All infection types were associated with subsequent acute ischemic stroke, with the greatest association for urinary tract infection.

Every infection type was associated with an increased likelihood of acute ischemic stroke. The greatest association was for urinary tract infection, with OR of 5.32 (95% CI, 3.69–7.68) within the 7-day window. The magnitude of association between urinary tract infection and intracerebral hemorrhage was of lesser magnitude, with OR of 1.80 (1.04–3.11) in the 14-day exposure period and OR of 1.54 (1.23–1.94) in the 120-day exposure period. Only respiratory infection was associated with subarachnoid hemorrhage, with OR of 3.67 (1.49–9.04) in the 14-day window and 1.95 (1.44–2.64) in the 120-day window.

We used the New York State Inpatient Databases and Emergency Department Databases (2006–2013). Validated International Classification of Diseases , Ninth Edition definitions identified index hospitalizations for acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, and emergency department visits and hospitalizations for infection (skin, urinary tract infection, septicemia, abdominal, and respiratory). We used case cross-over analysis with conditional logistic regression to estimate odds ratios (OR) for the association between each infection type during case periods compared with control periods 1 year before.

The relationships between different infection types and stroke subtype are not well-characterized. We examined exposure to infections in different organ systems in different time periods before the acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.

Stroke triggers are conditions that precipitate the acute occurrence of stroke. Acute infections have been studied as potential triggers of stroke.1–3 However, infections in different organ systems have been rarely examined comparatively in the same study, and studies failed to differentiate subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH).2

We sought to examine the differential associations between infection in different body systems and risk of stroke (ischemic, SAH, and ICH), hypothesizing that there would be a gradient of association, with a greater magnitude of association between infection and stroke during shorter time intervals before the stroke event.

Methods

We used the State Inpatient and Emergency Department Databases from 2006 to 2013, containing data on 97% of hospitalizations and emergency department visits for New York State at community hospitals, for all payers and the uninsured. The Mount Sinai Institutional Review Board reviewed and approved this study. The data are publicly available through Healthcare Cost and Utilization Project (HCUP), and the authors are bound by a data use agreement not to share the data.

We used validated International Classification of Disease, Ninth Revision, Clinical Modification codes in the primary diagnosis position to identify the main exposures of infection types (skin, urinary tract infection [UTI], septicemia, abdominal, and respiratory) and each index stroke subtype. International Classification of Disease, Ninth Revision codes for infections were previously validated with excellent sensitivity and specificity.4–8 Index admissions were defined with acute ischemic stroke (AIS), SAH, or ICH coded as the primary diagnosis, with excellent specificity and sensitivity.9,10

Statistical Analysis

To assess whether exposure to different infection types (skin, UTI, septicemia, abdominal, and respiratory) was associated with stroke events (AIS, ICH, and SAH), we performed a case-crossover analysis for each infection type and each stroke event in separate models. The case-crossover analysis only includes data on cases (ie, those with stroke events), and each individual serves as his or her own control, obviating the need to adjust for confounders. We tested whether exposure to infection within progressively longer case periods (7, 14, 30, 60, 90, and 120 days before index admission for stroke), compared with control periods exactly 1 year before the case period, was associated with the occurrence of the stroke event. We used conditional logistical regression models to estimate odds ratios and 95% CI for associations and show only significant associations. Analyses were performed in SAS version 9.4.

Results

There were 152 356 index AIS, 27 257 ICH, and 11 853 SAH admissions. Every infection type was associated with an increased likelihood of AIS (Table 1). The association was nominally greatest for UTI. For all infection types, the magnitude of risk decreased with longer time windows before the ischemic stroke. The most common infection was respiratory.

Table 1. Conditional Logistic Regression Results for the Index Event of Ischemic Stroke Case vs Control Periods: No. of Days Before Index Admission OR 95% CI P Value Exposure: skin infections 7 vs 365–372 1.47 0.98–2.23 0.065 14 vs 365–379 1.45 1.10–1.92 0.0095 30 vs 365–395 1.52 1.25–1.85 <0.0001 60 vs 365–425 1.41 1.22–1.63 <0.0001 90 vs 365–455 1.38 1.22–1.56 <0.0001 120 vs 365–485 1.36 1.22–1.51 <0.0001 Exposure: urinary tract infection 7 vs 365–372 5.32 3.69–7.68 <0.0001 14 vs 365–379 4.54 3.54–5.82 <0.0001 30 vs 365–395 3.24 2.74–3.83 <0.0001 60 vs 365–425 2.65 2.34–2.99 <0.0001 90 vs 365–455 2.32 2.09–2.58 <0.0001 120 vs 365–485 2.13 1.94–2.34 <0.0001 Exposure: septicemia 30 vs 365–395 2.29 1.22–4.28 0.0099 60 vs 365–425 2.48 1.49–4.11 0.0005 90 vs 365–455 2.63 1.69–4.10 <0.0001 120 vs 365–485 2.63 1.75–3.94 <0.0001 Exposure: abdominal infection 14 vs 365–379 3.00 1.35–6.68 0.0071 30 vs 365–395 2.08 1.29–3.35 0.0026 60 vs 365–425 1.63 1.13–2.35 0.009 90 vs 365–455 1.71 1.26–2.34 0.0007 120 vs 365–485 1.68 1.288–2.21 0.0002 Exposure: respiratory infection 7 vs 365–372 3.20 2.47–4.15 <0.0001 14 vs 365–379 2.99 2.50–3.57 <0.0001 30 vs 365–395 2.59 2.29–2.93 <0.0001 60 vs 365–425 2.23 2.03–2.45 <0.0001 90 vs 365–455 1.95 1.81–2.11 <0.0001

The association between UTI and ICH was of lesser magnitude (Table 2). As with AIS, there was a gradient for the odds ratio of ICH with exposure to respiratory infections, comparing the 7-day window to sequentially longer time windows. Although the total number of exposures to septicemia was low, there was a significant and large association with ICH.

Table 2. Conditional Logistic Regression Results for the Index Event of Intracerebral Hemorrhage Case vs Control Periods: No. of Days Before Index Admission OR 95% CI P Value Exposure: skin infections 30 vs 365–395 0.55 0.31–0.97 0.0386 Exposure: urinary tract infection 14 vs 365–379 1.80 1.04–3.11 0.0351 30 vs 365–395 1.83 1.22–2.75 0.0034 60 vs 365–425 1.43 1.06–1.92 0.0205 90 vs 365–455 1.54 1.19–2.01 0.0012 120 vs 365–485 1.54 1.23–1.94 0.0002 Exposure: septicemia 60 vs 365–425 3.25 1.06–9.97 0.0393 90 vs 365–455 2.83 1.12–7.19 0.0283 120 vs 365–485 2.86 1.21–6.76 0.0168 Exposure: respiratory infection 7 vs 365–372 2.11 1.21–3.70 0.009 14 vs 365–379 1.73 1.15–2.59 0.008 30 vs 365–395 1.98 1.47–2.68 <0.0001 60 vs 365–425 1.77 1.42–2.20 <0.0001 90 vs 365–455 1.57 1.31–1.88 <0.0001 120 vs 365–485 1.52 1.29–1.78 <0.0001

For SAH (Table 3), there were few exposures. Only respiratory infection showed an association with SAH, possibly because of limited power for other infections.

Table 3. Conditional Logistic Regression Results for the Index Event of Subarachnoid Hemorrhage Case vs Control Periods: No. of Days Before Index Admission OR 95% CI P Value Exposure: respiratory infection 7 vs 365–372 2.60 0.93–7.29 0.0694 14 vs 365–379 3.67 1.49–9.04 0.0048 30 vs 365–395 1.91 1.12–3.23 0.0168 60 vs 365–425 1.78 1.22–2.61 0.0031 90 vs 365–455 1.89 1.36–2.64 0.0002 120 vs 365–485 1.95 1.44–2.64 <0.0001

Discussion

In this case-crossover study, we found that all infection types triggered AIS. The greatest magnitude of association was seen with UTI, which was associated with a >3 fold increased risk of ischemic stroke within 30 days. With ICH, there were significant associations with preceding UTI, respiratory infection, and sepsis. Of the infection types, only preceding respiratory infection was associated with SAH admission. We also observed a gradient of decreasing magnitudes of association with longer time periods, across various infection types and stroke subtypes, supporting the concept of infection as a trigger of these events with a greater potential influence over a shorter time window.

There are several mechanisms by which infection can trigger stroke: increases in circulating leukocytes contributing to atherogenesis and thrombogenesis11; increased platelet activation1; increased risk of deep vein thrombosis because of immobilization, causing paradoxical embolism1; increased fibrinogen, leukocytes, clotting factor, and cytokines, and metabolism and function of endothelial cells and macrophages favoring atherosclerosis and thrombosis formation.12

Previous studies have shown that the risk of ischemic stroke is increased after herpes zoster infection.3,13 Respiratory infection had the highest odds ratio with ischemic stroke in our study. In a prior study, in a 3-day period before a diagnosis of stroke, respiratory infection was associated with stroke, with incidence rate ratio of 3.19 (95% CI, 2.81–3.62).14 In our study, UTI had the greatest association with an odds ratio of 5.32 for ischemic stroke but no association for ICH or SAH. Separate analyses on abdominal infections before stroke have not been performed.

There were several strengths of our study. With a case-crossover design, each patient serves as his/her own control, obviating the need to adjust for confounders. A large data set with long-term follow-up allowed us to examine rarer infection exposures, and the use of emergency department and inpatient data provided broad exposure and outcome information. A weakness included reliance on International Classification of Disease, Ninth Revision coding to identify conditions. Also, there were no available data about outpatient visits or medication use, and we could only identify patients admitted with infection. More research is also needed on potential interventions, such as vaccination or antibiotic regimens, or intensive antithrombotic treatments, to not only treat the infection but also potentially reduce thrombotic and bleeding risk.

Disclosures None.

Footnotes