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Individual and Joint Effects of Influenza-Like Illness and Vaccinations on Stroke in the Young: A Case-Control Study

Originally publishedhttps://doi.org/10.1161/STROKEAHA.121.038403Stroke. 2022;53:2585–2593

Abstract

Background:

Influenza-like illness (ILI) is an acute trigger for stroke, although joint effects of vaccinations and ILI have not yet been explored.

Methods:

Data for our case-control study was obtained from MarketScan Commercial Claims and Encounters between 2008 and 2014. Patients 18 to 65 years old who experienced a stroke were matched on age and admission date to a control, defined as patients with head trauma or ankle sprain at an inpatient or emergency department visit. Exposures were ILI in the prior 30 days, and any type of vaccination during the year prior. Our outcome was ischemic and intracerebral hemorrhagic strokes identified using International Classification of Diseases, Ninth Revision (ICD-9) codes. Logistic regression models estimated adjusted odds ratios (aORs) controlling for preventive care visits, diabetes, valvular heart disease, smoking, alcohol abuse, obesity, and hypertension.

Results:

We identified and matched 24 103 cases 18 to 44 years old and 141 811 45 to 65 years old. Those aged 18 to 44 years had increased stroke risk 30 days after ILI (aOR, 1.68 [95% CI, 1.51–1.86]) and reduced risk with any vaccination in the year prior (aOR, 0.92 [95% CI, 0.87–0.99]). Joint effects indicate that ILI was associated with increased stroke risk among those with (aOR, 1.41 [95% CI, 1.08–1.85]) and without (aOR, 1.73 [95% CI, 1.55–1.94]) vaccinations in the prior year (Pinteraction=0.16). Among those aged 45 to 65 years, adjusted analyses indicate increased stroke risk for those with ILI (aOR, 1.32 [95% CI, 1.26–1.38]), although there was no effect of vaccinations (aOR, 1.00 [95% CI, 0.97–1.02]). Joint effects indicate that ILI was not associated with stroke among those with any vaccination (aOR, 1.07 [95% CI, 0.96–1.18]) but was associated with increased risk among those without vaccinations ([aOR, 1.39 [95% CI, 1.32–1.47]; Pinteraction<0.001).

Conclusions:

ILI was associated with increased stroke risk in the young and middle-aged, while vaccinations of any type were associated with decreased risk among the young. Joint effects of ILI and vaccinations indicate vaccinations can reduce the effect of ILI on stroke.

See related article, p 2594

The incidence and prevalence of stroke among the young are increasing in the United States, with approximately 10% to 14% of ischemic strokes occurring in people aged 18 to 45 years.1 Further, this age group demonstrates greater heterogeneity in stroke etiology compared with the older stroke population, suggesting risk reduction efforts that apply to older populations may not be as beneficial in younger populations. As such, young patients with stroke present a unique population where identifying novel modifiable risk factors is a high priority.

Infections have been identified as both a potential chronic risk factor and acute trigger for stroke.2–7 Respiratory tract infections are the most common cause of infection in adults, and influenza-like illness (ILI) accounts for the majority of these infections.8 Though not a clinical diagnosis, ILI is used to identify a group of respiratory infection diagnoses regularly used for surveillance by the Department of Defense and Center of Disease Control and Prevention (CDC). Respiratory tract infections and ILI have been associated with short-term stroke risk in several studies, particularly in people aged 18 to 45 years.2,7,9–11 Vaccinating against infections, including influenza, reduces the risk of stroke.12

We aimed to evaluate the relationship between ILI, any type of vaccination, and the combined effects of ILI and vaccinations on stroke risk in young and middle-aged populations using a case-control study of an insurance-based administrative dataset. We hypothesized that ILI will be associated with an increase in odds of stroke, vaccines will be associated with a decrease in odds of stroke, and people who experience ILI in the absence of vaccines will have the highest odds of stroke, with vaccines attenuating the risk of stroke in those with ILI. Further, we hypothesize these associations will be stronger in the people aged 18 to 44 years than in those 45 and older.

Methods

Study Population and Study Design

MarketScan Commercial Claims and Encounters is an administrative database containing longitudinal data for patients with specific employee-sponsored insurance programs. MarketScan includes nearly 273 million de-identified patients with data on patient demographics, International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes, and ICD-9 procedure codes for all inpatient and outpatient visits.13 Data for each individual are linked by a de-identified patient identifier code allowing for tracking patients over time through multiple inpatient and outpatient admissions. Within MarketScan, claims data for each discharge, inpatient and outpatient, is collected, de-identified, standardized, and then made available to researchers. Data elements include demographic information such as age, sex, and location. For each admission discharge, data available included diagnosis codes, month of discharge, length of stay in hospital, and procedure codes. Due to restrictions in data licensing, we were limited to examining data between the of 2008 and 2014. Data are available through a purchase agreement with MarketScan.

We conducted a matched case-control study within the MarketScan database in which cases were defined as patients who had a stroke between January 1, 2008 and December 31, 2014 while enrolled in MarketScan and were 18 to 65 years of age. Health care utilization among this stroke population has been previously examined.14 For patients who had multiple strokes during this study period, only their first stroke was used. Strokes were defined as ischemic or intracerebral hemorrhagic identified using ICD-9 codes (Table S1). Subarachnoid hemorrhagic strokes were excluded. Controls were selected from patients 18 to 65 years of age presenting to the hospital with an injury (specifically head trauma or an ankle sprain) identified using ICD-9 codes (Table S1) during an inpatient or emergency department visit who had no indication of a stroke at time of injury. Head trauma and ankle sprain patients were selected as controls because these conditions are likely independent of our exposures. Controls were randomly matched to cases 1:1 on admission date (±14 days) and age (±3 years). Though head trauma patients may be at increased risk of stroke after the trauma event, time after trauma is not part of our study period, and, thus, would not affect our study. We categorized patients by their age at first stroke or age at head trauma/ankle sprain visit as 18 to 44 (young population) or 45 to 65 (middle-aged population) years.

Exposure Measures and Covariates

Our study assessed 2 exposures: (1) ILI at or before the time of stroke or control (index) visit, and (2) any vaccination in the year before index visit. The occurrence of ILI was assessed using previously validated ICD-9 codes associated with the stroke hospitalization or control visit (Table S1) or preceding inpatient, outpatient, or emergency department visits.15 Our main analysis evaluated the exposure of ILI during 1 to 30 days before index visit. In subsequent analyses, additional time frames were examined, including at time of index visit, 1 to 15 days prior, and 1 to 60 days prior. Any prior vaccination was assessed using MarketScan procedure group codes associated with outpatient or emergency department visits occurring within 1 year before index visit. Due to limitations in the availability of data on specific vaccination type, we were unable to identify vaccinations for influenza specifically; therefore, our study examined vaccinations for any illness. However, the majority were likely for influenza given they are administered annually. MarketScan procedure group codes are groups of related outpatient procedures, based on Healthcare Common Procedure Coding System, Current Procedural Terminology, 4th Edition, or ICD-9-CM procedure codes. Procedure group codes used for categorization of outpatient visits are presented in Table S1.

We examined demographics and medical history at the time of index visit, as well as health care utilization in the year prior including total number of visits, days from last visit, and whether they had a preventive care visit. To assess medical history and preventive care visits, we utilized ICD-9 codes and MarketScan procedure group codes, respectively (Table S1). Those without an ICD-9 code were assumed to not have the specified condition. No patients had a missing value for variables determined by ICD-9 codes. Preventive care refers to physical exams, counseling/guidance/risk factor reduction, and ordering of laboratory/diagnostic procedures. Mean number of preventative care visits was included in the analyses as preventative care visits could be an important confounder in the relationship between vaccination and stroke. MarketScan procedure group codes classify all immunizations as vaccinations and not as preventive care.

Statistical Analysis

We performed all analyses first for the entire study sample, and then stratified by age groups (18–44 and 45–65 years). Those with missing age or sex were not included in the analysis. We examined distributions of demographic characteristics and clinical risk factors assessed at time of index visit as mean (SD) for continuous variables and proportions as n (%) for categorical variables. Mean number of health care visits before index visit and, of those with at least one inpatient, outpatient, or emergency department visit, mean days from last visit were calculated. The median (interquartile range [IQR]) for the total number of visits prior and days from last visit were also examined.

We calculated odds ratios (ORs) and 95% CIs using unadjusted logistic regression to test the crude associations among ILI, vaccinations in the year prior and stroke events. We examined the combined effects of ILI and vaccinations using an interaction term. We then examined these relationships using a multivariable logistic regression model (adjusted model) adjusting for having a preventive care visit in the year prior, diabetes, valvular heart disease, smoking, alcohol abuse, obesity, and hypertension. Prior studies have demonstrated sex differences when examining ILI and stroke; therefore, in secondary analyses, we stratified by sex to examine potential differences.16 Due to small cell sizes, some stratifications were limited to our main ILI exposure assessed at 1 to 30 days before index visit. An alpha of P<0.05 was used for the main statistical analyses, and an alpha of P<0.1 was used for the interaction analyses. E-values were calculated for the association between ILI and stroke and the association between vaccination and stroke in the overall cohort to assess for the minimum strength necessary for a confounder to explain away observed associations.17

Results

We identified a total of 169 358 patients with stroke who met the case inclusion criteria for our study, consisting of 24 103 patients aged 18 to 44 years and 145 255 aged 45 to 65 years. A control pool of 1 071 259 eligible patients was identified, including 743 665 patients aged 18 to 44 years and 327 594 aged 45 to 65 years. We were able to match 100% of cases to a control for those aged 18 to 44 years, resulting in 24 103 cases and 24 103 controls. Of the 145 255 cases aged 45 to 65 years, we were able to match 97.6%, resulting in 141 811 cases and 141 811 controls. Patient characteristics for the entire cohort, and by age group are presented in Table 1. For those 18 to 44 years old, the median time from infection within 1 to 30 days before index visit was 15.0 days (IQR, 8.0–23.0) for cases and 17.0 days (IQR, 8.0–23.0) for controls. For those 45 to 65 years old, the median time from infection within 1 to 30 days to index visit was 12.0 days (IQR, 5.0–21.0) for cases and 12.0 days (IQR, 5.0–21.0) for controls. For those 18 to 44 years old, the median time from vaccination to index visit was 147.0 days (IQR, 63.0–244.0) for cases and 163.0 days (IQR, 75.0–260.0) for controls. For those 45 to 65 years old, the median time from vaccination to index visit was 147.0 days (IQR, 64.0–248.0) for cases and 157.0 days (IQR, 69.0–254.0) for controls.

Table 1. Demographics and Medical History Assessed at Time of Stroke (Case) or Trauma/Ankle Sprain Visit (Control) by Age Group and Visit Type

Entire population (ages 18–65)Young population (ages 18–44)Middle-aged population (ages 45–65)
CasesControlsCasesControlsCasesControls
(N=165 914)(N=165 914)(N=24 103)(N=24 103)(N=141 811)(N=141 811)
Age (mean, SD)54.029.1151.909.1436.226.9834.096.9257.045.0854.925.15
Sex, female (n, %)74 09544.66%105 15563.38%12 85353.33%13 69656.82%61 24243.19%91 45964.49%
Total no. visits prior*
 Mean, SD14.9821.0913.1717.3812.2319.3010.2415.1515.4421.3513.6717.69
 Median, IQR8.003.0–19.08.003.0–17.06.002.0–15.05.002.0–13.09.003.0–20.08.003.0–18.0
Days from last visit
 Mean, SD30.7357.8650.9267.7835.1663.6666.6979.083056.8248.3865.42
 Median, IQR6.001.0–28.023.007.0–67.06.001.0–35.03410.0–94.062.0–27.0216.0–63.00
Preventative care visit30 48918.38%47 08128.38%519321.55%681228.26%25 29617.84%40 26928.40%
Vaccination visit26 82116.17%29 57817.83%266111.04%318113.20%24 16017.0426 39718.61
Medical history (n, %)
 Diabetes29 80117.96%48032.89%19167.95%1310.54%27 88519.66%46723.29%
 Hypertension87 55252.77%13 7248.27%752231.21%4131.71%80 03056.43%13 3119.39%
 Obesity48432.92%4670.28%8073.35%350.15%40362.85%4320.30%
 Infections18 04810.88%30721.85%268911.16%1770.73%15 35910.83%28952.04%
 Coagulopathy63693.84%6800.41%16346.78%310.13%47353.34%6490.46%
 Hypercoagulable state24841.50%850.05%9283.85%<10<0.04%15561.10%810.06%
 Migraine69624.20%4110.25%272211.29%490.20%42402.99%3620.26%
 Valvular heart disease19 59711.81%6350.38%264510.97%240.10%16 95211.95%6110.43%
 Congenital heart disease1320.08%<100.00%610.25%00.00%710.05%<100.00%
 Patent foramen ovale56123.38%200.01%17167.12%<10<0.04%38962.75%190.01%
 Alcohol abuse24 69714.89%48332.91%297112.33%4761.97%21 72615.32%43573.07%
 Drug abuse/dependence43711.32%21720.65%7353.05%1750.73%36362.56%20251.43%
 Smoking22 19813.38%36242.18%260010.79%4091.70%19 59813.82%32152.27%
 Trauma25101.51%54 15232.64%7763.22%598524.83%17341.22%48 16733.97%

IQR indicates interquartile range.

*Including inpatient, outpatient, and/or emergency department.

† Calculated only for those who had at least 1 visit.

‡ Collected at the time of stroke/trauma visit.

In the entire cohort, unadjusted and adjusted analyses indicated increased odds of stroke for those with ILI 1 to 30 days before index visit (Table 2) and reduced odds of stroke for those having a vaccination in the year prior. The E-value for the association between ILI and stroke was 2.1 and was 1.5 for the association between vaccination and stroke. Results were consistent when stratified by sex. In analyses of combined effects of ILI and vaccinations, among those with no vaccinations in the prior year, those with ILI had increased odds of stroke (adjusted OR, 1.46 [1.39–1.53]) while for those with vaccination the risk associated with ILI was lower (adjusted OR, 1.11 [1.01–1.22]; adjusted Pinteraction<0.001).

Table 2. Individual and Joint Effects of ILI and Vaccines on Stroke Risk Among Those Aged 18 to 65 Years

Individual effects
Entire population (ages 18–65)Young population (ages 18–44)Middle-aged population (ages 45–65)
Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)
ILI vs no ILI1.30 (1.25–1.35)1.38 (1.32–1.44)1.66 (1.52–1.82)1.68 (1.51–1.86)1.24 (1.19–1.29)1.32 (1.26–1.38)
 ILI vs no ILI in males1.47 (1.39–1.56)1.54 (1.43–1.65)2.27 (1.94–2.65)2.26 (1.89–2.66)1.37 (1.28–1.46)1.42 (1.32–1.53)
 ILI vs no ILI in females1.32 (1.26–1.39)1.38 (1.31–1.46)1.40 (1.25–1.58)1.41 (1.24–1.61)1.30 (1.24–1.37)1.36 (1.28–1.45)
Vaccination vs no vaccination0.89 (0.87–0.91)0.96 (0.94–0.98)0.82 (0.77–0.86)0.92 (0.87–0.99)0.90 (0.88–0.92)1.00 (0.97–1.02)
 Vaccination vs no vaccination in males0.93 (0.91–0.96)0.97 (0.93–1.00)0.88 (0.81–0.96)0.99 (0.89–1.11)0.91 (0.89–0.94)0.97 (0.93–1.00)
 Vaccination vs no vaccination in females0.90 (0.87–0.92)0.94 (0.91–0.97)0.79 (0.74–0.85)0.88 (0.82–0.96)0.93 (0.90–0.95)1.00 (0.97–1.03)
Joint effects
Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)
Overall
 ILI vs no ILI among those with no vaccination1.35 (1.30–1.40)1.46 (1.39–1.53)1.70 (1.54–1.88)1.73 (1.55–1.94)1.29 (1.23–1.35)1.39 (1.32–1.47)
 ILI vs no ILI among those with a vaccination1.15 (1.07–1.25)1.11 (1.01–1.22)1.50 (1.18–1.90)1.41 (1.08–1.85)1.12 (1.03–1.22)1.07 (0.96–1.18)
 Vaccination vs no vaccination among those without ILI0.89 (0.88–0.91)0.97 (0.95–0.99)0.82 (0.77–0.86)0.93 (0.87–0.99)0.90 (0.88–0.92)1.00 (0.98–1.03)
 Vaccination vs no vaccination among those with ILI0.76 (0.70–0.83)0.73 (0.66–0.81)0.72 (0.56–0.92)0.76 (0.57–1.01)0.78 (0.71–0.86)0.77 (0.69–0.86)
Males
 ILI vs no ILI among those with no vaccination1.51 (1.41–2.62)1.62 (1.50–1.75)2.27 (1.92–2.67)2.25 (1.87–2.71)1.40 (1.30–1.51)1.50 (1.38–1.63)
 ILI vs no ILI among those with a vaccination1.33 (1.16–1.53)1.23 (1.05–1.44)2.36 (1.52–3.67)2.30 (1.41–3.78)1.25 (1.09–1.45)1.14 (0.96–1.35)
 Vaccination vs no vaccination among those without ILI0.93 (0.91–0.96)0.97 (0.94–1.01)0.88 (0.80–0.96)0.99 (0.89–1.10)0.91 (0.89–0.94)0.97 (0.94–1.01)
 Vaccination vs no vaccination among those with ILI0.82 (0.71–0.96)0.74 (0.62–0.88)0.91 (0.58–1.45)1.01 (0.60–1.70)0.82 (0.70–0.96)0.74 (0.62–0.89)
Females
 ILI vs no ILI among those with no vaccination1.38 (1.31–1.45)1.46 (1.37–1.55)1.45 (1.28–1.64)1.47 (1.28–1.70)1.35 (1.28–1.43)1.44 (1.34–1.54)
 ILI vs no ILI among those with a vaccination1.18 (1.07–1.30)1.14 (1.01–1.29)1.24 (0.93–1.66)1.15 (0.83–1.59)1.17 (1.05–1.30)1.13 (1.00–1.28)
 Vaccination vs no vaccination among those without ILI0.90 (0.88–0.92)0.95 (0.92–0.98)0.80 (0.74–0.86)0.89 (0.82–0.97)0.93 (0.91–0.96)1.01 (0.97–1.04)
 Vaccination vs no vaccination among those with ILI0.77 (0.68–0.86)0.74 (0.65–0.84)0.68 (0.50–0.93)0.69 (0.49–0.98)0.81 (0.72–0.91)0.79 (0.69–0.92)

Vaccinations were assessed during the year before stroke/trauma visit and ILI was assessed 1–30 days before stroke/trauma visit. ILI indicates influenza-like illness; and OR, odds ratio.

* Controlling for having a preventive care visit in the past year, diabetes, valvular heart disease, smoking, alcohol abuse, obesity, and hypertension P interaction <0.10.

Among the young population (18–44 years), unadjusted and adjusted analyses indicated increased odds of stroke for those with ILI 1 to 30 days before index visit (Table 2) and reduced odds of stroke for those having a vaccination in the year prior. Results were consistent when stratified by sex, albeit vaccinations in males were no longer significantly associated with reduced odds of stroke in the adjusted analyses. In analyses of the combined effects of ILI and vaccinations, there was no significant interaction between ILI and vaccination (adjusted Pinteraction=0.16). Among those with no vaccinations in the prior year, those with ILI had increased odds of stroke (Model 1 OR, 1.73 [1.55–1.94]) and among those with a vaccination in the prior year, those with ILI also had increased odds of stroke, although to a lesser magnitude (Model 1 OR, 1.41 [1.08–1.85]). Stratified analyses by sex produced similar results, with a greater magnitude of effect in males.

Among the middle-aged population (45–65 years), unadjusted and adjusted analyses indicated increased odds of stroke for those with ILI 1 to 30 days before index visit. Though in an unadjusted model, there was a reduced odds of stroke for those having a vaccination in the year prior, this effect was not significant in multivariable analyses. These results were consistent when stratified by sex, with the exception of vaccinations in males remaining statistically significant. In models assessing the combined effects of ILI and vaccinations, there was a significant interaction (adjusted Pinteraction <0.001). Among those with no vaccinations in the prior year, those with ILI had increased odds of stroke (Model 1 OR, 1.39 [1.32–1.47]). Among those with a vaccination in the prior year, ILI was not associated with any increase in risk (Model 1 OR, 1.04 [0.96–1.18]). Analyses stratified by sex produced similar results.

Evaluating different time periods, such as ILI at the time of index visit, 1 to 15 days prior, and 1 to 60 days prior provided results consistent with the main findings (Table 3). ILI had the strongest measure of effect at the time of index visit for both age groups. The magnitude of effect seen from ILI declined with increased preceding time intervals. When examining combined effects of ILI and vaccinations (Table 4), ILI assessed at index visit, 1 to 30 days prior, and 1 to 60 days prior demonstrated the largest increase in odds of stroke among those with no vaccinations in the prior year, with the greatest effects seen in the younger population.

Table 3. Individual Effects of ILI on Stroke Among Those Aged 18 to 65 Years at the Time of Stroke/Control Visit and the Days Prior

Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)
Entire population (ages 18–65)
 ILI vs no ILI6.23 (5.73–6.78)6.13 (5.59–6.71)1.62 (1.54–1.70)1.69 (1.60–1.79)1.30 (1.25–1.35)1.38 (1.32–1.44)1.09 (1.06–1.12)1.16 (1.12–1.20)
 In males5.04 (4.46–5.70)5.17 (4.54–5.89)1.81 (1.67–1.96)1.86 (1.70–2.04)1.47 (1.39–1.56)1.54 (1.43–1.65)1.23 (1.17–1.29)1.28 (1.22–1.36)
 In females7.14 (6.35–8.03)6.88 (6.06–7.81)1.64 (1.55–1.75)1.69 (1.58–1.82)1.32 (1.26–1.39)1.38 (1.31–1.46)1.12 (1.09–1.17)1.16 (1.12–1.22)
Young population (ages 18–44)
 ILI vs no ILI10.71 (8.16–14.07)10.75 (8.12–14.24)2.34 (2.06–2.65)2.36 (2.06–2.72)1.66 (1.52–1.82)1.68 (1.51–1.86)1.28 (1.19–1.37)1.31 (1.21–1.42)
 In males9.52 (6.57–13.78)9.97 (6.79–14.65)3.33 (2.68–4.12)3.35 (2.64–4.24)2.27 (1.94–2.65)2.26 (1.89–2.66)1.69 (1.50–1.91)1.67 (1.46–1.91)
 In females11.97 (8.00–17.89)11.78 (7.79–17.80)1.91 (1.63–2.23)1.92 (1.61–2.29)1.40 (1.25–1.58)1.41 (1.24–1.61)1.11 (1.02–1.21)1.14 (1.03–1.26)
Middle-aged population (ages 45–65)
 ILI vs no ILI5.79 (5.30–6.33)5.66 (5.13–6.23)1.52 (1.44–1.60)1.57 (1.48–1.67)1.24 (1.19–1.29)1.32 (1.26–1.38)1.06 (1.03–1.09)1.12 (1.08–1.16)
 In males4.57 (4.01–5.20)4.64 (4.04–5.33)1.63 (1.50–1.78)1.65 (1.49–1.82)1.37 (1.28–1.46)1.42 (1.32–1.53)1.17 (1.11–1.23)1.22 (1.15–1.29)
 In females6.74 (5.96–7.63)6.49 (5.66–7.44)1.60 (1.50–1.71)1.65 (1.52–1.78)1.30 (1.24–1.37)1.36 (1.28–1.45)1.12 (1.08–1.17)1.16 (1.11–1.22)

ILI indicates influenza-like illness; and OR, odds ratio.

Table 4. Joint Effects of ILI on Stroke Among Those Aged 18 to 65 Years at the Time of Stroke/Control Visit and the Days Prior

ILI at time of stroke/traumaILI at 1–15 d priorILI at 1–30 d priorILI at 1–60 d prior
Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)Unadjusted OR (95% CI)Adjusted* OR (95% CI)
Entire population (ages 18–65)
 ILI vs no ILI among those with no vaccination6.28 (5.73–6.90)6.21 (5.62–6.87)1.67 (1.58–1.76)1.77 (1.67–1.89)1.35 (1.30–1.40)1.46 (1.39–1.53)1.11 (1.07–1.14)1.19 (1.15–1.24)
 ILI vs no ILI among those with a vaccination5.98 (4.88–7.31)5.71 (4.58–7.11)1.47 (1.33–1.63)1.41 (1.25–1.60)1.15 (1.07–1.25)1.11 (1.01–1.22)1.05 (0.99–1.11)1.04 (0.97–1.12)
 Vaccination vs no vaccination among those without ILI0.89 (0.87–0.91)0.96 (0.94–0.98)0.89 (0.87–0.91)0.96 (0.94–0.98)0.89 (0.88–0.91)0.97 (0.95–0.99)0.89 (0.87–0.91)0.97 (0.94–0.99)
 Vaccination vs no vaccination among those with ILI0.85 (0.68–1.06)0.88 (0.69–1.12)0.78 (0.70–0.88)0.77 (0.67–0.88)0.76 (0.70–0.83)0.73 (0.66–0.81)0.84 (0.79–0.90)0.84 (0.78–0.91)
Young population (ages 18–44)
 ILI vs no ILI among those with no vaccination10.98 (8.19–14.72)10.99 (8.12–14.86)2.31 (2.02–2.65)2.34 (2.01–2.72)1.70 (1.54–1.88)1.73 (1.55–1.94)1.30 (1.21–1.41)1.34 (1.22–1.46)
 ILI vs no ILI among those with a vaccination8.84 (4.21–18.54)9.27 (4.31–19.95)2.57 (1.84–3.58)2.56 (1.78–3.69)1.50 (1.18–1.90)1.41 (1.08–1.85)1.21 (1.01–1.44)1.18 (0.97–1.45)
 Vaccination vs no vaccination among those without ILI0.82 (0.78–0.87)0.93 (0.87–0.99)0.81 (0.77–0.86)0.92 (0.86–0.98)0.82 (0.77–0.86)0.93 (0.87–0.99)0.82 (0.77–0.87)0.93 (0.87–0.99)
 Vaccination vs no vaccination among those with ILI0.66 (0.30–1.46)0.78 (0.34–1.78)0.90 (0.63–1.28)1.01 (0.68–1.49)0.72 (0.56–0.92)0.76 (0.57–1.01)0.76 (0.63–0.91)0.82 (0.67–1.02)
Middle–aged population (ages 45–65)
 ILI vs no ILI among those with no vaccination5.80 (5.25–6.39)5.71 (5.13–6.35)1.57 (1.48–1.66)1.65 (1.54–1.77)1.29 (1.23–1.35)1.39 (1.32–1.47)1.07 (1.04–1.11)1.15 (1.11–1.20)
 ILI vs no ILI among those with a vaccination5.76 (4.67–7.10)5.43 (4.31–6.84)1.38 (1.23–1.54)1.30 (1.13–1.48)1.12 (1.03–1.22)1.07 (0.96–1.18)1.03 (0.97–1.10)1.01 (0.93–1.09)
 Vaccination vs no vaccination among those without ILI0.90 (0.88–0.92)1.00 (0.97–1.02)0.90 (0.88–0.92)1.00 (0.98–1.02)0.90 (0.88–0.92)1.00 (0.98–1.03)0.90 (0.88–0.92)1.00 (0.98–1.03)
 Vaccination vs no vaccination among those with ILI0.89 (0.71–1.12)0.95 (0.74–1.22)0.79 (0.70–0.89)0.78 (0.67–0.91)0.78 (0.71–0.86)0.77 (0.69–0.86)0.86 (0.81–0.93)0.88 (0.81–0.95)

Vaccinations were assessed during the year before stroke/trauma visit and ILI was assessed at varying times. ILI indicates influenza-like illness; and OR, odds ratio.

* Controlling for having a preventive care visit in the past year, diabetes, valvular heart disease, smoking, alcohol abuse, obesity, and hypertension.

Discussion

Our case-control study uniquely assessed individual and joint effects of ILI and vaccinations on stroke risk in young and middle-aged commercially insured populations. Our results found ILI increased the odds of stroke, while vaccinations decreased the odds of stroke in the general population, particularly among younger adults (18–44 years). For the middle-age group (45–65 years), ILI similarly resulted in an increase in odds of stroke, however, to a lesser magnitude, and the effect of vaccinations was not statistically significant. Further, these associations were strongest at the time of index visit and 1 to 15 days prior, supportive of the potential for ILI to act as a trigger rather than long-term risk factor. In evaluating joint effects of ILI and vaccinations, our findings suggest that risk of stroke following ILI is greatest among younger individuals who had not been vaccinated in the year prior, particularly in males. These results highlight at-risk groups who may benefit from targeted interventions (eg, vaccination programs) to reduce risk of stroke.

Our findings are consistent with previous studies indicating increased stroke risk after ILI, although previous work was somewhat limited by their utilization of a case-crossover design, which does not account for increased odds of stroke associated with aging and the development of stroke risk factors over time16,18 A participant in a case-crossover study serves as their own control and they may have developed risk factors from the time they served as a control to the time they became a case. However, this difference in risk factors between cases and controls will not be captured in the case-crossover design. Through uses of a case-control design, our study overcame this limitation by matching on age and controlling for risk factors at time of index visit for both those with and without stroke. However, although we matched at time of the index date, we did not account for changes in risk factor profiles or risk factor management over time for either cases or controls.

While prior literature has demonstrated increased risk, the mechanisms by which infections such as ILI increase the risk for stroke are uncertain. Proposed mechanisms behind the relationship between infection and stroke include mediation through a pro-thrombotic state, inflammation-mediated injury of endothelium, infection-related platelet activation and aggregation, inflammation-induced thrombosis, dehydration-induced thrombosis, or through effects on cardiac endothelium.2–6 In response to the emerging role of infectious disease in stroke risk, vaccinations have been examined as potential interventions. Prior research indicates vaccinations are an important strategy in preventing not only infectious diseases but also the development of complications resulting from the infectious diseases including stroke, myocardial infarction, and death.19–22

Earlier studies identified a reduction in stroke risk for people who were vaccinated against influenza.12,23,24 Our study included a more diverse sample of any type of vaccination, though the vast majority of vaccinations year to year in adults are influenza vaccines.25 Interestingly, when assessing joint effects there was a statistical interaction between ILI and vaccination in the middle-aged population, but not in the young population. Reasons for this may include sample size variations, as strokes are rare in younger populations and possible differences in types of vaccines received by each age group, as younger age groups are less likely to be vaccinated for influenza.26 Additionally, biological differences related to sex and age may play a role. When examining the effect by sex within the younger age group, there appears to be no effect in males. This is further demonstrated when examining joint effects of ILI and vaccinations in males, where vaccinations do not seem protective among either males with or without ILI at 1 to 30 days before index visit. However, vaccines seem protective among females, particularly among those with ILI. While our results suggest no individual effect of vaccination among those middle-aged overall, vaccination demonstrated a significant reduction in stroke risk among those middle-aged with an ILI 1 to 30 days before index visit, supporting the hypothesized role vaccines may play in preventing stroke.

Unlike other available vaccines, the influenza vaccine is not similarly protective every year. Since the 2004 to 2005 influenza season, the CDC has provided estimates of the effectiveness of the influenza vaccination. In the years with increased vaccine effectiveness, the overall rates of ILI, stroke, and myocardial infarction were nominally lower, but the association between ILI and stroke remained the same.27 While the potential to become infected with influenza even after vaccination remains, the symptoms experienced may be less severe if vaccinated, and post-infectious complications like stroke, myocardial infarction and death are reduced.12,23,24,28–30 Our results support these prior findings through demonstrating a reduced effect of ILI among the vaccinated young populations. Consistent influenza vaccination done yearly even further reduces the risk of stroke.30 As such, the American Heart Association recommends influenza vaccination as a secondary stroke prevention strategy in patients with coronary or atherosclerotic vascular disease.29 While the bulk of the literature consistently indicates influenza vaccination reduces stroke risk, some studies have identified little or no benefit to influenza vaccination in stroke risk reduction, and thus, the topic remains unsettled.31,32 This could be due to differences in study populations, such as variations in age or perhaps sex differences. For example, our results support there to be limited to no individual effect of vaccination among older populations or among males. Further, as demonstrated by Lin et al,30 the frequency of receiving influenza vaccinations may influence the strength of effect, as only 1 to 2 influenza vaccines over 5 years had no effect on stroke risk while 3 to 4 and 5 vaccinations were associated with significant reductions in risk.

In addition to the influenza vaccine, other vaccines have been identified as protective factors against stroke. A prospective cohort study identified a 35% reduction in stroke risk at 1 year in patients who received the 23-valent pneumococcal vaccine.33 However, the protective benefits did not last longer than 3 years, and a separate cohort study among men found no reduction in stroke risk from the pneumococcal vaccine.34,35

Our study had several limitations. While utilizing administrative data allowed us to achieve a large sample size, particularly for the rare outcome of stroke among the young, we were limited to using ICD-9 codes for exposures, outcomes, and covariates. ICD-9 codes have been validated, but there is potential for misclassification. For our study, ILI had to result in an ICD-9 code associated with an outpatient, inpatient, or emergency department visit to be included. Therefore, we likely capture more moderate to severe ILI, limiting our capability to make conclusions about mild ILI. Further, vaccinations and preventive care visits were assessed through ICD-9 procedure codes associated with outpatient visits. Therefore, our study did not capture whether patients sought care or vaccinations through other sources, such as through work programs or a pharmacy. As a result, vaccination rates may also be underestimated; however, we expect misclassification resulting from use of ICD-9 codes to affect cases and controls similarly. We think influenza vaccinations to make up the majority of vaccinations observed our study given it is recommended annually. However, the proportion of vaccinations being for influenza and types of other vaccinations given likely vary by age group. Vaccinations may also be a surrogate for other healthy behavior, and thus associations may, in part, represent this. However, to reduce this potential bias we also controlled for preventive visits. Additionally, calculated E-values were moderate, suggesting observed associations may be explained by unmeasured confounders. Finally, MarketScan captures insurance claims data, and thus this study may not be representative of uninsured individuals or individuals with other types of insurance that are not included in MarketScan. However, we think the large sample size representative of a national population achieved through this study design outweighs this limitation, as it allows us to examine stratified analyses among populations where the outcome of stroke is rare.

In summary, our case-control study found ILI associated with increase in risk of stroke, while vaccines appeared to decrease the risk of stroke, particularly among the young. Further, our study uniquely examines joint effects of ILI and vaccinations on stroke with results indicating vaccinations can reduce the effect of ILI on stroke. Importantly, these findings aid in informing at-risk groups who may most benefit from vaccination programs for stroke prevention and may provide additional motivation for younger populations to get their yearly influenza vaccine. Building on our work, future investigations should further explore the potential for causality of the observed relationship between vaccinations and stroke. Elucidating potential mechanisms for increased stroke risk following ILI infection may further aid the identification of targeted and effective interventions.

Article Information

Supplemental Material

Table S1

STROBE Checklist

Nonstandard Abbreviations and Acronyms

ILI

influenza-like illness

ICD-9

International Classification of Diseases, Ninth Revision

IQR

interquartile range

OR

odds ratio

Disclosures None.

Footnotes

This manuscript was sent to Helmi Lutsep, Guest Editor, for review by expert referees, editorial decision, and final disposition.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.121.038403.

For Sources of Funding and Disclosures, see page 2692.

Correspondence to: Amelia K. Boehme, PhD, MSPH, Division of Neurology Clinical Outcomes Research and Population Sciences, Columbia University, 710 West 168th St, Room 642, New York, NY 10032. Email

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