Infection as a Stroke Risk Factor and Determinant of Outcome after Stroke

Abstract

Understanding the relationship between infection and stroke has taken on new urgency in the era of the coronavirus disease 19 (COVID-19) pandemic. This association is not a new concept, as several infections have long been recognized to contribute to stroke risk. The association of infection and stroke is also bidirectional. While infection can lead to stroke, stroke also induces immune suppression which increases risk of infection. Apart from their short-term effects, emerging evidence suggests that post-stroke immune changes may also adversely affect long-term cognitive outcomes in stroke patients, increasing the risk of post-stroke neurodegeneration and dementia. Infections at the time of stroke may also increase immune dysregulation after the stroke, further exacerbating the risk of cognitive decline. This review will cover the role of acute infections, including respiratory infections such as COVID-19, as a trigger for stroke; the role of infectious burden, or the cumulative number of infections throughout life, as a contributor to long-term risk of atherosclerotic disease and stroke; immune dysregulation after stroke and its effect on the risk of stroke-associated infection; and the impact of infection at the time of a stroke on the immune reaction to brain injury and subsequent long-term cognitive and functional outcomes. Finally, we will present a model to conceptualize the many relationships among chronic and acute infections and their short- and long-term neurological consequences. This model will suggest several directions for future research.

Introduction

The putative relationship between infections and cerebrovascular injury has been explored for centuries, but the concept has regained particular urgency in the era of the novel coronavirus pandemic that started in late 2019. In the second century A.D. Galen described apoplexy, the Greek term for stroke, as due to “some inflammatory disease that exists in the head,” perhaps the first reference to stroke as a consequence of infection.¹ In the late 1800s, European neurologists noted the link between acute infections and stroke in children.² Syphilis soon became a classic infectious cause of cerebral arteritis and stroke. By 1921, Stanford pathologist William Ophuls reported that cerebral arteriosclerosis was present earlier and more extensively in patients with a history of chronic systemic infection and inflammation.³ In the 1970s, investigators experimentally induced atherosclerosis in chickens by infecting them with an avian herpesvirus.⁴ Investigators also noted a seasonal variation in patients lacking traditional vascular risk factors and proposed a role for systemic infection in stroke pathogenesis in the young.⁵

More recently, epidemiological and laboratory studies have brought renewed attention to the many potential ways in which infections of various types may contribute to risk of stroke and to adverse outcomes after stroke. This review, written by a group of clinicians, epidemiologists, and laboratory scientists, will cover these developments, particularly the role of acute infections, including respiratory infections such as coronavirus disease 2019 (COVID-19), as a trigger for stroke; the role of infectious burden, or the cumulative number of infections throughout life, as a contributor to long-term risk of atherosclerotic disease and stroke; and the impact of infection at the time of a stroke on the immune reaction to brain injury and subsequent long-term cognitive and functional outcomes.

Infection as a stroke trigger

Many studies provide evidence that systemic infection may trigger, or precipitate, acute stroke.⁶ In the Cardiovascular Health Study, hospitalization for infection was associated with increased risk of ischemic stroke using both case-crossover and survival analyses.⁷ Hospitalization for infection was more than three times as likely during case than control time periods (for 90 days before stroke, odds ratio [OR] 3.4, 95% confidence interval [95%CI] 1.8 to 6.5); for 30 days, OR 7.3, 95%CI 1.9 to 40.9), and for 14 days, OR 8.0, 95%CI 1.7 to 77.3). In confirmatory time-dependent survival analyses, individuals were considered “exposed” for varying periods of time after their hospitalization for infection, after which they reverted to a state of non-infection until they were again hospitalized for infection. These analyses, also adjusted for other risk factors, showed associations of lesser magnitude (adjusted hazard ratio=2.4, 95%CI 1.6 to 3.4) for stroke risk after hospitalization for infection in the preceding 90 days. The risk was again higher for shorter time windows after infection, suggesting a time-limited effect of exposure to infection on stroke risk. This finding of a transient interval after infection during which patients are predisposed to stroke is consistent with the hypothesis that the infectious state, due to inflammation, thrombophilia, or other mechanisms, increases risk. Analyses in the Atherosclerosis Risk in Communities study found a similar increase in risk, and further provided evidence that the effect of infection on stroke risk was greater among those at lower baseline risk.⁸ A large prospective study in Britain, also including outpatients, found an increase in stroke risk in the days following acute upper respiratory or urinary tract infection (UTI).⁹ As in hospitalized patients, magnitude of effect diminished over time after infection.

Bacteremia is a particularly strong stimulus to inflammation and thrombosis. In a case-crossover analysis of administrative data from California (3188 ischemic and 1101 hemorrhagic stroke patients), sepsis was associated with markedly increased odds of ischemic (OR 28.4, 95%CI 20.0–40.1) and hemorrhagic (OR 12.1, 95%CI 7.5–19.4) stroke within 15 days.¹⁰ Risk diminished over time, but remained elevated as long as 365 days after sepsis. The risk was again significantly greater for younger patients–the risk of ischemic stroke within 180 days of sepsis increased 18% for every 10-year decrease in age. Despite the high relative increase in risk associated with sepsis, the absolute risk of stroke remains low–approximately 0.5% of patients with sepsis will experience stroke within a year.¹¹ Several features may be used to determine which stroke patients are at increased risk of stroke after sepsis, however. For example, among 121,947 sepsis patients, valvular heart disease, congestive heart failure, renal failure, lymphoma, peripheral vascular disease, pulmonary circulation disorders, and coagulopathy were all predictors of stroke after sepsis.¹¹ Potentially, a prognostic score incorporating risk factors could be used to select a group of patients for a trial of vascular protective therapy after sepsis.

Most infections in these analyses were either respiratory or urinary; details about specific organisms were rarely available, and studies were largely limited to ischemic strokes. An analysis in a large statewide administrative database, however, provides evidence that several types of infections could serve as triggers, and further that multiple stroke subtypes may be affected.¹² Using the New York State Inpatient and Emergency Department Databases (2006–2013), investigators identified hospitalizations for acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, and emergency department visits and hospitalizations for infections of the skin, abdomen, urine, and respiratory tract, as well as septicemia. Every infection type was associated with an increased likelihood of ischemic stroke, with the strongest association for UTI (OR 5.32, 95%CI, 3.69–7.68) within 7 days. UTI was also associated with intracerebral hemorrhage, and respiratory infection was associated with subarachnoid hemorrhage.

Few studies have examined laboratory-confirmed infections. Using self-controlled case series analysis of linked electronic Danish health records, investigators determined the relative incidence of the first stroke within 28 days after laboratory-confirmed respiratory infections compared with a baseline time period, after adjusting for age and season.¹³ Incidence ratios for stroke following Streptococcus pneumoniae infection were 25.5 at 1–3 days and 6.3 at 8–14 days, and following respiratory virus (mainly influenza) infection 8.3, 7.8 and 6.2 during 1–3, 4–7 and 8–14 days, respectively.

Influenza and other viral triggers

Many studies have focused on influenza as a stroke trigger, given its prevalence, particularly in high-risk, elderly populations. Because specific diagnoses of influenza are not always available, epidemiologists have used the diagnostic category of influenza-like illness (ILI) that is used for surveillance of emerging outbreaks. In a case-crossover analysis using California data, among 36,975 hospitalized ischemic strokes, the odds of ischemic stroke were greatest in the first 15 days after ILI (OR 2.88, 95%CI 1.86–4.47), the magnitude of association decreased as the interval from infection increased, and it was no longer significant after 60 days.¹⁴ The odds of stroke after ILI were significantly higher in younger individuals, increasing 7% with each 10-year decrease in age.

Viral infections other than influenza have been associated with short-term stroke risk, including in children. In the international Vascular Effects of Infection in Pediatric Stroke study, for example, among 326 children with stroke and 115 control children, serological evidence of recent infection with several herpesviruses (Epstein-Barr virus, varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus (HSV) 1 or HSV2) doubled the odds of stroke in children aged 29 days through 18 years (OR 2.2, 95%CI 1.2–4.0).¹⁵ HSV, found in one quarter of cases, was the most common herpesvirus to be detected. In a subsample of the children, parvovirus B19 (PVB19) was also detected. A single-stranded DNA virus, PVB19 commonly causes erythema infectiosum (“fifth disease”) in children. Maternal PVB19 infection during pregnancy is associated with intrauterine fetal death, and perivascular calcifications may be found in the fetal cerebral arteries.¹⁶ DNA evidence of PVB19 was found in serum from 6% of children with stroke and 0% of controls.¹⁷

The mechanisms by which infections may trigger stroke are uncertain, as much of the data come from human studies in which mechanistic explanations are less readily available (Table 1). Proposed mechanisms include infection-related platelet activation and aggregation, inflammation-induced thrombosis, impaired endothelial function, infection-provoked cardiac arrhythmias, and dehydration-induced thrombosis.¹⁸ Human studies may provide insight into mechanisms, as well. For example, in a retrospective analysis of administrative claims data (N=3,144,787 adults; n=49,082 with severe sepsis), new-onset atrial fibrillation occurred in 5.9% of patients with vs 0.7% of patients without severe sepsis (adjusted OR 6.82, 95%CI 6.54–7.11).¹⁹ Those with new-onset AF during severe sepsis were at greater risk of in-hospital stroke (adjusted OR 2.7, 95%CI 2.1–3.6), compared to those without.

Table 1.

Proposed mechanisms of stroke pathogenesis in connection with infection

Mechanism of pathogenesis	Examples
Direct invasion of arterial wall, or endotheliopathy	Syphilis, VZV, HSV, HIV, parvovirus B19
Acceleration of atherosclerosis through induction of cytokines (TNF-alpha, interleukin 2) in response to specific antigenic stimulus	Herpesviruses, HIV, Chlamydia pneumoniae
Acute systemic infection as stroke trigger (platelet activation, dehydration, infection-induced cardiac arrhythmias)	Influenza, upper respiratory infections, urinary tract infections
Chronic inflammation due to multiple infections (“infectious burden”)	Periodontal infection, Chlamydia pneumoniae, herpesviruses

The potential for acute infections to trigger stroke also suggests that vaccinations against these pathogens could prevent stroke and other cardiovascular events. Influenza vaccination has been associated with reduced stroke risk, particularly in older patients, and the benefits of influenza vaccination for stroke prevention appear to increase with successive yearly vaccinations.²⁰ The American Heart Association recommends influenza vaccination as a secondary prevention strategy in patients with coronary or atherosclerotic vascular disease.²¹ Other evidence suggests little or no benefit to influenza vaccination, however, and the topic remains controversial.²²

COVID-19

COVID-19, the pandemic illness caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has also been associated with stroke risk, although the magnitude of risk and stroke characteristics remain under investigation, given the limited global experience with this disease. Reports from heavily affected regions suggest that the stroke risk among patients hospitalized with COVID-19 is approximately 0.5–3%, while the risk in critically ill patients approaches 6%.^23,24,25 Unexplained large vessel occlusions appear to be a frequent presentation, even among patients without severe respiratory illness, suggesting a role for thrombophilia as a mechanism^24,26 (Figure 1). Elevated D-dimer levels, anti-phospholipid antibodies, and other markers of hypercoagulability as a consequence of COVID-19 have been reported.²⁷ Stroke subtypes, however, also include small vessel and cardioembolic ischemic strokes, as well as cerebral venous thrombosis and hemorrhages. This heterogeneity suggests that the mechanisms of stroke may not be specific to a particular pathophysiological feature of the SARS-CoV-2 virus, but rather the result of thrombophilia, endothelial dysfunction, thrombotic microangiopathy, and non-specific effects of inflammation.²⁸ Of note, vasculitis has not been demonstrated. Pre-existing risk factors likely also contribute. Critically ill patients may be at particular risk due to a systemic inflammatory response syndrome with associated thrombophilia (“thromboinflammation”), hypoxia, and hypotension. Emerging observational evidence suggests a possible benefit to full dose anticoagulation to improve mortality in patients with COVID-19.²⁹ There is some preliminary evidence that the risk of stroke after SARS-CoV-2 infection is higher than after influenza,²⁵ but further research is needed to determine the extent to which stroke is a complication specific to this novel coronavirus rather than an effect common to other bacterial or viral infections.

Figure 1. Stroke with COVID-19.

A 37 year old woman with a history of morbid obesity, type 2 diabetes mellitus, hypertension, and preeclampsia presented with acute left hemiplegia. She had a 3-day history of cough and dyspnea, with mild fever, but outpatient polymerase chain reaction (PCR) test of the nasopharynx was negative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). On examination, there was right gaze preference, mild left spatial neglect, left facial weakness, dysarthria, left arm plegia, left leg paresis, and intact sensation. Head CT showed a subtle dense right MCA sign. She received intravenous tissue plasminogen activator. CT angiography showed a retropharyngeal course of the right internal carotid artery with retropharyngeal edema and filling defect in the medial aspect of the artery (arrow) (A); the distal right carotid artery and middle cerebral artery stem were occluded, with distal collateralization (B). CT perfusion study (C) demonstrated no definite evidence of infarction, with a large perfusion defect in the right hemisphere. Angiography demonstrated occlusion of the right petrous carotid artery (D). Thrombectomy was performed with good recanalization. Repeat PCR testing for SARS-CoV-2 was positive. D-dimer and interleukin-6 levels were elevated. The patient had a good recovery and was discharged two days later.

Infections and infectious burden as long-term risk factors for arteriopathy, atherosclerosis, and ischemic stroke

Several infections can directly cause vasculopathy, including bacteria, fungi, parasites, and viruses (Table 2). A review of all the infectious causes of stroke is beyond the scope of this review, but we will focus on the role of several viral infections.

Table 2.

Selected Organisms Implicated in Stroke Pathogenesis

Organism	Infection	Postulated mechanisms
BACTERIAL INFECTIONS
Treponema pallidum	Neurosyphilis	Arteritis, Direct invasion of arterial wall, endotheliopathy
Chlamydia pneumoniae	Acute or chronic respiratory infections	Enhanced platelet aggregation, acceleration of atherosclerosis through induction of cytokines (tumor necrosis factor-alpha, interleukin 2) in response to specific antigenic stimulus, chronic inflammation due to multiple infections (“infectious burden”)
Helicobacter pylori	Gastritis, peptic ulcer disease	Enhanced platelet aggregation, prothrombotic state
Porphyromonas gingivalis (and other periodontal pathogens)	Periodontal disease	Chronic inflammation due to infectious burden; prothrombotic state
PARASITIC INFECTIONS
Trypanosoma cruzi	Chagas disease, Heart failure	Cardioembolism
Taenia solium	Neurocysticercosis	Arachnoiditis/small vessel arteritis; direct compression of large arteries by cysts
Plasmodium falciparum	Cerebral malaria	Occlusion of cerebral arteries by infected erythrocytes
FUNGAL INFECTIONS
Cryptococcus	Systemic and CNS infections (usually immunocompromises)	Meningitis; arteritis
Aspergillus	Systemic and CNS infections	Arteritis, infectious vasculopathy
Mucorales (including Rhizopus, Mucor, etc)	Mucormycosis	Vascular invasion of fungus with vascular necrosis, aneurysmal dilatation
VIRAL INFECTIONS
Human immunodeficiency virus (HIV)	HIV disease/AIDS	Non-inflammatory vasculopathy; susceptibility to opportunistic CNS infections, possible direct invasion of arterial wall, endotheliopathy
Cytomegalovirus	Often asymptomatic, latent; occasional mononucleosis-like syndrome	Inflammatory response with accelerated atherogenesis
Varicella zoster virus	Chickenpox, shingles	Arteritis or non-inflammatory vasculopathy, direct invasion of arterial wall, endotheliopathy
Herpes simplex virus (types 1 and 2)	Oral and genital infections	Non-inflammatory vasculopathy; possible stroke trigger in young people, direct invasion of arterial wall, endotheliopathy, chronic inflammation due to infectious burden
Parvovirus B19	“Fifth disease”	Direct invasion of arterial wall, endotheliopathy
Influenza	Upper respiratory infection	Acute systemic infection as stroke trigger (platelet activation, dehydration, infection-induced cardiac arrhythmias)
Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2)	Coronavirus 2019 (COVID-19)	Hypercoagulability, endotheliopathy, hyperinflammation, myocarditis, arrhythmia, complications of critical illness (renin-angiotensin system dysregulation, hypotension, hypoxemia)

Herpesviruses and human immunodeficiency virus

Many herpesviruses have a known neurotropic tendency, as well as the ability to remain latent in sensory ganglia and other cells for life. Evidence suggests a strong positive association and possible causal relationship between CMV and atherogenesis. A systematic review and meta-analysis, including 9000 cases and 8608 controls from 55 case-control studies (6 of which were prospective) found that serological evidence of CMV increased the odds of coronary disease.³⁰ In the population-based Multi Ethnic Study of Atherosclerosis, CMV antibody titer was strongly associated with a bias toward T-helper type 1 response and increased coronary artery calcification.³¹ Animal models suggest a toll-like receptor-mediated CMV-platelet interaction leading to pro-inflammatory and pro-angiogenic responses, ultimately producing atherosclerosis.³²

Other common herpesviruses, such as VZV, have been implicated in the pathogenesis of cerebral arteriopathy. VZV can invade the vessel walls of both small and large cerebral arteries in a patchy fashion, causing a broad spectrum of neurovascular disorders, from large vessel vasculopathy associated with ischemic stroke, to arterial dissections and aneurysmal subarachnoid hemorrhage.³³ Purported mechanisms include invasion by virions into the adventitia in early disease and the media in late disease, leading to chronic inflammation and eventual intimal thickening and arterial remodeling. VZV antigen was found in 74% of temporal arteries from patients with biopsy proven giant cell arteritis, compared to 8% of normal temporal arteries. These results support the hypothesis that VZV may be a causative organism in the pathogenesis of giant cell arteritis³⁴, though further confirmation is needed. VZV has also been associated with focal cerebral arteriopathy and stroke in children,³⁵ and zoster has been associated with an acute increase in risk of stroke in adults; vaccination against varicella was protective against stroke in retrospective analyses in children,³⁶ although whether zoster vaccine prevents stroke in adults is less certain.³⁷

Human immunodeficiency virus (HIV) may also cause cerebral vasculopathy, although patients with HIV may have strokes for a number of other reasons, including other opportunistic infections, comorbid vascular risk factors, and side effects, such as dyslipidemia, of anti-retroviral therapy. HIV is also associated with fusiform aneurysmal cerebral vasculopathy. Even after controlling for other risk factors, HIV increases the risk of both ischemic³⁸ and hemorrhagic³⁹ stroke. This increased risk, moreover, correlates with lower CD4 counts and higher viral load,⁴⁰ providing indirect evidence that the virus itself may be the causal agent rather than these other potential confounders. Pathological studies of both large and penetrating cerebral arteries of patients with HIV reveal thinning of the media, often accompanied by dilatation.⁴¹ Infarcts in HIV-positive patients appear to be associated with extremes of arterial remodeling: either accelerated atherosclerosis with severely stenotic vessels, or dilated, dolichoectatic vessels predisposing both to thrombotic and hemorrhagic strokes.⁴²

Infectious burden

More recently, the concept of “infectious burden” (IB) as a stroke risk factor has emerged. Exposure to increasing numbers of pathogens could have a cumulative effect, leading to increased progression of carotid and cerebral atherosclerosis.^43,44 This concept was explored in the Northern Manhattan Study, a large, prospective cohort study in a randomly selected, multi-ethnic urban stroke-free population.⁴⁵ Stroke-free patients were assessed for serological evidence of 5 common infections that have been linked to atherosclerotic risk in prior studies: Chlamydia pneumoniae, Helicobacter pylori, CMV, HSV1 and HSV2. While no individual infection showed a statistically significant association with increased stroke risk, all had a trend towards increased risk. A weighted IB index, based on the strength of each individual infection’s risk, determined increased risk of stroke (adjusted HR per standard deviation in the IB index 1.39, 95%CI 1.02–1.9), even after adjusting for demographic factors, vascular comorbidities, leukocyte count, and levels of C-reactive protein. IB was also associated with carotid plaque thickness, cognitive impairment,⁴⁶ and cognitive decline, particularly in domains of executive function and memory.⁴⁷ An inverse correlation between IB and cognition was also observed in a Chinese study of patients with Alzheimer disease, although the authors did not employ a weighted index.⁴⁸

Mean IB index was higher in Hispanics, non-Hispanic blacks, and women in the Northern Manhattan Study, providing indirect evidence that infectious burden could partly explain disparities in stroke risk. In a case-control study of 470 ischemic stroke patients and 809 age- and sex-matched controls,⁴⁹ investigators measured antibodies against periodontal microbial agents Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, C. pneumoniae, Mycoplasma pneumoniae, and CagA-positive H. pylori. Cumulative IgA seropositivity was associated with large vessel stroke in fully adjusted models, though the strong association of childhood socioeconomic status with stroke risk was not attenuated by infectious serologies, indicating that infection is likely not a major mediator of adverse effects of socioeconomic disparities.

Infectious burden may not be as important in childhood stroke as in adult stroke. In a population-based case-control study among 102 children with ischemic stroke and 306 age-matched controls, data on visits for minor infection within 2 years was abstracted from health records.⁵⁰ The cumulative number of infectious visits over 2 years was not associated with ischemic stroke risk, although there was a short-term increase in risk of stroke after infection, consistent with the triggering effect described above.

Infection caused by stroke

Infections are also the most frequent complication of stroke, affecting approximately 30% of patients,⁵¹ and adversely influencing survival and recovery. UTI and pneumonia are the most common types of infection, but pneumonia has a greater impact on clinical outcomes. Pneumonia occurs most commonly in the first week after stroke (stroke-associated pneumonia, or SAP), mainly within the first 2–3 days.⁵² The underlying microbial etiology of SAP is critical in guiding appropriate antibiotic therapy. SAP may include community-acquired or hospital-acquired organisms.⁵³ Most frequently cultured are aerobic Gram-negative bacilli and Gram-positive cocci, including Enterobacteriaceae (e.g. Klebsiella pneumoniae, Escherichia coli), Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumanii and Streptococcus pneumoniae.⁵²

Current paradigms of SAP propose an interplay between an infectious reservoir (oral bioburden, nasopharynx, upper gastrointestinal tract, exposure to hospital pathogens), mechanism for delivery to the lower respiratory tract (dysphagia, impaired cough reflex, reduced level of consciousness), and impaired host immune responses (stroke-induced immune suppression). Accurate prediction of patients at risk of developing SAP is a key step in designing clinical trials of preventative interventions and implementation of successful interventions. Several clinical risk scores for predicting SAP based on clinical and stroke characteristics (e.g., age, stroke severity, dysphagia) have been derived and validated, yet none are currently recommended for clinical practice without further evaluation of clinical utility.⁵⁴ The same holds true for blood biomarkers, since no single biomarker or set of biomarkers has been established to improve prediction of SAP over clinical parameters.⁵⁵

Prevention and Treatment of SAP

Several randomized trials of preventive antibiotics in acute ischemic stroke have failed to improve clinical outcomes.⁵⁶ Despite reducing infection incidence overall (mainly UTI), development of pneumonia was not reduced, even in one of the largest trials, which selected patients at risk due to dysphagia.⁵⁷ Antibiotics remain the mainstay of SAP treatment and consensus guidelines have recently been proposed.⁵⁸ However, different antibiotic classes have varying antimicrobial coverage (including effects on the gut microbiome) and anti-inflammatory or immune modulating effects (particularly macrolides). Additionally, some classes (e.g. macrolides) have neuroprotective effects in pre-clinical stroke models.⁵⁹ For these reasons, choice of antibiotic class may have important implications not only for treatment of post-stroke infections but also neurological outcome,⁶⁰ and additional studies are required to inform optimal antibiotic treatment algorithms for SAP. The role of blood biomarkers in guiding antibiotic initiation in SAP also remains uncertain. A randomized trial using ultrasensitive procalcitonin to guide antibiotic initiation in relatively severe ischemic stroke did not improve clinical outcomes and resulted in greater antibiotic prescribing compared to usual practice.⁶¹

Stroke-induced immune suppression – human studies

Stroke induces activation of immune and inflammatory pathways both in the CNS and periphery, characterized by microglial activation, recruitment of leukocytes, and activation of the hypothalamic-pituitary-adrenal axis and autonomic nervous system. In parallel, a simultaneous suppression of systemic cellular immune function accompanies an activation of systemic inflammatory responses.^62,63 This so-called stroke-induced immune suppression occurs within hours of stroke onset, affecting both innate and adaptive immunity, and may increase host susceptibility to post-stroke infection. In patients with acute ischemic stroke, there is both loss of immune cells and immune cell dysfunction. Lymphopenia is prominent and specific myeloid cellular subsets (e.g. CD14^dim CD16^high non-classical monocytes) are reduced. In addition, there is a deactivation of neutrophils, monocytes or T cell subsets, and an activation of invariant natural killer T (iNKT) cells as well as reduced production of IgG and IgM.^{64,65,66,67,68,69,70,71,72}

While several clinical studies have reported correlations between stroke severity and extent of immune suppression, discreet brain regions affected by infarction are also implicated in immune suppression and SAP, most of them known to be involved in the regulation of the autonomic nervous system.^73,74 This suggests that volume of infarction and strategic neural pathways (e.g., sympathetic nervous system) may be involved in peripheral immune suppression and risk of SAP. This is supported by the observation that serum cortisol and catecholamine concentrations correlate with stroke severity, immune suppression and development of post-stroke infections.^75,76,77

Stroke-induced immune suppression – animal studies

Similar findings are observed in mouse models of stroke. SAP develops spontaneously within the first 3 days after stroke,⁷⁸ and depends on the severity and location of cerebral ischemia, the mouse strain used, and animal housing conditions.^79,80,81 The identified pathogens of murine SAP are similar to those isolated in clinical studies (unpublished data). Unlike in humans, a causal relationship has been established between immune suppression after stroke and SAP.^61,62,82 Mouse lungs inoculated with bacteria 3 days after stroke require 1000-fold fewer bacteria to cause a pneumonia than in sham mice.⁸³ Similar immune cell changes are seen to those in humans, including loss and hypo-function of T cells, iNKT cells, and marginal zone B cells.^70,77,84

Stroke-induced lymphocyte loss and dysfunction are mediated by over-activation of the sympathetic nervous system.^70,77 The parasympathetic branch of the autonomic nervous system is also hyperactive within the first days after stroke. Parasympathetic cholinergic signaling targets innate immunity in the lung and inhibits pulmonary antibacterial defense.⁸⁵ While most experimental and clinical data demonstrate that micro-aspiration is an essential contributor to SAP, this concept has been challenged. Stroke also induces dysfunction of the gut immune barrier, facilitating the translocation and dissemination of bacteria from host gut microbiota.⁸⁶ Thus, there are multiple possible sources of bacteria, and multiple mechanisms whereby the immune system is impaired.

Stroke-induced CNS antigen-specific autoreactive immune responses

Within hours of ischemic injury, the release of damage-associated molecular patterns and reactive oxygen species activates microglia and recruits neutrophils and monocytes to the brain, where they phagocytose dead brain tissue and engender autoreactive immune responses.^62,81,87 Adaptive immune cells enter the brain in both antigen-independent⁸⁸ and antigen-dependent mechanisms,^89,90 in some cases stimulated by stroke-induced dysbiosis of the gut microbiome.^91,92 Once in the brain, both detrimental and protective features have been attributed to T lymphocytes depending on the type of subpopulation and timing of infiltration.^81,93,94,95

Specific alterations of the memory T cell compartment controlling autoreactive CNS antigen-specific responses have been observed in stroke patients.⁹⁶ Stroke activates and diversifies these T-cell responses, thereby exacerbating ischemic brain injury.⁹⁷ While stroke-induced immune suppression may diminish autoreactive CNS antigen-specific T cell responses in the ischemic brain, SAP may boost them.⁹⁸ Prevention of SAP may thus decrease the recruitment of proinflammatory T cell responses while increasing the influx of regulatory T lymphocytes correlating with an improved neurological outcome. Patients with post-stroke infections have increased autoreactive CNS-antigen specific immune responses in the blood compared to stroke patients without bacterial infections, which correlates with poorer stroke outcome.^99,100 This finding suggests that CNS inflammation is influenced by ongoing immune challenges in the periphery, including infections.

Recent findings suggest that B cells play a pivotal role in CNS antigen-specific autoreactive immune responses after stroke. B cells infiltrate the ischemic hemisphere in a delayed manner after experimental stroke.¹⁰¹ The inflammatory response to brain ischemia is notably more long-lasting than to cardiac ischemia, likely due to the pro-inflammatory lipid-rich environment in the brain.¹⁰² This may act as a local adjuvant, stimulating the accumulation of adaptive immune cells in the stroke scar and promoting autoimmune-like responses. Experimental findings demonstrate that B cells differentiate into plasma cells producing CNS antigen-specific antibodies (unpublished data). Late B lymphocyte responses also occur after stroke and CNS antibody production may increase over time, with about half of stroke survivors exhibiting intrathecal antibody synthesis after the first week.¹⁰³ Although antibodies against distinct CNS antigens after stroke have been described in the blood as well as in the CSF at several time points after stroke,^{104,105,106,107} their role remains elusive. Moreover, the functional consequences of CNS antigen specific antibodies for stroke outcome are uncertain.^108,109,110 However, antigen specificity, timing of occurrence, levels and type or subtype of autoantibodies may have different functional consequences. Moreover, B cells themselves can have direct effects by migrating into remote brain areas, supporting neurogenesis and functional recovery.¹¹¹

Post-stroke infections, autoimmunity and cognition

Infection leads to higher delirium risk, and delirium can lengthen hospital stay and worsen outcomes.¹¹² In the setting of post-stroke infections, immune responses in the blood and in the brain are implicated in longer-term cognitive decline and dementia after stroke. The risk of incident dementia is highest in the first six months after stroke, but persists for at least ten years, even accounting for other dementia risk factors.^113,114,115

Preclinical studies provide evidence that stroke can lead to detrimental chronic neuroinflammation, causing late cognitive decline. B lymphocytes that accumulate in the brain after stroke are required for the late development of impaired hippocampal long-term potentiation and impaired memory.¹⁰⁰ Although their function requires further confirmation, plasma cells that develop in the brain after stroke and make antibodies against brain antigens may directly cause neurodegeneration (unpublished data, A.M.). In addition, innate immune activation by toll like receptor 4 signaling increases neurogenesis that causes cognitive decline after stroke.^116,117

Evidence is building that autoimmune-like responses against brain antigens may confer a ~2-fold increased dementia risk after stroke. A more pro-inflammatory immune signature in peripheral blood two days after stroke is associated with cognitive decline between 3 and 12 months after stroke.¹¹⁸ This pro-inflammatory immune signature could be the result of pre-existing peripheral inflammation or post-stroke infection, and could act as an adjuvant, but the underlying mechanisms and significance require further clarification. In combination with the release of brain antigens into the bloodstream in the first week after stroke, autoimmunity against the brain may be more likely to develop. Autoantibodies against myelin basic protein are associated with increased cognitive decline in the first year after stroke.¹¹⁹ However, more research is needed to establish how often post-stroke neurodegeneration is caused by an autoimmune response, and the extent to which it contributes to post-stroke dementia risk. Further, the role of additional factors such as stroke severity or location in influencing post-stroke cognitive decline through disruption of the immune system and modification of the risk of post-stroke infection is uncertain.

Future Directions

The data presented here permit a conceptualization of the bidirectional and multiphasic relationship of infection with stroke (Figure 2). Over the course of life, individuals are potentially exposed to multiple infections, some more serious than others, that may contribute to chronic cerebral vasculopathies, including atherosclerosis, that increase the risk of stroke; host factors, such as genetic susceptibility and other exposures, likely play a role, as well. The chronic, cumulative effects of these infections may persist throughout the lifespan. After certain severe acute infections, such as influenza or sepsis (or possibly COVID-19), the risk of stroke increases transiently (i.e., a cerebrovascular vulnerable window), and stroke may occur. In the future, we may mitigate stroke risk by preventing infections. Also, much remains to be learned about the molecular mechanisms that lead from infection to stroke–in the future we may be able to directly prevent infections from provoking vascular disease and stroke.

Figure 2. Proposed model for short- and long-term associations of infection, stroke, cognitive decline and dementia.

Over the course of adult life (X-axis), individual cognition and function gradually decline, as represented by the blue line, which reflects cognitive or functional status (Y-axis). At the time of stroke, there is an acute decline in function, followed by gradual recovery. In many individuals, and in animal models, late cognitive decline, leading to dementia, occurs. The role of infectious events throughout the life course, neurological outcomes, and related mechanisms are depicted. Chronic infections include chronic or latent infections (such as syphilis and varicella zoster virus), as well as cumulative exposures to more acute infections (“infectious burden”); these may contribute to vasculopathies, including atherosclerosis, arteritis, or non-arteritic vasculopathies, and may contribute to long-term risks of stroke and cognitive decline/dementia. Certain severe acute infections (e.g., influenza, sepsis, possibly COVID-19), transiently increase stroke risk. After stroke, stroke-associated infections (e.g., stroke-associated pneumonia) and consequent immune changes may then lead to chronic autoreactivity against the brain, which in turn contributes to chronic neuroinflammation and neurodegeneration and associated clinical cognitive impairment and dementia. Stroke-induced immunodepression may both increase risk of post-stroke infections and reduce chronic autoreactivity against the brain. Conceptual short- and longer-term vulnerable windows to stroke, infection, and cognitive decline are depicted above the depiction of cognitive/functional trajectory. COVID-19, coronavirus disease 2019; SAP, stroke associated pneumonia; UTI, urinary tract infection.

Stroke and its consequent immune activation and dysregulation may then lead to vulnerability to cognitive decline and the ultimate diagnosis of dementia (a second neurological vulnerable window). This enhanced vulnerability likely accelerates the baseline cognitive decline that occurs with aging. Infections at the time of stroke, such as SAP, appear to enhance the adverse immune milieu that contributes to cognitive decline and eventual dementia. This second vulnerable window may persist indefinitely, moreover, and it is likely that chronic infectious exposures present prior to stroke may also influence long-term cognitive outcomes. Further research is needed, however, to confirm and better define the many steps along these pathways and their mechanisms. Ultimately therapies directed at infections and their secondary neuroimmunological effects may influence these outcomes and need to be tested.

A key question, for example, is whether functional immune suppression in the acute phase of stroke has a causal role in the development of post-stroke infections, or is an epiphenomenon associated with infarction. In animal models, blocking stroke-induced immune suppression can prevent SAP, suggesting a causal role.^77,82,83 Immunomodulatory therapies to reconstitute impaired host antibacterial immune defenses after stroke may provide a new therapeutic approach to improve outcome in affected patients. Several immunostimulatory mediators (e.g. interferon-γ, granulocyte-macrophage colony stimulating factor, α-galactosylceramide) have been proven experimentally.^77,83,120

Markers of suppressed immunity and dysphagia are independent risk factors for SAP in acute stroke.⁶⁹ No immunomodulatory treatments aiming to specifically prevent post-stroke infections, however, have been tested in phase 3 clinical trials. One promising therapy is interleukin-1 receptor antagonist (IL-1Ra). In a secondary analysis of a small phase 2 placebo-controlled randomized trial of IL-1Ra, treatment within the first 6 hours of stroke onset reversed some markers of innate cellular immune suppression. IL-1Ra treatment normalized suppressed induction of whole blood IL-1 and tumor necrosis factor-α ex vivo¹²¹, but did not affect reduced concentrations of circulating immunoglobulins or complement components.¹²² Although this study was not powered to detect differences in post-stroke infections between treatment groups, reversal of immune suppression in the acute phase of stroke could be a potential therapeutic approach to prevent SAP and other infections.

Many questions remain in understanding how post-stroke autoimmunity is generated in patients, how it is mediated by stroke severity and infections, and how much it contributes to long-term cognitive decline. Animal models are beginning to shed light on mechanisms but so far have been performed mostly in young, male mice. It will be imperative to understand how sex, age, and common co-morbidities affect risk and underlying mechanisms of post-stroke cognitive decline in animal models. Research is also needed in human populations to assess translatability of animal findings. The new NIH-funded “Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY” (DISCOVERY) study¹²³ aims to assess risk factors for cognitive decline after stroke. More focused smaller studies with comprehensive analysis of the immune response to stroke may also help to understand how much of the dementia risk after stroke is accounted for by autoimmunity.

Finally, stroke induced immune suppression may protect against brain injury by preventing harmful CNS-directed autoimmune responses (Figure 2).⁹⁷ Therefore, the potential impact of immunostimulation to prevent SAP on the trajectory of longer term immune responses, including autoimmunity to CNS antigens and host responses to recurrent infectious challenge, is of key importance. Preclinical studies of immunomodulatory therapies in the acute phase to prevent SAP should evaluate longer-term effects on CNS and peripheral immune responses, as well as cognitive outcomes. Many current biological therapies for chronic immune and inflammatory conditions are known to be associated with increased risk of infections. Therefore, clinical trial development of putative immunomodulatory therapies in stroke require longer-term follow-up to evaluate impact on incidence of recurrent infections as well as cognitive outcomes. In addition, there may be common mechanisms causing dementia after sepsis, where cognitive impairment is common and associated with vascular dysfunction as well as brain ischemia.^124,125,126 Stroke survivors whose strokes occurred in the context of an infection at the time of stroke may therefore be at higher risk of long-term cognitive sequelae.

Non-standard Abbreviations and Acronyms

95%CI

95% confidence interval

CMV

cytomegalovirus

CNS

central nervous system

COVID-19

coronavirus disease 2019

HIV

human immunodeficiency virus

HSV

herpes simplex virus

IB

infectious burden

IL-1Ra

interleukin-1 receptor antagonist

iNKT

invariant natural killer T

OR

odds ratio

PVB19

parvovirus B19

SAP

stroke-associated pneumonia

UTI

urinary tract infection

VZV

varicella zoster virus