# Presentation: 102545

## Adenovirus and Bone Marrow             Transplantation       

- Adenovirus and Bone Marrow             Transplantation

- Stephen J. Chanock
- Immunocompromised Host Section
- Pediatric Oncology Branch
- National Cancer Institute

## Issues for Adenoviral Infection in the Immunocompromised Host

- The State of the Host Immune Function
- Exposure to Primary Infection
- 	Multiple Serotypes Provides for Recurrent Risk
- Re-activation
- Underlying events:
- “New alterations in Immune function”
- Co-infection
- Oncogenic Potential

## Adenoviral Serology

- Defined on the basis of standard reference panel of sera
- Primary epitope: Capsid protein
- Reflects heterogeneity of Adenovirus genome
- DNA Homology Groups
- Specific serotypes are associated with specific clinical manifestations

## Clinical Features of Infection Vary Among 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 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 Healthy 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 with Adenoviral Infection in the Normal Host

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

## Epidemiology of Adenoviral Infection 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

## Definitions		

- _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 with Adenoviral Infection in the Immunocompromised 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 the 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 other 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 BMT

- Mortality:
- 	18-60% (Hierholzer 1992)
- 	Risk factors
- 		Age
- 		GVHD
- 		Conditioning
- 			T-cell depletion/HLA

## Adenoviral 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 Patients

- 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 Patients

- 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 Pediatric 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 Pediatric 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 Pediatric 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 Adenovirus 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. 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 Patients

- 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 Infection 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 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 the Immunocompromised Host

- The State of the Host Immune Function
- Exposure to Primary Infection
- 	Multiple Serotypes Provides for Recurrent Risk
- Re-activation
- Underlying events:
- “New alterations in Immune function”
- Co-infection
- Oncogenic Potential

## Future 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 Transfer 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