incidence of complications in the ensuing months with 20-40% presenting with abscess. How would that be for SAH if there is a delay?

CVST caused by vaccine is much more serious than a CVST caused by natural infections from an ethical point of view. This is also important since the risk for thrombosis with COVID infection seems to have been exaggerated based on what we know.

Reviewer #2: The authors present a retrospective cohort study evaluating the rates of SAH, ICH, and CVST in South Korea from 2007 - 2022. Rates of cancer, sepsis, hormone therapy, anticoagulation, aneurysm, HTN, renal disease, liver disease, etc. were also reported. The manuscript concludes that SAH and ICH rates declined during the pandemic, while CVST increased. The authors posit the conjecture that this may be related SARS-COV vaccination.

1) Please, replace the ICD-10 codes in your figures / tables with the names of the diseases.

2) I would recommend expanding your discussion around CVST. Particularly, it would be helpful to further discuss the limitations of your data (small N for CVST events versus model variable count, risk factors for CVST missing from dataset, lack of post vaccination push data...) and what additional studies you feel would be needed to better address this question.

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Reviewer #1: Yes: Michael R. Torkzad

Reviewer #2: No

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PLoS One. 2024 Oct 3;19(10):e0301313. doi: 10.1371/journal.pone.0301313.r002

Author response to Decision Letter 0

16 Jun 2024

June 2nd, 2024

Dear Dr. Bhaskar

Re: Manuscript ID PONE-D-24-10134

Title: Deciphering changes in the incidence of hemorrhagic stroke and cerebral venous sinus thrombosis during the coronavirus disease 2019 pandemic: a nationwide time-series correlation study

On behalf of the authors, We wish to express our gratitude toward the reviewers' meticulous review of our manuscript. We have made revisions according to the reviewers’ suggestions, and believe this change further improved our manuscript. Please find the enclosed letter addressing each of the reviewer's comments and the two versions (tracked-changes and clean) of the revised manuscript. The page and line references for the changes provided in this response letter are based on the tracked-changes version (marked copy) of the manuscript. We hope that you and the reviewers now find the revised paper suitable for publication.

Sincerely yours,

Jongmok Ha, MD

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine 81 Irwon-ro Gangnam-gu, Seoul, Republic of Korea (06351)

Tel: 82-2-3410-1426, Fax: 82-2-3410-3421

E-mail: jongmok3245@gmail.com

AND

Darda Chung, MD

Department of Neurology, Korea University Anam Hospital

64, Goryeodae-ro 17ga-gil, Seongbuk-gu, Seoul, Republic of Korea

Tel: +82-10-3088-2370, Fax: +82-2-920-5893

E-mail: vogmag0107@gmail.com

Reviewer #1: Thank you for the article.

The results of this study are not much different than what we expected from literature and clinical experience.

1. There are of course confounding factors that plague all studies related to COVID studies including this one:

-The vaccines became available very quickly from a historical perspective. This makes interpretation of temporal associations between the pandemic and vaccination difficult. This is especially important if there is delay in reporting.

Response: Thank you for this relevant remark. Indeed, the vaccine rollout was very quick and concerns on the ‘appropriate room’ to calculate for temporal association may seem tight. During vaccine rollout, COVID-19 Vaccination Task Force Adverse Event Investigation Team was set up inside Korea Disease Control and Prevention Agency to lead a government-led surveillance program to record a comprehensive list of adverse events following immunization (AEFIs) (REF 1). Relevant medical personnel or the patient reported to the Korea Immunization Management System (KIMS), a web-based event monitoring system, with the earliest convenience (mostly within a week), and the task force, along with the local authorities, performed weekly meetings to go over the reported cases and determined whether the vaccination was safe to proceed. We believe this process shortened the delay in adverse event reporting significantly. Furthermore, our study design uses nationwide population data and does not rely on this reporting system in entirety. We are less subject to reporting bias as we used the total number of hemorrhagic stroke and CVST cases that were recorded during set time frame, not confined to the cases reported in the AEFI monitoring system.

REF 1. Hwang I, Park K, Kim TE, Kwon Y, Lee YK. COVID-19 vaccine safety monitoring in Republic of Korea from February 26, 2021 to October 31, 2021. Osong Public Health Res Perspect. 2021;12(6):396-402.

-The study relies on reported risk factors. This seems to be dependent on bias of health care professionals. For instance, oral contraceptives as a risk factor for CVST seem to be exaggerated. Not surprising then, that women are more often imaged for CVST than men, and less often that scans show CVST.

Response: We agree that the reported risk factors are hand-picked preferentially by the authors and may be biased in clinical perspective. To point this out, we have mentioned in the limitation on the list not being exhaustive (page 17, lines 258 – 260). Moreover, we tried to use these ‘conventional risk factors’ as correlation benchmarks to COVID-19 infection or COVID-19 vaccination to figure out if temporal course of the disease was more likely influenced by well-known risk factors or potential newcomers to the roster. It may be important to point out that these risk factors were by design not individually checked and recorded by health care professionals per incident case yet estimated as a prevalence within incident population using claims data (if the patient had at least once been prescribed an OC, had cancer, or had sepsis in the relevant time frame, he or she was added to the numerator) (page 7, lines 84 – 86). Furthermore, the selected risk factors are clinically relevant because they make up the big portion of total risk seen in clinical practice. Regarding oral contraceptives (OC), OCs are by far one of the most important risk factors in CVST, with odd’s ratio up to 7.5 in a systemic review (REF 1). Although the risk factor itself may have been subject to bias in terms of screening as the reviewer suggested, we doubt this would have been detrimental to our analysis as no sexual preponderance in incidence was observed (Table 1).

REF 1: Amoozegar F, Ronksley PE, Sauve R, Menon BK. Hormonal contraceptives and cerebral venous thrombosis risk: a systematic review and meta-analysis. Front Neurol. 2015 Feb 2;6:7. doi: 10.3389/fneur.2015.00007. PMID: 25699010; PMCID: PMC4313700.

-After becoming apparent that some vaccines are associated with ICH, they were withdrawn at least for younger populations in some European countries. How was that in Korea?

Response: Thank you for this comment. In Korea, the adenoviral vector-based ChAdOx1-S/nCoV-19 (Oxford-Astrazeneca) vaccine and Ad26. COV2.S (Janssen) vaccine was disapproved for ages 30 and under, after reports of thrombosis with thrombocytopenia (TTS), TTS-related CVST, and possibly ICH associated with TTS-related CVST. ICH collectively on the other hand (ICH and SAH combined, regardless of mechanism), despite reports of association with mRNA-based vaccines in some studies as referenced in our manuscript (REF 1, 2, 3), did not have an impact in steering policies on vaccine rollout.

REF 1. Patone M, Handunnetthi L, Saatci D, et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nat Med. 2021;27(12):2144-2153.

REF 2. Torabi F, Bedston S, Lowthian E, et al. Risk of thrombocytopenic, haemorrhagic and thromboembolic disorders following COVID-19 vaccination and positive test: a self-controlled case series analysis in Wales. Scientific reports. 2022;12(1):16406.

REF 3. Simpson CR, Shi T, Vasileiou E, et al. First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland. Nature medicine. 2021;27(7):1290-1297.

-Definition of pandemic period can be discussed. By spring-summer of 2021 the number of severe cases had dropped drastically and for practical purposes the pandemic was mostly a common cold being diagnosed in asymptomatic individuals.

Response: As shown in figure 2, our country experienced a steep incline of new SARS-CoV-2 infection cases and deaths. The following are excerpts from Worldometer showing daily death counts due to COVID-19 (https://www.worldometers.info/coronavirus, REF 1), still showing relevant peaks throughout 2022. Excess mortality was also high during the same period (ourworldindata.org as reference, REF 2). The authors agree that since the introduction of omicron variant in December 2021, milder clinical manifestation, build-up of population immunity, and quick awareness of COVID symptoms had rendered the pandemic into common cold. However, it is unclear whether this also diminished the level of systemic immune response in patients. Regarding infections, many theories on mechanism have been suggested on how the virus could affect the patient. Aside from the fact that the virus could enter the bloodstream and directly influence the vasculature, secondary damage due to immune response (which is sometimes hyperinflammatory and detrimental) should not be neglected. As far as we are concerned, this immune response becomes increasingly robust with repeated exposures to the immune stimulus. Therefore, we believe that the pandemic period was reasonably set in our study, when confined to South Korea.

References)

REF 1. https://www.worldometers.info/coronavirus

REF 2. Edouard Mathieu, Hannah Ritchie, Lucas Rodés-Guirao, Cameron Appel, Charlie Giattino, Joe Hasell, Bobbie Macdonald, Saloni Dattani, Diana Beltekian, Esteban Ortiz-Ospina and Max Roser (2020) - "Coronavirus Pandemic (COVID-19)". Published online at OurWorldInData.org. Retrieved from: 'https://ourworldindata.org/coronavirus' [Online Resource]

2. The authors claim that the decrease in incidence of SAH might be related to less access to health care. While there is evidence for some conditions such as appendicitis in March-May 2020 in Europe, by June 2020 it was business as usual for us in Europe. In the case of appendicitis as an example there was increased incidence of complications in the ensuing months with 20-40% presenting with abscess. How would that be for SAH if there is a delay?

Response: We thank the reviewer for steering our view towards the aftermath of undetected acute disorders. SAH is in most cases an urgent disorder with immediate case fatality rate hovering around 40% if left untreated and reaching above 50% considering morbidity risks within 6 months (REF 1, 2). Our guess is that sudden deaths or death by unknown cause may have increased during the same period as a complication. This is an excellent segue to a follow-up study to confirm if our speculations were indeed valid. We included this feedback in our discussion section (page 15, lines 209 – 212).

REF 1. Lantigua H, Ortega-Gutierrez S, Schmidt JM, Lee K, Badjatia N, Agarwal S, Claassen J, Connolly ES, Mayer SA. Subarachnoid hemorrhage: who dies, and why? Crit Care. 2015 Aug 31;19(1):309. doi: 10.1186/s13054-015-1036-0. PMID: 26330064; PMCID: PMC4556224.

REF 2. Mahlamäki K, Rautalin I, Korja M. Case Fatality Rates of Subarachnoid Hemorrhage Are Decreasing with Substantial between-Country Variation: A Systematic Review of Population-Based Studies between 1980 and 2020. Neuroepidemiology. 2022;56(6):402-412. doi: 10.1159/000526983. Epub 2022 Oct 25. PMID: 36282049.

3. CVST caused by vaccine is much more serious than a CVST caused by natural infections from an ethical point of view. This is also important since the risk for thrombosis with COVID infection seems to have been exaggerated based on what we know.

Response: We agree that in ethical standpoint, CVST caused by vaccine can be a serious problem. There is evidence of both an increased CVST incidence due to SARS-CoV-2 infection (REF 1) and SARS-CoV-2 vaccination in the literature (REF 2). However, there is no head-to-head comparison on both etiologies in the literature. Mechanism-wise, SARS-CoV-2 infection is more prone to causing ischemic stroke due to large vessel occlusion due to vasculopathies than hypercoagulability (REF 3). Moreover, excess increase in thrombotic complications including CVST has been reported by the viral vector-based vaccine company and a withdrawal process commenced after diminishing of demands as a response to this allegation (REF 4).

REF 1. Ohaeri C, Thomas DR, Salmon J, Cottrell S, Lyons J, Akbari A, Lyons RA, Torabi F, Davies GG, Williams C. Comparative risk of cerebral venous sinus thrombosis (CVST) following COVID-19 vaccination or infection: A national cohort study using linked electronic health records. Hum Vaccin Immunother. 2022 Nov 30;18(6):2127572. doi: 10.1080/21645515.2022.2127572. Epub 2022 Oct 27. PMID: 36302124; PMCID: PMC9746546.

REF 2. Krzywicka K, Heldner MR, Sánchez van Kammen M, van Haaps T, Hiltunen S, Silvis SM, Levi M, Kremer Hovinga JA, Jood K, Lindgren E, Tatlisumak T, Putaala J, Aguiar de Sousa D, Middeldorp S, Arnold M, Coutinho JM, Ferro JM. Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency. Eur J Neurol. 2021 Nov;28(11):3656-3662. doi: 10.1111/ene.15029. Epub 2021 Aug 4. PMID: 34293217; PMCID: PMC8444640.

REF 3. Wijeratne T, Sales C, Karimi L, Crewther SG. Acute Ischemic Stroke in COVID-19: A Case-Based Systematic Review. Front Neurol. 2020 Sep 25;11:1031. doi: 10.3389/fneur.2020.01031. PMID: 33101164; PMCID: PMC7546832.

REF 4. https://www.ema.europa.eu/en/human-regulatory-overview/public-health-threats/coronavirus-disease-covid-19/covid-19-public-health-emergency-international-concern-2020-23/withdrawn-applications-products

Reviewer #2: The authors present a retrospective cohort study evaluating the rates of SAH, ICH, and CVST in South Korea from 2007 - 2022. Rates of cancer, sepsis, hormone therapy, anticoagulation, aneurysm, HTN, renal disease, liver disease, etc. were also reported. The manuscript concludes that SAH and ICH rates declined during the pandemic, while CVST increased. The authors posit the conjecture that this may be related SARS-COV vaccination.

1. Please, replace the ICD-10 codes in your figures / tables with the names of the diseases.

Response: Thank you for this comment. We replaced the ICD-10 codes in our figures and tables with the name of the disease as suggested by the reviewer.

2. I would recommend expanding your discussion around CVST. Particularly, it would be helpful to further discuss the limitations of your data (small N for CVST events versus model variable count, risk factors for CVST missing from dataset, lack of post vaccination push data...) and what additional studies you feel would be needed to better address this question.

Response: Thank you for this constructive feedback. We have expanded the list of limitations as recommended by the reviewer and discussed future studies that may help address these limitations (page 17, lines 260 – 265).

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18 Jun 2024

Deciphering changes in the incidence of hemorrhagic stroke and cerebral venous sinus thrombosis during the coronavirus disease 2019 pandemic: a nationwide time-series correlation study

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