Adenovirus and Bone Marrow Adenovirus and Bone Marrow Transplantation Transplantation

Stephen J. Chanock Immunocompromised Host SectionPediatric Oncology BranchNational Cancer Institute

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

The State of the Host Immune FunctionExposure to Primary Infection

Multiple Serotypes Provides for Recurrent RiskRe-activation

Underlying 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 proteinReflects heterogeneity of Adenovirus genome

DNA 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, TonsillopharyngitisB Hemorrhagic Cystitis, Respiratory TractC Endemic URI, TonsillopharyngitisD Keratoconjunctivitis (epidemic)E Conjunctivitis, Pharyngoconjunctival FeverF Gastroenteritis

Detection of AdenovirusDetection of Adenovirus

Culture:Inoculation into cell lines (i.e.A549)Fluorescent antibody staining

Tissue detectionin situ hybridizationSouthern blotPCR 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 tractMild illness lasts less than 10 daysLatency in lymphoid and renal tissueCommon 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 HostIn 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

DefinitionsDefinitionsInfection - 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 factorsAgeGVHD ConditioningT-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 children6% Adenovirus infectionRestricted to Hematologic MalignanciesDetection: 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 Cystitis7/13 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 BMTCompounded by Cyclophosphamide

Serotypes 11 and 35 (propensity for urinary tract)Ad35 infects neonates and establishes latency

until immunosuppressionScreening- 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 caseRibavirin (intravenous)Ganciclovir

Intravenous IgGDonor 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 mortalityChronic 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 FunctionExposure to Primary Infection

Multiple Serotypes Provides for Recurrent RiskRe-activation

Underlying events:“New alterations in Immune function”Co-infection

Oncogenic Potential

Future IssuesFuture Issues

Development of new antiviral therapiesUse of cytotoxic lymphocytes

(e.g., EBV, CMV)Early detection

Adenovirus PCR/Antigen detectionHost susceptibility factors

GeneticTherapy-induced

Adenovirus Infection in Gene Adenovirus Infection in Gene Transfer ProtocolsTransfer Protocols

Response and Site of InoculationHigh Risk Sites:PulmonaryHepatic

State of the Host Immune FunctionUndergoing ChangeIatrogenic vs Disease-Related

Recombination events between closely related serotypes