Chest
Volume 123, Issue 3, Supplement, March 2003, Pages 405S-410S
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Severe/Fatal Asthma

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Severe asthma is poorly understood clinically, physiologically, and pathologically. While milder forms of asthma are generally easily treated, more severe forms often remain refractory to the best current medical care. Although some patients with severe asthma have had severe disease for most of their lives, there appears to be a second group that develops severe disease in adulthood. Additionally, it is not clear which genetic and environmental elements may be the most important in the development of severe disease. Physiologically, these patients often have airtrapping and may have loss of elastic recoil, as well. The pathology demonstrates a heterogeneity of findings, including continued eosinophilic inflammation, structural changes, distal disease, and, in at least one third of patients, a different pathology. Treatment remains problematic and likely will remain so until a better understanding of this disease develops.

Section snippets

Definitions

Severe persistent asthma has been defined in guidelines, but the definitions have been somewhat limited in scope and difficult to apply. Severe or “refractory” asthma was given a working definition by the workshop sponsored by the American Thoracic Society, the proceedings of which were published in 2000.1 This definition included one of two major criteria (ie, continuous high-dose inhaled CS or oral CS for > 50% of the previous year), with two of seven additional minor criteria required for

Epidemiology

Surprisingly little is known about the development of severe asthma. Do most patients with severe asthma have a life-altering event in childhood that irreversibly alters their lungs, from which they will never recover, or do they slowly but steadily decline over the years? Did those patients with a history of adult-onset disease actually have some level of asthma as children that was ignored, or do they have a more rapid decline in function once the asthma begins? None of these questions has

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 genes. Severe asthma is not likely to be different and is less well-studied. There are reports67 of relevant mutations in both the interleukin-4 gene or the interleukin-4 receptor, some of which have been linked to loss of lung function, and others to near-fatal events. Interestingly, two non-T helper (Th) type 2 factors also have been

Physiologic Aspects

Although the classic measure of airflow limitation, FEV1, has been commonly used to indicate the presence of severe disease, it is becoming clear that the correlation between FEV1 and disease symptoms is poor, at best.17 While airflow limitation is clearly part of the physiologic changes of severe asthma, it is likely to be only part of the picture. One prevalent theory regarding severe asthma is that it develops due to a progressive increase in airflow limitation, which is often presumed to be

Pathology of Severe Asthma

Unlike many diseases, the pathology of asthma itself remains poorly understood, primarily due to limitations in tissue availability. With that in mind, the pathology of severe asthma is even more limited. Given the heterogeneity of the presentation and the physiology, it is likely that heterogeneity exists at the pathologic level as well.

Multiple different pathologic explanations for severe asthma certainly could exist. In this regard, it may be helpful to place these possible explanations into

Poor/Altered Response to Medications

Pathologic studies of severe asthma suggest that up to two thirds of patients with severe asthma have persistent tissue eosinophils, despite continued therapy with high-dose systemic steroids. In addition to high numbers of eosinophils, there are associated increases in T lymphocytes and markers for activation of a Th-2 pathway.23 This pattern of inflammation may be thought of as representing the classic form of steroid resistance, whereas a Th-2 pattern of inflammation persists despite the

Airway/Parenchymal Remodeling

In the last 5 years, it has been suggested that the apparent progressive loss of lung function in more severe forms of asthma is due to structural or remodeling changes in the airways and perhaps the parenchyma as well. However, what the precise changes are remains unclear. Numerous structures have been implicated, including the subbasement membrane (SBM), epithelium, smooth muscle, nerves, and blood vessels. In general, there is a paucity of data on any of these structures in relation to

Altered Location of Disease

Physiologic and pathologic data suggest that inflammatory changes exist in the lung periphery. Although the relationship to severity of disease remains unclear, autopsy studies3334 have suggested that both increased inflammation and wall thickness may exist in patients who have died of asthma, as opposed to those with milder asthma and healthy control subjects. Studies3536 of living asthma patients also have suggested that distal lung inflammation may be more important than proximal lung

A Different Underlying Disease

The definition of asthma remains a purely physiologic one, with the concept of the need for inflammation having only recently been added and having been poorly defined. In that regard, asthma can be diagnosed on the basis of reversible airflow limitation and/or bronchial hyperresponsiveness. Numerous other diseases could meet these basic requirements and, therefore, could be confused with asthma. The observation that not all patients with severe asthma have continued eosinophilic inflammation

Treatment

The treatment of severe asthma remains highly problematic. CS remain the drug of choice, likely because of their broad and nonspecific effects, and there are few alternatives in existence. Benefit may be seen in some cases with leukotriene modifiers, especially as a large percentage of patients with severe asthma may be aspirin-sensitive.41 Anti-IgE also appears to reduce hospitalizations in patients with more severe forms of asthma and may prove of benefit in some of these patients once it is

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    Dr. Wenzel is a consultant to Genentech/Novartis.

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