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Adenovirus and Bone Marrow Transplantation Stephen J. Chanock Immunocompromised Host Section...

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Marrow Marrow Transplantation Transplantation Stephen J. Chanock Immunocompromised Host Section Pediatric Oncology Branch National Cancer Institute
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Adenovirus and Bone Marrow Adenovirus and Bone Marrow Transplantation Transplantation

Stephen J. Chanock

Immunocompromised Host Section

Pediatric Oncology Branch

National Cancer Institute

Issues for Adenoviral Infection in Issues for Adenoviral Infection in the Immunocompromised Hostthe Immunocompromised Host

The State of the Host Immune Function

Exposure to Primary Infection

Multiple Serotypes Provides for Recurrent Risk

Re-activationUnderlying events:

“New alterations in Immune function”

Co-infection

Oncogenic Potential

Adenoviral SerologyAdenoviral Serology

Defined on the basis of standard reference panel of sera

Primary epitope: Capsid protein

Reflects heterogeneity of Adenovirus genomeDNA Homology Groups

Specific serotypes are associated with specific clinical manifestations

Clinical Features of Infection Vary Clinical Features of Infection Vary Among DNA Homology GroupsAmong DNA Homology Groups

A URI, Tonsillopharyngitis

B Hemorrhagic Cystitis, Respiratory Tract

C Endemic URI, Tonsillopharyngitis

D Keratoconjunctivitis (epidemic)

E Conjunctivitis, Pharyngoconjunctival Fever

F Gastroenteritis

Detection of AdenovirusDetection of Adenovirus

Culture:

Inoculation into cell lines (i.e.A549)

Fluorescent antibody staining

Tissue detection

in situ hybridization

Southern blot

PCR detection

Adenovirus Infection in the Adenovirus Infection in the Healthy ChildHealthy Child

>80% between 1 and 5 years have antibody to one or more serotypes

Most common site: Upper respiratory tract

Mild illness lasts less than 10 days

Latency in lymphoid and renal tissue

Common serotypes; 1, 2, 3, 5 ,7 and 41

Clinical Syndromes Associated Clinical Syndromes Associated with Adenoviral Infection in the with Adenoviral Infection in the

Normal HostNormal Host

In order of decreasing frequency: Pharyngitis Conjunctivitis Gastroenteritis Pneumonia Hemorrhagic Cystitis (young children)

Epidemiology of Adenoviral Epidemiology of Adenoviral Infection in the Normal HostInfection in the Normal Host

Infection rate– 40.8/100 person years, below age 1– 14.4/100 person years, above age 10

Acute Disease– 5% of URI– 8% of childhood pneumonia (3, 4 & 21)– Adult pneumonia (3, 4 & 7)– Subgenus 1, 2 & 5 particularly common during

infancy

DefinitionsDefinitions

Infection - Isolation of adenovirus from sterile (excluding gastrointestinal tract)

Disease - Positive culture from sterile site,

Typical adenoviral nuclear inclusion

+

Clinical signs and symptoms

Clinical Syndromes Associated Clinical Syndromes Associated with Adenoviral Infection in the with Adenoviral Infection in the

Immunocompromised HostImmunocompromised Host Disseminated disease (including two or more of

each of below)

Pneumonia Fulminant hepatits/pancreatitis Colitis/gastroenteritis Hemorrhagic cystitis Encephalitis (rare)

Distinct Serotypes Cause Disease in Distinct Serotypes Cause Disease in the Immunocompromised Hostthe Immunocompromised Host

Serotypes 5, 11, 34 & 35 commonly isolated from immunocompromised adults

Series of 46 patients with Adeno 35: – 36 AIDS – 5 BMT – 1 Renal transplant recipient– 1 SCID – 3 Healthy

Lessons Learned from Patients with Primary or Lessons Learned from Patients with Primary or other Secondary Immunodefcienciesother Secondary Immunodefciencies

Sporadic neonatal adenoviral pneumonia is severe but localized outbreaks have been reported

SCID population at high risk- even with benign serotypes Severe morbidity and mortality

DiGeoge syndrome-case reports of fatal hepatic necrosis Solid organ transplant-

– Infection of transplanted organ

– Source: reactivation and donor AIDS patients-

– Co-infection with other pathogens

– Diversity of serotype isolated

Adenovirus Infection and BMTAdenovirus Infection and BMT

Mortality:

18-60% (Hierholzer 1992)

Risk factors

Age

GVHD

Conditioning

T-cell depletion/HLA

Adenoviral Infection in BMTXAdenoviral Infection in BMTX

Risk for Adverse Outcomes:

Multiple sites (disseminated)

Serotype– 11, 34, 35 for hemorrhagic cystitis– 2,5,7,9 for pulmonary disease in young patients

Co-infection with Opportunistic Infection

Adenoviral Infections in BMT Adenoviral Infections in BMT PatientsPatients

Adenoviral infection 20.9%, adenoviral disease 6.5% in 201 BMT patients (Flomenberg 1994)

Risk Factors for Disease

– Isolation of virus from multiple sites

– Moderate to severe aGVHD

– Infection more common in children (31.3% vs. 13.6%) Time of onset of post transplant

– Pediatric, mean <30 days

– Adults, mean > 90 days ??Significance of primary infection

Adenoviral Infections in BMT Adenoviral Infections in BMT PatientsPatients

1300 adult patients (Mirza 1995)

– Allogeneic 6% vs. 1% in autologous

– GVHD not a risk factor

– 40% fatal, 50% self-limited , 10% asymptomatic Incidence 4.9% in 1051 (Shields 1985)

– 9.8% death rate due to adenovirus

– GVHD only risk factor for occurrence Incidence 13.5% among 74 T-cell-depleted allogenic BMT

patients (Blanke 1995)

– 50% adenovirus-related mortality

– GVHD and co-infection non-contributory

Adenoviral Infections in BMT Adenoviral Infections in BMT Pediatric Patients IPediatric Patients I

96 children reported by Wasserman (1988)

– Adenovirus in 18%, more common than adults– 20% with GVHD and 17% without GVHD– Ad12, uncommon in normal host, recovered

from 4 patients– Major risk factor: preconditioning regimen

Adenoviral Infections in BMT Adenoviral Infections in BMT Pediatric Patients IIPediatric Patients II

Hale (1999):Retrospective study of 206 children

6% Adenovirus infection

Restricted to Hematologic Malignancies

Detection: Median of 54 d (-4 to +333)

Type of graft:

Mismatch/MUD 11.6%

HLA-match sib 7.7%

Autograft 1.1%

Adenoviral Infections in BMT Adenoviral Infections in BMT Pediatric Patients IIIPediatric Patients III

Hale et al. (cont.)

Most Common: Hemorrhagic Cystitis

7/13 died (only 1 clearly due to adenovirus)

Sites involved: 1.77 (range 1-4)

Risk factors:TBI: OR=14.11 (by univariate and multiple logistic regression analysis)

Type of graft OR=9.92 (univariate only)

Hemorrhagic Cystitis and Hemorrhagic Cystitis and Adenovirus Infection in BMTAdenovirus Infection in BMT

Major complication in BMT

Compounded by Cyclophosphamide

Serotypes 11 and 35 (propensity for urinary tract)

Ad35 infects neonates and establishes latency until immunosuppression

Screening- Unproven

Primary Disease vs. Primary Disease vs. Reactivation Reactivation

Reactivation has been implicated in the majority of disease

Incidence of primary infection may be higher in children

Case reports of primary infection and fatal adenoviral disease in infants

Might expect an increased incidence of primary infection as more infants undergo BMT

Source of Adenovirus in BMT Source of Adenovirus in BMT PatientsPatients

Primary Infection

– Case reports document fatal primary infection

– Will primary infections increase as more infants receive BMT?

Re-infection

– Nosocomial transmission documented

– Altered susceptibility to re-infection?

Reactivation

– Incidence of viral gastroenteritis as high as 15 to 20%

Treatment of Adenovirus Treatment of Adenovirus Infection in BMTInfection in BMT

Treatment options are limited because no effective therapy is available

Antivirals:Poor record, occ. anecdotal case

Ribavirin (intravenous)

Ganciclovir

Intravenous IgG

Donor pool may not have sufficient serotype specific antibodies (i.e., 11, 35)

Adenoviruses in HIV InfectionAdenoviruses in HIV Infection

1. Not a major source of morbidity and mortality

Chronic diarrhea

2. Increased excretion in urine (esp serotype 35)

12% overall- mainly Group B (

Question of recombination 7 and 34 (closely related serotypes)

3. New serotypes identified

Issues for Adenoviral Infection in Issues for Adenoviral Infection in the Immunocompromised Hostthe Immunocompromised Host

The State of the Host Immune Function

Exposure to Primary Infection

Multiple Serotypes Provides for Recurrent Risk

Re-activationUnderlying events:

“New alterations in Immune function”

Co-infection

Oncogenic Potential

Future IssuesFuture Issues

Development of new antiviral therapies

Use of cytotoxic lymphocytes

(e.g., EBV, CMV)

Early detection

Adenovirus PCR/Antigen detection

Host susceptibility factors

Genetic

Therapy-induced

Adenovirus Infection in Gene Adenovirus Infection in Gene Transfer ProtocolsTransfer Protocols

Response and Site of Inoculation

High Risk Sites:

Pulmonary

Hepatic

State of the Host Immune Function

Undergoing Change

Iatrogenic vs Disease-Related

Recombination events between closely related serotypes


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