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Adenoviruses Clinical Presentation

  • Author: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Burke A Cunha, MD  more...
 
Updated: Mar 04, 2016
 

History

Because the manifestations of adenovirus infections are protean, the major syndromes are discussed separately. The major syndromes covered in this article include (1) acute respiratory disease (ARD), (2) pharyngoconjunctival fever, (3) epidemic keratoconjunctivitis, (4) acute hemorrhagic cystitis, (5) gastroenteritis, and (5) adenoviral infections in immunocompromised hosts.

Given the range of manifestations, the varying levels and effects of immunosuppressive therapies, and rapid advances in molecular methods of detection, a comprehensive review of adenovirus infection in the immunosuppressed host is beyond the scope of this article. The reader is encouraged to review the literature for more detail regarding infection in specific settings.

Acute respiratory disease (predominantly adenovirus types 1, 2, 4, 5, and 6; occasionally, 3 and 7)

As with many other viral syndromes, ARD is more common in spring and winter months. Approximately half of adenovirus respiratory infections do not cause symptoms. Adenoviruses account for 10% of all childhood lower respiratory tract infections.

The contagiousness of adenovirus is facilitated by very high levels of viral particles (100,000-1,000,000/mL) in the sputum or oral secretions of infected adults. Additionally, adults who lack antibody may be infected by the inhalation of as few as 5 virions in droplet nuclei.

Fever, rhinorrhea, cough, and sore throat, usually lasting 3-5 days, are typical symptoms of adenoviral ARD. Causes of sore throat may include pharyngitis, adenoiditis, or tonsillitis. Tonsillitis and otitis media were reported in up to 60% and 30%, respectively in a series of young children with serotype 4 predominance. Prolonged fevers, leukocytosis, and elevations in C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were also noted in over half of cases, suggesting potential for confusion of this viral syndrome with bacterial infections.[8]

Lower respiratory tract infections, including tracheobronchitis, bronchiolitis, and pneumonia, may mimic respiratory syncytial virus infection or influenza. Notably, conjunctivitis in the presence of bronchitis suggests adenoviral infection.

Fatal pneumonia is uncommon but is more likely in neonates and has been associated with serotypes 3, 7, 14, 21, and 30.[9]

Encephalitis, hepatitis, and myocarditis are uncommon.

From the 1950s to 1971 (prevaccine era), adenoviruses accounted for significant acute disease in 70% of military recruits. Adenovirus serotypes 4 and 7 were primarily involved. A live enteric-coated oral vaccine against these serotypes was introduced in 1971 and reduced adenovirus-related respiratory illness by more than 95% in recruits and thus attenuated outbreaks. Vaccine production ceased in 1996 for economic reasons, and vaccination administration was limited to high-risk periods until supplies ran out in 1999. In 1997, a large epidemic of more than 500 cases associated with serotypes 3 and 7 occurred in US Navy recruits. Most recent analyses suggest that serotype 4 has caused most military outbreaks since 1999, with the exception of Ad14. Outbreaks in basic trainees declined with the reintroduction of live oral enteric-coated adenovirus vaccine against types 4 and 7.[10, 11]

Adenovirus serotype 14

Ad14, referred to as the "super cold" in the media, has caused rare outbreaks of ARD since 1955.

Between May 2006 and June 2007, 141 cases of Ad14 infection were reported in clusters in New York, Oregon, Texas, and Washington. Almost 40% of affected persons were hospitalized, almost half in intensive care, with a 5% overall mortality rate. The cases in Texas involved military trainees at Lackland Air Force Base, and subsequent cases were reported at Lackland, three other Texas military bases, and one eye culture in a civilian unassociated with the military. Adenovirus may be isolated from children with whooping cough syndrome in the presence or absence of Bordetella pertussis infection; however, whether adenovirus is an etiologic cause of the syndrome remains unclear.[12, 13]

Pharyngoconjunctival fever (predominantly serotypes 3, 4, and 7)

This syndrome most often affects school-aged children. Contagious in nature, sporadic outbreaks of adenovirus infection occur in small groups, especially summer camps in the setting of an inadequately chlorinated water source such as a pool or lake. Interestingly, water sample cultures are often not confirmatory. Spread occurs via the respiratory route and contact with ocular secretions during the acute illness.

The classic presentation is characterized by fever, sore throat, coryza, and red eyes. Upper respiratory tract symptoms may precede ocular findings or may be absent.

Acute conjunctivitis may occur with or without pharyngitis or a respiratory syndrome. Encephalitis may occur but is rare.

Conjunctivitis usually begins in one eye and then spreads to the other, although both eyes may be affected simultaneously. Severe pain is atypical, but mild pain or discomfort, tearing, pruritus, and morning crusting are common.

It usually is self-limited to 5 days (incubation period is 5 days).

Uncommonly, an exanthem or diarrhea may occur.

Epidemic keratoconjunctivitis (predominantly serotypes 8, 19, and 37)

This is highly contagious, with approximately 10% transmission in household contacts via hands and fomites. Transmission has also been associated with instrumentation, industrial trauma (shipyard workers [ie, shipyard eye], welders, airborne particles), contaminated ophthalmic solutions, and the hands of health care workers.[14] Corneal trauma facilitates infection.

After an 8-day incubation period, an insidious onset of unilateral red eye occurs, spreading to involve both eyes. Patients have photophobia, tearing, and pain (indicating corneal involvement). Children may have fever and lymphadenopathy.

Malaise and headache are reported.

Inflammation may persist for weeks, and residual scarring and visual impairment may occur.

Acute hemorrhagic cystitis (serotypes 11 and 21) or nephritis

Acute hemorrhagic cystitis usually affects children aged 5-15 years but may also affect immunosuppressed adults (eg, from kidney or bone marrow transplantation, AIDS). Boys are affected more often than girls.

Dysuria, frequency, and grossly bloody urine are reported. Hematuria is self-limited to 3 days, and other symptoms resolve later. Symptoms may be more prolonged in hematopoietic stem cell recipients.

Nephritis has occurred in recipients of hematopoietic stem cell transplants and is associated with fever, hematuria, and flank pain.[15, 16]

Gastroenteritis (most commonly associated with serotypes 40 and 41, but others may be involved)

Enteric adenovirus infection is a common cause of infantile diarrhea in the daycare setting, but less common than rotavirus infection and, in some settings, less common than infection with astroviruses. It can also affect adults; in addition, a nosocomial outbreak in a hematology unit has been reported.[17] Adenoviruses replicate readily in the human intestine and may be cultured from asymptomatic individuals; thus, their presence in the setting of a diarrheal syndrome may be incidental.

Many serotypes are fastidious in culture. Serotypes 40 and 41 had been termed "noncultivatable." However, they have been cultured in the setting of diarrheal syndromes using newer cell lines. Monoclonal antibody assays, enzyme-linked immunosorbent assay, and electron microscopy support the association of these strains with enteric disease. However, one cannot assume that enteric disease is limited to these strains. In fact, various serotypes of adenovirus have been associated with infectious diarrheal syndromes in recipients of hematopoietic stem cell transplants.

Fever and watery diarrhea are usually limited to 1-2 weeks.

Mesenteric adenitis and intussusception have been associated with nonenteric adenovirus serotypes (ie, types 1, 2, 3, 5, 6). Approximately 40% of infants with intussusception have positive findings from cultures of stool or mesenteric lymph nodes for nonenteric serotypes, and most have no evidence of infection with enteric strains (ie, 40, 41). The role of adenovirus in this setting is unclear. Mesenteric lymphadenitis or hyperirritable small bowel associated with nonenteric adenoviral infection has been postulated to lead to intussusception. However, most patients with intussusception have no evidence of adenoviral infection (based on culture, serology, or histopathologic viral inclusion findings); thus, intussusception may be related to multiple etiologies.

Adenoviral infections in immunocompromised hosts (multiple serotypes)

Adenovirus is known to cause disease during the posttransplantation period in patients who have received hematopoietic stem cell transplants. Risk factors for adenovirus disease include allogeneic stem cell transplantation, T-cell depletion and nonmyeloablative conditioning regimens such as high-dose alemtuzumab (Campath) antibody therapy, lymphopenia, young age, and graft versus host disease. Prolonged neutropenia or immunosuppression also enhances the risk of adenoviral infections. Manifestations may vary but include hemorrhagic cystitis/nephritis, pneumonitis, hepatitis/liver failure, and gastroenteritis, particularly during the acute posttransplantation period prior to engraftment. In one series, nephritis was associated with acute renal failure in more than 90% of patients. Adenovirus should be considered in patients with a fever, hematuria, flank pain, and worsening renal function.[18, 5]

Uncommonly, T-cell immunodeficiency related to HIV infection has been associated with adenoviral infections, particularly in infants and children infected with HIV. Pneumonitis and hemorrhagic cystitis are cited most often. Cholecystitis, severe hepatitis, and liver failure have been reported.[19]

Immunosuppression in recipients of solid organ transplants has also been associated with the above syndromes, as has diffuse adenoviral infection of the allograft itself. Both allograft loss and recovery have been reported.[18] Adenoviral infection following pediatric lung transplantation has been reported.[20]

Importantly, note that a prior history of adenoviral infection in a patient with recovered immunocompetence may herald recurrence when the patient again becomes immunosuppressed. A high level of suspicion for adenovirus is warranted in these cases.

General considerations

Pulmonary infiltrates are often diffuse and reticulonodular, but they may be lobar.

Hematuria may occur in the setting of nephritis or hemorrhagic cystitis.

Abnormal transaminase levels, which may be dramatic, may indicate adenoviral hepatitis.

Diarrhea may indicate adenoviral gastroenteritis.

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Physical

Acute respiratory disease

Exudative pharyngitis and conjunctivitis may be seen.

Pulmonary rhonchi and rales may be found on auscultation.

Pharyngoconjunctival fever

Fever, coryza, pharyngitis (may be exudative), follicles in bulbar, and/or palpebral conjunctivae (typically mild granular appearance) may be observed.

Cervical lymphadenopathy may be seen.

Preauricular lymphadenopathy (ie, Parinaud syndrome), with small lymph nodes palpable just anterior to the ear is not common; however, its presence in the setting of a viral conjunctivitis is very suggestive of adenovirus infection.

Epidemic keratoconjunctivitis

Severe follicular keratoconjunctivitis has been reported (conjunctiva may be granular). Hemorrhagic conjunctivitis develops in some cases.

Palpebral edema is a finding.

Preauricular lymphadenopathy is not common but is a pathognomonic finding with adenovirus infection.

Visual haziness or impairment resulting from keratitis or corneal involvement may develop and may persist for months to years.

Acute hemorrhagic cystitis/nephritis

No significant features are described in the setting of hemorrhagic cystitis, other than evidence of blood in the urine. Fever is generally absent.

Flank pain and fever are seen in nephritis.

Gastroenteritis

Patients with severe gastroenteritis may have signs of dehydration.

Adenoviral infections in immunocompromised hosts

Features include dyspnea, dry cough, pulmonary rhonchi and rales, grossly bloody urine, and diarrhea.

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Contributor Information and Disclosures
Author

Sandra G Gompf, MD, FACP, FIDSA Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital

Sandra G Gompf, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Richard Oehler, MD Associate Professor, Department of Internal Medicine, Division of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Director of Clinical Education, Division of Infectious Diseases, Tampa Veterans Affairs Medical Center

Richard Oehler, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America

Disclosure: Nothing to disclose.

Dhanashree Kelkar, MD Lecturer, Department of Medicine, Dr Vasantrao Pawar Medical College, Maharashtra University of Health Sciences, India

Dhanashree Kelkar, MD is a member of the following medical societies: American Medical Association, American Association of Physicians of Indian Origin

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Richard B Brown, MD, FACP Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine

Richard B Brown, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Additional Contributors

David Hall Shepp, MD Program Director, Fellowship in Infectious Diseases, Department of Medicine, North Shore University Hospital; Associate Professor, New York University School of Medicine

David Hall Shepp, MD is a member of the following medical societies: Infectious Diseases Society of America

Disclosure: Received salary from Gilead Sciences for management position.

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A virus image from the International Committee on Taxonomy of Viruses, in The Big Picture Book of Viruses, available at http://www.virology.net/Big_Virology/BVDNAadeno.html.
Transmission electron micrograph of adenovirus. Image courtesy of the US Centers for Disease Control and Prevention.
 
 
 
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