OVERVIEW OF EXPERT CARE FOR ASTHMA

ANNOTATED BIBLIOGRAPHY

• Epidemiology and economics of asthma
• Expert care for asthma
• Allergen control for asthma
• Immunotherapy for asthma
• Practice parameters and quality of care for asthma

OVERVIEW OF EXPERT CARE FOR ASTHMA

The medical literature on asthma offers important information about expert care and immunotherapy. The following conclusions are based on a review of that literature.

Expert care for moderate and severe asthma:

• Can reduce hospitalizations for asthma by an average of 77% and can reduce emergency room visits for asthma by an average of 53%.
• Can, therefore, save as much as $1.3 billion in annual direct costs for hospital and emergency care costs.

Allergen identification, allergen avoidance, and allergen immunotherapy by experts in properly selected asthma patients:

• Reduces symptoms of asthma and improves pulmonary function
• Achieves less dependence on health care resources, including medications, which leads to progressive cost savings

PURPOSE OF THIS REVIEW

This review was performed to provide physicians, managed care organizations, and patients with direct access to the diverse research literature bearing on the value of specialist (expert) care for asthma [1-57]. This report consists of a brief summary of the current status of knowledge, accompanied by an annotated bibliography which documents and expands on the narrative summary.

The studies selected address three important questions.

1. Given the constraints on time and other considerations, can primary care physicians be expected to effectively manage most moderate and severe asthmatics?
2. Can specialists provide care that leads to less urgent care and less morbidity, and, if so, at what expense?
3. What role should allergy assessment and care play in overall expert care for asthma?

EPIDEMIOLOGY, MORBIDITY, AND COSTS [1-3]

Approximately 6% of children and 5% of adults in this country have had active asthma within the last year. [1,2] Current patterns of care for asthma, overall, are associated with substantial residual morbidity and mortality as reflected in mortality (~5,000 deaths per year: 1 death per 2,400 asthmatics/yr), hospitalization (~500,000 per yr: 4 admissions per 100 asthmatics/yr), emergency care (~1,500,000 per year: 12 ER visits per 100 asthmatics/yr), absences, and limitation of function. [1,2]

Asthma is a common illness that causes considerable morbidity and even death [1,2] despite powerful, scientifically validated methods to control asthma.[4-48] While the mortality rate for asthma in the United States is lower than any other country in the world, by a sizable margin, many of the deaths should be avoidable if current knowledge is applied to the care of the population at risk for death. Similarly, much of the gross morbidity caused by asthma should be avoidable if the widely documented undertreatment of the moderate and severe asthmatics by general physicians [12,57] is eliminated.[4-48,56,57]

In the comprehensive analysis of asthma for the year 1990 reported by Dr. Weiss and coworkers [1], the economic costs of our current "rescue" focused approach to asthma are documented. Of the $3.64 billion spent in 1990 on direct costs for asthma, $1.56 billion (43%) was spent on hospital care for patients with severe asthma. Another $295 million (8%) was spent on emergency room visits for poorly controlled asthma. Overall, $1.86 billion (51%) of the dollars spent on asthma were spent on emergency and hospital care to rescue patients with poorly controlled asthma.

IMPACT OF EXPERT CARE COMPARED TO GENERALIST CARE [4-13]

Can specialists provide care for asthma that achieves fewer hospitalizations, fewer emergency room visits, less chronic morbidity, and improved quality of life? Currently outpatient chronic care for asthma is provided primarily by general physicians (65%), Allergy and Immunology specialists (26%), and Pulmonary Medicine specialists (5%) [1]. While expert care usually is focused on the patients with more severe asthma, medical care for moderate and severe asthma often is provided by primary care physicians [1,55].

Expert care clearly can provide more effective care for asthma. While the situations and outcomes varied to some degree, these studies indicate that the morbidity and resource utilization attributable to asthma can be strikingly reduced if moderate and severe asthmatics receive expert care [4-11,13, 55].

On the basis of these published studies, if all of the moderate and severe asthma patients at risk of needing ER care or hospitalization for asthma were referred to expert care, a marked reduction in severity of disease would be expected. This might be accompanied by an increase in medication costs of 6-24% [9,11], but expert care would be expected to save approximately $1.3 billion in direct costs for hospitalization and ER visits (the reduction expected if patients at risk were referred for expert care).

Clearly, expert care for moderate and severe asthma can achieve improved clinical outcomes, while at the same time markedly reducing overall resource utilization and net costs [4-10,13, 55].

Asthma is an illness with many variations in cause and severity, and patients with this illness are equally varied [2]. The validated strategies available for management are diverse [51]. Precise analysis of the impact and value of each aspect of care is made difficult by the realization that the interaction of the physician with the patient is a very important, but hard to quantify, aspect of effective care. Expert care for asthma involves achieving sustained control of the severe disease using carefully selected human, pharmaceutical, and immunologic skills [51].

IMPACT OF ALLERGY ASSESSMENT AND CARE [14-48]

Assessment of the role of allergy in all but the mildest forms of asthma is generally regarded as essential to proper care [14-48,51]. Knowledge of the specific causes of a patient's asthma leads to relevant, effective environmental control measures [14,15] , and clarifies the relevance and feasibility of immunotherapy for the individual patient [16-38,48,51]. Knowledge of the role of allergy and non-specific triggers of asthma also permits rational planning of premedication or altered therapeutic regimens to prevent predictable exacerbations [51]. Antigen immunotherapy has been shown to be effective for allergic rhinitis and asthma in properly selected patients and can be a powerful adjunct to the chronic management of asthma [16-48].

RECENT CONTROVERSY AND REVIEW OF THE ROLE OF IMMUNOTHERAPY FOR ASTHMA

There are ample scientific data to document that immunotherapy is an effective therapy for properly selected patients. Beyond this unambiguous proof of principle is the current issue of how immunotherapy should be used in the array of approaches to asthma.

Immunotherapy is used as a strategy for consolidation of control of the disease. Antigen avoidance and medications are used to gain immediate control of the disease. Antigen avoidance has progressive impact over time. Immunotherapy is used in appropriate patients to reduce the degree of allergy and thereby reduce the severity of the disease. Immunotherapy reduces or eliminates the need for relentless use of expensive medications, while maintaining or improving the control of the disease [16-48].

Recent discussions have focused on whether or not this kind of consolidation therapy is needed, and if so, for whom [40-48].

In one recent study, Creticos and coworkers [39] found a significant but modest impact of immunotherapy with ragweed extracts on asthma exacerbations associated with ragweed pollen exposure. No attempt was made to treat other antigens contributing to the patients' asthma. Since ragweed therapy was the issue under study, dramatic overall impact was not expected. The study provided support for the concepts that seasonal ragweed exposure does cause exacerbations of asthma in some people and that ragweed immunotherapy can diminish this flare.

An editorial accompanying the Creticos paper, which questioned the need for immunotherapy, initiated a spirited set of responses [16,41-48]. These papers have emphasized the importance of being aware of the relevant literature - important for patients to make informed decisions, for physicians to make informed decisions, and for rational health care policy formulation. Indeed, the intent of this review is to provide access to this important body of data and opinion.

Overall perspective was provided by a meta-analysis of 20 double blind, placebo controlled, randomized, prospective cohort studies of the impact of immunotherapy on asthma reported recently by Abramson and coworkers [16]. They concluded that:

Immunotherapy:

• Consistently improves asthma symptoms
• Reduces airway reactivity
• Improves FEV1
• While at the same time reducing the need for medications

Control patients continued to require relatively stable amounts of medication to maintain control of their asthma. The data are so consistent and significant, Abramson calculated that 33 negative studies would have to be reported to offset the data from studies performed up until 1990 [16]. Additional positive data have been reported [24,39] since 1990, making the conclusions even more certain.

COST-EFFECTIVENESS OF IMMUNOTHERAPY FOR ASTHMA

Antigen immunotherapy for asthma in properly selected patients consistently results in reduced symptoms of asthma, and improved pulmonary function, while at the same time reducing the need for medications for asthma [16-48]. When current protocols are used for immunotherapy with modern reagents, particularly when relevant antigen avoidance measures are instituted, the results can be striking (for examples see references 24 and 35). Immunotherapy also is quite beneficial for allergic rhinitis, a condition present in over half of asthmatic patients [2].

Immunotherapy is appropriate for patients in whom an important role for allergic triggers has been demonstrated [23]. The basic decision is whether to rely upon avoidance of trigger factors and suppression of disease with medications through the many year course of asthma, or to use these measures plus immunotherapy, which gradually reduces the severity of the disease.

Decreased need for expensive medications results in progressive monetary savings, since asthma can be expected to persist for many years or even to be a life-long condition. When the patient has both allergic rhinitis and asthma, as is the case in over half of asthmatics [2], both diseases can be expected to respond to the same immunotherapy [21,22,24-32,35], resulting in clinical improvement and reduction in need for medications for both diseases.

The exact financial impact of the diseases and alternative forms of therapy require formal study to reach precise estimates of overall savings from immunotherapy- induced reduction in disease severity and in need for medication. Asthma and allergic rhinitis have quite different intensities and causes in individual patients, making the construction of a representative "reference case" [49,50,58] difficult. Despite the obvious potential problems, prospective cost-effectiveness analysis studies, using modern methods including the construction and analysis of "reference cases" [49,50,58] would be very helpful in refining our insight into the financial impact of immunotherapy.

One important issue in considering cost-effectiveness analyses is when the intervention is introduced in the course of the disease [58]. Both patient benefit and financial impact would be optimized if interventions such as expert care and immunotherapy are introduced early in the course of the disease. Assessing the impact of expert care and immunotherapy in financial terms requires a decision on whether to calculate according to the average time in the course of the disease the interventions occur under current practices and policies, or the optimal time (early in the course of the disease).

In this regard, the optimal time for introduction of immunotherapy is far from a settled scientific question. Most studies have not considered the duration of the disease as a factor in patient selection, or in analyzing outcomes. Johnstone and Dutton [29 ] reported in 1968 that immunotherapy for allergic rhinitis in children significantly reduced the chances of development of asthma. Recent data suggest that this may be true [48,59]. The issue of optimal timing of use of immunotherapy deserves careful investigation. Immunotherapy may both prevent and improve asthma.

If a patient has daily symptoms of allergic rhinitis and of asthma, and is being treated with topical intranasal steroids, non-sedating antihistamines as needed, topical intra-pulmonary steroids, and bronchodilators as needed, the costs for medications can exceed $1,000 per year. These costs will continue indefinitely unless changes are made that can reduce the severity of the disease (allergen avoidance and allergen immunotherapy). Immunotherapy can be expected to reduce the need for medications for allergic rhinitis or asthma, or both, by more than 50% [21,22,24-32,35]. Current total direct costs for immunotherapy at Emory University in 1996 average approximately $800 for the first year and $170 for the next 2 to 4 years. After 3 to 5 years, immunotherapy usually is halted. Clearly, the costs of immunotherapy are soon balanced by large reductions in costs for medication. As the years pass the savings continue to accrue and can amount to many thousands of dollars per patient. The exact cost relationships will depend on the individual patient's medication needs and the costs of medications to the person or organization paying for them. In general, the patient will have durable clinical improvement while requiring less medication - a clinical and economic success.

Mortality, hospitalization for asthma, emergency care for asthma, awakening at night because of asthma, limitation of exercise or social activities because of asthma, absences from school or work, and altered quality of life are now considered indices of morbidity largely avoidable with the full array of current expert management procedures [4-48].

PRACTICE PARAMETERS, MANAGED CARE POLICIES, QUALITY OF CARE STANDARDS & POLICIES [51-57]

Practice parameters for expert care for asthma have been formulated and published [51], offering objective expectations for expert consultation and care. Clinical outcome studies have validated the approaches that constitute these practice parameters [4-48]. Recent research in the managed care setting has provided additional evidence that expert care is effective in controlling moderate and severe asthma, but this improvement associated with expert care could not be linked to specific process parameters [55].

There is a consensus that any use of structure or process parameters to rate physicians or managed care organizations must be validated in clinical outcome studies [52-55]. In the evolving efforts to rate quality of care by physicians and managed care organizations, structure and process and clinical outcome measures have been proposed [52-55 ]. Assessments of the quality of care for asthma by general physicians have indicated that in general compliance with guidelines for asthma management is poor [12,57 ]. Process assessments using guidelines may be effective in improving care by generalists [12,57 ].

Expert care encompasses special knowledge and ability to assess, teach, and manage patients with asthma [51]. Advanced knowledge of the use of medications for asthma is essential. Assessment and management of the allergic component of asthma also are essential parts of such expert care [17-48,51]. Practice parameters for the diagnosis and management of asthma by experts have been accepted by the major Allergy and Immunology professional associations and are now the standard of care for this discipline [51]. The studies and reviews presented in the annotated bibliography below provide an unambiguous demonstration of the value of these approaches.

Structure and process assessments are easier to perform than outcome assessments, but, in the area of asthma care by experts, adherence to specific approaches in all patients has not been proven valid as a predictor of clinical outcomes. Effective approaches to the management of asthma are incorporated into the asthma practice parameters [51].

But, expert care for moderate and severe asthma involves integrated use of many components of approaches that must be individualized for specific patients. These clinically validated approaches [4-48] do not appear to lend themselves to simple analysis or process rating [55 ] for the very reason expert care succeeds for the more severe asthmatics. The value of expert care, at least in part, is the ability to select and implement the interventions appropriate for a specific patient. Outcome data appear to be essential for assessment of asthma care by experts. The formulation of policy relating to expert care for asthma should be based on the large body of clinical outcome data already available [4-48,51,55].

SUMMARY

• Assessment and management of asthma by experts appears to be very effective and is particularly cost-effective for moderate and severe asthmatics [4-13].
• The management of asthma recommended in current guidelines and practice parameters emphasizes outcome-based decision making [17-23,48,51]. Existing data indicate that generalists as a group do not have the time, knowledge, or in some cases the equipment necessary to assess, teach, and monitor most moderate and severe asthmatics.
• Assessment and management of the allergic component of asthma also are essential parts of expert care [17-48,51]. Allergen avoidance and immunotherapy are clinically effective and are cost-effective.
• The data suggest that assessment of the quality of care by experts should be based on clinical outcomes and the practice parameters, not rigid aderence to specific approaches to every patient. Consistent adherence to specific approaches for all patients in a category of asthma may improve general physician care of mild asthma. But, carefully individualized approaches define the expert contribution to care and account for the improved outcomes.
• The current challenge for patients, physicians, and managed care organizations is to develop guidelines or policies that assure that the moderate and severe asthmatics receive expert care before asthma causes altered quality of life, a need for emergency care, or hospitalization.

ANNOTATED BIBLIOGRAPHY

The Impact of Expert Care on Asthma

EPIDEMIOLOGY AND ECONOMICS OF ASTHMA

1. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med 1992; 326:862-866. The first thorough economic evaluation of asthma in the United States. Numerous important quantitative observations.

Estimates of costs in 1990 based on most recent available data:

Physicians providing services :

2. Evans R. Epidemiology and natural history of asthma, allergic rhinitis, and atopic dermatitis. In: Allergy Principles and Practice. Fourth edition. Eds: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW. Mosby, St. Louis, 1993, pp 1109-1136. Review of relationships, prevalence, natural histories of these atopic diseases. Allergic rhinitis is present in over half of patients with asthma.

3. Mellis CM, Peat JK, Bauman AE, Woolcock AJ. The cost of asthma in New South Wales. Med J Aust 1991; 155:522-528. Estimated that total costs/ asthmatic person/ year were $769 AUS, or $15 AUS per week, of which 89% were direct costs. In the US the average total cost per asthmatic per year is approximately $564, $11/week, of which 41% or $4.42/week are direct costs.

EXPERT CARE FOR ASTHMA

4. Hughes DM, McLeod M, Garner B, Goldbloom RB. Controlled trial of a home and ambulatory program for asthmatic children. Pediatrics 1991;87:54-61. Randomized, controlled study of 95 Canadian children with asthma who had required hospitalization for asthma. Expert care was compared to routine generalist care.

• Subsequent hospital days for asthma reduced 67%,
• ER visits were reduced 26%,
• Absences from school were reduced 33%.

5. Mayo PH, Richman J, Harris HW. Results of a program to reduce admissions for adult asthma. Annals Intern Med 1990; 112:864-802. Random allocation of 47 adults with severe asthma, who had frequent admissions for asthma at Bellevue Hospital in New York, to expert care or routine care.

• Hospital admissions for asthma decreased 63%,
• Admissions per patient decreased 67%,
• Re-hospitalization days decreased 62%,
• Re-hospitalization days per patient decreased 54% in patients with expert care when prospectively compared to routine care.
• Total direct costs reduced 62%.

6. Ross RN, Morris M, Berman BA. Cost effectiveness of including cromolyn sodium in the treatment programme for asthma: a retrospective, record based study. Clin Therap 1988; 10:188-203. Retrospective study of impact of routine inhaled anti-inflammatory drug therapy on asthma costs in severe asthmatics receiving expert care.

• Hospital costs reduced 91%
• Emergency room costs reduced 96%

7. Zeiger RS, Heller S, Mellon MH, Wald J, Falkhoff R, Schatz M. Facilitated referral to asthma specialist reduces relapses in asthma emergency room visits. J Allergy Clin Immunol 1991; 87:1160-1168. Alternate allocation of patients seen for asthma in the San Diego Kaiser Health Plan ER to allergist care or generalist care. A total of 309 adult and pediatric asthma patients were studied. Patients then managed by allergists had:

• 75% fewer episodes of nocturnal awakening because of asthma,
• 50% fewer ER visits,
• 50% fewer acute relapses,
• 39% fewer absences from school or work,
• 58% fewer hospitalizations (difference not statistically significant, thought to be the result of small numbers of admissions).
• Facilitated referral considered effective.

8. Mahr TA, Evans R. Allergist influence on asthma care. Ann Allergy 1993; 71:115-120. Analysis of the outcomes of 209 children at Children's Memorial Hospital in Chicago who had an Allergy and Immunology assessment as part of care of asthma. Patients followed by allergists were compared to patients who returned to generalist care after assessment and recommendations were made. Patients subsequently followed by allergists had:

• 63% fewer admissions for asthma, and
• 62% fewer ER visits

than the patients followed by generalists. This study suggests that chronic expert care is much more effective than assessment and recommendations by an expert to be executed by a generalist.

9. Doan T, Grammer LC, Yarnold P, Greenberger P, Patterson R. An intervention program to reduce the hospitalization cost of asthmatic patients requiring intubation. Ann Allergy Asthma Immunol 1996; 76:513-518. Prospective assessment of the impact of expert care on 9 severe asthmatics, comparing the year before intervention to the year following intervention.

• Mean total costs of care reduced from $43,066 to $4,914 (89% decrease)
• Mean hospital costs reduced from $40,253 to $1,926 (95% decrease)
• Emergency room costs ($783 v $626),
• outpatient costs ($939 v $1203), and
• medication costs ($1091v $1159) were not significantly changed.

10. Coifman RE. Dynamic approach to asthma. J. Asthma 1983;20:45-52. The impact of expert care on the need for emergency room or hospital care for asthma was assessed in 32 consecutive patients with asthma that had required 2 or more ERV or hospitalizations in the 12 months preceding referral for expert care. Follow-up was for a total of 27 patient years. Hospitalization rate was reduced from 1.82/patient year to 0.04/patient and the emergency room visit rate was reduced from 5.29/patient year to 0.04/patient year. In this study year a 99% reduction in hospitalizations and ERV was achieved. After stabilization the patients required 2.9 physician encounters/patient year.

11. Weinstein AG, McKee L, Stapleford J. An economic evaluation of short-term inpatient rehabilitation for children with severe asthma. J Allergy Clin Immunol 1996;98:264-273. 59 children with severe asthma were enrolled in a comprehensive asthma assessment and treatment program. Costs for the year before and for 4 years after intervention were calculated. Expert assessment, refinements in medication use, teaching, counseling of parents, and any needed phychiatric interventions were made during an initial inpatient period. The interventions were essentially what are now regarded as routine expert interventions [51] compressed into an inpatient rehabilitation program. Costs for hospitalizations decreased an average of 92% and emergency room costs decreased an average of 85%.

12. Dales RE, Kerr PE, Schweitzer I, Reesor K, Gougeon L, Dickinson G. Asthma management preceding an emergency department visit. Arch Intern Med 1992;152:2041-2044. Pre-existing care was poor by current standards in a significant proportion of adults requiring emergency care.

13. Storms B, Olden L, Nathan R, Bodman S. Effect of allergy specialist care on the quality of life in patients with asthma. Ann Allergy Asthma Immunol 1995;75:491-494. Prospective study of impact of care using standardized asthma QOL questionnaire. Total QOL scores improved significantly as did scores for breathlessness, mood scores, and concern for health. The first study of the impact of specialty care for asthma on quality of life.

ALLERGEN CONTROL FOR ASTHMA

14. Duff AL, Platts-Mills TA. Allergens and asthma. Pediatric Clin North America 1992;1277-91. A review of the data linking indoor antigens and clinical asthma. The relevance of levels of these antigens to the incidence and severity of asthma and the evidence that antigen control can be effective in the treatment of asthma are reviewed.

15. Ehnert B, Lau-Schadendorf S, Weber A, Buettner P, Schou C, Wahn U. Reducing domestic exposure to dust mite allergen reduces bronchial hyperreactivity in sensitive children with asthma. J Allergy Clin Immunol 1992;90:135-138. A recent example of quantitative measures of both the degree of success of alternative antigen control measures and their impact on clinical asthma. Encasing of pillows, mattress, and box springs can reduce mite antigen levels 98% and in turn can significantly reduce bronchial hyperreactivity in mite sensitive subjects.

IMMUNOTHERAPY FOR ASTHMA

16. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med 1995;151:969-974. This analysis of all 20 published prospective, randomized, placebo controlled trials of immunotherapy for asthma, published between 1960 and 1990, was conducted by the School of Public Health in Prahran, Australia. They concluded that the odds of symptomatic improvement were 3.2 (95%CI 2.2-4.9), reduction in medications 4.2 (2.2-7.9), reduction in bronchial hyperreactivity 6.8 (3.8-12). In addition there was a mean improvement in FEV1 of 0.71 l (0.43 - 1.00) which corresponded to an average 7.1% increase in FEV1. These were highly statistically significant, consistent findings. The conclusion is that immunotherapy is a consistently effective therapy for selected patients with asthma. 33 similar studies with negative results would have to be published to negate these published results.

17. Bousquet J, Michel F-B. Specific immunotherapy in asthma: Is it effective? J Allergy Clin Immunol 1994;94:1-11. Comprehensive review of the subject. Presents access to literature and position statements of European societies. Concludes that immunotherapy is an effective method of treatment to be used in selected patients as part of a comprehensive plan of management.

18. National Heart Lung and Blood Institute guidelines for the management of asthma. J Allergy Clin Immunol 1991;88:425-434. Guidelines for the diagnosis and management of asthma compiled and agreed to by representatives of Allergy and Immunology, Pulmonary, Family Practice, and Internal Medicine physician societies. Assessment of the role of allergy in moderate or severe asthma regarded as essential; relevant allergen avoidance regarded as very important aspect of care; allergen immunotherapy recommended in properly selected patients.

19. Hargreave FE, Dolovich J, Newhouse MT. The assessment and treatment of asthma. A conference report. J Allergy Clin Immunol 1990;90;85:1098-1111. Canadian conference report on the assessment and management of asthma. Advocated allergy assessment, relevant avoidance measures, and relevant allergen immunotherapy for moderate and severe asthma. Commissioned and supported by the Medical Research Council of Canada with support also contributed by Glaxo Canada.

20. International Consensus Report on diagnosis and management of asthma. Allergy 1992; 47 (Supplement): 1-61. European report on the assessment and management of asthma. Advocated allergy assessment, relevant avoidance measures, and relevant allergen immunotherapy for moderate and severe asthma.

21. Ohman JL Jr. Clinical and immunologic responses to immunotherapy. In: Allergen Immunotherapy. Eds: Lockey RF, Bukantz SC. Marcel Dekker, Inc., New York, 1991, pp 209-232. Summary of clinical and laboratory studies of allergen immunotherapy for asthma. Reviews unambiguous evidence of proof of principle that allergen immunotherapy can be beneficial in pediatric and adult patients treated with a wide range of antigens.

22. Van Metre TE, Adkinson NF Jr. Immunotherapy for aeroallergen disease. In: Allergy Principles and Practice. Fourth edition. Eds: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW. Mosby, St. Louis, 1993, pp 1489-1510. Summary of immunotherapy for asthma trials.

23. Bush RK, Huftel MA, Busse WW. Selection of patients. In: Allergen Immunotherapy. Eds: Lockey RF, Bukantz SC. Marcel Dekker, Inc., New York, 1991, pp 25-50. Addresses criteria for selection of patients for allergen immunotherapy. The prevailing opinion is that this therapy is to be undertaken in severe asthmatics or elderly patients only under restricted circumstances.

24. Alvarez-Cuesta E, Cuesta-Herranz J, Puyana-Ruiz J, Cuesta-Herranz C, Blanco-Quiros A. Monoclonal antibody-standardized cat extract immunotherapy: Risk:benefit effects from a double blind placebo study. J Allergy Clin Immunol 1994;93:556-66. Randomized, double-blind, placebo controlled trial of cat immunotherapy involving 28 cat sensitive adult asthmatics who had no cat in thehome, but had continued to have otherwise unexplained chronic asthma. Complete or nearly complete remission in 7 of 14 actively treated patients compared to 0 of 14 placebo treated patients. Aqueous extracts used for initial therapy. Maintenance doses were given adsorbed to aluminum hydroxide. This study bears on the problem of cat antigen known to be carried on clothing of cat owners contributing to ongoing disease in patients without a cat at home. Cat immunotherapy appears to be very effective when antigen levels in the home are reduced. This study illustrates the value of combining antigen control measures with specific immunotherapy. The study also illustrates that omission of important antigens could confound immunotherapy.

25. Bousquet J, Hejjaoui A, Skassa-Brociek W, Guerin B, Maasch HJ, Dhivert H, Michel FB. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. I Rush immunotherapy with allergoids and standard orchard grass-pollen extract. J Allergy Clin Immunol 1987; 80:591-598. Randomized, double-blind, placebo controlled trial of immunotherapy for grass pollen-induced allergic rhinitis in 45 patients. Medication use was reduced 68% in the conventional immunotherapy group, 42% in the rush immunotherapy group. Aqueous extracts were used.

26. Bousquet J, Hejjaoui A, Soussanna M, Michel FB. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular weight allergoid.. J Allergy Clin Immunol 1990; 85:490-497. Randomized, double-blind, placebo-controlled trial of immunotherapy for grass pollen-induced asthma and allergic rhinitis in 57 patients. Asthma symptoms were reduced 77% and the medication use reduced by an unspecified amount in the actively treated group. Medication use was reduced 47% and symptoms 47% for allergic rhinitis in the actively treated group. Rush immunotherapy with aqueous extracts treated with formaldehyde was used.

27. Cockcroft DW, Cuff MT, Tarlo SM, Dolovich J, Hargreave FE. Allergen injection therapy with glutaraldehyde-modified-ragweed pollen- tyrosine adsorbate. A double blind trial. J Allergy Clin Immunol 1977; 60:56-62. Randomized, double-blind, placebo-controlled trial of immunotherapy for ragweed-induced allergic rhinitis in 43 patients. Medication use was reduced 48%, intranasal steroid use 52%, in actively treated patients. Used an aqueous extract treated with glutaraldehyde adsorbed to tyrosine.

28. Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J. Double-blind, placebo controlled rush immunotherapy with a standardized Alternaria extract. J Allergy Clin Immunol 1990; 85:460-472. Randomized, double-blind, placebo-controlled trial of immunotherapy for Alternaria-induced asthma and allergic rhinitis in 24 patients. Combined symptom-medication scores for both asthma and allergic rhinitis reduced 76% in the actively treated group. Aqueous extract prepared by Stallergenes Laboratories.

29. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children: a 14 year study. Pediatrics 1968;42:793. Immunotherapy for allergic rhinitis appeared to protect against the development of asthma. A follow-up rigorous study is now underway in Europe [59].

30. Lowell FC, Franklin W. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N Engl J Med 1965:675-679. Randomized, double-blind, placebo controlled trial of immunotherapy for ragweed-induced allergic rhinitis in 24 allergic patients. Approximately 73% reduction in medication requirements as well as significant clinical improvement. Aqueous extracts were used.

31. Ortolani C, Pastorello E, Moss RB, et.al. Grass pollen immunotherapy: a single year double-blind, placebo-controlled study in patients with grass pollen-induced asthma and rhinitis. J Allergy Clin Immunol 1984; 73:283-290. Randomized, double-blind, placebo-controlled trial of immunotherapy for grass pollen-induced asthma and allergic rhinitis in 15 patients. Combined asthma and allergic rhinitis scores reduced 69% in actively treated patients. Aqueous extracts from Hollister Steir.

32. Parker WA, Whisman BA, Apaliski SJ, Reid MJ. The relationships between late cutaneous responses and specific antibody responses with the outcome of immunotherapy for seasonal allergic rhinitis. J Allergy Clin Immunol 1989;84:667-677. Randomized, double-blind, placebo-controlled trial of immunotherapy for mountain cedar induced allergic rhinitis in 51 patients. 56% decrease in symptom-medication scores in actively treated group. Aqueous extracts supplied by Hollister Steir.

33. Price JF, Warner JO, Hey, EN, Turner MW, Soothill JF. A controlled trial of hyposensitization with adsorbed tyrosine Dermatophagoides pteronyssinus antigen in childhood asthma: in vivo aspects. Clin Allergy 1984; 14:209-219. Randomized, double-blind, placebo-controlled trial of immunotherapy for mite-induced asthma in 51 children. Medication use decreased 93% at 1 year, 96% at 2 years in actively treated patients. Some actively treated patients went into complete remission. Aqueous extract treated with glutaraldehyde and adsorbed to tyrosine used for therapy (Migen, Bencard).

34. Rak S, Lowenhagen O, Venge P. The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. J Allergy Clin Immunol 1988; 82:470-480. Randomized trial of immunotherapy for birch pollen-induced asthma and allergic rhinitis. Asthma symptoms were reduced 45% with a 79% reduction in medication use in the actively treated group. Allergic rhinitis symptoms were reduced 16% and medication use 82% in the actively treated group. Aqueous extract from Pharmacia.

35. Reid MJ, Moss RB, Hsu Y-P, Kwasnicki JM, Commerford TM, Nelson BL. Seasonal asthma in northern California: Allergic causes and efficacy of immunotherapy. J Allergy Clin Immunol 1986; 78:590-600. Randomized, double-blind, placebo controlled trial of immunotherapy for grass pollen-induced asthma and allergic rhinitis in 18 patients. Symptom medication scores reduced 74% for asthma and 43% for allergic rhinitis in actively treated group. Aqueous extracts from Hollister Steir were used.

36. Sarpong SB, Hamilton RG, Eggleston PA, Adkinson NF. Socioeconomic status and race as risk factors for cockroach allergen exposure and sensitization in children with asthma. J Allergy Clin Immunol 1996;97:1391-1401. Socioeconomic status and African American race found to be independent risk factors for cockroach antigen exposure and sensitization among 87 mild to moderate asthmatics 5-17 years of age. Levels of exposure strongly related to rates of sensitization. Review case-control studies that indicate that sensitization and exposure are risk factors for much higher rates of acute asthma exacerbations. As with cat sensitization and exposure, cockroach allergy is a critical consideration when assessing and treating asthma with immunotherapy. Failure to detect exposure and sensitivity to mites, cat, and now cockroach; control relevant antigen exposures; and consider these antigens in immunotherapy may completely defeat immunotherapy, as well as unnecessarily prolong or worsen the asthma.

37. Sharkey P, Portnoy J. Rush immunotherapy. Ann Allergy Asthma Immunol 1996;76:175-180. Study of 22 patients 4-18 years of age (5 with allergic rhinitis and 17 with asthma, 7 steroid-dependent asthmatics). All premedicated with astemizole, ranitidine, and prednisone. One day rush immunotherapy permitted rapid benefit with acceptable levels of reactions.

38. Warner JO, Price JF, Soothill JF, Hey EN. Controlled trial of hyposensitization to Dermatophagoides pteronyssinus in children with asthma. Lancet 1978; 2:912-915. Randomized, double-blind, placebo controlled trial of immunotherapy for mite-induced asthma in 85 children. Medication use decreased in actively treated patients approximately 85% within 6 months and by approximately 93% by 12 months of therapy. Symptoms and other clinical dimensions also markedly improved in active group. Aqueous extract treated with glutaraldehyde and adsorbed to tyrosine used for therapy (Migen, Bencard).

39. Creticos PS, et. al. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;334:501-6.

• Approximately 1000 candidates screened to obtain 90 patients who had worsening of their asthma during ragweed pollen exposure, who had positive skin test responses to ragweed, and "less reactive to concomitant and possibly confounding allergens". The role of ragweed in these exacerbations was not known with certainty.
• In a sense, the trial asked the question of the relevance of ragweed to asthma in these patients. (As noted above in the study of Alvarez-Cuesta [24], immunotherapy was very effective in asthmatics with cat allergy and limited cat antigen exposure, proving the relevance of the cat allergy as well as the utility of immunotherapy in such patients.)
• 77 entered the study (indicating that ragweed rarely is a significant factor in asthma), 64 completed one year of treatment and 53 completed 2 years of treatment. Eight centers participated (Baltimore, Rochester MI, Madison WI, Iowa City IA, Cincinnati, Minneapolis, Ann Arbor, Fairfax VA, Greenbelt MD).
• Pollen counts recorded in Baltimore and Rochester MI only (antigen exposures not known for most centers).
• Asthma was mild in both placebo and treated groups, before and during the seasons. Asthma symptoms rated mild even during exacerbations.
• Year one was during buildup to maintenance, year two was during maintenance therapy. PEFR significantly better in treated group (480±12 vs 461±13, p = 0.03); asthma medication and symptom scores not different in year 2.
• Medication costs were reduced in the treated group ($420 vs $597), but this was balanced by the cost of immunotherapy.
• Overall, there was statistically significant impact on the exacerbations of mild asthma in the fall in ragweed allergic patients. (Contrast this to the more striking results of Reid [35] reviewed above who studied immunotherapy for pronounced exacerbations of asthma and rhinitis caused by high grass pollen exposures).
• Taken in the context of what is now known about immunotherapy for asthma (e.g., see Abramson [16]), this study addresses the ragweed factor, and is consistent with previous reports of positive results.

40. Barnes PJ. Is immunotherapy for asthma worthwhile? N Engl J Med 1996;334:531-2. In this editorial accompanying the Creticos paper [39], Dr. Barnes (a pulmonary physician who does not use immunotherapy) raised important issues regarding the appropriate use of immunotherapy to treat asthma. His points were:

• Several national and international guidelines for the treatment of asthma recommend immunotherapy for properly selected patients.
• Immunotherapy is not offered under the National Health Service in Great Britain.
• A recent meta-analysis of immunotherapy for asthma found definite evidence of efficacy.
• The Creticos study found a weak but significant effect of immunotherapy on asthma when only ragweed was used.
• Immunotherapy can induce local and systemic allergic reactions and, rarely, fatal reactions.
• In Dr. Barnes' view the role of immunotherapy for most patients with asthma is likely to be very limited.
• Medications alone are seen by Dr. Barnes as more effective and have different adverse effects. (Medication alone is not likely to be more effective than medications plus immunotherapy. In this instance Dr. Barnes contrasts using medications vs. using immunotherapy as the sole therapy, not the clinical practice of using medications or medication plus immunotherapy.)
• The cost of immunotherapy may outweigh the gain.
• The mechanisms by which immunotherapy works are "far from clear". (Unclear to Dr. Barnes - for reviews of the impact of immunotherapy on immune responses, inflammation, and clinical correlations see reference 21.)
• "..., indeed, when the treatment (immunotherapy) is discontinued, symptoms of asthma rapidly recur." (A remarkable description of therapy said to have little value)
• Drug therapy combined with antigen avoidance is recommended (by Dr. Barnes) as adequately effective, safe, and less costly than the same therapy plus immunotherapy.

The following papers were written in response to the Creticos study [39] and the Barnes editorial [40]

41. Weiner J, Abramson M, Puy R, Wilson J. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;335:203. (letter from the authors of the recent meta-analysis [16]). These authors raised several issues about the Creticos paper. The criteria for a fall exacerbation of asthma were not stated. There were more dropouts from the placebo group (16 of 40) vs. the active treatment group (8 of 37). This could have biased the results toward no effect. Bronchodilator and anti-inflammatory drug use were scored together. Nasal steroid use was included as part of the asthma score. Systemic steroid use also was a potential confounding variable. Separation of kinds of medications was suggested as an important factor. Finally, a less intense pollen season in the second year (not measured at most test sites) could account for the reduced difference between placebo and active treatment patients in the second year.

42. Portnoy J, Finegold I. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;335:203. (letter). The authors emphasize that immunotherapy in the Creticos study improved peak flow rates and decreased sensitivity to inhaled antigen, while allowing decreased medication use. Symptom scores were comparable, but the placebo patients were taking more medication to achieve this level of control. They point out that patients sensitive to ragweed alone are rare. It is remarkable that treating only one allergic factor was able to have a significant effect.

43. Platts-Mills TAE. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;335:203. (letter). The author points out that hospital admissions and mortality from asthma have steadily increased in Great Britain despite the widespread use of inhaled glucocorticoids as recommended by Dr. Barnes. He points out that the study cited by Dr. Barnes indicating greater efficacy and fewer adverse effects of glucocorticoids vs. immunotherapy was a study of allergic rhinitis, not asthma, and involved the use of an ineffective form of immunotherapy. Dr. Platts-Mills points out that immunotherapy in the United Kingdom was deemed unsafe when performed by general practitioners. Since there are few specialists in the management of allergic disease in the United Kingdom, a decision was made not to use the procedure. In the US this form of therapy is administered safely by experts. He emphasizes that many studies have demonstrated efficacy of immunotherapy in properly selected patients when using modern reagents and methods. The Creticos study confirms this finding in the context of ragweed, a minor factor in most asthma.

44. Klein JS. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;335:203. (letter). The author reiterates that ragweed is not a prominent contributor to most asthma, in part because little antigen is carried on particles small enough to penetrate the lungs efficiently. He suggests that perennial antigens commonly linked to asthma would be more logical subjects for immunotherapy trials.

45. Chmelik F, Doughty A. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;335:203. (letter). The authors criticize reliance on peak flow and symptom/medication diaries. Published studies are cited that show some level of inaccuracy of these self-reported measurements. This may have made differences more difficult to discern.

46. Creticos PS, Norman PJ, Reed C. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;335:203. (letter). The authors respond to these and the Barnes criticisms. They emphasize that despite possible biases, their study did demonstrate significant improvement in the medication plus immunotherapy group at roughly the same total cost as medication alone. Improved clinical status was achieved by immunotherapy without overall cost increase, since, as expected, medication needs decreased as clinical status improved.

47. Barnes PJ. Ragweed immunotherapy in adult asthma. N Engl J Med 1996;335:203. (letter). Dr. Barnes reiterated his belief that the benefits of immunotherapy are not strong enough to compel Britain to change its policy of not offering the procedure. (Among other problems, such a change in policy would require training specialists in Allergy and Immunology currently not present in adequate numbers in Britain [43]) He bases this resistance to change in part on unpublished data from one study. He does not address the scientific context of this issue, which overall shows significant efficacy in multiple double-blind, placebo-controlled, prospective, randomized studies (reviewed in the meta-analysis by Abramson [16]). Abramson et. al. [16] calculate that 33 similar studies would be needed to overturn the scientific data now in hand bearing on immunotherapy for asthma. One unpublished study, of any design, can not begin to discount the large body of reliable scientific evidence in the published literature.

48. McGrath CM. Immunotherapy in the treatment of asthma. Pediatr Asthma Allergy Immunol 1996;10:47-57. An extensive, current review of the published data bearing on evidence that allergens cause airway inflammation, bronchial hyperreactivity, clinical asthma, and decline in lung function. A summary and assessment of the evidence that immunotherapy decreases airway inflammation in allergic asthmatics, improves the clinical course, and may even prevent the development of asthma is presented.

49. Russell LB, Gold MR, Siegel JE, et. al. The role of cost-effectiveness analysis in health and medicine. JAMA 1996;276:1172-1177. The authors present the recommendations of a US Public Health Service ad hoc expert Panel on Cost-Effectiveness in Health and Medicine. The notion of using a standardized "reference case" is presented. This is the first of a three part series on the goals, methods, and reporting recommendations of the panel.

50. Smith JM. Effectively costing out options. JAMA 1996;276:1180. The author reviews the importance of cost analysis as one dimension of medical decision making and the need to have standardized methods of assessment and reporting.

PRACTICE PARAMETERS AND QUALITY OF CARE FOR ASTHMA

51. Spector SL, Nicklas RA, et. al. Practice Parameters for the Diagnosis and Treatment of Asthma. J Allergy Clin Immunol 1995;96:707-870. This is a 163 page detailed document prepared by the American Academy of Allergy, Asthma, and Immunology; the American College of Allergy, Asthma, and Immunology; and the Joint Council of Allergy, Asthma, and Immunology. The paper presents practice parameters for expert assessment and management of asthma. Patients, primary care physicians, managed care organizations, and groups interested in quality of care assessment now have access to what current expert assessment and management should be. These are the dimensions and expectations for expert care.

52. Blumenthal D. Quality of Health Care. Part I: Quality of Care - What is it? N Engl J Med 1996;335:891-893. An overview of quality of care from patient, physician, and health care organization points of view.

53. Brook RH, McGlynn PD. Part II: Measuring Quality of Care. N Engl J Med 1996;335:966-970. Discussion of evaluation based on structure, process, and outcome measures. Any credible process measure must have validated relationship to clinical outcomes.

54. Inglehart JK. The National Committee for Quality Assurance. N Engl J Med 1996;335:995-999. An overview of efforts to provide quality assessment of managed health care plans and organizations.

55. Outcomes Management System Consortium of the Managed Health Care Association. Specialist Care for Asthma. 1995 Report. Study of health status before and after specialist referral for asthma compared to generalist care. 15 managed care organizations studied. Controlled for severity of disease, age, sex, co-morbid conditions. Notable improvement on specialist care. One of the first studies assessing quality of care for asthma in a group of managed care organizations, and assessing the impact of specialist care for more severe asthma.

56. Sly M. Managed care - the key to quality of management of asthma. Ann Allergy Asthma Immunol 1996;76:161-163. A concise summary of the issues confronting physicians and managed care administrators working to optimize the care of asthmatics. Dr. Sly points out the opportunity, and also the obligation, to optimize care by assuring access to modern methods of care and developing methods to assure that effective care is being delivered.

57. Bousquet J, Knani J, Henry C, et.al. Undertreatment in a nonselected population of adult patients with asthma. J Allergy Clin Immunol 1996;98:514-521. Population samples from Paris and Montpellier, France, were randomly selected from the voter registration rolls. Over 3000 subjects were contacted in each city and 5% indicated that they had active asthma within the last year. The asthma severity and the nature of the treatment they were receiving, if any, were assessed by the investigators in person. None was thought to be overtreated. Among moderate asthmatics, 54-72% were not receiving anti-inflammatory therapy. Among severe asthmatics, 62-84% were not receiving anti-inflammatory therapy. The authors conclude that most asthmatics who, according to international guidelines, should be receiving anti-inflammatory therapy are undertreated. They cite similar data from other countries.

58. Weinstein MC, Siegel JE, Gold MR, et. al. Recommendation of the Panel on Cost-Effectiveness in Health and Medicine. JAMA 1996;276:1253-1258. In this report, the modern principles of constructing cost-effectiveness studies are reviewed and a consensus statement is presented on how such studies should be performed. Of particular relevance to the issues of expert care and immunotherapy are recommendations about what direct and indirect costs should be considered and the issue of timing of interventions. Should the impact of immunotherapy be counted from the average time in the course the disease the therapy is introduced in current practices or should the analysis be based on the impact if introduced very early in the course of the disease. Obviously, both financial and patient benefits would be improved the earlier in the course of the disease the therapy is introduced.

59. Jacobsen L. Preventive Allergy Treatment (PAT). In: Symposium on Specific Allergy '96. Clin. Exp. Allergy 1996;26:80-85. In a preliminary report of an ongoing multicenter, randomized, prospective European study of the ability of immunotherapy for allergic rhinitis to prevent the development of asthma. Among the 149 patients ages 7-13 studied to date, immunotherapy has significantly (P<0.05) reduced the incidence of asthma. Asthma has appeared only in the children who did not receive immunotherapy.

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Last modified October 4,1998