22/10/22, 16:02 Diagnosis, treatment, and prevention of adenovirus infection - UpToDate

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Diagnosis, treatment, and prevention of adenovirus

infection
Authors: Flor M Munoz, MD, MSc, Phyllis Flomenberg, MD
Section Editors: Martin S Hirsch, MD, Morven S Edwards, MD
Deputy Editors: Sheila Bond, MD, Mary M Torchia, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2022. | This topic last updated: May 11, 2022.

INTRODUCTION

Adenoviruses are a family of deoxyribonucleic acid (DNA) viruses that are an important cause of
febrile illnesses in young children. They are most frequently associated with upper respiratory
tract syndromes such as pharyngitis or coryza but can also cause pneumonia. Less commonly,
adenoviruses cause gastrointestinal, ophthalmologic, genitourinary, neurologic, and
disseminated disease. Most adenoviral diseases are self-limiting, although fatal infections can
occur in immunocompromised hosts and occasionally in healthy children and adults.

The available diagnostic tests and strategies for treatment and prevention of adenovirus
infection will be reviewed here. The virology, epidemiology, and clinical manifestations of
adenovirus infection are discussed separately. (See "Pathogenesis, epidemiology, and clinical
manifestations of adenovirus infection".)

OVERVIEW

Since adenoviruses are associated with a variety of clinical syndromes and nonspecific
manifestations, diagnosis based upon clinical criteria alone is challenging. The diagnosis of
adenovirus disease should be confirmed in outbreaks of infection and in individual patients
with serious disease manifestations. Confirmation of adenovirus infection is important in order
to decide on the use of antiviral agents, exclude other treatable infections, establish a
prognosis, and initiate infection control measures when appropriate.

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DIAGNOSTIC TESTS

A number of different approaches are available for the specific diagnosis of adenovirus
infection ( table 1). Viral culture, adenovirus-specific viral antigen assays, and polymerase
chain reaction (PCR) assays are used most frequently.

Viral culture — All adenovirus serotypes except types 40 and 41 cause a characteristic

cytopathic effect (CPE) in human epithelial cell lines such as HeLa, A549, or HEp2 and in primary
human embryonic kidney cells. CPE generally occurs within 2 to 7 days with the common lower
serotypes, but some others, especially subgroup D serotypes (which cause epidemic
keratoconjunctivitis [EKC]), can require up to 28 days.

Adenoviruses are relatively stable and can be readily recovered from clinical samples early in
the course of the disease. Appropriate samples include nasopharyngeal swabs or aspirates,
throat swabs or washes, sputum, tracheal aspirates, bronchoalveolar lavage (BAL) fluid,
conjunctival swabs or scrapings, stool or rectal swabs, urine, blood, cerebrospinal fluid (CSF),
and tissue samples. Swabs and tissue biopsies should be placed in a viral transport medium to
prevent drying and to inhibit bacterial overgrowth. Specimens should be transported to the
laboratory on ice. The duration of viral excretion at the time of acute disease is approximately
one to three days from throat in adults with upper respiratory infection; three to five days from
nose, throat, and eye in patients with pharyngoconjunctival fever; and two weeks from eye
cultures in patients with keratoconjunctivitis. Viral excretion may be prolonged (for weeks) in
young children [1-4].

After acute infection, adenoviruses may be intermittently excreted in stool (or upper respiratory
tract, less commonly) for months in some patients. In immunocompromised hosts,
adenoviruses may be continuously shed from stool or urine for months without symptoms.
Therefore, a positive culture result needs to be interpreted based upon the current clinical
manifestations. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus
infection".)

Viral antigen assay — Direct detection of adenovirus antigens in clinical samples may be

performed by an adenovirus-specific enzyme immunoassay (EIA) or immunofluorescence assay.
These assays are more rapid but less sensitive than viral culture for the detection of most
serotypes [5]. They are insufficiently sensitive for diagnosis in immunocompromised hosts [6].

Commercially available assays use adenovirus-specific monoclonal antibodies that react with
common antigenic determinants on all serotypes. In particular, antigen assays are the test of

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choice for the detection of the fastidious adenovirus types 40 and 41 in stool samples [7]. These
enteric adenoviruses are an important cause of diarrhea in infants.

Another application for direct antigen assays is in the rapid diagnosis of EKC. (See 'Epidemic
keratoconjunctivitis' below.)

Direct adenovirus antigen assays can also be used to screen cell cultures before the
development of CPE, as well as to confirm the presence of adenovirus in cell cultures positive
for CPE.

Polymerase chain reactions — PCR is a highly sensitive and specific assay that can be used to
detect adenovirus DNA from a variety of clinical specimens including fixed tissues. PCR is
particularly helpful in samples from normally sterile sites such as blood, CSF, and tissues. A
positive result from upper respiratory tract or stool samples is more difficult to interpret as it
may represent virus shedding rather than symptomatic infection. Therefore, PCR results must
be interpreted in the context of the clinical findings of adenovirus disease. Because different
adenovirus serotypes are heterogeneous at the DNA level, PCR primers may be selected to
detect specific serotypes or related serotypes [8]. Commercial adenovirus PCR assays use
universal primers and probes that detect most or all serotypes [9,10].

Detection of adenovirus DNA in the blood by quantitative PCR is increasingly utilized for the
evaluation of adenovirus infections in immunocompromised patients [9,11]. Studies have
demonstrated an association between rising or high-level viremia and the risk of both invasive
disease and mortality [12,13]. In addition, quantification of adenovirus DNA can be used to
assess response to antiviral treatment [14-17]. In one study, a greater than 10-fold decrease in
viral load one week after the first dose of antiviral therapy was associated with a favorable
clinical course, whereas all patients with fatal disease failed to show a significant reduction in
viral load [14]. PCR can also be used in conjunction with sequencing in order to rapidly
genotype adenovirus isolates [18]. (See 'Serotyping and genotyping' below.)

PCR has been used to diagnose adenovirus myocarditis. Routine viral cultures and
histopathology are rarely positive in cases of presumed viral myocarditis. In one study, 38
myocardial tissue samples from 34 patients with acute myocarditis and 17 control patients with
congenital heart disease or hypertrophic cardiomyopathy were tested by PCR for adenovirus
and enterovirus [19]. Although enteroviruses have been implicated as the major etiology of viral
myocarditis, adenovirus DNA was detected more commonly (15 samples) than enterovirus DNA
(8 samples). All control samples were negative. In another report, PCR was used to make a
diagnosis of intrauterine adenovirus myocarditis [20]. (See "Myocarditis: Causes and
pathogenesis", section on 'Adenovirus' and "Clinical manifestations and diagnosis of

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myocarditis in adults", section on 'Identifying the cause of myocarditis' and "Clinical

manifestations and diagnosis of myocarditis in children", section on 'Endomyocardial biopsy'.)

In addition, detection of adenovirus by PCR in heart biopsies of cardiac transplant recipients

may correlate with increased graft loss [21].

Histopathologic studies — Definitive diagnosis of adenovirus disease may require tissue

biopsy. Specimens should be obtained for both pathology and viral culture or PCR because
routine histopathology may be nonspecific, especially in the early stages of infections.

Adenoviruses can cause characteristic intranuclear inclusions ( picture 1) [22]. Early post-
infection, cells may display small eosinophilic inclusions. During the later stages of infection,
basophilic inclusions appear, which initially may be surrounded by a clear halo within the
nucleus. When these intranuclear inclusions enlarge and obscure the nuclear membrane, the
cells are referred to as "smudge" cells ( picture 1). Occasionally, adenovirus inclusions may be
confused with cytomegalovirus (CMV) inclusions, but, unlike CMV, adenoviruses cause neither
intracytoplasmic inclusions nor multinucleated cells [23].

If routine histopathology is non-diagnostic and viral culture of tissue is negative (or not done),
more specialized tests may be performed on tissue samples. Electron microscopy can be used
to detect the characteristic icosahedral virions that typically form large paracrystalline
aggregates with the nuclei of infected cells [24]. Adenovirus-specific immunohistochemical
assays and in situ DNA assays are also available [25,26].

Serology — Recent infection may be documented by assay of paired acute and convalescent

sera for adenovirus-specific antibodies [27]. It is important to document a fourfold or greater
rise in antibody titer because there is a high prevalence of anti-adenovirus antibodies in the
general population, and there are numerous cross-reactions between related serotypes.

Commercially available EIAs and complement fixation assays measure adenovirus-specific anti-
hexon antibodies but do not provide information about the serotype. In contrast, detection of
hemagglutination inhibition antibodies or neutralizing antibodies is more sensitive and is
serotype specific. These assays are primarily performed in reference laboratories and are best
interpreted when the patient's sera is tested against the patient's own isolate.

Serotyping and genotyping — After recovery of a clinical isolate on tissue culture, further

evaluation can be performed by serotype analysis in a reference virology laboratory. Certain
serotypes are associated with distinct clinical manifestations ( table 2). (See "Pathogenesis,
epidemiology, and clinical manifestations of adenovirus infection".)

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The serotype is determined by first grouping the isolate by hemagglutination pattern with rat
and rhesus red blood cells. Then, hemagglutination inhibition and/or serum neutralization
assays can be performed using a selected panel of type-specific sera. Genotyping can also be
accomplished by PCR and sequencing, which is substantially faster than the traditional
serotyping methods, although it is not widely available. (See 'Polymerase chain reactions'
above.)

Restriction endonuclease analysis — Restriction endonuclease (RE) analysis can distinguish

between different clinical isolates of the same serotype. RE analysis is useful for epidemiologic
analysis (eg, during outbreaks of adenovirus infection). As an example, RE was used to analyze
isolates obtained during an outbreak of EKC caused by adenovirus serotype 8 [28]. In this
epidemic, cases occurred simultaneously in two childcare centers, followed by prolonged
outbreaks within the community and among staff at the local hospital. RE analysis of the
genomes of five isolates revealed they were identical and distinct from the prototype
adenovirus serotype 8, supporting the conclusion that the cases in the larger outbreak were
connected.

DIAGNOSTIC TESTS OF CHOICE FOR DIFFERENT ADENOVIRUS SYNDROMES

The diagnostic test of choice varies depending upon the clinical scenario ( table 3).

Upper respiratory illness — Adenoviruses should be suspected as one of the causes of febrile

illnesses with respiratory symptoms in infants and young children. Adenoviruses are a common
cause of tonsillitis in young children. Conjunctivitis accompanied by pharyngeal symptoms,
known as pharyngoconjunctival fever, is a characteristic, though less frequent, adenovirus
syndrome. Adenoviruses are also implicated in outbreaks of febrile respiratory disease in
summer camps and swimming pools. (See "Pathogenesis, epidemiology, and clinical
manifestations of adenovirus infection", section on 'Respiratory tract'.)

When warranted, such as during an epidemic, diagnosis can be confirmed by viral culture of the
nasopharynx or throat. If viral culture is unavailable, the specimen may be tested with the less
sensitive adenovirus-specific enzyme-linked immunosorbent assay (ELISA).

The differential diagnosis includes:

● Rhinovirus (see "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus

infections")

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● Influenza (see "Seasonal influenza in children: Clinical features and diagnosis", section on
'Whom to test' and "Seasonal influenza in adults: Clinical manifestations and diagnosis")

● Respiratory syncytial virus (see "Respiratory syncytial virus infection: Clinical features and
diagnosis", section on 'Laboratory confirmation')

● Parainfluenza (see "Parainfluenza viruses in children", section on 'Diagnosis' and

"Parainfluenza viruses in adults", section on 'Diagnosis')

Epidemic keratoconjunctivitis — Adenoviruses are the most common cause of epidemic

keratoconjunctivitis (EKC), a syndrome characterized by eye pain and inflammation, fever, and
preauricular lymphadenopathy. EKC is highly contagious and often occurs in outbreaks.

It is best to obtain conjunctival swabs for both viral culture and adenovirus-specific ELISA or
polymerase chain reaction (PCR) assay to make a diagnosis of EKC, since subgroup D isolates,
which are frequently implicated, can take two to four weeks to grow in tissue culture.

A rapid (10-minute) point-of-care immunoassay for adenoviral conjunctivitis is commercially

available [29]. In a prospective multicenter study, it had a sensitivity of 90 percent and
specificity of 96 percent compared with viral culture and a sensitivity of 85 percent and
specificity of 98 percent when compared with PCR [30]. In a subsequent study in the emergency
department setting, sensitivity was 39.5 percent and specificity was 95.5 percent compared with
PCR [31]. Given the broad range for sensitivity, negative results do not exclude adenovirus
conjunctivitis.

The differential diagnosis includes bacterial conjunctivitis as well as other viral pathogens such
as enteroviruses and herpes simplex virus. (See "Conjunctivitis", section on 'Bacterial
conjunctivitis' and "Enterovirus and parechovirus infections: Clinical features, laboratory
diagnosis, treatment, and prevention", section on 'Ocular infections' and "Epidemiology, clinical
manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Keratitis'.)

Pneumonia — Adenoviruses are an important etiology of fever and interstitial pulmonary

infiltrates in infants and children. Although uncommon in adults, there have been well-
described outbreaks of adenovirus pneumonia among military recruits and among adults in
chronic care facilities [32,33]. A diagnosis can be made by viral culture, direct antigen assay, or
PCR assay on a nasopharyngeal aspirate or swab, throat swab, sputum sample, or
bronchoalveolar lavage fluid.

Multiplex PCR assays that detect a panel of respiratory viruses including adenovirus from
nasopharyngeal specimens are especially useful for evaluation of hospitalized patients with

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suspected respiratory viral pneumonia or other influenza-like illness [34,35]. However, in a

prospective study that compared the prevalence of viruses in the upper respiratory tracts of
children and adults with community-acquired pneumonia with the prevalence in asymptomatic
controls, detection of adenovirus was associated with pneumonia only in children <2 years of
age [36]. This suggests that adenovirus may not be the causative pathogen of pneumonia in all
patients in whom it is detected (especially in those ≥2 years of age).

The differential diagnosis includes:

● Respiratory syncytial virus (see "Respiratory syncytial virus infection: Clinical features and
diagnosis", section on 'Laboratory confirmation')

● Influenza (see "Seasonal influenza in children: Clinical features and diagnosis", section on
'Whom to test' and "Seasonal influenza in adults: Clinical manifestations and diagnosis")

● Parainfluenza (see "Parainfluenza viruses in adults", section on 'Diagnosis' and

"Parainfluenza viruses in children", section on 'Diagnosis')

● Human metapneumovirus (see "Human metapneumovirus infections", section on 'Clinical

manifestations')

Diarrhea in young children — Although norovirus is the more common pathogen, enteric

adenoviruses (types 40 or 41) can cause a prolonged diarrheal syndrome in infants, especially in
the setting of clusters (eg, in daycare centers or as a healthcare-associated infection). The test
of choice is an adenovirus-specific PCR or ELISA on a stool specimen because enteric
adenoviruses do not grow on routine tissue culture. Symptoms are self-limited and treatment is
supportive. Strict infection control methods in daycare centers may help to prevent
transmission.

Hepatitis — Beginning in October 2021, adenovirus has been associated with clusters of

unexplained severe hepatitis in previously healthy children in the United Kingdom, the United
States, and multiple other countries, but causality has not been confirmed. During the
outbreak, the United States Centers for Disease Control and Prevention provides guidance for
adenovirus testing and typing in children being evaluated for acute hepatitis of unknown
etiology. (See "Acute liver failure in children: Etiology and evaluation", section on 'Outbreak
2022' and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection",
section on 'Acute hepatitis'.)

The evaluation for adenovirus hepatitis in immunocompromised hosts is discussed below.

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Infections in immunocompromised hosts — Adenoviruses cause a wide range of clinical

syndromes in immunocompromised hosts, including pneumonia, hemorrhagic cystitis,
nephritis, colitis, hepatitis, encephalitis, and disseminated disease. Adenovirus infections
commonly occur in immunocompromised children resulting from either reactivation of latent
infection or primary infection. Because adenoviruses may be shed asymptomatically in throat,
stool, or urine, it is often necessary to obtain tissue to diagnose some types of disease. (See
"Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on
'Infections in immunocompromised hosts'.)

Adenoviruses may cause severe, sometimes fatal, disease in hematopoietic stem cell transplant
recipients. After hematopoietic stem cell transplantation, recovery of T cell function and
adenovirus-specific T cells has been associated with a favorable outcome [37,38]. Recipients of T
cell-depleted grafts or those with graft-versus-host disease are at highest risk for disease and
mortality. (See "Overview of infections following hematopoietic cell transplantation".)

The specific diagnosis of adenovirus infection in immunocompromised patients may require the
use of multiple diagnostic modalities on various specimens. PCR, viral culture, or direct antigen
assays of upper nasopharyngeal, throat, urine, and stool or rectal samples will detect viral
shedding. Results should be interpreted in the context of clinical manifestations consistent with
adenovirus infection. In addition, testing of blood and affected sites (including lower respiratory
tract secretions collected by tracheal aspirate or bronchoalveolar lavage in patients with
pneumonia; urine in patients with hemorrhagic cystitis; cerebrospinal fluid in patients with
central nervous system involvement; and tissue biopsy in patients with pneumonia, colitis,
nephritis, or hepatitis) may be needed to diagnose adenovirus infection. Quantitative PCR of
blood is helpful to establish a diagnosis, evaluate risk for dissemination and prognosis, and
monitor response to antiviral therapy [13-17,39].

As has been shown for cytomegalovirus (CMV) infections, early identification of patients at risk
for adenovirus disease by monitoring for viremia by PCR is beneficial; thus, some centers have
adopted routine weekly surveillance measures for pediatric recipients of allogeneic
hematopoietic stem cell transplants [13,40-42]. If viremia is detected, then patients should be
carefully evaluated for evidence of disease, such as pneumonia, hepatitis, cystitis, and colitis,
and specimens should be obtained for adenovirus testing from affected sites. Although viremia
is self-limited in some patients, a rising viral load has been associated with invasive disease
[12,13]. In contrast to CMV, the benefit of preemptive treatment based on viremia alone has not
been established for adenovirus and is not currently recommended because of the toxicity of
the most commonly used antiviral agent, cidofovir. Further clinical studies are also needed to
identify effective and safe treatments. (See 'Treatment' below.)

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TREATMENT

Most adenovirus infections are self-limited and treatment is supportive. However, adenovirus
infections can be fatal in neonates and immunocompromised hosts and rarely in healthy
children and adults. Antiviral therapy is generally reserved for patients with severe adenovirus
disease, the majority of whom are immunocompromised.

Approach to antiviral therapy — Cidofovir has been the antiviral agent most frequently used
to treat adenovirus infections, but severe nephrotoxicity is a major dose-limiting toxicity.
Brincidofovir, an experimental lipid ester of cidofovir that has lower potential for nephrotoxicity
than cidofovir, is being studied for adenovirus but is no longer available for use through an
expanded access protocol [43].

Given the potential toxicities of the therapy for adenovirus infections (especially nephrotoxicity
with cidofovir), an infectious diseases specialist should be consulted when treatment is being
considered.

There have been no controlled trials demonstrating benefit for any antiviral agent in human
adenoviral disease.

Antiviral agents

Cidofovir — Cidofovir appears more active against adenovirus in vitro than other antiviral
drugs such as ganciclovir [44] and also appears active in vivo as demonstrated by reductions in
adenoviral load measured by real-time polymerase chain reaction (PCR) [14,15]. Published data
on the efficacy of cidofovir for adenovirus infection in humans are limited to case reports and
small nonrandomized studies [14,15,45-49]. In hematopoietic stem cell and lung transplant
recipients, cidofovir therapy has been associated with clinical improvement and a suggestion of
increased survival [15,45-47].

Prior to the use of cidofovir, the mortality in patients with invasive adenoviral disease following
allogeneic hematopoietic cell transplantation (HCT) varied from 25 to 75 percent in different
series [50,51], with the higher rates being described in patients with pneumonia and
disseminated disease [15,51,52]. In contrast, the mortality rate from adenoviral disease was
only 19 percent in a review of 70 published cases of definite or probable adenovirus infection
treated with two or more doses of cidofovir; most of these patients were severely
immunocompromised (eg, graft-versus-host disease and/or T cell-depleted allografts) [15].
However, in a report of 11 severely immunocompromised patients with adenovirus infection
who were treated with cidofovir, five died, including all three with pneumonia [53]. Therefore,

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although early diagnosis and treatment of adenovirus infections in this patient population may
improve outcomes, lymphocyte reconstitution also appears crucial for recovery from disease
[54].

Nephrotoxicity is a major dose-limiting factor for cidofovir. As a result, doses of 1 mg/kg every
other day or three times per week instead of the standard treatment dose of 5 mg/kg weekly
have been used in an attempt to reduce this toxicity [47]. Cidofovir can also cause a Fanconi-
type syndrome, with proteinuria, glucosuria, and bicarbonate wasting. When cidofovir is used, it
is given together with probenecid and aggressive hydration. Renal function, urine protein, and
electrolytes must be monitored closely. Further clinical studies are needed to assess the efficacy
and the nephrotoxicity of cidofovir in various dosing schedules. (See "Cidofovir: An overview".)

Little is known about the appropriate duration of therapy. In patients who tolerate cidofovir, it is
often continued until resolution of symptomatic disease or viremia. The decision of how long to
continue therapy should be made on a case-by-case basis.

Brincidofovir — Brincidofovir, an oral lipid ester of cidofovir, is an investigational agent that is

being studied for the treatment of adenovirus infections [55,56]. This class of agents exhibits
enhanced in vitro activity against adenoviruses [57] and has lower potential for nephrotoxicity
than cidofovir [58]. Diarrhea has been reported as the most common side effect [59].

In a report of therapy with brincidofovir in 13 immunocompromised patients (including 11

allogeneic HCT recipients), 9 of 13 demonstrated a virologic response [55]. Patients with a
virologic response had longer survival than those without a virologic response (median 196
days versus 55 days).

In a randomized trial that compared brincidofovir once per week, twice per week, and placebo
for asymptomatic adenovirus viremia (>100 copies/mL) in 48 allogeneic HCT recipients with
asymptomatic adenovirus viremia (>100 copies/mL), no reduction in treatment failure (disease
or rising viremia) was detected with brincidofovir compared with placebo [56]. However, in a
post hoc analysis of patients with viremia >1000 copies/mL, significantly more patients assigned
to twice weekly brincidofovir than to placebo had undetectable viremia after one week of
therapy (8 of 12 versus 2 of 8). There was no evidence of nephrotoxicity or myelotoxicity.
However, diarrhea was more common in the treatment group and led to discontinuation in one
patient.

In a retrospective multicenter study of preemptive therapy of adenovirus viremia (>1000

copies/mL) in 27 pediatric allogeneic HCT recipients, virologic responses were observed in 9
percent of patients treated with cidofovir, compared with 83 percent treated with brincidofovir,
including cidofovir-unresponsive patients [60].
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Other — Ganciclovir has limited activity against adenovirus in vitro [61] and in a hamster
model [62]. Neither ribavirin nor vidarabine has consistent activity against adenovirus in vitro
[63]. There are case reports of patients responding to treatment with each of these agents, but
the evidence for efficacy in vivo remains anecdotal [64-66].

Monitoring during antiviral therapy — When using antivirals, the patient should be

monitored with weekly quantitative viral load assessment of blood (if viremic) and respiratory
specimens (if the patient has pneumonia) to guide decisions about the duration of therapy.
Treatment is usually continued at least until resolution of viremia.

Patients receiving cidofovir require close monitoring for nephrotoxicity and Fanconi-type
syndrome. (See 'Cidofovir' above.)

Immunotherapy — Hypogammaglobulinemia has been associated with severe adenovirus

infections [67]. There is some evidence for the use of immunotherapy in the treatment of
adenovirus disease in immunocompromised patients. Pooled intravenous immune globulin
(IVIG) contains high levels of neutralizing antibodies against common lower adenoviral
serotypes [68] and is commonly used as adjunctive therapy in immunocompromised patients
[15,38]. In one case, a child with severe combined immunodeficiency (SCID) and a severe
adenovirus serotype 7 pneumonia responded rapidly to therapy with high-dose IVIG containing
a high titer of neutralizing antibody against serotype 7 [69]. In a murine model of mouse
adenovirus infection, passive transfer of adenovirus-specific IgG resulted in a marked delay in
mortality [70].

T cell immunity is critical for recovery from adenovirus infection following hematopoietic stem
cell transplantation [71]. Pilot studies of adoptive transfer of T cell immunity have been
performed in children with adenovirus infection after stem cell transplantation. In one study,
virus-specific donor T cells were isolated and infused into nine children with systemic
adenovirus infection [72]. In vivo expansion of adenovirus-specific T cells was demonstrated
and viral clearance was attained in five of six evaluable patients. In one patient, adoptive T cell
transfer led to exacerbation of preexisting graft-versus-host disease.

In a study of pediatric HCT recipients treated with donor lymphocytes stimulated in vitro with
adenovirus, reductions in viral load were documented in three of three patients with active
infection, and clinical improvement was documented in one patient with adenovirus pneumonia
[73]. In another study, treatment of two haploidentical HCT recipients who had rising
adenovirus loads with donor-derived virus-specific T cells (expanded in vitro using overlapping
polypeptides in combination with interleukin-15) resulted in viral clearance in one and reduction
of >1.5 log in viral load in the other [74].

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In another study, treatment of adenovirus infections in 17 pediatric stem cell transplant

recipients with banked third-party virus-specific T cells (from individuals with common human
leukocyte antigen polymorphisms) resulted in complete or partial responses in 78 percent (7
with complete response and 7 with partial response) [75]. There were no significant acute
reactions or de novo graft-versus-host disease (GVHD), but several patients had recrudescence
of GVHD (in conjunction with steroid taper because of the viral infection).

PREVENTION

Vaccination and infection control measures have been applied in certain settings to prevent
adenovirus infections.

Vaccination — Live oral enteric-coated vaccines directed against adenovirus serotypes 4 and 7

had been used for years in military recruits [76]. They are safe and effective in the prevention of
epidemics of acute respiratory disease in military training camps. In the 1990s, the
manufacturer of the vaccines stopped production. Subsequently, new outbreaks of adenovirus
serotypes 4 and 7 disease in training camps occurred, including several fatalities, underscoring
the continued need for the vaccine [77-79]. In addition, adenovirus serotype 14, a subtype B2
adenovirus, emerged in military recruit training sites and became the predominant strain. (See
"Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on
'Adenovirus serotype 14'.)

In 2011, a new live, oral adenovirus vaccine against adenovirus serotypes 4 and 7 was approved
for use in United States military personnel aged 17 through 50 years [80,81]. During the two
years following reintroduction of the vaccine, United States military trainees had a 100-fold
decline in adenovirus disease burden (from 5.8 to 0.02 cases per 1000 person-weeks) [82].
There was also a marked decline in the incidence of disease caused by adenovirus serotypes
other than 4 and 7, including adenovirus serotype 14. These data suggest that the emergence
of adenovirus 14 in military recruits during the non-vaccination period was related to the
discontinuation of the adenovirus serotypes 4 and 7 vaccine program, since heterotypic
antibodies to adenovirus 14 develop following adenovirus 7 immunization [79,83,84]. (See
"Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on
'Adenovirus serotype 14'.)

Infection control — Adenoviruses can stay viable for prolonged periods on environmental

surfaces such as sinks and hand towels, and they are not susceptible to some commonly used
disinfectants such as alcohol and ether [85]. Therefore, decontamination of environmental
surfaces and instruments may be difficult and requires specific agents such as chlorine,

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formaldehyde, or heat. Outbreaks of pharyngoconjunctival fever from swimming pool exposure

have usually been associated with inadequate water chlorination [86].

Adenoviruses can cause significant healthcare-associated infections [87-89]. In one report, 126
(7 percent) of 1870 ophthalmology clinic patients developed epidemic keratoconjunctivitis (EKC)
due to adenovirus serotype 8 [87]. Transmission was attributed to inadequate disinfection of
instruments and to finger-to-eye transmission by healthcare workers. Of note, hand washing
did not reliably remove adenoviruses from contaminated fingers. The recommendations from
this study included using gloves to examine patients with EKC and decontaminating
instruments with 10% bleach. In another study, contamination of multidose dilating eye drop
vials was implicated in an outbreak at a large, hospital-affiliated eye clinic that affected 44
patients [90].

In another report, an epidemic of adenovirus serotype 7 occurred in a neonatal intensive care

nursery resulting in the death of two patients [88]. Symptomatic infection occurred in 9
patients, 10 staff, and 3 parents. The outbreak was controlled by cohorting patients, using
gloves, gowns, and goggles, and excluding symptomatic staff from the unit.

Prolonged infection control measures may be necessary to ensure elimination of adenovirus

following a healthcare-associated outbreak [91]. The Committee on Infectious Diseases of the
American Academy of Pediatrics recommends the following [92]:

● For patients with conjunctivitis and for patients with gastroenteritis who are incontinent or
in diapers, contact precautions should be maintained for the duration of the illness. (See
"Infection prevention: Precautions for preventing transmission of infection", section on
'Contact precautions'.)

● For those with respiratory tract infections, contact and droplet precautions are
recommended for the duration of the hospitalization. (See "Infection prevention:
Precautions for preventing transmission of infection", section on 'Droplet precautions' and
"Infection prevention: Precautions for preventing transmission of infection", section on
'Contact precautions'.)

● Disposable gloves and assiduous hand washing should be used when caring for infected
patients.

● Healthcare personnel with known or suspected adenoviral conjunctivitis should avoid

direct patient contact until symptoms have resolved.

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Children who participate in group childcare, particularly during the first two years of life, are at
increased risk for adenoviral respiratory tract infections and gastroenteritis. Specific preventive
measures in this setting have not been established.

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or email these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Adenovirus infections (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Clinical criteria are not sufficient to accurately diagnose adenovirus infection. Laboratory
confirmation of adenovirus infection should be performed if there is suspicion of this
diagnosis and confirmation would be helpful in making decisions about antiviral therapy,
excluding other treatable infections, establishing a prognosis, and continuing infection
control measures when appropriate. (See 'Overview' above.)

● Diagnostic tests for adenovirus include viral culture, viral antigen assays (adenovirus-
specific enzyme-linked immunosorbent assay or immunofluorescence assay), polymerase
chain reaction assays, histopathologic studies, and serology ( table 1). (See 'Diagnostic
tests' above.)

● The diagnostic test of choice varies depending upon the clinical scenario ( table 3). (See
'Diagnostic tests of choice for different adenovirus syndromes' above.)

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● Most adenovirus infections are self-limited and treatment is supportive. Antiviral therapy
generally is reserved for immunocompromised hosts and patients with severe disease, but
controlled clinical trials have not been performed. (See 'Treatment' above.)

● When treatment is indicated, cidofovir has been the antiviral agent most frequently used.
Nephrotoxicity is a major dose-limiting factor for cidofovir. Brincidofovir, an experimental
oral lipid ester of cidofovir that has lower potential for nephrotoxicity than cidofovir, has
enhanced in vitro activity against adenoviruses but is not available for compassionate use.
An infectious diseases specialist should be consulted when treatment is being considered.
(See 'Approach to antiviral therapy' above and 'Cidofovir' above.)

● Pooled intravenous immune globulin has been used as adjunctive therapy in

immunocompromised patients, but controlled clinical trials have not been reported.
Adoptive transfer of donor or third-party adenovirus-specific T cells appear promising for
treatment of adenovirus infections in stem cell transplant recipients. (See
'Immunotherapy' above.)

● Prevention of adenovirus transmission requires decontamination of environmental

surfaces and instruments with agents such as chlorine, formaldehyde, or heat;
adenoviruses are not susceptible to alcohol, ether, or many other commonly used
disinfectants. (See 'Infection control' above.)

● Hospitalized patients with gastrointestinal, conjunctival, and respiratory adenovirus

infection should be placed on contact precautions; those with respiratory infection should
also be placed on droplet precautions. (See "Infection prevention: Precautions for
preventing transmission of infection", section on 'Droplet precautions' and "Infection
prevention: Precautions for preventing transmission of infection", section on 'Contact
precautions'.)

Use of UpToDate is subject to the Terms of Use.

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GRAPHICS

Diagnostic tests for adenovirus

Appropriate
Diagnostic test Comments
samples

Viral culture Nasopharyngeal Samples should be placed in viral transport

swabs or medium and transported on ice.
aspirates
Results available in 2 to 7 days for most
Throat swabs or serotypes, but up to 28 days for subgroup D
washes serotypes (which cause epidemic
Sputum, keratoconjunctivitis).
tracheal
All adenovirus serotypes except 40 and 41
aspirates, or
cause characteristic CPE in human epithelial cell
BAL fluid
lines and human embryonic kidney cells.
Conjunctival
swabs or
scrapings
Stool or rectal
swabs
Urine
Cerebrospinal
fluid
Tissue samples

Viral antigen assays (eg, Nasopharyngeal Results available in less than 30 minutes.
adenovirus-specific enzyme- swabs or
Specific, but less sensitive than viral culture for
linked immunosorbent aspirates
respiratory secretions.
assay or Throat swabs or
immunofluorescence assay) Test of choice for adenovirus serotypes 40 and
washes
41 (which cause infantile gastroenteritis);
Tracheal
adjunct to viral culture for epidemic
aspirate or BAL
keratoconjunctivitis (more rapid results for
material
subgroup D serotypes).
Conjunctival
swabs or
scrapings
Stool or rectal
swabs

Polymerase chain reaction Nasopharyngeal Rapid diagnosis of adenovirus infection in

swabs or immunocompromised patients and other
aspirates hospitalized patients.

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Throat swabs or
washes
Sputum,
tracheal
aspirates, or
BAL fluid
Blood
Urine
Stool
Cerebrospinal
fluid
Biopsy
specimens
Fixed tissue

Histopathologic studies Tissue Adenoviruses cause characteristic intranuclear

inclusions; should be performed in conjunction
with viral culture because histopathologic
changes may be nonspecific, especially during
the early stage of adenovirus infection.

Immunohistochemistry, in situ hybridization, or

electron microscopy can be used to definitively
identify adenoviruses in tissue sections.

Serology Blood Adenovirus-specific IgM antibody suggests

acute infection. Fourfold or greater rise in
adenovirus-specific IgG antibodies confirms
recent infection.

BAL: bronchoalveolar lavage; CPE: cytopathic effect.

Graphic 59727 Version 5.0

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Adenoviral inclusions

Light micrograph of adenovirus type 5 hepatitis in a bone marrow

transplant recipient who died from fulminant liver failure.
Intranuclear viral inclusions are present within multiple hepatocytes,
representing cells at different stages of infection with adenovirus
(arrows). A "smudge" cell with a large inclusion that obscures the
nucleus is present (center arrow).

Courtesy of Phyllis Flomenberg, MD.

Graphic 56007 Version 1.0

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Adenovirus serotypes and associated diseases

Species Serotypes Clinical syndromes

A 31 Infantile gastroenteritis*

B 3, 7, 21 Upper respiratory disease, pneumonia, pharyngoconjunctival fever

11, 34, 35 Hemorrhagic cystitis, interstitial nephritis

14 Pneumonia

C 1, 2, 5 Upper respiratory disease, pneumonia, hepatitis

D 8, 19, 37 Epidemic keratoconjunctivitis

E 4 Upper respiratory disease, pneumonia

F 40, 41 Infantile gastroenteritis

Remaining serotypes are infrequently isolated or not clearly associated with disease.

* Association with gastroenteritis not as firmly established as with types 40 and 41.

Graphic 63104 Version 5.0

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Approach to diagnostic testing for adenovirus based upon the clinical

syndrome

Clinical syndrome Suggested test(s) for adenovirus if diagnosis is necessary*

Upper respiratory Viral culture if available and/or viral antigen assay on respiratory
illness specimen(s) (eg, nasopharyngeal swab or aspirate; throat swab or wash)

Epidemic Viral culture and/or adenovirus-specific antigen assay on conjunctival swab

keratoconjunctivitis or scraping

Pneumonia Viral culture or PCR of nasopharyngeal aspirate or swab, throat swab,

sputum, tracheal aspirate or BAL material

Prolonged diarrhea in Adenovirus-specific antigen assay on stool specimen

young children

Immunocompromised Viral culture or PCR of affected sites; quantitative PCR of blood; biopsy if
hosts clinically indicated​¶

PCR: polymerase chain reaction; BAL: bronchoalveolar lavage.

* If there is a potential outbreak or an individual patient has a severe manifestation (to make
decisions about antiviral therapy, exclude other treatable infections, determine prognosis, and/or
initiate infection control measures).

¶ The appropriate diagnostic tests depend upon the severity and site(s) of infection, as well as the
degree of immunocompromise.

Graphic 81573 Version 4.0

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Contributor Disclosures
Flor M Munoz, MD, MSc Grant/Research/Clinical Trial Support: Centers for Disease Control and
Prevention [Respiratory virus epidemiology]; Abt/CDC [Influenza epidemiology]; National Institutes of
Health [Zika epidemiology, COVID-19 vaccine in pregnancy, vaccines]; Pfizer [COVID-19 vaccine].
Consultant/Advisory Boards: CDC [Grant review]; Moderna [DSMB]; NIH [DSMB]; Pfizer [DSMB]. All of the
relevant financial relationships listed have been mitigated. Phyllis Flomenberg, MD No relevant financial
relationship(s) with ineligible companies to disclose. Martin S Hirsch, MD No relevant financial
relationship(s) with ineligible companies to disclose. Morven S Edwards, MD Grant/Research/Clinical Trial
Support: Pfizer [Group B Streptococcus].
Other Financial Interest: Texas State University personal services
agreement [Chagas disease].
All of the relevant financial relationships listed have been mitigated. Sheila
Bond, MD No relevant financial relationship(s) with ineligible companies to disclose. Mary M Torchia,
MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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