Rapid Progressors Speed to End-Stage Pulmonary Fibrosis

May 31, 2007

MEXICO CITY -- 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.

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 Moiss 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

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