ADENOVIRUS IN THE TRANSPLANT POPULATION
Adenoviruses are a large group of viruses that cause a variety of self-limiting infections in the normal, healthy population. However, in the transplant population adenovirus infections can be quite serious, sometimes leading to graft failure, disseminated disease, or even death. Morbidity and mortality from adenovirus infections are more common in the pediatric transplant population, especially hematopoietic stem cell transplant and liver transplant patients. Unfortunately, adenovirus infections are difficult to treat as there are no specific antiviral agents available.
Adenoviruses are non-enveloped, double-stranded DNA viruses comprised of 6 subgroups (A through G) based on common biologic, morphologic and genetic features. Adenovirus was first isolated from adenoid tissue-derived cell cultures which were observed to spontaneously degenerate over time2. Specific subgroups and serotypes of adenovirus 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. Adenoviral infection may occur through direct contact, inhalation of respiratory droplets, or ingestion. After recovery from an active infection, a patient may harbor latent infections in the tonsils, adenoids, other lymphoid tissues, or in the intestines. Some adenoviruses establish persistent, asymptomatic infection's and viral shedding may occur for years. Infection most commonly occurs in children, people living in close quarters, and immunocompromised patients3.
Severe morbidity and mortality due to adenovirus infection affects both allogeneic HSCT and solid organ transplant recipients, particularly in pediatric patients4. Common illnesses due to adenovirus infection in immunocompromised patients include hemorrhagic cystitis/nephritis, pneumonitis, hepatitis, liver failure, and gastroenteritis5. Symptoms of adenovirus infection vary widely depending on the organ involved. Adenoviral nephritis was associated with acute renal failure in 90% of infected patients7. Graft-versus-host disease (GVHD) is also associated with adenovirus infection, and allograft failure may occur in solid organ transplant recipients3. In bone marrow transplant patients with adenovirus infection, an overall mortality rate of 26% was reported with much higher mortality rates in patients with pneumonia (76%) or disseminated disease (61%)8. Retrospective studies of HSCT patients found the incidence of adenovirus infection ranged from 4% to 20%, with similar percentages developing into invasive disease, and mortality rates approaching 26%9. Among patients with T-cell depleted or mismatched allografts, adenoviral infection rate increased to between 20% and 30%, with 30% to 40% of those patients developing invasive disease9. This research confirms other reports that found T-cell depletion of a graft was associated with a higher incidence of adenoviral infection after transplantation10. Polymerase chain reaction (PCR) assays used to detect adenoviral DNA in peripheral blood have demonstrated a strong correlation between viremia and the risk of severe adenovirus disease11,12.
HIGHER RISKS ARE FOUND IN PEDIATRIC PATIENTS
Adenovirus infections are particularly associated with significant rates of morbidity and mortality in children who undergo HSCT as well as solid organ transplants4,13. In one retrospective study of 328 pediatric HSCT recipients, 37 (11.3%) were infected with adenovirus within six months of the transplant procedure14. Infection with adenovirus delayed recovery of immunity after HSCT, resulting in seven deaths (2.1% mortality)14. Another retrospective study found that over a four-year period, 42 of 201 HSCT patients (21%) had positive adenovirus cultures after transplantation, with the incidence of infections significantly higher in pediatric patients than in adults15. In this study, pediatric patients also had an earlier onset of infection, averaging less than 30 days after transplantation, compared to an average onset of 90 days among adults. Interestingly, moderate to severe acute graft-versus-host disease (GVHD) and isolation of adenovirus from two or more sites have been reported as significant risk factors for developing adenovirus disease15.
DIAGNOSIS AND MONITORING OF ADENOVIRUS
Several methods can be used to detect adenoviruses in patients, including virus isolation, serology, and molecular amplification methods such as PCR. However, not all methods are appropriate for testing transplant recipients. Rates of seroconversion to adenoviruses are high because people commonly contract adenoviruses during childhood1. Therefore, serology has limited diagnostic value in a clinical setting. Virus isolation through cell culture techniques is a slow process, generally taking two weeks for completion to achieve reasonable levels of sensitivity16. Thereby limiting culture's 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 undergoing treatment. Methods such as fluorescence antibody staining and immunohistologic staining utilize biopsy specimens, which require invasive procedures to obtain, and are not sensitive enough to distinguish between active adenovirus infection and residual markers from prior infection.
In contrast to these methods, PCR techniques are both 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 biopsy, throat swab specimens, or other fluids and tissues17. Real-time PCR technology for adenovirus detection has recently become available and has overcome significant limitations (such as sensitivity and the propensity for false positives) of earlier conventional PCR technologies12,18. Real-time PCR allows accurate quantification of viral genomic DNA over a range of fewer than 10 copies to as many as 107 copies. These methods are rapid and results can be provided within hours of specimen receipt. This approach provides a substantial advantage over other methods, since patients with viral loads over 106 copies/ml of adenovirus are considered to be at increased risk for fatal complications19. Compared to cell cultures, PCR testing has produced 99% sensitivity and 98% specificity for detection of adenovirus in throat cultures17. In addition to providing early detection, real-time PCR can also be used to monitor infection progression and response to therapy6.
No specific antiviral therapy has been shown to produce a definite clinical effect against adenovirus infection. The efficacy of cidofovir and related compounds such as the lipid esters of cidofovir and HPMPA, while promising, are still under evaluation. In general, ribavirin and vidarabine have been associated with poor outcomes3. If antiviral therapy is used, it should be initiated early in the clinical course and used with restraint to avoid hematologic toxicity and nephrotoxicity associated with these therapies. High dose intravenous immunoglobulin 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 therapy3. Standardized treatment guidelines for transplant recipients have not been developed; therefore, treatment decisions should be made on an individual basis. Careful monitoring of viral load during treatment is necessary for optimal effects.
Although adenovirus can produce severe illness in transplant recipients, quantitative real-time PCR can quickly and accurately identify the virus due to its rapid and sensitive nature, thereby allowing for early diagnosis. Furthermore, quantitative real-time PCR allows for monitoring of the infection and response to interventions. This allows the transplant patient the best opportunity of recovery from a potentially devastating adenovirus infection.
1. Wold WSM, Horwitz MS. Adenoviruses. Fields Virology. Eds. DM Knipe and PM Howley, Lippincott, Williams and Wilkins, Philadelphia, PA. pp. 2395-2436.
2. Rowe WP, Huebner RJ, Gilmore LK, et al. Isolation of a cytopathogenic agent from human adenoids undergoing spontaneous degeneration in tissue culture. Proc Soc Exp Biol Med. 1953;84:570-573.
3. Ison MG. Adenovirus infections in transplant recipients. Clin Infect Dis. 2006;43:331-339.
4. Hoffman JA. Adenoviral disease in pediatric solid organ transplant recipients. Pediatr Transplant. 2006 Feb;10(1):17-25.
5. Krilov LR. Adenovirus infections in the immunocompromised host. Pediatr Infect Dis. 2005;24:555-556.
6. 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;102:1114-1120.
7. Bruno B, Zager RA, Boeckh MJ, et al. Adenovirus nephritis in hematopoietic stem-cell transplantation. Transplantation. 2004;77:1049-57.
8. La Rosa AM, Champlin RE, Mirza N, et al. Adenovirus Infections in Adult Recipients of Blood and Marrow Transplants. Clin Infect Dis. 2001;32:871-876.
9. Suparno C, Milligan DW, Moss PA, Mautner V. Adenovirus infections in stem cell transplant recipients: recent developments in understanding of pathogenesis, diagnosis and management. Leuk Lymphoma. 2004;45:873-885.
10. Walls T, Hawrami K, Ushiro-Lumb I, Shingadia D, Saha V, Shankar AG. Adenovirus infection after pediatric bone marrow transplantation: is treatment always necessary? Clin Infect Dis. 2005;40:1244-1249.
11. Schilham MW, Claas EC, van Zaane W, Heemskerk B, Vossen JM, Lankester AC, Toes RE, Echavarria M, Kroes AC, van Tol MJ. High levels of adenovirus DNA in serum correlate with fatal outcome of adenovirus infection in children after allogeneic stem-cell transplantation. Clin Infect Dis. 2002;35(5):526-532.
12. Leruez-Ville M, Minard V, Lacaille F, Buzyn A, Abachin E, Blanche S, Freymuth F, Rouzioux C. Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection. Clin Infect Dis. 2004;38(1):45-52.
13. Howard DS, Phillips GL, Reece DE. Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 1999;29:1494-1501.
14. 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 Transplant. 2005; 36:39-50.
15. Flomenberg P, Babbitt J, Drobyski WR, et al. Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis. 1994;169:775-781.
16. Dunn JJ, Woolstenhulme RD, Langer J, et al. Sensitivity of respiratory virus culture when screening with R-mix fresh cells. J Clin Microbiol 42:79-82.
17. Echavarria M, Sanchez JL, Kolavic-Gray SA, et al. Rapid detection of adenovirus in throat swab specimens by PCR during respiratory disease outbreaks among military recruits. J Clin Microbiol. 2003;41:810-812.
18. 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(2):228-239.
19. 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;43:1738-1744.