Diagnosis, treatment, and prevention of adenovirus infection
- Flor M Munoz, MD, MSc
Flor M Munoz, MD, MSc
- Associate Professor of Pediatrics
- Baylor College of Medicine
- Phyllis Flomenberg, MD
Phyllis Flomenberg, MD
- Associate Professor of Medicine
- Jefferson Medical College
- Section Editors
- Martin S Hirsch, MD
Martin S Hirsch, MD
- Editor-in-Chief — Infectious Diseases
- Section Editor — Viral Infections
- Professor of Medicine
- Harvard Medical School
- Morven S Edwards, MD
Morven S Edwards, MD
- Section Editor — Pediatric Infectious Diseases
- Professor of Pediatrics
- Baylor College of Medicine
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 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 "Epidemiology and clinical manifestations of adenovirus infection".)
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.
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 (HEK) 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), can require up to 28 days.
- Fox JP, Hall CE, Cooney MK. The Seattle Virus Watch. VII. Observations of adenovirus infections. Am J Epidemiol 1977; 105:362.
- Edwards KM, Thompson J, Paolini J, Wright PF. Adenovirus infections in young children. Pediatrics 1985; 76:420.
- Munoz FM, Piedra PA, Demmler GJ. Disseminated adenovirus disease in immunocompromised and immunocompetent children. Clin Infect Dis 1998; 27:1194.
- Basu G, Rossouw J, Sebunya TK, et al. Prevalence of rotavirus, adenovirus and astrovirus infection in young children with gastroenteritis in Gaborone, Botswana. East Afr Med J 2003; 80:652.
- Levent F, Greer JM, Snider M, Demmler-Harrison GJ. Performance of a new immunochromatographic assay for detection of adenoviruses in children. J Clin Virol 2009; 44:173.
- Raboni SM, Siqueira MM, Portes SR, Pasquini R. Comparison of PCR, enzyme immunoassay and conventional culture for adenovirus detection in bone marrow transplant patients with hemorrhagic cystitis. J Clin Virol 2003; 27:270.
- Herrmann JE, Perron-Henry DM, Blacklow NR. Antigen detection with monoclonal antibodies for the diagnosis of adenovirus gastroenteritis. J Infect Dis 1987; 155:1167.
- Wiley LA, Roba LA, Kowalski RP, et al. A 5-year evaluation of the adenoclone test for the rapid diagnosis of adenovirus from conjunctival swabs. Cornea 1996; 15:363.
- Allard A, Albinsson B, Wadell G. Detection of adenoviruses in stools from healthy persons and patients with diarrhea by two-step polymerase chain reaction. J Med Virol 1992; 37:149.
- Claas EC, Schilham MW, de Brouwer CS, et al. Internally controlled real-time PCR monitoring of adenovirus DNA load in serum or plasma of transplant recipients. J Clin Microbiol 2005; 43:1738.
- Damen M, Minnaar R, Glasius P, et al. Real-time PCR with an internal control for detection of all known human adenovirus serotypes. J Clin Microbiol 2008; 46:3997.
- Heim A, Ebnet C, Harste G, Pring-Akerblom P. Rapid and quantitative detection of human adenovirus DNA by real-time PCR. J Med Virol 2003; 70:228.
- Echavarria M, Forman M, van Tol MJ, et al. Prediction of severe disseminated adenovirus infection by serum PCR. Lancet 2001; 358:384.
- Lion T, Baumgartinger R, Watzinger F, et al. Molecular monitoring of adenovirus in peripheral blood after allogeneic bone marrow transplantation permits early diagnosis of disseminated disease. Blood 2003; 102:1114.
- Leruez-Ville M, Minard V, Lacaille F, et al. Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection. Clin Infect Dis 2004; 38:45.
- Neofytos D, Ojha A, Mookerjee B, et al. Treatment of adenovirus disease in stem cell transplant recipients with cidofovir. Biol Blood Marrow Transplant 2007; 13:74.
- Lankester AC, Heemskerk B, Claas EC, et al. Effect of ribavirin on the plasma viral DNA load in patients with disseminating adenovirus infection. Clin Infect Dis 2004; 38:1521.
- Lankester AC, van Tol MJ, Claas EC, et al. Quantification of adenovirus DNA in plasma for management of infection in stem cell graft recipients. Clin Infect Dis 2002; 34:864.
- Gray GC, McCarthy T, Lebeck MG, et al. Genotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004-2006. Clin Infect Dis 2007; 45:1120.
- Martin AB, Webber S, Fricker FJ, et al. Acute myocarditis. Rapid diagnosis by PCR in children. Circulation 1994; 90:330.
- Towbin JA, Griffin LD, Martin AB, et al. Intrauterine adenoviral myocarditis presenting as nonimmune hydrops fetalis: diagnosis by polymerase chain reaction. Pediatr Infect Dis J 1994; 13:144.
- Shirali GS, Ni J, Chinnock RE, et al. Association of viral genome with graft loss in children after cardiac transplantation. N Engl J Med 2001; 344:1498.
- Becroft DM. Histopathology of fatal adenovirus infection of the respiratory tract in young children. J Clin Pathol 1967; 20:561.
- Landry ML, Fong CK, Neddermann K, et al. Disseminated adenovirus infection in an immunocompromised host. Pitfalls in diagnosis. Am J Med 1987; 83:555.
- Pinkerton H, Carroll S. Fatal adenovirus pneumonia in infants. Correlation of histologic and electron microscopic observations. Am J Pathol 1971; 65:543.
- Matsuoka T, Naito T, Kubota Y, et al. Disseminated adenovirus (type 19) infection in a neonate. Rapid detection of the infection by immunofluorescence. Acta Paediatr Scand 1990; 79:568.
- Wu TC, Kanayama MD, Hruban RH, et al. Virus-associated RNAs (VA-I and VA-II). An efficient target for the detection of adenovirus infections by in situ hybridization. Am J Pathol 1992; 140:991.
- Horwitz MS. Adenoviruses. In: Fields Virology, 3rd ed, Fields BN, Knipe DM, Howley PM (Eds), Lippincott-Raven Publishers, Philadelphia 1996. p.2160.
- McMinn PC, Stewart J, Burrell CJ. A community outbreak of epidemic keratoconjunctivitis in central Australia due to adenovirus type 8. J Infect Dis 1991; 164:1113.
- Klinger JR, Sanchez MP, Curtin LA, et al. Multiple cases of life-threatening adenovirus pneumonia in a mental health care center. Am J Respir Crit Care Med 1998; 157:645.
- Yang E, Rubin BK. "Childhood" viruses as a cause of pneumonia in adults. Semin Respir Infect 1995; 10:232.
- Lee WM, Grindle K, Pappas T, et al. High-throughput, sensitive, and accurate multiplex PCR-microsphere flow cytometry system for large-scale comprehensive detection of respiratory viruses. J Clin Microbiol 2007; 45:2626.
- Caliendo AM. Multiplex PCR and emerging technologies for the detection of respiratory pathogens. Clin Infect Dis 2011; 52 Suppl 4:S326.
- Self WH, Williams DJ, Zhu Y, et al. Respiratory Viral Detection in Children and Adults: Comparing Asymptomatic Controls and Patients With Community-Acquired Pneumonia. J Infect Dis 2016; 213:584.
- Chakrabarti S, Mautner V, Osman H, et al. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood 2002; 100:1619.
- Myers GD, Bollard CM, Wu MF, et al. Reconstitution of adenovirus-specific cell-mediated immunity in pediatric patients after hematopoietic stem cell transplantation. Bone Marrow Transplant 2007; 39:677.
- Erard V, Huang ML, Ferrenberg J, et al. Quantitative real-time polymerase chain reaction for detection of adenovirus after T cell-replete hematopoietic cell transplantation: viral load as a marker for invasive disease. Clin Infect Dis 2007; 45:958.
- Yusuf U, Hale GA, Carr J, et al. Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients. Transplantation 2006; 81:1398.
- Sivaprakasam P, Carr TF, Coussons M, et al. Improved outcome from invasive adenovirus infection in pediatric patients after hemopoietic stem cell transplantation using intensive clinical surveillance and early intervention. J Pediatr Hematol Oncol 2007; 29:81.
- Watson T, MacDonald D, Song X, et al. Risk factors for molecular detection of adenovirus in pediatric hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant 2012; 18:1227.
- Kodama E, Shigeta S, Suzuki T, De Clercq E. Application of a gastric cancer cell line (MKN-28) for anti-adenovirus screening using the MTT method. Antiviral Res 1996; 31:159.
- Legrand F, Berrebi D, Houhou N, et al. Early diagnosis of adenovirus infection and treatment with cidofovir after bone marrow transplantation in children. Bone Marrow Transplant 2001; 27:621.
- Ljungman P, Ribaud P, Eyrich M, et al. Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2003; 31:481.
- Doan ML, Mallory GB, Kaplan SL, et al. Treatment of adenovirus pneumonia with cidofovir in pediatric lung transplant recipients. J Heart Lung Transplant 2007; 26:883.
- Hoffman JA, Shah AJ, Ross LA, Kapoor N. Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001; 7:388.
- Flomenberg P, Babbitt J, Drobyski WR, et al. Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis 1994; 169:775.
- La Rosa AM, Champlin RE, Mirza N, et al. Adenovirus infections in adult recipients of blood and marrow transplants. Clin Infect Dis 2001; 32:871.
- Baldwin A, Kingman H, Darville M, et al. Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplant 2000; 26:1333.
- Symeonidis N, Jakubowski A, Pierre-Louis S, et al. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis 2007; 9:108.
- Heemskerk B, Lankester AC, van Vreeswijk T, et al. Immune reconstitution and clearance of human adenovirus viremia in pediatric stem-cell recipients. J Infect Dis 2005; 191:520.
- Hartline CB, Gustin KM, Wan WB, et al. Ether lipid-ester prodrugs of acyclic nucleoside phosphonates: activity against adenovirus replication in vitro. J Infect Dis 2005; 191:396.
- Ciesla SL, Trahan J, Wan WB, et al. Esterification of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney. Antiviral Res 2003; 59:163.
- Florescu DF, Pergam SA, Neely MN, et al. Safety and efficacy of CMX001 as salvage therapy for severe adenovirus infections in immunocompromised patients. Biol Blood Marrow Transplant 2012; 18:731.
- Phase III, open-labeled, multicenter study of the safety and efficacy of brincidofovir (CMX001) in the treatment of early versus late adenovirus infection (CMX001 adv). https://clinicaltrials.gov/ct2/show/NCT02087306?term=NCT02087306&rank=1 (Accessed on November 13, 2014).
- Taylor DL, Jeffries DJ, Taylor-Robinson D et al. The susceptibility of adenovirus infection to the anti-cytomegalovirus drug, ganciclovir (DHPG. FEMS Microbiol Lett 1988; 49:337.
- Ying B, Tollefson AE, Spencer JF, et al. Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters. Antimicrob Agents Chemother 2014; 58:7171.
- Baba M, Mori S, Shigeta S, De Clercq E. Selective inhibitory effect of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and 2'-nor-cyclic GMP on adenovirus replication in vitro. Antimicrob Agents Chemother 1987; 31:337.
- Sabroe I, McHale J, Tait DR, et al. Treatment of adenoviral pneumonitis with intravenous ribavirin and immunoglobulin. Thorax 1995; 50:1219.
- Hromas R, Clark C, Blanke C, et al. Failure of ribavirin to clear adenovirus infections in T cell-depleted allogeneic bone marrow transplantation. Bone Marrow Transplant 1994; 14:663.
- Kawakami M, Ueda S, Maeda T, et al. Vidarabine therapy for virus-associated cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 1997; 20:485.
- Mawhorter S, Yamani MH. Hypogammaglobulinemia and infection risk in solid organ transplant recipients. Curr Opin Organ Transplant 2008; 13:581.
- Flomenberg PR, Chen M, Munk G, Horwitz MS. Molecular epidemiology of adenovirus type 35 infections in immunocompromised hosts. J Infect Dis 1987; 155:1127.
- Dagan R, Schwartz RH, Insel RA, Menegus MA. Severe diffuse adenovirus 7a pneumonia in a child with combined immunodeficiency: possible therapeutic effect of human immune serum globulin containing specific neutralizing antibody. Pediatr Infect Dis 1984; 3:246.
- Lenaerts L, Kelchtermans H, Geboes L, et al. Recovery of humoral immunity is critical for successful antiviral therapy in disseminated mouse adenovirus type 1 infection. Antimicrob Agents Chemother 2008; 52:1462.
- Hromas R, Cornetta K, Srour E, et al. Donor leukocyte infusion as therapy of life-threatening adenoviral infections after T-cell-depleted bone marrow transplantation. Blood 1994; 84:1689.
- Feuchtinger T, Matthes-Martin S, Richard C, et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol 2006; 134:64.
- Leen AM, Myers GD, Sili U, et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med 2006; 12:1160.
- Geyeregger R, Freimüller C, Stemberger J, et al. First-in-man clinical results with good manufacturing practice (GMP)-compliant polypeptide-expanded adenovirus-specific T cells after haploidentical hematopoietic stem cell transplantation. J Immunother 2014; 37:245.
- Top FH Jr, Dudding BA, Russell PK, Buescher EL. Control of respiratory disease in recruits with types 4 and 7 adenovirus vaccines. Am J Epidemiol 1971; 94:142.
- Barraza EM, Ludwig SL, Gaydos JC, Brundage JF. Reemergence of adenovirus type 4 acute respiratory disease in military trainees: report of an outbreak during a lapse in vaccination. J Infect Dis 1999; 179:1531.
- Centers for Disease Control and Prevention (CDC). Two fatal cases of adenovirus-related illness in previously healthy young adults--Illinois, 2000. MMWR Morb Mortal Wkly Rep 2001; 50:553.
- Metzgar D, Osuna M, Kajon AE, et al. Abrupt emergence of diverse species B adenoviruses at US military recruit training centers. J Infect Dis 2007; 196:1465.
- Lyons A, Longfield J, Kuschner R, et al. A double-blind, placebo-controlled study of the safety and immunogenicity of live, oral type 4 and type 7 adenovirus vaccines in adults. Vaccine 2008; 26:2890.
- Adenovirus type 4 and type 7 live oral vaccine prescribing information. http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM247515.pdf (Accessed on June 14, 2011).
- Radin JM, Hawksworth AW, Blair PJ, et al. Dramatic decline of respiratory illness among US military recruits after the renewed use of adenovirus vaccines. Clin Infect Dis 2014; 59:962.
- Binn LN, Sanchez JL, Gaydos JC. Emergence of adenovirus type 14 in US military recruits--a new challenge. J Infect Dis 2007; 196:1436.
- PRINS A. Studies of the significance of the recall phenomenon in the antibody response to adenovirus vaccine and infection. J Immunol 1960; 84:562.
- Buehler JW, Finton RJ, Goodman RA, et al. Epidemic keratoconjunctivitis: report of an outbreak in an ophthalmology practice and recommendations for prevention. Infect Control 1984; 5:390.
- D'Angelo LJ, Hierholzer JC, Keenlyside RA, et al. Pharyngoconjunctival fever caused by adenovirus type 4: report of a swimming pool-related outbreak with recovery of virus from pool water. J Infect Dis 1979; 140:42.
- Jernigan JA, Lowry BS, Hayden FG, et al. Adenovirus type 8 epidemic keratoconjunctivitis in an eye clinic: risk factors and control. J Infect Dis 1993; 167:1307.
- Finn A, Anday E, Talbot GH. An epidemic of adenovirus 7a infection in a neonatal nursery: course, morbidity, and management. Infect Control Hosp Epidemiol 1988; 9:398.
- Faden H, Wynn RJ, Campagna L, Ryan RM. Outbreak of adenovirus type 30 in a neonatal intensive care unit. J Pediatr 2005; 146:523.
- Piedra PA. Adenovirus in the neonatal intensive care unit: formidable, forgotten foe. J Pediatr 2005; 146:447.
- American Academy of Pediatrics. Adenovirus infections. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.226.
- DIAGNOSTIC TESTS
- Viral culture
- Viral antigen assay
- Polymerase chain reactions
- Histopathologic studies
- Serotyping and genotyping
- Restriction endonuclease analysis
- DIAGNOSTIC TESTS OF CHOICE FOR DIFFERENT ADENOVIRUS SYNDROMES
- Upper respiratory illness
- Epidemic keratoconjunctivitis
- Diarrhea in young children
- Infections in immunocompromised hosts
- Antiviral agents
- - Cidofovir
- - Lipid-ester derivatives of cidofovir
- - Other
- Infection control
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS