Breathing easier Gregory King, MD, PhD; Peter D. Paré, MD CMAJ 1997;157:1677-9 Drs. King and Paré are with the University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, BC. © 1997 Canadian Medical Association lthough the fight to reduce the incidence of lung disease and respiratory conditions is far from over, recent advances in the treatment of chronic obstructive pulmonary disease (COPD) and asthma are giving hope to both patients and physicians. Chronic obstructive pulmonary disease Despite the incontrovertible evidence that cigarette smoking is responsible for lung cancer and COPD, smoking continues unabated in industrialized nations and is increasing at alarming rates in developing nations. In a recent study of the global burden of disease, COPD was ranked the 12th most important contributor to disability-adjusted life-years worldwide and was projected to rank 5th by the year 2020.1 Pulmonary emphysema, which is characterized by destruction of the lung surface and loss of alveoli, is a major consequence of smoking and the most important cause of the airflow limitation that defines COPD. In emphysema the lung's elastin fibre network is disrupted, a process that has been accepted as irreversible. However, 2 recent studies have suggested that the concept of irreversibility needs to be re-examined. Massaro and Massaro2 used retinoic acid to reverse emphysema that had been induced in rats with the proteolytic enzyme elastase. Retinoic acid plays an important role in regulating alveolar septation in the developing lung of the fetus, but the concept that it might aid in stimulating the formation of new alveoli in mature lung tissue is novel and exciting. Although public health policies designed to decrease the prevalence of cigarette smoking remain the most important means of preventing COPD, it may not be long before we see clinical trials examining whether lungs partially destroyed by emphysema can be repaired. Additional evidence that loss of elastin is not irreversible comes from studies showing that new elastin can be synthesized and damaged elastin repaired by lung interstitial fibroblasts.3 Asthma Asthma is the most common respiratory illness after the common cold, affecting about 5% of adults and about 10% of children. The increasing incidence and prevalence of asthma, along with other atopic diseases (such as allergic rhinitis and eczema), prompted the Ciba Foundation to sponsor an international guest symposium in 1997 to address the reasons for "Rising Trends in Asthma."4 The epidemiologists, geneticists, and basic and clinical scientists in attendance agreed that the increase was real, and not due simply to increased awareness or a modification in disease classification, and that it must be related to a change in the environment. However, the experts could not agree on whether the important environmental change was air pollution, diet, allergen exposure or the prevalence of viral or other respiratory infections, all of which are known cofactors contributing to the development of allergic disorders in genetically susceptible individuals. It is clear that there is a genetic contribution to the pathogenesis of asthma and allergy. However, the pattern of inheritance does not conform to classical Mendelian genetics as do the much less common respiratory genetic disorders *1-antitrypsin deficiency and cystic fibrosis, because asthma is a so-called complex genetic disease. The complex genetic diseases, which include atherosclerosis, hypertension, diabetes and the major psychoses, are polygenic, and different combinations of genes contribute to the relevant condition in different families (a situation known as genetic heterogeneity). In addition, an interaction with environmental factors is necessary for disease expression. Despite this complexity the technical revolution in molecular genetics has made it possible to localize and characterize the genes responsible for complex genetic diseases, and for asthma and allergy the hunt is on! Identifying the genes involved in the pathogenesis of asthma and allergy will depend on collaboration among many investigators. One such group effort is the American Collaborative Study on the Genetics of Asthma, which recently reported the identification of 6 novel regions linked to asthma and allergy phenotypes and confirmed linkage at 5 previously reported loci in the human genome.5 Two of the replicated loci are particularly interesting. One is on the long arm of chromosome 5 in a region of the genome rich in cytokine genes including those for interleukins 4, 5 and 9; the hypothesis that variants of these proteins are involved in the pathogenesis of allergic disorders is attractive. Another linked locus is on the long arm of chromosome 14, in the region that contains the genes for the * and * chains of the T-cell receptor. The central role of T-cell receptors in host responses to allergens makes this a logical candidate gene for these disorders. It can be a long road from the identification of a linked locus to the discovery of disease-causing mutations in specific genes; however, such large-scale collaborations encourage optimism that diagnostic and therapeutic interventions based on genetic risk factors will be possible before the turn of the millennium. Paradoxically, asthma is increasing in prevalence and severity in an era when effective new therapies are being introduced. Until recently, the mainstays of asthma therapy have been inhaled steroids and short-acting ß-adrenergic agonists. The underlying defect in asthma is believed to be persistent allergic inflammation of the airway wall, which fosters acute episodes of airway narrowing as well as more prolonged remodelling of air- way structure. The current treatment paradigm is to prescribe the short-acting ß-agonists to reverse the acute episodes of airway smooth-muscle constriction and inhaled steroids to inhibit the underlying inflammatory process. This 2-pronged attack is sufficient to reduce symptoms to acceptable levels in many patients, but the persistence of refractory symptoms and the worry that long-term, high-dose inhaled steroid medication might have detrimental side effects have stimulated the search for new medications. One completely new class of asthma medication is the leukotriene receptor and synthesis antagonists, several of which have been or will soon be released for use in Canada. The leukotrienes, which are lipid derivatives of arachadonic acid, are powerful pro-inflammatory mediators. Several strategies have been devised to block their function in allergic disorders, including inhibition of synthesis by 5-lipoxygenase blockers and inhibition of action by leukotriene receptor antagonists. Although the exact place of the leukotriene receptor antagonists in the pharmacotherapeutic armamentarium is still unclear, one recent study suggests that they may be beneficial and cost-effective in mild to moderate asthma. In a double-blind randomized, placebo-controlled trial of one such drug,6 the treated patients had fewer symptoms, used less short-acting ß-adrenergic agonist and experienced fewer exacerbations of asthma. In addition, they had fewer contacts with health care workers and less absenteeism from school or work. Another group of new players on the asthma pharmacotherapy scene are long-acting ß-adrenergic agonists. ß-Adrenergic agonists are the most effective relaxers of airway smooth muscle and, in the form of short-acting inhaled medication, are the most widely used of asthma medications, producing near-instant relief from bronchoconstriction. The long-acting agents salmeterol and formoterol have a slower onset, but their prolonged duration of action has led to the suggestion that they be used as prophylactic agents, to prevent rather than reverse bronchoconstriction. Wilding and associates7 used a randomized, double-blind crossover study to compare salmeterol with placebo, each given for 6 months. The patients were all taking inhaled steroids at the outset but were instructed to modify their steroid dose according to a guideline based on symptoms and lung function. While receiving the active drug, participants had fewer symptoms and better lung function, despite a significantly lower dose of inhaled steroids. These results suggest that "steroid sparing" may be an additional benefit of some of the new asthma therapies. Equally important, the results of this and other studies have diminished the anxiety of some clinicians that prolonged stimulation of the ß-adrenergic receptor could have detrimental effects, perhaps related to agonist-induced receptor down-regulation. This worry stemmed from reports of an increased risk of death from asthma in patients taking excessive short-acting preparations of the ß-agonists. Although it is still unclear whether the association between excessive ß-agonist use and death from asthma was confounded by severity, it is reassuring that prolonged therapy with the long-acting ß-agonists has not been associated with a worsening of asthma control or increased mortality. References Murray CJL, Lopez A. Evidence based health policy -- lessons from the Global Burden of Disease Study. Science 1996;274:740-3. Massaro GD, Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med 1997;3:675-7. Stone PJ, Morris SM, Thomas KM, Schuhwerk K, Mitchelson A. Repair of elastase-digested elastic fibers in acellular matrices by replating with neonatal rat-lung lipid interstitial fibroblasts or other elastogenic cell types. Am J Respir Cell Mol Biol 1997;17:289-301. Holgate ST, editor. Rising trends in asthma. Ciba Foundation Symposium 206. Chichester (UK): Wiley; 1997. The Collaborative Study on the Genetics of Asthma (CSGA). A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet 1997;15:389-92. Suissa S, Dennis R, Ernst P, Sheehy O, Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild- to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997;126:177-83. Wilding P, Clark M, Coon JT, Lewis S, Rushton L, Bennett J, et al. Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study. BMJ 1997;314:1441-6. Send a letter to the editor responding to this article Envoyez une lettre à la rédaction au sujet de cet article | CMAJ December 15, 1997 (vol 157, no 12) / JAMC le 15 décembre 1997 (vol 157, no 12) |