epidemiology of adenovirus infections l ubiquitous dna viruses l cause 5 -10% of febrile illnesses...
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Epidemiology of Adenovirus Infections
Ubiquitous DNA viruses Cause 5 -10% of febrile illnesses in
early childhood Nearly all adults have Abs to endemic
serotypes 1, 2, 5, or 6
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Clinical Manifestations
Vary according to the age and immune status of host
Different serotypes are associated with distinct syndromes
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Adenovirus Transmission
Easily transmissable to individuals w/o serotype-specific Ab
Specific epidemic serotypes» Pharyngoconjunctival fever in summer camps,
public swimming pools – Ad3, Ad7» Hemorrhagic keratoconjunctivitis in medical
facilities – Ad8, Ad37» Acute respiratory disease in military recruits – Ad4,
Ad7 Minimal infectious dose?
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Adenovirus Pneumonia
Adenoviruses cause about 10% of pneumonias in healthy children – Ad3, 7» Disease more severe in infants
Extrapulmonary symptoms may occur w/o viral-specific histopathology » Meningoencephalitis, hepatitis, myocarditis,
nephritis, neutropenia, DIC» Toxin?, Immune-mediated?
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Adenovirus Infections in Immunocompromised
Hosts
Range from asymptomatic shedding to fatal disseminated disease
Disease may result from » Primary infection» Reactivation of infection in patient» Reactivation of infection in donor organ
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Adenoviruses in Bone Marrow Transplant
Recipients
Wide range of clinical syndromes» Pneumonia» Gastroenteritis, hepatitis» Hemorrhagic cystitis, nephritis» Encephalitis, myocarditis
Incidence of infection higher in children vs. adults
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Adenovirus disease in BMT recipients
Mortality of invasive disease 50 -60% Risks factors for invasive disease
» Allogeneic transplants– especially T-cell depleted transplants
» GVHD» 2 or more culture-positive sites
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1985 Seattle Study
Reviewed 1051 BMT recipients» Patient characteristics
– Most had unmodified grafts from related matched donors
– Proportion of children not stated
Incidence of adenovirus infection 5% 1% incidence of disease (10)
» mortality 50%
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1994 Milwaukee Study
Reviewed 201 BMT recipients» Patient characteristics
– 85% T-cell depleted grafts– 50% unrelated or partially-matched donors– 40% children
Incidence of adenovirus infection 21% 6.5% incidence of disease (13)
» mortality of disease 54%
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1994 Milwaukee Study
Higher incidence of adenovirus infections in children
– 31% vs. 14% in adults
Earlier time of onset in children– mean <30 days vs. >90 days in adults
Ad35 and endemic types were most common isolates
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1999 Kentucky Study
Reviewed 532 BMT recipients» Patient characteristics
– 72% allogeneic– 40% T-cell depleted– 24% children
» Incidence of adenovirus infection 12%– Higher in children 23% vs. adults 9%
» Incidence of disease 7.7% (41)– Overall mortality 73%
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2000 Bristol Study
Reviewed 572 BMT recipients» Patient characteristics
– 45% had T-cell depleted grafts– 45% unrelated donors– 2/3 children
» Incidence of adenovirus disease 17% (100)– Incidence of infection not documented– Definition of disease not vigorous– Mortality much lower than other studies - 6%
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Solid Organ Transplantation
Adenovirus infection usually involves donor organ » Hepatitis in 3% pediatric liver transplants
– Mortality 50%
» Pneumonia in 1% lung transplants» Hemorrhagic cystitis in 1% renal
transplants– Mortality <20%
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Congenital Immunodeficiency
Syndromes
SCID patients may develop severe infections» Mortality 50% » Pneumonia and hepatitis are most frequent
syndromes Patients with Ig deficiencies have less
severe but more protracted illnesses
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Adenoviruses in AIDS Patients
Adenoviruses frequently isolated in stool and/or urine w/o symptoms
Case reports of fatal infections including» Hepatitis, pneumonia, encephalitis,
nephritis
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Adenoviruses in Cancer Patients
More common in children than adults Case reports of fatal infections including
» Pneumonia, hepatitis, encephalitis, nephritis
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Treatment
Discontinue immunosuppressive therapy
No antiviral documented to be of benefit» Cidofovir has best in vitro activity
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Cidofovir
Broad spectrum nucleoside mono-phosphate analog » Inc. HSV, VZV, CMV, EBV, HHV-6, HPV
Has in vitro activity against adenovirus» However resistance may develop
Active in rabbit eye model
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Therapy
Case reports » Hemorrhagic cystitis in BMT pts
– response to IV ribavirin or vidarabine
» Ad7 colitis in unrelated donor recipient d37– No response to IV ribavirin. – Sx resolved on cidofovir w/i 2 wks.
» Ad colitis and cholecystitis in AIDS pt– Prompt improvement with cidofovir
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Immunotherapy
IV IgG may be helpful for lower serotypes» Most preps have good titers of neutralizing
antibodies Case report using donor lymphocytes in
BMT recipient
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Immune Responses Against Adenoviruses
Cell-mediated immunity » Severe infections occur primarily in hosts
with cellular immune defects Humoral immunity
» Neutralizing antibodies protect against re-infection with same serotype
» By age 10, most have Ab to endemic types
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Adenovirus-specific T cell Responses
Most healthy adults have detectable proliferative and cytotoxic memory T cell responses
Adenovirus-specific T cells recognize epitopes conserved across different serotypes» In contrast to serotype-specific neut. Abs
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Pathogenesis
Direct lysis of susceptible cells Immunopathology? Persistence
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Adenovirus Persistence
Isolated from tonsils in asymptomatic children
Shed in stool for months post-infection Cases of transmission from donor
organs Cases of reactivation in BMT patients
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Transmission of adenovirus from solid
organ transplants
Cases reports» Renal transplant pts with Ad34/35
hemorrhagic cystitis– documented seroconversion to Ad34/35 c/w
with transmission from donor kidney (or primary infection)
» Pediatric liver transplant pts with Ad5 hepatitis
– 6/9 seronegative pre-transplant; donors Ab pos– Median time of onset 25 days
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Reactivation of adenovirus in BMT recipients
Cases reports» Ad5 hepatitis
– Ad5-specific neutralizing Ab present in pre-transplant sera
– c/w reactivation of endogenous virus
» Ad35 cystitis, nephritis, colitis – 6/6 adult pts had neutralizing Ab to own isolate
pre-transplant (PF data)
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Mechanism of Persistence
Remains episomal in long-lived lymphocytes?» Ad types 11,34,35 may establish
persistence more readily – Infect hematopoietic cells more efficiently than
other serotypes
Low level replication in tissue? Integration?
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Adenovirus Early Region 3
E3 region codes for proteins that inhibit host responses» Down-regulate MHC class I antigens» Inhibit lysis by tumor necrosis factor» Inhibit apoptosis by Fas
Reduces immunogenicity? Facilitates persistence?
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Adenovirus Persistence
Reservoirs?» Lymphoid tissue
– tonsils– Peyer’s patches in gut
» Kidney» Liver» Lung, brain – PCR data
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Are Lymphocytes a Reservoir?
Old data that PBMC from most donors positive for Ad2 by Southern blot
Not confirmed when assayed PBMC by PCR for Ad2 DNA» Used nested primers to E1A and hexon
– 72 of 73 asymptomatic children and adults were negative
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Adenovirus Reservoirs
Lung » Detected E1A by PCR in 20/20 biopsies from lung
cancer pts – Detected E1A by ISH in 2 pts– Detected E3 DNA by PCR in 10 pts– Authors suggest E1A may integrate into host DNA
Brain» Detected E1A in brain microglial cells by ISH and
immunohistochemical staining in 7/7 senile pts No negative controls
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Live Adenovirus Vaccine
Live type 4 and type 7 vaccines used for years in military» Enteric-coated for oral administration » Safe and effective
Example of safety of RCA» via oral route» in healthy military population
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RCA in Adenovirus Gene Therapy Vectors
Minimal infectious dose unknown» Likely dependent on multiple factors inc.
– Route of administration – Presence or absence of serotype-specific Ab
Severity of disease dependent on:» Route of administration» Status of cellular immunity» Serotype
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RCA in Adenovirus Gene Therapy Vectors
Elimination of RCA from E1-deleted vectors may be feasible» Altered 293 cell lines have been developed
that prevent E1 recombination events “Gutted” or helper-dependent vectors
» Must purify away from E1-deleted helper adenovirus and RCA
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Issue of Recombination
Recombination of E1-deleted vectors may occur in vivo with » persistent adenoviruses » newly acquired adenoviruses
Clinical significance?