1. Infection in Solid-Organ Transplant Recipients Jay A. Fishman NEJM 2007;357:2601-14

3. General concepts  Infection in transplant recipients – difficult to recognize  Sign & symptoms are often diminished  Noninfectious cause of fever (allograft rejection)  Antimicrobial therapy  Toxic effects  Interactions with immunosuppressive agents  Broad spectrum of pathogens  Early and specific microbiologic diagnosis  Essential for guiding treatment and minimizing nonessential drug therapy

4. Risk of Infection

5. Modifications in immunosuppression  changes in risk of infection after transplantation

6. Epidemiologic exposures  Donor-derived infections and screening  Via transplanted organs  CMV, TB, Trypanosoma cruzi – latent in tissues  Active donor infection – viremia, bacteremia  Nosocomial organisms resistant to routine surgical antimicrobial prophylaxis (VRE, azol-resistant candida spp.)

7.  Pneumonia from donor- derived HSV infection  Fever & pneumonia (D3)  Abnormal LFT  Blood & sputum – HSV  Donor serum – HSV PCR (+)  Other recipients (heart, liver, other kidney) – HSV (+)  Antiviral therapy

8.  Screening of transplant donor – limited by  Available technology  Short period during which organs from deceased donors can be used  Routine evaluation  Ab detection for common infections  Seroconversion  Unidentified pathogens  Improved donor screening  More sensitive and rapid assays by organ procurement organizations

9.  Transplantation of organs from deceased donors with fever or viral syndrome – controversial  Need for improved microbiologic screening tools

10.  Recipients-derived infections and detection  Active infection should be eradicated before transplantation  Common recipient-derived pathogens  TB  certain parasites (Strongyloides stercoralis & T. cruzi)  Viruses (CMV, EBV, HSV, VZV, HBV, HCV & HIV)  Endemic fungi (Histoplasma capsulatum, Coccidoides immitis, & Paracoccidioides brasiliensis)

12.  Nosocomial infections and antimicrobial resistance  Colonization with nosocomial, antimicrobial-resistant organisms  After transplantation, pneumonia and, infection of hematomas, ascitic fluid, wounds, and catheters  Community infections  Relatively benign in normal host  major infection  Common microorganisms: pathogens in soil (aspergillus, nocardia spp.), C. neoformans in birds, respiratory viruses with subsequent bacterial/fungal superinfection

13. Net state of immunosuppression and monitoring of immune function The factors contributing to the degree of immunologic impairment and standard assays that assess the patient’s risk of infection will be supplemented in the future by new quantitative measures of allograft- and pathogen-specific immune function and the risk of infection Dose, duration, and sequence of immunosuppressive therapy

14. Multiple simultaneous quantitative (multiplex) assays

15. Genomic arrays measuring the up- regulation or down-regulation of host genes during infection Lytic and latent epitopes – viral Ags presented in either the lytic or latent phase of EBV

16. Prevention of Infection

17.  Antimicrobial prophylaxis  altered incidence & severity of post-transplantation infections  3 general preventive strategies  Vaccination  Universal prophylaxis  Preemptive therapy  Vaccination  Before transplantation – need for immunization against measles, mumps, rubella, diphtheria, pertussis, tetanus, HBV infection, poliomyelitis, varicella, influenza, and pneumococcal pneumonia?  Less effective during immunosuppression  Live vaccines – generally contraindicated after transplantation

18.  Lifestyle changes after transplantation  To limit exposures to some potential pathogens  Hand washing after food preparation, gardening, & contact with feces or secretions  Avoiding close contact with people with respiratory illness, and environments such as construction sites  Avoidance of well & lake water, undercooked meats, unwashed fruits & vegetables, and unpasteurized diary products  Routine surgical prophylaxis  Organ transplanted & local epidemiologic factors  Known colonization patterns with pseudomonas, MRSA, VRE or fungi

19.  Antifungal prophylaxis  Risk and epidemiologic factors  Most invasive fungal infections  Non-albicans candida and aspergillus spp.  Greatest risks associated with early fungal infections  Aspergillus at the tracheal anastomosis after lung transplantation  Candida spp. after pancreas or liver transplantation  IFI – most common in liver recipients requiring admission to ICU, surgical re-exploration or retransplantation, or transfusion of large amounts of blood products and in liver recipients with metabolic dysfunctions, respiratory failure, CMV infection, or HCV infection  After broad-spectrum antimicrobial therapy

20.  TMP-SMZ prophylaxis for ≥3mo  PCP, Toxoplasma gondii, Isospora belli, Cyclospora cayetanensis, nocardia & listeria spp., common urinary, respiratory, & GI pathogens  Alternative agents for PCP  Dapsone, atovarquone, & pentamidine  Prevention of post-transplant CMV and other herpesvirus  Oral antiviral agents  Universal prophylaxis vs. preemptive therapy

21. Changing the Pattern of Infection

22.  Corticosteroid-sparing regimens & PCP prophylaxis  less common pneumocystis pneumonia  Antiviral prophylaxis  uncommon herpesvirus infection  Changes in typical immunosuppression  new patterns of infection  Sirolimus-based regimens – idiosyncratic noninfectious pneumonitis  T-lymphocyte-depleting Ab – viral activation  Cellular depletion after induction therapy beyond the period of antimicrobial prophylaxis  Late infections with viruses (CMV, JC polyomavirus,..), fungus and malignant conditions

23. Viral pathogens and allograft rejection Opportunistic infections are generally absent Chronic viral infections  allograft injury CT showing a liver abscess at the site of an ischemic graft injury

24. CMV EBV Polyomavirus CNS pneumonitis Common Infections in Transplantation

25. CMV infection

26.  Epidemiology  Primary infection, reactivation or viral superinfection  Serologic assays  Useful in determining patient’s risk of infection  Little useful in diagnosis of acute infections  Prevention  Universal prophylaxis and preemptive therapy  Special consideration  Induction therapy with depleting antilymphocyte Ab  Heart and lung transplant – longer prophylaxis  Ganciclovir resistance – uncommon  UL97 gene or UL54 gene

27.  Diagnosis and therapy  Diagnosis  Qauntitative diagnostic assays  PCR, Ag detection (pp65 antigenemia)  Biopsy  Treatment  Oral valganciclovir  IV ganciclovir – preferred for the initiation of therapy for GI disease

28. EBV and PTLD  PTLD  3-10% of adult SOT recipient  Mortality of 40-60%  More than half of post-transplantation malignant conditions in pediatric SOT recipients  Risk factors  Primary EBV infection after transplantation  Allograft rejection  Exposure to antilymphocyte antiserum  CMV coinfection  CD20+ & B cell origin PTLD in the 1 st yr – related to EBV  Later disease – EBV (-), T ell, NK cell or null cell, poor Px

30.  Diagnosis  Quantitative EBV viral-loading testing, flow cytometry, analysis of immunogolbulin gene rearrangements and histologic analysis with staining for EBV-derived RNA  Treatment  Reduction of immunosuppression  regression of polyclonal form PTLD  CTx, irradiation, anti-CD20 Ab  Adoptive immunotherapy – under investigation

31. Polyomavirus BK and JC  BK virus  nephropathy & ureteral obstruction  JC virus  Progressove multifocal leukoencephalopathy (PML)  Diagnosis  Detection of BK virus nucleic acid in blood & urine in BK nephropathy  Treatment  No effective antiviral therapy  Reduction in immunosuppression  Experimental therapy: cidofovir, leflunomide, IVIG

32. CNS infection  Broad spectrum of causative organisms  Listeria, HSV, JC virus, & C. neoformans  DDx – noninfectious causes  Toxic effect of calcineurin inhibitors  Lymphoma

33. Pneumonitis and pneumocystis infection  PCP  Marked hypoxemia, dyspnea, and cough in spite ofa paucity of P/Ex or radiologic findings  Noninfectious causes of pneumonitis  Toxic effects of sirolimus