Calculating the risk: Lower respiratory tract infection in transplant recipients

From the Boeckh Lab, Clinical Research and Vaccine and Infectious Disease Divisions

Hematopoietic cell transplantation is associated with risks for the patients involved. One such risk is contracting lower respiratory tract infections (LRTI) that can cause additional health problems and, in some cases, an increased risk of mortality. Previous research in this field has focused on developing a risk score assessment - termed the immunodeficiency scoring index (ISI) - which aimed to accurately predict factors linked to LRTI development, allowing for potential clinical intervention post-transplant. However, studies evaluating the utility of ISI had limited participants with RSV requiring additional investigation into its efficacy in determining risk of progression from an upper respiratory tract infection (URTI) to a potentially more serious LRTI. According to a new study from Dr. Chikara Ogimi and Dr. Michael Boeckh, a member of Fred Hutch’s Clinical Research and Vaccine and Infectious Divisions, additional risk factors warrant evaluation of their role in LRTI risk. For example, they noted that transplant conditioning regimens are constantly evolving and often require the patient to undergo multiple transplant procedures causing a weakened immune state that may contribute to an increased risk of progressing to a LRTI. Further, based on recent research demonstrating that hyperglycemia in SARS-CoV-2 infection was linked to worse prognosis, the authors hypothesized that this could be true of other seasonal viruses and infection status could potentially predict worse outcomes for transplant recipients. Their work, recently published in Bone Marrow Transplantation, sought to determine the role of these risk factors in causing progression to LRTI, in addition to applying the ISI to a cohort of patients with a wide range of circulating viruses. Excitingly “this study identified novel risk factors for viral disease progression to LRTI in allogeneic hematopoietic cell transplant recipients presenting with URTI, including a history of multiple transplants, hyperglycemia and type of virus. We demonstrated that patients with ≥3 independent risk factors are highly likely to progress to LRTI, and, on the other hand, patients without any risk factors are highly unlikely to progress,” stated Dr Ogimi.

In order to test their hypotheses, the authors designed a study comprising patients who underwent transplant procedures at Fred Hutchinson Cancer Research Center and had undertaken molecular testing on samples derived from their respiratory tract. Of the over 1,000 patients who were deemed eligible to participate in their study, the most common URTIs observed were human rhinovirus, parainfluenza and seasonal coronaviruses, and almost a fifth of these patients had evidence of LRTI within a 90-day timeframe. Moreover, within their cohort of participants, 15% had undergone several transplant procedures, likely due to these individuals having Non-Hodgkin’s Lymphoma or multiple myeloma which require multiple transplant procedures. The authors then developed a statistical model and input potential risk factors for developing a LRTI, including hyperglycemia, number of transplant procedures, circulating virus infection status, and other important risk factors. Their model determined an association between risk of progression to LRTI with a high glucose value, a history of multiple transplants, or a metapneumovirus or RSV infection. Importantly, when seeking to determine the capability of the ISI in predicting risk, the authors noted that patients assigned a high-risk ISI score had a higher probability of progression to LRTI than those with lower scores, a finding that was consistent for different viruses. 

Hyperglycemia and multiple transplant procedures are risk factors for viral disease progression in transplant recipients.
Top: Cumulative incidence of progression to LRTI (%) by day 90 according to number of risk factors, Bottom: Cumulative incidence of progression to LRTI (%) by day 90 according to type of virus. Image provided by Dr.Ogimi.

Next, the authors aimed to determine how many risk factors were predictive for risk of progression to LTRI. They noted that very low numbers of patients progressed to LRTI with 0-1 risk factors, but those patients who had the presence of 3 or more risk factors had a very high risk of progression to LRTI. Lastly, given that both high glucose level (hyperglycemia) and steroid usage after transplant were associated with risk of progression to LRTI, the authors assessed both factors simultaneously and described an increased risk for these individuals when compared to patients without a high glucose score or who did not use steroids. These findings have promising clinical relevance as “the significance of hyperglycemia raises the question of whether glycemic control may improve the outcome of hematopoietic cell transplant recipients with URTI. Risk stratification using clinical factors that can be easily assessed at the bedside can be used for clinical management and clinical trial design,” said Dr. Ogimi.

This research benefitted from cross collaboration between multiple institutions. “The UW Virology lab developed the multiplex PCR testing platform for respiratory virus diagnostic more than 15 years ago. We then adopted that assay and subsequently another multiplex platform used at Seattle Children Hospital for our respiratory symptom-based surveillance strategy at the [Seattle Cancer Care Alliance] SCCA. This resulted in a large dataset with which we were able to analyze using databases that are maintained by Fred Hutch-based Clinical Research Data Systems,” explained Dr. Ogimi. Together, the published findings from this collaboration provide insights aimed to improve the care of patients receiving a hematopoietic cell transplant.

This work was funded by grants from the National Institutes of Health, Fred Hutchinson Cancer Research Center Vaccine and Infectious Disease Division (biorepository), and Seattle Children’s Research Institute Clinical Research Scholars Program Award.

UW/Fred Hutch Cancer Consortium members Chikara Ogimi, Alpana Waghmare, Keith R. Jerome, Wendy M. Leisenring, Paul A. Carpenter, Janet A. Englund and Michael Boeckh contributed to this work.

Ogimi C, Xie H, Waghmare A, Jerome KR, Leisenring WM, Ueda Oshima M, Carpenter PA, Englund JA, Boeckh M. Novel factors to predict respiratory viral disease progression in allogeneic hematopoietic cell transplant recipients. Bone Marrow Transplant. 2022 Feb 16:1–9. doi: 10.1038/s41409-022-01575-z. Epub ahead of print. PMID: 35173288; PMCID: PMC8853301.