Trends in respiratory medicine: Asthma and allergy
G. Douglas Campbell
Providing appropriate patient education can make a vast difference
ABSTRACT: Are anti-inflammatory agents being used appropriately in patients with asthma? What is the current role for theophylline, long-acting [beta]-agonists, and leukotriene modifiers? Here the Editorial Board addresses these and other important issues concerning the management of asthma, including the use of peak flow meters, asthma education, immunotherapy, and the concept of airway remodeling. They also discuss the increased awareness of gastroesophageal reflux disease and the management of allergic rhinitis. (J Respir Dis. 1999;20(10):676- 683)
The Journal of Respiratory Diseases (JRD): Ten years ago, one of the key developments in asthma was the recognition of the importance of inflammation. The challenge then was to communicate that information to physicians and patients. More recently a number of asthma guidelines have been published, all emphasizing the importance of anti-inflammatory therapy. [1] Are anti-inflammatory agents now being used appropriately, or are they still being underused in certain patient groups?
Dr Lillington: I would like to begin with two quotations. One is from Sir William Osler’s first edition of Principles and Practice of Medicine, which was published in 1892. In his chapter on asthma, he said, “Death from asthma is unknown.” I made a slide of that quote with the caption, “The good old days.” The second quotation comes from a symposium on asthma in which one of the speakers said, “People are dying now from asthma who’ve never died before.”
The point, of course, is that asthma mortality has markedly increased. It is not spectacularly high, but it is increasing. The [beta]-agonist metered-dose inhalers (MDIs) were good enough to make asthmatic patients think they could get through the night but not quite good enough to always ensure that. Despite the newer therapies, we are still treating asthma inadequately. The evaluation of drugs dispensed from hospital formularies indicates that only about 50% of patients hospitalized with asthma are receiving an anti-inflammatory drug.
With the growing popularity of some of the anti-inflammatories, we should anticipate a decrease in mortality. However, the treatment of asthma differs tremendously depending on location. In one study, 25% of asthma-related deaths in persons 5 to 30 years of age in the United States occurred in two counties–Cook County in Illinois and King’s County in New York. [2] Having access to doctors who are familiar with the current approach to treating asthma is crucial.
JRD: Is the jury still out concerning the effects of inhaled corticosteroids on growth in children? Is “steroid phobia” still an obstacle?
Dr Squillace: There is still intense interest on the part of primary care providers about the risks of both intranasal and inhaled corticosteroids. This reflects the fact that there are gray areas concerning the use of corticosteroids.
Although corticosteroids are generally safe when used at recommended doses, there are case reports of systemic effects in the pediatric and elderly populations. And, despite evidence that children taking inhaled corticosteroids generally reach a normal final height, the possibility of slowed growth is naturally a concern for parents and pediatric providers.
Bronchodilator therapy
Dr Campbell: My impression is that theophylline is not used as frequently on the general medicine wards as it once was. Is its use still decreasing, or is it going back up?
Dr Matthay: I think theophylline is used much less often. In our hospital, it is added to the regimen if the asthmatic patient is not doing well despite substantial doses of intravenous corticosteroids.
Dr Lillington: Theophylline has been on somewhat of a roller coaster over the years. In 1950, when I was an intern, there were no MDIs available, and intravenous theophylline was the most spectacular drug for asthma. If a therapeutically naive patient came to the emergency department (ED) wheezing, intravenous theophylline was very effective. Then it fell out of favor.
Dr Matthay: The attitude toward theophylline is an example of how asthma therapy in the United States has been directed by our British colleagues. More than 10 years ago, when theophylline was popular in the United States, the British told us that we were misguided–that theophylline was not the appropriate agent to use, largely because it had a very narrow therapeutic range relative to complications and side effects. They advocated using inhaled [beta]-agonists, at least four times a day.
So we decreased the use of theophylline and markedly increased the use of [beta]-agonists. Then the British said, “You are overusing [beta]-agonists. You should be using inhaled corticosteroids, which are anti-inflammatory.” Within the past 2 or 3 years, the British, led by Dr Peter Barnes, announced that their studies showed that theophylline itself has anti-inflammatory properties and that it probably should have a significant place in the treatment of asthma. So we have come full circle. I think that in certain settings, theophylline will have a modest resurgence.
Dr Lillington: I have continued to prescribe theophylline. Studies have shown that it can reduce the need for corticosteroids. Theophylline is not a panacea, but it is relatively safe. With long-acting theophylline, toxicity is less likely because you can achieve a fairly steady blood level. You check the blood level after about 1 week; if it is within a reasonable range, you do not have to keep checking it. But you do have to be aware of the factors that can affect theophylline metabolism. For example, there are about 22 drugs that decrease theophylline elimination and about 8 that increase it (a 20% change or greater). [3]
Dr Campbell: Have long-acting [beta]-agonists replaced theophylline for the treatment of nocturnal asthma?
Dr Matthay: I do not use a long-acting [beta]-agonist to eliminate theophylline, but I use it if an asthmatic patient is routinely waking up at night wheezing or short of breath despite oral theophylline. I give the long-acting [beta]-agonist at bedtime. If the patient requires many inhalations of a short-acting [beta]-agonist during the day, I might try to reduce that total number of inhalations by having him or her inhale 2 puffs of the long-acting [beta]-agonist in the morning.
Dr Squillace: I have found that to be a useful alternative to increasing the dosage of the inhaled corticosteroid in patients who have persistent asthma despite a reasonable regimen.
Dr Lillington: Martin [4] has recommended long-acting theophylline for nocturnal asthma. Theophylline is about as effective as the long-acting [beta]-agonist but, when given orally, the blood level is more likely to peak at about 4 AM, when nocturnal asthma is the most severe. Giving theophylline–or corticosteroids–in the evening provides better 24-hour coverage than giving the same dose in the morning, which is very important. There has been an increasing realization that all asthmatic patients have nocturnal asthma.
Leukotriene modifiers
Dr Campbell: How often do you use the leukotriene modifiers?
Dr Squillace: The leukotriene modifiers are effective in patients with mild to moderate asthma but are less useful in those with severe disease. They are easy to use but are also expensive.
Dr Campbell: We have used these agents in certain patients who have difficulty in using MDIs.
Dr Matthay: In a recent review, Drazen and colleagues [5] suggested that in certain circumstances, leukotriene modifiers may be first-line therapy for asthma. That surprised me. I have many asthmatic patients, and only a few are taking a leukotriene modifier; and I see some difficult asthma cases. I took a poll at a Connecticut conference of lung physicians and found that leukotriene modifiers help reduce the corticosteroid dosage in about half of patients who require substantial doses of corticosteroids. It does not mean the patients can stop taking the corticosteroid.
Dr Lillington: Many doctors are finding the results you mentioned. The question is: Do the leukotriene modifiers have enough anti-inflammatory activity so that they could be substituted for an inhaled corticosteroid in patients with mild persistent asthma? Biopsy and bronchoalveolar lavage results in Great Britain suggest that these agents cause eosinophil counts to decline, so there appears to be an anti-inflammatory effect. But we do not know the magnitude yet.
Dr Matthay: I would be cautious in the use of these new agents until we know more about them. (Editor’s note: See “The role of the leukotriene modifiers.”)
Gastroesophageal reflux
Dr Campbell: Gastroesophageal reflux disease (GERD) as a cause of cough and asthma also represents an interesting development. GERD presents so differently–I have seen patients present with a wet cough, and others present with asthma. Ten years ago, I would not have suspected GERD. Its prevalence has been largely unrecognized.
Dr Matthay: Does reflux of acid to the back of the throat and into the airways occur largely at night, or does it occur all day?
Dr Lillington: The mechanism is not completely understood. How much of the acid is aspirated is not known. It has been shown that stimulating the vagus nerve with hydrochloric acid can cause bronchospasm; that may be the mechanism. Most persons have some reflux at nighttime, but it is not usually a problem.
Dr Matthay: Does anybody feel comfortable with a “best test” or tests to establish the diagnosis of GERD?
Dr Campbell: Give empiric therapy, and see if the patient’s symptoms resolve. Therapy for GERD has produced some remarkable turn-arounds.
Dr Lillington: If the patient complains of heartburn and therapy is beneficial, you can be pretty sure of the diagnosis.
JRD: When would you order pH monitoring for diagnosing GERD?
Dr Lillington: It depends on whether you have the equipment available.
Dr Squillace: It is important to establish the diagnosis of GERD in infants with apnea. Also, if a patient has atypical chest pain and you have ruled out a myocardial infarction but are still worried and need to establish this is noncardiac pain, a pH monitor would be helpful. If that is unavailable, you could do a Bernstein test for pH.
Dr Lillington: One of the problems with asthma is that wheezing has many other causes. You have to make sure that the patient has true asthma. There is no infallible diagnostic test; the diagnosis is based on a conglomeration of clinical findings. I am reminded of a famous quotation from one of the great figures in the field of allergy,
Dr Rackemann. [6] In the 1930s, he presented a paper before the Association of American Physicians, and he said: “There is lots of asthma that is, and lots of asthma that ain’t.” This is still true. We mistakenly call some conditions asthma, and we overlook the diagnosis of asthma in many patients with chronic cough–patients who have cough-variant asthma.
The effects of managed care
JRD: What effects has managed care had on asthma-related office visits or hospitalizations?
Dr Squillace: There is controversy about who provides the best asthma care. Clearly, if you are not giving the right drugs, you are not offering the best care. Some of the literature suggests that primary care physicians do not provide adequate care for asthma patients. [7] Asthma could become a disease in which the patient is allowed to bypass the primary care physician and go straight to the specialist. This is not very practical, particularly considering the prevalence of mild persistent and mild intermittent asthma, which do not require specialist care.
Managed-care companies and prescription benefit managers are trying to educate primary care providers about how to use asthma medications appropriately and to use them early in patients who have persistent disease, regardless of how mild it is. If they need their [beta]-agonist twice a day, they should be taking an anti-inflammatory. But it is difficult to get physicians to change their prescribing habits or to get patients to become more compliant.
Dr Lillington: Part of the problem is that primary care doctors may have to see five or six patients an hour. They do not have enough time to treat asthma appropriately even if they are well-informed about the most current recommendations. This is where the nurse’s role is so important; a nurse who is experienced in asthma education can make an enormous contribution. It has been shown that having a nurse who can occasionally go to a patient’s home and talk to the patient’s family can lessen the number of visits to the ED. The improvement is impressive.
Dr Matthay: The preventive approach with asthma education will most likely net significant cost savings to the health care system. We found at our institution that once we started educating patients, ED visits dropped dramatically, and hospitalization decreased. After patients had their first asthma attack, we told them to use oral corticosteroids at home if necessary to control their asthma, even while they were calling their physicians. Empowering patients is important.
Peak flow meters
Dr Campbell: One change I have observed over the last 10 years is the wider use of peak flow meters (Table). With the integrated devices that are becoming available, the patient can breathe into the device, and the forced expiratory volume in 1 second ([FEV.sub.1]) and forced vital capacity can be downloaded over the phone.
Dr Lillington: I have always recommended peak flow meters. They are inexpensive, and they do not break if you drop them on the floor! And children enjoy using them because they can see the results. Most important, peak flow meters give an objective measurement of asthma; subjective measurements are very misleading.
Dr Campbell: But the peak flow measurements are variable.
Dr Lillington: Yes, and a few recent studies suggest that the use of peak flow meters may not affect outcome. [8]
Dr Squillace: The studies show that peak flow meter use does not affect outcome in patients with mild disease, but it probably does make a difference in patients who have moderate to severe disease. [9-11] In these patients, the use of peak flow meters can affect how much medication they use, how frequently they go to the ED, and how frequently they are hospitalized.
There is solid evidence that patient outcomes can be improved by using asthma action plans that incorporate multiple modalities, particularly self-directed care, which involves the use of peak flow meters and the early use of oral corticosteroids. If patients have oral corticosteroids available at home and know when to use them–if they have a clear action plan–it can make a big difference. Oral corticosteroids are just as effective as intravenous corticosteroids, if the patient can tolerate them.
Dr Lillington: I agree that the action plan is crucial.
Prevention, future trends
JRD: Is there any evidence that asthma can be prevented?
Dr Squillace: A number of studies have assessed the role of atopy, the mother’s diet during pregnancy and during breast-feeding, and late introduction of variables that we know cause problems. So far, the intervention studies have not shown any benefit. [12] The most interesting information I heard this year at the American Academy of Asthma, Allergy, and Immunology meeting was that asthma is less likely to develop in children from larger families. One theory is that these children are getting more infections, and that somehow the infections prevent the development of asthma.
Dr Lillington: Infections are good for you. Brace yourself for this one!
Dr Squillace: At least pediatric viral ones, as long as you don’t treat them with antibiotics.
Dr File: It is interesting to note, however, that recent reports link Chlamydia pneumoniae with acute “asthma,” and respiratory syncytial virus infection in adults often presents as new bronchospasm.
Dr Campbell: There is a theory that the reason we are seeing more autoimmune diseases is because we are living in a cleaner world. We are giving more vaccinations, which are somehow disrupting the autoimmune system.
What are your thoughts concerning the asthma gene?
Dr Matthay: The great hope for gene therapy was in cystic fibrosis, but that has not worked out yet. Some experts suggest that the gene project could yield great advances in respiratory medicine, but my sense is we need more time. Maybe 10 years from now we will be there.
JRD: What about the concept of airway remodeling in the pathogenesis of asthma? This seems to be a hot topic.
Dr Squillace: Airway remodeling is the theory that the chronic inflammation of untreated asthma changes the basic architecture of the bronchial tree and causes progressive decline in [FEV.sub.1]. One study found that over a 15-year period, [FEV.sub.1] declined to a greater extent in persons with asthma. [13]
Dr Lillington: There probably is a thickening of the basement membrane. It becomes thickened with collagen and becomes more rigid.
Dr Campbell: So asthma is no longer a reversible obstructive airways disease?
Dr Lillington: It is partly reversible, but irreversible changes in the tracheobronchial tree occur overtime. However, most asthmatic patients do not get chronic obstructive pulmonary disease, unless they are smokers, and they do not die of chronic respiratory failure.
Dr Matthay: Is the implication that if one treats more aggressively–and early–with an anti-inflammatory, these changes will be less severe?
Dr Lillington: Yes, that’s the theory.
Dr Campbell: Can we expect to see improvements in immunotherapy, such as monoclonal antibodies to certain T cells?
Dr Lillington: Yes, I think we will see improvements. A good deal of research is being conducted. The understanding of the basic mechanisms of asthma and the immunologic treatment of it has lagged behind other aspects of immunology. There have been advances in the ability to measure these mechanisms, and it has been established that allergy injections help a fair number of patients. The key questions are how many patients will be helped by immunotherapy, and how long do they need to be given such therapy?
Dr Squillace: And what diseases does immunotherapy really affect?
Dr Lillington: The effectiveness of immunotherapy is most evident in seasonal allergic rhinitis. The results of recent asthma studies that have looked at allergy from a different viewpoint and correlated it with inflammation have suggested that the role of allergy may be greater than previously recognized. We used to think that most asthmatic patients did not have true atopic disease, but that may not be correct. Many of them may not have typical atopic disease, but they may be affected by a number of environmental factors, even though the specific problem cannot be clearly identified by skin testing, for example. Apparently, we still do not understand asthma very well.
Dr Matthay: I have become more and more humbled by this disease. The more we learn from research about how heterogeneous asthma is, how many factors can potentially exacerbate it–everything from the cytokines, lymphocytes, epithelial cells, and dendritic cells–the clearer it is that this disease is amazingly complex. Ten years from now, we will be a little further along, but I do not think we will see a cure for asthma in the next 10 or 20 years.
Allergic rhinitis
JRD: There has been considerable growth of direct-to-consumer advertising in the last 5 years. This has been particularly noticeable in advertising for antihistamines for allergic rhinitis. Have you seen increased interest in antihistamines from your patients as a result of direct-to-consumer advertising?
Dr Squillace: Patients have always been interested in antihistamines. Multiple studies and a recent meta-analysis have shown that intranasal corticosteroids are better than antihistamines at controlling allergic rhinitis symptoms. [14] However, antihistamines are considered first-line agents in many treatment algorithms because patients tend to be more compliant with antihistamine therapy. This may not have a significant effect on long-term outcome, but symptom control is not generally as good as it would be with intranasal corticosteroids.
Dr Matthay: Are there any data that show an additive or synergistic effect by combining antihistamines and intranasal corticosteroids?
Dr Squillace: I know of one study that found that adding an antihistamine to an intranasal corticosteroid regimen did not have a significant effect. [15]
Dr Lillington: The corticosteroid aspect of therapy is very important. The problem is that some patients will not take corticosteroids because they find it a nuisance. The newer antihistamines are much better than the older antihistamines, because the patient can take a sufficient amount to relieve symptoms without falling asleep while driving … which is considered by most people to be advantageous, except possibly in California.
Dr Squillace: One potential obstacle is that managed care may force us to use the older antihistamines before we can use the nonsedating ones because the older agents are less expensive. But we know the economic impact of untreated disease is also quite significant because of missed days from work and loss of productivity.
Dr Lillington: Another important point is that several studies suggest that better control of allergic rhinitis results in better control of asthma. [16-18]
Dr Matthay: We learned many years ago that if you do not control the patient’s upper airway problems–allergic rhinitis and rhinosinusitis, for example–you are probably not going to be able to control the asthma. To achieve sustained control in the lower airway, you first have to get the upper airway under control.
Roundtable participants
* G. Douglas Campbell, Jr, MD, Professor of Medicine, Division of Pulmonary/Critical Care Medicine, Louisiana State University, Shreveport.
* Thomas M. File, Jr, MD, Professor of Internal Medicine, Northeastern Ohio Universities College of Medicine, Rootstown; Chief, Infectious Disease Service, Summa Health System, Akron.
* Glen A. Lillington, MD, Clinical Professor of Medicine, Stanford University, Stanford; Professor of Medicine Emeritus, Division of Pulmonary Medicine/Critical Care, University of California, Davis.
* Richard A. Matthay, MD, Professor of Medicine; Associate Director, Pulmonary and Critical Care Section, Yale University, New Haven, Conn.
* Susan P. Squillace, MD, Associate Professor of Family Medicine; Assistant Professor of Internal Medicine, University of Virginia, Charlottesville.
Editorial Board member William W Busse, MD (Professor of Medicine and Chief, Section of Allergy and Clinical Immunology, University of Wisconsin, Madison), was unable to attend.
REFERENCES
(1.) Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report II. Bethesda, Md: National Institutes of Health; 1997. Publication 97-4051.
(2.) McFadden ER Jr, Warren EL. Observations on asthma mortality. Ann Intern Med. 1997;127:142-147.
(3.) Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med. 1966;334:1380-1388.
(4.) Martin RJ. Effective treatment strategies for nocturnal asthma. J Respir Dis. 1944;15 (suppl):S47-S53.
(5.) Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med. 1999;340:197-206.
(6.) Rackemann FM, Green JE. Periarteritis nodosa and asthma. Trans Assoc Am Physician. 1939;54:112.
(7.) Vollmer WM, O’Halloren M, Ettinger KM, et al. Specialty differences in the management of asthma. A cross-sectional assessment of allergists’ patients and generalists’ patients in a large HMO. Arch Intern Med. 1997;157:1201-1208.
(8.) Donohue JF. Asthma: indications, benefits, and pitfalls of peak flow monitoring. Consultant. 1966;36:2589-2596.
(9.) Beasley R, Cushley M, Holgate ST. A self-management plan in the treatment of adult asthma, Thorax. 1989;44:200-204.
(10.) Ignacio-Garcia JM, Gonzalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory flow. Am J Respir Crit Care Med. 1995;151:353-359.
(11.) Lahdensuo A, Haahtela T, Herrala J, et al. Randomised comparison of guided self management and traditional treatment of asthma over one year. BMJ. 1996;312:748-752.
(12.) Kramer MS. The register of clinical trials maintained and updated by the Cochrane Pregnancy and Childbirth Group. Updated August 14, 1996.
(13.) Lange P. Parner J, Vestbo J, at al. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339:1194-1200.
(14.) Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral [H.sub.1] receptor antagonists in allergic rhinitis: systematic review of randomized controlled trials. BMJ. 1998;317:1624-1629.
(15.) Ratner PH, van Bavel JH, Martin BG, at al. A comparison of the efficacy of fluticasone propionate aqueous nasal spray and loratadine, alone and in combination, for the treatment of seasonal allergic rhinitis. J Fam Pract. 1998;47:118-125.
(16.) Watson WT, Becker A, Simons E. Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness. J Allergy Clin Immunol. 1993;91:97-101.
(17.) Welsh PW, Stricker WE, Chu-Pin C, et al. Efficacy of beclomethasone nasal solution, flunisolide and cromolyn in relieving symptoms of ragweed allergy. Mayo Clin Proc. 1987;62:125-134.
(18.) Corren J, Adinoff AD, Buchmeier AD, et al. Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma. J Allergy Clin Immunol. 1992;90:250-256.
Major developments and future trends in asthma
Major developments in the past 10 years
Increased recognition of the importance of anti-inflammatory therapy
Growing awareness of the role of environmental factors
Increased appreciation of the importance of patient education, including the use of peak flow meters
Greater recognition of the link between gastroesophageal reflux disease and asthma
What to expect in the next 5 to 10 years
Improved anti-inflammatory drugs
Greater understanding of the role of leukotriene modifiers
The role of the leukotriene modifiers
Since Editorial Board member Dr William Busse was unable to attend the roundtable discussion, and he is, after all, an asthma expert, we asked him to summarize his perspective on the role of the leukotriene modifiers for asthma. Here is his response:
The leukotriene modifiers represent an exciting new drug class. Although their role in the treatment of asthma has not yet been firmly established, they may prove to be extremely effective in certain patients. For example, patients with excessive 5-lipoxygenase secretion may prove very responsive. Furthermore, there is some evidence that the leukotriene modifiers may have anti-inflammatory activity. Therefore, these agents may be most effective when used in addition to inhaled corticosteroids.
It took nearly 10 years to fully understand and position inhaled corticosteroids in asthma therapy. I think it is far too early to conclusively define the role of leukotriene modifiers in the treatment of asthma.
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