Post- Kidney Transplant Infectious Disease Complications

1. Post- Kidney Transplant Infectious Disease Complications Kenneth Bodziak, MD Associate Professor of Medicine Oklahoma Transplant Center Oklahoma Health Sciences Center

2. OBJECTIVES 1). Understand the timeline as to when certain infections are more likely to occur after kidney transplantation. 2). Know the rationale behind providing prophylactic antibiotics following renal transplantation. 3). Learn the pre-transplant serologic testing conducted prior to wait- listing a patient for kidney transplantation.

3. Infection in Solid-Organ Transplant Recipients:Epidemiologic Exposures • I). Donor-derived infections • II). Recipient-derived infections • III). Nosocomial infections • IV). Community infections

4. How Much Immunosuppression? Too little: Rejection Too much: Infection & Cancer Dose, Duration, Sequence of drugs

5. Watch out for that spelunking “Transmission of Rabies Virus from an Organ Donor to Four Transplant Recipients.” Arjun Srinivasan, M.D., et al. N Engl J Med 2005;352:1103-11. Background: In 2004, four recipients of kidneys, a liver, and an arterial segment from a common organ donor died of encephalitis of an unknown cause. Intracytoplasmic viral inclusions in neurons (Negri bodies). Immunohistochemical staining (red) of rabies viral antigens in CNS)

6. Organ Donor Disease Transmission • Similar stories for M&M among solid organ transplant recipients due to transmission of: • WNV – West Nile Virus • LCMV- lymphocytic choreomeningitis virus • Cruetzfeldt-Jakob disease (corneas) • Chagas disease • HIV • Stongyloides

7. Data to be collected regarding eligibility of organ donors • Medical history (e.g. hemophilia, sickle cell disease) • Previous infections • Vaccinations • Occupational exposures • Travel history • Transfusions with blood or blood products • Contact with people with HIV, HBV, HCV, or other transmissible diseases • Tattooing, ear piercing or body piercing • Use of illicit drugs • Sexual behavior (e.g. prostitution) • Incarceration • Contact with bats, stray dogs or rodents (including pets)

8. Standard Screening Tests for Prospective Donors • Human immunodeficiency virus (HIV) antibody (NAT testing, if necessary) • Hepatitis B (HBV) serologies, including HBV surface antigen, core antibody, surface antibody and Hepatitis delta antigen and/or antibody in HBsAg-positive donors • Hepatitis C (HCV) antibody • Treponemal or non-treponemal testing (Treponemapallidum hemaggutination assay (TPHA) orVDRL + Rapid plasma reagin {RPR}) • Cytomegalovirus (CMV) antibody • Epstein-Barr virus (EBV) antibody panel • Herpes simplex virus (HSV) antibody • Varicella-zoster virus (VZV) antibody • Blood and urine cultures (usually available well after the transplant) • Chest X-Ray • Toxoplasma antibody: if from endemic area

9. Possible Strategies Based on Microbiologic Donor Screening Data Serologic finding Intervention Antibody to HIV Exclude from organ donation Antibody to HCV If used, usually reserve organ for recipient with HCV infection (HCV-RNA +) or severely ill Antibody to CMV Preventive strategy based on risk to recipient Antibody to EBV PCR monitoring of the seronegative or pediatric recipient HBsAg+ or HBcAb IgM+ Exclude from organ donation or use in life-threatening situations with intensive prophylaxis HBsAb+ Safe for organ donation if documented donor vaccination; use in vaccinated recipients and with negative NAT testing if donor vaccination unknown HBcAb IgG+ High-risk for transmission if liver used for donation, but generally used with intensive prophylaxis; nonhepatic organs carry a small risk of transmission of HBV; generally used for immunized recipients RPR+ Not a contraindication to donation. Recipients should receive standard prophylaxis (ceftriaxone or benzathine PCN). Antibody to Toxoplasma Not a contraindication to donation. Prophylaxis with bactrim.

10. Recipient-Derived Infections and DetectionScreening • Epidemiology history: Travel, Occupation, Hobbies, Food/water • Vaccination history • Serologies: VDRL, HIV, CMV, EBV, HSV, VZV, HBV, and HCV • Tuberculin skin testing • Microbiologic testing of blood and urine (as needed) • Chest X-Ray • Current and past Infectious disease history (colonization) • Special testing (e.g. HCV PCR, titers for Histoplasmosis, etc.)

11. Case Presentation of Recipient-Borne Disease A 45-year-old man underwent cadaveric renal transplantation at Duke University Medical Center for chronic renal failure. Pretransplantation evaluation showed 3 to 5 eosinophils/100 leukocytes, but the cause was not investigated. Posttransplantation recovery was uneventful except for a mild episode of transplant rejection, which was treated with high-dose prednisone, azathioprine, and local irradiation. He was discharged 1 month after transplant on 60 mg of prednisone and 50 mg of azathioprine daily. Three days after discharge he returned complaining of headache and fever. Lumbar puncture showed 1500 leukocytes/mm% 98% of which were neutrophils. Subsequent cultures of the cerebrospinal fluid were positive for enterococcus. He initially did well on ampicillin therapy; however, on the fourth day of hospitalization he became increasingly dyspneic and cyanotic. At physical examination, diffuse rales were heard. Arterial blood gas values on room air were arterial oxygen tension, 28 mm Hg; arterial carbon dioxide tension, 29 mm Hg; and pH, 7.50. Chest radiograph showed bilateral alveolar infiltrates. The patient was intubated and mechanical ventilation started. Transtracheal aspirate of sputum revealed larval forms of S. stercoralis. In addition, larval forms were recovered from his stool. He was begun on thiabendazole therapy, but developed gross hemoptysis, gastrointestinal bleeding, hypotension, and renal failure. He died on the 12th hospital day. At autopsy, the patient's lungs were grossly congested and edematous. The stomach, duodenum, and small intestine were dilated and filled with sanguineous fluid. Microscopically the lungs contained many larval forms of 5. stercoralis, both in the vascular space and in the alveoli . There was marked pulmonary congestion and edema with multiple areas of bronchopneumonia. The duodenum was invaded by larval and adult forms, as well as eggs, of 5. stercoralis. Scoggins CH and Call NB. Ann Int Med 1977;8:456-458.

12. Disseminated strongyloidiasis in an immunocompromised patient Chest X-Ray showing a diffuse bilateral infiltrate. Gram stain of sputum showing filariform larvae of S. stercoralis

13. Nosocomial Infections • MRSA • VRE • Fluconazole-resistant candida species • Clostridium difficile • Antimicrobial-resistant gram-negative bacteria • Aspergillus

14. Community Infections • Soil pathogens, e.g. aspergillus or nocardia species • Air-borne pathogens, e.g. C. neoformans from pigeons or respiratory pathogens. • Salmonella from reptiles or uncooked eggs. • Water-borne pathogens

15. Prevention of Infection • Vaccination: MMR, DPT, HBV, Poliomyelitis, Varicella, Influenza, Pneumococcal pneumonia • Universal Prophylaxis: Peri-operative antibiotics; Antifungal in case of pancreas transplant; TMP-SMX for prophylaxis against pneumocystis pneumonia, Toxoplasma gondii, Iospora belli, Cyclospora cayetanensis, Nocardia and Listeria sps, common urinary, respiratory and GI pathogens. • Preemptive Therapy: Monitor patients at predefined intervals in order to detect infection before patient becomes symptomatic. (CMV)

16. Timeline for Infection after Solid Organ Transplant Fishman JA. NEJM 357 (25); 2601-2614, 2007

17. CMV Disease in Renal Transplant Recipients (a) • Seroprevalence ranging from 30 to 97% in the general population. • CMV establishes life-long latency following primary infection. • CMV post-transplant infection: evidence of CMV replication regardless of symptoms. • CMV post-transplant disease: evidence of CMV infection with attributable symptoms. Can be further characterized as either a viral syndrome with fever and/or malaise, leukopenia, thrombocytopenia or as tissue invasive disease (e.g. pneumonitis, hepatitis, retinitis, colitis).

18. CMV Disease in Renal Transplant Recipients (b) • CMV has a predilection to invade the graft. • CMV has an immunomodulatory effect, setting up secondary infections with fungus, EBV, and bacteria. • CMV has been implicated in causing acute and chronic allograft injury. • Highest risk of disease are in D+/R- pairings; use of antilymphocyte antibody preparations. • Prophylaxis with valganciclovir for 3-6 months recommended. • May pre-emptively treat by only giving valganciclovir if viral replication appreciated (+ CMV PCR). • Look out for CMV ganciclovir resistance (~2% with VGCV).

19. Direct and Indirect Effects of CMV Infection Kotton CN and Fishman JA. J Am Soc Nephrol 16: 1758-1774, 2005

20. EBV Disease Post-Renal Transplant and PTLD Report of the Collaborative Transplant Study, 1997-2005. Opelz G, Volker D, Cord N, and Bernd D. Transplantation 2009;88:962-967.

21. EBV Disease Post-Renal Transplant and PTLD Report of the Collaborative Transplant Study, 1997-2005. Opelz G, Volker D, Cord N, and Bernd D. Transplantation 2009;88:962-967.

22. EBV Disease Post-Renal Transplant and PTLD Report of the Collaborative Transplant Study, 1997-2005. Opelz G, Volker D, Cord N, and Bernd D. Transplantation 2009;88: 962-967.

23. EBV Disease Post-Renal Transplant and PTLD Report of the Collaborative Transplant Study, 1997-2005. Opelz G, Volker D, Cord N, and Bernd D. Transplantation 2009;88: 962-967.

24. BK Nephropathy Risk FactorsNon-Risk Factors * rabbit-ATG * mTOR inhibitor * Tacrolimus * Female gender * Mycophenolate * Live donor * African-American recipient * Hispanic recipient * More recent transplant year * Large volume center * Acute rejection in first 6 mos. • - BK virus, a polyomavirus, establish latency in renal epithelium and other tissues. • Up to 85% adults express serologic evidence of prior exposure to the virus. • Renal dysfunction may occur from necrosis of tubular epithelial cells and eventual interstitial fibrosis with tubular atrophy in the immunocompromised host.

25. BK Nephropathy Intranuclear inclusions are present within tubular epithelial cells. SV40 immunoperoxidase stain highlights intranuclear Polyomavirus inclusions.

26. Diagnosis and Treatment of BK Nephropathy • Screen blood for BK PCR • Allograft biopsy required to make accurate diagnosis • Treat by lowering CNI and/or antimetabolite (e.g. Mycophenolate) • Consider substituting Mycophenolate with Leflunomide (no benefit per meta- analysis) • Cidofovir treatment (no benefit per meta-analysis) or Ciprofloxacin treatment • Safe in retranslating recipients who lost prior allograft to BK

27. QUESTIONS