Pneumonia is a major problem for patients undergoing bone marrow transplants. Despite testing for specific pathogens, up to 10% of transplant recipients are diagnosed with “idiopathic pneumonia syndrome” (IPS), where the cause is unknown and is generally associated with a higher risk of death. “Human Herpesvirus 6 (HHV-6) has long been suspected as a potential cause of pneumonia after bone marrow transplant,” says Dr Joshua Hill, first author on a recent paper in Nature Communications, which implicates HHV-6B as a cause of pneumonia in bone marrow transplant recipients. One of the first studies to explore HHV-6 as a possible cause of pneumonia was lead by Dr. Larry Corey, former president and director of Fred Hutch, in a seminal paper in the New England Journal of Medicine over 30 years ago. “Since then, a number of studies have been conducted but have been limited by various methodologic approaches related to testing for the virus, heterogeneous patient populations, and small sample sizes.” In a previous paper in the Journal of Clinical Oncology, Dr. Hill and his team observed a two-fold increase in mortality of bone marrow transplant patients with pneumonia when HHV-6 was detected in lung washes. Despite the availability of HHV-6 testing and antiviral drugs to treat HHV-6 infection, testing for HHV-6 is still not routinely carried out in this patient population as HHV-6 has not definitively been proven to cause pneumonia.
In their new study, Dr. Hill and his team prospectively collected and preserved samples from bone marrow transplant patients with pneumonia to allow for the next level of HHV-6 testing. They wanted to know not only whether HHV-6 was present in the lungs of these patients but if it was actively replicating – the smoking gun needed to directly implicate HHV-6B as a cause or contributor to the illness. Among 116 trial participants, they found HHV-6B DNA in around 40% of the samples, of which just under half had detectable levels of viral RNA, suggesting the virus was actively replicating in these patients. In turn, these patients had a significantly increased risk for dying within the following 4-8 weeks. “We believe this study provides strong evidence to implicate HHV-6B as a pulmonary pathogen in allogeneic HCT recipients, supporting the role for routine testing and consideration for treatment in the appropriate clinical context,” says Dr Hill. They were also able to profile human gene expression from paired blood samples to demonstrate that individuals with HHV-6B detected in their lungs had enriched expression for genes related to interferons: a group of molecules produced by the body to fight viral infections.
Moving forward, Dr. Hill hopes the findings in this paper will not only convince other doctors to consider HHV-6 infection in patients with pneumonia after transplant but will also stimulate drug development for herpesviruses, including HHV-6. “The currently available therapies for HHV-6 have side effects that require judicious use,” says Dr. Hill. The study also highlights the importance of post-transplant care for improving outcomes for cancer patients. “We at Fred Hutch continue to innovate and improve supportive care for our cancer patients, which has become a critical aspect of improvement in post-transplant survival over the years,” notes Dr. Hill.
The spotlighted research was supported by the National Institutes of Health, the American Society for Transplantation, and the Cellular Therapy/National Marrow Donor Program/Be The Match Foundation.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Joshua Hill, Alpana Waghmare, Guang-Shing Cheng, Geoffrey Hill, Keith Jerome, Wendy Leisenring, Danielle Zerr and Michael Boeckh contributed to this work.
Hill JA, Lee YJ, Vande Vusse LK, Xie H, Chung EL, Waghmare A, Chen G-S, Zhu H, Huang M-L, Hill GR, Jerome KR, Leisenring WM, Zerr DM, Gharib SA, Dadwal S, Boeckh M 2024 Nat. Commun. 15(1):542.