1 Infections Following Renal Transplantation and An Update on CMVK.Vinay Ranga MD, MRCP (UK) Associate Professor Internal Medicine / Nephrology UTHSC

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3 INFECTION IN IMMUNOSUPPRESSED PATIENTS: BASIC PRINCIPLESInflammatory response attenuated by immunosuppression. may abolish typical signs/symptoms decreased sensitivity of serological, radiological tests Effects of established infection may be devastating. Treatment may have more toxicities ! Rifampin - decrease CNI Erythromycin, azoles increase CNI Synergistic nephrotoxicity - aminoglycosides, Amphotericin B, high dose Co-trimoxazole

4 Infections in Transplant RecipientsNet state of immunosuppression Epidemiological exposure

5 Modified presentationMore potent immunosuppression Widespread prophylaxis KNOWN PATHOGEN Modified presentation Symptoms Timing Spectrum Drug resistance

6 The Net State of Immune DeficiencyImmunosuppression (current and past) Prior therapies-chemotherapy, Antibiotics Muco-cutaneous barrier integrity (catheters, lines, drains) Neutropenia, lymphopenia Underlying immune deficiencies (e.g. hypogammaglobulinemia, SLE) Metabolic: uremia, malnutrition, DM, cirrhosis Viral co-infection (e.g. CMV, HCV, HBV) Risk assessment in transplantation

7 Greater infectious riskInduction therapy–lymphocyte depletion High-dose steroids Plasmapheresis High rejection risk Early graft rejection Graft dysfunction Active/latent D/R infection Technical complications  Anastomotic leak   Bleeding   Wound infection/poor wound healing   Prolonged intubation/ ICU care   Surgical, vascular or urinary catheters

8 Lower infectious risk Good HLA match Technically successful surgeryGood graft function Appropriate surgical prophylaxis Effective antiviral prophylaxis PCP prophylaxis Appropriate vaccination AJT. Fishman JA.Volume 9, Supp. S4, pages S3–S6, December 2009

9 Epidemiological ExposureDonor derived infections Recipient derived infections Community aquired infections Nosocomial infections

10 EPIDEMIOLOGICAL EXPOSURESOverlapping 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

11 DONOR DERIVED INFECTIONPARASITIC Malaria Chagas disease Strongyloides Schistosomiasis Flukes VIRAL Hepatitis A, B, C, D… HIV HHV 1 - 8 Rabies West Nile Virus LCMV PATHOGENS FUNGAL Candida Cryptocococcus Coccidioides Histoplasma Aspergillus BACTERIAL Gram positive Gram negative Mycobacterial Spirochetes PRION vCJD

12 HOW DO YOU RECOGNIZE UNUSUAL DONOR TRANSMITTED INFECTION?These infections often (but not always) occur early post-transplant They are often clinically very aggressive and may be difficult to diagnose Rare or unexpected infection, unusual presentation, lack of seroconversion Infections in multiple recipients of a common donor is often the best (or only) clue

13 WNV and TRANSPLANTATIONNumerous 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

14 ENCEPHALITIS Four recipients of kidneys, liver, and of an illiac artery graft died of encephalitis of unknown cause. Onset within days of surgery Donor presented 4 days prior (fever, mental status changes) Cocaine-induced subarachnoid hemorrhage In retrospect had a bat bite earlier Rabies virus inclusions Srinivasan et al. NEJM 2005

15 YET ANOTHER UNUSUAL DONOR TRANSMITTED PATHOGENIn 2003, 2005, 2-clusters of unusual infections 8 patients (2 donors): mental status changes, fever, rash, graft dysfunction, multi-organ failure (7/8 died 9-76 days) In 2005 cluster, donor had pet hamster IHC staining, RT-PCR, ELISA and culture: Lymphocytic Choriomeningitis (LCMV). Fischer et al. NEJM 2006

16 Notable Organ Transplant- Transmitted Infections: Published LiteratureHIV, 1985 Hepatitis C, 2000 Chagas Disease (T. cruzi), 2001 West Nile Virus (WNV), GA 2002 Lymphocytic Choriomeningitis Virus (LCMV), WI 2003 and MA/RI 2005 Rabies, 2004 WNV, NY/PA 2005 Chagas, 2006 HIV/HCV 2007 Arenavirus 2007

17 Aspects of Solid-Organ Transplantation That Should Be Disclosed during the Consent ProcessKnown risks of transplantation include the rare risks of transmission of HIV, hepatitis B and C virus, and other infectious agents. Because of the scarcity of organs, organs from expanded-criteria donors, donors after circulatory determination of death, and donors with a slight risk of certain infections are sometimes used. Patients may decline nonstandard-criteria organs, but doing so may delay their receipt of an organ and possibly even result in death while they are on the waiting list.

18 Aspects of Solid-Organ Transplantation That Should Be Disclosed during the Consent ProcessPhysicians’ understanding of donor characteristics that confer risk is incomplete and continually evolving. New risks may arise in the future (e.g., as new transmittable infections are identified), and all efforts to minimize these risks will be made.

19 CDC HIGH RISK BEHAVIOR Men who have had sex with another man in the preceding 5 years. Persons who report nonmedical intravenous, intramuscular, or subcutaneous injection of drugs in the preceding 5 years. Persons with hemophilia or related clotting disorders who have received human-derived clotting factor concentrates Men and women who have engaged in sex in exchange for money or drugs in the preceding 5 years. Persons who have had sex in the preceding 12 months with any person described above or with a person known or suspected to have HIV infection.

20 CDC HIGH RISK BEHAVIOR Persons who have been exposed in the preceding 12 months to known or suspected HIV-infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane. Inmates of correctional systems. (This exclusion is to address issues such as difficulties with informed consent and increased prevalence of HIV in this population.)

21 Renal Transplants from CDC High-Risk Donors: What’s the Risk and for Whom Is It Justified?METHODS: All high-risk donors underwent nucleic acid testing (NAT) for HIV, HCV, and HBV. Patients were counseled during evaluation and consent obtained rom all recipients highlighting the CDC high-risk status of the organ at the time of transplant. ATC 2010, ABSTRACT # 308

22 Adult recipients were transplanted over the year beginning September, Given the increased risk, offers were directed towards older and diabetic patients, those with elevated PRA>50, and those already infected with HCV and/or HIV. All recipients had NAT at transplant and serially at 1, 3, and 6 months

23 CONCLUSIONS: Although NAT reduces the window period between donor viralinfection and detectability, the risk of transmission through transplant with these organs is ill-defined. Here, with prospective recipient NAT, we show safe use of high-risk kidneys with excellent short-term graft function. Risk of infection, however low, will clearly not be zero. With continued use of these organs and careful followup,we will be able to further gauge donor risk and match it to recipient need to optimize patient benefit.

24 Donor Screening Epidemiologic historySerologic testing for VDRL, HIV,CMV, EBV, HSV, VZV, HBV (HBsAg, anti-HBsAg), and HCV Microbiologic testing of blood and urine Chest radiography Known infections (appropriate therapy?) Possible infections (e.g., encephalitis,sepsis) Special serologic testing, nucleic acid assays, or antigen detection based on epidemiologic factors and recent exposures (e.g., toxoplasma,West Nile virus, HIV, HCV

25 Additional Donor Testing?NAT testing HIV - reduction in window period from 21 to 7 days HCV - reduction in window period - 70 to 7 days HBV West Nile Virus Other TB, Fungal, Chagas/T.cruzi, Strongyloides

26 Recipient Screening Epidemiologic historyVaccination history, TB skin test Serologic testing for VDRL, HIV, CMV, EBV, HSV, VZV, HBV (HbsAg, anti-HbsAg), and HCV Microbiologic testing of blood and urine Chest radiography

27 Recipient Screening Epidemiologic historyVaccination history, TB skin test Serologic testing for VDRL, HIV, CMV, EBV, HSV, VZV, HBV (HbsAg, anti-HbsAg), and HCV Microbiologic testing of blood and urine Chest radiography

28 Recipient Screening Known infections (e.g., strongyloides, histoplasma, coccidioides, HBV or HCV viral load) Known infections Past colonization: prophylaxis? Active infection: appropriate therapy? Possible infections (e.g., encephalitis, sepsis) Special serologic testing, nucleic acid assays, or antigen detection based on epidemiologic factors and recent exposures

29 Standard Assays Serologic tests for seroconversionMicrobiologic cultures and susceptibility testing Quantitative viral-load assay and antigen tests Histopathological tests and immunostaining

30 Advanced Assays Multiplex microbiologic assaysMolecular antimicrobial-susceptibility testing Nonspecific immunoassays for degree of immunosuppression Intracellular ATP Biomarkers of rejection (cytokines) Proteomics

31 Advanced Assays Assays of pathogen-specific immunityCytotoxic lymphocytes Mixed lymphocyte cultures HLA-linked tetramers Intracellular cytokine staining Enzyme-linked immunospot assay Interferon-release assays

32 Advanced Assays Genomics (patterns of gene expression) in:Immunosuppression Infection Rejection Drug metabolism

33 Fishman JA. Infection in solid-organ transplant recipientsFishman JA. Infection in solid-organ transplant recipients. NEJM 2007; 357: 2601–2614.

34 Tx ID TIMELINE: 0-1 MONTH Post-op InfectionsTechnical / anastamotic related infection Nosocomial pneumonia, wound infection, UTI 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

35 Tx ID TIMELINE 1-6 MONTH Account for CMV, PCP prophylaxisBK viruria / viremia, BKVAN CMV EBV viremia D+/R- HCV recurrence (OLTx) C. difficile, fungal, mycobacterial, respiratory virus VZV post-prophylaxis

36 Tx ID TIMELINE >6 MONTHDepends 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

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

38 FUNGAL INFECTIONS With improved strategies against CMV, fungal infection have become the most important cause of infectious mortality. Candida and Aspergillus account for ~ 80% of invasive fungal infections. Other 20% cryptococcus, other molds, and endemic mycosis.

39 Incidence of Invasive fungal infectionRenal 0-14% Heart 2-21% Liver 4-42% Lung % Intestinal % Pancreas %

40 PREVENTION OF INFECTIONPCP, UTI, others CMV disease Toxoplasmosis Other herpes viruses Candida Aspergillus Strongyloides Tuberculosis Endemic mycosis Bactrim Multiple strategies Bactrim, Pyrimethamine Acyclovir Azoles, echinocandins Voriconazole, candins, others Albendazole INH, ?others Voriconazole, others

41 VACCINATIONS IN TRANSPLANT RECIPIENTS

42 PRETRANSPLANT VACCINATION BOOSTERS TO BE GIVEN TO ALL TRANSPLANT RECIPIENTS UNLESS RECENT ADMINISTRATION CAN BE DOCUMENTED 1. Td (Tetanus toxoid, diphtheria) 2. Pneumococcal vaccine 3. Hepatitis B 4. Influenza

43 PRETRANSPLANT VACCINATIONS TO BE GIVEN IF SERONEGATIVE OR PAST INFECTION BY HISTORY CANNOT BE DOCUMENTED 1. Measles-mumps-rubella vaccine 2. Polio 3. Varicella 4. Haemophilus influenza type B

44 INACTIVATED VACCINES THAT ARE CONSIDERED SAFE AND MAY BE GIVEN AS NEEDED POST-TRANSPLANT FOR ANTICIPATED EXPOSURE 1. Anthrax 2. Cholera 3. Rabies vaccine absorbed 4. Human diploid cell rabies vaccine 5. Inactivated typhoid vaccine, capsular polysaccharide parenteral vaccine, or heat phenol-treated parenteral vaccine 6. Japanese encephalitis virus vaccine 7. Meningococcal vaccine 8. Plague vaccine

45 VACCINES THAT MAY NOT BE GIVEN (LIVE ATTENUATED VACCINES)1. Bacille Calmette-Guérin (BCG) 2. Measles 3. Mumps 4. Rubella 5. Oral polio 6. Oral typhoid 7. Yellow fever

46 WHATS NEW? Changing immunosuppression Widespread prophylaxisEmerging infections Evolving infections Donor Derived infection Molecular diagnostics Host-pathogen interactions

47 Clinical reactivation Subclinical reactivation

48 Cytomegalovirus (CMV)Largest known virus to infect human beings greek cyto-, "cell", and -megalo-, "large”. In humans it is commonly known as HCMV or Human Herpesvirus 5 (HHV-5). belongs to the Betaherpesvirinae subfamily Other herpesviruses include Alphaherpesvirinae (HSV1/2 and VZV) Gammaherpesvirinae (including EBV).

49 All herpesviruses share a characteristic ability to remain latent within the body over long periods.Nature Medicine, 6: 2000

50 Prevalence of CMV In all geographic locations and S/E groups,infects between 50% and 80% of adults in the US  presence of antibodies (IgG) in much of the general population. Seroprevalence is age-dependent: 58.9% of individuals aged 6 & over-CMV+ & 90.8% of individuals aged 80 & over- CMV+.

51 Spectrum of CMV In normal hosts: asymptomatic or causes an acute mono-like illness. Establishes latency in PMNs, T cells, endothelial cells, renal epithelium cells, and salivary gland. Wide spectrum of disease in immunocompromised hosts. One of the most important opportunistic pathogens, with more than 1 strain.

52 Pathology CMV demonstrated by intranuclear inclusion bodies, showing the virus replicates in the nucleus rather than the cytosol. These inclusion bodies stain dark pink on an H&E stain, and are also called "Owl's Eye" inclusion bodies. Replicating virus disrupts the cytoskeleton, causing massive cell enlargement, which is the source of the virus' name.

53 Definitions CMV infection CMV diseaseEvidence of CMV replication regardless of symptoms CMV disease Evidence of CMV infection with attributable symptoms Viral syndrome with fever and/or malaise, leukopenia, thrombocytopenia, or tissue invasive disease

54 Dynamics of TransplantationImmunosuppression Rejection Infection

55 Impact of CMV on SOT DIRECT EFFECTS: Tissue Invasive DiseaseGI disease, Hepatitis Pneumonitis, Nephritis CNS disease, Retinitis Pancreatitis, Carditis Others Mortality INDIRECT EFFECTS: Acute allograft rejection Chronic allograft failure BOOP,vasculopathy, if/ta Vanishing duct syndrome OI: Fungal, Bacterial, PTLD, Hep.C recurrence, HHV-6, -7 NODAT

56 Factors Influencing Reactivation of CMV and Progression to CMV Disease CMV reactivation Allogeneic stimulation Allograft rejection Depleting antibodies Stress- critical illness, surgical procedure, bacterial & fungal sepsis progression to disease Lack of innate immunity (D+/R-) IS: depleting antibodies, MMF (> 2gm/day) High dose methylprednione Viral load

57 Factors Influencing Reactivation of CMV and Progression to CMV Disease CMV reactivation Allogeneic stimulation Allograft rejection Depleting antibodies Stress- critical illness, surgical procedure, bacterial & fungal sepsis progression to disease Lack of innate immunity (D+/R-) IS: depleting antibodies, MMF (> 2gm/day) High dose methylprednione Viral load

58 Mechanisms of Acquiring CMV Infection After SOTPrimary CMV infection (D+ /R-)- HIGH RISK (VIA TRANSPLANTED ORGAN OR TRANSUFION) Reactivation (D-/R+) -INTERMEDIATE RISK Superinfection (D+/R+) -INTERMEDIATE RISK Naïve (D-/R-) - LOW RISK (UNLESS TRANSFUSED D+ BLOOD PRODUCTS) Fishman JA et al. Clin Transplant 2007;21: ,

59 Therapeutic Strategies for CMVUNIVERSAL PROPHYLAXIS: For the whole cohort, typically D+/R- (high risk) PRE-EMPTIVE THERAPY: For intermediate risk group (R+) vs Universal  2 weekly CMV-Pcr for 6 months, and initiate treatment doses of Valgancyclovir if positive STANDARD THERAPY: for patients with disease- treat with Vangancyclovir 900 mg bid until symptoms resolved, virologic clearance, or 2 week minimum. Then check Pcr & short course of prophylaxis (1-3 mo)

60 CMV Prevention Universal Prophylaxis Pre-emptive Therapy EfficacyYes: large RCT Yes: smaller trials, fewer D+/R- Ease Relatively easy to coordinate More difficult to coordinate Late onset disease Potential problem Less commonly seen Cost Higher drug costs Higher lab costs Toxicity Potential for greater drug toxicity (myelosuppression) Potential for less drug toxicity with shorter courses of antivirals Indirect effects (graft loss, mortality, & opportunistic infections) Consistent and positive impact based on meta-analyses and limited comparative trials Limited data For pre-emptive therapy in CMV positive recip. What pp65 or pp67 designates increased risk for infection or dz??

61 Recommendations Valganciclovir (Valcyte®)CrCl (ml/min) Valganciclovir Induction dose (mg) Dosing interval (hrs) Valganciclovir Maintenance dose (mg) Dosing Interval (hrs) ≥60 900 12 24 40-59 450 25-39 48 10-24 2 x week < 10 Not recommended 900 mg valganciclovir daily = 5 mg/kg/day IV ganciclovir

62 6-29% with prophylaxis for 3 months CMV R+ 8-10% with NO prophylaxis ESTIMATED INCIDENCE RATES OF CMV DISEASE AFTER KIDNEY AND/ OR PANCREAS TRANSPLANT CMV D+/ R- 45-65% with NO prophylaxis 6-29% with prophylaxis for 3 months CMV R+ 8-10% with NO prophylaxis 1-2% with prophylaxis for 3 months Eid AJ, Razonable R. Curr Opn Organ transplant, 2007:12;

63 6-29% with prophylaxis for 3 months CMV R+ 8-10% with NO prophylaxis ESTIMATED INCIDENCE RATES OF CMV DISEASE AFTER KIDNEY AND/ OR PANCREAS TRANSPLANT CMV D+/ R- 45-65% with NO prophylaxis 6-29% with prophylaxis for 3 months CMV R+ 8-10% with NO prophylaxis 1-2% with prophylaxis for 3 months Eid AJ, Razonable R. Curr Opn Organ transplant, 2007:12;

64 Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR study Randomized, international trial, txp patients with CMV disease 900 mg po valganciclovir or 5 mg/kg IV ganciclovir BID for 21 days, followed by 900 mg daily valganciclovir for 28 days Rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI –14.0% to +8.0%), and at Day 49; 67.1% and 70.1% (p=NS) Treatment success was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS) Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs.19 days, p = 0.076) Asberg. Am J Transplant 2007; 7:

65 IMPACT study Multicentered, double-blind, RCT326 high risk (D+/R-) kidney transplant patients randomized to 200 day vs 100 day valganciclvoir prophylaxis (900 mg daily) Inclusion criteria: ≥ 16 yo, D+/R-, CrCl > 10ml/min, tolerate oral study drug within 10 days of txp Exclusion criteria: HIV, HBV, HCV, suspected CMV disease at enrollment, anti-CMV therapy within 30 days prior to study, multiple organ txp, uncontrolled diarrhea or malabsorption, LFTs > 3xULN Humar Am J Transplant 2010;10:

66 IMPACT study DefinitionsCMV syndrome: CMV viremia, fever, malaise, leuokopenia, LFTs > 2 x ULN Tissue invasive CMV disease: evidence of localized CMV infection in biopsy or other specimen Primary endpoint: proportion of D+/R- patients who developed CMV disease within 1 year Secondary endpoint: CMV disease at 6 & 9 months, CMV viremia, and acute rejection .

67 IMPACT study Results: CMV disease lower in 200 day vs 100 day (16.1% vs 36.8%, p <0.0001) Confirmed CMV viremia lower in 200 day vs 100 day (37.4% vs 50.9%, p=0.015) at month 12 Rejection in 200 day vs 100 day (11% vs 17%, p=0.114) Incidence of leukopenia 200 vs 100 day was 38% vs. 26% GCSF was similar bw 2 groups for leukopenia Humar Am J Transplant 2010;10:

68 IMPACT study Immunosuppressive regimens were not controlledHLA matching not analyzed Kidney transplant patients only Discontinuation of immunosuppression not assessed Humar Am J Transplant 2010;10:

69 CMV Resistance Risk factors Ganciclovir resistance incidence 5-10%Prolonged antiviral drug exposure Ongoing active viral replication Lack of prior CMV immunity Inadequate antiviral drug delivery Ganciclovir resistance incidence 5-10% 90% ganciclovir resistant CMV isolates contain UL97 mutations Less common UL54, pol mutation

70 Do you agree with the rec to wait 2 weeks after UL97 testing is negative to do pol(UL54) testing??

71 Foscarnet Treatment dose Adjust for renal dysfunction90 mg/kg IV every 12 hours x 2 weeks Followed by 120 mg/kg daily for ≥ 2 weeks Infused over 1 hour Pre-treat with 500mls NSS over 1 hour prior to each dose, and repeat 500mls NSS over 1 hour after dose Adjust for renal dysfunction Since Foscarnet is used for mutations how long should prophy be after treated???

72 Our practice at UTHSC D+/R- : 900 mg valgancyclovir qd (renal adjusted dose) for 6 months R+ : 450 mg qd (renal adj) for 90 days OR po Valacyclovir (as below) + q 2wk CMV-PCR for 6 months- if PCR turns +VE, 900 mg bid for 2-4 wks, then ↓ to 900 mg qd D-/ R- : Valacyclovir 500 mg qd for 90 days

73 Kiran Babu, MD STAY TUNED !BK Virus Nephropathy Kiran Babu, MD STAY TUNED !