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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Understanding Viral Infections in the Context of Hematopoietic
Cell Transplantation
Willis Navarro, MD Medical Director
Transplant Medical Services, NMDP
CRPDM Session -- February 1, 2012
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Overview
• Background• Why do HCT patients get viral infections?• What is the origin of the viruses?• Which viruses are a problem?
• Specific Viral Pathogens• What do these viruses do to HCT patients?
• Laboratory Tests for Viruses• Reporting
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Viruses
• Acellular infectious agents which require cells in order to propagate
• “Hijack” the infected cell’s biochemical machinery to make more viral copies and then the cell is killed, releasing more virions
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Causes of Death after
Transplants
HLA-ID SIB
Infection(17%)
Other(13%)
Organ toxicity(13%)
Relapse (38%)
IPn (5%)
GVHD (14%)
AUTO
Infection (6%)
Other (9%)
Organ toxicity(8%)
Relapse (75%)
IPn (2%)
UNRELATED
Infection (19%)
Other(17%)
Organ toxicity
11%)
Relapse (32%)
IPn (7%)
GVHD(14%)
SUM05_20.ppt
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Why do HCT patients in particular get viral infections?
• Depth: Degree of immunodeficiency affects risk– Patient Factors: Cellular/humoral immunodeficiency,
prior history of viral infections, vaccinations– HCT Factors
• Auto vs Allo• Allo cell source (adult donor vs cord blood)• Preparative regimen• Match/GVHD risk->immunosuppression intensity,
duration• Graft processing (e.g. T cell depletion ex vivo, in vivo)
• Duration: Immune reconstitution speed affects risk
• HCT affects both humoral and cellular immunity
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Cellular and Humoral Immunity
6Source: http://www.zuniv.net/physiology/book/chapter32.html
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Common/Less Common Viral Pathogens in HCT
• Cytomegalovirus (CMV)• Epstein-Barr Virus (EBV)• Herpes Zoster Virus (HZV)• Respiratory Syncytial Virus (RSV)• Adenovirus• BK polyoma virus• Parainfluenza virus/influenza virus• Others
7 NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Where do these viruses come from?
• Some are reactivated when immuno-surveillance fails…e.g.– Herpes Zoster– CMV– EBV
• Some are newly acquired…e.g.– RSV– Influenza/Parainfluenza
• Some could be either pre-existing or newly acquired
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Cytomegalovirus (CMV)
• Cyto [cell]- megalo [large]; member of the herpesvirusfamily
• Infected cells become large• ~60% of the US adult population is CMV (+)• Manifestations of reactivated or new disease: retinitis,
hepatitis, colitis, pneumonia, uveitis, encephalitis, myelitis• Treatment: ganciclovir, foscarnet, cidofovir, experimental
therapy
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Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Epstein-Barr Virus (EBV)
• Herpesvirus family• Infects 90% of Americans by age 25• Like many herpesviruses, there is latent
infection• Associated with a variety of tumors
– Burkitt lymphoma in Africa– Nasopharnygeal cancer in Asia– Post-transplant lymphoproliferative disorder
in the HCT setting• No treatment for EBV per se but PTLD may respond
to rituximab therapy (off-label use) or chemo or cellular therapy
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Respiratory Syncytial Virus (RSV)
• Seasonal virus (late fall to early spring)• Causes a severe pneumonia in immuno-
compromised hosts• Treated with inhaled ribavirin or RSV-
specific monoclonal Ab (palivizumab)
11 NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Herpes Zoster Virus (Varicella, HZV)
• Chickenpox (varicella) recrudescing• Reactivating from the latent state (herpesvirus family
again…)• Shingles (dermatomal presentation) or disseminated
infection; if corneal, can cause blindness• Treatment: acyclovir oral, or IV for severe disease
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Other viruses of note
• Adenovirus– More common in children, GI and GU
manifestations– Treatment includes decreasing
immunosuppresssion, cidofovir, cellular therapy
• BK polyomavirus– Causes hemorrhagic cystitis– Decreasing immunosuppression is the usual Rx
13 NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Testing
• Test types– Antibody tests
• IgM• IgG
– Antigen tests• Polymerase Chain Reaction (PCR)
– Quantitative• Direct Fluorescence Antibody (DFA)• Nucleic Acid Test (NAT)
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Reporting Viral Infection Data
15 NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Prior Viral Exposure-Form 2000 Recipient Baseline Data
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Form 2048: HIV—Pre-HSCT Data
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YES: Lymphomas: (NHL, Hodgkin); NO: AML, ALL, MDS, SAA, CML
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Form 2048: HIV—Pre-HSCT Data
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Form 2048: HIV—Pre-HSCT Data
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Be aware that there are several combination therapies available for HIV;you will need to indicate each component of the combo tabs if not listedExamples: Truvada®: emtricitabine + tenofovir
Combivir®: lamivudine + zidovudineSee also http://en.wikipedia.org/wiki/Fixed-dose_combination_(antiretroviral)
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Infectious Disease MarkersForm 2004: Donors/CBUs
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Hepatitis B: vaccine is sAg so immunity yields a (+) HepB SAbOnly prior actual infection results in HepB cAb
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM 21
More ofForm 2004
HIV tests include HIV Ab (ELISA-based, or EIA), HIV viral load (by PCR), p24, HIV NAT;
Western blot looks for HIV protein bands as a confirmatory test
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Yet More of Form 2004
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Prophylaxis vs Treatment
• Prophylaxis: started about the time of conditioning to PREVENT infections– Usually includes:
• Antibiotics– Quinolones– Bactrim (TMP/SMX)
• Antifungals• Antivirals
• Treatment: drugs used for MANAGEMENT of the infection– Example: d/c of Acyclovir and start Ganciclovir
at time of CMV infection/reactivation
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Infection Prophylaxis—Form 2100/2200
Antivirals
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Reporting Duration of Therapy
• Date started• Date stopped
– If therapy held for < 7 days and then restarted, DO NOT list as stopped
– If on treatment until death, mark therapy stopped “NO”
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Reporting Doses
• Form will attempt to use a “standard” unit– Convert dose into the unit requested
(i.e. mg)– Consult with pharmacist if needed
• Report the first dose as the starting dose• Report maximum dose (if asked)• What if the dose changes within a course
of therapy????– Report only the starting dose
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Example: Hepatitis Treatment
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
What is the same infection? (i.e. don’t report again)
Bacteria Virus Fungal≤7 days• All bacteria (except Clostridium Difficile)
≤30 days• Clostridium Difficile
≤ 365 days•Helicobacter pylori
≤14 days• VZV • HZV• Adenovirus• Enterovirus• Influenza virus• Parainfluenza• Rhinovirus≤60 days• CMV • HSV• Polyomavirus
≤14 days• Yeasts
CandidaCryptococcus
≤90 days• Molds
AspergillusFusariumMucor
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Infections at Follow-Up—Forms 2100, 2200
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Don’t forget to reportCMV viremia…
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Form 2900:Cause of death codes
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
What is done with the data you send?• Reasons for specific dates
– Calculate• Time to infection• Survival after infection and after
transplant– Study effect of prophylaxis or treatment on
outcomes after infections• Reasons for specific drugs
– Identify impact of certain medications on development or outcome of infections
NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Questions?
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Quiz Time!
Question 1• TRUE OR FALSE: On Form 2000, you are
asked to complete a Form 2047 when the recipient has a positive HepB cAb but not a positive HepB sAb
33 NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Quiz Time!
Question 2JD, a 55 year old man with AML in CR2 underwent an unrelated alloHCT from a well-matched donor. On day 76, he is admitted from clinic for rapid onset severe diarrhea and low grade temp. He also notes visual change. He undergoes a rectal biopsy showing CMV inclusion bodies but no GVHD and his serum CMV PCR is positive for 80,000 copies. Ophthalmologic exam shows evidence of CMV retinitis. He is started on IV ganciclovir.
Seven days into admission, he develops profound hypotension and respiratory failure, and is intubated. Bronchoscopy reveals CMV inclusion bodies. Blood cultures grow Pseudomonas aeruginosa. The patient develops refractory hypotension, acute renal failure, and expires on hospital day 8 (day 83 of HCT).
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NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Quiz Time!
Question 2On which form(s) will these events be reported?1) Form 22002) Form 21003) Form 29004) Both 2 and 35) None of the above
35 NATIONAL MARROW DONOR PROGRAM®
Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match RegistrySM
Quiz Time!
Question 3How will you report the CMV infection for JD?1) Organism: CMV; and Sites: blood, eyes2) Organism: CMV; and Sites: blood, lower respiratory tract3) Organism: CMV; and Sites: disseminated
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