Adenovirus and Bone Marrow Transplantation

1
Adenovirus and Bone Marrow
Transplantation

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

2
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

3
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

4
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

5
Detection of Adenovirus

• Culture
• Inoculation into cell lines (i.e.A549)
• Fluorescent antibody staining
• Tissue detection
• in situ hybridization
• Southern blot
• PCR detection

6
Adenovirus Infection in the Healthy Child

• gt80 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

7
Clinical Syndromes Associated with Adenoviral
Infection in the Normal Host

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

8
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

9
Definitions

• Infection - Isolation of adenovirus from sterile
  (excluding gastrointestinal tract)
• Disease - Positive culture from sterile site,
• Typical adenoviral nuclear inclusion
• Clinical signs and symptoms

10
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)

11
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

12
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

13
Adenovirus Infection and BMT

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

14
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

15
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 lt30 days
• Adults, mean gt 90 days
• ??Significance of primary infection

16
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

17
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

18
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

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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 OR14.11 (by univariate and multiple
  logistic regression analysis)
• Type of graft OR9.92 (univariate only)

20
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

21
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

22
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

23
Treatment of Adenovirus Infection in BMT

• Treatment options are limited because no
  effective therapy is available
• AntiviralsPoor record, occ. anecdotal case
• Ribavirin (intravenous)
• Ganciclovir
• Intravenous IgG
• Donor pool may not have sufficient serotype
  specific antibodies (i.e., 11, 35)

24
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

25
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

26
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

27
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