Vol. 12 •Issue 3 • Page 38
Taking Aim at Asthma
Magic Bullet Remains Elusive
The fact that no one “magic bullet” has been found leading to the resolution of airway inflammation attests to the complexity of asthma. Asthma isn’t a specific disease but a syndrome with multiple causes and presentations. Accordingly, a great deal of research has gone into the epidemiology, diagnosis and treatment of asthma over the past decade.
Asthma is characterized by reversible airflow obstruction, airway inflammation, and increased airway responsiveness to various stimuli. A genetic and environmental basis for the development of asthma exists.
Asthma is present in 25 percent of children born to a parent with asthma, and monozygotic twins have higher concordance rates than dizygotic twins. No genes directly responsible for asthma have been found, but markers for asthma, such as bronchial hyperresponsiveness, have been linked to certain chromosomes.1
Recent studies have shed light on the role of the environment in the development of asthma. It was long thought that exposure to allergens, such as dust mites and animal dander, led to allergic disease; however, a recent article casts doubt on this idea. Researchers followed 474 children from birth up to age 6 to age 7 for the development of atopy. They found that exposure to two or more dogs or cats in the first year of life may reduce the risk of allergic sensitization and asthma.2
Other papers have focused on the “hygiene hypothesis,” which proposes infectious diseases, such as measles, mumps, tuberculosis and hepatitis, are protective against the development of immune-mediated diseases such as asthma.3 Industrialized countries have higher rates of allergic disorders than undeveloped countries. The increased incidence of infectious diseases and decreased antibiotic use in undeveloped countries may account for this fact.
Exposure to bacterial endotoxin, which triggers an innate immune response in animals, also has been shown to help develop tolerance to environmental allergens. Because asthma is closely tied to allergic sensitization, exposure to endotoxin early in life may reduce the likelihood of asthma.4 Endotoxin is more common in households with animals and in areas like farms, as compared to urban households.
NEW APPROACHES TO DIAGNOSIS
Asthma has been diagnosed classically on the basis of history, pulmonary function testing and methacholine challenge, a measure of airway hyperresponsiveness. Newer modalities under investigation include exhaled nitric oxide or breath condensate and induced sputum. Nitric oxide is elevated in asthma, and its level increases with exacerbations and decreases with glucocorticoid treatment. Nitric oxide levels can be checked easily in the office and may be helpful both in the diagnosis of asthma and in assessing a patient’s response to treatment. However, given the cost of the detector, it isn’t available currently for routine clinical use.
When an exhaled breath is passed through a condensing chamber, exhaled breath condensate is obtained. This fluid is mainly water but also contains dissolved cytokines, lipids, ions, surfactant and volatile water-soluble compounds. Increased levels of leukotrienes, hydrogen peroxide and certain inflammatory cytokines, as well as a reduced pH, are found in breath condensate in patients with asthma. Examination of sputum induced by saline nebulization for eosinophils and various cytokines is also being assessed for determining the role of mediators, assessing disease severity and effects of medications.
Fiberoptic bronchoscopy arguably has played the most important role in the development of new therapeutic strategies and the understanding of the pathogenesis of asthma. Under light sedation, a flexible scope can visualize the airway epithelium. Small biopsies may be taken, or saline can be instilled into the airways and suctioned back to collect cells and mediators in a technique called bronchoalveolar lavage.
Antigen challenges can be performed by instilling an agent to which the patient is allergic, such as ragweed, directly into the airway. Levels of inflammatory markers can be measured in patients before and after antigen challenges via bronchoalveolar lavage. This allows targeting of new therapies toward these inflammatory mediators and assessment of these new therapies with repeat antigen challenges.
Asthma initially was thought of as a disease characterized by smooth muscle and airway constriction. With information gained from bronchoscopies, we now understand asthma is an inflammatory disease. Biopsies show inflammatory cellular infiltration, and lavage techniques reveal more than 20 different cell types and 100 mediators now known to be involved in asthma. This change in understanding is reflected in the 1997 National Institutes of Health guidelines for asthma treatment, which stress inhaled steroids as the mainstay of therapy.
PATHOGENESIS OF ASTHMA
Through bronchoscopies, leukotrienes have been shown to be central in the pathogenesis of asthma. Leukotrienes are more than 100 times more potent than histamine in inducing bronchoconstriction when instilled in airways via inhalation challenge. This has allowed the targeting of leukotrienes with successful medicines, such as zileuton (Zyflo®, Abbott Laboratories), which blocks the formation of leukotrienes, and montelukast (Singulair®, Merck and Co.), which blocks the action of leukotrienes.
Several other mediators, such as interleukins (messengers that can activate or suppress the immune system), complement proteins (components of our innate, or natural, immune system) and CD23 (a receptor for the pro-allergic antibody IgE) are currently being studied.
Two inflammatory mediators recently studied are the soluble IL-4 receptor and IL-5 monoclonal antibodies. A soluble receptor is a novel agent that binds its target before it can exert its effect by activating its native receptor on a cell. Mono-clonal antibodies bind to their target and signal the immune system to clear them from our body. IL-4 is an interleukin that is critical for the production of IgE by B lymphocytes and differentiation to a TH2 immune response. TH2 responses focus on allergic inflammation while TH1 responses are directed against infectious agents.
It’s thought that if a patient’s immunogenic profile can be shifted from a TH2 response to a TH1 response, allergic inflammation can be reduced. Researchers started 62 subjects on weekly inhaled soluble IL-4 receptor at the same time their inhaled steroids were discontinued. Patients receiving the placebo had worsening of their FEV1 and symptom scores compared to patients in the active treatment arm.5 Despite promising results in this study, subsequent studies have failed to show any benefit, and future studies have been halted.
IL-5 is essential for the production, maturation, activation and survival of eosinophils. Eosinophils are a key cell in allergic inflammation, and thus an inhibitor of IL-5 offers an attractive target for asthma therapy. A study showed a single injection of monoclonal antibodies to IL-5 in humans reduces eosinophil levels in blood for 16 weeks and sputum eosinophils for four weeks. Eosinophil recruitment to the lung after airway antigen challenge was diminished compared to placebo.
However, IL-5 antibody treatment failed to show improvement in airway hyperreactivity or the late asthmatic response, and studies with this agent have been stopped.6 This suggests that eosinophils are only one component of asthmatic inflammation, and asthma can persist despite a reduction of eosinophils.
IgE has been a recent target for immunomodulation because asthma is an atopic disease associated with increased IgE production. Omalizumab (Xolair™, Genentech) is a monoclonal antibody against human IgE. It’s developed in mice and is then “humanized” to prevent triggering an allergic reaction. Ninety-five percent of the molecule is replaced with human IgG1, which acts as a frame for the mouse-derived IgE binding regions.
When IgE antibody is administered, it binds to free IgE and forms complexes. These complexes are then cleared from the circulation. Omalizumab decreases serum free IgE levels by 89 percent and attenuates early and late phase allergic reactions.
In phase II and III clinical trials, patients with moderate to severe asthma were treated with intravenous or subcutaneous omalizumab. Asthma symptom scores, need for steroids and asthma exacerbations were modestly reduced, and there were no serious adverse effects.7,8
This agent should be approved pending results of long-term studies evaluating the effect a mouse derived agent has on the human immune system. Because of the possibility of the immune system recognizing this product as foreign, it will probably be reserved for severe asthma.
Several other immune modulating strategies currently are under investigation for the treatment of asthma. Already mentioned was current interest in the CD23 receptor and complement proteins. Researchers are studying agents that can block the effects of IL-13, STAT-6, and VCAM-1. IL-13 is an interleukin similar in structure and function to IL-4. It’s linked with IgE production and the TH2 immune response. STAT-6 is a signaling pathway shared by IL-4 and IL-13. Interruption of this pathway would inhibit the function of both cytokines. VCAM-1 is an adhesion molecule that directs the migration of inflammatory cells, such as T lymphocytes, eosinophils, monocytes and basophils to the lung, in the late-phase asthmatic response. Blocking VCAM-1 could lead to reduction in this late response.
Currently our best treatment modality is inhaled steroids due to their far-reaching anti-inflammatory effects. Other current effective long-term treatments include long-acting bronchodilators, leukotriene modifying agents, mast cell stabilizers and methylxanthines. Further research should identify additional steroid-sparing agents in the near future, but the magic bullet for asthma remains elusive.
1. Potsma DS, Bleecker ER, Amelung PJ, et al. Genetic susceptibility to asthma-bronchial hyper-responsiveness co-inherited with a major gene for atopy. N Engl J Med. 1995;333:894-900.
2. Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. JAMA. 2002;288:.963-72.
3. Bach JF. The effect of infections on susceptibility to autoimmune and allergic disease. N Engl J Med. 2002;347:911-20.
4. Braun-Fahrlander C, Riedler J, Herz U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002;347:869-77.
5. Borish LC, Nelson HS, Corren J. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 2001;107:963-70.
6. Leckie MJ, Brinke A, Khan J, et al. Effects of IL-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet. 2000;356:2144-8.
7. Milgrom H, Fick RB, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med. 1999;341:1966-73.
8. Busse WW, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108;184-90.
Dr. Amrol and Dr. Murray conduct asthma research at Vanderbilt University Medical Center, Nashville, Tenn.
ASTHMA ADDS UP
The National Heart, Lung, and Blood Institute developed a data fact sheet on asthma statistics to indicate the magnitude of the problem:
• Asthma is the most common chronic disease of children and affects 14.9 million people of all ages in the United States.
• Asthma caused more than 1.5 million emergency department visits, 500,000 hospitalizations and more than 5,500 deaths in 1995.
• Estimated asthma related costs for 1998 were $11.3 billion.
For more information, visit http://www.nhlbi.nih.gov