NavarroW ViralInfection3...– 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

Understanding Viral Infections in the Context of Hematopoietic

Cell Transplantation

Willis Navarro, MD Medical Director

Transplant Medical Services, NMDP

CRPDM Session -- February 1, 2012



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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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



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

5 NATIONAL MARROW DONOR PROGRAM®


Cellular and Humoral Immunity

6Source: http://www.zuniv.net/physiology/book/chapter32.html

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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



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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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



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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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)



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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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



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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Reporting Viral Infection Data



Prior Viral Exposure-Form 2000 Recipient Baseline Data

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Form 2048: HIV—Pre-HSCT Data

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YES: Lymphomas: (NHL, Hodgkin); NO: AML, ALL, MDS, SAA, CML




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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)



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


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



Yet More of Form 2004

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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



Infection Prophylaxis—Form 2100/2200

Antivirals

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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”



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



Example: Hepatitis Treatment



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



Infections at Follow-Up—Forms 2100, 2200

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Don’t forget to reportCMV viremia…



Form 2900:Cause of death codes

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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



Questions?

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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



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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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



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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Documents

NavarroW ViralInfection3...– Herpes Zoster –CMV –EBV • Some are newly acquired…e.g. –RSV – Influenza/Parainfluenza • Some could be either pre-existing or newly acquired