Sex-Related Differences in the Risk of Hospital-Acquired Sepsis and Pneumonia Post Acute Ischemic Stroke

doi:10.1016/j.jstrokecerebrovasdis.2016.06.008

Journal of Stroke and Cerebrovascular Diseases

Volume 25, Issue 10, October 2016, Pages 2399-2404

https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.06.008 Get rights and content

Background and Objective

Infectious complications after ischemic stroke are frequent and lead to neurological deterioration, poor functional outcomes, and higher mortality. Local and systemic inflammatory responses to brain ischemia differ between males and females, but little is known about differences in poststroke susceptibility to infection by sex. The purpose of this study was to compare sex-related differences in the risk of hospital-acquired sepsis and pneumonia after acute ischemic stroke (AIS).

Materials and Methods

This is a retrospective, secondary analysis of the 2010-2011 California State Inpatient Database. Previously validated International Classification of Disease, Ninth Revision (ICD-9) codes were used to identify adult hospitalizations for AIS. The primary outcome was hospital-acquired sepsis or pneumonia, also identified using ICD-9 codes. Associations between sex and hospital-acquired sepsis or pneumonia were adjusted for baseline characteristics and comorbidities using multivariable logistic regression.

Results

There were 91,643 hospitalizations for AIS included in this analysis, of which 1027 had hospital-acquired sepsis and 1225 had hospital-acquired pneumonia. The in-hospital mortality without infection was 4.6%; the presence of hospital-acquired infections was associated with higher mortality for sepsis (32.7%) and pneumonia (21.9%). Female (versus male) sex was associated with lower adjusted odds of hospital-acquired sepsis (odds ratio [OR] .74, 95% confidence interval [CI] .65-.84) and pneumonia (OR .69, 95% CI .62-.78). This difference was similar across age strata. Among hospitalizations with either hospital-acquired sepsis or pneumonia, sex did not influence mortality.

Conclusions

Female sex was associated with a lower risk of hospital-acquired sepsis and pneumonia after AIS. Further investigation is needed to determine the mechanisms underlying this clinical observation.

Introduction

Acute ischemic stroke (AIS) is a leading cause of death and adult neurological disability worldwide. Sepsis and pneumonia are common, and highly morbid, infectious complications in stroke patients.¹ The development of poststroke infection leads to multiple poor outcomes including neurological deterioration,² prolonged hospital length of stay,³ poor functional outcome, and death.⁴ The high clinical impact and limited effective strategies for prevention or treatment of poststroke infection indicate the need for further investigation into underlying mechanisms and potential therapeutic options.

The etiology for increased susceptibility to infection during the poststroke period is multifactorial; however, compelling evidence indicates that brain ischemia leads to clinically important changes in immune function.⁵ In addition to local brain inflammatory responses contributing to the evolution of injury, emerging evidence indicates that depression of immune function is a natural defense mechanism to minimize excessive inflammation in the injured brain.⁵ While likely limiting inflammation-related brain injury after stroke, this immunosuppression also leads to increased susceptibility to infection. This pathway is mediated by dysregulated autonomic signaling and changes in peripheral immune cell numbers and function.⁶

Sex-related differences in ischemic stroke outcomes have been the topic of prior epidemiological research,⁷ but little has been focused on poststroke infectious complications. One prior retrospective study reviewed 568 admissions for AIS to develop a scoring system to predict the likelihood of poststroke infection. Friedant et al⁸ identified age, diabetes, and stroke severity as predictors of infection, whereas sex was not found to be predictive of this outcome. Rodent studies have shown sexual dimorphisms in functional outcomes and inflammatory response after experimental brain ischemia, suggesting that poststroke infectious complications may also be sex dependent.⁹ The objective of the present study was to compare sex-related differences in the risk of hospital-acquired sepsis and pneumonia after AIS.

Section snippets

Study Design

This was a secondary analysis of the 2010-2011 California State Inpatient Database, which includes data from all hospitalizations in California. We chose California because it has a large and diverse population, and equivalent national data do not contain a “present on admission” indicator variable, considered key to our analysis. Detailed methodology for the State Inpatient Database is provided by the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project (//www.hcup-us.ahrq.gov

Results

We identified 91,643 California hospitalizations for AIS in 2010-2011, of which 1027 met our case definition for hospital-acquired sepsis and 1225 for hospital-acquired pneumonia. Table 1 shows the baseline characteristics and comorbidities of hospitalizations with diagnoses of sepsis or pneumonia stratified by whether the diagnosis code was hospital acquired or present on admission. As previously described, the presence of hospital-acquired infection markedly increased in-hospital mortality,

Discussion

In this large, diverse cohort, female sex was independently associated with a markedly lower risk of hospital-acquired sepsis and pneumonia after AIS. This difference was present across all age groups, suggesting that these sex-related differences in infection risk might not depend on variation in sex hormones throughout the female life span. Our data also confirm prior observations of increased morbidity and mortality associated with the development of hospital-acquired sepsis or pneumonia

Conclusions

Female sex was associated with a strikingly lower risk of hospital-acquired sepsis and pneumonia after AIS. The mechanisms underlying this difference will require further investigation, but may be due to local and systemic inflammatory response driven by sex hormones or sex differences in noradrenergic input. Understanding this physiology and potential therapeutic implications is important for reducing the incidence and severity of infectious complications after stroke, particularly given the

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Female gender, in addition to age 65-74 years versus ages less than 65 or older than 74, white race and location of non-urban geographic area, has been associated with prolonged response times; having a dispatch code of stroke may shorten response times.2, 8 Furthermore, women are at an increased lifetime risk of stroke, suffer higher stroke morbidity and mortality, and are less likely to receive guideline-concordant in-hospital care9-12 relative to men, making the finding of prolonged response times for them even more important. To date, however, contemporary EMS nationwide concordance with ASA guidelines for prehospital care have not been analyzed, especially in respect to the potential disparities in care between men and women.
Emergency Medicine Service (EMS) providers play a pivotal role in early identification and initiation of treatment for stroke. The objective of this study is to characterize nationwide EMS practices for suspected stroke and assess for gender-based differences in compliance with American Stroke Association (ASA) guidelines.
Using the 2019-2020 National Emergency Medical Services Information System (NEMSIS) Datasets, we identified encounters with an EMS designated primary impression of stroke. We characterized patient characteristics and EMS practices and assessed compliance with eight metrics for “guideline-concordant” care. Multivariable logistic regression modeled the association between gender and the primary outcome (guideline-concordant care), adjusted for age, EMS level of service, EMS geographical region, region type (i.e. urban or rural), and year.
Of 693,177 encounters with a primary impression of stroke, overall compliance with each performance metric ranged from 18% (providing supplemental oxygen when the pulse oximetry is less than 94%) to 76% (less than 90sec from incoming call to EMS dispatch). 2,382 (0.39%) encounters were fully guideline-concordant. Women were significantly less likely than men to receive guideline-concordant care (adjusted OR 0.82, 95% CI 0.75-0.89; 0.36% women, 0.43% men with guideline-concordant care).
A minority of patients received prehospital stroke care that was documented to be compliant with ASA guidelines. Women were less likely to receive fully guideline-compliant care compared to men, after controlling for confounders, although the difference was small and of uncertain climical importance. Further studies are needed to evaluate the underlying reasons for this disparity, its impact on patient outcomes, and to identify potential targeted interventions to improve prehospital stroke care.
Association Between Chronic Inflammatory Diseases and Stroke-Associated Pneumonia – An Epidemiological Study
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See appendix Table 1 for ICD-9 and ICD-10 codes for each diagnosis. ICD codes were identified from https://www.icd10data.com/ and https://www.icd9data.com/ were consistent with prior studies.27,28 Statistical Analysis: We characterized the cohort using descriptive statistics.
Pneumonia, the most common post-acute ischemic stroke (AIS) infection, accounts for up to 30% of deaths after a stroke. Multiple chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease, are associated with increased risk of stroke and stroke morbidity. This study assessed the relationship between chronic inflammatory diseases and stroke-associated pneumonia (SAP).
Using data from the 2015-2017 National Inpatient Sample, we classified hospital discharges with a diagnosis of AIS as having ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, other chronic inflammatory diseases, multiple chronic inflammatory diseases, or none. With multivariable logistic regression, we assessed for associations between chronic inflammatory disease and in-hospital SAP or death.
Among AIS discharges, there was a decreased risk of SAP among those with psoriasis or other chronic inflammatory diseases (adjusted odds ratio (aOR) 0.70, 95%CI 0.63-0.99; aOR 0.64, 95%CI, 0.46-0.89, respectively), compared to those without psoriasis and without other chronic inflammatory disease, respectively. Rheumatoid arthritis, psoriasis, and other chronic inflammatory diseases were associated with reduced in-hospital mortality (aOR 0.89, 95%CI 0.78-1.00; aOR 0.77, 95%CI 0.59-1.00; aOR 0.69, 95%CI 0.50-0.94, respectively).
The risk of SAP and in-hospital mortality varies by chronic inflammatory disease – psoriasis and other chronic inflammatory diseases are associate with reduced rates of SAP, whereas rheumatoid arthritis, psoriasis and other chronic inflammatory disease were associated with reduced in-hospital mortality. Further investigations are needed to determine a relationship between the potential role of immunomodulation and the reduction in SAP and mortality in chronic inflammatory diseases.
Lipopolysaccharide-induced sepsis-like state compromises post-ischemic neurological recovery, brain tissue survival and remodeling via mechanisms involving microvascular thrombosis and brain T cell infiltration
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Infections, namely pneumonia and urinary tract infection, are risk factors predisposing for poor stroke outcome (Kumar et al., 2010). Via the development of sepsis, infections are the major cause of stroke-associated deaths (Silver et al., 1984; Ferreira Machado et al., 2013; Popović et al., 2013; Colbert et al., 2016). In 91,643 patients admitted to hospital for treatment of acute ischemic stroke, 3.4% exhibited sepsis upon admission and 1.1% developed hospital-acquired sepsis (Colbert et al., 2016).
Sepsis predisposes for poor stroke outcome. This association suggests that sepsis disturbs post-ischemic tissue survival and brain remodeling. To elucidate this link, we herein exposed mice to 30 min intraluminal middle cerebral artery occlusion (MCAO) and induced a sepsis-like state at 72 h post-ischemia by intraperitoneal delivery of Escherichia coli lipopolysaccharide (LPS; three doses of 0.1 or 1 mg/kg, separated by 6 h), a major component of the bacterium’s outer membrane. Neurological recovery, ischemic injury, brain remodeling and immune responses were evaluated over up to 56 days post-sepsis (dps) by behavioral tests, immunohistochemistry and flow cytometry. Delivery of 1 mg/kg but not 0.1 mg/kg LPS reduced rectal temperature over 48 h by up to 3.4 ± 3.1 °C, increased general and focal neurological deficits in the Clark score over 72 h and increased motor-coordination deficits in the tight rope test over up to 21 days. Notably, 1 mg/kg, but not 0.1 mg/kg LPS increased intercellular adhesion molecule-1 abundance on ischemic microvessels, increased microvascular thrombosis and increased patrolling monocyte and T cell infiltrates in ischemic brain tissue at 3 dps. Infarct volume was increased by 1 mg/kg, but not 0.1 mg/kg LPS at 3 dps (that is, 6 days post-MCAO), as was brain atrophy at 28 and 56 dps. Microglial activation in ischemic brain tissue, evaluated by morphology analysis of Iba-1 immunostainings, was transiently increased by 0.1 and 1 mg/kg LPS at 3 dps. Our data provide evidence that neurological recovery and brain remodeling are profoundly compromised in the ischemic brain post-sepsis as a consequence of cerebral thromboinflammation.
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The prevalence of pneumonia after strokes varies between 2% and 14% in different studies (Matz et al., 2016). Pneumonia and respiratory tract infections are suggested to be more common in men after stroke (Arboix et al., 2001; Eriksson et al., 2009; Finlayson et al., 2011; Colbert et al., 2016; Matz et al., 2016). Colbert et al. also report female sex to be associated with a lower risk of hospital-acquired sepsis.
Sex disparities within the field of stroke, including subarachnoid hemorrhages (SAHs), have been in focus during the last 2 decades. It is clear that stroke incidence is higher in men, and also that men have their first stroke earlier than women. On the other hand, women have more severe strokes, mainly because cardioembolic strokes are more common in women. This leads to higher case fatality and worse functional outcome in women. It has often been pointed out that women more often have nontraditional stroke symptoms, and therefore may seek medical help later. After discharge from the hospital, female stroke survivors live alone in many cases and are dependent on external care. Therefore, these women frequently rate their quality of life (QoL) lower than men do. Female spouses more often provide help to their male stroke survivors than the reverse, and they accept a heavier burden. These caregivers are at high risk for depression, low QoL, and low psychologic wellbeing. SAH is a special form of stroke, often caused by a ruptured aneurysm. It is about 20% more common in women. The case fatality is high, but does not differ between the sexes.
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: Grant support: Dr. Colbert was supported by National Institutes of Health grant 5T32AG000279. Dr. Ginde was supported by NIH grant 1K23AG040708.

View full text

Sex-Related Differences in the Risk of Hospital-Acquired Sepsis and Pneumonia Post Acute Ischemic Stroke

Background and Objective

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Study Design

Results

Discussion

Conclusions

J Stroke Cerebrovasc Dis

J Stroke Cerebrovasc Dis

J Stroke Cerebrovasc Dis

J Neuroimmunol

Lancet

Post-stroke infection: a systematic review and meta-analysis

BMC Neurol

Hospital-acquired infection underlies poor functional outcome in patients with prolonged length of stay

ISRN Stroke

The immune system in stroke: clinical challenges and their translation to experimental research

J Neuroimmune Pharmacol