Quantitative temporal and spatial distribution of adenovirus type 2 correlates with disease manifestations and organ failure during disseminated infection

Abstract

Disseminated adenovirus (HAdV) infections are serious complications in allogenic stem cell transplant (SCT) recipients. Quantitative HAdV DNA detection in blood samples demonstrated the association of high virus loads with disease and improved early diagnosis. However, the pathogenesis of disseminated HAdV disease, for example sources of HAdV DNA shedding in the blood stream and association of HAdV replication sites with disease manifestations, remained obscure. In this report, 24 bioptic and autoptic organ and tissue samples of an adult SCT recipient suffering from disseminated infection were quantitatively analyzed for HAdV DNA. Results indicate subsequent virus replication in the colon, bone marrow and liver as origin of HAdV DNAemia, which increased from 1.4 x 10(4) copies/ml to a peak of 2 x 10(9) copies/ml over a period of 84 days in spite of antiviral therapy. Symptoms as diarrhoea, bone marrow failure and hepatic failure were clearly linked to high HAdV DNA concentrations in affected organs. For example, the HAdV DNA level was 2.2 x 10(3) copies/cell in a colon biopsy when the patient suffered from diarrhoea whereas only 1.1 x 10(1) copies/cell were detected when symptoms had improved. Focal HAdV infection of the liver as demonstrated by laser microdissection was followed by fulminant virus replication with 1.3 x 10(5) copies of HAdV DNA/cell causing terminal hepatic failure. In conclusion, pathogenesis of disseminated HAdV disease was associated with virus replication in affected organs and not immune mediated as suggested recently by a fatal case of gene therapy with a non-replication competent HAdV-C5 vector.

High lethality of human adenovirus disease in adult allogeneic stem cell transplant recipients with high adenoviral blood load

“…6,11,31 Our results showed that patients with fatal HAdV disease had significantly higher HAdV peak loads, indicating that high HAdV DNAaemia levels are predictive of a poor outcome of HAdV disease in adults, as reported also by others. 23,24,26 However, as the peak HAdV blood load mostly occurs shortly before death, systematic monitoring should be implemented for adult SCT patients and HAdV DNAaemia threshold levels requiring initiation of therapy should be defined. An arbitrary threshold of 1.0 × 10 4 copies/ml may be used for identification of HAdV DNAaemia positive patients at high risk of a clinically significant disseminated disease.…”

“…5,6,22 Moreover, data concerning the association between high HAdV blood loads and disseminated disease in adults are scarce. 23,24 A recent study including 77 adult SCT-recipients reported a 2.6% prevalence of HAdV DNAaemia, but no HAdV-related deaths. 25 Another study showed HAdV DNAaemia in 5 out of 107 (4.7%) adult SCT recipients including one fatal case of disseminated HAdV disease.…”

Unique sequence features of the Human Adenovirus 31 complete genomic sequence are conserved in clinical isolates

“…For example, an outbreak of the strictly enterotropic HAdV-F41 did not cause any fatalities in paediatric hSCT recipients [17], which might be due to the missing integrin binding RGD motif within the penton protein of species F adenoviruses. Since fatal dissemination of adenoviruses affects various organic systems, a more promiscuous behaviour in cell attachment and entry can be assumed to be favourable [58]. Interestingly, the protein IX of HAdV-A31 revealed an RGD motif at amino acid position 102 - 106, which is conserved within all seven analyzed clinical isolates.…”

Adenovirus Infections in Immunocompetent and Immunocompromised Patients

“…In allo-HSCT recipients, the spectrum of HAdV-associated diseases can range from mild gastroenteric or respiratory symptoms to severe manifestations, including hemorrhagic enteritis or cystitis, pneumonia, hepatitis, nephritis, encephalitis, myocarditis, and, occasionally, concomitant involvement of several organs, which may lead to a lethal outcome by multiorgan failure (69,182,183). Postmortem investigation of the affected organs, including the liver in particular, reveals massive replication of the virus, with lysis of the infected cells and release of viral particles into peripheral blood (184), underlining the diagnostic relevance of viremia. In a study performed at our institution in the pediatric allo-HSCT setting, transplant-related mortality associated with HAdV reached 6% of the entire patient cohort investigated (69,71), but fatal disease attributable to HAdV infection has been reported in up to 50% of patients with DNAemia (69,133).…”