Scientists have made impressive strides the past few years. Is a cure next?

The concept of asthma as an inflammatory disease has predominated for more than a decade. New medications concentrate on reducing inflammatory response as a method for alleviating or eliminating symptoms. In fact, the respiratory care community considers the subject closed. The rest of the medical community has yet to jump on the inflammatory bandwagon, however. “That concept still requires a lot of emphasis, because either physicians don’t know it or they aren’t following what ought to be the natural reaction to that information,” says Harold S. Nelson, MD, senior staff physician, department of medicine, National Jewish Medical and Research Center, Denver.

Respiratory specialists had hoped that the National Asthma Education and Prevention Program guidelines, first published in 1991 and updated in 1997 by the National Heart, Lung, and Blood Institute, would convince primary care practitioners to alter their asthma treatment protocols. Primary care physicians in particular, however, have demonstrated resistance to prescribing inhaled steroids for asthma patients, either because they have not heard the news about inflammatory response, because traditional treatment methods are too ingrained, or because they “fear the word steroid [so much] that they’re reluctant to place patients on them, even though inhaled steroids are associated with far fewer side effects than oral steroids,” Nelson says.

Stanley J. Szefler, MD, director of clinical pharmacology, National Jewish Center for Immunology and Respiratory Medicine, and professor of pediatrics and pharmacology, University of Colorado Health Sciences Center, Denver, cautions not to give up hope too quickly. “The National Heart, Lung, and Blood Institute at the National Institutes of Health has led the charge in terms of bringing attention to asthma, organizing the literature, and prompting investigators to ask good questions about how we can advance the management of asthma,” he says. “We’ve seen the positive impact of their leadership in education about heart disease and cholesterol and hypertension. If they have the same energy and success now, we’ll see similar advances in asthma care.”

TRACKING ASTHMA TRENDS

In recent years, the treatment that asthma patients receive has started to catch up with the latest pharmacological advances. “If you look at prescribing habits, what has happened is that the use of b-agonists has continued to increase as a percentage of prescriptions, the use of theophylline has plummeted, and the use of inhaled steroids has moved up,” Nelson says. “But the ratio is still not anything like it ought to be between inhaled steroids and other inflammatory agents and b-agonists.”

The most recent pharmacological findings promise to improve asthma treatment dramatically, Szefler says. Pharmaceutical companies are introducing a series of more potent inhaled steroids, including budesonide inhalation powder, which should reach the market this spring, Nelson says. Inhaled steroids represent an important step forward, Szefler notes, because they deliver medication more effectively. “These new inhaled steroids have certainly altered the use of oral steroids; it’s been possible to take many patients off oral steroids using the more potent inhaled steroids,” Nelson says.

In mid-1997, the asthma care community welcomed its newest development, leukotriene pathway modifiers. These follow the trend of treating asthma as an inflammatory disease. “Treatment has taken a sharp turn from developing medications that are just symptom relievers to developing medications that work at preventing symptoms,” Szefler says of leukotriene modifiers and the latest round of pharmacological advances. “There’s a lot of activity going on in terms of evaluating medicines, trying to understand how they work, looking at safety and efficacy, and profiling medications to put them in an order of choice,” he says. For most researchers, that work centers around inhaled corticosteroids and the latest developments regarding leukotrienes and cytokines, which can enhance or inhibit inflammatory responses at the cellular level.

INHALED STEROIDS

Asthma patients-particularly those with severe asthma-have taken steroids to control their symptoms for years. The new inhaled steroids, however, elevate treatment to another level, Nelson says. “In the short term, they’re far and away the best therapy we have. If everybody who should be on them was on them, there would be a lot less morbidity from asthma and, probably, mortality,” he says. Which patients should be taking inhaled steroids to control their asthma? “Actually, inhaled steroids should be given to any patient with persistent asthma-mild, moderate, or severe,” Nelson says.

The newest inhaled steroids, fluticasone propionate and budesonide, have a demonstrated ability to decrease airway response. A recent study1 that examined the efficacy of fluticasone found that patients who received inhaled fluticasone demonstrated significantly higher peak expiratory flow (PEF) rates and forced expiratory volume in 1 second (FEV1) levels than did those who received a placebo or oral fluticasone.

Further studies emphasize the positive impact of inhaled steroids. Researchers2 at Karolinska Hospital, Stockholm, Sweden, studied the effects of budesonide in newly diagnosed asthma patients, who received the inhaled steroid or a placebo for a year. Those who received budesonide displayed a mean PEF increase of 28 L/min (-1); those who received the placebo displayed no increase. The dose of histamine required to cause a 20 percent fall in FEV1 also increased (by approximately two double-dosing steps) among budesonide users. “The evidence for what inhaled steroids can do is there. In the short term, if they were used where they should be, it would have an impact on morbidity and mortality,” Nelson says.

Some patients have continued to display asthma symptoms even after using inhaled steroids, either for physiological reasons or because they do not use their medications as prescribed.3 Szefler notes that some patients prefer the oral medications because they are easier to administer. Still other patients may develop a resistance to steroids.4 The new, more potent inhaled steroids may alleviate some of these problems, while patients who develop drug resistance may benefit from higher doses of of medication.

Studies also indicate that combining inhaled steroids with another course of treatment, such as b2-agonists, can improve their effect on asthma symptoms. One study5) compared the effect of combining inhaled corticosteroid treatment with inhaled formoterol (a b2-agonist) to that of simply increasing the dose of inhaled steroid (in this case, budesonide). More than 800 patients were randomly assigned to receive low-dose budesonide and a placebo; low-dose budesonide and formoterol; high-dose budesonide and a placebo; or high-dose budesonide and formoterol. Researchers found that high doses of budesonide alone decreased severe and mild asthma exacerbations by 49 percent and 37 percent, respectively. By comparison, the formoterol/low-dose budesonide combination reduced severe and mild exacerbations by 26 percent and 40 percent, respectively. The formoterol/high-dose combination yielded the largest reductions in severe (63 percent) and mild (62 percent) exacerbations. Additional studies6,7 have found comparable results with the long-acting b2-agonist salmeterol xinafoate.

Clinicians should employ b2-agonists with caution, particularly if used alone. “The drugs in themselves don’t carry a significant risk, but they do serve as a marker for poorly controlled asthma,” Szefler explains. “The more you need them, the more that’s an indication your overall care should be reevaluated.”

At least one low-dose inhaled steroid, beclomethisone dipropionate, has, in some studies, demonstrated a connection to a slowed rate of growth in prepubescent children, Nelson says. Studies of the drug were never conducted for more than 1 year, however, and have not been conducted on the more potent new inhaled steroids. Nelson cautions against eliminating inhaled steroids from a patient’s treatment protocol. “It’s well recognized that poorly controlled asthma itself can cause slowing of growth; therefore, you don’t sacrifice asthma control over concern about this effect from beclomethisone,” he says.

LEUKOTRIENE MODIFIERS

With the introduction of leukotriene modifiers, clinicians have a second means of treating the inflammatory component of asthma. These medications have been shown to be both effective and popular with patients. The leukotriene modifiers have the advantage of being available in an oral form, with twice- or even once-daily administration (which patients prefer, Szefler notes).

Leukotrienes are produced by the 5-lipoxygenase enzyme pathway and have several biological activities that can trigger asthma problems. They increase mucus secretion, smooth-muscle contraction, and swelling of the airways.8 “It appears that they also have some effect on bringing some of the inflammatory cells into the airway,” Nelson says. Antileukotriene medications act either as leukotriene receptor antagonists or as leukotriene synthesis inhibitors to prevent their impact on inflammatory response and reduce asthma symptoms. Two antileukotriene agents, zileuton and zafirlukast, are currently available. Zafirlukast has been implicated in Churg-Strauss syndrome9 (allergic granulomatosis angiitis), a rare type of vasculitis, but research indicates that patients had the syndrome prior to zileuton treatment; it became evident because they were able to decrease oral steroid treatments, Nelson says.

Researchers investigated the clinical and economic impact of zafirlukast in a 13-week study.10 They found that patients on zafirlukast had 89%ore days without asthma symptoms (7, compared with 3.7 for placebo users) and 98 percent more days without an asthma episode (10.1 days versus 5.1 days). Researchers also found that zafirlukast had a positive impact on the costs associated with asthma: those who took zafirlukast had 55 percent fewer health care contacts and 55 percent fewer absences from work or school. Another study compared the effects of zileuton and theophylline on patients with chronic asthma.11 Patients who took zileuton achieved a long-term improvement in FEV1 of 30 percent to 34 percent, as compared with patients who took theophylline.

Based on these positive results, many clinicians have welcomed leukotriene modifiers and have even considered them a substitute for inhaled steroids. However, Nelson cautions against such a reaction. “The leukotriene pathway modifiers only act on leukotrienes,” he says. “They’re not anywhere near as potent as inhaled steroids, and they probably, with rare exceptions, shouldn’t be used alone as the sole anti-inflammatory agent in asthma.”

That role, he says, should be filled by inhaled steroids in most cases. Leukotriene pathway modifiers can then be added if a patient on inhaled steroids needs more medication because the mediators that antileukotriene agents affect are not receptive to steroids. “[Leukotriene modifiers] are complementary, and it makes a lot of sense to use them in conjunction with inhaled steroids,” Nelson explains. “In fact, that may be more effective than pushing the dose of inhaled steroids up, because they complement the effects of inhaled steroids. But in a head-to-head competition, in the studies that have been done, low-dose inhaled steroids have uniformly been somewhat more effective than the leukotriene- modifying agents. I don’t think that’s going to change.”

A CURE FOR ASTHMA?

Asthma care has made such impressive strides during the past 2 decades that some practitioners finally see hope for a cure. At the very least, it should be possible to control asthma to the point at which patients remain unaffected by symptoms, Nelson says. “The emerging information suggests that the earlier you intervene with steroids, the more effective you can be in terms of controlling the overall disease,” Szefler says. Control does not equal a cure, though, even when it comes to inhaled steroids. “The two are unconnected because the anti-inflammatory treatment of asthma, with the drugs that we have today, is strictly suppressive and doesn’t cure anything,” Nelson says. “As soon as you stop the inhaled steroids, the disease comes right back to its original severity.”

The Stockholm study2 followed the participants’ 12 months of budesonide or placebo treatment with 6 months without inhaled steroid treatment. During the follow-up period, PEF values among the same patients decreased by 18 L/min (-1)-a 64 percent drop-and the provocative dose of histamine decreased by one double-dosing step (a 500drop). “In the long run, we probably need something a little bit more specific and something that is easy to use, free of side effects, and that maybe even has a lasting effect so you can stop it after a while,” Nelson says. “We don’t have anything like that, or even anything close.”

Still, a cure can seem tantalizingly near. “People are thinking of primary prevention because of the strong association between allergy and childhood asthma,” Nelson explains. “Asthma is a disease of civilization. If you take native children growing up under native circumstances in Africa, for example, asthma is almost unknown. If you move the same kids to the city-still in Africa, but start introducing a Western lifestyle-you start getting asthma.” In other words, asthma might be preventable if we can determine what it is in our lifestyles that causes the disease to develop and, Nelson notes, if you can get people to give up whatever it is.

THE NEXT 10 YEARS

Asthma research during the next several years will explore some exciting concepts, Nelson says. “One particular development has been in the understanding of the T1 and T2 lymphocytes. The T1 lymphocyte is the normal one that defends the body against a lot of infections and basically has a good response. The T2 lymphocyte response, on the other hand, doesn’t appear to have a lot of use. It probably was beneficial back when parasites were a major problem, and now it is the response that underlies the allergic reaction.” New research is focusing on ways to change the lymphocyte response from T2 to T1, and on discovering those cytokines and lymphokines that are desirable in terms of the reaction they produce.

One study12 conducted at the UK National Heart and Lung Institute, London, addressed the effect of budesonide on interleukin-10 (an anti-inflammatory cytokine) and on proinflammatory cytokines. Not only did the study find that budesonide reduced bronchial hyperresponsiveness and improved baseline FEV1 in a group of patients with mild asthma, but it also found that the subjects’ alveolar macrophages released significantly fewer pro-inflammatory cytokines. In addition, corticosteroid therapy stimulated release of anti-inflammatory cytokines.

Allergy immunotherapy (which, Nelson says, is no longer in vogue) appears capable of shifting the T2 response to the more desirable T1 response for allergens that have been injected. “That’s causing a renewed enthusiasm in some areas for allergy immunotherapy for treating asthma,” he explains.

Nelson predicts that, over the next several years, this research will continue. “I think we’re going to see studies on a lot of very novel treatments aimed at particular cytokines, lymphokines, adhesion molecules, or other components of the inflammatory reaction,” he says. As for actual treatments, though, “we won’t see them for another 5 or 10 years, minimum.”

Kathryn Olson is a contributing writer for RT.


REFERENCES

  1. Lawrence M, Wolfe J, Webb DR, et al. Efficacy of inhaled fluticasone propionate in asthma results from topical and not systemic activity. Am J Respir Crit Care Med. 1997;153:744-751.
  2. Osterman K, Carlholm M, Ekelund J, et al. Effect of 1 year daily treatment with 400 micrograms budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics. Eur Respir J. 1997;10:2210-2215.
  3. Nelson HS. The pharmacotherapy of severe asthma. Presented at the American College of Allergy, Asthma and Immunology plenary session, Asthma: New Approaches and Novel Therapies in Asthma; November 9, 1997; San Diego, Calif.
  4. Nimmagadda SR, Spahn JD, Leung DYM, Szefler SJ. Steroid-resistant asthma: evaluation and management. Ann Allergy Asthma Immunol. 1996;77:345-356.
  5. Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med. 1997;337:1405-1411.
  6. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet. 1994;344:219-224.
  7. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol in inhaled steroids with doubling of the dose of inhaled steroid. Am J Respir Crit Care Med. 1996;153:1481-1488.
  8. Smith LJ. Leukotrienes in asthma. The potential therapeutic role of antileukotriene agents. Arch Intern Med. 1996;156:2181-2189.
  9. Wechsler ME, Garpestad E, Flier SR, Kocher O, Weiland DA, et al. Pulmonary infiltrates, eosinophilia and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA. 1998;279:455-457.
  10. 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;126:177-183.
  11. Schwartz HJ, Petty T, Dube LM, Swanson LJ, Lancaster JF. A randomized controlled trial comparing zileuton with theophylline in moderate asthma. Arch Intern Med. 1998;158:141-148.
  12. John M, Lim S, Sybold J, et al. Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1 alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma. Am J Respir Crit Care Med. 1998;157:256-262.

r