NHLBI Workshop summary
Pathophysiology of severe asthma,☆☆,

https://doi.org/10.1067/mai.2000.111307Get rights and content

Abstract

Although asthma affects nearly 8% of the adult population, most of these patients have mild-to-moderate disease that can be controlled with appropriate treatment. It is estimated, however, that 5% to 10% of patients with asthma have severe disease that is unresponsive to typical therapeutics, including corticosteroids. Because patients with severe asthma are disproportionately affected by their disease, in terms of both impaired lifestyle and health care costs, the National Heart, Lung, and Blood Institute sponsored a workshop on the pathogenesis of severe asthma. The goals of this workshop were to begin to define the characteristics of severe asthma. In these discussions, it was clear that many characteristics need to be considered in defining this phenotype of asthma, including symptoms, intensity of therapy (including administration of systemic corticosteroids), and impairment of lung function. Also discussed were potential mechanisms of severe asthma including the role of allergic diseases, which may play less of a role in severe asthma than in mild-to-moderate disease, and infections. A major limitation to control of severe asthma is the recalcitrant response of these patients to usual therapy including systemic corticosteroids; the potential of other therapies was reviewed. From these discussions, recommendations were made for future research needs to gain insights into a difficult therapeutic and possibly novel mechanistic area of asthma. (J Allergy Clin Immunol 2000;106:1033-42.)

Section snippets

Background on severe asthma

Although asthma affects an increasing number of patients, the severity and chronicity of this disease can vary considerably. In categorizing the severity of asthma, many factors need to be considered (Table I).

. Features to consider in defining severe asthma

1. Symptoms
 Exacerbations
  •Frequency
  •Severity
2. Medication use
 Response to treatment or intensity of treatment required to control symptoms
3. Pulmonary functions
4. Bronchial responsiveness
5. Airway inflammation
6. Development of airway remodeling

Epidemiology of asthma

Predictors of asthma severity may include disease duration, female gender, African American race, level of lung function, and degree of allergy. Although the need for hospitalization is also used, it may not be an accurate reflection of severe asthma because the threshold for this intervention is highly variable. Additional results suggest that it was inappropriate to equate control of asthma with disease severity and to measure health care utilization as a feature of severity. Symptoms may

Pathology of severe asthma

The European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA) is a multicenter cross-sectional project including 13 centers in 9 European countries in which approximately 150 patients with severe and an equal number of patients with well-controlled asthma as a comparison group were recruited. Patients with brittle asthma were considered as a separate well-defined group. The patients with chronic severe asthma had several interesting characteristics that separated them from those

Is severe asthma one disease or several?

Asthma is defined and diagnosed by a combination of clinical symptoms and physiologic abnormalities without reliance on pathologic/biologic markers. In fact, the physiologic definition of asthma is nonspecific, consisting of airflow limitation during expiration, which is variable and/or reversible to bronchodilators, in the presence of airway hyperresponsiveness. These definitions leave room for multiple pathologic processes to produce similar physiologic (and clinical) endpoints. Several lines

Genetics of asthma

Genetic studies of asthma and atopy have progressed rapidly during the past 5 years.19 Genome-wide screenings have been completed in 5 population samples identifying at least 19 regions that show evidence for linkage to asthma in multiple studies. This suggests that asthma per se is influenced by many genes, each with relatively small effects. Some candidate genes, such as IL13, CD14, and IL4RA, have also been associated with asthma or atopy in multiple studies, suggesting that these genes may

Inflammatory factors

The inflammatory processes in asthma are influenced by many factors including the generation of cytokines. With the use of bronchoscopy, biopsy, and lavage, a number of proinflammatory cytokines have been associated with the severity of disease process including the novel cytokines IL-9 and IL-11. These cytokines have been found to be increased in relationship to the disease severity. This contrasts to the presence of other cytokines (ie, IL-4 and IL-5), which may relate to general components

Pulmonary physiology

Severe asthma may be defined not only by difficult-to-control airway disease symptoms but also by the severity of abnormalities and measurements of pulmonary function. Careful physiologic characterizations of patients with well-defined severe asthma are lacking. In experiments performed in patients with more severe disease who exhibit nocturnal worsening of the disease, measurements of peripheral airway resistance (Rp) have been performed. These results clearly demonstrate that in patients with

Discussion

There was unanimous opinion that the study of severe asthma is a critical issue and important for study. Currently in the United States, this problem is greatly understudied. It was the opinion of the workshop participants that it is unlikely that any one center would have enough subjects to conduct meaningful studies. Therefore a cooperative-approach arrangement should be considered for success of this study. The centers should be skilled in the conduct and performance of bronchial lavage and

Recommendations for future directions

As a result of the workshop, together with the experiences gained from the study of severe asthma by the ENFUMOSA, the following recommendations were formulated for future research directions:

  • 1.

    Establish a uniform working definition of severe asthma to promote a reproducible classification system.

  • 2.

    Assemble a national cohort of patients with severe asthma that can be studied extensively to characterize the clinical, physiologic, radiologic, genetic, pathologic, histologic, and anatomic features of

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    Workshop supported by the Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, May 11-12, 2000.

    ☆☆

    Workshop participants: Jack A. Elias, MD, John Fahy, MD, Allison D. Fryer, PhD, Warren B. Gefter, MD, Stephen Holgate, MD, DSc, Charles G. Irvin, PhD, Nizar N. Jarjour, MD, Robert F. Lemanske, Jr, MD, Donald Y. M. Leung, MD, PhD, Craig M. Lilly, MD, Richard Martin, MD, Fernando D. Martinez, MD, Patricia Noel, PhD, Carole Ober, PhD, Reynold A.Panettieri, Jr, MD, Stephen P. Peters, MD, PhD, Thomas A. Platts-Mills, MD, Scott T. Weiss, MD, and Rosalind J. Wright, MD.

    Reprint requests: Susan Banks-Schlegel, PhD, Division of Lung Diseases, National Heart, Lung, and Blood Institute, 2 Rockledge Center, Suite 10018, 6701 Rockledge Dr, MSC 7952, Bethesda, MD 20892-7952.

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