Cytokine Immunopathogenesis of Enterovirus 71 Brain Stem Encephalitis

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 876241, 8 pages doi:10.1155/2012/876241 Review Article Cytokine Immunopathogenesis of Enterovirus 71 Brain Stem Encephalitis Shih-Min Wang,1, 2 Huan-Yao Lei,2, 3 and Ching-Chuan Liu2, 4 1 Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan 2 Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70428, Taiwan 3 Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan 4 Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan Correspondence should be addressed to Shih-Min Wang, and Ching-Chuan Liu, Received 21 March 2012; Accepted 27 July 2012 Academic Editor: Hiroyuki Shimizu Copyright © 2012 Shih-Min Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Enterovirus 71 (EV71) is one of the most important causes of herpangina and hand, foot, and mouth disease. It can also cause severe complications of the central nervous system (CNS). Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death. EV71 replicates in leukocytes, endothelial cells, and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease. Cytokines, as a part of innate immunity, favor the development of antiviral and Th1 immune responses. Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis. Both the CNS and the systemic inflammatory responses to infection play important, but distinctly different, roles in the pathogenesis of EV71 pulmonary edema. Administration of intravenous immunoglobulin and milrinone, a phosphodiesterase inhibitor, has been shown to modulate inflammation, to reduce sympathetic overactivity, and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema. 1. Introduction Humoral mediators including cytokines are the molecular proteins of the innate and immune response and play key roles in the pathophysiology of viral infection [1]. Systemic inflammatory response syndrome (SIRS) caused by infection is a typical condition within which proinflammatory mediators released from infected cells and persistent hypercytokinemia may result in progression to multiple organ failure [2]. It is known that activation of cytokine networks increases levels of various cytokines in blood. The burst of cytokine release that follows sepsis, toxin-mediated shock syndrome (e.g., Streptococcus pyogenes and Staphylococcus aureus) [3, 4], some virus infections such as severe acute respiratory syndrome (SARS) [5], influenza [6], dengue virus [7], and Epstein-Barre virus [8] induce an overwhelming stimulation of innate and/or immune responses that storm the physiology of the body. 2. Clinical Manifestation of EV71 Brain Stem Encephalitis Human enterovirus (EV71) is member of the genus Enterovirus, family Picornaviridae, which consists of a nonenveloped capsid surrounding a core of single-stranded, positive-polarity RNA approximately 7.5 kb in size and 27– 30 nm in diameter [9, 10]. EV71 produces a broad spectrum of clinical manifestations. The majority of infected individuals have asymptomatic infection. Mild cases are characterized 2 as cutaneous diseases such as hand, foot, and mouth disease (HFMD) and herpangina. However, potentially lifethreatening neurological complications such as brain stem encephalitis (BE) are of the greatest clinical and public concern [11–14]. EV71 has been recognized as highly neurotropic and associated with a diverse range of neurological diseases, such as aseptic meningitis, BE, encephalomyelitis, acute flaccid paralysis (AFP), and postinfectious neurological syndromes. During the 1998 Taiwan epidemic several clinical stage categories of disease were developed for the severity of BE to help monitor the clinical course of EV71 infection and to aid management. These systems are not, however, widely used, possibly because they are not always easy to follow by primary care physicians. In 2010, World Health Organization Regional Office (WHO) for the Western Pacific and the Regional Emerging Diseases Intervention (REDI) Centre documented guide for clinical management on hand, foot, and mouth disease that has proposed simple clinical stages of disease manifestation to describe the disease severity as we suggested previously [15, 16]. The EV71 BE was stratified into three important critical stages by disease severity, including uncomplicated BE, autonomic nervous system (ANS) dysregulation, and pulmonary edema (PE). It is a continuous and dynamic disease sequence. It may be a reversible disease because each critical stage is a turning point. Through this staging, the pathogenesis of BE was explored and then effective ways to manage the patients were developed. BE is defined as an illness characterized by myoclonus, ataxia, nystagmus, oculomotor palsies, and bulbar palsy in various combinations, with or without neuroimaging. ANS dysregulation is defined by the presence of cold sweating, mottled skin, tachycardia, tachypnea, and hypertension. PE is defined as respiratory distress with tachycardia, tachypnea, rales, and frothy sputum that developed after ANS dysregulation, together with a chest radiograph that showed bilateral pulmonary infiltrates without cardiomegaly. If the diagnosis of EV71 BE once was delayed, usually because of the clinical symptoms are not recognized in the early stages. Myoclonic jerks are seen more often in EV71 than in other serotypes of enteroviruses and could be an early indicator of brain stem involvement. Diagnostic workup of EV71 BE should include the search for one or more neurological symptoms, especially myoclonus jerk and limb paralysis, and the measurement of disease markers, such as peripheral white blood cell count, platelet count, glucose level, inflammatory cytokines, immune cell subsets, and cerebrospinal fluid analysis [17–22]. In the 2008 outbreak of Taiwan, 238 virologically and clinically confirmed severe cases were identified, including 41% uncomplicated BE, 44% ANS dysregulation, and 15% PE [23]. 3. Pathogenesis of Complicated EV71 Brain Stem Encephalitis Both innate and adaptive immune mechanisms are important for host defense against viral infection. The innate immune system provides the first line of defense against virus through activation of adaptive immunity through Clinical and Developmental Immunology antigen presentation as well as secretion of proinflammatory cytokines. Th (...truncated)