Evaluate Airway Remodeling in Asthma to Guide Steroid Dosing

KEYSTONE, COLO. – It doesn’t take a long stretch of the imagination to surmise that chronic airway remodeling has an impact on airway obstruction in persistent asthma. But to what degree? And should steroid dosing be adjusted to mediate its progression at younger ages?

Biopsies alone don’t adequately address these questions. The impact of airway narrowing is more of a "reasonable correlation" that physicians must formulate by evaluating asthma-related damage and epithelial tissue thickening over time, then comparing it to airway constriction in the patient, said Dr. Anthony N. Gerber of the University of California, San Francisco.

"What [physicians] are forced to do is perform biopsies and correlate the amount of airway smooth muscle thickening or the quantity of basement membrane thickening with the severity of airway obstruction," he said at a meeting on allergy and respiratory diseases, which was sponsored by National Jewish Health. "I don’t know if it’s really possible to deconvolute the precise amount that airway remodeling is contributing to airway obstruction."

Correlating CT scans with bronchial biopsies and histologic analysis sets the stage for a comparison of findings with forced expiratory volume in 1 second (FEV1 ) readings. The physician can then evaluate remodeling in a more relative sense by analyzing how actively it conspires with three additional airway obstruction components – acute asthmatic inflammation, airway hyperreactivity, and mucus formation.

The central hallmarks of chronic remodeling are increased airway smooth muscle mass and subepithelial fibrosis, or thickening in the lamina reticularis from dense fibrotic responses as a result of accumulated collagens. Inflamed airway smooth muscle mass has been associated with a decline in FEV1 (Am. J. Respir. Crit. Care Med. 2010;182:317-24) and is characterized by abnormal cell turnover and proliferation, presumably in response to the chronic inflammatory stimuli that trigger the patient’s asthma. The proliferating cell nuclear antigen (PCNA) is an acknowledged marker for this part of the process, with patients more likely to demonstrate higher levels of PCNA-positive cells as their asthma severity scores increase, Dr. Gerber said.

In addition, subepithelial fibrosis progression may be chronic, with increased smooth muscle narrowing seen in older patients (Am. J. Respir. Crit. Care Med. 2000;162:663-9).

"The real question I think that comes up is, should we treat people with airway remodeling differently than you would treat a typical asthmatic, where you’re just trying to manage their symptoms? I think that the unfortunate answer to this is that we really don’t know enough about the natural history of airway remodeling. Nor do we know enough about the effects of giving high doses of inhaled corticosteroids to potentially reverse airway remodeling," the pathologist said. "But I do think that there’s evidence to maybe give pause to the idea that we should try and find the lowest corticosteroid dose that effectively controls symptoms."

Dr. Gerber’s presentation didn’t explicitly address the chicken-or-egg quandary: Does persistent asthma bring on airway remodeling, or does remodeling worsen an existing case of asthma?

"In general, asthma comes first and leads to remodeling over time," he said in an interview. "However, some people appear more prone to develop remodeling than others. And for some, they may eventually have more symptoms from the remodeling than they ever had from acute asthma attacks."

Only after quantifying the impact of airway remodeling can the physician make an informed decision on adjustments to steroid therapy. Glucocorticoid use remains something of a gamble in consideration of the fact that many of the genes that glucocorticoids act on to control catabolism are not inflammatory regulators. But some early findings have identified KLF15 as a possible glucocorticoid target and regulator of airway remodeling, he said.

Dr. Gerber sits on the advisory board and consults for Breathe Technologies.

KEYSTONE, COLO. – It doesn’t take a long stretch of the imagination to surmise that chronic airway remodeling has an impact on airway obstruction in persistent asthma. But to what degree? And should steroid dosing be adjusted to mediate its progression at younger ages?

Biopsies alone don’t adequately address these questions. The impact of airway narrowing is more of a "reasonable correlation" that physicians must formulate by evaluating asthma-related damage and epithelial tissue thickening over time, then comparing it to airway constriction in the patient, said Dr. Anthony N. Gerber of the University of California, San Francisco.

"What [physicians] are forced to do is perform biopsies and correlate the amount of airway smooth muscle thickening or the quantity of basement membrane thickening with the severity of airway obstruction," he said at a meeting on allergy and respiratory diseases, which was sponsored by National Jewish Health. "I don’t know if it’s really possible to deconvolute the precise amount that airway remodeling is contributing to airway obstruction."

Correlating CT scans with bronchial biopsies and histologic analysis sets the stage for a comparison of findings with forced expiratory volume in 1 second (FEV1 ) readings. The physician can then evaluate remodeling in a more relative sense by analyzing how actively it conspires with three additional airway obstruction components – acute asthmatic inflammation, airway hyperreactivity, and mucus formation.

The central hallmarks of chronic remodeling are increased airway smooth muscle mass and subepithelial fibrosis, or thickening in the lamina reticularis from dense fibrotic responses as a result of accumulated collagens. Inflamed airway smooth muscle mass has been associated with a decline in FEV1 (Am. J. Respir. Crit. Care Med. 2010;182:317-24) and is characterized by abnormal cell turnover and proliferation, presumably in response to the chronic inflammatory stimuli that trigger the patient’s asthma. The proliferating cell nuclear antigen (PCNA) is an acknowledged marker for this part of the process, with patients more likely to demonstrate higher levels of PCNA-positive cells as their asthma severity scores increase, Dr. Gerber said.

In addition, subepithelial fibrosis progression may be chronic, with increased smooth muscle narrowing seen in older patients (Am. J. Respir. Crit. Care Med. 2000;162:663-9).

"The real question I think that comes up is, should we treat people with airway remodeling differently than you would treat a typical asthmatic, where you’re just trying to manage their symptoms? I think that the unfortunate answer to this is that we really don’t know enough about the natural history of airway remodeling. Nor do we know enough about the effects of giving high doses of inhaled corticosteroids to potentially reverse airway remodeling," the pathologist said. "But I do think that there’s evidence to maybe give pause to the idea that we should try and find the lowest corticosteroid dose that effectively controls symptoms."

Dr. Gerber’s presentation didn’t explicitly address the chicken-or-egg quandary: Does persistent asthma bring on airway remodeling, or does remodeling worsen an existing case of asthma?

"In general, asthma comes first and leads to remodeling over time," he said in an interview. "However, some people appear more prone to develop remodeling than others. And for some, they may eventually have more symptoms from the remodeling than they ever had from acute asthma attacks."

Only after quantifying the impact of airway remodeling can the physician make an informed decision on adjustments to steroid therapy. Glucocorticoid use remains something of a gamble in consideration of the fact that many of the genes that glucocorticoids act on to control catabolism are not inflammatory regulators. But some early findings have identified KLF15 as a possible glucocorticoid target and regulator of airway remodeling, he said.

Dr. Gerber sits on the advisory board and consults for Breathe Technologies.

KEYSTONE, COLO. – It doesn’t take a long stretch of the imagination to surmise that chronic airway remodeling has an impact on airway obstruction in persistent asthma. But to what degree? And should steroid dosing be adjusted to mediate its progression at younger ages?

Biopsies alone don’t adequately address these questions. The impact of airway narrowing is more of a "reasonable correlation" that physicians must formulate by evaluating asthma-related damage and epithelial tissue thickening over time, then comparing it to airway constriction in the patient, said Dr. Anthony N. Gerber of the University of California, San Francisco.

"What [physicians] are forced to do is perform biopsies and correlate the amount of airway smooth muscle thickening or the quantity of basement membrane thickening with the severity of airway obstruction," he said at a meeting on allergy and respiratory diseases, which was sponsored by National Jewish Health. "I don’t know if it’s really possible to deconvolute the precise amount that airway remodeling is contributing to airway obstruction."

Correlating CT scans with bronchial biopsies and histologic analysis sets the stage for a comparison of findings with forced expiratory volume in 1 second (FEV1 ) readings. The physician can then evaluate remodeling in a more relative sense by analyzing how actively it conspires with three additional airway obstruction components – acute asthmatic inflammation, airway hyperreactivity, and mucus formation.

The central hallmarks of chronic remodeling are increased airway smooth muscle mass and subepithelial fibrosis, or thickening in the lamina reticularis from dense fibrotic responses as a result of accumulated collagens. Inflamed airway smooth muscle mass has been associated with a decline in FEV1 (Am. J. Respir. Crit. Care Med. 2010;182:317-24) and is characterized by abnormal cell turnover and proliferation, presumably in response to the chronic inflammatory stimuli that trigger the patient’s asthma. The proliferating cell nuclear antigen (PCNA) is an acknowledged marker for this part of the process, with patients more likely to demonstrate higher levels of PCNA-positive cells as their asthma severity scores increase, Dr. Gerber said.

In addition, subepithelial fibrosis progression may be chronic, with increased smooth muscle narrowing seen in older patients (Am. J. Respir. Crit. Care Med. 2000;162:663-9).

"The real question I think that comes up is, should we treat people with airway remodeling differently than you would treat a typical asthmatic, where you’re just trying to manage their symptoms? I think that the unfortunate answer to this is that we really don’t know enough about the natural history of airway remodeling. Nor do we know enough about the effects of giving high doses of inhaled corticosteroids to potentially reverse airway remodeling," the pathologist said. "But I do think that there’s evidence to maybe give pause to the idea that we should try and find the lowest corticosteroid dose that effectively controls symptoms."

Dr. Gerber’s presentation didn’t explicitly address the chicken-or-egg quandary: Does persistent asthma bring on airway remodeling, or does remodeling worsen an existing case of asthma?

"In general, asthma comes first and leads to remodeling over time," he said in an interview. "However, some people appear more prone to develop remodeling than others. And for some, they may eventually have more symptoms from the remodeling than they ever had from acute asthma attacks."

Only after quantifying the impact of airway remodeling can the physician make an informed decision on adjustments to steroid therapy. Glucocorticoid use remains something of a gamble in consideration of the fact that many of the genes that glucocorticoids act on to control catabolism are not inflammatory regulators. But some early findings have identified KLF15 as a possible glucocorticoid target and regulator of airway remodeling, he said.

Dr. Gerber sits on the advisory board and consults for Breathe Technologies.