infections-after-transplantation.ppt

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

3. INFECTION IN IMMUNOSUPPRESSED PATIENTS:
BASIC PRINCIPLES
•Inflammatory 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 Recipients
•Net state of immunosuppression
•Epidemiological exposure

5. KNOWN PATHOGEN
More potent
immunosuppression
Widespread
prophylaxis
Modified presentation
-Symptoms
-Timing
-Spectrum
Drug resistance

6. The Net State of Immune Deficiency
•Immunosuppression (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 risk
•Induction 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
surgery
•Good 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 Exposure
•Donor derived infections
•Recipient derived infections
•Community aquired infections
•Nosocomial infections

10. 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

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

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 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

14. ENCEPHALITIS
Srinivasan et al. NEJM 2005
Rabies virus inclusions
•Four recipients of kidneys, liver, and of an illiac
artery graft died of encephalitis of unknown cause.
•Onset within 21-27 days of surgery
•Donor presented 4 days prior (fever, mental status
changes)
•Cocaine-induced subarachnoid hemorrhage
•In retrospect had a bat bite earlier

15. YET ANOTHER UNUSUAL DONOR
TRANSMITTED PATHOGEN
Fischer et al. NEJM 2006
•In 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).

16. Notable Organ Transplant-
Transmitted Infections: Published Literature
•HIV, 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 Process
•Known 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 Process
•Physicians’ 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, 2008.
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 viral
•infection 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,wewill be
able to further gauge donor risk and
match it to recipient need to optimize
patient benefit.

24. Donor Screening
•Epidemiologic history
•Serologic 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 history
•Vaccination 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 history
•Vaccination 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 seroconversion
•Microbiologic cultures and susceptibility
testing
•Quantitative viral-load assay and antigen
tests
•Histopathological tests and
immunostaining

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

31. Advanced Assays
•Assays of pathogen-specific immunity
•Cytotoxic 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 recipients. NEJM 2007; 357: 2601–2614.

34. TxID TIMELINE: 0-1 MONTH
•Post-op Infections
–Technical / anastamoticrelated infection
–Nosocomial pneumonia, woundinfection, 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. TxID TIMELINE
1-6 MONTH
Account for CMV, PCP prophylaxis
•BK viruria/ viremia, BKVAN
•CMV
•EBV viremia D+/R-
•HCV recurrence (OLTx)
•C. difficile, fungal, mycobacterial,
respiratory virus
•VZV post-prophylaxis

36. TxID 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

37. TxID 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

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

39. Incidence of Invasive fungal infection
•Renal 0-14%
•Heart 2-21%
•Liver 4-42%
•Lung 15-35%
•Intestinal 40-59%
•Pancreas 18-38%

40. PREVENTION OF INFECTION
•PCP, 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. Haemophilusinfluenza 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. BacilleCalmette-Guérin(BCG)
2. Measles
3. Mumps
4. Rubella
5. Oral polio
6. Oral typhoid
7. Yellow fever

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

47. Clinical reactivation
Subclinicalreactivation

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
–Evidence 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 Transplantation
Immunosuppression
Infection
Rejection

55. Impact of CMV on SOT
DIRECT EFFECTS:
•Tissue Invasive
Disease
GI 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 SOT
•Primary 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;21:149-158,

59. Therapeutic Strategies for CMV
•UNIVERSAL 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 ProphylaxisPre-emptiveTherapy
Efficacy Yes: large RCT Yes: smaller trials, fewer
D+/R-
Ease Relatively easyto
coordinate
More difficult to
coordinate
Lateonset disease Potential problem Lesscommonly 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
Indirecteffects (graft
loss, mortality, &
opportunistic infections)
Consistentand positive
impact based on meta-
analyses and limited
comparative trials
Limited data

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

62. 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;610-617

63. 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;610-617

64. Oral ValganciclovirIs Noninferiorto
Intravenous Ganciclovirfor 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; 7:2106-13.

65. IMPACT study
•Multicentered, double-blind, RCT
•326 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;10:1228-37.

66. IMPACT study
•Definitions
–CMV 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%
Humar Am J Transplant 2010;10:1228-37.

68. IMPACT study
•Immunosuppressive regimens were not
controlled
•HLA matching not analyzed
•Kidney transplant patients only
•Discontinuation of immunosuppression not
assessed
Humar Am J Transplant 2010;10:1228-37.

69. CMV Resistance
•Risk factors
–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

71. Foscarnet
•Treatment dose
–90 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

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. BK Virus
Nephropathy
KiranBabu, MD
STAY TUNED !