Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 10, Issue 2, 2010

In this fascinating special topic issue, contributors from various centres in the UK, Europe and the US have reviewed a range of subjects on the theme of infection and stroke. What is perhaps most surprising is that relatively little attention has been devoted to such a clinically important topic until very recently. The relationships between infection and stroke are wide ranging, as illustrated by the diversity of topics covered in this collection. Infection occurring before and after stroke has huge clinical implications, and a better knowledge of mechanisms in paediatric as well as adult populations - and in other specific populations such as individuals with HIV infection - is likely to be increasingly important from a global perspective. Relatively recent developments also include the increasing recognition of VZV vasculopathy in stroke, and the concept of aggregate chronic infectious burden in stroke risk. In addition to well established risk factors for infection poststroke, evidence for poststroke immunodepression is increasing. Models of infection before and after stroke should facilitate the investigation of new targets. From a clinical viewpoint there is increasing recognition that greater account needs to be taken of infection when considering both established and novel acute stroke treatments. The swine flu pandemic has of course also brought influenza into sharp focus and there can be little doubt about the importance of vaccination uptake in appropriate groups. Catherine Amlie-Lefond and Heather Fullerton have reviewed the topical and important subject of infection and childhood ischaemic stroke in a comprehensive manner. They have considered potential mechanisms to include vascular injury (including arteriopathy and vasculitis) and effects on the coagulation system. One senses a somewhat dynamic relationship between paediatric stroke and infection - for example, whilst there has been a diminished role of meningitis in areas with widespread vaccination uptake, the potential role of minor infections in the pathogenesis of childhood stroke is probably of increasing importance and interest. In Myles Connor's review of HIV and stroke, he also opens by discussing a range of proposed mechanisms through which HIV infection causes stroke, before covering a range of other key issues. Perhaps of particular note is the role of antiretroviral therapy - whilst life expectancy is increased, thereby inherently increasing the duration of exposure to conventional stroke risk factors, antiretroviral therapy also causes pro-atherosclerotic metabolic and endothelial dysfunction. New antiretroviral agents would ideally eradicate HIV without the accompanying drug induced vascular dysfunction associated with current drugs. In contrast to the role of individual infectious pathogens, Mitchell Elkind discusses the relatively recent concept that aggregate burden of several common chronic bacterial and viral (particularly herpes virus) infections may contribute to stroke risk via both atherosclerosis and atherosclerosis-independent mechanisms. It seems likely that a range of host factors, including genetic, interact with such infections to influence vascular disease risk. He highlights the fact that further studies will be needed to determine the role of antibiotics or vaccines in this context. Steve Hopkins and I (HE) have discussed the emerging concept of poststroke immunodepression. After briefly reviewing innate and adaptive immune responses after stroke, we have considered the experimental and clinical evidence for poststroke immunodepression and discussed potential mechanisms. Odilo Engel and Andreas Meisel have considered the impact of infections after stroke as well as pre-existing infection predisposing to stroke, and relate these topics to models of strokeassociated pneumonia and pre-stroke infection. Their discussion also covers poststroke immunodepression in the experimental setting, importantly highlighting its apparent dependence upon severity of cerebral ischaemia, indeed consistent with the concept that in stroke patients the occurrence of poststroke immunodepression is associated with greater stroke severity [1]. Future research in this field should better define immune changes that follow acute stroke, the potential utility of markers of immunodepression beyond existing clinical markers such as the National Institutes of Health Stroke Scale score to predict complications, and the implications of immunodepression for novel therapeutic strategies in stroke. Maria Nagel, Ravi Mahalingam, Randall Cohrs and Don Gilden have provided an overview of the difficult topic of viral vasculopathies and stroke, concentrating on VZV for which the greatest evidence base exists. Indeed perhaps a striking common theme in this collection of articles is the apparent importance of herpes viruses in stroke. In addition to the article by Don Gilden and colleagues, herpes viruses feature in the discussion by Amlie-Lefond & Fullerton in terms of VZV vasculopathy and paediatric stroke, in the review by Elkind insofar as the association of herpes virus infections with subclinical measures of atherosclerosis and clinical outcome, and in the account by Connor given the implication of VZV in HIV vasculopathy.

Major infections-sepsis, meningitis, encephalitis-have long been recognized as causes of pediatric arterial ischemic stroke. However, minor infections may also contribute to the pathogenesis of stroke, either by causing a systemic prothrombotic state or direct or indirect vascular injury. A focal cerebral arteriopathy has been identified in a large proportion of otherwise healthy children present with a first ischemic stroke. Both histologic data and small association studies suggest that varicella zoster virus can cause this childhood arteriopathy. Other viruses have been implicated in case reports. New data demonstrate an association between recent upper respiratory infection and this arteriopathy, suggesting a non-specific effect of infection. This manuscript reviews the evidence supporting a role for infection in ischemic stroke of childhood.

Human immunodeficiency virus (HIV) infection causes stroke through several mechanisms. Stroke results from opportunistic infection and neoplasia, HIV induced cardiac disease, HIV associated cerebral vasculopathy, and perhaps by HIV induced facilitation of some forms of systemic vasculitis and prothrombotic haematological conditions. HIV causes more ischaemic stroke than cerebral haemorrhage. Although stroke is currently a relatively infrequent manifestation of HIV infection, the incidence of stroke in HIV infected individuals is likely to increase with current combination antiretroviral therapy. HIV infection per se induces endothelial activation and dyslipidaemia, predisposing to accelerated atherosclerosis. Antiretroviral therapy, which increases life expectancy and therefore inherently increases ischaemic stroke risk with advancing age and length of exposure to traditional risk factors, also causes pro-atherosclerotic metabolic and endothelial dysfunction. Antiretroviral induced vascular dysfunction together with pre-existing HIV induced vascular disease has the potential to increase atherosclerotic causes of ischaemic stroke. New antiretroviral agents should ideally eradicate the human immunodeficiency virus thereby reducing vascular risk and HIV related causes of stroke without inducing metabolic or endothelial dysfunction. Future studies of vascular disease in HIV infected individuals, particularly studies investigating the impact of current and future antiretroviral agents, should ideally assess stroke as a specific outcome, and provide data by pathological stroke type and ischaemic stroke subtype, to clarify the mechanisms of stroke and guide the approach to treatment and prevention of stroke.

Atherosclerosis is a chronic inflammatory process, and several common bacterial and viral infections have been hypothesized to contribute to the inflammation of the vascular wall that leads to atherosclerosis. More recently, investigators have found preliminary evidence that the aggregate burden of these chronic infections, rather than any single organism, may contribute to atherosclerosis and risk of clinical vascular events, including ischemic stroke. This aggregate burden of infections, which has been variably labeled “infectious burden” or “pathogen burden,” may be associated with stroke through mechanisms independent of atherosclerosis, as well, including platelet aggregation and endothelial dysfunction. Host factors, moreover, may interact with infectious burden to modify the risk of disease associated with these infections. Currently there is no commonly accepted group of organisms or method of assessing infectious burden, and not all studies confirm an association of infection and stroke risk. Nonetheless, if infectious burden does play a role in atherosclerosis or stroke, it is plausible that preventive anti-infective treatment, such as vaccination, or antibiotics, would reduce the risk of incident or recurrent stroke. While influenza vaccination has been recommended to prevent recurrence among those with coronary disease, similar recommendations for stroke patients have not yet been made. Large scale randomized clinical trials of macrolide antibiotics for coronary patients, moreover, have been negative. Further studies are needed, however, to determine whether an association between infectious burden and stroke exists, and whether infectious burden may be a target for intervention.

Infections occur commonly following stroke and adversely influence outcome. Dysphagia, greater stroke severity and increasing age are associated with post-stroke infection, but post-stroke immunodepression is now recognised as an independent factor associated with increased susceptibility. Counter-regulatory responses, triggered by the proinflammatory response to stroke, appear to effect systemic immunodepression via suppression of both innate and adaptive immune responses. Experimental and clinical studies have identified a range of anti-inflammatory and immunosuppressive changes, including reduced mononuclear phagocyte and natural killer cell function, induction of antiinflammatory cytokines, apoptotic lymphocyte loss and altered T lymphocyte activity. A range of mechanisms has been proposed, including hypothalamo-pituitary-adrenal axis (HPAA) and sympathetic nervous system (SNS) activation. The post-stroke balance of pro- and anti- inflammatory mechanisms may be aimed at restricting the extent of inflammation and contributing to the restoration of immune homeostasis. However, severe inflammation in the brain may trigger major systemic, counter-inflammatory responses that ultimately compromise immune mechanisms required to combat pathogens. Although key pathways have been identified, the extent to which the various elements of post-stroke immunodepression are clinically relevant remains to be discovered. The identification of markers of immunodepression in the early post-stroke phase may prove useful for identifying patients that may have increased susceptibility to infection. It also seems likely that post-stroke immunodepression will need to be taken into account where stroke treatments impact upon inflammatory and immune pathways.

Infectious diseases are the most common medical complication after cerebral ischemia, inpairing both the neurological and the general medical outcome. The most frequent infectious complications are bacterial pneumonia and urinary tract infections. There is a growing body of evidence that a secondary immunosuppressive state accounts for the increased risk of infection following stroke. Infections do not only have an important impact on outcome after stroke but also are known risk factors for stroke. Thus, suitable models for investigating the relation between infections and stroke are urgently needed. Elucidating the underlying mechanisms might facilitate the development of new therapeutic strategies and improve patient outcome. Here we present recent insights into the relationship between infections and stroke, based on experimental models of poststroke infection. In addition we give a brief overview of models that explore the impact on stroke of preceding infections.

While arteriosclerotic disease and hypertension, with or without diabetes, are the most common causes of stroke, viruses may also produce transient ischemic attacks and stroke. The three most-well studied viruses in this respect are varicella zoster virus (VZV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV), all of which are potentially treatable with antiviral agents. Productive VZV infection in cerebral arteries after reactivation (zoster) or primary infection (varicella) has been documented as a cause of ischemic and hemorrhagic stroke, aneurysms with subarachnoid and intracerebral hemorrhage, arterial ectasia and as a co-factor in cerebral arterial dissection. CMV has been suggested to play a role in the pathogenesis of arteriosclerotic plaques in cerebral arteries. HIV patients have a small but definite increased incidence of stroke which may be due to either HIV infection or opportunistic VZV infection in these immunocompromised individuals. Importantly, many described cases of vasculopathy in HIV-infected patients were not studied for the presence of anti-VZV IgG antibody in CSF, a sensitive indicator of VZV vasculopathy. Unlike the well-documented role of VZV in vasculopathy, evidence for a causal link between HIV or CMV and stroke remains indirect and awaits further studies demonstrating productive HIV and CMV infection of cerebral arteries in stroke patients. Nonetheless, all three viruses have been implicated in stroke and should be considered in clinical diagnoses.

Infection is the commonest complication of stroke and has a major impact on morbidity and mortality. The relationships between susceptibility to infection after stroke and the influence of infection on stroke outcome are complex, but have considerable clinical relevance. Both pharmacological and non-pharmacological interventions in acute stroke may affect the risk of developing infection by influencing potentially modifiable risk factors, for example exposure to infectious organisms (dysphagia/aspiration), or immune susceptibility to infectious challenge. Treatment of infection itself may also reduce ischaemic injury, and influence outcome following stroke. In this review we discuss the role of current and emerging treatments for stroke and their effects on infection, considering possible underlying mechanisms and implications for the development of new therapies.

There is increasing evidence that acute bacterial and viral infection represent trigger factors that temporarily elevate the risk of ischemic stroke. During and after influenza epidemics vascular death rates and hospitalizations for stroke are increased. Influenza vaccination is an effective measure to reduce hospitalization and mortality in the elderly and work incapacity in adults of working age. Results of several observational studies support the hypothesis that influenza vaccination is associated with reduced odds of stroke. As randomized studies are lacking, a causal role of influenza vaccination in stroke prevention is not proven, however. According to current guidelines in many countries, that recommend the vaccination in all patients with chronic vascular disease, all patients with a history of stroke or TIA should receive an influenza vaccination annually. Furthermore, patients with diabetes mellitus or with a combination of risk factors that increase stroke risk should obtain the vaccination. In addition, there is evidence from observational data that the neuraminidase inhibitor oseltamivir reduces the risk of stroke within 6 months after influenza infection.