- Email: [email protected]
Asthma: best treatment options
Asthma: best treatment options Betty B. Wray, MD
Learning Objectives: To understand the principles of asthma management in patients of different ages, and to outline major avoidance measures, classes of medications available, and indications for immunotherapy (IT). Data Sources: MEDLINE and major textbooks of allergy and immunology. Conclusions: There has been an understanding of asthma as a chronic inflammatory disease for many decades but recent information about mediators and cytokines has led to new therapies and better understanding of the effects of IT and other preventive measures. The best treatment for any individual patient depends upon many factors and is a decision to be made between the patient and the physician. It seems that the best response to IT occurs in those who are highly sensitive to unavoidable allergens, and who experienced a late-phase asthmatic response to the allergen initially. New data suggest that IT should be considered early, as it may prevent progression of asthma to more severe, less reversible disease. The best therapy results in the ablation of airway early- and late-phase reactivity. Ann Allergy Asthma Immunol 2001;87(Suppl):9–12.
INTRODUCTION The best treatment depends upon many factors, which are discussed below. It is always necessary to have an accurate diagnosis, although that is sometimes difficult and may only be confirmed by response to therapy. Age The best treatment for the patient with asthma depends upon the individual patient’s needs. The age of the patient is a major consideration. Young infants may require oral or nebulizeradministered medications because of difficulty coordinating metered-dose inhalers (MDIs) even with spacers. They also may have a specific etiology such as milk allergy and may respond to avoidance measures.1,2 Sensitization to outdoor allergens usually requires several years of exposure; thus, immunotherapy (IT) is usually not indicated under age 4. Indoor sensitization can usually be managed by avoidance measures such as impermeable mattress and pillow covers, removal of carpets, etc.3 In addition to 2-agonists, ipratroAllergy-Immunology Section, Medical College of Georgia, Augusta, GA. Received for publication November 10, 2000. Accepted for publication November 15, 2000.
VOLUME 87, JULY, 2001
pium, theophylline, and several corticosteroids, the leukotriene (LT) modifier montelukast is approved for children as young as age 2. If nebulized corticosteroids are used, care must be taken to avoid contact with the eyes. Older adults are more likely to be receiving medications for other conditions that may interact with asthma medications. They are more likely to have chronic conditions such as sinusitis, nasal polyposis, gastroesophageal reflux, chronic bronchitis from cigarette smoke exposure, and even airway remodeling from long-standing asthma. However, if there are clearly documented IgE antibodies and history of exposure-precipitated symptoms, then IT may be helpful at any age. Young adults show the most skin reactivity and may continue to be symptomatic despite regular use of several classes of medications. These patients may benefit greatly from IT if it is administered carefully, with peak expiratory flow rate monitoring before each injection. “Cause” of Asthma Clearly, asthma symptoms may be precipitated by gastroesophageal reflux,4 by viral infections, and, possibly, by
mycoplasma and chlamydial infections.5 These factors may contribute in patients who have atopic asthma and should be addressed before consideration of IT. Compliance Expectations If a patient or family clearly have transportation difficulties or other problems which will interfere with their ability to keep appointments for allergy shots, that would preclude their administration. However, in many instances, patients who are not compliant with daily medications will regularly come for allergy injections. At times, a physician closer to their home or place of work has to be identified to administer the vaccine. Affordability Allergen IT can be costly and timeconsuming for the patient and family. In many states, special programs are available to assist patients up to age 21. Older indigent patients may find such care assistance at academic centers or public hospitals, or from a philanthropic allergist. Individual Patient Preferences Some patients prefer oral medications, and others appreciate inhalers. Some simply do not want to be taking “so many medicines” and prefer injections as a way to decrease sensitivity and the need for medications. Most patients who have had sudden severe symptoms appreciate having injectable epinephrine on hand, as well as oral corticosteroids, which can be taken under certain conditions. Severity of the Disease The patient with very mild asthma may be managed largely by short-term use of 2-agonists, but many of these patients will go on to have more persistent hyperreactive airways. If such patients have bronchospasm triggered by allergen exposure, then avoidance
9
measures should be instituted. If these are impossible or ineffective, the patients may benefit from IT. However, often it is only when patients are having persistent symptoms that IT is considered. The patient with severe persistent asthma may not tolerate IT.
TREATMENT MODALITIES Pharmacotherapy6–Quick-Relief Medications 2-agonists orally, by MDI, by nebulizer, by injection Anticholinergics: ipratropium by MDI or nebulizer Epinephrine by injection LT modifiers? Theophylline? Magnesium? Pharmacotherapy–Long-Term Controllers Cromolyn by MDI or nebulizer Nedocromil by MDI Corticosteroids by MDI, DPI, nebulizer, or oral LT modifiers orally Theophylline? Long-acting 2 agents, salmeterol Avoidance Measures Careful studies have shown efficacy of dust control measures in patients with dust mite as major allergens.7 Cockroach allergen is more difficult to reduce. Visible mold and mildew can be reduced but complete avoidance is not possible. Animal allergens, particularly cat, are small particles that remain airborne and may be partially removed by HEPA filters, although removal of the animal is the better measure. Pollen avoidance is usually impractical except for measures such as keeping windows closed or going on a long cruise. Exercise/Weight Reduction Some studies have demonstrated benefit from fitness training and/or breathing exercises. Obesity has been shown to be a risk factor for asthma. Patients should be counseled and encouraged to exercise and to lose weight if that is a problem.
10
Treatment of Related Problems Sinusitis is a potentiator if not precipitator of asthma. Allergic rhinitis is common and frequently precedes the onset of asthma. Allergic conjunctivitis and atopic dermatitis may be present. If patients are receiving medications that which may aggravate asthma symptoms, such as  blockers, then alternate drugs must be sought. Allergy Vaccines (IT) Indications8 Symptoms severe enough to warrant intervention (or potential severity). Evidence of IgE-mediated allergy by skin testing or in vitro testing, with symptoms that correlate with the positive tests. Continued symptoms after practical avoidance measures. Contraindications Other serious immunopathologic disorders, malignancies, poor compliance, serious psychological disorders, treatment with -blocking agents, even topically. What are the Pathologic Mechanisms that will Guide our Treatment? The description of asthma in A Manual of Clinical Allergy, published in 1967,9 was as follows: “Symptoms related to spasm of bronchial walls with hypersecretion of tenacious mucus. Edema and eosinophilic infiltration of mucosa, hypertrophy of mucous glands, thickened bronchial smooth muscle, hyalinized bronchial basement membrane, increased goblet cells, patchy shedding of mucosa and loss of ciliated epithelium. . . . Treatment is predicated on careful identification of the factors which cause asthma. These are treated by avoidance when possible, by specific hyposensitization and by regular use of medication designed to prevent symptoms and mitigate those that do occur.” This description and recommendations have not changed drastically over the intervening decades. The National Institutes of Health National Heart,
Lung, and Blood Institute6 convened a panel of experts who updated Guidelines for the Diagnosis and Management of Asthma in 1997. These guidelines stress the importance of an evaluation of airway obstruction by lung function tests and avoidance of precipitating factors, which implies that allergy testing will be done. The goals of pharmacotherapy are reversal and prevention of inflammation plus treatment of exacerbations. There is emphasis on patient education, including the basic facts, the role of medications, the importance of self-management and environmental changes. The goals of pharmacotherapy in the 1997 guidelines are control of chronic and nocturnal symptoms, maintenance of normal activity levels including exercise, maintenance of near-normal pulmonary function, prevention of acute episodes, and avoidance of side effects of medications. The administration of medications in a stepwise fashion is promoted.10 The medications are divided into quick-relief and long-term control groups. The quick-relief control group includes short-acting  2 agonists and anticholinergics. Little mention is made of the rapid onset of bronchodilation by theophylline or magnesium. The long-term control medications include anti-inflammatory agents such as cromolyn, nedocromil, and inhaled corticosteroids. These also include the longacting bronchodilator salmeterol and the LT modifiers. Theophylline is included as well. Other less used therapies, such as inhaled xylocaine and use of antioxidants or mucolytics, are not included. Why is it so Difficult to Control These Symptoms? In the 1950s, Herxheimer11 noted three patterns of response after attempts to hyposensitize allergic asthmatic patients by inhalation of antigens: early bronchoconstriction within 1 to 15 minutes; dual, in which the early airway response was followed by more prolonged late airway response 4 hours later; and late airway response. This
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
late airway response occurs in 30% to 50% of patients and tends to be reproducible in the same patients over time. What are determinants of the latephase airway response?12,13 The latephase response does not invariably occur in those with more severe baseline disease. However, some have noted a more severe drop in forced expiratory volume in 1 second (FEV1) initially in patients who will have a late-phase response (LPR). Those with LPR require a smaller dose of antigen to produce an early reaction. Patients who have seasonal allergies have variation in the severity of LPR after the allergy season. Prolonged airways dysfunction occurs after late-phase response.14 These airflow abnormalities persist for several days, compared with early responders. There is an increase in nonspecific airways reactivity for at least 1 week after an allergen challenge, demonstrated with histamine and methacholine reactivity.15 There is also an increase in nonspecific reactivity after the pollen season. Priming Effect on the Airway A group of 12 asthmatic children with positive prick tests to Dermatophagoides pteronyssinus and cockroach underwent randomized placebo-controlled crossover study. They were challenged with one allergen followed by challenge with the other allergen 48 hours later. The mean 20% fall in FEV1 from control (PD20) was 12-fold less. A 6-fold less dose administered in the second challenge provoked a similar late-phase response. It was concluded that the preceding airway response led to a priming effect with an increase in early- and late-phase responses.16 There were changes in bronchoalveolar lavage fluid after IgE-mediated reactions following allergen challenge; within minutes there was a decrease in the CD4/CD8 ratio and an increase in -glucuronidase. Within 2 hours there was an increase in eosinophils, neutrophils, macrophages, and activated CD4 T cells and basophils. Mast cells were decreased. Within 1 hour, the tryptase,
VOLUME 87, JULY, 2001
histamine, LTC4, prostaglandin D2, and thromboxane increased. Within 2 hours, there was an increase in histamine, LTC4, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-␣, interleukin (IL)-1, IL-4, IL-5, IL-6, and IL-8.12 These are the attenuations of the pulmonary early airway response (EAR) and late airway response (LAR) in humans by medications; short-acting 2-agonists only had effect on EAR, whereas corticosteroids only had effect on LAR. Long-acting 2-agonists, cromolyn, nedocromil, cyclooxygenase inhibitors, 5-lipoxygenase inhibitors, LT D4 blockade, theophylline, furosemide, colchicine had effect on both EAR and LAR. The effect of H1 antihistamine is variable but recent data suggest an effect.17 Effects of Allergen IT on EAR and LAR18 Eight patients with allergic asthma who were sensitive to Dermatophagoides farinae were treated with rush IT for ⬎2 weeks, 8 with placebo. Six months later, the treated patients had decreased eosinophils, eosinophil cationic protein, and T cell production of IL-5. There was also a decreased earlyand late-phase bronchoconstriction and airway responsiveness to mite. Who will Benefit from “Hyposensitization”? A study by Mosbech19 involved 31 asthmatic patients who were treated with extract of Der p for 2 years and compared with 15 controls. Patients improving in bronchial Der p-sensitivity after 1 year had been more sensitive to Der p pretreatment in bronchial and basophil release studies, and had a lower FEV1 compared with the patients not improving (P ⫽ ⬍0.05). Occurrence of late-phase bronchospasm to pretreatment Der p-challenge increased the chance of clinical improvement approximately 3-fold (P ⫽ ⬍ 0.05). Also, the patients with higher mite exposure on their mattresses were more likely to show improvement.
According to 1997 NAEPP guidelines,6 “Atopy, the genetic predisposition for the development of an IgE-mediated response to common aeroallergens, is the strongest identifiable predisposing factor for developing asthma.” However, indications for IT in allergic asthma are difficult to find in the document. According to 1991 NAEPP guidelines,6 IT for asthma is indicated “when avoidance is not possible and appropriate medication fails to control symptoms of allergic asthma.” Subsequent groups suggested consideration of the severity of asthma, efficacy of available IT, cost, risk, and duration of medication needs versus IT. Bousquet and Michel20 have suggested that factors to consider include the greater efficacy in children and young adults, greater likelihood of success with a single sensitivity, and the risk in asthmatic patients unless they are asymptomatic with FEV1 at least 70% predicted. According to practice parameters published in 1995,21 IT can be effective and may reduce the effect of chronic allergen stimulation of hyperresponsive airways. Patient compliance is essential. Immediate and delayed local and systemic reactions may occur and patients must be fully informed. Fatalities may occur, so proper instruction and preparation of staff is necessary.
CONCLUSION The decision to prescribe IT seems to be based on the documentation of an IgE-mediated response to an unavoidable allergen. At the present time, the patient must have significant disease, although patients with milder symptoms may have indications to help with prevention of onset or persistence of asthma if further studies confirm the preventive efficacy of shots.22,23 The availability of facilities and physician supervision is essential. Adequate extracts for the allergen must be available. When all those factors are ful-
11
filled, the choice then becomes a matter of the physician’s and patient’s preference. The best therapy ablates both the early- and late-phase airway responses and decreases airways reactivity. REFERENCES 1. Bock SA, Lee WY, Remigio LK, May CD. Studies of hypersensitivity reactions to foods in infants and children. J Allergy Clin Immunol 1978;62: 327–334. 2. Chipps BE, Chipps DR. Approach to the difficult pediatric asthmatic. Curr Opin Pulm Med 1999;5:52–57. 3. Zeiger RS. Development and prevention of allergic disease in childhood. In: Middleton E, Reed CE, Ellis E, et al, eds. Allergy: Principles and Practice. 3rd ed. St. Louis, MO: CV Mosby, 1993:1137–1171. 4. Patterson PE, Harding SM. Gastroesophageal reflux disorders and asthma. Curr Opin Pulm Med 1999;5: 63– 67. 5. Hahn DL. Chlamydia pneumoniae, asthma, and COPD: what is the evidence? Ann Allergy Asthma Immunol 1999;83:271–288, 291–292. 6. Guidelines for the Diagnosis and Management of Asthma. Highlights of Expert Panel Report 2. National Asthma Education and Prevention Program, National Institutes of Health, 1997. NIH Publication No 97-4051A. 7. Murray AB, Ferguson AC. Dust-free bedrooms in the treatment of asthmatic children with house dust or house dust mite allergy: a controlled trial. Pediatrics 1983;71:418 – 422.
12
8. Bousquet J, Michel FB. Specific immunotherapy in allergic rhinitis and asthma. In: Busse WW, Holgate S, eds. Asthma and Rhinitis. Oxford: Blackwell Science Publishers, 1995: 1311. 9. Sheldon L, Matthews A. “Description of Asthma” in A Manual of Clinical Allergy, 1967:88 –96. 10. Kemp JP. Comprehensive asthma management: guidelines for clinicians. J Asthma 1998;35:601– 620. 11. Herxheimer H. The late bronchial reaction in induced asthma. Int Arch Allergy 1952;3:323–328. 12. Peters SP, Zangrilli JG, Fish JE. Late phase allergic reactions. In: Middleton E, Reed CE, Ellis ET, et al, eds. Allergy: Principles and Practice, 5th Edition, Vol I, Mosby-Year Book, 1998:347–349. 13. Shaver JR, O’Connor JJ, Pollice M, et al. Pulmonary inflammation after segmental ragweed challenge in allergic asthmatic and nonasthmatic subjects. Am J Respir Crit Care Med 1995;152: 1189 –1197. 14. Cockcroft DW, Ruffin RE, Dolovich J, et al. Allergen-induced increase in non-allergic bronchial reactivity. Clin Allergy 1977;7:503–513. 15. Altounyan REC. Changes in histamine and atropine responsiveness as a guide to diagnosis and evaluation of therapy in obstructive airways disease. In: Pepys J, Frankland AW, eds. Disodium Cromoglycate in Obstructive Airways Disease. London: Butterworth, 1969:47–53. 16. Koh YY, Choi JW, Lee MH, et al. A preceding airway reaction to one allergen may lead to priming of the airway
17.
18.
19.
20. 21.
22.
23.
responses to another allergen. Allergy 1997;52:284 –292. Roquet A, Dahlen B, Kumlin M, et al. Combined antagonism of leukotriene and histamine produces predominant inhibition of allergen-induced earlyand late-phase airway obstruction in asthmatics. Am J Respir Crit Care Med 1997;155:1856 –1863. Kohno Y, Minoguchi K, Oda N, et al. Effect of rush immunotherapy on airway inflammation and airway hyperresponsiveness after bronchoprovocation with allergen in asthma. J Allergy Clin Immunol 1998;102:927–934. Mosbech H. Who will benefit from hyposensitization? Predictive parameters in house dust mite allergic asthmatics. Allergy 1990;45:209 –212. Bousquet J, Michel FB. Specific immunotherapy in asthma: is it effective? J Allergy Clin Immunol 1994;94:1–11. Spector S, Nicklas RA. Practice parameters for the diagnosis and treatment of asthma. J Allergy Clin Immunol 1995;96:707– 870. Rackemann FM, Edwards MC. Asthma in children: a follow-up study of 688 patients after an interval of twenty years. N Engl J Med 1952;246: 815– 863. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children: a 14-year study. Pediatrics 1968;42:793– 802.
Requests for reprints should be addressed to: Betty B. Wray, MD Allergy-Immunology Section Medical College of Georgia Augusta, GA 30912-3790 E-mail: [email protected]
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Learning Objectives: To understand the principles of asthma management in patients of different ages, and to outline major avoidance measures, classes of medications available, and indications for immunotherapy (IT). Data Sources: MEDLINE and major textbooks of allergy and immunology. Conclusions: There has been an understanding of asthma as a chronic inflammatory disease for many decades but recent information about mediators and cytokines has led to new therapies and better understanding of the effects of IT and other preventive measures. The best treatment for any individual patient depends upon many factors and is a decision to be made between the patient and the physician. It seems that the best response to IT occurs in those who are highly sensitive to unavoidable allergens, and who experienced a late-phase asthmatic response to the allergen initially. New data suggest that IT should be considered early, as it may prevent progression of asthma to more severe, less reversible disease. The best therapy results in the ablation of airway early- and late-phase reactivity. Ann Allergy Asthma Immunol 2001;87(Suppl):9–12.
INTRODUCTION The best treatment depends upon many factors, which are discussed below. It is always necessary to have an accurate diagnosis, although that is sometimes difficult and may only be confirmed by response to therapy. Age The best treatment for the patient with asthma depends upon the individual patient’s needs. The age of the patient is a major consideration. Young infants may require oral or nebulizeradministered medications because of difficulty coordinating metered-dose inhalers (MDIs) even with spacers. They also may have a specific etiology such as milk allergy and may respond to avoidance measures.1,2 Sensitization to outdoor allergens usually requires several years of exposure; thus, immunotherapy (IT) is usually not indicated under age 4. Indoor sensitization can usually be managed by avoidance measures such as impermeable mattress and pillow covers, removal of carpets, etc.3 In addition to 2-agonists, ipratroAllergy-Immunology Section, Medical College of Georgia, Augusta, GA. Received for publication November 10, 2000. Accepted for publication November 15, 2000.
VOLUME 87, JULY, 2001
pium, theophylline, and several corticosteroids, the leukotriene (LT) modifier montelukast is approved for children as young as age 2. If nebulized corticosteroids are used, care must be taken to avoid contact with the eyes. Older adults are more likely to be receiving medications for other conditions that may interact with asthma medications. They are more likely to have chronic conditions such as sinusitis, nasal polyposis, gastroesophageal reflux, chronic bronchitis from cigarette smoke exposure, and even airway remodeling from long-standing asthma. However, if there are clearly documented IgE antibodies and history of exposure-precipitated symptoms, then IT may be helpful at any age. Young adults show the most skin reactivity and may continue to be symptomatic despite regular use of several classes of medications. These patients may benefit greatly from IT if it is administered carefully, with peak expiratory flow rate monitoring before each injection. “Cause” of Asthma Clearly, asthma symptoms may be precipitated by gastroesophageal reflux,4 by viral infections, and, possibly, by
mycoplasma and chlamydial infections.5 These factors may contribute in patients who have atopic asthma and should be addressed before consideration of IT. Compliance Expectations If a patient or family clearly have transportation difficulties or other problems which will interfere with their ability to keep appointments for allergy shots, that would preclude their administration. However, in many instances, patients who are not compliant with daily medications will regularly come for allergy injections. At times, a physician closer to their home or place of work has to be identified to administer the vaccine. Affordability Allergen IT can be costly and timeconsuming for the patient and family. In many states, special programs are available to assist patients up to age 21. Older indigent patients may find such care assistance at academic centers or public hospitals, or from a philanthropic allergist. Individual Patient Preferences Some patients prefer oral medications, and others appreciate inhalers. Some simply do not want to be taking “so many medicines” and prefer injections as a way to decrease sensitivity and the need for medications. Most patients who have had sudden severe symptoms appreciate having injectable epinephrine on hand, as well as oral corticosteroids, which can be taken under certain conditions. Severity of the Disease The patient with very mild asthma may be managed largely by short-term use of 2-agonists, but many of these patients will go on to have more persistent hyperreactive airways. If such patients have bronchospasm triggered by allergen exposure, then avoidance
9
measures should be instituted. If these are impossible or ineffective, the patients may benefit from IT. However, often it is only when patients are having persistent symptoms that IT is considered. The patient with severe persistent asthma may not tolerate IT.
TREATMENT MODALITIES Pharmacotherapy6–Quick-Relief Medications 2-agonists orally, by MDI, by nebulizer, by injection Anticholinergics: ipratropium by MDI or nebulizer Epinephrine by injection LT modifiers? Theophylline? Magnesium? Pharmacotherapy–Long-Term Controllers Cromolyn by MDI or nebulizer Nedocromil by MDI Corticosteroids by MDI, DPI, nebulizer, or oral LT modifiers orally Theophylline? Long-acting 2 agents, salmeterol Avoidance Measures Careful studies have shown efficacy of dust control measures in patients with dust mite as major allergens.7 Cockroach allergen is more difficult to reduce. Visible mold and mildew can be reduced but complete avoidance is not possible. Animal allergens, particularly cat, are small particles that remain airborne and may be partially removed by HEPA filters, although removal of the animal is the better measure. Pollen avoidance is usually impractical except for measures such as keeping windows closed or going on a long cruise. Exercise/Weight Reduction Some studies have demonstrated benefit from fitness training and/or breathing exercises. Obesity has been shown to be a risk factor for asthma. Patients should be counseled and encouraged to exercise and to lose weight if that is a problem.
10
Treatment of Related Problems Sinusitis is a potentiator if not precipitator of asthma. Allergic rhinitis is common and frequently precedes the onset of asthma. Allergic conjunctivitis and atopic dermatitis may be present. If patients are receiving medications that which may aggravate asthma symptoms, such as  blockers, then alternate drugs must be sought. Allergy Vaccines (IT) Indications8 Symptoms severe enough to warrant intervention (or potential severity). Evidence of IgE-mediated allergy by skin testing or in vitro testing, with symptoms that correlate with the positive tests. Continued symptoms after practical avoidance measures. Contraindications Other serious immunopathologic disorders, malignancies, poor compliance, serious psychological disorders, treatment with -blocking agents, even topically. What are the Pathologic Mechanisms that will Guide our Treatment? The description of asthma in A Manual of Clinical Allergy, published in 1967,9 was as follows: “Symptoms related to spasm of bronchial walls with hypersecretion of tenacious mucus. Edema and eosinophilic infiltration of mucosa, hypertrophy of mucous glands, thickened bronchial smooth muscle, hyalinized bronchial basement membrane, increased goblet cells, patchy shedding of mucosa and loss of ciliated epithelium. . . . Treatment is predicated on careful identification of the factors which cause asthma. These are treated by avoidance when possible, by specific hyposensitization and by regular use of medication designed to prevent symptoms and mitigate those that do occur.” This description and recommendations have not changed drastically over the intervening decades. The National Institutes of Health National Heart,
Lung, and Blood Institute6 convened a panel of experts who updated Guidelines for the Diagnosis and Management of Asthma in 1997. These guidelines stress the importance of an evaluation of airway obstruction by lung function tests and avoidance of precipitating factors, which implies that allergy testing will be done. The goals of pharmacotherapy are reversal and prevention of inflammation plus treatment of exacerbations. There is emphasis on patient education, including the basic facts, the role of medications, the importance of self-management and environmental changes. The goals of pharmacotherapy in the 1997 guidelines are control of chronic and nocturnal symptoms, maintenance of normal activity levels including exercise, maintenance of near-normal pulmonary function, prevention of acute episodes, and avoidance of side effects of medications. The administration of medications in a stepwise fashion is promoted.10 The medications are divided into quick-relief and long-term control groups. The quick-relief control group includes short-acting  2 agonists and anticholinergics. Little mention is made of the rapid onset of bronchodilation by theophylline or magnesium. The long-term control medications include anti-inflammatory agents such as cromolyn, nedocromil, and inhaled corticosteroids. These also include the longacting bronchodilator salmeterol and the LT modifiers. Theophylline is included as well. Other less used therapies, such as inhaled xylocaine and use of antioxidants or mucolytics, are not included. Why is it so Difficult to Control These Symptoms? In the 1950s, Herxheimer11 noted three patterns of response after attempts to hyposensitize allergic asthmatic patients by inhalation of antigens: early bronchoconstriction within 1 to 15 minutes; dual, in which the early airway response was followed by more prolonged late airway response 4 hours later; and late airway response. This
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
late airway response occurs in 30% to 50% of patients and tends to be reproducible in the same patients over time. What are determinants of the latephase airway response?12,13 The latephase response does not invariably occur in those with more severe baseline disease. However, some have noted a more severe drop in forced expiratory volume in 1 second (FEV1) initially in patients who will have a late-phase response (LPR). Those with LPR require a smaller dose of antigen to produce an early reaction. Patients who have seasonal allergies have variation in the severity of LPR after the allergy season. Prolonged airways dysfunction occurs after late-phase response.14 These airflow abnormalities persist for several days, compared with early responders. There is an increase in nonspecific airways reactivity for at least 1 week after an allergen challenge, demonstrated with histamine and methacholine reactivity.15 There is also an increase in nonspecific reactivity after the pollen season. Priming Effect on the Airway A group of 12 asthmatic children with positive prick tests to Dermatophagoides pteronyssinus and cockroach underwent randomized placebo-controlled crossover study. They were challenged with one allergen followed by challenge with the other allergen 48 hours later. The mean 20% fall in FEV1 from control (PD20) was 12-fold less. A 6-fold less dose administered in the second challenge provoked a similar late-phase response. It was concluded that the preceding airway response led to a priming effect with an increase in early- and late-phase responses.16 There were changes in bronchoalveolar lavage fluid after IgE-mediated reactions following allergen challenge; within minutes there was a decrease in the CD4/CD8 ratio and an increase in -glucuronidase. Within 2 hours there was an increase in eosinophils, neutrophils, macrophages, and activated CD4 T cells and basophils. Mast cells were decreased. Within 1 hour, the tryptase,
VOLUME 87, JULY, 2001
histamine, LTC4, prostaglandin D2, and thromboxane increased. Within 2 hours, there was an increase in histamine, LTC4, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-␣, interleukin (IL)-1, IL-4, IL-5, IL-6, and IL-8.12 These are the attenuations of the pulmonary early airway response (EAR) and late airway response (LAR) in humans by medications; short-acting 2-agonists only had effect on EAR, whereas corticosteroids only had effect on LAR. Long-acting 2-agonists, cromolyn, nedocromil, cyclooxygenase inhibitors, 5-lipoxygenase inhibitors, LT D4 blockade, theophylline, furosemide, colchicine had effect on both EAR and LAR. The effect of H1 antihistamine is variable but recent data suggest an effect.17 Effects of Allergen IT on EAR and LAR18 Eight patients with allergic asthma who were sensitive to Dermatophagoides farinae were treated with rush IT for ⬎2 weeks, 8 with placebo. Six months later, the treated patients had decreased eosinophils, eosinophil cationic protein, and T cell production of IL-5. There was also a decreased earlyand late-phase bronchoconstriction and airway responsiveness to mite. Who will Benefit from “Hyposensitization”? A study by Mosbech19 involved 31 asthmatic patients who were treated with extract of Der p for 2 years and compared with 15 controls. Patients improving in bronchial Der p-sensitivity after 1 year had been more sensitive to Der p pretreatment in bronchial and basophil release studies, and had a lower FEV1 compared with the patients not improving (P ⫽ ⬍0.05). Occurrence of late-phase bronchospasm to pretreatment Der p-challenge increased the chance of clinical improvement approximately 3-fold (P ⫽ ⬍ 0.05). Also, the patients with higher mite exposure on their mattresses were more likely to show improvement.
According to 1997 NAEPP guidelines,6 “Atopy, the genetic predisposition for the development of an IgE-mediated response to common aeroallergens, is the strongest identifiable predisposing factor for developing asthma.” However, indications for IT in allergic asthma are difficult to find in the document. According to 1991 NAEPP guidelines,6 IT for asthma is indicated “when avoidance is not possible and appropriate medication fails to control symptoms of allergic asthma.” Subsequent groups suggested consideration of the severity of asthma, efficacy of available IT, cost, risk, and duration of medication needs versus IT. Bousquet and Michel20 have suggested that factors to consider include the greater efficacy in children and young adults, greater likelihood of success with a single sensitivity, and the risk in asthmatic patients unless they are asymptomatic with FEV1 at least 70% predicted. According to practice parameters published in 1995,21 IT can be effective and may reduce the effect of chronic allergen stimulation of hyperresponsive airways. Patient compliance is essential. Immediate and delayed local and systemic reactions may occur and patients must be fully informed. Fatalities may occur, so proper instruction and preparation of staff is necessary.
CONCLUSION The decision to prescribe IT seems to be based on the documentation of an IgE-mediated response to an unavoidable allergen. At the present time, the patient must have significant disease, although patients with milder symptoms may have indications to help with prevention of onset or persistence of asthma if further studies confirm the preventive efficacy of shots.22,23 The availability of facilities and physician supervision is essential. Adequate extracts for the allergen must be available. When all those factors are ful-
11
filled, the choice then becomes a matter of the physician’s and patient’s preference. The best therapy ablates both the early- and late-phase airway responses and decreases airways reactivity. REFERENCES 1. Bock SA, Lee WY, Remigio LK, May CD. Studies of hypersensitivity reactions to foods in infants and children. J Allergy Clin Immunol 1978;62: 327–334. 2. Chipps BE, Chipps DR. Approach to the difficult pediatric asthmatic. Curr Opin Pulm Med 1999;5:52–57. 3. Zeiger RS. Development and prevention of allergic disease in childhood. In: Middleton E, Reed CE, Ellis E, et al, eds. Allergy: Principles and Practice. 3rd ed. St. Louis, MO: CV Mosby, 1993:1137–1171. 4. Patterson PE, Harding SM. Gastroesophageal reflux disorders and asthma. Curr Opin Pulm Med 1999;5: 63– 67. 5. Hahn DL. Chlamydia pneumoniae, asthma, and COPD: what is the evidence? Ann Allergy Asthma Immunol 1999;83:271–288, 291–292. 6. Guidelines for the Diagnosis and Management of Asthma. Highlights of Expert Panel Report 2. National Asthma Education and Prevention Program, National Institutes of Health, 1997. NIH Publication No 97-4051A. 7. Murray AB, Ferguson AC. Dust-free bedrooms in the treatment of asthmatic children with house dust or house dust mite allergy: a controlled trial. Pediatrics 1983;71:418 – 422.
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Requests for reprints should be addressed to: Betty B. Wray, MD Allergy-Immunology Section Medical College of Georgia Augusta, GA 30912-3790 E-mail: [email protected]
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