Approach to Infection in the Organ Transplant Recipient

1. Approach to Infection in the Organ Transplant Recipient Ajit P. Limaye, M.D. University of Washington Seattle, WA

2. General Concepts Infection risk assessment PRE-transplant • PPD, h/o TB exposure • Travel/residence history (endemic mycoses, Strongyloides, T. cruzi) • Baseline serologies • Vaccination review • Infection history (recurrent Staph, etc)

3. General Concepts (cont.) • Signs and symptoms of infection are muted by immunosuppression • Specific, predictable risk periods for specific pathogens (unusual timing may be a clue to exposure) • Link between immunosuppression and infection risk • Consider the possibility of donor-derived infection (viral, fungal, bacterial, mycobacterial, etc.)

4. Prophylaxis CMV: 3 months of antiviral (valganciclovir [valcyte], valacyclovir [valtrex]) for D+R- and R+ PCP: 6-12 mo TMP/SMX (or dapsone, pentamidine) UTI: 1-3 mo TMP/SMX (or quinolone) for K txp Candida: all KP, selected liver transplant recipients 1-3 mo fluconazole

5. Evaluation of the Patient Baseline patient data critical for appropriate work-up • Donor/recipient serologies (CMV, EBV, HSV, VZV, Toxoplasma) • Underlying disease • Time post-transplant • Allograft function • Prophylactic medications • Rejection (and its treatment)

6. Evaluation of the Patient (cont.) • Early and aggressive diagnostic investigation • - adequate tissue • - routine “staging” • Appropriate notification and coordination with pathology and microbiology laboratories

7. “Timetable” of Infections After Organ Transplantation • General guidelines, NOT absolute • Epidemiology altered by prophylaxis • Unusual timing may be a clue to unusual exposure

8. Early Period (first post-transplant month) • Nosocomial/”surgical” infections • Multi-drug resistant organisms (e.g., GNR, MRSA, VRE) • Importance of adjunctive therapy (anatomical problems, adequate drainage) • Opportunistic infections are uncommon (except Aspergillus, Candida, HSV— in absence of prophylaxis)

9. Middle Period(from post-transplant months 2-6) • Greatest risk period for “classic” opportunists (e.g., PCP, Aspergillus, Toxoplasma, Cryptococcus, etc.) • Immunomodulating viruses (e.g., CMV, EBV, HHV-6)

10. Late Period (after the 6th post-transplant month) • “Typical” community-acquired infections in patients with good allograft function • Continued risk of opportunistic infections in patients with poor allograft infection and/or chronic rejection

11. Selected References 1. AST Guidelines for the Prevention & Treatment of Infections in Solid Organ Transplant Recipients. Am J Transplant 2009 (supplement 4) 3. Fishman JA. Infection in organ transplant recipients. N Engl J Med 2007;357(25):2601-14

12. Case: fever & abdominal pain in a kidney transplant recipient A 54 yo woman 3 mo s/p kidney transplant presents with 10 days of fatigue, weakness, vague abdominal symptoms. Serologies: CMV D+R-, EBV+, VZV+, HSV1+/2- Meds: tacrolimus, MMF, pred, Bactrim, Amlodipine. PE: T 38.2, tired-appearing, non-focal except mild abdominal tenderness

13. cont. Fever & abdominal pain in a kidney transplant recipient • Differential diagnosis? • What diagnostic testing (labs & other studies) would you order? • Treatment? Complications of treatment?

14. CMV After Organ TransplantationEpidemiology • Typically occurred 1-3 months post-transplant (in the absence of prophylaxis) • Later disease in the era of routine antiviral prophylaxis (4-12 months) • May result from primary infection, reactivation, or super-infection • Most important risk factors for infection and disease are: donor/recipient serostatus, organ transplanted, and immunosuppression

15. CMV After Organ TransplantationClinical Aspects • Manifestations • “CMV syndrome” (~60%) vs Tissue-invasive CMV (~40%) • CMV syndrome: systemic febrile illness without specific localizing symptoms • Tissue invasion/focal organ involvement (pneumonitis, enteritis, hepatitis, nephritis, retinitis) • Associated with increased risk for other opportunistic infections (fungal infections, PTLD) • “Bi-directional” association with allograft rejection • Independently associated with increased risk of death (mediated through indirect effects)

16. CMV After Organ Transplantation Diagnosis • CMV disease = CMV infection AND compatible symptoms or histopathology) • Ubiquitous virus (distinguishing CMV “excretion” from CMV disease is critical) • Most useful screening tests for diagnosing CMV infection are: • 1. buffy coat CMV pp65 antigen • 2. blood/plasma PCR • 3. buffy coat viral culture • Demonstration of CMV by histopathology and/or culture from affected site is the “gold standard” for diagnosis

17. CMV After Organ TransplantationTreatment • Typical duration of therapy = 3-4 weeks, guided by blood CMV levels (? longer for GI disease) • IV Ganciclovir is standard therapy • Oral valganciclovir for SELECTED cases • Foscarnet for ganciclovir-resistant CMV disease • ? CMV-IG or IVIG (often used in combination with antivirals for CMV pneumonitis)

18. CMV After Organ TransplantationPrevention • Major strategies • Prophylaxis • Preemptive therapy • Agents • High dose acyclovir (800 mg QID) • Valacyclovir (2 g QID) • Oral ganciclovir (1g TID) • Valganciclovir (900 mg BID)

19. What’s New About CMV? • · Changing epidemiology/late disease • · Ganciclovir resistance • Individualizing/tailoring therapy • · Valganciclovir

20. What’s New About CMV?Changing Epidemiology • Emergence of “late” CMV infection & disease • Median onset of CMV disease is now ~4-5 months post-transplant (compared to ~1.5 months post- transplant in the past) • result of effective prophylaxis • D+R- and patients treated for rejection are at greatest risk • implications: education/coordination with referring providers re: diagnosis/testing/treatment

21. What’s New About CMV?Ganciclovir Resistance • Newly recognized problem • Occurs late, KP and lung recipients at highest risk • Almost exclusively in D+R- patients • Diagnostic tests are limited (must suspect on the basis of slow clinical and/or virologic response) • Treatment includes: foscarnet + ganciclovir, decrease immunosuppression, ?CMVIG • ?Reduced incidence with valganciclovir

22. What’s New About CMV?Individualizing Therapy • Change from previous “one size fits all” approach (i.e., 2-3 weeks of IV ganciclovir) • Identification of risk factors for relapse after therapy [Sia et al J Infect Dis 2000, Humar et al J Infect Dis 2002] • High viral load • Kinetics of viral load reduction (time to viral clearance) • Persistent viral load at end of therapy

23. What’s New About CMV?Individualizing Therapy Implications for managing CMV disease • obtain baseline (pre-treatment) viral load • monitor viral load on therapy (Q week) • treat until viral load has cleared • minimum of 14-21 days • may require prolonged duration in some patients

24. What’s New About CMV?Valganciclovir • FDA-approved for treatment of CMV retinitis in HIV-infected patients • Better bioavailability than oral ganciclovir • Theoretically better compliance? (QD vs tid, fewer pills) • Price is ~same as oral ganciclovir • Toxicity (similar to oral gcv, higher rate leukopenia) • What is the “correct” dose? • trials used 900 mg po QD • many centers anecdotally using 450 mg po QD • Possibly lower risk of resistance?

26. Case: skin lesion in an OLT recipient It’s Friday 4:00 pm before a long weekend. A 54 yo man who is 2 mo s/p OLT is found to have a small non-painful skin ulcer on his leg during a routine post-txp f/u visit. No trauma to site. He was recently discharged after long hospital stay, and wants to go back to her home in Eastern Washington. Post-op course: delayed graft function, hemodialysis-dependent, rejection treated with steroid pulse and ATG Serologies: CMV D+R-, EBV+, HSV-, VZV+ Meds: pred, tacrolimus, MMF, valcyte PE: T-38.4, chronically-ill appearing, skin lesion as shown

27. Case: Skin lesion in a liver transplant recipient It’s Friday 4:00 pm before a long weekend. A 54 yo man who is 2 mo s/p OLT is found to have a small non-painful skin ulcer on his leg during a routine post-txp f/u visit. No trauma to site. He was recently discharged after long hospital stay, and wants to go back to her home in Eastern Washington. Post-op course: delayed graft function, hemodialysis-dependent, rejection treated with steroid pulse and ATG Serologies: CMV D+R-, EBV+, HSV-, VZV+ Meds: pred, tacrolimus, MMF, valcyte PE: T-38.4, chronically-ill appearing, skin lesion as shown

29. What is the differential diagnosis? What should be the pace of the work-up (in- versus out-patient, etc.)? What diagnostic w/u should be done?

34. Aspergillosis After Organ Transplantation Epidemiology • Overall incidence is low (1-5%) and varies significantly according to organ transplanted and center • Lungs~ heart/lungs > livers > kidney/pancreas > heart > kidney • Sporadic cases and outbreaks have been described (especially in association with hospital construction or renovation)

35. Aspergillosis After Organ Transplantation Epidemiology • Corticosteroids, antilymphocyte antibodies, allograft dysfunction, neutropenia, renal failure, smoking (especially marijuana), CMV infection, intra-op and post-op variables are risk factors • Specific risk factors vary according to organ transplanted • Peak onset is within the first several months post-transplant

36. Aspergillosis After Organ Transplantation Clinical Aspects • Pulmonary disease is most common (cough, fever and pulmonary infiltrate) • No specific clinical or laboratory findings • Evaluation for dissemination is mandatory • 10-20%% mortality

37. Aspergillosis After Organ Transplantation Diagnosis • Diagnosis is complicated by “ubiquity” of the organism in the environment and by occasional “colonization” or contamination of cultures • NEVER ignore Aspergillus in a transplant patient (requires thorough evaluation for invasive disease) • Biopsy of affected site for histopathology and culture is “gold standard” • Serum/BAL/CSF galactomannan, PCR • Evaluation for dissemination is mandatory for all patients

38. Aspergillosis After Organ Transplantation Treatment • Voriconazole (Vfend) now considered treatment of choice • Major drug interactions • Hepatotoxicity, visual symptoms • Combination therapy • Vori + Caspo • Ampho + Caspo • Modulation of immunosuppression, especially corticosteroid dose • ? surgical excision for localized disease

39. Aspergillosis After Organ Transplantation Prophylaxis • Preemptive therapy for documented Aspergillus colonization • Targeted prophylaxis • History of disease or colonization

40. What’s new about Aspergillosis? • Antifungal agents • Extended spectrum azoles [voriconazole, posaconazole] • Combination therapy (echinocandin + either polyene OR azole) • · Newer diagnostic tools (Galactomannan, B-1,3-D-Glucan, PCR)

42. A 31 yo man from Montana receives a cadaveric kidney transplant. Post-transplant course uneventful, good allograft function. Immunosuppression: tacrolimus, steroids, MMF. 8 months post-transplant • admitted for evaluation of fevers, weight loss, and pan-cytopenia • blood cultures positive for Histoplasma capsulatum (disseminated disease) • treatment with amphotericin (good clinical response)

43. The next appropriate step after clinical management of the patient is: • No further steps are necessary • Surveillance renal allograft biopsy • Increase maintenance immunosuppression • Celebrate the fact that Histoplasmosis was diagnosed and appropriately treated • Evaluate for donor-transmitted infection

44. Histoplasma capsulatum Endemic Areas, U.S. Seattle, WA Vaughn, MT

45. Next Steps in the Investigation Contact the organ procurement organization (OPO) • Report suspicion of donor transmission • Additional donor information • donor clinical history • clinical findings • autopsy results • Status of other recipient(s)

46. Olympia, WA Vaughn, MT Eugene, OR Seattle, WA Portland, OR Kansas City, KS

47. Limaye et al N Engl J Med 2000

48. Difficulties in recognizing organ-transmitted infections • Prolonged period between transplant and infection • Naturally-occurring community-acquired infections • distinguishing community-acquired from organ-transmitted • Distribution of organs across broad geographic regions • better organ preservation techniques • new rules for organ allocation

49. Washington Post July 2, 2004 The Boston HeraldMay 23, 2005 Transplant shock as 3 die from hamster virus; Victims include 2 from Bay State

50. 40 persons received organs or other tissues from HCV seronegative donor (HCV PCR+) • Index case occurred 1.5 yr AFTER donor death--reported by primary provider • Recipients located in 16 states and 3 countries • 8 of 30 (27%) recipients developed hepatitis C infection • 3 of 8 recipients diagnosed with acute Hep C (before the index case) NOT recognized as transplant-transmitted