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Diagnosis, treatment, and prevention of adenovirus infection

Diagnosis, treatment, and prevention of adenovirus infection
Literature review current through: Jan 2024.
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.

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 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 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".)

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")

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 in infants and children", 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 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 in infants and children", 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.

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.)

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, 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].

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].

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, 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.

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.)

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'.)

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Topic 8348 Version 28.0

References

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