BY KURT SAMSON
Asking bone marrow recipients to rate their breathing difficulties on a scale of 0 to 3 appears to identify lung involvement due to graft-versus-host disease (GVHD) and predict overall survival, including non-relapse mortality, researchers have found.
Reporting in the journal Biology of Blood and Marrow Transplantation (2014;20:337-344), a team led by Stephanie J. Lee, MD, MPH, Professor of Oncology at the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, conducted a prospective analysis of 1,591 visits by 496 patients at various treatment centers. The results showed a clear association between increased mortality among patients with worse breathing scores, but even those with less pronounced problems had shorter survival than those without any problems.
The study, part of the Chronic GVHD Consortium, included patients recently diagnosed with chronic GVHD as well as those who had had it for several years.
For marrow recipients, the likelihood of developing chronic GVHD is in the range of 30 to 50 percent, and of those who do develop it, about 15 to 20 percent have lung involvement, the team noted.
In 2005 the National Institutes of Health recommended testing lung function in patients with chronic GVHD, using both pulmonary function tests and symptom assessment, including a three-point questionnaire – 0 for no symptoms, 1 for shortness of breath walking up stairs, 2 for shortness of breath while walking on flat ground, and 3 for shortness of breath when resting or when oxygen therapy is necessary.
A comparison of survival rates with clinician- and self-reported lung function based on this technique revealed that a score of 3 was strongly associated with short survival, but that even patients with a score of 1 or 2 had worse outcomes than those with a score of 0.
The results showed that the questionnaire outperformed other tests typically used to assess lung function, including spirometry, lung volume measurement, lung diffusion capacity, and measurement of oxygen levels.
Pulmonary function test (PFT) data, including the higher lung function score (LFS) and obstructive physiology, were not associated with overall survival or non-relapse mortality, nor was a diagnosis of bronchiolitis obliterans syndrome (BOS).
In the study, lung function scoring was based on forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO). Obstructive disease was defined as a decreased FEV1 (tested at <50%, <75%, and <80%) and FEV1/FVC of less than 0.70.
Obstructive physiology (FEV1<80%) was found in 184 patient visits, and 54 visits (6%) had FEV1< 50%. BOS was reported on 122 visits. Median follow-up time was 20 months, with a range of 2.9 to 47.7 months. Median survival had not been reached by the time of the paper’s publication.
The researchers cautioned that there were limitations regarding inconsistent practices in performing the tests, and that of the 1,591 patient visits used in the analysis, only half had recorded PFTs.
Could Hasten Treatment
Use of the questionnaire scoring system could help physicians identify early GVHD lung problems and hasten treatment to reduce or manage symptoms, said Lee, who provides hematopoietic cell transplants for patients with leukemia and myelodysplastic syndromes.
“The results put us on notice to be more careful and attentive to lung symptoms in people with chronic GVHD,” she said in an interview. “A poor score can also serve as a reminder to make sure the patient has had a pneumonia vaccination and is taking other precautions to minimize ongoing loss of lung function.
“It is important that we pay closer attention to patients with poor lung scores. If we can identify patients when they first develop lung problems, we can try to intervene and prevent severe loss of lung function. Currently, physicians tend to focus on other health issues, but we need to look at the entire spectrum of this disease, and lung function needs more attention.”
Patients need to be asked directly about any breathing problems, she emphasized, although this can be difficult because lung involvement typically evolves slowly and patients often get used to symptoms or attribute them to other causes like not exercising, she said.
“Not all breathing problems can be attributed to GVHD, but the combination of chronic GVHD and lung symptoms is concerning. Patients with chronic GVHD should be asked at every clinic visit whether they have noticed any shortness of breath.”
She said that because the research team now has a large number of patients and stored blood samples, they are looking to collaborate with other investigators to better understand lung involvement in chronic GVHD.
“Researchers are searching for other ways to identify patients at higher risk of lung involvement as well as possible biomarkers in the blood,” she noted. There is a lot of activity in this field, especially for biomarkers, and there are a lot of leads.”
What leads up to worsening lung function is unknown, added the study’s first author, Jeanne Palmer, MD, of the Blood and Marrow Transplant Program at the Mayo Clinic in Phoenix, Ariz.
How best to identify those who will develop pulmonary complications remains a subject of investigation, she said, and investigators are evaluating CT imagining modalities in this direction. There are also ongoing studies to evaluate the effect of early therapy among patients who show a decline in lung function.
In addition to improved screening to identify patients when they have subclinical disease, improved understanding of the underlying biology is also needed, she said.
“The basic takeaway message is that if GVHD is bad enough that a patient has pulmonary symptoms, it correlates with worse outcomes, and we need to identify these patients before they develop pulmonary symptoms.”
Greater Awareness Needed
Asked for his opinion for this article, Gerhard Carl Hildebrandt, MD, Medical Director of the Huntsman Cancer Hospital Blood and Marrow Transplant Program and Associate Professor of Medicine, at the University of Utah, said the paper should help raise awareness of the potential for lung involvement in GVHD.
“This is a very important paper because it highlights the fact that the lungs are a potential target organ and confirms clinical observations of this issue over the long-term,” he said. “The study illustrates not only that these patients might be at risk, but that both patients and physicians to be more aware of the potential for lung involvement.”
He said most primary care physicians presented with a patient experiencing breathing problems typically assume that there is an infection, but they need to be aware that the lungs are sensitive to GVHD in transplant recipients for years after treatment. Physicians need to ask the appropriate questions and test patients for lung function, which will in turn provide more data for researchers and transplant centers.
“This simple questionnaire can provide primary care doctors with an easy way to ask patients about pulmonary symptoms and document potential GVHD lung involvement,” he said.
Regarding the study limitations, he also noted that the follow-up period was too short to gauge the full scope of the scoring system, and the lack of LFT data in about one-third of the trial subjects was also problematic.
“Many centers do ongoing serial lung function testing of all transplant recipients,” he said. “At our center we test them at three, six, 12, 18, and 24 months after a transplant, and then annually afterwards, and we also exclude infection at each visit. Some centers do not do, and a general advisory for annual testing would be welcomed.”