Diagnosis and treatment of adenovirus infection in immunocompromised patients

Abstract

In immunocompromised patients, human adenovirus (HAdV) infections can cause life-threatening multiorgan disease. This review summarizes the incidence and risk factors of invasive human adenovirus infections in immunocompromised patients as well as the recently developed standards for diagnostic methods and strategies according to the predominant risk factors in adults and children. Recommendations for preemptive and therapeutic treatment strategies and the outcome in different risk groups are presented. Novel therapeutic approaches including CMX001, a new orally bioavailable lipid conjugate of cidofovir and the transfer of adenovirus-specific donor T cells in the context of allogeneic stem cell transplantation are discussed.

Keywords::

• adenovirus
• chemotherapy
• cidofovir
• CMX001
• immunocompromised patients
• organ transplantation
• stem cell transplantation
• viral infection
• virus-specific T cells

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with he subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • HAdV infections can cause life-threatening multiorgan disease in immunocompromised patients.

• • Transmission between individuals occurs by viral shedding in feces, respiratory secretions or tears of infected individuals. Patients shedding the virus should be placed on droplet and contact precautions in order to avoid outbreaks.

• • In immunocompromised patients, endogenous reactivation seems to be the predominant mechanism of infection.

• • Main risk factors are severe lymphopenia (<300 CD3⁺ cells/μl peripheral blood), allo-hematopoietic stem cell transplantation (HSCT) with in vivo or ex vivo T-cell depletion, allo-HSCT with unrelated cord blood graft and treatment with alemtuzumab. The spectrum of human adenovirus (HAdV)-associated diseases ranges from fever, enteritis, elevated liver enzymes and secondary pancytopenia to severe hemorrhagic enteritis, hemorrhagic cystitis, nephritis, pneumonia, encephalitis, myocarditis and hepatitis. Lethal disease is frequently associated with hepatic failure.

• • Cytotoxic HAdV-specific T cells targeting the adenoviral hexon protein, which contains the generic antigenic component common to all adenoviruses, seem to be cross-reactive with all types of the virus.

• • PCR-based assays have been established as a standard diagnostic tool for rapid, specific, quantitative and highly sensitive detection of HAdV in any diagnostic material. PCR screening of HSCT patients at risk is mandatory. In other immunocompromised patients with unexplained fever, enteritis, cytopenia or elevated liver enzymes, HAdV infection should be excluded by PCR screening in peripheral blood and analysis other diagnostic specimens of interest.

• • Treatment with cidofovir is state of the art in the presence of HAdV disease and in HSCT patients at risk. Moreover, preemptive therapy with cidofovir is recommended in asymptomatic patients with DNAaemia, despite the lack of controlled clinical studies confirming its efficacy. CMX001 is currently being evaluated as an oral and less toxic therapeutic alternative.

• • In the context of allogeneic HSCT, rising viral load despite virostatic treatment is associated with up to 100% HAdV-related mortality.

• • Following HSCT, adoptive transfer of donor-derived HAdV-specific T cells seems to be effective in patients not responding to virostatic treatment.

Notes