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EMERGING TRENDS IN TRANSPLANT INFECTIONS

EMERGING TRENDS IN TRANSPLANT INFECTIONS. Atul Humar Transplant Infectious Diseases University of Toronto. EMERGING TRENDS IN INFECTION. EMERGING TRENDS. CHANGING OLD INFECTIONS. NOVEL INFECTIONS. Respiratory viruses. Bacteria Fungus Viruses. Vector borne viruses.

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EMERGING TRENDS IN TRANSPLANT INFECTIONS

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  1. EMERGING TRENDS IN TRANSPLANT INFECTIONS Atul Humar Transplant Infectious Diseases University of Toronto

  2. 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

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

  4. CMV: Is it still a problem? • Despite wide-spread use of preventative measures, CMV infection (viremia) and disease (symptoms) continues to be common in certain settings • Generally • Decrease in incidence of disease • More commonly asymptomatic or mildly symptomatic viremia • Fewer cases of severe tissue invasive disease

  5. Gan, valgan, valac prophylaxis Potent Immunosuppression: SRL, campath, others CMV • Modified presentation • Symptoms • Timing Drug resistance

  6. LATE CMV DISEASE: DEFINITION • CMV disease occurring >3 monthspost-SOT • 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

  7. 100 90 80 70 60 % Patients with no CMV Disease 50 40 30 20 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) Time to CMV disease up to 6 mths (n=364) 364 D+/R- SOT patients Prophylaxis period

  8. 100 90 80 70 60 % Patients with no CMV Viral Load > BLQ 50 40 30 20 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) Time to first CMV VIREMIA (n=364) VGCV GCV Prophylaxis Period

  9. HOW DO WE DEAL WITH LATE ONSET DISEASE? • OPTIONS • Do nothing – accept the risk of late onset disease and treat as it arises • Prolong prophylaxis – Is more better? • Not necessarily – push disease further, High NNT • Use better prophylaxis? • Careful virologic monitoring of high-risk patients after completing prophylaxis

  10. HOW DO WE DEAL WITH LATE ONSET DISEASE? • What about monitoring? • Molecular diagnostics e.g. quantitative PCR testing well demonstrated as useful for pre-emptive therapy in absence of prophylaxis and early post-transplant • What happens when you apply these tests post-prophylaxis?

  11. 364 D+/R- patients 1- YEAR F/U 3 Months of Antiviral Prophylaxis

  12. Analysis • CMV viral load quantified by Roche Amplicor PCR (Detection limit: 400 copies/mL) • At baseline, every two weeks until day 100, and then at 4, 4.5, 5, 6, 8 and 12 months post-transplant • Relationship between viral load measurement and subsequent CMV disease investigated

  13. Monitoring: PREDICTIVE VALUE • Incidence of CMV disease was 64/364 (17.6%) mostly after day 100. For prediction of subsequent disease, viral load had a: Humar et al AJT 2004

  14. Results: Predicting CMV Disease by Viral Load • Sensitivity 38% • Only 24 of 64 patients with CMV disease had a positive viral load at some time prior to onset of CMV • Positive Predictive Value 17% • If positive viral load, then 17% chance of developing subsequent CMV disease (majority of patients with viremia do not develop disease)

  15. What about host response? • CMI (CD8, CD4) responses critical for control of CMV • Number of relatively complicated methods to assess this • Elispot, HLA tetramers, CFC, ICS, • Can a more simple test like seroconversion in a D+/R- patient predict immunity and risk of disease?

  16. 80 75.3 IgG IgM 63.4 60 54.9 41.8 Patients 40 (%) 26.9 19.6 20 16.2 8.3 2.6 1.6 0 Day 28 Day 56 Day 100 Month 6 Month 12 CMV IgM and IgG seroconversion

  17. P=0.34 17.8 20 P=0.002 16 13.2 10.0 12 CMV disease (%) Patients with subsequent 8 4 1.3 0 Seropositive Seropositive Seronegative Seronegative End of prophylaxis (day 100) Month 6 Predictive value of IgG seroconversionfor CMV disease Humar et al AJT 2005

  18. GANCICLOVIR RESISTANCE • Are we shooting ourselves in the foot by over use of antiviral for CMV prevention • Will emergence of ganciclovir resistance lead to more harm than good in the long run? • Risk factors1: • D+/R- patients • Prolonged oral ganciclovir therapy • More potent immunosuppression (Limaye et al. Lancet 2000)

  19. Viral Protein Kinase (UL97) MECHANISM OF ACTION Cellular Enzymes GCV GCV-MP GCV-DP GCV-TP Inhibits Viral DNA Polymerase (UL54) Intracellular Extracellular

  20. RESISTANCE : The Good News Kidney, liver, heart 2/88 (2.3%) in pts with CMV disease *Evidence suggests these are unlikely to be resistance mutations Boivin et al. JID, 2004

  21. Resistance: The bad news! • 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.

  22. WHAT DOES THE FUTURE HOLD • Use of translational research to establish better predictive tools • Host response – CD8, CD4 responses to specific herpesvirus antigens • Viral factors – immune evasion gene expression • Understand the impact of herpesvirus interactions • Novel targets – tailored drug therapy, selective immunosuppression, immunosuppression with co-existing antiviral activity • Novel preventative strategies • Vaccine strategies- DNA vaccine, multi-epitope vaccines • Cell Mediated therapeutic modalities

  23. NOVEL INFECTIONS & TRANSPLANTATION Emerging Infections Old pathogens Old Pathogens New Pathogen Previously unrecognized New disease New disease (in transplant pts) HHV-6/7 BKVAN SARS Xenotransplantion adenovirus West Nile virus

  24. Prevalence of significant HHV-7 DNAemia (1000 copies/ml)* Prophylaxis 7 6 5 Patients (%)with HHV-7DNAemia 4 3 2 1 0 Day 14 Day 42 Day 70 Day 100 Month 4 Month 6 Month 8 Month 12 Month 4.5 Day 7 In press JID *Data for valganciclovir and ganciclovir recipients combined (n = 263)

  25. Adenovirus viremia (n=263) 10 8 8.3 Incidence of 6 6.7 6.5 viremia (%) 4 2 0 0 Liver kidney Heart kidney- pancreas Transplant type Humar et al AJT in press

  26. Clinical reactivation Sub-clinicalreactivation

  27. CASE PRESENTATION • 58 y.o. female kidney 2 years ago • Well since transplant; On neoral and MMF. • Not working; ++ outdoor activity / recent cottage visit (no protection measures). • Fever and chills then confusion and a headache. • LP: WBC 58 mil/L and elevated protein (0.6 g/L). • WNV serology negative initially – positive 1 month later

  28. Hospital day 6 DWI ADC FLAIR

  29. Hospital day 65

  30. WEST NILE VIRUS Neurotropic ssRNA virus

  31. USA WNV Meningoencephalitis 2002 CANADA – first ever WNV in 2002 – large epidemic in the Toronto Area (~400 cases of mostly meningoencephalitis)

  32. WNV in Transplantation • Transplant patients can acquire WNV in 3 ways: Organ transmitted Community- acquired Transfusion- transmitted

  33. WNV: Transfusion Transmitted • In the U.S. 23 cases of TTWNV (2002) • 13/23 developed meningoencephalitis • 10 patients Immunocompromised (cancer,transplant,others) • Mortality of TTWNV 29% • ? Immunocompromised patients may have a higher risk of severe disease Pealer et al. NEJM, 2003

  34. RISK OF Transfusion Transmitted Infections • HIV (AIDS VIRUS): 1 in 4,000,000 • Hepatitis C: 1 in 3,000,000 • Hepatitis B: 1 in 275,000-1,000,000 • HTLV 1: in 2,000,000 • West Nile Virus: 1 in 30,000* • Across US; Much higher in areas with epidemic (possibly as high as 1:1000). PCR screening now done to reduce risk

  35. WNV Blood Screening • Blood products • Screened by minipool (6 donor samples) • This screening was performed on approximately 6 million units during June-Dec 2003 • 818 viremic blood donations removed from the blood supply. • 6 cases of TTWNV (low level donor viremia)

  36. ORGAN DONOR TRANSMITTED WNV • Of the 23 cases of TTWNV • One of these patient went on to donate 4 organs • 3 / 4 recipients meningoencephalitis, • 1 WNV fever • 7-17 days post-transplant Iwamoto et al., NEJM, 2003

  37. To Screen or not to screen • Decision to screen must be based on numerous factors • Sensitivity/Specificity of test • A recent medical decision analysis suggested that screening would result in a net loss of 452 life years due to false positive tests • Other issues include local WNV activity, availability of rapid turnaround time and medico-legal concerns Kiberd et al. (AJT 2004)

  38. WNV and Organ Transplant Kumar et al. Transplantation, 2004

  39. Community Acquired WNV • Seroprevalence study of 816 organ transplant patients following the 2002 epidemic • All patients enrolled in Oct 2002; outpatients only • IgG, IgM testing • Questionnaire on knowledge and behavior patterns • This followed specific educational attempts by the transplant program in August and September :

  40. Community Acquired WNV • The seroprevalence of IgM antibody to West Nile was 2/816 (0.25%;95%CI 0.03-0.88%) • Both these patient recalled a febrile illness • Based on application of the seroprevalence data to our population of ~ 2500 transplant patients, and using data from hospital based surveillance of meningoencephalitis… :

  41. Community Acquired WNV • The estimated risk of meningoencephalitis in transplant patient infected with WNV is 40% (95%CI 16-80%). • MUCH HIGHER RATE OF SEVERE DISEASE VS. GENERAL POPULATION (< 1%) :

  42. Knowledge / Behaviors

  43. “BIRD FLU” • How do novel viral RTIs impact transplant patients? • Avian Influenza • pandemic influenza

  44. RTI IN A TRANSPLANT PATIENT • Given contact with Health care setting high risk for exposure • Once exposed, more rapidly progressive lethal disease • Higher viral shedding - Increased infectivity – “Super-spreaders” • Potential for donor transmission

  45. SARS CoV TISSUE VIRAL LOADS (x103 copies/gram) Kumar et al. AJT, 2004 [ABS]

  46. CONCLUSIONS • Infections complications continually evolve in transplant patients • Understand the spectrum • Research in to the sequelae • Build prospective monitoring in immunosuppressive trials

  47. Acknowledgments • University of Toronto- D Kumar, G Levy, U Allen, T Mazzulli • PV16000 Study Group - C Paya, R Razonable, M Pescovitz, Roche • National Microbiology Lab of Canada- M Drebot, H Artsob, P Buck • Laval University – Guy Boivin • CDC -D Erdman • CIHR, PSI foundation

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