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

Clinical Manifestations

Vary according to the age and immune status of host

Different serotypes are associated with distinct syndromes

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?

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?

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

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

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

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%

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%

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

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%

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%

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%

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

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

Adenoviruses in Cancer Patients

More common in children than adults Case reports of fatal infections including

» Pneumonia, hepatitis, encephalitis, nephritis

Treatment

Discontinue immunosuppressive therapy

No antiviral documented to be of benefit» Cidofovir has best in vitro activity

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

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

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

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

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

Pathogenesis

Direct lysis of susceptible cells Immunopathology? Persistence

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

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

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)

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?

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?

Adenovirus Persistence

Reservoirs?» Lymphoid tissue

– tonsils– Peyer’s patches in gut

» Kidney» Liver» Lung, brain – PCR data

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

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

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

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

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

Issue of Recombination

Recombination of E1-deleted vectors may occur in vivo with » persistent adenoviruses » newly acquired adenoviruses

Clinical significance?