Respiratory therapists can benefit by learning about potential treatments in immunotherapy and asthma such as anti-DNA therapy, soluble recombinant human IL-4R, and the use of recombinant humanized monoclonal anti-IgE antibodies.
In this new millennium, physicians and respiratory therapists have more clinical options in their therapeutic armamentarium than ever before. The number of new, more efficacious medications available for asthma treatment has increased dramatically in the last decade. In spite of this, we are facing an asthma epidemic in this country. The prevalence of asthma has more than doubled since the beginning of the 1980s through the end of the 20th century.1 Asthma appears to be increasing at a rate of about 5% per year in the United States, yielding approximately 500,000 new cases each year. Current estimates place the number of asthma patients in the United States at 17 million, with 1.5 million emergency department (ED) visits, 500,000 hospitalizations, and more than 5,500 deaths reported in 1995.2
Respiratory therapists commonly utilize such medications as bronchodilators and inhaled corticosteroids on a daily basis in their treatment of asthma patients; however, the use of immunotherapy in the fight against asthma is a weapon unfamiliar to many practicing in the field today. Recommendations contained in the Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma3 issued by the National Institutes of Health state that clinicians may consider allergen immunotherapy for asthma patients when there is “clear evidence of a relationship between symptoms and exposure to an unavoidable allergen to which the patient is sensitive; symptoms occur all year or during a major portion of the year; and there is difficulty controlling symptoms with pharmacologic management either because the medication is ineffective, multiple medications are required, or the patient is not accepting of medication.”3
Allergies and Asthma
There appears to be a strong connection between allergies and asthma. No one is actually born with allergies; however, they may inherit the tendency to develop allergies. This genetic tendency is called atopy. Atopy is considered to be the most important predictor for a person to develop asthma.4 It is estimated that 90% of children under 16 years of age with asthma have allergies, 70% of adults under 30, and 50% of adults over 30 with asthma report allergies as well.5
The human immune system is the main defense against outside invaders such as bacteria and viruses. It is the role of the white blood cells to defend the body against infection. There are two types of specialized white blood cells called lymphocytes that play an important part in allergies and asthma. T cells form and release cytokines, which target and kill the bacteria, virus, or other foreign substances that enter the body. B cells manufacture immunoglobulins, which are specialized antibodies that learn to recognize the specific invader and identify it for the immune system to destroy. It also “remembers” the specific antigen in any future exposures. This process is called sensitization.
When an invader is recognized, the B cells are signaled to produce antibodies. Although there are many different antibodies produced by the body to fight disease, one specific antibody, immunoglobulin E (IgE), plays a prominent role in allergic asthma. No one is sure what the specific role of IgE was originally meant to be, although there is some evidence that its job was to fight off parasites. IgE is not needed to perform this function today, but the body continues to produce it. IgE makes up only about 1% of the antibodies produced by the human body, but persons with allergic asthma manufacture too much of it—in some cases up to 20 times the normal amount. In addition, a different IgE antibody is produced for each substance for which the individual is sensitive.
When the susceptible individual breathes in an allergen such as grass pollen, the IgE antibodies attach themselves to the mast cells in the airways and lungs. This facilitates an “unlocking” of the mast cells, causing them to release chemical mediators such as histamines, leukotrienes, eosinophils, and prostaglandins into the surrounding tissues. These mediators trigger the increased inflammation, mucus production, and bronchoconstriction that mark an asthma exacerbation.
The asthmatic person’s immune system is in a constant state of alert and frequently overreacts to otherwise harmless environmental factors perceived to be threatening. This leaves the airways of the asthma patient chronically inflamed.
The Role of Immunotherapy
Nearly 100 years ago, physicians were looking for a means of desensitizing individuals with allergies and asthma to the substances that triggered their symptoms. In 1911, two doctors, Leonard Noon and John Freeman, began giving watery extracts of boiled grass pollen via injection to their patients with allergies and asthma.6 This pioneering work was the basis for the immunotherapy of today.
How does it work? Scientists are still investigating the exact mechanism that makes immunotherapy effective, but it seems to involve the following factors. When the immune system is exposed to an allergen, the body’s B cells can be directed to produce more IgE (a type 2 or allergic response) or IgG (a type 1 response). IgG antibodies are blocking-type antibodies, which prevent the IgE from binding to the mast cells. This prevents the allergens from triggering allergy and asthma symptoms.
Basically, immunotherapy works in the same way as vaccinations against disease. When the allergen is introduced via injection in very dilute amounts, the immune system responds by producing the IgG antibodies and inhibiting the asthmatic response. The first injections contain a tiny amount of the allergen diluted to the point that no reaction is seen. These injections are repeated once or twice a week at the physician’s office. Depending on the sensitivity of the patient, the concentration of the allergen vaccine is gradually increased as the visits continue. Eventually, the patient will reach a maintenance dose, which contains the highest concentration of allergen. This process can take 4 to 6 months. The frequency is gradually decreased until the visits are approximately a month apart. Allergists usually keep a patient on immunotherapy for 3 to 5 years. During this time, the amount of IgE antibodies gradually decreases and the patient becomes far less sensitive to the triggering allergens.
Immunotherapy is targeted specifically to particular allergens. The most common used for asthma patients are grasses, pollens, mold spores, dust mites, and animal dander. In order to determine what allergens a particular patient might be sensitive to, testing must be performed. A careful history must be taken to gain some insight into possible asthma triggers. At this point, the patient would most frequently undergo prick-puncture skin testing. In this procedure, a drop of the suspected allergen solution is placed on the arm or back. The skin is then pricked, punctured, or scratched with a special device or a multitest can be used, which has multiple applicators with various allergens on them. Testing for inhaled allergens may require up to 70 individual tests. Testing for insect venom and food allergies is not recommended for asthmatics. After 15 to 20 minutes, the doctor will check the testing area looking for raised, red wheals denoting a reaction to a specific allergen. This procedure targets which allergens to use in the immunotherapy treatment.
In some cases, a different type of testing is done. A blood test known as radioallergosorbent testing (RAST) can test for many allergies at once. This option is used for patients who are taking medications such as antihistamines, antidepressants, or beta blockers, which can interfere with allergy testing. In addition, it can be used where the sensitivity level may be high enough to cause potentially serious side effects such as an asthma episode. In general, however, RAST is not as sensitive as skin testing. It is also more expensive and takes longer to get the results.
How safe is immunotherapy for the asthmatic? Neither skin testing nor immunotherapy injections are completely benign. Side effects can range from localized redness and itching to fatal anaphylactic reactions. One study by Hepner et al7 identified 25 reactions out of 2,989 patients receiving immunotherapy over a 7-month period with no fatalities noted. Every precaution is taken to reduce any chance of a severe reaction.
Silverio Santiago, MD, clinical professor of pulmonary medicine and critical care at UCLA Medical Center, Los Angeles, states, “Many people are concerned about possible risks of immunotherapy. In reality, these risks are quite small. Allergy vaccinations are given only for those substances revealed to be allergic asthma triggers during skin testing.” He continues, “One has to keep in mind that the patient must be compliant with frequent visits to the clinic over a long period of time to receive any potential benefit from immunotherapy. It is also expensive. One must be sure that it is providing benefit to the patient. If it isn’t working, don’t do it.”
EFFECTIVENESS OF IMMUNOTHERAPY
Researchers have made a concentrated effort to investigate whether immunotherapy is an effective treatment for asthma. The majority of these studies have indicated that immunotherapy benefits many patients with allergic asthma. This type of treatment may do more than just treat symptoms of allergy and asthma. Immunotherapy may actually prevent allergic reactions from occurring in certain individuals, change the way that the immune system responds to allergens, and actually alter the disease process in allergic asthma itself.
Busse and Lemanske8 have hypothesized that one reason asthma has shown such dramatic increases over the past 2 decades is that many children in the United States grow up in a more hygienic environment. Individuals are born with many TH2 immune cells designed to battle parasites and, in this modern day, otherwise harmless allergens. In contrast, TH1 immune cells develop when the individual is exposed to infections, building a stronger immune system. They found lower asthma rates for children in day care, living with other siblings or with pets in the home, or living on a farm. Higher rates of allergies and asthma were found only in children in urban environments possibly because of their reduced exposure to infections.8
Ebner et al9 studied a group of patients treated for at least a year who were receiving allergen-specific immunotherapy. They were able to see a shift from an allergic response to a TH1 response demonstrated through an increase in IgG antibodies.
Alvarez-Cuesta et al10 studied a group of 28 adult asthmatics with cat allergies who had no cats in their home environment. These patients were selected because they had chronic asthma symptoms. The results of this randomized trial showed that seven out of the 14 patients treated with immunotherapy for cat allergen had virtually complete resolution of their asthma, whereas none of the 14 placebo patients showed any improvement. This study has widespread applications because many schoolchildren are affected by cat dander carried on the clothing of their schoolmates.
A classic study by Johnstone and Dutton11 followed a group of children who received allergy shots for allergic rhinitis for a period of 14 years. They found that these children were far less likely to develop asthma than children with allergies who did not receive the therapy.
The Preventive Allergy Treatment (PAT) study12 is a multicenter trial being conducted at several European centers that looks at this same question; 205 children aged 7 to 15 years were studied with 191 being followed for 2 or 3 years. Half the group received immunotherapy while the rest received a placebo. Patients treated with immunotherapy had fewer asthma symptoms than the untreated group. In addition, no patients in the immunotherapy group developed asthma, while the placebo group had several new reports of asthmatic symptoms.
Studies have also shown that medication use and symptom scores can decrease significantly in asthmatic patients receiving immunotherapy. Price et al13 studied 51 children with dust-mite sensitive asthma in a randomized trial over a 2-year period. They found that medication use in the treatment group decreased by 96%, and some patients went into complete remission. Another study by Reid et al14 looked at soldiers stationed in the Sacramento area where exposure to grass pollen was extremely high. They found that asthma symptoms and medication scores were reduced by 74% in the soldiers receiving immunotherapy.
One of the criticisms leveled at many of the studies published on asthma and immunotherapy has been that the sample sizes are quite small. In recent years, a few meta-analyses have been compiled to include the results of several studies, which increases their overall statistical power.
In 1995, Abramson and colleagues15 conducted an analysis of all 20 published prospective, randomized, placebo-controlled trials of immunotherapy for asthma conducted between 1960 and 1990. They found that asthmatics receiving immunotherapy were 3.2 times more likely to experience improvement in symptoms, 4.2 times more likely to show a reduction in medication use, and 6.8 times more likely to show reduced bronchial hyperreactivity, and had a mean increase of 7.1% in FEV1. They concluded that immunotherapy is effective in patients with allergic asthma. In fact, they surmised that 33 similar studies with negative results would be necessary to contradict these findings.
A more recent meta-analysis was performed by Ross et al,16 which looked at 24 studies involving 962 asthmatics with documented allergies. They found that immunotherapy proved effective in 71% of the studies with significance in the areas of reduced asthma symptoms, bronchial challenge, reduced medication, and improved pulmonary function.
Guidelines for Immunotherapy
The American College of Allergy, Asthma & Immunology offers the following guidelines17 for the use of immunotherapy in asthma:
• the first steps in clinical management require allergen avoidance and the use of appropriate medications;
• immunotherapy should be prescribed only by an allergist-immunologist or other physicians who are expertly trained in the therapy;
• immunotherapy should be administered under the supervision of an allergist-immunologist or other physician specifically trained in immunotherapy, the early signs and symptoms of anaphylaxis, and appropriate emergency procedures and medications;
• patients must be suitably selected for immunotherapy and patients with severe or unstable asthma are not candidates;
• immunotherapy should be given only in facilities equipped to treat anaphylaxis;
• the health status of the patient should be evaluated prior to every injection. Patients who are acutely ill, especially with asthma symptoms or respiratory difficulties, should not receive immunotherapy until their disease is stabilized;
• patients should always be asked about current medications prior to treatment to avoid interactions with beta blockers and other conflicting medications; and
• patients must wait at the health care facility a minimum of 20 minutes after an allergen injection—the time period may be extended for high-risk patients.
The Future
Larry Borish, MD, associate professor in medicine, Asthma and Allergic Diseases Center, University of Virginia, Charlottesville, states, “There is a desperate need for new treatments of asthma. Despite the availability of bronchodilators and inhaled corticosteroids, patients aren’t doing well. They continue to be plagued by asthma symptoms which interfere with their ability to sleep, or perform their activities of daily living, and they experience ongoing symptoms that interfere with exercise, work, and school. Patients continue to require urgent care including ED visits and hospitalizations and, worst of all, patients are still dying from this disease.”
Our understanding of the mechanisms of asthma has expanded exponentially in just the past few years. Because of this, researchers are looking at new therapeutic approaches to treat allergic asthma. One approach that has received a lot of attention is the use of recombinant humanized monoclonal anti-IgE antibodies in immunotherapy. Clinical trials18-20 indicate that the anti-IgE antibodies bind with the natural IgE in the body and prevent it from attaching to the mast cells. This prevents the mast cells from releasing histamine and other mediators that initiate the inflammatory response to an asthma allergen. Patients participating in these trials showed that serum-free IgE levels diminished within 5 minutes to 24 hours depending on the mode of administration and could be reduced to a barely detectable level for 4 to 6 weeks after a single dose. No skin testing is needed for specific allergens. Allergic rhinitis symptoms decreased as well. Results after 32 weeks showed decreased symptom scores, bronchodilator use, reliance on oral and inhaled steroids, and improvement in quality of life scores.
Jonathan Corren, MD, medical director of the Allergy Research Foundation, Los Angeles, explains that “One of the advantages of a systemic treatment for patients with allergic asthma is that 95% of the time, those patients also have allergic rhinitis, which may in some cases be very significant. This treatment offers a single modality of therapy for patients who up to this point in time may require multiple other drugs to control their symptoms.” He goes on to say, “In addition, patients who have historically been noncompliant may benefit from an injection that can be given once a month to control their symptoms.”
There has been some delay in bringing this therapy into clinical use. In July 2001, the Food and Drug Administration asked the manufacturers of the anti-IgE drug to submit additional data on preclinical, clinical, and pharmacokinetic information. On November 1, 2001, a joint statement was released by the companies involved in the development of rhuMAb-E25, stating that they will answer these inquiries and submit an amendment to their Food and Drug Administration application in the fourth quarter of 2002.
Another promising therapy involves a soluble recombinant human interleukin-4 receptor (IL-4R). According to Borish, this drug “acts like a sponge that soaks up all the IL-4 so you don’t have an allergic response. It stops the inflammatory cascade of asthma before it can get started.” This IL-4 receptor is a naturally occurring human protein, so it has a long half-life. This enables patients in clinical trials to take one weekly inhalation treatment of the drug. Researchers found that the patients could be tapered off their inhaled corticosteroids without significant decline in either their pulmonary function measurements or their asthma symptom scores.21
The future of asthma therapy is moving rapidly in new directions, which are beyond what we could imagine just a few short years ago. Progress in the Human Genome Project has led to some investigations in anti-DNA therapy. In the future, researchers may be able to tailor the perfect therapy for each person with asthma based on a DNA test. Respiratory therapists should make every effort to become involved in these exciting new investigations.
Peggy Walker, RRT, RCP, is a pulmonary research associate at the VA Greater Los Angeles Healthcare System, Los Angeles.
References
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17. Nicholas RA, Bernstein IL, Blessing-Moore J, Finerman S. Joint task force on practice parameters representing the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 1990;85:526-527.
18. Tillinghast JP. Physician and patient global evaluation of an anti-IgE antibody in patients with moderate-to-severe asthma. Paper presented at CHEST 2000; October 24, 2000; San Francisco.
19. Milgrom H, Fick RB Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb Study Group. N Engl J Med. 1999;341:1966-1973.
20. Busse W, Corren J, Lanier BQ, et al. RhuMAb-E25, a novel therapy for the treatment of allergic asthma. Paper presented at the 56th American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting; March 2000; San Diego.
21. Borish LC, Nelson HS, Lanz MJ, et al. Interleukin-4 receptor in moderate atopic asthma, a phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999;160:1816-1823.
