The number of immunosuppressed patients has grown steadily as a result of both a larger number of patients receiving solid organ transplants and HSCT and their longer times of survival. In addition, the use of newer, more potent immunosuppressive regimens has increased the frequency of severe adenovirus infections documented in major medical centers. In addition, improvements in the control of cytomegalovirus infections after transplantation have changed the focus to other opportunistic viral infections, including adenovirus infection. On the other hand, the development of more sensitive and rapid diagnostic methods has also improved adenovirus detection.
Human adenoviruses are a wide group of viruses, represented by at least 52 serotypes with various genotypes divided into genomic clusters, which may cause a broad variety of clinical manifestations. The genetic diversity among them should be considered for diagnosis, typing, and therapeutic interventions.
A significantly higher incidence of adenovirus infections is observed mainly in pediatric SCT recipients. This condition may well represent specific characteristics of virus pathogenesis regarding the mode of infection and reactivation. The persistence of adenovirus species C, demonstrated by the presence of DNA in T lymphocytes from tonsils, is higher in younger age groups (37
The development and implementation of molecular methods, especially the application of PCR assays to test blood samples, have significantly contributed to the identification of patients with disseminated adenovirus disease. Dissemination has been recognized more widely among transplant patients, especially among HSCT recipients, who are at higher risk of developing a severe or fatal disease. This manifestation has been underestimated in the past, since conventional methods failed to detect viremia. In 1999, Echavarría et al. reported the utility of PCR methods for serum or plasma for detection of adenovirus disease among BMT recipients (31
). Furthermore, a subsequent study demonstrated that the presence of adenoviral DNA in serum was associated with severe or fatal disease (32
). Nowadays, PCR in blood is broadly used for screening of adenovirus infection in SCT recipients, who are at higher risk for developing disease. Since proper management of these patients depends on early diagnosis and differentiation from other conditions, PCR can offer a valuable tool as an early marker for disease (67
More recently, the development of real-time PCR assays has permitted the quantification of the virus. The determination and blood monitoring of adenovirus viral load for the treatment and prognosis of these infections are gaining wide acceptance, especially for the pediatric population. Most real-time PCR assays are home-brew approaches, and currently there is only one commercial assay available. Interlaboratory comparisons are limited due to the lack of an international standard and FDA-cleared or -approved assays. No absolute viral load threshold in blood has yet been determined for adenoviruses, due to the lack of standardization and to assay performance at different centers as well as to individual variations in viral replication. Adenovirus DNA can be detected in peripheral cells, whole blood, plasma, or serum, with some different results. Therefore, determination of the changes in the viral load over time by regular monitoring (i.e., weekly) of the same specimen type performed at the same institution may be more useful than determination of the absolute viral load.
The clinical interpretation of adenovirus viral load determinations is still controversial. In one study, the viral load was significantly higher in peripheral blood mononuclear cells from symptomatic than from asymptomatic patients (114
). However, another study showed no significant correlation between clinical presentation, disease severity, and quantitation of viral load in blood (109
). The same study also showed that lower viral loads were cleared earlier than higher viral loads (109
). Not all children with adenovirus viremia will develop symptoms, and in fact, some are able to clear the virus spontaneously.
In some cases, asymptomatic adult allogeneic SCT recipients were able to clear the virus spontaneously (60
). Therefore, host immunity plays a significant role in controlling the infection. Patients who died with adenovirus viremia had continuously increasing viral loads without lymphocyte recovery (45
). Close surveillance of patients at higher risk of developing disease is of utmost importance, since early interventions may contribute to clinical response and may avoid fatal outcomes. Boosting of immunity by decreasing immunosuppression or adoptive immunotherapy with adenovirus-specific T cells or infusion of donor cells seems to be a significant tool for patients at risk of adenovirus disease.
Although there is no specific treatment for adenovirus, different antiviral drugs have been used (79
). Cidofovir is currently the most widely used drug among SCT recipients. Furthermore, the use of preemptive therapy with cidofovir is a common practice in many centers. Active surveillance for adenovirus and preemptive therapy should be strongly considered, particularly for pediatric SCT recipients at high risk of developing disease, until sufficient restoration of T-cell function occurs. Antiviral treatment should be considered for patients with adenovirus detected at two or more sites and for those with evidence of end organ disease or with severe lymphopenia, in which case reduction of immunosuppression is not feasible (19
The presence of coinfections with various adenovirus strains and the finding of sequential emergence of multiple adenovirus serotypes after pediatric SCT are characteristic features of adenovirus infection compared to other viral diseases. This observation is relevant for diagnostic purposes and therapeutic interventions, including antiviral treatment or immunotherapy (65
Sensitive diagnostic tests for adenovirus can contribute to the early detection and successful treatment of life-threatening adenovirus infections, especially in complex immunocompromised patients who may be thought to have other diagnoses, such as graft-versus-host disease. The wider availability of these tests has led to a better understanding of the frequency and potential severity of adenovirus infection in immunocompromised hosts. Diagnostic accuracy is essential to minimize immunosuppression in patients with adenoviral infections. In addition, improved adenovirus diagnosis should greatly facilitate the evaluation of more effective and less toxic adenovirus therapies. Large prospective multicenter controlled clinical trials with different patient populations will be needed and are likely to rely on the improved molecular diagnostic tests that are now becoming available.