Asthma

[]Asthma is a syndrome characterized by airway inflammation, airway hyperresponsiveness, and reversible airflow limitation. Despite the significant advances in the therapy and understanding of the pathogenesis over the last 20 years, the prevalence of the disease has increased 75% over the last 2 decades to approximately 6 to 10% of the population. Ethnicity and age appear to be predisposing factors because blacks, Hispanics, and young children appear disproportionately affected. Morbidity, as defined by emergency room visits and hospitalizations, has been increasing worldwide, and mortality, although thankfully still low, has also been increasing. This issue of Seminars assembles nine state-of-the-art contributions from esteemed experts in the field to examine these areas.

In the first of nine articles, Drs. Keller and Lowenstein review the epidemiology of asthma and give us a perspective as to why its prevalence, morbidity, and mortality are increasing. The good news is that the prevalence may be at or near a plateau, but it is still not clear why specific ethnic groups and children are specifically at risk. In addition, they comment on how the prevalence of asthma and allergic diseases is increasing in Western, affluent societies. They speculate that aspects of the affluent lifestyle may predispose individuals to asthma.

Another possibility may be the genetic predisposition to asthma, as discussed by Drs. Wechsler and Israel in the second article. They outline what is known currently about the genetics of asthma, and the many active areas of investigation, including a discussion of the difficulties in determining the genes that regulate a complex disease such as asthma, the results of genome-wide screens, and the candidate gene approach. Several loci have been identified, but it is likely that many genes will be involved in the regulation and expression of inflammation and bronchial hyperresponsiveness. Therefore, it is clear that there is no ``asthma gene,'' but advances in genetics have changed the way we view response to therapy, which will be discussed later in the issue.

Continuing along the lines of pathogenesis, two new areas of interest are highlighted by Drs. Brooks and Lemanske and Drs. Tulic and Hamid. Drs. Brooks and Lemanske discuss the role of infection in asthma, not just as an exacerbating factor, but also as a component in asthma pathogenesis. Recent data suggest that specific infections with viruses such as respiratory syncytial virus and bacteria such as Mycoplasma pneumoniae may result in the development of asthma, particularly in children. Thus infectious organisms may be involved in asthma pathogenesis, but may also be protective in some settings.

Drs. Tulic and Hamid address the issue of the distal lung in asthma, another area of increasing interest in asthma pathogenesis. They and others have shown that inflammation does exist in this compartment and may be a reason that inhaled corticosteroids do not completely normalize bronchial hyperresponsiveness. This compartment of the lung is challenging to evaluate in chronic, stable asthma. Investigations are under way to determine the ideal physiological test that reflects the distal lung, and to understand how it contributes to airway inflammation and remodeling in asthma.

The term airway remodeling is a difficult one because it appears to have many definitions. However, we know that the airways undergo structural changes in asthma, as discussed by Drs. Woodruff and Fahy. This active area of investigation includes work in the areas of smooth muscle, angiogenesis, mucous gland hyperplasia, and collagen deposition, all of which are felt to contribute to the ``remodeling'' process. The mechanisms driving these changes are not well understood, and whether our therapies alter this process is not clear. However, Drs. Woodruff and Fahy provide an interesting discussion on the topic, and the role of anti-inflammatory medications in abating this process.

Moving on to therapeutics, Drs. Iqbal, Sunmonu, and Ford provide an interesting and important discussion on the use of inhaled beta2-agonists in asthma. Because these medications have been a mainstay of treatment for some time, we are now learning that responses to these medications can vary depending on the genetics at the beta2 receptor. The authors discuss the issues of beta2 polymorphisms, and whether certain polymorphisms are associated with reduced response to beta2-agonists. This area of asthma therapeutics, pharmacogenetics, will play an increasing role in how we determine the best asthma therapy for a particular patient.

Corticosteroids are considered first-line therapy for persistent asthma, and Drs. Spahn and Szefler discuss how different corticosteroid preparations are not created equal. In fact, there are distinct differences in receptor binding, half-life, and deposition, all of which influence the response to this class of medications. They describe, through their work as part of the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network, a model to study responses to different inhaled corticosteroids and how to compare them ``head to head.'' These issues are extremely relevant and timely for the clinician because it is initially often difficult to choose an inhaled corticosteroid and to determine dosing.

Of course, the issue of steroid responsiveness can be very important, particularly if the patient is steroid unresponsive, as discussed by Drs. Spahn, Szefler, and Leung. It appears that steroid unresponsiveness is driven by persistent immune activation, and particular cytokines such as interleukins 2, 4, and 13 may have significant roles. It is also important to elucidate and treat factors that may increase inflammation indirectly in asthma, such as atopy, sinusitis, gastroesophageal reflux disease, and obstructive sleep apnea. By reducing the impact of these contributing factors, some patients can move from steroid unresponsive to responsive.

Finally, we have other options in asthma therapeutics, and one includes the use of leukotriene receptor antagonists in the treatment of asthma, as discussed by Drs. Krawiec and Jarjour. These agents can and have been used to treat persistent asthma, mainly as add-on therapy, but potentially also as monotherapy. The issue of compliance is critical to asthma therapy, and these oral agents provide an alternative to inhaled medications.

In summary, I am happy to recommend this issue of Seminars in Respiratory and Critical Care Medicine to both the practicing clinician and the researcher. I believe it provides a state-of-the-art review of new areas in asthma pathogenesis, as well as the challenges associated with the treatment of asthma. I am honored to serve as guest editor, and am thankful to my colleagues for their excellent reviews. I would also like to thank Dr. Joseph Lynch for the opportunity to serve as a guest editor.