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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