Adenovirus infections in immunocompetent and immunocompromised patients

Abstract

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.

FIG 1

Adenoviremia with multiple HAdV species. Different HAdV types or species can be detected in peripheral blood and/or other sites, both concomitantly and sequentially. The example displayed shows a rare constellation of invasive infection, associated with HAdV species E, F, and occasionally B, during the posttransplantation course (x axis) of a pediatric patient (86, 269). This observation highlights the fact that very unusual findings are possible, which must be accounted for by the implementation of appropriate diagnostic techniques for HAdV detection and monitoring. The y axis indicates the virus copy number per ml of blood determined by real-time PCR.

FIG 2

Temporal correlation between intestinal HAdV infection and viremia. The median time span between the observation of rapidly rising HAdV copy numbers in serial stool specimens (blue line), exceeding the threshold of 10⁶ virus copies per gram of stool (left arrow), and the first detection of viremia (right arrow; red line) was 11 days (69), providing a rational basis for early start of treatment.

FIG 3

Algorithm for diagnosis and treatment of HAdV infections. This algorithm was established based on the insights provided by studies performed at our center (69). It is important, however, that the indicated absolute threshold value of 10⁶ virus copies/g of stool may be dependent on the specific real-time quantitative PCR (RQ-PCR) approach used in our study and may require adjustment when using other quantitative approaches. Initiation of antiviral therapy at the proposed preinvasive stage may inhibit or slow down proliferation of the virus until recovery of the immune system permits control of the infection. This approach may be instrumental in preventing life-threatening disseminated HAdV disease in individuals at high risk, while limiting the rate of overtreatment in patients after allogeneic HSCT. Screening of PB specimens is usually terminated after documentation of stable PCR negativity. However, the risk of relapse after successful treatment of adenovirus and resolution of HAdV DNAemia may be difficult to assess. Further molecular monitoring should therefore be based on the individual risk profile. In high-risk situations, continued monitoring of both stool and blood specimens may be warranted. *, high-risk parameters include T-cell depletion, GvHD (≥grade II), other, concomitant viral infections, and CD3⁺ counts of <300/μl PB; **, for patients who are HAdV positive in stool, with <10³ virus copies/g after day 28, and do not display any high-risk features, the intervals of testing can be extended further; ***, ribavirin may be indicated only in the presence of HAdV species C; ****, <1-log reduction of viral load within ∼2 weeks of treatment. w/o, without. (Reprinted from reference with permission.)

FIG 4

Course of adenoviremia with switch of HAdV species A to C. (Top) Kinetics of HAdV viremia during the posttransplantation course in a pediatric patient, revealing the disappearance of DNAemia caused by HAdV species A to below the detection level of real-time PCR, with a recurrence of HAdV positivity for a different HAdV species in peripheral blood after about 6 weeks of negative PCR findings. (Bottom) The switch observed in peripheral blood was preceded by corresponding kinetics of HAdV loads in serial stool specimens.