Figure provided by Dr. Joshua Hill.
Patients transplanted with donor hematopoietic stem cells are highly immunodepressed due to the chemotherapy they receive to prepare their bodies for the new immune system. This conditioning regimen, required for successful transplantation, increases the engraftment of the newly transplanted cells while avoiding graft rejection. As a consequence of immunosuppression, patients are at risk to get infected with viruses and other pathogens or to have viral reactivation from previous infection. These events can significantly increase morbidity and mortality in the transplanted individuals. The impact of infection by multiple viruses in transplanted individuals and frequency of these events has been poorly described.
In a recent study published in Blood, Drs. Joshua Hill and Michael Boeckh, along with other colleagues from the Fred Hutch (Vaccine and Infectious Disease and Clinical Research Divisions) investigated the presence of double stranded DNA (dsDNA) viruses in a cohort of transplanted individuals. The authors focused on a selection of dsDNA viruses known for contributing to increased morbidities and mortalities in transplanted patients.
Four hundred and four patients who underwent allogeneic (from a different donor to the recipient) hematopoietic stem cell transplant (HCT) were included in the analyzed cohorts. Patients were separated equally into three groups based on the type of transplant: human leukocyte antigen (HLA)-matched, HLA-mismatched and cord-blood recipients. Patients who had been previously treated for dsDNA virus infections, as well as patients with integrated DNA viruses, were excluded from the study. For each of these patients, weekly plasma samples from the Infectious Disease Sciences Biorepository were available to test for the detection of DNA viruses between days 0 and 100 following the transplantation. Samples were analyzed for the presence of cytomegalovirus (CMV), BK polyomavirus (BKV), human herpesvirus-6B and -6A (HHV-6B, HHV-6A), adenovirus (AdV) and Epstein-Barr virus (EBV) by real-time quantitative PCR. These viruses are of interest because of their implication in morbidities and mortalities following HCT, as well as a lack of low-toxicity treatment options, which is especially relevant to transplanted individuals.
90% of the analyzed individuals had been infected with at least one type of virus, 62% were infected with two or more, 28% with 3 or more and 5% were positive for 4 or 5 different viruses. CMV was the most frequent infection, detected in 65% of the individuals, followed by BKV, HHV-6B, AdV and EBV. Consistent with this observation, the most frequent combination of infections included CMV, BKV and HHV-6B, among others. In individuals infected with only one virus, CMV was again the most often detected (24%). Viruses were first detected a median of twenty days following the transplant.
Individuals younger than 21 years old were more likely to be positive for at least four different viruses and more frequently with BKV and AdV. Relative to HLA-matched transplant patients, more viruses were detected within patients who underwent cord-blood and HLA-mismatched transplantation. Other risk factors for increased infection include more severe acute graft-versus-host-disease, lymphodepletion (absolute lymphocyte count < 200cells/mm3), and higher intensity conditioning regimen prior to the HCT.
Patients infected with 3 viruses at any time or 2 or more at the same time had significantly higher overall mortality (cause of death for any reason). Viruses were directly associated with 6% of the deaths after one year. However, there was evidence supporting that detection of more viruses in the blood, even when not directly linked to cause of death, increased the risk for mortality in these patients. Other potential reasons for increased mortality risk include immunomodulation following virus detection by the immune system, increased medication to treat infection, or other complications associated with the infection such as respiratory failure. Thus, there may be opportunities for earlier intervention, such as prophylactic treatment strategies, to reduce viral reactivation and improve patient outcomes.
Most viral infections face a lack of approved therapies or toxicities, especially in immunosuppressed individuals. Dr. Hill commented: “what I am most excited to explore is the use of new antiviral therapeutic strategies, such as small molecules with broad antiviral activity or adoptive immunotherapy with multi-virus specific T cells, to mitigate the frequency, magnitude, and duration of viral reactivation after HCT that we demonstrated in this paper. If we can show efficacy of treatments with limited side effect profiles, these treatments have potential to reduce many post-HCT complications ranging from BK virus-associated cystitis to life-threatening disseminated adenovirus with gastrointestinal and pulmonary disease“. Such studies are critical to better understand the risks faced by transplanted individuals and improve patients quality of life and the success rate following HCT.
Funding for this study was provided by Chimerix, Inc. and the National Institutes of Health.
Hill JA,Mayer BT,Xie H,Leisenring WM,Huang ML,Stevens-Ayers T,Milano F,Delaney C,Sorror ML,Sandmaier BM,Nichols G,Zerr DM,Jerome KR,Schiffer JT,Boeckh M. 2017. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood. pii: blood-2016-10-748426. Epub ahead of print.