Stroke-induced immunosuppression: implications for the prevention and prediction of post-stroke infections

Faura et al. Journal of Neuroinflammation https://doi.org/10.1186/s12974-021-02177-0 (2021) 18:127 REVIEW Open Access Stroke-induced immunosuppression: implications for the prevention and prediction of post-stroke infections Júlia Faura1, Alejandro Bustamante2*, Francesc Miró-Mur3 and Joan Montaner1,4 Abstract Stroke produces a powerful inflammatory cascade in the brain, but also a suppression of the peripheral immune system, which is also called stroke-induced immunosuppression (SIIS). The main processes that lead to SIIS are a shift from a lymphocyte phenotype T-helper (Th) 1 to a Th2 phenotype, a decrease of the lymphocyte counts and NK cells in the blood and spleen, and an impairment of the defense mechanisms of neutrophils and monocytes. The direct clinical consequence of SIIS in stroke patients is an increased susceptibility to stroke-associated infections, which is enhanced by clinical factors like dysphagia. Among these infections, stroke-associated pneumonia (SAP) is the one that accounts for the highest impact on stroke outcome, so research is focused on its early diagnosis and prevention. Biomarkers indicating modifications in SIIS pathways could have an important role in the early prediction of SAP, but currently, there are no individual biomarkers or panels of biomarkers that are accurate enough to be translated to clinical practice. Similarly, there is still no efficient therapy to prevent the onset of SAP, and clinical trials testing prophylactic antibiotic treatment and β-blockers have failed. However, local immunomodulation could open up a new research opportunity to find a preventive therapy for SAP. Recent studies have focused on the pulmonary immune changes that could be caused by stroke similarly to other acquired brain injuries. Some of the traits observed in animal models of stroke include lung edema and inflammation, as well as inflammation of the bronchoalveolar lavage fluid. Keywords: Stroke, Immunosuppression, Biomarkers, Inflammation, Infection, Pneumonia Background Stroke-induced immunosuppression (SIIS) is a set of processes that lead to a peripheral suppression of the immune system after the occurrence of stroke. One of the main and direct consequences of this SIIS is that it makes stroke patients more susceptible to bacterial infections. Strokeassociated infections (SAIs) represent one of the major complications post-stroke, which worsens the functional outcome of patients and increases their mortality rates [1]. Approximately 30% (24–36%) of patients develop * Correspondence: 2 Stroke Unit, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, s/n, 08916 Badalona, Barcelona, Spain Full list of author information is available at the end of the article infections after stroke, with pneumonia and urinary tract infections (UTI) being the most common forms, both having a frequency of 10% [2]. Among these infections, stroke-associated pneumonia (SAP) is usually the most acute type of SAI and has the worst impact on functional outcome [3]. It increases mortality for up to 1 year, prolongs hospital stays, and worsens the functional outcome at discharge [4]. The clinical definition of pneumonia after stroke has differed in many studies in both the terminology and the diagnosis of the complication [5]. To address this issue, the Pneumonia in Stroke Consensus (PISCES) Group proposed the term SAP, to encompass all terms referring to lower respiratory tract infections in stroke patients © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Faura et al. Journal of Neuroinflammation (2021) 18:127 within the first 7 days after stroke onset [6]. In the same publication, new diagnostic criteria were proposed based on the criteria for the definition of healthcare-associated infection from the Centers for Disease Control and Prevention (CDC) of the United States of America, which were the most used criteria by that point [7]. However, SAP assessment is still challenging, especially due to the limited role of chest radiography. For this, chest computed tomography has been proposed as a complement to PISCES criteria in the screening of SAP in stroke patients. In a small cohort, thorax high-resolution computed tomography (THRCT) was able to differentiate between bronchopneumonia and other low respiratory tract infections in SAP patients, demonstrating a high accuracy in the diagnosis of SAP [8]. More recently, Kishore et al. [9] have also addressed this issue, but they have observed that conventional chest X-rays have limited accuracy for the diagnostic of SAP when compared with THRCT. Similarly, they found in their work some discrepancies between PISCES criteria and THRCT. Larger studies, including perhaps serial imaging, are needed in this field, to validate whether PISCES criteria and THRCT might be combined for the diagnosis of SAP. Nowadays, the clinical strategies against SAP are based on wide-spectrum antibiotics once an infection is diagnosed through clinical criteria, along with prevention by dysphagia screening in stroke units. Recently, the PISC ES consortia launched a recommendation for a standardized approach to antibiotic therapy in post-stroke pneumonia [10]. Nonetheless, early treatment before the development of clinical signs could prevent the onset of SAP or ameliorate its consequences. This would have benefits for patients and saving also a great number of resources for health care systems [11]. Several clinical trials have explored this idea through the administration of prophylactic antibiotics to acute stroke patients. However, the meta-analysis performed by Vermeij et al. [12] showed that preventive antibiotics neither reduce the risk of pneumonia nor the risk of death or poor outcome after stroke. The treatment did reduce the occurrence of overall infections and UTIs, but did not show any effect regarding the occurrence of SAP. These results were translated into recommendations against the routine us (...truncated)