Acute Viral Infection: Dengue and Herpes Infection

Transcription

1 The 8 th Annual Meeting of Thai Association for the Study of the Liver Acute Viral Infection: Dengue and Herpes Infection Watcharasak Chotiyaputta Gastroenterology Siriraj Hospital, Mahidol University

2 Outline Dengue virus Herpes simplex virus 1 (Alpha-herpesvirus) Herpes simplex virus 2 (Alpha-herpesvirus) Epstein-Barr virus (Gamma-Herpesvirus) Human Cytomegalovirus (Beta-Herpesvirus)

3 Dengue Infection Febrile phase Recovery phase Mechanism of hepatocyte damage: poor understanding (direct viral invasion and immune) Simmons CP et al. NEJM 2012

4 Clinical Manifestation Fever, myalgia, hepatomegaly, sign of vascular leakage, leucopenia, thrombocytopenia Study Total Age Abn AST/ALT Mean AST Mean ALT ALT>10ULN Lee (27-43) 86%/46% DF 93 (55-165) DHF103 (64-203) DF 52 (31-107) DHF 60 (37-118) 1%# Trung 2010 Souza 2004 Parkash (15-35) 96.6% 108 ( ) 93 ( ) NA 1, ± %/45% 93.3±117 86± % ± %/86% % Kuo %/82% 11% Data were showed in mean±sd, median (range), or percent) # AST/ALT > 1,000 U/L Lee LK et al. PLOS 2012 Trung DT et al. Am J Med Hyg 2010 Souza LJ et al. Braz J of Infect Dis 2004 Parkash O et al. BMC Gastroenterology 2010 Kuo MC et al. Am J Med Hyg 1992

5 Diagnosis Change of Ab titer Duration Convalescent Ab titer Interpretation > 4 times > 7 days < 1:1280 Primary infection > 4 times Anytime > 1:1280 Secondary infection > 4 times < 7 days < 1:1280 Recent infection (1 or 2)? < 4 times > 7 days < 1:1280 Not DF Simmons CP et al. NEJM 2012

6 Histopathology Hepatocellular necrosis in midzonal and centrilobular area Microvesicular steatosis, mononuclear cell infiltrate Councilman bodies Gasperino J et al. Liver international 2007 Lawn SD et al. CID 2003

7 Clinical Manifestation Fulminant hepatic failure Total Male Age (years) Peak AST (U/L) Peak ALT (U/L) Peak TB (mg/dl) Dead % 26 (0.7-64) 4,080 (1,410-20,480) 2,950 (1,049-19,800) 6.4 (2-22.9) 43.8% Treatment Self-limited disease IV N-acetylcysteine Total 10 patients: survive 7 patients MARS 1 patient: survive LT: Dead Lim G and Lee JH. J Trop Pediatrics 2012 Ling LM et al. J Clin Virol 2007 Kumarasena RS et al. Hepatol int 2010 Jhamb R et al. Asian Pacific J Trop Med 2011 Poovorawan Y et al. Annals Trop Pediatrics 2006 Subramanian V et al. Dig Dis Sci 2005

8 Herpes Simplex Virus

9 Herpes Simplex Virus HSV-1, HSV-2 Hepatic involvement is rare, leading to acute liver failure (mortality rate 90%) Clinical fever (82%), severe abdominal pain (33%), hepatomegaly (45%), leukopenia (<5,000 /mm 3 ), thrombocytopenia (43%), minor increased in bilirubin Risk Neonates Malnourished children Pregnant women On immunosuppressive Talwani R et al. Clin Liver Dis 2011

10 Mechanisms for HSV Hepatitis Large HSV inoculums at primary infection Impairment in macrophages, cytotoxic T lymphocytes Virulence of HSV may be enhanced by activation of a latent virus with reinfection by a second strain Hepatovirulent virus Kaufman B et al. CID 1997

11 Underlying Conditions with Herpes Simplex Virus Hepatitis Underlying Conditions Number (%) Total 166 Immunocompetent 35 (21%) Immunosuppressed 81 (48.8%) Transplant (Bone marrow, liver and kidney) 47 Nontransplant 34 On chemotherapy Myelodysplastic syndrome HIV infection Systemic lupus erythematosus Post thymectomy Pregnant (third trimester) 34 (20.5%) Neonate 16 (9.6%) Adapted from Kaufman B et al. CID 1997

12 Demographics and Clinical Presentation of HSV Hepatitis Number (%) Mean age (yr) 34 ± 15 Gender (male) 51/137 (38%) Fever 98/100 (98%) Herpetic lesions Mucocutaneous 33/123 (27%) Disseminated 21/123 (17%) Mean peak ALT or AST (IU/L) 4,927 ± 4,099 Mean Peak total bilirubin (mg/dl) 6.0 ± 8.1 Leucopenia 50/70 (71.4%) Thrombocytopenia 59/63 (93.6%) HSV serotype AST, ALT varied ,136 IU/L Most pts had peak AST/ALT >1,000 IU/L Most were AST > ALT Type I 36/93 (38.7%) Type II 57/93 (61.3%) Norvell JP et al. Liver Transpl 2007

13 Diagnosis HSV IgM, IgG HSV quantitative or qualitative assay Patient Diagnosis HSV-1/2 (IgM) HSV-1/2 (IgG) HSV PCR (cpm) 1 Autopsy -ve/-ve +/-ve 3.6 X Oral lesion, autopsy -ve/-ve -ve/+ 1.2 X Liver biopsy +/+ +/+ 1.2 X Skin/liver biopsy +/+ +/+ 3.5 x 10 8 Levitsky J et al. Liver transplantation 2008

14 Histopathology Gallegos-Orozco JF and Rakela-Brodner. Rev Med Chile 2010;138: Navaneethan U et al. J Gastrointestin Liver Dis 2011;20:93-6

15 Treatment Acyclovir 10 mg/kg IV every 8 hrs Acyclovir (n=49) No acyclovir (n=84) Mean age (yr) 32.9 ± ±18.1 Male gender (%) 15/49 (30.1) 35/84 (41.6) Immunocompromised (%) 25/49 (51) 45/84 (53.6) Encephalopathy (%) 21/25 (84) 36/46 (78.3) Rash (%) 19/44 (43.2) 35/78 (44.8) Mean ALT or AST (IU/L) 4398 ± ± 4375 Mean plt (10 3 /mm 3 ) 68 ± ± 39 Death/LT (%) 25/49 (51) 74/84 (88.1) Norvell JP et al. Liver Transpl 2007

16 Patients with HSV Hepatitis Listed for LT 30 patients with HSV-hepatitis listed for LT 19 children 11 Adults 2 Dead on waiting list 7 spontaneous recovery (without transplant) 10 liver transplants (69% 5 yr survival) 3 dead on waiting list 0 spontaneous recovery (without transplant) 8 liver transplant (38% 5 yr survival) Overall 5 yr survival 74% Overall 5 yr survival 27% Moldovan B et al. J Hepatol 2011

17 Epstein-Barr Virus Infectious mononucleosis Fever Pharyngitis Lymphadenopathy Severe EBV hepatitis Post organ transplantation AIDS patients Combined immunodeficiency X-linked lymphoproliferative disease (SH2D1A gene) Luzuriaga K and Sullivan JL. NEJM 2010

18 EBV Hepatitis Study Total Age IM Lympho cytosis Hepato megaly Spleen Peak ALT (U/L) Peak ALP (U/L) Peak TB (mg/dl) Vine LJ (18-68) 12% 100% N/A 88% 395 ( ) 345 ( ) 4 ( ) Kofteridis DP (18-51) N/A 90% 27% 66% N/A Crum NF (18-21) % 66.7% 66.7% 400 ( ) 369 ( ) 6 ( ) Other Studies 5 24 (20-68) 60% 100% 40% 80% 1141 ( ) 544 ( ) 4 ( ) Vine LJ et al. aliment Pharmacol Ther 2012 Kofteridis DP et al. European J of Int Med 2011 Crum NC. South Med Journal 2006 Pagidipati N et al. Dig Dis Sci 2010 Ulug Mehmet et al. J Infect Dev Ctries 2010

19 Cholestatic Hepatitis Total Age IM Hepatomegaly Splenomegaly Peak ALT (U/L) 9 31 (21-73) 33.3% 44.4% 55.6% 164 (30-400) Peak ALP (U/L) 919 ( ) Peak TB (mg/dl) 8.4 ( ) Mechanism: unknown Effect of virus and cytokine that interfere with the activity of the sinusoidal and canalicular Infection of biliary epithelial cells and high concentration of enzyme against the antioxidative enzyme Bile duct damage Hinedi TB and Koff RS. Dig Dis Sci 2003 Barlow G et al. J R Soc Med 2000 Edoute Y et al. J Gastroenterol and Hepatol 1998 Losavio AD and Te HS. Gastroenterology&Hepatology 2007

20 Diagnosis Condition Heterophile Anti-VCA Anti-EBNA IgM IgG Acute IM ve Convalescence ± -ve + + Past infection -ve -ve + + Reactivation with immunodeficiency -ve -ve ++ ± VCA: viral capsid antigens EBNA: EBV nuclear antigen Luzuriaga K and Sullivan JL. NEJM 2010

21 Histopathology Idian beads Drebber U et al. J Hepatol 2006;44: Pagidipati N et al. Dig Dis Sci 2010;55:1182-5

22 Supportive care Medications Treatment Corticosteroid Acyclovir, ganciclovir Liver transplantation Luzuriaga K and Sullivan JL. NEJM 2010 Adams LA et al. J Gastroenterol Hepatol 2006

23 Cytomegalovirus Immunocompetent hosts Asymptomatic Minimally symptomatic 10% Infectious mononucleosis-like AST/ALT elevation in up to 91% Only 2.8% total bilirubin > 2 mg/dl Splenomegaly is less frequent Unusual presentation cholestatic hepatitis Supportive treatment Talwani R et al. Clin Liver Dis 2011

24 Cytomegalovirus Immunocompromised hosts May develop severe disease HIV infection Cancer Organ transplantation Low risk: Kidney transplantation 8% Moderate risk: Liver transplantation High risk: Heart, lung, pancreas transplantation 39% CMV disease: fever, malaise, leucopenia, thrombocytopenia, or as tissue invasive disease Lautenschlager I et al. Transplant International 2009

25 Histopathology Microabscess Gallegos-Orozco JF and Rakela-Brodner. Rev Med Chile 2010

26 Conclusions Dengue HSV EBV CMV Symptoms Fever with myalgia Fever IM IM like Signs CBC Petichiae hemorrhage, hepatomegaly Atypical L, thrombocytopenia Skin lesions Leucopenia, thrombocytopenia Adenopathy, splenomegaly lymphocytosis Less splenomegaly AST/ALT AST>ALT AST>ALT ALT>AST ALT>AST Cholestasis -ve -ve + + Diagnosis NS1, PCR, dengue IgM, IgG PCR for HSV EBV IgM CMV IgM Treatment None Acyclovir None Ganciclovir

27 Thank You for Your Attention

28 Direct and Indirect Clinical Effects of CMV After Solid Organ Transplantation Direct effects CMV syndrome Fever Myelosuppression Malaise Tissue invasive CMV disease GI disease (colitis, esophagitis, gastroenteritis) Hepatitis Pneumonia Retinitis Mortality Indirect effects Acute allograft rejection Chronic graft rejection Vanishing bile duct syndrome Chronic ductopenic rejection Hepatitis C virus recurrence Vascular thrombosis Mortality Razonable RR. World J Gastroenterol 2008

29 Risk Factors for CMV Disease After LT Lack of pre-existing CMV-specific immunity CMV D+/R- Drug induced immunodeficiency OKT3, antithymocyte globulin Alemtuzumab Defects in innate and CMV-specific cell mediated immunity Genetic polymorphism in Toll-like receptor (TLR)-2 gene Allograft rejection Virus-to-virus interaction HHB-6, HCV Degree of CMV replication Razonable RR. World J Gastroenterol 2008

30 CMV Hepatitis Post LT CMV in 24/1,146 (2%) patients Developed 4-8 weeks 1.8X ULN 3.7X ULN Seehofer D et al. Liver Transplantation 2002