INTRODUCTION — Adenoviruses are a family of 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, and neurologic diseases. Most adenoviral diseases are self-limiting, although fatal infections can occur in immunocompromised hosts and occasionally in healthy children and adults.
In addition to their importance as infectious agents, adenoviruses are being studied intensively as vectors to deliver foreign genes both for gene therapy and for immunization against tumors and certain infections, such as human immunodeficiency virus (HIV)-1 and malaria; some are already in clinical use as vectors for vaccines against Ebola and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral diseases .
The epidemiology, pathogenesis, and clinical manifestations of adenovirus infections will be reviewed here. Issues relating to diagnosis and treatment are discussed separately. (See "Diagnosis, treatment, and prevention of adenovirus infection".)
VIRION STRUCTURE — Human adenoviruses are a family of >60 serotypes divided into seven subgroups or species (A through G). They have a double-stranded deoxyribonucleic acid (DNA) genome of approximately 35 kb surrounded by a nonenveloped icosahedron with fiber-like projections from each of the 12 vertices. The fiber protein is attached noncovalently to the icosahedron by a pentameric polypeptide named penton base. The fiber protein from most adenoviruses, except species B, binds to the cellular receptor CAR (coxsackie-adenovirus receptor), which also binds coxsackie B virus . Group B adenoviruses have been shown to bind to CD46, a complement-related protein [3,4]. The penton base mediates internalization via interaction with specific cellular alpha v integrins .
The major surface protein of the virion is the trimeric polypeptide hexon. Group-reactive antigenic determinants are present on the hexon proteins from all human adenoviruses. Serotype-specific neutralizing epitopes are present both on the fiber and hexon proteins with minor sites on the penton base. In addition, many adenoviruses hemagglutinate rat or rhesus red blood cells; this property is related to the fiber protein.
Most adenoviruses readily infect human epithelial cell lines, exhibiting a characteristic cytopathic effect. This property is often used to isolate adenoviruses from clinical specimens in diagnostic virology laboratories.
Serotype differences — Over 60 human adenovirus serotypes have been described, based upon antigenic determinants detected by viral neutralization assay (51 serotypes) and other new "types" identified by molecular analyses . Serotypes are further classified into seven species, A to G, based upon characteristics such as hemagglutination patterns, phylogenetic analysis, and genome organization. Certain serotypes are associated with distinct clinical manifestations, reflecting preferential infection of the respiratory, gastrointestinal, and urinary tracts and conjunctiva (table 1). (See 'Overview' below.)
Serotype-specific clinical manifestations may be partially determined by differences in cell tropism, manifested by their binding to different cellular receptors. Naturally occurring recombinant strains (eg, containing fiber of one serotype and hexon of another serotype) have been documented and may exhibit modified tropism and host pathology . Thus, serotype differences in the fiber, hexon, and penton likely contribute to serotype-specific clinical manifestations.
Immune response to adenoviruses — Adenoviruses are immunogenic and elicit strong innate and adaptive immune responses. Recovery from adenovirus infection is associated with the development of serotype-specific neutralizing antibodies directed mainly at the major capsid protein hexon. Neutralizing antibodies protect against infection with the same serotype of the virus but not against other serotypes. The commercial assays for adenovirus antibodies, such as complement fixation and enzyme immunoassay, detect other adenovirus-specific antibodies that cross-react with all serotypes.
The most important host defense against many viruses, including adenoviruses, is cell-mediated immunity. Fatal adenovirus infections occur most commonly in immunocompromised patients, especially those with defects in cell-mediated immunity [8-10]. Adenovirus-specific memory CD4+ T cells can be detected in most healthy adults and can exhibit cross-reactivity against different serotypes . As an example, a specific CD4+ T cell epitope on the hexon is highly conserved among different serotypes and is recognized by 75 percent of healthy individuals . Adenovirus-specific CD8+ cytotoxic T lymphocytes (CTLs) are detected at lower frequencies, some of which also target conserved epitopes [13,14].
Adenovirus proteins modulate host responses — A number of mechanisms to downregulate nonspecific and specific inflammatory responses have been demonstrated in adenoviruses. Several proteins expressed early in the adenovirus replicative cycle may modulate the host immune response. Adenoviruses express early regulatory proteins under the control of the early region 1A (E1A). E1A is a trans-activating region that controls expression from the other early regions E1B, E2, E3, and E4. Viral DNA replication takes place after expression of the early proteins, followed by synthesis of late structural viral proteins and inhibition of host protein synthesis . Virions are then assembled in the nucleus and released when the cell dies. This process of virus release is facilitated by the E3 region 11.6K protein .
The E3 region, which is not essential for viral replication, encodes several proteins that modulate host functions in response to viral infection. The E3-19K transmembrane glycoprotein is localized in the endoplasmic reticulum and binds to newly synthesized MHC class I molecules. As a consequence, the intracellular transport and cell surface expression of class I molecules is dramatically inhibited . E3-19K also binds TAP and may inhibit class I molecule maturation by delaying peptide loading . Downregulation of class I antigens, which are required for antigen presentation to CD8+ CTLs, may help adenovirus-infected cells evade recognition and resist apoptosis and CTL killing.
Furthermore, the E3 region protects cells from apoptosis-inducing cytokines, such as tumor necrosis factor (TNF), Fas ligand, and TNF-related apoptosis-inducing ligand (TRAIL). The E3 14.7K protein is a potent inhibitor of TNF-mediated apoptosis . The E3 10.4K and 14.5K complex, also known as RID (receptor internalization and degradation), downregulates Fas, TNF, and TRAIL receptors [20-22]. Fas-mediated apoptosis is a major pathway for CTL-mediated cell lysis. In fact, these E3 region proteins have been employed in murine models to prevent rejection of transplanted hepatocytes  or transplanted islet cells .
The fact that adenoviruses have developed diverse mechanisms to evade host responses suggests that these must be important modes of adaptation for the virus. One postulate is that these proteins play a role in reducing inflammation during acute infection. Another explanation is that these proteins may facilitate the establishment of persistent infections.
Persistent infection — Adenoviruses are frequently shed in stool for weeks after acute infection in immunocompetent individuals  and for months in immunocompromised patients. There are case reports of transmission of adenoviruses to recipients of infected solid organ transplants [26,27]. Adenoviral disease may also be caused by reactivation of endogenous infection in hematopoietic cell transplant recipients, analogous to reactivation of herpesviruses in these hosts [28,29]. However, the reservoirs and mechanisms for persistent adenovirus infections in humans are not well understood.
Adenoviruses can be detected in long-term cultures of tonsillar tissue and have been shown to persist in CD4+ T cells isolated from tonsils . Adenoviral DNA is also highly prevalent in intestinal lymphocytes. In one study, adenoviral DNA was detected by polymerase chain reaction in intestinal tissue from 21 of 58 surgical specimens and in the intestinal lymphocytes from 21 of 24 specimens . Adenovirus DNA was also detected in 31 percent of gastrointestinal biopsy specimens from children undergoing endoscopy, primarily in the terminal ileum; species C adenoviruses were most commonly detected. Adenovirus was localized to lymphoid cells of the lamina propria by in situ hybridization and immunohistochemistry . Although adenoviruses infect lymphocytes and monocytes very inefficiently in vitro, one study demonstrated that a subset of B and T cell lines supported adenovirus replication . Taken together, these data suggest that adenoviruses can persist in some human cell types without causing cell lysis and that tonsillar and intestinal lymphocytes are likely important viral reservoirs.
EPIDEMIOLOGY — Adenoviruses have a worldwide distribution, and infections occur throughout the year without seasonality. Adenoviruses cause 5 to 10 percent of all febrile illnesses in infants and young children . Most individuals have serologic evidence of prior adenoviral infection by the age of 10, and nearly all adults have serologic evidence of past infection with one or more adenoviruses.
Adenovirus infections are prevalent in daycare centers and in households with young children. Nosocomial transmission also has been documented.
Epidemics of adenovirus infections occur globally, in communities and in closed or crowded settings. Examples include pharyngoconjunctival fever in summer camps and in association with public swimming pools , keratoconjunctivitis in medical facilities [35,36], respiratory illnesses on college campuses , and serious acute respiratory disease in military recruits [38,39]. (See 'Military recruits' below.)
Transmission — Transmission of adenovirus can occur via aerosol droplets, the fecal-oral route, and by contact with contaminated fomites. Adenoviruses can survive for long periods (commonly over seven days) on environmental surfaces and medical instruments; they are resistant to lipid disinfectants because they are nonenveloped, but they are inactivated by heat, formaldehyde, or bleach (sodium hypochlorite).
There are other modes of adenovirus transmission:
●Neonates can acquire adenoviral infection from exposure to cervical secretions at birth [40-42]. The presence of adenovirus has been documented in cervical cells from the mother of a neonate who died from adenoviral pneumonia . Intrauterine infection has also been detected in fetal tissue by polymerase chain reaction assay .
●Serologic evidence that adenoviruses can be transmitted from donor kidney and liver transplants suggests that these organs occasionally harbor adenoviruses in a latent form .
Overview — Serotypes within each species are closely related at the DNA level and frequently share similar biologic properties. As examples, species B serotypes 11, 34, and 35 cause hemorrhagic cystitis, whereas species D serotypes 8, 19, and 37 are associated with keratoconjunctivitis (table 1).
The prevalence of the different serotypes cannot be determined with confidence since the vast majority of patients with adenovirus infection are not tested. From 2003 to 2016, the most commonly detected serotypes were 3, 2, 1, 4, 7, and 14; 82 percent of the specimens were of respiratory origin, and thus the most common reported serotypes were those associated with respiratory tract disease. These serotypes accounted for 1283 of 1497 reports (86 percent) in which the serotype was identified . There was variation in the frequency with which individual serotypes were reported from year to year. To help better define the epidemiology of adenovirus infections, the United States Centers for Disease Control and Prevention established the National Adenovirus Type Reporting System in 2014, a passive surveillance system that coordinates the reporting of adenoviral infections in clinical laboratories.
Military recruits — Beginning in 1971, military recruits in the United States received a highly effective, enteric-coated, oral live vaccine with adenovirus serotypes 4 (species E) and 7 (species B); manufacture of this vaccine was discontinued in 1996 . Since that time, both susceptibility and clinical infection due to adenovirus increased in military recruits. Rare fatalities were reported in recruits due to probable adenovirus pneumonia with or without accompanying encephalitis .
The following observations illustrate the range of findings:
●A study of 341 military recruits in 2004 found that more than three-quarters were susceptible to either adenovirus serotype 4 or serotype 7 infection and, during active surveillance, one-quarter developed a febrile respiratory illness attributable to adenovirus serotype 4 . Furthermore, the percentage of recruits seropositive for this strain increased from 34 percent at enrollment to 97 percent by the end of the study. Potential sources of transmission included environmental contamination and extended pharyngeal shedding of virus.
●Among 584 clinical adenovirus isolates from military recruits collected between 2004 and 2006, 93 percent were serotype 4 . However, the distribution appears to be changing. In a series of 1867 military recruits with adenovirus respiratory infections, serotype 4 was the most prevalent serotype between 2002 and 2005 , while in 2006 species B adenoviruses became more prevalent, including serotypes 3, 7, 21, and 14. The emergence of adenovirus 14 outbreaks is discussed in detail below. (See 'Adenovirus serotype 14' below.)
As a result, the vaccine program in the military was reinstituted [46,47,50]. 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 [51,52] (see "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Vaccination'). Since the reinstitution of the vaccination program, the incidence of febrile respiratory illnesses and adenovirus disease has decreased dramatically among military basic trainees [53,54].
Adenovirus serotype 14 — Adenovirus serotype 14 is a species B serotype that was first identified in military recruits in the Netherlands in 1955 and has subsequently caused sporadic outbreaks throughout Europe. A variant of that serotype emerged in 2005 in the United States and has caused several outbreaks of pneumonia in both military recruits and civilians.
Adenovirus 14 was reported in the United States in 2006 when it was associated with a fatal respiratory illness in a 12-day-old infant in New York . Clusters of severe acute adenovirus 14 respiratory disease were subsequently identified in Oregon, Washington, Texas, and Alaska [55-57]. In a report that included 140 patients, 38 percent were hospitalized, 17 percent were admitted to intensive care units, and 5 percent died . In a retrospective review published subsequently, it was shown that adenovirus 14 had emerged in Oregon in 2005 and became the prevalent serotype in 2006 and 2007, causing over 50 percent of adenovirus infections .
The cluster in Texas involved military recruits at an Air Force base . Preexisting antibodies against adenovirus 7 were detected in 7 of 19 individuals with mild illness but in none of 16 individuals with pneumonia caused by adenovirus 14, suggesting that adenovirus 7–specific antibodies might provide some degree of cross-protection against adenovirus 14. Among military recruits in Texas hospitalized with pneumonia during the outbreak, adenovirus 14 was not associated with excess morbidity or mortality compared with other causes of pneumonia . However, women with adenovirus 14 infection had higher rates of hospitalization than men (83 versus 40 percent). After reintroduction of vaccination against adenovirus 4 and 7 in 2011, adenovirus 14 surpassed these two viruses as the most prevalent type reported in these settings .
Adenovirus 14 has also been identified in military recruits at a number of other bases [49,61], in health care workers (HCW) and a household contact of a HCW [62,63], and in two children and an adult in California with severe pneumonia superimposed upon chronic pulmonary disease . It also caused an outbreak of pneumonia among a group of individuals who socialized and smoked together in Alaska . A study of health care personnel at a military hospital where 15 trainees were hospitalized with pneumonia caused by adenovirus 14 suggested likely nosocomial transmission .
An analysis of 99 isolates from military and civilian cases of adenovirus 14 infection in the United States showed that all isolates were identical and suggested that they arose from recombination among adenovirus 11 and adenovirus 14 ancestral strains .
CLINICAL PRESENTATION — The clinical manifestations of adenoviral disease vary according to the age and immunocompetence of the host (table 2). Severe disease has been associated with serotype 7 [66-70], serotype 5 , serotype 21 [48,71], and, more recently as noted in the previous section, serotype 14 [55,64].
Respiratory tract — Adenoviruses are among the most common viruses isolated from young children with febrile respiratory illnesses. The usual duration of illness is five to seven days, although symptoms may persist for up to two weeks. Bacterial superinfections can occur. A multicenter, prospective, viral surveillance study of 18,000 febrile children with respiratory symptoms at seven United States sites detected adenoviruses in 6 percent of samples, among whom about half had co-detection with at least one other respiratory virus .
Pharyngitis and coryza — Pharyngitis and coryza are common presentations of adenovirus infection [73,74]. Pharyngitis is frequently associated with conjunctivitis, laryngotracheitis, bronchitis, or pneumonia. Fever and other systemic manifestations such as malaise, headache, myalgia, and abdominal pain are common . In many cases, exudative tonsillitis and cervical adenopathy may be present, a syndrome that can be clinically indistinguishable from group A streptococcal infection. Adenoviruses are among the most common cause of tonsillitis in young children.
Otitis media and bronchiolitis — Otitis media is another common presentation, especially in children under age 1 [73,74]. However, the presence of adenovirus in middle ear fluid has only been documented in a few cases . Adenoviruses can also cause a pertussis-like syndrome, bronchiolitis, or an exanthem.
Pneumonia — A number of adenovirus serotypes (1, 2, 3, 4, 5, 7, 14, 21, and 35) have been reported to cause pneumonia [55,64,77-79]. Species B serotypes 3, 7, 14, and 21 have been associated with severe and complicated pneumonia [55,64,80-83]. Adenovirus serotype 7 was recognized as an important cause of severe respiratory illness in a community outbreak in Oregon in 2014 ; 136 (69 percent) of 198 persons with adenovirus-positive respiratory tract specimens were hospitalized, out of which 18 percent required mechanical ventilation, and 5 patients died. In a study of 2638 hospitalized children with pneumonia, adenoviruses were detected in 15 percent of children younger than five years of age compared with 3 percent of older children . 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 . 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).
Pneumonia is more severe in infants than older children and may be associated with lethargy, diarrhea, and vomiting. Extrapulmonary complications occasionally occur, including meningoencephalitis, hepatitis, myocarditis, nephritis, neutropenia, and disseminated intravascular coagulation [87,88]. In a retrospective study of over 200 pediatric patients with febrile respiratory illnesses at a single center, patients infected with species C serotypes 1, 2, and 5 were more likely to be younger, hospitalized, and have a higher frequency of seizures compared with those with infected with group B serotypes 3, 7, and 14 .
Chest radiography in adenoviral pneumonia reveals diffuse bilateral pulmonary infiltrates similar to those of other viral pneumonias. Pathologic changes include necrotizing bronchitis, bronchiolitis, and pneumonia with mononuclear cell infiltration, hyaline membranes, and necrosis. Advances in and the availability of viral molecular diagnostics have improved the diagnosis of adenoviral pneumonia; differentiating adenoviral from other suspected causes of pneumonia significantly improves management strategies in the young as well as the immunocompromised. Further research in establishing the role of quantitative adenoviral load assays in determining patients’ clinical severity and prognosis is ongoing .
Neonates and infants with underlying diseases are at high risk for fatal adenoviral pneumonia. On the other hand, pneumococcal vaccination has been associated with a reduction in the incidence of pneumonia in infants with adenovirus and other respiratory virus infections . This observation suggests that the pneumococcus is an important pathogen in virus-associated pneumonia. (See "Pneumococcal vaccination in children", section on 'Efficacy and effectiveness'.)
There is a high incidence of pulmonary sequelae following adenoviral pneumonia in young children, including bronchiectasis and bronchiolitis obliterans [71,92,93]. In a meta-analysis of pneumonia in children under age 5, adenovirus infection was associated with the highest risk (55 percent) of long-term sequelae compared with other causes of pneumonia .
Acute respiratory disease — In young adults, a syndrome of acute respiratory disease can occur, especially under the special conditions of fatigue and crowding present in military training camps [38,39]. Symptoms include fever, pharyngitis, cough, hoarseness, and conjunctivitis. Pneumonitis can also occur, resulting in rare deaths [55,60,64]. Epidemics of acute respiratory disease have been associated with adenovirus species E serotype 4 and species B serotypes 3, 7, 11, 14, and 21. Data suggest that adenovirus serotype 4 might be an underestimated causative agent of acute respiratory disease among civilian adults .
Eyes — Pharyngoconjunctival fever is a classic adenoviral syndrome that consists of a benign follicular conjunctivitis often accompanied by a febrile pharyngitis and cervical adenitis. Outbreaks of pharyngoconjunctival fever have been described, especially in summer camps in association with swimming pools or lakes . Adenovirus species B serotypes 3 and 7 are the most common isolates, but multiple serotypes from species B, C, D, and E have been implicated.
Epidemic keratoconjunctivitis (EKC) is a more serious disease associated primarily with the species D serotypes 8, 19, and 37. It is characterized by bilateral conjunctivitis with preauricular adenopathy, followed by the development of painful corneal opacities. Although the disease is self-limited and virtually never results in permanent corneal damage, it can run a protracted course lasting up to four weeks. It causes severe pain and blurry vision and incurs significant economic losses in the workplace.
EKC may be transmitted in medical offices and hospitals by the ophthalmologist's hands and contaminated instruments or eye drops [35,36,96]. In one report of EKC due to adenovirus serotype 8 in a neonatal intensive care unit where premature infants underwent repetitive eye exams, the outbreak spread from neonates to the staff and then to their families . In another review of an adenovirus serotype 8 epidemic, the authors demonstrated that almost 50 percent of patients diagnosed with EKC carried virus on their hands and that the virus remained viable on inanimate surfaces for up to 35 days .
Diarrheal illness — In young children, 5 to 10 percent of acute diarrheal illnesses are caused by the subgroup F adenoviruses serotypes 40 and 41. These enteric adenoviruses were first identified in stool specimens by electron microscopy and require special cell lines for growth. Specific adenovirus antigen assays or polymerase chain reaction (PCR) assays can be used for detection of these agents. (See "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Diarrhea in young children'.)
In one study of over 400 cases of acute infantile gastroenteritis, enteric adenoviruses were the sole recognizable cause of diarrhea in 7.2 percent of cases; no isolates were found among 200 controls . Diarrhea was prolonged, lasting from 8 to 12 days. A review of another outbreak in several daycare centers found that 38 percent of 249 young children had positive stool specimens, although only one-half were symptomatic . In a study from Brazil, adenoviruses were detected by PCR in 25 percent of stool samples of children with diarrhea, 68 percent of whom were under five years old. Adenovirus serotypes 40 and 41 accounted for nearly half of sequenced samples. The highest incidence was in children between 6 to 24 months, without marked seasonality .
Enteric adenoviruses also may be a cause of nosocomial infection, as suggested by one report of 14 cases of enteric adenovirus-related diarrhea in hospitalized infants over a three-month period .
Unlike serotypes 40 and 41, epidemiologic studies have not shown a clear correlation between most other serotypes and gastroenteritis. However, the species A serotype 31 has been associated with infantile diarrhea in some reports . In addition, lower serotype adenoviruses have been associated with mesenteric adenitis, which may mimic appendicitis and occasionally cause intussusception .
Adenoviruses may be excreted in feces for months after a primary infection. Thus, detection of adenovirus in the stool is not usually clinically significant. However, in immunocompromised hosts, symptomatic gastroenteritis has been associated with a range of adenovirus serotypes.
●Immunocompromised hosts – Hepatitis is a well-described complication of adenovirus infections in immunocompromised hosts, especially with species C serotype 5 . Adenovirus hepatitis is a particular problem in pediatric liver transplant recipients and may be fatal in these individuals. In a review of 89 cases of adenovirus hepatitis, 48 percent occurred in liver transplant recipients and 21 percent in hematopoietic cell transplant recipients .
●Immunocompetent hosts – Adenovirus has also been detected in cases of acute hepatitis in immunocompetent children [106-108].
It is unclear whether adenovirus infection is a cause of the 2022 outbreak of severe acute unexplained hepatitis in children . In early 2022, an outbreak of acute hepatitis was identified among young children (most <5 years) in the United Kingdom and Ireland, and other clusters with similar characteristics were subsequently reported in at least 35 countries, including the United States [110-114]. A systematic review of 22 case series and case-control studies identified 1643 cases of acute hepatitis of unknown etiology in children, among whom 7.3 percent required liver transplantation and 1.5 percent died . There is no established link with coronavirus disease 2019 (COVID-19) vaccine or hepatitis viruses (A, B, C, E, and D) [115-118], and no common exposures (eg, travel or toxins) have been identified .
Although the cause of acute hepatitis in these cases remains uncertain, adenovirus (primarily type 41) was the pathogen most commonly detected by PCR in the United Kingdom (142/216 tested), sometimes with other common pediatric viruses (eg, rhinovirus, enterovirus, influenza virus, SARS-CoV-2) [119-122]. In addition, adenovirus was detected in 100 (44.6 percent) of 224 cases tested in the United States . In contrast, adenovirus was detected in only 9 percent of cases (5/58) in Japan.
Interim guidance from the World Health Organization encourages testing for adenovirus in addition to more typical causes of hepatitis in children with acute unexplained hepatitis [111,115,123]. (See "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Hepatitis'.)
Adenovirus does not typically cause hepatitis in healthy children, and evidence of adenovirus-mediated tissue damage is lacking, suggesting that it may be an innocent bystander or is one of multiple factors involved . Preprints (nonpeer reviewed studies) from the United Kingdom suggest that coinfection with adeno-associated virus 2 (AAV2) may play a role [124,125]. Using genomic methods, AAV2 DNA (and ribonucleic acid [RNA]) was detected in the liver of 9 of 9 cases and the blood of 25 of 26 children with acute unexplained hepatitis; adenovirus and human herpesvirus 6B were also detected in most children. In contrast, AAV2 was not detected in most controls, including children with adenovirus who had normal liver function. AAV2 is a member of the parvovirus family that often accompanies adenovirus but is not known to cause disease. It cannot replicate without a helper virus (eg, adenovirus, herpesvirus). Additional study is necessary to determine whether adenovirus and AAV2 play an etiologic role in these cases of acute unexplained hepatitis.
The United States Centers for Disease Control and Prevention summarizes other hypotheses under investigation in a technical report . One such hypothesis is that the combination of current, persistent, or past infection with SARS-CoV-2 and adenovirus causes an autoimmune phenomenon or superantigen reaction [126,127]. Although current or past SARS-CoV-2 infection has been detected in some cases , direct evidence that SARS-CoV-2 is involved is lacking . (See "COVID-19: Clinical manifestations and diagnosis in children".)
Moreover, analysis of data in the United States through March 2022 showed no overall increase in hospitalizations for hepatitis of unknown cause compared with that before the COVID-19 pandemic and no increase in adenovirus types 40/41 positivity . Thus, it is unclear whether the case series in the United States represents a novel cause of acute hepatitis versus a previously existing phenomenon and whether there is a relationship with adenovirus infection. (See "Diagnosis, treatment, and prevention of adenovirus infection".)
Genitourinary tract — Adenovirus species B serotypes 11 and 21 have been associated with acute hemorrhagic cystitis in children . This self-limited disease is more common in males and is usually not accompanied by fever or hypertension. Its significance lies in the potential confusion with other, more serious diseases of the kidney, such as glomerulonephritis.
In adults, adenovirus species D serotypes 19 and 37 have been occasionally associated with urethritis [131,132]. In immunocompromised patients, adenovirus species B serotypes 11, 34, and 35 can cause hemorrhagic cystitis and tubulointerstitial nephritis [133,134].
Nervous system — Meningitis and encephalitis have been reported occasionally in association with adenovirus infection . Neurologic involvement may be a primary manifestation or found in association with severe pneumonia, especially when infection is due to species B serotype 7 . In a review of 48 immunocompetent children with adenovirus-associated central nervous system disease, including febrile seizures, encephalitis, and aseptic meningitis, seizures were identified as significant risk factors for adverse outcome .
Disseminated — Disseminated adenovirus infection has been reported in both immunocompromised and immunocompetent children  and in adults who have undergone hematopoietic cell or solid organ transplantation [138,139]. Disseminated adenovirus can affect almost any organ and can cause pneumonia, colitis, hepatitis, nephritis, and encephalitis. In a retrospective review of children with adenovirus infection, 2.5 percent (11 of 440) had disseminated disease . Of these, 54 percent (6 of 11) were immunocompromised. Mortality from disseminated disease was 73 percent overall (83 percent among immunocompromised and 60 percent among immunocompetent hosts).
Myocarditis — In two series of acute myocarditis in children, adenovirus was the most common cause of viral myocarditis, occurring in 60 percent of polymerase chain reaction-proven cases of viral myocarditis [140,141].
Other — Adenovirus has occasionally been associated with viral myositis accompanied by rhabdomyolysis [142,143] (see "Overview of viral myositis"). Fewer than 10 cases of adenovirus-associated arthritis have also been reported [144,145].
INFECTIONS IN IMMUNOCOMPROMISED HOSTS — A variety of clinical syndromes can occur in immunocompromised individuals with adenovirus infection . Reactivation of endogenous persistent adenovirus infection plays a major role in adenoviral diseases in these patients.
Transplant recipients — The spectrum of adenovirus infection can range from asymptomatic shedding to fatal disseminated disease in patients who have undergone organ or hematopoietic cell transplantation (HCT) [10,138]. Disease can be caused by primary infection, reactivation of latent infection in the transplant recipient, or reactivation of infection transmitted in the donated organ .
In a retrospective hospital-based study, adenoviral infections were compared between pediatric HCT and solid organ transplant recipients . Infection occurred at a median of 1.6 months post-transplantation. All deaths from adenoviral disease occurred exclusively among HCT recipients, likely related to their more severe immune dysfunction.
Hematopoietic cell transplantation — Adenoviral diseases are well characterized in HCT recipients. A wide range of clinical syndromes has been reported, including pneumonia, colitis, hepatitis, hemorrhagic cystitis, tubulointerstitial nephritis, encephalitis, and disseminated disease [9,28,138,147,148]. In addition to the common lower serotypes, there is a preponderance of species B serotypes 11, 34, and 35, which are infrequent isolates in the general population [9,28]. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)
In one study of 1050 adult HCT recipients, 51 (4.8 percent) shed adenoviruses and 10 (0.9 percent) had invasive adenoviral disease . Another report documented a higher incidence of adenoviral infection and disease in a HCT patient population (both children and adults) treated with T cell–depleted bone marrow grafts and more intensive immunosuppressive regimens; 42 of 210 patients (20.9 percent) had evidence of infection, while 13 (6.5 percent) developed invasive disease . A Japanese registry database evaluated the cumulative incidence of adenoviral disease, risk factors, and survival among 25,000 patients who underwent autologous HCT and 48,000 patients who underwent allogeneic HCT between 2005 and 2019. The one-year cumulative incidences after autologous and allogeneic HCT were 0.18 and 1.5 percent, respectively, in children, and 0.5 and 3 percent, respectively, in adults. Reno-urinary disease was the most common disease manifestation . Treatment and outcomes of adenovirus infections in HCT recipients are discussed separately. (See "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Treatment'.)
Adenoviruses cause more frequent disease and appear earlier post-transplant in pediatric HCT recipients compared with adults [147,150]. In one study of 204 pediatric HCT recipients, 31 had adenovirus infections (15.1 percent) and 18 (8.8 percent) developed severe disease . Allogeneic recipients and, in particular, recipients of unrelated or mismatched related grafts had an increased risk of infection. In a study of 123 pediatric allogeneic recipients, adenovirus infection was a major independent risk factor for treatment-related mortality .
Solid organ transplantation — Adenovirus infections in solid organ transplant recipients may range from asymptomatic to severe and disseminated, with prolonged viral shedding and significant morbidity and mortality, including associated graft dysfunction and rejection [152,153]. Adenovirus more frequently affects pediatric than adult solid organ transplant recipients. Infection after transplant may be associated with reactivation of a prior latent infection in the recipient or the graft or with a newly acquired infection. Outbreaks of adenovirus infections among hospitalized solid organ transplant recipients have also been reported .
Three clinical scenarios are possible: asymptomatic viremia or infection documented by detection of adenovirus from specimens by culture, polymerase chain reaction, or specific antigen tests in the absence of clinical symptoms; adenovirus disease with specific organ involvement and manifestations (eg, pneumonia, enteritis, meningoencephalitis) documented by viral detection and/or histopathology; and disseminated disease, when two or more organs are involved . Adenovirus infection is more likely to occur during the first several months after transplantation. The incidence appears higher among liver transplant recipients, followed by heart and kidney transplant recipients [27,146]. Severe disease has been reported in lung, heart, and multivisceral organ recipients .
In contrast with the HCT population, adenoviral disease typically involves the donor organ in solid organ transplant recipients. As an example, the primary clinical manifestation in those who have undergone renal transplantation is acute hemorrhagic cystitis, sometimes complicated by interstitial nephritis . This syndrome is almost exclusively associated with species B serotypes 11, 34, and 35. The incidence has not been well defined but is low. The prognosis is generally good, although infection occasionally results in fatal disseminated disease .
Similarly, adenoviral pneumonia is described as an early complication following lung transplantation. In one study of 308 lung transplant recipients, four (1.3 percent) developed adenovirus pneumonia, three of whom were children . (See "Viral infections following lung transplantation".)
The most common manifestation of invasive adenoviral disease is hepatitis in pediatric patients who have undergone liver transplantation. In one large study of 484 liver transplant recipients, 14 patients (3 percent) developed adenovirus hepatitis . Adenovirus serotype 5 was the most common isolate; serotypes 1 and 2 also were identified. Six of 14 patients (43 percent) died; four recovered with a decrease in immunosuppressive therapy, while four other survivors required retransplantation. In another study, examination of pre- and post-transplant sera from recipients and donors suggested that latent virus was transmitted with the donated organ . Biopsies of small bowel transplants have also yielded a high incidence of adenovirus isolates. Progression of the infection and systemic dissemination have been associated with intensive immunosuppressive therapy .
In a study of pediatric cardiac transplant recipients, adenoviruses were implicated as a cause of graft loss and coronary vasculopathy . Adenovirus was detected by polymerase chain reaction in myocardial biopsies from 24 of 149 patients (16 percent) and was associated with reduced graft survival.
Congenital immunodeficiency syndromes — Primary adenoviral infections can cause severe disease that is frequently fatal in children with immunodeficiency syndromes, such as severe combined immunodeficiency disease (SCID). In patients with SCID, species A serotype 31 and several species B and C serotypes have been associated with fatal pneumonia and hepatitis [104,159].
Neonates — Adenovirus can cause fatal disseminated neonatal infections. In a review of adenovirus disease in 26 neonates requiring hospitalization, respiratory signs and temperature instability were the most common presenting features . Only one neonate was premature (34 weeks), and one had congenital heart disease. Five neonates (19 percent) had disseminated disease; the mean age of onset was seven days, and mortality was 80 percent. In contrast, 21 neonates with localized disease had a mean day of onset of 18 days and none died.
Malignancy — Various manifestations of adenoviral infections, including viral triggered hemophagocytic lymphohistiocytosis, have been reported in children and adults with hematologic malignancies [161,162]. In a meta-analysis of 228 cases of adenovirus disease in adults published between 2000 to 2020, hematological malignancy was the most common underlying condition (32 percent), followed by solid organ transplantation (28.1 percent) and hematopoietic cell transplantation (23.2 percent) . In one cited report of four non-transplant cancer patients with adenovirus pneumonia, three had lymphoid malignancies and one was on active treatment for breast cancer; three (75 percent) died . In contrast, only a few cases were associated with advanced HIV infection or autoimmune disease (10 of 228, 4.4 percent each).
POSSIBLE ASSOCIATION WITH OBESITY — Animals infected with adenovirus species D serotype 36 have increased body weight . Some human studies have also found an association between the presence of adenovirus serotype 36 antibodies and obesity [166,167], but others have not . Possible explanations for the association include a true causal link, vulnerability to adenovirus infection among individuals with obesity, and the presence of unmeasured confounders.
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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)")
●Common clinical features − Adenoviruses are a family of DNA viruses that are an important cause of febrile illnesses in young children.
•They are most frequently associated with upper and lower respiratory tract infections, such as pharyngitis coryza, and pneumonia.
•Less commonly, adenoviruses cause gastrointestinal, ophthalmologic, and genitourinary diseases.
Most adenoviral diseases are self-limiting, although pneumonia can be severe, and fatal infections can occur in immunocompromised hosts and occasionally in healthy children and adults. (See 'Introduction' above and 'Clinical presentation' above.)
●Virology − Adenoviruses have a double-stranded DNA genome of approximately 35 kb surrounded by a nonenveloped icosahedron with fiber-like projections. (See 'Virion structure' above.)
●Worldwide distribution − Adenoviruses have a worldwide distribution, and infections occur throughout the year. Most individuals have serologic evidence of prior adenoviral infection by the age of 10. Adenovirus infections are prevalent in daycare centers and in households with young children. (See 'Epidemiology' above.)
●Epidemics − Many epidemics of adenoviral disease have been described, including pharyngoconjunctival fever in summer camps and in association with public swimming pools, keratoconjunctivitis in medical facilities, and serious acute respiratory disease in military recruits and other closed and crowded settings. (See 'Epidemiology' above.)
●Serotypes − Over 60 human adenovirus serotypes have been described, based upon antigenic determinants detected by viral neutralization assay (51 serotypes) and new "types" identified by molecular analysis. Serotypes are further classified into seven species, A to G.
•Serotypes within each species frequently share similar biologic properties. As examples, species B serotypes 11, 34, and 35 cause hemorrhagic cystitis, whereas species D serotypes 8, 19, and 37 are associated with keratoconjunctivitis (table 1).
•Severe disease has been associated primarily with species B and C serotypes.
●Clinical features vary by age and immune status – The clinical manifestations of adenoviral disease vary according to the age and immunocompetence of the patient (table 2). (See 'Clinical presentation' above and 'Infections in immunocompromised hosts' above.)
●Spectrum of illness in transplant recipients − A wide range of clinical syndromes has been reported in immunocompromised hosts such as hematopoietic cell transplant (HCT) recipients, including pneumonia, colitis, hepatitis, hemorrhagic cystitis, encephalitis, and disseminated disease. In contrast with HCT recipients, adenoviral disease typically involves the donor organ in solid organ transplant recipients (See 'Hematopoietic cell transplantation' above and 'Solid organ transplantation' above.)
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