HSV hepatitis after liver transplantation

Case Presentation #2 Daniel Caplivski, M.D. Clinical Presentation     Cc: Jaundice HPI: 26 y/o w c h/o primary sclerosing cholangitis s/p living-related donor liver transplant in 2000 a/w increasingly yellow skin and dark urine. The patient was admitted 8/31 c jaundice, icterus and light colored stools which she he noted over the previous day. She denied chills, fevers, dysuria, headache, nausea, vomiting, pruritis, edema, or rashes. She admitted to mild increase in abdominal girth for 2 days She has a 5 year-old son that had a mild uri a few days prior to her admission. Past Medical History     PMH: Diagnosed with primary sclerosing cholangitis in 2000, shortly before transplant. Initial presentation included jaundice, severe intractable pruritis, and liver failure. She had had 3 previous episodes of jaundice after the transplant. Once immediately post transplant and two other subsequent times. All were treated with either steroids or OKT-3. She did not know her CMV status or that of her father prior to transplant. She denied any history of tuberculosis, tuberculosis exposure, or sexually transmitted diseases. She had recently been tested for HIV, and was negative. Medications  Outpatient medications included: tacrolimus 2tabs q12, prednisone 7.5 mg po qd, mycophenolate mofetil 500mg po bid, aspirin, calcium, famotidine, and acyclovir 2 tabs po bid.  She had been on ganciclovir until about one year prior to admission.  She reported compliance with all of her medications. Social History, Family History, Travel History  SH: Denied alcohol, tobacco, heroine, cocaine or other drug use. She worked in the Post-office.  FH: significant for a maternal uncle and a maternal grandmother with liver disease.  TH: 2 weeks prior to admission she had been in Orlando. She had an episode of nausea after one of her meals, but this resolved after 1 day. She had also been in Puerto Rico 1 year prior to her admission. Physical Exam on HD # 10 (similar to admission) VS Tmax36.3 bp100/60 hr 84 rr 16 Gen—Jaundiced, but well appearing, nad Heent—Icteric, Perrl, Eomi, no thrush, no oropharyngeal lesions Neck—supple, no lan Cor—rrr s1s/2, no murmur Lungs—cta B/l Abd—soft, nt/nd, nl bs, with no organomegaly, no ascites detected Ex—no edema, no palmar erythema Neurologically—intact with no asterixis Admission and Baseline Laboratory Values Wbc Hbg Plts Na K Cl Bun Cr. Glu Ca Mg PO4 5.0 11.3 108 139 3.8 106 7 0.7 91 8.5 1.7 2.8 alph ggt Alt Ast Bili Dbil Tp ldh alb Ptt Pt inr 444 1259 382 720 4.9 4.1 7.7 237 3.1 35.1 16.2 1.5 145 180 44 41 0.3 0.1 237 3.9 Radiologic Studies  Chest x-ray revealed no infiltrates or effusions  Ultrasound on day of admission showed patent hepatic vessels, and echogenic liver c/w fatty infiltration versus mild parenchymal disease. No evidence of biliary obstruction was seen.  CT scan of the abd on Day#8 showed splenomegaly, ascites, patent hepatic vessels, and two 1cm nonspecific enhancing lesions in the right hepatic lobe Hospital Course    On admission the patient was started on dexamethasone, tacrolimus, mycophenolate mofetil, and valganciclovir for presumed acute rejection and concomitant cmv infection. Initial transcutaneous biopsy showed acute moderate cellular rejection (RAI 5). Liver function tests continued to worsen and transplant ID was consulted. 2 subsequent biopsies were performed secondary to persistent elevation of the liver function tests. Progression of Liver Function Tests date Alk phos Ggt Alt Ast Tbili D.bili Alb LDH 8/31 444 1259 382 720 4.9 4.1 3.1 237 9/1 538 1047 453 675 8.1 4.7 3.3 301 9/2 524 1005 368 414 6 3.6 2.8 203 9/3 517 1021 363 356 4.9 3.4 2.7 275 9/4 501 1159 377 309 4.6 2.8 2.6 236 9/5 487 1188 369 286 4.7 3.5 2.4 205 9/6 469 1366 371 253 4.9 3.3 2.3 188 9/7 460 1391 327 205 5.7 3.6 2.3 187 9/8 438 1354 327 188 6.6 4.1 2.1 237 9/9 404 1299 314 205 8.7 6.8 2.1 211 Differential Diagnosis       1. 2. 3. 4. 5. 6. Rejection Infectious—Bacterial, Viral, Fungal, Parasitic Recurrence of primary disease—PSC Vascular Event Medication Related Anatomic Obstruction Common Infectious Causes of Hepatitis After Liver Transplant CMV—can see microabscesses on liver biopsy HBV—worse prognosis when circulating E ag is seen HCV—possibly better prognosis than HBV HSV—usually fulminant presentation w severe necrosis EBV—primary or reactivation of latent infection VZV—more common in children Disseminated Candida Less common: Adenovirus, Histoplasmosis, and Aspergillus Biopsy #1 Moderate portal mixed inflammatory infiltrates including eosinophils, mild endotheliitis, bild duct damage, bile ductular proliferationaccompanied by neutrophils. Lymphoplasmactic spillage into liver parenchyma noted. Mild lobular inflammation with foci of histiocytes and acidophil bodies Mild intrahepatocytic cholestasis with feathery degeneration Acute moderate cellular rejection (RAI 5/9) vs. recurrence of PSC. MS-03-29189 MS-03-29189 MS-03-29189 Biopsy #2 9/5  Liver allograft needle biopsy specimen with punched out areas of hepatocyte necrosis accompanied by neutrophils and ballooning degeneration of hepatocytes.  Portal Tracts show mild proliferation of the ductules.  No rejection seen. Trichrome stain with portal fibrosis and fibrous septum formation . Immunohistochemical Stains were positive for HSV I and HSV II. IHC stains are negative for CMV. AFB, gram, and GMS stains were negative for other organisms MS-03-30037 MS-03-29818 MS-03-29818 Control IHC for HSV MS-03-29818 HSV hepatitis in transplant recipients     Usually causes a fulminant hepatitis clinical picture. However, when caught early can be focal and may respond to treatment. Usually represent reactivation of latent virus Can present with markedly elevated liver enzymes, fever, and DIC On pathology severe necrosis is seen, and HSV may be detected with culture, immunohistochemistry, or immunofluoresence Herpes Simplex Virus Hepatitis after Solid Organ Transplantation in Adults Kusne et al. The Journal of Infectious Diseases 1991; 163 1001-1007 12 cases of biopsy-confirmed hsv hepatitis 8 patients had liver grafts, 1 had a heart graft, and 3 had kidney grafts 8 patients presented with disseminated disease, DIC, and death—5 were reactivation, 3 were primary) Of the four who survived, all had focal disease and 3 of the 4 were reactivation of latent disease, and all were liver transplant recipients Herpes Simplex Virus Hepatitis after Solid Organ Transplantation in Adults      Overall rate of HSV hepatitis was 0.3% for all organs Median time to infection was 18 days after transplantation, though 1 patient presented >2 years after transplantation. 8/12 cases were seropositive prior to transplantation, suggesting recurrence of latent infection. Clinical findings included prolonged fever, abdominal pain and tenderness, elevated alt, ast, bilirubin, thrombocytopenia, and pulmonary infiltrates. No patient in this series received acyclovir prophylaxis Conclusion     On further questioning, the patient related that she had had oral herpetic lesions (cold sores) yearly since she was a teenager. While in Florida 10 days prior to admission, she had had a cold sore. She denied any vaginal discharge or lesions Her HSV IgG antibody was positive. CMV pcr was <400copies on admission and on 9/9. Hepatitis B sab, sag, Hepatitis A Ab were all non-reactive. HCV Rna was negative She did not know if her father also had cold sores or any history of HSV. She is being treated with acyclovir 10mg/kg iv q8hours. References     Mandell, Principles and Practice of Infectious Diseases 4th edition. pp 2728-2729 Herpes Simplex Virus Hepatitis after Solid Organ Transplantation in Adults Kusne et. alThe Journal of Infectious Diseases 1991; 163 1001-1007 Herpes simplex Virus Hepatitis in a Renal Transplant Recipient: Successful Treatment with Acyclovir. Gabel et al. Scandinavian Journal of Infectious Diseases. 20:435-8, 1988. Five Cases of Fulminant Hepatitis Due to Herpes Simplex Virus in Adults. Pinna, et al. Digestive Diseases and Sciences 47, no4. 2002. 750-754  Acknowledgements—thanks to Dr. Bu-Ghanim, and Dr. Fiel of Pathology for providing histology slides from the liver biopsies, and to Dr. Keller and Dr. Huprikar for help providing references.