https://www.uphs.upenn.edu/bugdrug/antibiotic_manual/oipreventidsacdcstemcell2009.pdf

Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.

Human adenoviruses (HAdVs) are an important cause of infections in both immunocompetent and immunocompromised individuals, and they continue to provide clinical challenges pertaining to diagnostics and treatment. The growing number of HAdV types identified by genomic analysis, as well as the improved understanding of the sites of viral persistence and reactivation, requires continuous adaptions of diagnostic approaches to facilitate timely detection and monitoring of HAdV infections. In view of the clinical relevance of life-threatening HAdV diseases in the immunocompromised setting, there is an urgent need for highly effective treatment modalities lacking major side effects. The present review summarizes the recent progress in the understanding and management of HAdV infections.

Adenovirus Infections in Immunocompetent and Immunocompromised Patients

Summary: The number of patients with acquired immunodeficiency has grown steadily as a result of both a larger number of patients receiving solid organ and hematopoietic stem cell transplants and their longer survival times. The use of newer, more potent immunosuppressive regimens has increased the frequency of severe adenovirus infections. Human adenoviruses are a large group of viruses, represented by at least 52 serotypes with various genotypes divided into genomic clusters, and these may cause a broad variety of clinical manifestations. The development of molecular methods has increased the sensitivity and rapidity of adenovirus infection diagnosis. The implementation of PCR assays has significantly contributed to the identification of patients with disseminated adenovirus disease. More recently, the development of real-time PCR assays has permitted virus quantification and patient follow-up. There is no treatment for adenovirus with demonstrated efficacy, although cidofovir is widely used. Sensitive diagnostic tests for adenovirus can contribute to the early diagnosis and successful treatment of life-threatening adenovirus infections, especially in complex immunocompromised patients. The development of improved adenovirus therapy still remains a challenge. Adenovirus genetic diversity should be considered for diagnosis, typing, and therapeutic interventions.

Adenoviruses in Immunocompromised Hosts

Adenoviruses (AdVs) are DNA viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal tract, or conjunctiva. Rare manifestations of AdV infections include hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, or meningoencephalitis. AdV infections are more common in young children, due to lack of humoral immunity. Epidemics of AdV infection may occur in healthy children or adults in closed or crowded settings (particularly military recruits). The disease is more severe and dissemination is more likely in patients with impaired immunity (e.g., organ transplant recipients, human immunodeficiency virus infection). Fatality rates for untreated severe AdV pneumonia or disseminated disease may exceed 50%. More than 50 serotypes of AdV have been identified. Different serotypes display different tissue tropisms that correlate with clinical manifestations of infection. The predominant serotypes circulating at a given time differ among countries or regions, and change over time. Transmission of novel strains between countries or across continents and replacement of dominant viruses by new strains may occur. Treatment of AdV infections is controversial, as prospective, randomized therapeutic trials have not been conducted. Cidofovir is the drug of choice for severe AdV infections, but not all patients require treatment. Live oral vaccines are highly efficacious in reducing the risk of respiratory AdV infection and are in routine use in the military in the United States, but currently are not available to civilians.

/pdf/adenovirus-epidemiology-global-spread-of-novel-serotypes-and-2u0jbhsjjp.pdf

Adenovirus: Epidemiology, Global Spread of Novel Serotypes, and Advances in Treatment and Prevention

Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective

/pdf/guidelines-for-preventing-infectious-complications-among-2f9bm5loaz.pdf

Background We have previously reported that human adenovirus (HAdV) reference strains clearly show species-dependent resistance to ribavirin, whereas different species of HAdV are equally sensitive to cidofovir All the serotypes tested were susceptible to cidofovir, whereas only serotypes from species C were sensitive to ribavirin Here, we aimed to extend these investigations to clinical isolates Methods In vitro, we tested 126 isolates obtained from 65 patients included in a European survey of HAdV infection Results Among the 126 isolates tested, all presented cidofovir 50% inhibitory concentration (IC50) in the same range as the HAdV 5 reference strain Regarding ribavirin, all isolates from species C (79 tested) showed an IC50 comparable with previously reported results for reference strains; however, 24/32, 2/6 and 3/3 tested isolates from species A, B and D, respectively, were shown to have a ribavirin IC50 comparable with the HAdV 5 reference strain (species C), contrary to previous observations for reference strains of the same species Among patients who were treated with cidofovir for disseminated HAdV infection, > or = 4 sequential isolates could be obtained from 9 patients; no variation in cidofovir susceptibility could be detected Conclusions Cidofovir is active in vitro in all HAdV clinical isolates Ribavirin was revealed to be active on most HAdV isolates from species A, B and D, and in all isolates from species C Finally, no resistance to cidofovir became apparent in sequential isolates obtained from treated patients

Differential susceptibility of adenovirus clinical isolates to cidofovir and ribavirin is not related to species alone.

Adenovirus infections are a frequent and serious complication following allogeneic haematopoietic stem cell transplantation (HSCT). The antiviral drugs cidofovir and ribavirin have been used as first-line therapy for disseminated infections with variable results. In the present study, in vitro susceptibility to these two drugs was evaluated on HEp-2 cells in adenovirus reference strains representing serotypes of each of the six species and in clinical isolates. Susceptibility to cidofovir was comparable between species with inhibition of replication of all tested serotypes in a narrow dose range (IC50=17-81 microM). However, susceptibility to ribavirin was highly dependent on the species. Serotypes from species A, B, D, E and F were all resistant to ribavirin (IC50=396 to >500 microM). Only replication of serotypes from species C was inhibited by ribavirin (IC50=48-108 microM). This species-dependent susceptibility of adenovirus to ribavirin was confirmed in clinical isolates. When tested on other cell lines (PLC, A549 and 293), all species were revealed to be resistant to ribavirin. If our in vitro findings are predictive of virological responses in vivo, these results suggest that ribavirin would not be effective for management of non-C species adenovirus infections after HSCT.

https://www.intmedpress.com/serveFile.cfm?sUID=e0b1d6eb-c342-4ef6-946c-e08117c9806c

In vitro susceptibility of adenovirus to antiviral drugs is species-dependent.

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Differential susceptibility of adenovirus clinical isolates to cidofovir and ribavirin is not related to species alone.

In vitro susceptibility of adenovirus to antiviral drugs is species-dependent.