腸病毒71型感染以手口足症及咽唊炎為主要的臨床表徵，少部分會引起腦炎併肺水腫。1998、2000及2001年腸病毒71型的流行在台灣地區分別造成78、35及40個病童的死亡，主要原因皆為腦幹腦炎引發肺水腫致心肺衰竭。細胞激素在病毒性及細菌性腦膜炎或腦炎的致病機轉中扮演了重要的角色，我們比較不同嚴重度腸病毒71型腦幹腦炎的病患其腦脊髓液中細胞激素和疾病嚴重度的相關性，並和伊科病毒腦膜炎做比較。腸病毒71型腦幹腦炎的病童依疾病嚴重度分為stage II、stage IIIa、stage IIIb。腦脊髓液中平均葡萄糖、蛋白質總量、乳酸，均隨腸病毒71型腦幹腦炎嚴重度增加而增加。在腸病毒71型腦幹腦炎stage IIIb的病患其腦脊髓液中乙型間白質素-1、間白質素-6及丙型干擾素均顯著高於腸病毒71型腦幹腦炎stage II的病患。在腸病毒71型腦幹腦炎stage IIIa的病患其腦脊髓液中間白質素-6及丙型干擾素亦顯著高於腸病毒71型腦幹腦炎stage II的病患。在各種不同嚴重度腸病毒71型腦幹腦炎的病患和伊科病毒腦膜炎的病患其中樞神經系統發炎反應是明顯不同的形式。為了能闡明腸病毒71型腦幹腦炎及其致命的併發症-肺水腫的全身性發炎反應於其致病機轉中所扮演的角色，我們分析腸病毒71型感染後併腦幹腦炎病童的實驗室數據、細胞激素及免疫細胞表現型。腸病毒71型腦幹腦炎stage IIIb的病童白血球及血小板均呈現顯著地增加。且血漿中間白質素-10、間白質素-13及丙型干擾素亦顯著地上升。此外，腸病毒71型腦幹腦炎stage IIIb病童的血中CD4和CD8 T細胞，和自然殺手細胞數也較低。全身性發炎反應和中樞神經系統發炎反應兩者都參與腸病毒71型腦幹腦炎併肺水腫的致病機轉。Milrinone為一種磷酸雙酯酶抑制劑，曾用於敗血性休克及鬱血性心衰竭的病人，我們進一步評估其用於治療腸病毒71型腦幹腦炎stage IIIb的病患的效果。我們從事一項歷史背景控制的研究，將病童分為引進milrinone治療之前和之後兩組。在使用milrinone治療病童的死亡率較未使用者來的低，交感神經性頻脈在接受milrinone治療的病童相較於控制組也較低。此外，在使用milrinone治療的病童有顯著間白質素-13、白血球和血小板的下降。此結果顯示milrinone的治療可提供一個有效的治療方式於腸病毒71型腦幹腦炎stage IIIb的病童，藉由調節交感神經系統活性及降低間白質素-13產生的作用機轉。靜脈注射免疫球蛋白曾被用於治療各種不同的發炎性和感染性的疾病。我們研究腸病毒71型腦幹腦炎stage IIIa和腸病毒71型腦幹腦炎stage IIIb的病患在接受靜脈注射免疫球蛋白前後其血中細胞激素的變化。腸病毒71型腦幹腦炎stage IIIb的病患在接受靜脈注射免疫球蛋白後其血中細胞激素丙型干擾素、間白質素-6、間白質素-8、間白質素-10、間白質素-13均顯著下降。至於腸病毒71型腦幹腦炎stage IIIa的病患在接受靜脈注射免疫球蛋白後其血中細胞激素間白質素-6、間白質素-8亦均顯著下降。所有stage IIIa的病患接受治療後均存活且無惡化至stage IIIb。這些發現顯示，於治療腸病毒71型腦幹腦炎的stage IIIa病患給予靜脈注射免疫球蛋白可經由調節其細胞激素的作用來改善臨床症狀。總結此研究，我們發現不同的細胞激素參與了腸病毒71型腦幹腦炎病患的中樞神經系統和周邊系統性發炎反應，其周邊系統性發炎反應中的細胞激素受milrinone及靜脈注射免疫球蛋白的治療而阻斷其作用，進而改善臨床疾病的預後。

Enterovirus 71 (EV71) brainstem encephalitis (BE) is a complication clinically characterized by fever, hand-foot-and-mouth disease (HFMD), and myoclonus jerk after the infection. High neurovirulence and fatalities with a rapid course from BE to pulmonary edema (PE) were noted. The first part of this study was designed to determine whether there is a quantitative relationship of specific cytokine in the cerebrospinal fluid (CSF) among various severity of EV71 BE, and compared to those echovirus meningitis (EM). Mean CSF glucose, total protein and lactate levels were significantly increased in associated with EV71 BE severity. CSF interleukin (IL)-1, IL-6 and interferon (IFN)- were significantly higher in patients of stage IIIb than in patients of stage II. In comparison with patients of stage II, CSF IL-6 and IFN- were also significantly higher in patients of stage IIIa. Higher CSF IFN- and lower IL-1 were in patients of stage IIIb than in EM. There is distinct pattern of the CNS inflammation among children with various severity of EV71 BE and EM. The pathogenesis of PE may be related to brainstem lesions and/or systemic inflammatory response syndrome and the release of cytokines. To elucidate the role of systemic inflammatory responses in the pathogenesis of EV71 BE and its fatal complication, PE, we analyzed the laboratory findings, cytokine, and immunophenotypes of patients with EV71 BE. Leukocytosis and thrombocytosis were significantly more frequent among patients with PE. A significant elevation of plasma IL-10, IL-13, and IFN- levels were observed in patients of stage IIIb. Patients of stage IIIb also had lower circulating CD4+ T cells, CD8+ T cells, and natural killer (NK) cells. An extensive peripheral inflammatory response appears to be responsible for the pathogenesis of EV71 PE. Both systemic and CNS inflammatory responses are involving in the pathogenesis of EV71 PE. The third part of this study was designed to evaluate the potential therapeutic effect of milrinone, a phosphodiesterase (PDE) inhibitor, in the treatment of patients with EV71 PE (stage IIIb). Patients were divided into groups treated before and after the introduction of milrinone therapy. The mortality was lower in the milrinone-treated vs. nontreated group. Sympathetic tachycardia was decreased in patients treated with milrinone compared to controls. A marked decrease in IL-13 was observed in milrinone-treated patients compared to controls. There was a significant reduction in white blood cell and platelet counts in milrinone-treated patients compared to controls. Milrinone therapy may provide a useful therapeutic approach for this highly lethal disorder. We also performed the study to determine the changes in cytokine profiles associated with administration of intravenous immunoglobulin (IVIG) in patients of stage IIIa and stage IIIb. Plasma levels of IFN-, IL-6, IL-8, IL-10, and IL-13 levels significantly decreased in patients stage IIIb after administration of IVIG. Plasma levels of IL-6 and IL-8 were significantly decreased in patients of stage IIIa after administration of IVIG. All the satage IIIa patients were survived without deteriorated to stage IIIb. These findings suggest that IVIG might be considered to have a therapeutic role in stage IIIa EV71 BE. In summary, both systemic and CNS inflammatory responses have participate in the pathogenesis of EV71 BE. The peripheral inflammatory responses can be attenuate by milrinone and IVIG. Milrinone and IVIG therapy may provide a useful therapeutic approach for complicated EV71 BE.

Abe Y, Horiuchi A, Miyake M, Kimura S. Anti-cytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy. Immunol Rev 1994;139:5-19.
Abzug MJ, keyserling HL, Lee ML, Levin MJ, Rotbart HA. Neonatal enterovirus infection: virology, serology, and effects of immune globulin. Clin Infect Dis 1995;20:1201-6.
Alexander JP Jr, Baden L, Pallansch MA, Anderson LJ. Enterovirus 71 infections and neurologic disease—United States, 1977-1991. J Infect Dis 1994;169:905-8.
Andersson J, Skansen-Saphir U, Sparrelid E, Andersson U. Intravenous immunoglobulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol 1996;104(suppl 1):10-20.
Aukrust P, Froland SS, Liabakk NB, et al. Release of cytokines, soluble cytokine receptors, and interleukine-1 receptor antagonist after intravenous immunoglobulin administration in vivo. Blood 1994;84:2136-43.
Aukrust P, Muller F, Svenson M, Nordoy I, Bendtzen K, Froland SS. Administration of intravenous immunoglobulin (IVIG) in vivo downregulatory effects of the IL-1 system. Clin Exp Immunol 1999;115:136-43.
Baker AB. Poliomyelitis: a study of pulmonary edema. Neurology 1957; 7:745–51.
Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res 2004;78:151-6.
Basta M, Van Goor F, Luccioli S, et al. F(ab)’2-mediated neutralization of C3a and C5a anaphylatoxins:a novel effector function of immunoglobulins. Nat Med 2003;9:431-8.
Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV. Intravenous immunoglobulin for infectious diseases: back to the pre-antibiotic and passive prophylaxis era? Trends Pharmacol Sci 2004;25:306-10.
Beck GC, Oberacker R, Kapper S, von Zabern D, Schulte J, van Ackern K, van der Woude FJ, Yard BA. Modulation of chemokine production in lung microvascular endothelial cells by dopamine is mediated via an oxidative mechanism. Am J Respir Cell Mol Biol 2001;25:636-43.
Binder GK, Griffin DE. Interfern--mediated site-specific clearance of alphavirus from CNS neurons. Science 2001;293:303-6
Blasczyk R, Westhoff U, Grossewilde H. Soluble CD4, CD8, and HLA molecules in commercial immunoglobulin preparations. Lancet 1993;341:789-90.
Boehm U, Klamp T, Groot M, Howard JL. Cellular responses to interferon-. Annu Rev Immunol 1997; 15:749-95.
Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function, and mechanism of function. Am J Physiol 1992;263:C1-C16.
Brown RH Jr, Beyerl BD, Iseke R, et al. Medulla oblongata edema associated with neurogenic pulmonary edema. J Neurosurgery 1986; 64:494-500.
Burnouf C, Pruniaux MP. Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. Curr Pharm Des 2002;8:1255-96.
Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G. Interleukin-10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes: evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J Exp Med 1993; 178:2207-11.
Centers for Disease Control and Prevention. Progress toward global eradication of poliomyelitis. Morbidity and Mortality Weekly Report 1996;45:565-8.
Chai CY,Wang SC. Localization of central cardiovascular control mechanism in lower brain stem of the cat. Am J Physiol 1962;202:25-30.
Chang LY, Huang YC, Lin TY. Fulminant neurogenic pulmonary edema with hand, foot and mouth disease. Lancet 1998;352:367-8.
Chen YC, Yu CK, Wang YF, Liu CC, Su IJ, Lei HY. A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol 2004;85(Pt 1):69-77.
Chen HI, Liao JF, Kuo L, Ho ST. Centrogenic pulmonary hemorrhage edema induced by cerebral compression in rats, mechanism of volume and pressure loading in the pulmonary circulation. Circ Res 1980;47:366-73.
Cherry JD. Enteroviruses: polioviruses (poliomyelitis), coxsackievirus, echoviruses, and enteroviruses. In: Feign RD, Cherry JD, eds. Textbook of pediatric infectious diseases. 5th ed. Philadephia: WB Saunders, 2004:1984-2027.
Chonmaitree T, Menegus MA, Schervish-Swierkosz EM, Schwalenstocker E. Enterovirus 71 infection: report of an outbreak with two cases of paralysis and a review of the literature. Pediatrics 1981;67:489-93.
Corbin JG, Kelly D, Rath EM, Baerwald KD, Suzuki K, Popko B. Targeted CNS expression of interferon-gamma in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. Mol Cell Neurosci 1996;7:354-70.
Corada M, Mariotti M, Thurston G, et al. Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci USA 1999;17:9815-20.
Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, Massie BM, O’Connor CM, Pina H, Quigg R, Silver MA, Gheorghiade M. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002;287:1541-7.
Dalakas MC. Intravenous immune globulin therapy for neurologic diseases. Ann Intern Med 1997 ;126:721-30.
Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA 2004;291:2367-75.
Dalal I, Tzhori S, Somekh E, Mandelberg A, Levine A, Ballin A. Cytokine profile in cerebrospinal fluid of children with echovirus type 4 meningitis. Pediatr Neurol 2003;29:312-6.
De Vries JE. The role of IL-13 and its receptor in allergy and inflammatory responses. J Allergy Clin Immunol 1998;102:165-9.
Delpy E, Coste H, Gouville AC. Effects of cyclic GMP elevation on isoprenaline-induced increase in cyclic AMP and relaxation in rat aortic smooth muscle: role of phosphodiesterase 3. Br J Pharmacol 1996;119:471-8.
Dent G, Magneussen H, Rabe KF. Cyclic nucleotide phosphodiesterases in the human lung. Lung 1994;172:129-46.
Donnelly SC, Strieter RM, Reid PT, et al. The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fields of patients with the adult respiratory distress syndrome. Ann Intern Med 1996; 125:191 6.
Drummond GI, Severson DL. Cyclic nucleotides and cardiac function. Circ Res 1979;44:145-53.
Dwyer JM. Manipulating the immune system with immune globulin. N Engl J Med 1992;326:107-16.
Elenkov IJ, Chrousos GP: Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol Metab 1999;10:359-68.
Enk AH, Angeloni VL, Udey MC, Katz SI. Inhibition of Langerhans cell antigen-presenting function by IL-10: a role for IL-10 in induction of tolerance. J Immunol 1993; 151:2390-8.
Eppinger MJ, Ward PA, Bolling SF, Deeb GM. Regulatory role of IL-10 in rat lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 1996;112:1301-5.
Frei K, Leist TP, Meager A, et al. Production of B cell stimulatory factor-2 and interferon- in the central nervous system during viral meningitis and encephalitis. Evaluation in a murine model infection and in patients. J Exp Med 1988;168:449-53.
Frei K, Nadal D, Pfister HW, Fontana A. Listeria meningitis: identification of a cerebrospinal fluid inhibitor of macrophage listericidal function as interleukin 10. J Exp Med 1993;178:1255-61.
Essayan DM, Kagey-Sobotka A, Lichtenstein LM et al. Regulation of interleukin-13 by type 4 cyclic nucleotide phosphodiesterase (PDE) inhibitors in allergen-specific human T lymphocyte clones. Biochem Pharmacol 1997;53:1055-60.
Gallo P, Sivieri S, Rinaldi L, et al. Intrathecal synthesis of interleukin-10 (IL-10) in viral and inflammatory diseases of the central nervous system. J Neurol Sci 1994;126:49-53.
Geller TJ, Condie D. A case of protracted coxackie virus meningoencephalitis in a marginally immunodeficient child treated successfully with intravenous immunoglobulin. J Neurol Sci 1995;129:131-3.
Gilbert GL, Dickson KE, Waters MJ, Kennett ML, Land SA, Sneddon M. Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr Infect Dis J 1988;7:484-8.
Goodman RB, Pugin J, Lee JS, Matthay MA. Cytokine-mediated inflammation in acute lung injury. Cytokine & Growth Factor Reviews 2003;14 523-35.
Grilli M, Barbieri I, Basudev H, et al. Interleukin-10 modulates neuronal threshold of vulnerability to ischemic damage. Eur J Neurosci 2000;12:2265 72.
Hackett SJ, Thomson APJ, Hart CA. Cytokines, chemokines, and other effector molecules involved in meningococcal disease. J Med Microbiol 2001;50:847-59.
Hall WA. Infectious lesions of the brain stem. Neurosurg Clin North Am 1993;4:543-51.
Hagiwara A, Tagaya I, Yoneyama T. Epidemic of hand, foot and mouth disease associated with enterovirus 71 infection. Intervirology 1978;9:60-3.
Hagiwara A, Yoneyama T, Takami S, Hashimoto I. Genetic and phenotypic characteristics of enterovirus 71 isolates from patients with encephalitis and with hand, foot and mouth disease. Arch Virol 1984;79:273-83.
Hayward JC, Gillespie SM, Kaplan KM, et al. Outbreak of poliomyelitislike paralysis associated with enterovirus 71. Pediatr Infect Dis J 1989; 8:611-6.
Hensler T, Sauerland S, Reiss P, et al. The effect of additional brain injury on systemic interleukin (IL)-10 and IL-13 levels in traumatic patients. Inflamm Res 2000;49:524-8.
Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. N Engl J Med 1999;341:929-35.
Hosoda K, Tamaki N, Masumura M, Matsumoto S. Magnetic resonance images of brain-stem encephalitis. J Neurosurg 1987;66:283-5.
Hosoi T, Yasunobu O, Nomura Y. Electrical stimulation of afferent vagus nerve induce IL-1b expression in the brain and activates HPA axis. Am J Physiol 2000;279:R141-7.
Hsiung GD. Picornaviridae. In: Hsiung GD, Fong CKY, Laudry ML, eds. Hsiung’s diagnostic virology. 4th ed. New Haven, Connecticut: Yale University Press, 1994:119-40.
Hsu YH, Kao SJ, Lee RP, Chen HI. Acute pulmonary edema: rare causes and possible mechanisms. Clin Sci 2003;104:259-64.
Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurological complications in children with enterovirus 71 infection. N Engl J Med 1999; 341:936-42.
Huang YC, Lin TY, Lin YJ, Lien RI, Chou YH. Prophylaxis of intravenous immunoglobulin and acyclovir in perinatal varicella. Eur J Pediatr 2001;160:91-4.
Ishimaru Y, Nakano S, Yamaoka K, Takami S. Outbreaks of hand, foot and mouth disease by enterovirus 71: high incidence of complication disorders of central nervous system. Arch Dis Child 1980;55:583-8.
Kao SJ, Yang FL, Hsu YH, Chen HI. Mechanism of fulminant pulmonary edema caused by enterovirus 71. Clin Infect Dis 2004;38:1784-8.
Kaufman HH, Moake JL, Olson JD, Miner ME, duCret RP, Pruessner JL. Delayed and recurrent intracranial hematomas related to disseminated intravascular clotting and fibrinolysis in head injury. Neurosurgery 1980; 7:445-52.
Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55.
Kimura-Kuroda J, Yasui K. Protection of mice against Japanese encephalitis virus by passive administration with monoclonal antibodies. J Immunol 1988;141:3606-10.
Kitamura A, Narisawa T, Hayashi A, AshiharaY, IshikoH. Serotype determination of enteroviruses that cause hand-foot-mouth disease: Identification of enterovirus 71 and Coxsackie virus A 16 from clinical specimens by using specific probe. J Jpn Assoc Infect Dis 1997;71:715-23.
Knezevic-Maramica I, Kruskall MS. Intravenous immune globulins: an update for clinicians. Transfusion 2003;43:1460-80.
Kondo K, Umemura K, Miyaji M, Nakashima M. Milrinone, a phosphodiesterase inhibitor, suppresses intimal thickening after photochemically induced endothelial injury in the mouse femoral artery. Artherosclerosis 1999;142:133-8.
Kupperman DA, Huang X, Koth LL, et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med 2002; 8:885-9.
Lam L, Whitsett CF, McNicholl JM, Hodge TW, Hooper J. Immunologically active proteins in intravenous immunoglobulin. Lancet 1993;342:678.
Lam SK. Emerging infectious diseases—Southeast Asia. Emerg Infect Dis 1998;4:145-7.
Landry ML, Fonseca SNS, Cohen S, Bogue CW. Fatal enterovirus type 71 infection: rapid detection and diagnostic pitfalls. Pediatr Infect Dis J 1995;14:1095-100.
Lemieux R, Bazin R, Neron S. Therapeutic intravenous immunoglobulins. Mol Immunol 2005 ;42:839-48.
Lin TY, Chang LY, Huang YC, Hsu KH, Chiu CH, Yang KD. Different proinflammatory reactions in fatal and non-fatal enterovirus 71 infections: implications for early recognition and therapy. Acta Paediatr 2002;91:632-5.
Lin TY, Chang LY, Hsia SH, Hunag YJ, Chiu CH, Hsueh C, Shih SR, Liu CC, Wu MH. The 1998 enterovirus 71 outbreak in Taiwan: pathogenesis and management. Clin Infect Dis [Suppl] 2002;34:52-7.
Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis 2003; 36:269-74.
Liu CC, Huang KJ, Lin YS, Yeh TM, Liu HS, Lei HY. Transient CD4/CD8 ratio inversion and immune deviation during dengue virus infection. J Med Virol 2002; 68:241-52.
Liu CC, Tseng HW, Wang SM, Wang JR, Su IJ. An outbreak of enterovirus 71 infection in Taiwan, 1998: epidemiologic and clinical manifestations. J Clin Virol 2000; 17:23-30.
Loughnan PM, Brown TCK, Edis B, Klug GL. Neurogenic pulmonary oedema in man: aetiology and management with vasodilators based on haemodynamic studies. Anaesth Intens Care 1980;8:65-71.
Lum LCS, Wong KT, Lam SK, et al. Fatal enterovirus 71 encephalomyelitis. J Pediatr 1998;133:795– 8.
Malik AB. Pulmonary embolism. Physiol Rev 1983; 63:1114-207.
Maron MB, Holcomb PH, Dawson CA, Rickby DA, Clough AV, Linehan JH. Edema development and recovery in neurogenic pulmonary edema. J Appl Physiol 1994; 77:1155-63.
Martin S, Maruta K, Burkart V, Gillis S, Kolb H. IL-1 and IFN-gamma increase vascular permeability. Immunology 1988; 64:301-5.
Maurice DH, Haslam RJ. Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP. Mol Pharmacol 1990;37:671-81.
Maurice DH, Palmer D, Tilley DG, et al. Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol Pharmacol 2003;64:533-46.
McKinney RE, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987;9:334-56.
Melnick JL, Schmidt NJ, Mirkovic RR, Chumakov MP, Lavrova IK, Voroshiloba MK. Identification of Bulgarian strain 258 of enterovirus 71. Intervirology 1980,12:297-302.
Melnick JL, Wenner HA, Phillips CA. Enteroviruses. In: Lennette EH, Schmidt NJ, eds. Diagnostic procedures for viral, rickettsial and chlamydial infections. 5th ed. Washington, DC: American Public Health Association, 1979:471-534.
Melnick JL. Enterovirus type 71 infections: a varied clinical pattern sometimes mimicking paralytic poliomyelitis. Rev Infect Dis 1984;6(suppl 2):S387-90.
Ministry of Health, The Executive Yuan, Taiwan, ROC. Deaths among children during an outbreak of hand, foot, and mouth disease—Taiwan, Republic of China, April–July 1998. MMWR Morb Mortal Wkly Rep 1998;47:629-32.
Minty A, Chalon P, Derocq JM, et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature 1993; 362:248-50.
Moore KW, O’Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin 10. Annu Rev Immunol 1993;11:65-90.
Muir P, van Loon AM. Enterovirus infections of the central nervous system. Intervirology 1997;40:153-66.
Mulligan MS, Jones ML, Vaporciyan AA, Howard MC, Ward PA. Protective effects of IL-4 and IL-10 against immune complex induced lung injury. J Immunol 1993;151:5666-74.
Mullins JA, Khetsuriani N, Nix WA, et al. Emergence of echovirus type 13 as a prominent enterovirus. Clin Infect Dis 2004;38:70-7.
Nagy G, Takatsy S, Kukan E, Mihaly I, Domok I. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol 1982;71:217-27.
Opavsky MA, Penninger J, Aitken K, et al. Susceptibility to myocarditis is dependent on the response of T lymphocytes to coxsackieviral infection. Circ Res 1999; 85:551 8.
Olsson T, Kelic S, Edlund C, et al. Neuronal interferon- immunoreactive molecule bioactivities and purification. Eur J Immunol 1994;24:308-14.
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML. Effect of oral milrinone on mortality in severe chronic heart failure: the PROMISE Study Research Group. N Engl J Med 1991;325:1468-75.
Patscheke H. Role of activation in epinephrine-induced aggregation of platelets. Thromb Res 1980;17:133-42.
Plas DR, Rathmell JC, Thompson CB. Homeostatic control of lymphocyte survival: potential origins and implications. Nat Immunol 2002;3:515-21.
Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW. Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Rev 1999;30:77-105.
Ramsingh AI, Lee WT, Collins DN, Armstrong LE. T cells contribute to disease severity during coxsackievirus B4 infection. J Virol 1999;73:3080-6.
Ren R, Racaniello VR. Poliovirus spreads from muscle to the central nervous system by neural pathways. J Infect Dis 1992;166:747-52.
Rennick D, Davidson N, Berg D. Interleukin-10 gene knock-out mice: a model of chronic inflammation. Clin Immunol Immunopathol 1995;76:S174-8.
Ross C, Svenson M, Hansen MB, Vejlsgaard GL, Bendtzen K. High activity IFN-neutralizing antibodies in pharmaceutically prepared human IgG. J Clin Invest 1995;95:1974-8.
Rotbart HA. Enteroviral infections of the central nervous system. Clin Infect Dis 1995;20:971-81.
Rybalkin SD, Beavo J. Multiplicity within cyclic nucleotide phosphodiesterases. Biochem Soc Trans 1996;24:1005-9.
Samuda GM, Chang WK, Yeung CY, Tang PS. Monoplegia caused by enterovirus 71: an outbreak in Hong Kong. Pediatr Infect Dis J 1987;6:206-8.
Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291:484-6.
Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis 2002;186 (Suppl 2):S225-S233.
Schlesinger. Neurogenic pulmonary edema due to puncture wound of the medulla oblongata. J Nerv Ment Dis 1945;102:247-55.
Schmidt NJ, Lennette EH. Advances in the serodiagnosis of viral infections. Prog Med Virol 1973;15:244-308.
Schmidt NJ, Lennett EH, Ho HH. An apparently new enterovirus isolated from patients with disease of central nervous system. J Infect Dis 1974;129:304-9.
Selbing A, Josefesson A, Dahle LO, Lindgren R. Parvovirus B19 infection during pregnancy treated with high-dose intravenous immunoglobulin. Lancet 1995;11:660-1.
Shimoni Z, Niven MJ, Pitlick S, Bulvik S. Treatment of West Nile virus encephalitis with intravenous immunoglobulin. Emerg Infect Dis 2001;7:759.
Shindarov LM, Chumakov MP, Voroshilova MK, et al. Epidemiological, clinical and patholomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol 1979:23;284-95.
Shipley JB, Tolman D, Hastillo A, Hess ML. Review: milrinone: basic and clinical pharmacology and acute and chronic management. Am J Med Sci 1996;311:286-91.
Sim DS, Merrill-Skoloff G, Furie BC, Furie B, Flaumenhaft R. Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels. Blood 2004;103:2127-34.
Sosman JA, Vema A, Moss S, et al. Interleukin 10 induced thrombocytopenia in normal healthy adult volunteer: evidence for decreased platelet production. Br J Hematol 2000; 111:104-11.
Stoll G, Jander S, Schroeter M. Cytokines in CNS disorders: neurotoxicity versus neuroprotection. J Neural Transm 2000;59(Suppl):81-9.
Suttorp N, Ehreiser P, Hippenstiel S, Fuhrmann M, Krull M, Tenor H, Schudt C. Hyperpermeability of pulmonary endothelial monolayer: protective role of phosphodiesterase isoenzymes 3 and 4. Lung 1996;174:181-94.
Tagaya I, Takayama R, Hagiwara A. A large-scale epidemic of hand, foot and mouth disease associated with enterovirus 71 infection in Japan in 1978. Japan J Med Sci Biol 1981;34:191-6.
Talavera D, Castillo AM, Dominguez MC, Gutierrez AE, Meza I. IL8 release, tight junction and cytoskeleton dynamic reorganization conducive to permeability increase are induced by dengue virus infection of microvascular endothelial monolayers. J Gen Virol 2004;85:1801-13.
Teixieira MM, Gristwood RW, Cooper N, Hellewell PG. Phosphodiesterase (PDE4) inhibitors: anti-inflammatory drugs of the future? Trends Pharmacol Sci 1997;18:164-71.
Theodore J, Robin ED. Pathogenesis of neurogenic pulmonary edema. Lancet 1975;2:749 –51.
Theodore J, Robin ED. Speculations on neurogenic pulmonary edema (NPE). Am Rev Respir Dis 1976;113:405-11.
van der Flier M, Geelen SP, Kimpen JL, Hoepelman IM, Tuomanen EI. Reprogramming the host response in bacterial meningitis: how best to improve outcome? Clin Microbiol Rev 2003;16:415-29.
Van der Poll T, De Waal Malefyt R, Coyle S.M, Lowry SF. Antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: Sequential measurements of plasma soluble interleukin 1 receptor type II, IL-10 and IL-13. J Infect Dis 1997;175:118-22.
van Furth AM, Seijmonsbergen EM, Langermans JAM, Groenenveld PHP, de Bel CE, van Furth R. High levels of interleukin-10 and tumor necrosis factor alpha in cerebrospinal fluid during the onset of bacterial meningitis. Clin Infect Dis 1995;21:220-2.
Wang JR, Tsai HP, Huang SW, Kuo PH, Kiang D, Liu CC. Laboratory diagnosis and genetic analysis of an echovirus 30-associated outbreak of aseptic meningitis in Taiwan in 2001. J Clin Microbiol 2002;40:4439-44.
Wang SM, Liu CC, Chen YJ, Chang YC, Huang CC. Alice in wonderland syndrome caused by coxsackievirus B1. Pediatr Infect Dis J 1996;15: 470-1.
Wang SM, Liu CC, Yang YJ, Yang HB, Lin CH, Wang JR. Fatal coxsackievirus B infection in early infancy characterized by fulminant hepatitis. J Infect 1998:37;270-3.
Wang SM, Liu CC, Tseng HW, et al. Clinical spectrum of enterovirus 71 infection of children in southern Taiwan: emphasis on the neurological complications. Clin Infect Dis 1999;29:184–190.
Wang SM, Lei HY, Huang KJ, et al. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: the roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis 2003;188:564-70.
Wang SM, Lei HY, Huang MC, et al.The therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. Pediatr Pulmonol 2005;39:219-223.
Wang SM, Lei HY, Huang MC, et al. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol 2006 (accepted)
Wang YF, Chou CT, Lei HY, et al. A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol 2004;78:7916-24.
Ware LB, Matthay MA. The acute respiratory syndrome. N Engl J Med 2000;342:1334-49.
Weigle WO, Goodman MG, Morgan EL, Hugli TE. Regulation of immune response by components of the complement cascade and their activated fragments. Springer Semin Immunopath 1983;6:173-94.
Weiner LP, Fleming JO. Viral infections of the nervous system. J Neurosurg 1984;61:207-24.
Wills-Karp M, Luyimbazi J, Xu X, et al. Interleukin 13: central mediator of allergic asthma. Science 1998; 282:2258-61.
Woiciechowsky C, Asadullah K, Nestler D, et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 1998;4:808-13.
Wu JM, Wang JN, Tsai YC, et al. Cardiopulmonary manifestations of fulminant enterovirus 71 infection. Pediatrics 2002;109:E26.
Wu TN, Tsai SF, Li SF, Lee TF, Huang TM,Wang ML, Hsu KH, ChenCY. Sentinel surveillance for Enterovirus 71, Taiwan, 1998. Emerging Infect Dis 1999;5:458-60.
Wynn TA. IL-13 effector functions. Annu Rev Immunol 2003;21:425-56.
Yan JJ, Wang JR, Liu CC, Yang HB, Su IJ. An outbreak of enterovirus 71 infection in Taiwan 1998: A comprehensive pathological, virological, and molecular study on a case of fulminant encephalitis. J Clin Virol 2000;17:13-22.
Yang KD, Yang MY, Li CC, et al. Altered cellular but not humoral reactions in children with complicated enterovirus 71 infections in Taiwan. J Infect Dis 2001;183:850-6.
Yoshida N, Shimizu Y, Kitaichi K, et al. Differential effect of phosphodiesterase inhibitors on IL-13 release from peripheral blood mononuclear cells. Clin Exp Immunol 2001;126:384-9.
Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiological abnormalities, and eotaxin production. J Clin Invest 1999;103:779-88.
Zurawski G, de Vries JE. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B-cells, but not on T cells. Immunol Today 1994;15:19-26.