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Approach to Infection in the Organ Transplant Recipient. Ajit P. Limaye, M.D. University of Washington Seattle, WA. General Concepts. Infection risk assessment PRE -transplant PPD, h/o TB exposure Travel/residence history (endemic mycoses, Strongyloides, T. cruzi) Baseline serologies
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Approach to Infection in the Organ Transplant Recipient Ajit P. Limaye, M.D. University of Washington Seattle, WA
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)
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.)
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
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)
Evaluation of the Patient (cont.) • Early and aggressive diagnostic investigation • - adequate tissue • - routine “staging” • Appropriate notification and coordination with pathology and microbiology laboratories
“Timetable” of Infections After Organ Transplantation • General guidelines, NOT absolute • Epidemiology altered by prophylaxis • Unusual timing may be a clue to unusual exposure
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)
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)
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
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
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
cont. Fever & abdominal pain in a kidney transplant recipient • Differential diagnosis? • What diagnostic testing (labs & other studies) would you order? • Treatment? Complications of treatment?
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
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)
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
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)
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)
What’s New About CMV? • · Changing epidemiology/late disease • · Ganciclovir resistance • Individualizing/tailoring therapy • · Valganciclovir
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
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
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
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
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?
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
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
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?
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)
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
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
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
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
Aspergillosis After Organ Transplantation Prophylaxis • Preemptive therapy for documented Aspergillus colonization • Targeted prophylaxis • History of disease or colonization
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)
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)
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
Histoplasma capsulatum Endemic Areas, U.S. Seattle, WA Vaughn, MT
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)
Olympia, WA Vaughn, MT Eugene, OR Seattle, WA Portland, OR Kansas City, KS
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
Washington Post July 2, 2004 The Boston HeraldMay 23, 2005 Transplant shock as 3 die from hamster virus; Victims include 2 from Bay State
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