9/29/2016 General Pearls • Immunocompromised patients with Management of post transplant infections – are often sicker than they look infections – often have more extensive disease than is What’s new in 2016 apparent – may require longer treatment than others Peter V. Chin-Hong, MD MAS – may have unusual infections Twitter: PCH_SF – often require invasive procedures September 29, 2016 – may need to have immunosuppression reduced Case Case • 71 y.o. female who • Donor has sputum has severe acute on +gram-negative chronic hypoxic rods respiratory failure due to interstitial Question: Treat lung disease, now recipient? s/p bilateral lung A. Yes transplant B. No 1
9/29/2016 Multidrug-resistant bacterial Case donor-derived infections in SOT • POD#8 – purulent pleural • Between 2009-2015, & pericardial drainage 17/33 (52%) recipients • Multi-drug resistant infected with MDR Acinetobacter infection gram-negative (CRAB) organisms • Taken to the OR for wash • 41% died; 59% died or out • EMCO POD#9 for suffered allograft loss • Most cases worsening hypoxemia • POD#30 – increasing unexpected oxygen requirements. Lewis, J.D. & Sifri, C.D. Curr Infect Dis Rep (2016) 18: 18. Comfort care “Poop pills” • Open-label feasibility World leaders agree at study UN on steps to curb • 20 patients rising drug resistance • Failed vancomycin taper New York Times 9/21/16 for C. difficile infection • 30 frozen FMT capsules on The world’s leaders are 2 consecutive days finally holding a summit • Diarrhea resolved in on superbugs 14/20 and retreatment of Washington Post 4/6 nonresponders 9/20/16 Youngster I et al, 2014, JAMA 312(17) 2
9/29/2016 Infection-related mortality in transplant recipients Cliff vs Angus 1980-1985 1985-1987 1987-1990 Dummer JS, In Kaye MP et al eds, Heart and Lung transplantation 2000 Indication for hospitalization post- transplantation 90 % of SOT recipients hospitalized for 80 70 infection vs. rejection 60 50 40 infection 30 rejection 20 10 0 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Years Dharnidharka VR. AJT. 04 Grulich AE et al, 2007,Lancet 370:59-67 3
9/29/2016 Determinants of Infection Infection Timetable Treatment for rejection • Technical aspects of surgery NOSOCOMIAL, OPPORTUNISTIC COMMUNITY ACQUIRED 9 TECHNICAL (Donor, recipient, exposure) 8 – Liver, lung > heart > kidney Degree of immunosuppresion 7 CMV Valganciclovir • Environmental exposure 6 SSI Nocardia Aspergillus – TB, endemic mycoses, Strongyloides Voriconazole 5 Listeria TMP-SMX VAP Toxo – Gardening: Aspergillus, Nocardia Pneumococcal 4 PCP PNA TMP-SMX – Food and water: Salmonella, Listeria 3 C. diff Crypto Voriconazole Endemic 2 Voriconazole BK virus Respira t ory Biliary mycoses • Degree of immunosuppression HSV viruses 1 leak – Medications , host factors, VZV Valganciclovir Tuberculosis 0 CRBSI EBV immunomodulating infections (CMV) 1 2 3 4 5 6 7 8 9 10 11 12 Months post-transplant • Type of immunosuppression Relationship of OR time to incidence of Case infections • 36 year old female s/p cadaveric renal transplant (chronic GN) 2 years prior to admission presents with SOB X 3 weeks and fevers to 39.8 C. • Meds: Mycophenolate Kusne et al, 1988, Medicine; 67:132 4
9/29/2016 Pulmonary infections Approach 1. When is the patient presenting in relation to the transplant? 2. What is the degree of immunosuppression? 3. What is the nature of the pulmonary infiltrates? 4. What is the tempo of the pulmonary symptoms? 5. What is the Aa gradient? 5
9/29/2016 CMV CMV Spectrum • Single most important pathogen in transplant CMV Ag/ Clinical recipients PCR CMV infection Asymptomatic + • >50% SOT patients affected by CMV Fever, myelosuppression CMV “syndrome” + • Indirect effects: GNR/fungal infections, organ Pneumonia, GI, hepatitis, CMV tissue invasive/ + injury/rejection CNS, retinitis, nephritis, etc. end-organ disease Pneumonia, GI, retinitis, “Compartmentalized” - • Risk factors: D+/R-, OKT3 rx, HHV-6 infection, CNS CMV disease cadaveric, lung/heart transplant >> kidney Ljungman. CID. 2002 CMV CMV Treatment Method Principle Clinical use Comments Isolate virus Dx CMV disease ↑Sensi�vity Viral culture • GCV induction 5mg/kg BID x 14-21 days plus ↓Specificity IVIG 500mg/kg QOD x 14-21 days Detect Pre-transplant CMV risk Serology antibody assessment assessment • But poor evidence: • Survival: 15% historical vs. 52% GCV + IVIG Antigenemia Detect pp65 Rapid dx, limited if ↓Sensitive vs. PCR antigen in ↓PMNs, Guide ↑ Specificity vs. Cx • CMV-specific IVIG does not improve outcome PMNs preemptive Rx, Guide duration of Rx • Prevention: V-ACV, GCV po, V-GCV Detect DNA Rapid dx, Guide ↑ Sensitivity vs. Ag PCR preemptive Rx, Guide ↓Specificity at low • Future: Monitor T-cell mediated response to CMV duration of Rx copy numbers Identify Dx end-organ disease Sensitive and Histology infection viropathic specific changes 6
9/29/2016 CMV Zika Prophylaxis Total 3315 USA acquired 43 (all FL) 9/21/16 Humar A et al, 2010, Am J Transplant. 2010 May;10(5):1228-37 Zika Zika Guidance for OPOs Transmission Regulatory body Medical & Social Exclude as donor if: Test History • Mosquitoes Human cells and FDA Screen for Zika -Zika diagnosed in past 6 tissues months (live and deceased) • Sex -Residence in, or travel to Zika area in past 6 months (live) • Sweat or tears? -Sex with male with above risk factors (live) Organs Organ Procurement Screen for Zika: “focus -Travel to Zika-endemic Zika, Dengue, and area in past 28 days and Chikungunya and Transplantation on recent travel recipient pregnant or of Network (OPTN) history, epidemiologic child-bearing age <4 days symptoms: RT risk factors, -Donor with active Zika PCR …symptoms” of donor (live) 4-7 days: IgM Ab and …”Do not believe convalescent concern for Zika >7 days: IgM Ab should…exclude donors” Swaminathan S et al, 2016, NEJM 9/28/16 7
9/29/2016 Zika Zika What MIA is doing (LAORA and transplant centers) What MIA is doing (LAORA and transplant centers) • No screening recipients • No screening living donors “Still no clear answer as to what to do with • For all deceased donors positives. We are evaluating on each positive (8/1/16): (not many so far) based on risk:benefit on a case – OPTN Policy 2.9 by case basis. I wish I had more answers .” – Urine and plasma PCR – Plasma Zika IgM & IgG – Not sure what to do with Transplant ID specialist University of Miami positives Zika Zika 2.6 billion at risk 2.6 billion at risk Global distribution of A. aegypti mosquitos Global distribution of A. albopictus mosquitoes Kraemer M et al, Oxford Kraemer M et al, Oxford K 8
9/29/2016 Polyomaviruses BK and JC •Usually activated post- transplant •JC Virus – PML Who is this handsome guy? – Presentation: Progressive A. Julio Iglesias motor, sensory and cognitive deficits B. Johnny Cash (circa 1972) – Rx: None C. Peter Stock •BK Virus – Tubointerstitial nephritis – Risk factor: Immunosuppression (esp. tacrolimus and mycophenolate) – Rx: Reduce immunosuppression Obama lifts ban on HIV organ transplants Who is this handsome guy? SF Gate A. Julio Iglesias 11/21/13 B. Johnny Cash (circa 1972) C. Peter Stock HIV-positive organ donation: HOPE Act signed into law Slate 11/22/13 9
9/29/2016 Case • 42 year old male from Guam with ESRD secondary to glomerulonephritis, s/p living unrelated kidney transplant 4 months PTA (UCSF) presented with fevers to 39 and chills and soaking night sweats for 2 months • One month ago he was discharged from UCLA after a “negative” fever workup • HD#3: CXR: ill-defined nodular opacity seen on CXR • HD#6: CT chest Case What is the most likely scenario? A. Tuberculosis B. Organ Rejection C. Invasive Aspergillosis D. All of the Above 10
9/29/2016 Case What is the most likely scenario? A. Tuberculosis B. Organ Rejection C. Invasive Aspergillosis D. All of the Above Fungus Organ Transplanted Incidence (%) Liver 7-42 Pancreas 18-38 Heart-Lung/Lung 15-36 Heart 5-32 Kidney 1-14 Singh, CID 2000:31 Paya, CID 1993:16 11
9/29/2016 Fungus Fungus Mortality Trends Risk group Fatality rate (%) Aspergillosis 45-54 Non-Aspergillus hyalohyphomycetes 80 • 53 consecutive heart and liver transplant recipients with invasive mold infections in 11 centers 1998-2002 (Scedosporium spp, Fusarium spp) • Spectrum of fungus is changing dramatically: Zygomycosis 100 – ↓ Aspergillus infections 70% (Rhizopus, Mucor) • prior studies in 1990s: 98% – ↑ Non-Aspergillus mold infections 30% Phaeohyphomycosis 20 • Scedosporium, Fusarium, Zycomycetes, Phaeohypomycetes • prior studies in 1990s: 2% Candida 29 Hussain et al, CID 2003:37 Pappas, ICAAC 2003 Singh et al, Transplantation 2002:73 Broad and hyposeptate, with wide angle branching 12
9/29/2016 Voriconazole available Phaeohyphomycosis Kontoyiannis et al, JID, 2005 Fungus Diagnosis • Patient characteristics • Radiology • Microbiology • Non-culture tests – Galactomannan (Antigen) assay – PCR • Pathology: the best way to demonstrate invasive disease “Halo sign” 13
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