Published: May 31, 2007
Reviewed by
Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine
MEXICO CITY, May 31 -- A difference in genetic patterns may explain why some idiopathic pulmonary fibrosis patients, especially men who smoke, die more quickly after diagnosis than others do.
These rapid progressors were 6.5-fold more likely to be men and seven-fold more likely to have been smokers than slow progressors, found Moisés Selman, M.D., of the Instituto Nacional de Enfermedades Respiratorias here, and colleagues.
In the retrospective study, gene expression patterns differed between fast and slow progressors, implying biologically-distinct phenotypes of the disease, they wrote online in the journal Public Library of Science ONE.
The findings suggest that physicians should pay more attention to the time of onset of symptoms to identify these patients who are at greater risk, they said.
Most idiopathic pulmonary fibrosis patients have symptoms long before diagnosis, then slowly progress, with death coming within five years of diagnosis, they noted.
But, they said, distinct patterns of disease progression have become increasingly clear clinically.
To characterize these patterns, the researchers reviewed the charts of 167 consecutive patients with the disease who were evaluated at a single center between 1995 and 2004. Seven healthy volunteers as well as lung samples from autopsies were also studied as controls for immunohistochemistry, cellular and genetic profiling.
Rapid progressors were defined as those with no more than six months of symptoms before seeking medical attention.
From symptom onset, these 26 patients had a median follow-up of 13.5 months and median survival of 27 months. From diagnosis, median follow-up was 10 months and survival was 25 months.
Slow progressors were defined as those with at least 24 months of symptoms before presentation.
From symptom onset, these 88 patients had a median follow-up of 60.5 months and median survival of 93 months. From diagnosis, median follow-up was 17 months and median survival was 32 months.
In a multivariate analysis, significant factors in survival among the overall cohort included time from symptom onset to first consult, smoking, male gender, and lung function as measured by forced vital capacity.
Among the 80% to 85% of patients with known vital status, rapid progressors had significantly lower survival rates than slow progressors (hazard ratio 9.0, 95% confidence interval 4.48 to 18.3, P<0.001) or intermediate progressors (P=0.045).
Mortality determined from the time of diagnosis also tended to be higher in the rapid progressors (HR 1.5, 95% CI 0.81 to 2.87, P=0.18).
Among rapid progressors, significantly more patients were:
- Male (odds ratio 6.5, 95% CI 1.4 to 29.5, P=0.006).
- Ever smokers (OR 3.04, 95% CI 1.1 to 8.3, P=0.04).
- Current smokers (OR 7.1, 95% CI 1.2 to 40.9, P=0.02)
These rapid progressors, though, were not simply patients presenting at a different stage of disease or an acute exacerbation, the researchers said. Their physiologic, radiologic, and histopathologic parameters were similar to those of slow progressors.
Socioeconomic and educational background -- which can influence when patients seek treatment -- as well as initial treatment were similar between groups, they said. And there were no differences between rapid and slow progressors in pack-years smoked.
Nor were there baseline differences in age, lung function alterations, oxygen saturation, extent of changes seen on high resolution computed tomography, or bronchoalveolar lavage cellular profile, the researchers noted.
Lung biopsies done on 31% of patients showed no differences in baseline morphology for interstitial inflammation, pulmonary hypertension changes, smooth muscle hyperplasia, type 2 cell hyperplasia, or extent of fibrosis or honeycombing.
However, Dr. Selman wrote, there were important differences showing that "rapid progressors appear to represent a distinct biological phenotype among patients with idiopathic pulmonary fibrosis."
In a global gene expression analysis in a subset of patients, the researchers found that 437 genes were expressed differently between groups.
Rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration and proliferation, and fibroblast and smooth muscle cell function.
This upregulation was seen on immunohistochemistry for the adenosine-2B receptor, which is involved in a key process of fibrotic remodeling, and prominin-1/CD133, which is found in hematopoietic stem cells and embryonic epithelium.
Furthermore, bronchoalveolar lavage showed that rapid progressors had more than a twofold increase in active matrix metalloproteinase-9, which may contribute to abnormal tissue repair and remodeling, compared with slow progressors.
Rapid progressors also had higher fibroblast migration than slow progressors (238% versus 123%, P<0.05) or controls (238% versus 30%, P<0.01).
While these subgroup studies were of limited size, "the relatively stringent selection of genes, the protein verification by immunohistochemistry on additional samples, and the biological relevance of the genes suggest that our results are biologically meaningful," the investigators wrote.
They also noted, however, that their study was preliminary and limited by retrospective data collection and dependence on patient recall of symptom duration.
However, "taken together with reports of the impact of acute exacerbations of idiopathic pulmonary fibrosis on morbidity and mortality, our results further highlight the variability in the progression and outcome of [the disease]," they concluded.
"These findings may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with idiopathic pulmonary fibrosis," they added.
| The study was partially supported by a grant from the Universidad Nacional Autónoma de México. One of the researchers was supported by grants from the National Institutes of Health and by a donation from the Simmons family. The researchers reported no conflicts of interest. |
