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Adenovirus: An Overview for Pediatric Infectious Diseases Specialists
Clinical Prediction Rules
EDITORIAL BOARD
Co-Editors: Delane Shingadia and Irja Lutsar
Board Members
David Burgner (Melbourne, Australia)
Luisa Galli (Florence, Italy)
Cristiana Nascimento-Carvalho
(Bahia, Brazil)
Ville Peltola (Turku, Finland)
Nicole Ritz (Basel, Switzerland)
Ira Shah (Mumbai, India)
Matthew Snape (Oxford, UK)
George Syrogiannopoulos
(Larissa, Greece)
Tobias Tenenbaum (Mannhein, Germany)
Marc Tebruegge (Southampton, UK)
Marceline van Furth (Amsterdam,
The Netherlands)
Anne Vergison (Brussels, Belgium)
Adenovirus: An Overview for Pediatric Infectious
Diseases Specialists
Marc Tebruegge, MRCPCH, MSc, MD*†‡§ and Nigel Curtis, FRCPCH, PhD†‡§
A
denoviruses are nonenveloped doublestranded DNA viruses that were first isolated from adenoidal cells in 1953 as part of
a project searching for the virus causing the
common cold. There are currently 57 recognized serotypes of human adenovirus, which
can be divided into the subgroups (or species) A to G. There is tropism among these
subgroups, with subgroups A and F typically
causing infection of the gastrointestinal tract,
and subgroups B, C and E showing tropism
for the respiratory tract.1 Epidemic keratoconjunctivitis is predominantly caused by
serotypes of subgroup D.
ADENOVIRUS INFECTIONS IN THE
IMMUNOCOMPETENT HOST
Adenovirus is typically transmitted
from person-to-person by respiratory droplets, and less commonly by the conjunctival
and fecal–oral route. The incubation period
is relatively short, ranging between 2 and 14
days. Epidemiological data suggest that the
majority of adenovirus infections occur in
From the *Academic Unit of Clinical & Experimental
Sciences, Faculty of Medicine, University of
Southampton, United Kingdom; †Department of
Paediatrics, The University of Melbourne; ‡Infectious Diseases Unit, Royal Children’s Hospital
Melbourne; and §Murdoch Children’s Research
Institute, Parkville, Australia.
The authors have no funding or conflicts of interest
to disclose.
Address for correspondence: Marc Tebruegge,
MRCPCH, MSc, MD, Wellcome Trust Clinical
Research Facility, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD,
UK. E-mail: [email protected].
Copyright © 2012 by Lippincott Williams & Wilkins
ISSN: 0891-3668/12/3106-0626
DOI: 10.1097/INF.0b013e318250b066
the first 5 years of life, with a peak incidence
during the first 2 years.2,3 Adenovirus infections are common, accounting for approximately 5–15% of upper respiratory tract and
approximately 5% of lower respiratory tract
infections during childhood.2,4 In temperate
climates, the peak incidence of adenoviral respiratory infections occurs during the winter
months. In immunocompetent individuals,
adenovirus infections are generally mild and
self-limiting. Typical manifestations in immunocompetent children include pharyngitis, otitis media, bronchiolitis, gastroenteritis
and keratoconjunctivitis. Primary adenovirus
infection results in production of neutralizing antibodies, which are thought to confer
lifelong immunity against the particular serotype. However, some individuals shed adenovirus in the stool for weeks to months;
others develop longstanding asymptomatic
infection with persistence of adenovirus in
lymphoepithelial tissue. The latter phenomenon complicates the interpretation of results
in the transplant setting, as discussed in the
subsequent section.
ADENOVIRUS INFECTIONS IN THE
IMMUNOCOMPROMISED HOST
During the last 2 decades, adenovirus
has emerged as an important pathogen in immunocompromised individuals, particularly
in the transplant setting. Adenovirus infection
occurs in up to 40% of pediatric human stem
cell transplant (HSCT) recipients, and in approximately 5–10% of solid organ transplant
recipients.5–8 Further at-risk groups include
children with primary or secondary immunodeficiency, including those with severe
combined immunodeficiency or HIV infection, and children undergoing chemotherapy
for malignancy. It is important to note that
these patients frequently develop more severe
manifestations, such as hemorrhagic cystitis
and hemorrhagic enteritis, and, less commonly, encephalitis, pneumonitis, hepatitis,
nephritis and multiorgan failure. In the solid
organ transplant setting, adenovirus disease
typically affects the transplanted organ, the
underlying mechanism for which is incompletely understood. Well-documented risk
factors for adenovirus disease in the transplant setting include T cell depletion (eg, the
use of T cell–depleted grafts, alemtuzumab
or antithymocyte globulin), allogenic HSCT
and young age.1,6,9
DIAGNOSTIC METHODS
A wide range of diagnostic methods is
available for the detection of adenovirus infection. Conventional culture can take up to
5–10 days for a positive result; shell vial assays need shorter incubation times and have
high sensitivity. Direct immunofluorescence
staining provides more rapid results, and can
be done on nasopharyngeal aspirates, bronchoalveolar lavage fluid and conjunctival
scrapings. Serology has limited usefulness,
as a positive result may simply reflect previous infection. Nevertheless, a significant rise
in antibody titer in paired serum samples can
sometimes be informative. Polymerase chain
reaction, typically using primers that bind to
conserved regions in the hexon gene, has high
specificity and sensitivity, and is ideally suited for clinical samples from normally sterile
sites, including blood and cerebrospinal fluid.
The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved
independently by the Editorial Board of ESPID.
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The Pediatric Infectious Disease Journal • Volume 31, Number 6, June 2012
The Pediatric Infectious Disease Journal • Volume 31, Number 6, June 2012
Positive polymerase chain reaction results
from upper respiratory tract specimens (ie,
throat swabs and nasopharyngeal aspirates)
and stool samples are difficult to interpret, as
they may reflect viral shedding, rather than
being indicative of adenoviral disease. Currently, most transplant centers routinely use
real-time polymerase chain reaction, which
allows the quantification of viral load in
blood. Analysis of the viral load, particularly
when done serially, can provide valuable information to guide treatment decisions. There
is good evidence that a viral load >105 copies/
mL in blood and/or a 10-fold rise are poor
prognostic indicators. Measuring viral load
can also help in the monitoring of response
to treatment.1,9,10
TREATMENT OF ADENOVIRUS
DISEASE IN THE
IMMUNOCOMPROMISED HOST
The decision-making process for starting antiviral treatment for adenovirus in immunocompromised children is complex, and a
detailed discussion is beyond the scope of this
review, but can be found elsewhere.1 Factors
that have to be taken into account include the
age of the patient (prognosis is generally worse
in children compared with adults), the type of
transplant (prognosis is worse in HSCT than
in solid organ transplant), the degree and duration of immunosuppression and the likely time
frame for immune recovery. To date, there are
no published randomized controlled trials on
the treatment of adenoviral disease.
Most experts agree that in an asymptomatic patient, detection of adenovirus from
nasopharyngeal aspirates, urine or stool samples does not necessarily warrant treatment.
Conversely, most agree that treatment is indicated in a symptomatic patient in whom
adenovirus is detected from the corresponding site of the disease in the absence of an
alternative explanation. Currently, there is no
consensus on the treatment of immunocompromised patients with adenovirus viremia
alone. However, several centers have moved
to using preemptive treatment for all patients
in whom adenovirus is detected in blood (ie,
irrespective of viral load), which appears to
have led to a reduction in fatal outcome compared with historical figures.9,11
Currently, there are no antiviral agents
that are approved for the treatment of adenovirus. Furthermore, in the absence of
published randomized controlled trials the
optimal antiviral agent for treating adenovirus
disease remains uncertain. Antiviral agents
that have been shown to have activity against
adenovirus in in vitro or in animal models
© 2012 Lippincott Williams & Wilkins
include ganciclovir, zalcitabine, vidarabine
and ribavirin. Successful treatment with ribavirin has been reported in a number of immunocompromised patients.12–14 However, more
recent data have revealed that ribavirin only
has activity against species C adenoviruses
(serotypes 1, 2, 5, 6).15 The currently available data, despite their limitations, suggest
that cidofovir is the most effective drug for
the treatment of adenovirus disease. Recent,
comparatively large studies using cidofovir in
HSCT patients have reported a considerable
reduction in adenovirus-related mortality
compared with historical data.11,16 The optimal
dosing regimen for intravenous cidofovir remains controversial. Notably, data to support
the notion that a 1 mg/kg 3 times a week regimen is less nephrotoxic than the conventional
5 mg/kg once a week regimen remain limited.17 Recent reports on CMX001, an orally
bioavailable lipid formulation of cidofovir
that is potentially less nephrotoxic, have been
encouraging, but more data are needed.18,19 A
multicenter phase II/III study investigating
CMX001 is currently underway.
There is good evidence that reducing
immunosuppression has a substantial impact on the control of adenovirus disease in
transplant patients, and should therefore be
considered whenever possible.6,20 Directed
immunotherapy, including adoptive transfer
of adenovirus-specific T cells, in patients
who show poor response to antiviral treatment is likely to play an increasing role in the
future.21,22
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ESPID Reports and Reviews
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