About Adenovirus

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Adenoviruses are members of the Adenoviridae family and are nonenveloped, double-stranded DNA viruses comprised of 6 subgroups, A through F, based on common biologic, morphologic, and genetic features. Adenovirus was first isolated in 1953 from adenoid tissue-derived cell cultures, which were observed to spontaneously degenerate over time.

 

ADENOVIRUS CLINICAL MANIFESTATIONS

Viral infection may occur through direct contact, inhalation of respiratory droplets, or ingestion. After recovery from an active infection, a patient may harbor persistent infections in the tonsils, adenoids, other lymphoid tissues, or intestines. Some adenoviruses establish persistent, asymptomatic infections, and viral shedding may occur for years. Infection most commonly occurs during childhood.

Severe infections are caused primarily by subgroup C adenoviruses1. Specific serotypes have been associated with particular diseases. For example, serotypes 40 and 41 are commonly associated with gastroenteritis, while subgroup C serotypes 1, 2, 5, and 6 are commonly associated with respiratory tract illnesses and conjunctivitis in children1. In immunocompromised patients, however, multiple localized infections can occur as a manifestation of disseminated infection from a single serotype1.

Severe morbidity and mortality due to adenovirus infection affect both hematopoietic stem cell transplant (HSCT) and solid organ transplant recipients1. Common illnesses due to adenovirus infection include hemorrhagic cystitis/nephritis, pneumonitis, hepatitis, liver failure, and gastroenteritis, particularly during the acute post-transplant period prior to engraftment. Symptoms of adenovirus infection vary widely, depending on the organ involved. Adenovirus nephritis was associated with acute renal failure in 90% of infected patients2. Graft-versus-host disease (GVHD) is also associated with adenovirus infection, and allograft failure may occur in solid organ transplant recipients1.

Retrospective studies of HSCT patients found the incidence of adenovirus infection ranging from 5 to 50%, with similar percentages developing into invasive disease1. However, among patients with T cell depleted or mismatched allografts, the infection rate increased to between 20 and 30%, with 30 to 40% of those patients developing invasive disease3. Polymerase chain reaction (PCR) assays used to detect adenovirus DNA in peripheral blood have demonstrated a strong correlation between viremia and the risk of disseminated adenovirus disease1,4-6.

Adenovirus infections are particularly associated with significant rates of morbidity and mortality in children who undergo HSCT. In one retrospective study of 328 pediatric HSCT recipients, 37 (11.3%) were infected with adenovirus within 6 months of the transplant procedure. Infection with adenovirus delayed recovery of immunity after HSCT, and infection resulted in 7 deaths (2.1% mortality)7. Another retrospective study found that over a 4-year period, 42 of 201 HSCT patients (21%) had positive adenovirus cultures post-transplant8. The incidence of infection was significantly higher in pediatric patients than in adults. Pediatric patients also had an earlier onset of infection, averaging less than 30 days after transplantation, compared with an average onset of 90 days among adults8.

 

LABORATORY DIAGNOSIS

Several methods can be used to detect adenoviruses in patients, including virus isolation, serology, and molecular amplification methods, such as PCR. Rates of seroconversion to adenoviruses are high because individuals commonly contract adenoviruses during childhood. Therefore, serology has limited diagnostic value in a clinical setting. Virus isolation through cell culture techniques is a slow process, often taking days to weeks for completion, limiting the clinical usefulness. Furthermore, virus isolation is technically demanding and requires careful sample handling to preserve virus infectivity and, thus, can have low diagnostic sensitivity and yield false negative results. Isolation of viruses may be particularly complicated in immunocompromised patients who have received transfusions of blood products that contain adenovirus antibodies. Additionally, virus isolation does not yield quantitative results, which limits the usefulness of cell culture isolation in monitoring the clinical progress of patients following treatment. In contrast to these methods, PCR techniques are fast, and extremely sensitive and can identify adenoviruses using many different types of clinical specimens, such as plasma, urine, cerebrospinal fluid, lung tissue, bone marrow aspirate, throat specimens and fecal specimens, among other fluids and tissues. Clinical management of adenovirus infection in HSCT recipients is based on early diagnosis. In this case, detection of adenovirus DNA by quantitative PCR (qPCR) is the gold standard for these patients. The sensitivity of molecular methods allows early detection of adenovirus disseminated infection, defined by the presence of adenovirus DNA in circulation9,10, and helps prevent severe clinical virological complications in HSCT recipients5. Additionally, precise quantification of adenovirus in plasma is a useful indicator of adenovirus dissemination after HSCT 6. In addition, adenovirus DNA detection in stool samples by PCR could be associated with adenovirus DNA detection in whole blood. Combining these two parameters provides an optimal tool for managing the risk of adenovirus-associated morbidity and mortality11.

 

TREATMENT

No specific antiviral therapy has been shown to produce a definite clinical effect against adenovirus infection. The efficacy of ribavirin and cidofovir are under evaluation12-15. High-dose intravenous immunoglobulin (IVIG) treatment has been successfully used to treat some patients, and donor leukocyte transfusions for solid organ transplant recipients may be useful as adjunctive treatment with antiviral therapy15. Standardized treatment guidelines for transplant recipients have not been developed; treatment decisions should be made on an individual basis.

 

CONCLUSION

Although adenovirus can produce severe illness in transplant recipients, sensitive, rapid, quantitative, real-time PCR techniques can quickly and accurately identify the virus. This method allows early diagnosis and differentiation from other infections, giving patients the best chance for recovery. Early diagnosis and intervention provides the best chance of reducing the risk of illness and death among transplant recipients. Real-time PCR may provide the most effective means of detecting adenovirus infection early so that preemptive therapy can be administered.

 

REFERENCES

1. Echavarria M. Adenoviruses in immunocompromised hosts. Clinical Microbiology Reviews. Oct 2008;21(4):704-715.
2. Bruno B, Zager RA, Boeckh MJ, et al. Adenovirus nephritis in hematopoietic stem-cell transplantation. Transplantation. Apr 15 2004;77(7):1049-1057.
3. Suparno C, Milligan DW, Moss PA, Mautner V. Adenovirus infections in stem cell transplant recipients: recent developments in understanding of pathogenesis, diagnosis and management. Leukemia & Lymphoma. May 2004;45(5):873-885.
4. Lindemans CA, Leen AM, Boelens JJ. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood. Dec 16 2010;116(25):5476-5485.
5. Gustafson I, Lindblom A, Yun Z, et al. Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients. Journal of Clinical Virology : The Official Publication of the Pan American Society for Clinical Virology. Sep 2008;43(1):79-85.
6. 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. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. Oct 15 2007;45(8):958-965.
7. van Tol MJ, Kroes AC, Schinkel J, et al. Adenovirus infection in paediatric stem cell transplant recipients: increased risk in young children with a delayed immune recovery. Bone Marrow Transplantation. Jul 2005;36(1):39-50.
8. Flomenberg P, Babbitt J, Drobyski WR, et al. Increasing incidence of adenovirus disease in bone marrow transplant recipients. The Journal of Infectious Diseases. Apr 1994;169(4):775-781.
9. Flomenberg P, Piaskowski V, Truitt RL, Casper JT. Characterization of human proliferative T cell responses to adenovirus. The Journal of Infectious Diseases. May 1995;171(5):1090-1096.
10. Robin M, Marque-Juillet S, Scieux C, et al. Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome. Haematologica. Sep 2007;92(9):1254-1257.
11. 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 transplantation. Jun 2007;39(11):677-686.
12. 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 Transplantation. Mar 2003;31(6):481-486.
13. 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 Transplantation. Mar 2001;27(6):621-626.
14. Nagafuji K, Aoki K, Henzan H, et al. Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients. Bone Marrow Transplantation. Nov 2004;34(10):909-914.
15. Lenaerts L, De Clercq E, Naesens L. Clinical features and treatment of adenovirus infections. Reviews in Medical Virology. Nov-Dec 2008;18(6):357-374.