Transcript EBV Disease Post-Renal Transplant and PTLD

Post- Kidney Transplant Infectious Disease
Complications
Kenneth Bodziak, MD
Associate Professor of Medicine
Oklahoma Transplant Center
Oklahoma Health Sciences Center
OBJECTIVES
1). Understand the timeline as to when certain infections are more
likely to occur after kidney transplantation.
2). Know the rationale behind providing prophylactic antibiotics
following renal transplantation.
3). Learn the pre-transplant serologic testing conducted prior to waitlisting a patient for kidney transplantation.
Infection in Solid-Organ Transplant Recipients:
Epidemiologic Exposures
• I). Donor-derived infections
• II). Recipient-derived infections
• III). Nosocomial infections
• IV). Community infections
How Much Immunosuppression?
Too little: Rejection
Too much: Infection & Cancer
Dose, Duration, Sequence of drugs
Watch out for that spelunking
“Transmission of Rabies Virus from an Organ Donor to Four Transplant
Recipients.” Arjun Srinivasan, M.D., et al. N Engl J Med 2005;352:1103-11.
Background: In 2004, four recipients of kidneys, a liver, and an arterial segment from a
common organ donor died of encephalitis of an unknown cause.
Intracytoplasmic viral inclusions
in neurons (Negri bodies).
Immunohistochemical staining (red)
of rabies viral antigens in CNS)
Organ Donor Disease Transmission
• Similar stories for M&M among solid organ transplant
recipients due to transmission of:
• WNV – West Nile Virus
• LCMV- lymphocytic choreomeningitis virus
• Cruetzfeldt-Jakob disease (corneas)
• Chagas disease
• HIV
• Stongyloides
Data to be collected regarding eligibility
of organ donors
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Medical history (e.g. hemophilia, sickle cell disease)
Previous infections
Vaccinations
Occupational exposures
Travel history
Transfusions with blood or blood products
Contact with people with HIV, HBV, HCV, or other transmissible diseases
Tattooing, ear piercing or body piercing
Use of illicit drugs
Sexual behavior (e.g. prostitution)
Incarceration
Contact with bats, stray dogs or rodents (including pets)
Standard Screening Tests for Prospective Donors
• Human immunodeficiency virus (HIV) antibody (NAT testing, if necessary)
• Hepatitis B (HBV) serologies, including HBV surface antigen, core antibody,
surface antibody and Hepatitis delta antigen and/or antibody in HBsAgpositive donors
• Hepatitis C (HCV) antibody
• Treponemal or non-treponemal testing (Treponema pallidum
hemaggutination assay (TPHA) or VDRL + Rapid plasma reagin {RPR})
• Cytomegalovirus (CMV) antibody
• Epstein-Barr virus (EBV) antibody panel
• Herpes simplex virus (HSV) antibody
• Varicella-zoster virus (VZV) antibody
• Blood and urine cultures (usually available well after the transplant)
• Chest X-Ray
• Toxoplasma antibody: if from endemic area
Possible Strategies Based on
Microbiologic Donor Screening Data
Serologic finding
Intervention
Antibody to HIV
Antibody to HCV
Antibody to CMV
Antibody to EBV
HBsAg+ or HBcAb IgM+
HBsAb+
HBcAb IgG+
RPR+
Antibody to Toxoplasma
Exclude from organ donation
If used, usually reserve organ for recipient with HCV infection
(HCV-RNA +) or severely ill
Preventive strategy based on risk to recipient
PCR monitoring of the seronegative or pediatric recipient
Exclude from organ donation or use in life-threatening
situations with intensive prophylaxis
Safe for organ donation if documented donor vaccination; use in
vaccinated recipients and with negative NAT testing if donor
vaccination unknown
High-risk for transmission if liver used for donation, but
generally used with intensive prophylaxis; nonhepatic organs
carry a small risk of transmission of HBV; generally used for
immunized recipients
Not a contraindication to donation. Recipients should receive
standard prophylaxis (ceftriaxone or benzathine PCN).
Not a contraindication to donation. Prophylaxis with bactrim.
Recipient-Derived Infections and Detection
Screening
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Epidemiology history: Travel, Occupation, Hobbies, Food/water
Vaccination history
Serologies: VDRL, HIV, CMV, EBV, HSV, VZV, HBV, and HCV
Tuberculin skin testing
Microbiologic testing of blood and urine (as needed)
Chest X-Ray
Current and past Infectious disease history (colonization)
Special testing (e.g. HCV PCR, titers for Histoplasmosis, etc.)
Case Presentation of Recipient-Borne Disease
A 45-year-old man underwent cadaveric renal transplantation at Duke University Medical Center for chronic
renal failure. Pretransplantation evaluation showed 3 to 5 eosinophils/100 leukocytes, but the cause was not
investigated. Posttransplantation recovery was uneventful except for a mild episode of transplant rejection,
which was treated with high-dose prednisone, azathioprine, and local irradiation. He was discharged
1 month after transplant on 60 mg of prednisone and 50 mg of azathioprine daily. Three days after discharge he
returned complaining of headache and fever. Lumbar puncture showed 1500 leukocytes/mm% 98% of which
were neutrophils. Subsequent cultures of the cerebrospinal fluid were positive for enterococcus. He initially did
well on ampicillin therapy; however, on the fourth day of hospitalization he became increasingly dyspneic and
cyanotic. At physical examination, diffuse rales were heard. Arterial blood gas values on room air were arterial
oxygen tension, 28 mm Hg; arterial carbon dioxide tension, 29 mm Hg; and pH, 7.50. Chest radiograph showed
bilateral alveolar infiltrates. The patient was intubated and mechanical ventilation started. Transtracheal
aspirate of sputum revealed larval forms of S. stercoralis. In addition, larval forms were recovered from his
stool. He was begun on thiabendazole therapy, but developed gross hemoptysis, gastrointestinal bleeding,
hypotension, and renal failure. He died on the 12th hospital day. At autopsy, the patient's lungs were grossly
congested and edematous. The stomach, duodenum, and small intestine were dilated and filled with
sanguineous fluid. Microscopically the lungs contained many larval forms of 5. stercoralis, both in the vascular
space and in the alveoli . There was marked pulmonary congestion and edema with multiple areas of
bronchopneumonia. The duodenum was invaded by larval and adult forms, as well as eggs, of 5. stercoralis.
Scoggins CH and Call NB. Ann Int Med 1977;8:456-458.
Disseminated strongyloidiasis in an
immunocompromised patient
Chest X-Ray showing a diffuse
bilateral infiltrate.
Gram stain of sputum showing
filariform larvae of S. stercoralis
Nosocomial Infections
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MRSA
VRE
Fluconazole-resistant candida species
Clostridium difficile
Antimicrobial-resistant gram-negative bacteria
Aspergillus
Community Infections
• Soil pathogens, e.g. aspergillus or nocardia species
• Air-borne pathogens, e.g. C. neoformans from pigeons or
respiratory pathogens.
• Salmonella from reptiles or uncooked eggs.
• Water-borne pathogens
Prevention of Infection
• Vaccination: MMR, DPT, HBV, Poliomyelitis, Varicella,
Influenza, Pneumococcal pneumonia
• Universal Prophylaxis: Peri-operative antibiotics; Antifungal in
case of pancreas transplant; TMP-SMX for
prophylaxis against pneumocystis pneumonia,
Toxoplasma gondii, Iospora belli, Cyclospora
cayetanensis, Nocardia and Listeria sps,
common urinary, respiratory and GI pathogens.
• Preemptive Therapy: Monitor patients at predefined intervals in
order to detect infection before patient
becomes symptomatic. (CMV)
Timeline for Infection after Solid Organ
Transplant
Fishman JA. NEJM 357 (25); 2601-2614, 2007
CMV Disease in Renal Transplant Recipients (a)
• Seroprevalence ranging from 30 to 97% in the general
population.
• CMV establishes life-long latency following primary infection.
• CMV post-transplant infection: evidence of CMV replication
regardless of symptoms.
• CMV post-transplant disease: evidence of CMV infection with
attributable symptoms. Can be further characterized as either
a viral syndrome with fever and/or malaise, leukopenia,
thrombocytopenia or as tissue invasive disease (e.g.
pneumonitis, hepatitis, retinitis, colitis).
CMV Disease in Renal Transplant Recipients (b)
• CMV has a predilection to invade the graft.
• CMV has an immunomodulatory effect, setting up secondary
infections with fungus, EBV, and bacteria.
• CMV has been implicated in causing acute and chronic
allograft injury.
• Highest risk of disease are in D+/R- pairings; use of
antilymphocyte antibody preparations.
• Prophylaxis with valganciclovir for 3-6 months recommended.
• May pre-emptively treat by only giving valganciclovir if viral
replication appreciated (+ CMV PCR).
• Look out for CMV ganciclovir resistance (~2% with VGCV).
Direct and Indirect Effects of CMV Infection
Kotton CN and Fishman JA. J Am Soc Nephrol 16: 1758-1774, 2005
EBV Disease Post-Renal Transplant and PTLD
Report of the Collaborative Transplant Study,
1997-2005. Opelz G, Volker D, Cord N, and
Bernd D. Transplantation 2009;88:962-967.
EBV Disease Post-Renal Transplant and PTLD
Report of the Collaborative Transplant Study,
1997-2005. Opelz G, Volker D, Cord N, and
Bernd D. Transplantation 2009;88:962-967.
EBV Disease Post-Renal Transplant and PTLD
Report of the Collaborative Transplant Study,
1997-2005. Opelz G, Volker D, Cord N, and
Bernd D. Transplantation 2009;88: 962-967.
EBV Disease Post-Renal Transplant and PTLD
Report of the Collaborative Transplant Study, 1997-2005.
Opelz G, Volker D, Cord N, and Bernd D. Transplantation
2009;88: 962-967.
BK Nephropathy
- BK virus, a polyomavirus, establish latency in renal epithelium and other tissues.
- Up to 85% adults express serologic evidence of prior exposure to the virus.
- Renal dysfunction may occur from necrosis of tubular epithelial cells and eventual
interstitial fibrosis with tubular atrophy in the immunocompromised host.
Risk Factors
* rabbit-ATG
* Tacrolimus
* Mycophenolate
* African-American recipient
* More recent transplant year
* Acute rejection in first 6 mos.
Non-Risk Factors
* mTOR inhibitor
* Female gender
* Live donor
* Hispanic recipient
* Large volume center
BK Nephropathy
Intranuclear inclusions are present
within tubular epithelial cells.
SV40 immunoperoxidase stain highlights
intranuclear Polyomavirus
inclusions.
Diagnosis and Treatment of BK Nephropathy
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Screen blood for BK PCR
Allograft biopsy required to make accurate diagnosis
Treat by lowering CNI and/or antimetabolite (e.g. Mycophenolate)
Consider substituting Mycophenolate with Leflunomide (no
benefit per meta- analysis)
• Cidofovir treatment (no benefit per meta-analysis) or
Ciprofloxacin treatment
• Safe in retranslating recipients who lost prior allograft to BK
QUESTIONS