CHICAGO-- "There is as yet no evidence that the airway wall thickening and other changes in airway wall remodeling related to asthma are reversible," stated Peter K. Jeffery, DSc, PhD, at the annual meeting of the American College of Allergy, Asthma, and Immunology. Nevertheless, Prof. Jeffery highlighted differences in lung pathology and inflammation between asthma patients and smokers with chronic obstructive pulmonary disease (COPD).

In a complementary presentation, Tari Haahtela, MD, cited evidence of an asthma-like condition that may prove to be an early stage of asthma. Treatment at this early stage may prevent permanent lung damage, which is often unavoidable once the patient develops full-blown asthma, he said.

MECHANISMS OF AIRWAY WALL THICKENING

Repeated exposure to allergens contributes to airway wall thickening in patients with allergic asthma, and research has provided clues to exactly how this happens. Prof. Jeffery, who is on the faculty of the Imperial College School of Medicine in London, noted that allergens can pass through the epithelial tight junction and interact within antigen-presenting cells at the base of the airway epithelium. In response to this invasion, lymphocytes release regulatory cytokines, such as interleukin (IL)-4 and IL-5. That response, if repeated, causes allergic eosinophilic inflammation, which, in asthma, is associated with a homogeneous thickening of the reticular basement membrane.

Eosinophil cytolysis can precipitate the release of transforming growth factor-ß, which is thought to stimulate fibroblasts below the airway epithelial surface. Fibroblasts can increase production of reticulin and thereby thicken the basement membrane.

Prof. Jeffery and other researchers have examined the late-phase response to allergens by studying the appearance and increase of myofibroblasts in bronchial biopsy specimens of the airway wall. "We were amazed at the extent of the change in this myofibroblastic phenotype," he said. They found large, irregularly shaped myofibroblasts that were often in direct contact with lymphocytes.

Within these cells, stressed Prof. Jeffery, were electron-dense condensations identical to the contractile apparatus in bronchial smooth muscle. Those structural changes suggest that the myofibroblasts observed after the late-phase response were likely derived from existing bundles of smooth muscle. Subsequently, the myofibroblasts migrate to other parts of the airway wall to form new bundles of bronchial smooth muscle, which contribute to the increase in bronchial smooth muscle mass seen in patients with fatal asthma.

NORMAL AND ABNORMAL REMODELING

The process of tissue and cell remodeling can be perfectly normal, Prof. Jeffery pointed out. Remodeling in response to a cut, for example, involves exudation of fluid; infiltration of neutrophils, monocytes, and lymphocytes; production of reticulum and granulation tissue; epithelial restitution; and contraction of the wound by myofibroblasts.

The same process occurs in asthma, but it persists and leads to structural changes associated with abnormal lung function. Regardless of the severity of asthma, an especially damaging result of allergen exposure is the fragility, and, sometimes, loss of surface airway epithelium, which may slough off into the airway lumen.

Prof. Jeffery has studied the relationship between the amount of surface epithelium and the degree of airway hyperresponsiveness. "The less epithelium present, the more hyperresponsive the airway," he said, noting that other studies have found the same relationship.

ASTHMA VERSUS COPD

Asthmatic patients and smokers with chronic lung disease have some interesting differences in lung pathology, said Prof. Jeffery. For example, despite treatment with inhaled corticosteroids, nonsmoking patients with asthma have a significantly thicker reticular basement membrane than do patients with COPD or normal healthy subjects. It has also been shown that the airway epithelium of smokers with COPD is often intact, though squamous and metaplastic, whereas the airway epithelium of asthma patients is not.

Asthma and COPD are also associated with different types of lymphocytes. In asthma, the ratio of CD4 helper cells to CD8 suppressor cells is about 3 to 1. "In smokers with COPD, that ratio is completely reversed," Prof. Jeffery said. He therefore concluded that asthma is a CD4-driven condition, whereas COPD is a CD8-driven condition.

ASTHMA-LIKE INFLAMMATION

Researchers have identified a group of patients with cough, wheeze, and other asthma-like symptoms but normal or near-normal lung function. Disease in these patients is characterized by eosinophilic inflammation of the bronchial mucosa, a condition that may be twice as common as asthma itself, according to Dr. Haahtela, an assistant professor at the Skin and Allergy Hospital of Helsinki University Central Hospital.

Because patients with eosinophilic inflammation do not meet the diagnostic criteria for asthma, they do not receive treatment. And that could be devastating. "Patients with symptoms suggesting asthma, and especially those who have eosinophilic inflammation, carry an increased risk of asthma in the future," Dr. Haahtela explained. In a Finnish study of 7- to 12-year-old children with this condition, one third developed clinical asthma during the two-year follow-up.[1]

EARLY TREATMENT IS POSSIBLE

Physicians commonly mistake eosinophilic inflammation for respiratory infections, colds, allergies, or other respiratory conditions and thus initiate inappropriate treatments, such as antibiotics or antihistamines. That is understandable, Dr. Haahtela said, because definitive and convenient methods for diagnosing eosinophilic inflammation are lacking.

However, induced sputum analysis may help improve the detection of eosinophilic inflammation. Studies have shown that sputum induced by hypertonic saline is similar to spontaneously expectorated lower respiratory secretions. Furthermore, induced sputum analysis appears to yield results comparable to those of bronchoalveolar lavage and bronchial biopsy.

Accurate diagnosis of eosinophilic inflammation improves the chance of early treatment, preferably with an inhaled corticosteroid. That, in turn, may help prevent permanent lung damage, according to Dr. Haahtela.

To support this hypothesis, he described a study involving patients whose asthma symptoms had manifested for less than one year and who had no previous anti-inflammatory therapy.[2] These patients inhaled 1,200 µg/d of the corticosteroid budesonide or 750 µg/d of the ß₂-agonist terbutaline. After two years, the budesonide group displayed nearly normal lung function and almost complete clinical recovery. The terbutaline group had improved, although not to the same extent. Bronchial biopsy specimens obtained at three months revealed a significantly greater reduction in inflammatory cells in the budesonide group.[3]

To assess in more detail the effect of early corticosteroid therapy, the researchers switched the patients receiving terbutaline to treatment with budesonide.[4] A year later, these patients still had not achieved the same lung function as those treated with budesonide from the start. Studies of infants with bronchiolitis have also demonstrated the importance of early corticosteroid treatment in patients with lung inflammation.

"The good news," Dr. Haahtela concluded, "is that airway inflammation can be detected early with induced sputum analysis, and perhaps even with exhaled nitrogen oxide and some other new methods that are coming. And we now know, at least from a few studies, that early treatment often leads to complete recovery, even though the predisposition to asthma remains."

--Timothy Begany

References
1. Remes ST, Korppi M, Remes K. Outcome of children with respiratory symptoms without objective evidence of asthma: a two-year, prospective, follow-up study. Acta Paediatr. 1998;87:165-168.
2. Haahtela T, Jarvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med. 1991;325:388-392.
3. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol. 1992;90:32-42.
4. Haahtela T, Jarvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med.1994;331:700-705.