TRANSPLANT ID: A PRACTICAL APPROACH

1. TRANSPLANT ID: A PRACTICAL APPROACH Atul Humar Transplant Infectious Diseases University of Alberta

2. WHATS NEW? • Changing immunosuppression • Widespread prophylaxis • Emerging infections • Evolving infections • Donor Derived infection • Molecular diagnostics • Host-pathogen interactions

3. INFECTION: BASIC PRINCIPLES • Inflammatory response attenuated by immunosup. • may abolish typical signs/symptoms • decreased sensitivity of serological, radiological tests • Efffects of established infection may be devastating • Treatment may have more toxicities • Rifampin - decrease CNI • Erythromycin, azoles increase CNI • Synergistic nephrotoxicity - aminoglycosides, AmB, high dose septra,

4. INFECTION: BASIC PRINCIPLES • Determinants of infection • Technical issues with transplantation • Vascular anastomoses – leak, thrrombosis, stricture • Non-vascular anastomoses- leak, stricture • Net state of immunosuppression • Epidemiologic exposures

9. Major determinants of the risk of infection INFECTIONS IN TRANSPLANTATION The net state of Immunosuppression Epidemiological exposures

10. NET STATE OF IMMUNOSUPPRESSION • Immunosuppressive therapy: dose, duration, temporal sequence - ‘area under the curve’ • Induction therapy – especially ALG, Alemtuzimab • Mucocutaneous barrier integrity: intubation, drains, catheters, central lines • Neutropenia, lymphopenia • Viral co-infection – CMV, HCV, HIV

11. NET STATE OF IMMUNOSUPPRESSIONCAN WE MEASURE? • Non-specific immunoassays • Intracellular ATP, biomarkers, proteomic-based technologies • Pathogen-specific immunity • ICS • IFN-g assays, • HLA tetramers • Elispot

12. EPIDEMIOLOGICAL EXPOSURES Overlapping but distinct exposures Community – CAP, CA-MRSA, Endemic mycosis, respiratory viruses, enteric viruses Nosocomial – MRSA, aspergillus, MDR gram negatives, VRE Donor – latent or active infection Recipient – latent or active infection

13. AN EXAMPLE OF EPIDEMIOLOGIC EXPOSURE • 61 y.o. male heart transplant 1991 • Stable immunosuppression x years • cylosporin, prednisone • 3 week history of progressive leg cellulitis, fever unresponsive to antibiotics • Intermittent confusion

16. What was the exposure? • This patient generally will not get an OI unless some excess exposure • Exposure: • Delivery of topsoil to his home • Legs knee deep in topsoil while he was spreading it

18. Tx ID TIMELINE: 0-1 MONTH • Post-op Infections • Technical / anastomotic related infection • nosocomial pneumonia, wound, etc • MRSA, VRE, Candida, C. difficile • Donor Derived Infection • These are rare but diagnosis can be missed • Recipient derived infection • Ongoing pneumonia • Colonization to infection • Most OI absent: exceptions include certain fungal infections, HSV, occasional others

21. Tx ID TIMELINE 1-6 MONTH Account for CMV, PCP prophylaxis • BK viruria – viremia. BKVAN • CMV: D+/R- month 3-6; augmented immunosuppression • EBV viremia D+/R- • HCV recurrence (OLTx) • C. difficile, Fungal, mycobacterial, respiratory virus • VZV post-prophylaxis

25. BRONCHOSCOPY: TESTS • Gram stain and culture • Fungal stain and culture • AFB smear and culture • Legionella DFA, culture • CMV shell vial culture • Respiratory viruses culture; DFA for HSV, Influenza, parainfluenza, RSV, adenovirus • stain for PCP • Cytology • Molecular testing replacing traditional testing

27. Tx ID TIMELINE >6 MONTH • Depends on outcome: good vs. bad graft function. Tapering immunosuppression vs. ongoing high level – problems with rejection • Some patients at ongoing risk of OI despite minimal exposures • Others only get OI if significant exposure

28. Tx ID TIMELINE >6 MONTH • Late viral infections • CMV (colitis, recurrence), BKVAN, PTLD, HCV • Community acquired infection • Respiratory virus, CA-MRSA, atypical mould infection, • Other OI based on exposures

29. Hospital day 6 DWI ADC FLAIR

31. EMERGING TRENDS IN INFECTION EMERGING TRENDS CHANGING OLD INFECTIONS NOVEL INFECTIONS Respiratory viruses Bacteria Fungus Viruses Vector borne viruses Blood/body fluid transmitted Enteric transmitted

32. More potent immunosuppression Widespread prophylaxis KNOWN PATHOGEN • Modified presentation • Symptoms • Timing • Spectrum Drug resistance

33. Aspergillus 9.4% Aspergillus Scedosporium Fusarium 30.2% Phaeohyphomycetes 9.4% Non-Aspergillus 69.8% 5.7% Zygomycetes 5.7% Other MOULD INFECTIONS in ORGAN TRANSPLANT RECIPIENTS Hyalohyphomycetes Husain et al. Clin Infect Dis 2003

34. Gan, valgan, prophylaxis Potent Immunosuppression CMV • Modified presentation • Symptoms • Timing Drug resistance

36. TIME to CMV DISEASE UP to 6 MONTHS (n=364) 100 90 364 D+/R- SOT patients 80 70 • May present with atypical symptoms (no fever – malaise, fatigue); diagnosis can be missed • Patient may not be followed by primary center or may not be followed as closely 60 50 % Patients with no CMV Disease 40 30 20 Prophylaxis period 10 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 Time (days) Paya et al. Am J Transplant 2004; 4: 611

37. CMV RESISTANCE • Overall resistance rates low in most transplant populations • In certain subpopulations, resistance rates of up to 10% described in some studies • Especially lung transplant • Bharade et al. JHLT 2002, Limaye et al. JID 2002 • D+/R- lung recipients at highest risk • The two alternative therapies are • Foscarnet and cidofovir • Both have significant toxicities

38. NOVEL INFECTIONS & TRANSPLANTATION Emerging Infections Old Pathogens Previouslyunrecognized Old Pathogens New disease (in transplant pts) New Pathogen New disease HHV-6/7 adenovirus BKVAN West Nile virus H1N1 influenza Xenotransplantion

39. DWI ADC HHV-6 encephalitis Viral load 1.2 million copies/ml HHV-6 pneumonitis

40. Clinical reactivation Subclinicalreactivation

41. NEW PATHOGENS and the Transplant Patient 1. More likely to develop symptomatic disease if exposed to a pathogen 2. Once exposed, more rapidly progressive lethal disease ‘SENTINEL CHICKEN’ CONCEPT

42. NEW PATHOGENS and the Transplant Patient 3. Higher viral burden – longer viral shedding with increased amounts of virus • Increased infectivity • Super-spreaders 4. Lack of response to therapeutic measures • Standard antiviral may have less efficacy • Decreased immunogenicity of vaccines

43. EMERGING INFECTIONS AND TRANSPLANT • Transplant patients can potentially acquire a new pathogen in 3 ways: Transfusion- transmitted Community- acquired Organ- transmitted

44. WNV and TRANSPLANTATION • Numerous case reports/series of TTWNV • High mortality (~ 30%) • Two instances of organ donor transmission of WNV (2003, 2005) • Most common is community acquired WNV • Immunocompetent : severe disease in 1:140

45. 816 TRANSPLANT PATIENTS WNV IgG/IgM Seroprevalence study (0.25%; 95%CI 0.03-0.88%) Estimated risk of severe neuroinvasive disease 40% (95%CI 16-80%) Kumar D et al.Am J Transplant 2004; 4:1883

46. Kumar/Humar Am J Transplant2005

47. Pandemic (Novel) H1N1 virus • AST ID COP – 25 center study of epidemiology of H1N1 in transplantation (Kumar et al. ATC 2010)

48. Figure 1: Time of onset of symptoms during the pandemic.

49. Table 1: Demographics of solid organ transplant recipients with Influenza A BMI Body Mass Index

50. Table 2: Clinical presentation and complications of Influenza A in adult and pediatric solid organ transplant recipients.