strait-laced asthma is poorly understood clinically.

strait-laced asthma is poorly understood clinically, physiologically, and pathologically. While milder forms of asthma are generally easily treated, more strait-laced forms often remain refractory to the best rife medical care. Although some patients with unadorned asthma have had severe disease for in the greatest degree of their lives, there appears to be a other group that develops severe disease in adulthood. Additionally, it is not clear which genetic and environmental constituents may be the most important in the evolution of severe disease. Physiologically, these patients oftentimes have airtrapping and may have los of elastic recoil, as well. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, structural changes, distal disease, and, in at least single in kind third of patients, a different pathology. Treatment remains problematic and likely will remain likewise until a better understanding of this disease develops

[i]clavis[/i] words: asthma; inflammation; phenotypes; physiology; remodeling; treatment

Abbreviations: BO = bronchiolitis obliterans; C = corticosteroids; GR = glucocorticoid receptor; SBM = subbasement membrane; TGF = transforming bourgeoning factor; Th = T helper

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chaste or refractory asthma afflicts a small percentage (likely < 5%) of the population of patients who have asthma. However, as these patients remain difficult to treat and apt to severe exacerbations, they contribute disproportionately to the overall prices of asthma. The introduction of high-potency inhaled corticosteroids (CS) had a marked impact forward the numbers of patients who were hanging on therapy with oral C However, beyond those medications, little further progres has been made in understanding the disease and improving its treatment.

DEFINITIONS

inexorable persistent asthma has been defined in guidelines, moreover the definitions have been somewhat limited in length and difficult to apply. harsh or "refractory" asthma was given a working definition from the workshop sponsored by the American Thoracic Society, the proceedings of which were published in 2000 (1) This definition included the same of two major criteria (ie, continuous high-dose inhaled C or oral C for > 50% of the previous year), with sum of two units of seven additional minor criteria required for diagnosis. The minor criteria included aspects of lung function, exacerbations, disease stability, and amount of additional medications. Patients also must have had compliance and exacerbating factors completely addressed. Although these definitions are a start (the author of this article was the chair of that workshop), the list of criteria still may not be definitive. For instance, it is not clear whether a stable patient with symptoms of asthma who is receiving therapy with a fluticasone/salmeterol combination (500/50) and has an FE[Vsub1] of 78% predicted in good earnest has refractory asthma. Yet, the general definition would include that patient. Expanding the minor criteria requirements to three would likely improve the capture of those who fulfill the "spirit" of the definition, rather than the "letter" of the definition.

EPIDEMIOLOGY

Surprisingly little is known about the progress to maturity of severe asthma. Do in the greatest degree patients with severe asthma have a life-altering conclusion in childhood that irreversibly alters their lung from which they will at no time recover, or do they slowly if it were not that steadily decline over the years? Did those patients with a history of adult-onset disease actually have a certain quantity of level of asthma as children that was ignored, or do they have a more rapid decline in function one time the asthma begins? None of these questions has been answered satisfactorily. a information has come from the large cohort of asthma patients studied in Melbourne, Australia, which has been followed for 35 years. (2) Those data refer to that if a person has reduc lung function in childhood, that someone is likely to have reduc lung function in adulthood, as well, yet that there is little "progressive decline" of the mean data. Interestingly, sum of two units studies (3,4) from Europe have hinted that late-onset asthma is associated with a more rapid decline in lung function. In the database of > 100 patients with unadorned asthma who were seen at National Jewish Medical and Research Center (Denver CO) approximately couple thirds of patients had storming in childhood, and the remaining undivided third experienced onset after the age of 20 years. (5) Whether there are distinct phenotypic differences in adult-onset v childhood-onset asthma or relentless asthma is not known.

RISK FACTORS

As is the case for many diseases, risk factors can be divided into genetic and environmental. Unfortunately, asthma itself is a disease involving multiple gene chaste asthma is not likely to be different and is les well-studied. There are reports (67) of relevant mutations in the pair the interleukin-4 gene or the interleukin-4 receptor, a of which have been linked to los of lung function, and others to near-fatal marked occurrences Interestingly, two non-T helper (Th) emblem 2 factors also have been associated with severity of asthma, transforming vegetation factor (TGF)-[beta]1 and monocyte chemotactic protein-1, the couple of which can promote fibrotic reactions. (89) Whether mutations of the receptors for the primary treatments for asthma ([[beta].sub.2] and glucocorticoid receptors [GRs]) decrease responsiveness to medications and influence issues is not yet clear.

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