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Dr. Joshua Hill, a physician-researcher in the Infectious Disease Sciences Program at Fred Hutchinson Cancer Research Center, received an Amy Strelzer Manasevit Research Program grant earlier this year at the BMT Tandem Meetings in Salt Lake City, Utah, the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation. The grant — one of the most coveted in the transplantation field — supports early-career scientists who study post-transplant complications.
Hill plans to use the $240,000, three-year grant to explore a new way to diagnose infectious lung diseases by using advanced pathogen detection methods in combination with measuring the host inflammatory response, both in the lung and in the blood. Moving beyond focusing on just the pathogen to examine the host response is “a paradigm shift that hasn’t been done in studies of infections in transplant recipients,” Hill said.
It may sound counterintuitive, but detecting certain pathogens in patients with acute lung diseases does not necessarily implicate that organism as the cause.
“Often we detect pathogens, but their clinical significance is not always clear,” Hill said. “You may have the same pathogen in two different people, and one person is asymptomatic while the other is critically ill.”
This is especially true for transplant patients, whose compromised immune systems are no longer able to keep chronic viral infections in check, for example. Viruses that become activated and detectable may cause problems — or just be bystanders.
Using data to improve diagnostics
Most clinicians now use PCR, or polymerase chain reaction, to look for the DNA or RNA of viruses that frequently cause pneumonia. However, targeting the usual suspects could miss others that are actually driving the infection. “You only find what you look for,” Hill said.
On the other hand, new approaches such as next-generation sequencing that look for whatever is there rather than for specific pathogens may be too sensitive and pick up pathogens that are not causing trouble.
Understanding the host response in the context of different infectious and noninfectious syndromes may improve the interpretation of pathogen detection.
Working with transplant infectious disease physicians and pulmonologists locally and across multiple cancer centers, Hill hopes to establish a cohort of about 200 allogenic hematopoietic stem cell transplant patients with acute lower respiratory tract diseases. In collaboration with the University of Washington Clinical Virology Laboratory, he will employ novel molecular tools to test the patients’ blood, lung fluid and lung tissue for human herpesvirus 6B, or HHV-6B, a typically latent virus that may reactivate and cause pneumonia in post-transplant patients — or not. To collect data on the host response, he will work with the Fred Hutch Genomics Shared Resource and Dr. Sina Gharib to use state-of-the-art RNA sequencing technology to analyze thousands of genes to see which are differentially turned on or off.
The objective is to establish whether host gene-expression profiling of the blood can be used as a noninvasive diagnostic tool to identify the cause of pulmonary disease, whether it is due to HHV-6B, another pathogen, or a noninfectious process.
“Our goal is to enroll enough patients with a spectrum of causes of lower respiratory tract disease to allow for comparisons that may identify distinct gene-expression signatures,” Hill said. “These data may also identify patients who are going to have progressive pulmonary disease versus not.”
Leaders in transplant research
Hill is focusing on HHV-6B, but what he learns will likely have applications toward other pathogens, said Infectious Disease Sciences head and Hill’s mentor Dr. Michael Boeckh, who helped Hill generate the ideas and concepts behind the study.
“It will be essential for future studies of therapeutics for these diseases, for both prevention and treatment,” Boeckh said.
Boeckh noted that previous winners of the prestigious Amy Strelzer Manasevit Award have gone on to become key leaders in the field of stem cell transplantation.
“I have no doubt that Josh will follow in their footsteps,” he said.
The research grant was established in 1997 in memory of a young mother who received a successful marrow transplant to treat multiple myeloma but died of pneumonia six weeks after returning home. Administered by the National Marrow Donor Program/Be the Match, the grant has supported 27 scholars and 13 postdoctoral fellows, including inaugural 1998 awardee Dr. Stephanie Lee, who was then at Dana-Farber Cancer Institute and is now a transplant physician-scientist in Fred Hutch’s Clinical Research Division and director of its Long-Term Follow-Up Program.
“The Amy Strelzer Manasevit award helped me during a critical time in transitioning from a trainee to an independent investigator,” said Lee, who studies chronic graft-vs.-host-disease. “That was the vision of the award founders — to provide substantial funds to promising young investigators to allow them to devote time to their research. I’m thrilled that Dr. Hill was chosen for this award.”
