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Allergy testing and immunotherapy in an academic otolaryngology practice: A 20-year review
Allergy testing and immunotherapy in an academic otolaryngology practice: A 20-year review ANDREW P. LANE, MD, HAROLD S. PINE, MD, and HAROLD C. PILLSBURY, III, MD, Chapel Hill, North Carolina
OBJECTIVE: Allergic disease plays a central role in the clinical practice of otolaryngology. The purpose of this study was to review the 20-year experience of an allergy clinic integrated within an otolaryngology practice at a major academic institution. STUDY DESIGN: We performed a retrospective database review of over 3300 otolaryngology patients referred for allergy skin testing between 1979 and 1999. RESULTS: Approximately 80% of patients referred for allergy testing in our clinic had positive test results, of which 75.7% went on to undergo desensitization. The most common allergen was house dust, with allergies to mites, ragweed, and grass also prevalent. Among current allergy immunotherapy patients, 30.8% have undergone nasal septal, turbinate, and/or endoscopic sinus procedures in addition to allergy management. Nasal obstruction was the symptom most frequently persistent despite immunotherapy and the one most frequently reported to be improved by surgery. CONCLUSIONS: The otolaryngologist–head and neck surgeon is uniquely qualified to perform comprehensive medical and surgical management for patients with complex disease processes involving a component of allergy. We believe that an integrated approach to allergy within an otolaryngology practice optimizes the treatment of such patients. (Otolaryngol Head Neck Surg 2001;124:9-15.)
A
llergy, as it pertains to the head and neck, is a core component of the specialty of otolaryngology–head and neck surgery and a required area of education for all
From the Division of Otolaryngology–Head and Neck Surgery, The University of North Carolina School of Medicine. Presented at the Annual Meeting of the American Academy of Otolaryngic Allergy, New Orleans, LA, September 23-25, 1999. Reprint requests: Andrew P. Lane, MD, Division of Otolaryngology– Head and Neck Surgery, Department of Surgery, The University of North Carolina School of Medicine, 610 Burnett-Womack Building, CB# 7070, Chapel Hill, NC 27599-7070. Copyright © 2001 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2001/$35.00 + 0 23/1/111602 doi:10.1067/mhn.2001.111602
training programs receiving accreditation. It has been estimated that 50% of patient complaints encountered in an otolaryngology clinic have some component of allergic disease.1 Inhalant allergy is particularly prevalent, with between 14% and 22% of all Americans affected by allergic rhinitis and rhinosinusitis.2-4 A key element in the diagnosis and treatment of inhalant allergy is the use of skin testing. At this time, however, the majority of academic otolaryngology clinics do not directly provide this service. To date, no significant review of allergy testing and immunotherapy has been reported from an academic otolaryngology department. As specialists of the head and neck, otolaryngologists are uniquely qualified to give comprehensive care for a vast array of conditions in which allergy is an underlying or contributing element. The experience gained in the primary diagnosis and management of otolaryngic allergy is critical to the training of residents, as well as in defining the future role of otolaryngologists in the care of patients with head and neck manifestations of allergy. The well-trained otolaryngologist must be proficient in the available techniques of testing for allergy and must understand the treatment options. Since 1983, the American Academy of Otolaryngic Allergy has promoted a standardized protocol for the skin endpoint titration (SET) method of allergy testing.5 This technique both serves to identify allergic patients and to guide dosing for subsequent immunotherapy. It is simple to perform in the office setting and rapidly yields valuable clinical information. Although a positive SET test result for aeroallergens is an indication for immunotherapy, the goal is to control the allergic symptoms quickly and effectively whether by avoidance, pharmacotherapy, or immunotherapy. Additionally, as surgeons, otolaryngologists are in the position to treat anatomic or infectious problems that may be acting in concert with allergy to cause the patient’s specific complaints. Ultimately, the appropriate form of therapy must be individualized to a given patient and supported by personal or institutional experience with large numbers of patients. For more than 20 years, an integrated allergy clinic has existed within the otolaryngology clinic at the University of North Carolina (UNC) Hospitals. The clinic is staffed by an attending otolaryngologist and 2 allergy nurses. Referrals for allergy testing are made through resident and attending clinics and are generally 9
10
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Table 1. Patient symptoms at time of presentation: Effects of immunotherapy and surgical intervention
Symptom
Patients reporting symptom (n = 273)
Symptom improved with immunotherapy (n = 228)
Symptom not improved with immunotherapy (n = 212)
Symptom improved with surgery (n = 74)
Symptom not improved with surgery (n = 69)
78.8 68.9 66.7 60.8 60.8 41.4
30.3 32.0 38.6 33.3 31.1 5.3
27.4 9.4 20.8 24.5 10.8 11.3
74.3 27.0 20.2 5.4 0 4.1
18.8 24.6 15.4 21.7 7.2 14.5
Blockage (%) Recurrent infections (%) Headache-pressure (%) Rhinorrhea (%) Sneezing (%) Other (%)
Surgical intervention subjectively improved nasal blockage in 74.3% of allergy clinic patients who underwent surgery. This is compared with 30.3% of allergy clinic patients who reported improvement in nasal congestion after immunotherapy alone. Other symptoms of allergy, including recurrent sinus infections and headache or pressure, were reported to be improved by both surgery and immunotherapy, although more so with immunotherapy. Nonobstructive symptoms of allergy, such as rhinorrhea and sneezing, were seldom reported to be improved with surgery; however, one third of the allergy clinic patients believed these symptoms were improved by immunotherapy alone.
performed either the same day or scheduled in conjunction with the return visit with the referring physician. In the UNC experience over 3300 patients have been skin tested for allergy, and approximately 630 patients are currently undergoing immunotherapy. In 1 year, there are between 9000 and 10,000 allergy clinic visits and about 325 new allergy tests performed. In this article the results of allergy testing for the population of patients seen at UNC between 1979 and 1999 are reviewed, and the experiences of current immunotherapy patients are surveyed. METHODS AND MATERIAL Allergy records from 3329 patients tested between 1979 and 1999 in the otolaryngology clinic at the UNC Hospitals were reviewed retrospectively. For each patient, the age, sex, dates of testing, and results of SET were recorded into a database by using Microsoft Access software. Where available, other information concerning patient symptoms, duration of therapy, and in vitro testing were also entered. Patients undergoing allergy testing in our clinic were referred from within the general otolaryngology clinic, where they were being seen for otolaryngologic complaints. Indications for allergy testing vary somewhat from physician to physician but usually are based on a history and physical examination suggestive of allergy as a factor in the patient’s complaints. Before testing, a complete head and neck examination was performed by the referring otolaryngologist to identify nonallergic causes. Any patient tested in the allergy clinic stopped taking all medications that might affect the skin test results. For the patients currently undergoing immunotherapy, a questionnaire was used to obtain further information about symptoms, surgical history, and effectiveness of therapy. In addition, the UNC Hospitals electronic medical record was used to review surgical procedures and outpatient clinic notes in this patient group. The questionnaire specifically asked the patients to rate the effectiveness of immunotherapy on a 1 to
5 scale, with 5 being most effective. Also, patients were asked to list the symptoms that were most and least helped by immunotherapy and, when applicable, by surgery. The number of symptoms listed was variable, and some patients did not offer responses to these questions at all. The data from the questionnaires were compiled in Microsoft Access and transferred to Microsoft Excel for statistical analysis with unpaired t tests, Spearman correlations, and analysis of variance. Intradermal SET was performed in a standard fashion with a panel of aeroallergens diluted serially in 5-fold decreasing concentrations.5 Antigens were purchased from Hollister-Stier. All patients were tested for epidermals; mold mix; Trichophyton, Candida, and Epidermophyton (TOE) species; cotton; house dust mixture (without mite antigens); mite (Der f 1); ragweed; weed mix; grass mix; tree mix; and fescue. The mold mix (MMP) contained the following species: Aspergillus, Dematiaciae, Penicillin, Thycomycetes, Fusarim, Chaetomium, Botytiscinis, Monilia, Mycogone, and Paecilomyces. The house dust extract was supplied as a mixture that did not contain any mite antigens. A subset of patients with exposure to pets was also tested for cat and dog antigens. In general, the starting dose of antigen for desensitization was derived from the endpoint concentration. Mixes were used for desensitization, although this is not recommended under the current American Academy of Otolaryngic Allergy policy. Patients were treated twice weekly for 2.5 weeks, then weekly for 2 weeks, and then every 2 weeks after that with an escalating dose until the maintenance level was reached. This dose was altered if symptoms persisted or if systemic or large local reactions occurred. There are no specific criteria for the cessation of immunotherapy, although the decision is ideally reached jointly between the patient and otolaryngologist on the basis of a perceived control of symptoms or a failure of therapy. RESULTS
Allergy clinic records for 3329 patients undergoing SET testing between 1979 and 1999 were entered into
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Table 2. Percentage of positive SETs by allergens tested Endpoint dilution ≥4
Positive skin test responses
Allergen
Dust mix Mite Ragweed Grass mix Tree mix Fescue MMP Weed mix TOE Cotton Epidermals Cat *Positive
Patients with positive SETs* (% of all patients tested)
Positive SET at lowest dilution (2) only (% of all positive skin test responses)
81.0 61.6 55.3 55.0 54.7 52.6 52.3 52.0 50.8 36.6 45.3 20.9
36.9 51.5 56.3 52.2 59.1 53.4 62.4 61.0 53.0 77.7 49.3 56.5
Patients with positive SETs at dilution ≥4 (% of all patients tested)
30.5 14.2 17.5 18.4 11.8 19.6 7.6 11.5 10.3 2.4 8.5 6.4
SET is defined as a skin response at any dilution of allergen.
the database. Of this group, 637 patients were currently undergoing immunotherapy, 297 of whom were treated in the UNC clinic and another 340 who were desensitized elsewhere. The remainder of patients had either completed or never started immunotherapy. The average age was 45.2 ± 14.5 years. There were 2653 (79.7%) patients with positive skin test responses, as defined by 3 or more 2+ reactions or 1 or more 3+ reactions. Of these patients, 2008 (75.7%) went on to have desensitization performed (60.3% of the total patients referred for testing). The average duration of therapy was 24.65 months (SD, 25.84 months) for those who have completed therapy. For the group being treated currently, 28% have been treated for less than a year, 45% for less than 3 years, and 67% for less than 5 years. Fifty-eight percent of the patients tested were female. A slightly lower percentage of women had negative skin test responses than did men (20.8% vs 23.9%), and more women with positive test responses began immunotherapy than did men (73% vs 67.9%). Neither of these differences achieved statistical significance. The most common presenting symptom was nasal congestion (71.5%). The other most common symptoms are listed in Table 1. Of patients currently being desensitized, the greatest improvement reported was in headache or pressure, with fewer noting relief of rhinorrhea or congestion. The symptom most often cited as not improving with therapy was congestion, with rhinorrhea following closely. On a 1- to 5-point scale of overall effectiveness of immunotherapy, the average rating was 3.9. Among patients who reported no improvement in nasal congestion, the average rating was significantly lower at 3.57 (P = 0.015). This level of dissatisfaction associated with continued congestion was
greater than that observed with other symptoms, such as headache, sneezing, and rhinorrhea (Fig 1). The most prevalent allergen in the population tested was dust, with 81.2% having a skin endpoint of 2+ or greater and 30.6% having an endpoint of 4+ or greater. The next most common allergen causing a 2+ or greater endpoint was mite; however, fewer than 25% of these responses had an endpoint of 4+ or greater. Ragweed, grass mix, and tree mix were the next most common allergens, followed closely by MMP, fescue, weed mix, and TOE. Of these, fescue and grass mix had the greatest proportion of 4+ or greater endpoints. A summary of the allergens tested and the associated skin test results appears in Table 2. For most allergens, 75% to 85% of patients with 4+ endpoints went on to be treated with desensitization. Although cat allergy was not prevalent, greater than 94% of patients with a 4+ or greater endpoint were treated. Very few patients were allergic to weed mix, tree mix, or fescue without being allergic to multiple antigens. In contrast, among the patients with allergies isolated to one or two antigens, 73.5% were sensitive to dust, ragweed, or TOE. A subset of 275 patients who are currently undergoing therapy returned surveys and had medical information available for review on the electronic medical record. Of this group, 84 (30.5%) have a documented history of nasal or sinus surgery. Surgery was performed after starting desensitization in 57.8% of these patients and before desensitization in 35.6%, and 6% had surgery at approximately the same time that immunotherapy was started. The period of time elapsed between surgery and immunotherapy was variable. When surgery came first, the mean interval was 9.5 years, with an SD of 10.5 years. The mean interval
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A Fig 1. Effectiveness of immunotherapy as rated by patients with a 1- to 5-point visual analogue scale, where 5 is most effective. Recurrent sinus infection was defined as recurrent purulent nasal discharge, usually with pain, fever, or both, requiring antibiotic therapy by a physician. Error bars represent SEM. Comparisons between groups were made by using unpaired t tests. A, The subset of patients reporting improvement in any presenting symptom after immunotherapy tended to rate the effectiveness of their immunotherapy higher than the group as a whole (P = 0.06). Statistical significance was reached only in the group of patients reporting improvement in recurrent sinus infections (mean rating, 4.12 vs 3.57; P = 0.04).
when immunotherapy preceded surgery was 5.3 years, with an SD of 8.6 years. The types of procedures and their frequencies are depicted in Fig 2. The symptom most often reported to be improved with surgery was congestion (74.3%), and the most frequent persistent complaint after surgery was recurrent sinus infection (24.6%). The mean rating for the overall effectiveness of immunotherapy was not significantly different between the groups of patients who had and had not undergone surgery. DISCUSSION
In the UNC experience, the predominant complaints that bring patients with sinonasal disease to the otolaryngology clinic include congestion, rhinorrhea, sinus pressure or headache, irritation-sneezing, and recurrent infections. Allergic rhinosinusitis, which is prevalent in the US population, is frequently suggested by the history and physical examination. The presence of an integrated allergy clinic within the otolaryngology clinic allows for
prompt allergy testing, which greatly facilitates the diagnosis and ultimate management of the patient’s symptoms. It is important to recognize that allergy may be only one component in the overall disease process and that the complete care of the patient may involve modalities other than allergy therapy. In our experience over 30% of patients being treated with immunotherapy for allergy have also undergone nasal or sinus surgery at some point in their treatment. This finding suggests that sinonasal disease in allergic patients often requires both medical and surgical approaches and underlines the important role of the otolaryngologist in the management of rhinosinusitis with allergic manifestations. The symptom of nasal obstruction particularly illustrates the importance of a comprehensive approach to sinonasal disease. Nasal blockage is often reported to be the most common complaint of patients with allergic rhinitis.6,7 Among patients referred to the UNC allergy clinic, more than 78% had a chief complaint of nasal
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B Fig 1. Con’t. B, Patients with persistent complaints of nasal congestion despite immunotherapy gave a mean rating of their immunotherapy that was significantly lower than that of the group as a whole (3.57 vs 3.9, P = 0.015). No other persistent symptom had a significant effect on the mean ratings of immunotherapy.
obstruction. Interestingly, although congestion is frequently improved by immunotherapy, it was the symptom most often reported to be unimproved with immunotherapy in our survey. If immunotherapy was not effective for congestion, patients felt significantly less positive about the overall benefit of desensitization. No other symptom affected the allergy patient’s overall perception this strongly. When surgery has been performed, nasal obstruction is, by a wide margin, the symptom most often reported to be improved. Nasal obstruction certainly has the potential to be multifactorial and can be improved surgically when related to anatomic problems, such as septal deformity, turbinate hypertrophy, or polyp disease. About 85% of the surgical procedures that allergy patients had undergone involved septoplasty, turbinate reduction, or both. Additional procedures reported as sinus surgery may also have involved removal of polyps and therefore, in effect, also addressed congestion. Clearly, although immunotherapy reduces allergic inflammation enough to provide relief of obstruction in many patients, a surgical approach is often needed to achieve complete resolution of this bothersome complaint.
The interrelationship between allergy and sinusitis has long been known and described in the literature.8,9 Failure to address allergy when it is a contributing factor to sinus disease diminishes the probability of a successful surgical intervention. Among allergy patients at UNC with a history of recurrent sinusitis, those who felt helped by immunotherapy in this regard rated their treatment significantly more positively than the group as a whole. About half of the patients who underwent sinus surgery believed that the surgery alone was not sufficient to completely resolve the recurrent episodes of infection. Again, medical and surgical management must often be blended to achieve optimal patient treatment outcomes. The patient population served by UNC Hospitals is largely derived from the rural and suburban southeastern United States. As might be expected, ragweed, grass, and trees are common allergens, seen in about 50% of patients referred for SET. The even greater percentage of patients with sensitivities to dust and mite antigens is somewhat surprising. However, several recent reports have also demonstrated similar findings in both urban and rural populations.10-12 In the UNC allergy clinic population this may also reflect a tenden-
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Otolaryngology– Head and Neck Surgery January 2001
Fig 2. Venn diagram representing distribution of surgical procedures performed on patients currently undergoing immunotherapy. Fifty-eight percent of procedures were performed after starting immunotherapy, 36% before immunotherapy, and 6% approximately concurrent with the beginning of immunotherapy.
cy to refer patients with perennial symptoms for testing and immunotherapy more than those with seasonal allergies. It should be realized that allergens generating positive SET responses might not necessarily represent clinically relevant allergies, especially when the response occurs only at the lowest dilutions. For example, very few of the positive responses to molds, cotton, and mites were greater than 3+, whereas over one third of responses to dust, fescue, and grass mix were 4+ or greater. Of the more than 300 UNC otolaryngology clinic patients per year referred for allergy testing, approximately 80% have positive test responses, as defined by 3 or more 2+ reactions or at least one 3+ reaction. This high rate of positive skin test response speaks to the fact that patients are first screened with a complete history and head and neck examination by an otolaryngologist. At our institution, over 75% of patients with positive test responses proceed to undergo immunotherapy. This can be seen as a high proportion, considering that approximately 2% of patients with asthma or rhinitis diagnoses received immunotherapy in a recent study of health maintenance organization patients in Boston.13 There are at least 2 plausible reasons for our large percentage. First, many patients with an obvious clinical presentation of allergy are tested specifically to guide dosing for anticipated immunotherapy. Second, the subset of
patients who are willing to undergo skin testing are likely to be those who would consider immunotherapy as a mode of treatment. Large numbers of patients with allergy symptoms do not elect to undergo intradermal testing and therefore undergo in vitro testing or are treated empirically with avoidance, pharmacotherapy, or both. Once a patient is started on immunotherapy, the eventual duration of therapy is variable. Several factors may contribute to the length of treatment, such as concurrent medical problems, noncompliance, change of residence, inconvenience, and allergic reactions.14 The mean treatment period of 2 years in the UNC experience is lower than the recommended 3 to 5 years but is comparable with that described elsewhere in the literature.14 The SD of 25 months, however, reflects the wide range of treatment duration in our allergy clinic. The UNC medical record usually does not provide the reason for discontinuation of therapy. A survey of patients who have completed immunotherapy or a prospective study would be needed to further investigate this issue. It is not known how the duration of therapy affects the long-term effectiveness of immunotherapy. Naclerio et al15 observed a partial recrudescence of immediate sensitivity to ragweed within 1 year of discontinuation of immunotherapy given for greater than 3 years. A recent study by Durham et al16 reported prolonged clinical remissions in
Otolaryngology– Head and Neck Surgery Volume 124 Number 1
patients undergoing 3 to 4 years of immunotherapy for grass pollen. Further study would again be needed to address the efficacy of immunotherapy over the range of treatment durations seen in our clinic population. In summary, the data presented in this article reviews a 20-year experience of successful otolaryngic allergy diagnosis and therapy at UNC. Because head and neck manifestations of allergy are prevalent and encountered daily in clinical otolaryngology, it is critical that otolaryngologists be experts in this area. Otolaryngologists are uniquely qualified to provide complete and comprehensive management of medical and surgical problems of the upper aerodigestive tract. The ability to perform the necessary diagnostic and therapeutic procedures without outside referral or consultation should be included in an otolaryngologist’s armamentarium. The presence of integrated allergy clinics within academic otolaryngology practices provides important benefits with respect to patient care, residency training, and the establishment of expertise in allergy management within the specialty. We thank our allergy nurses, Libby Drake and Judy Miles, for their excellent patient care and their assistance in accumulating and sorting the large amount of data reviewed in this article. This work is dedicated to the late Dr Paul W. Biggers, without whom there would not have been an allergy clinic at Chapel Hill. His specific interest and expertise in otolaryngic allergy was ahead of its time and kept the allergy clinic at the forefront of the field. His tireless dedication to student and resident education at UNC Chapel Hill enriched the otolaryngology experience of all that had the opportunity to learn from him.
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REFERENCES 1. Hadley JA. Evaluation and management of allergic rhinitis. Med Clin North Am 1999;83:13-25. 2. Nathan RA, Meltzer EO, Selner JC, et al. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol 1997;99:S808-13. 3. NIAD. Task force report: asthma and other allergic diseases. Bethesda (MD): National Institutes of Health; 1979. Publication No. 79-387. 4. Hadley JA. Overview of otolaryngic allergy management: an eclectic and cost-effective approach. Otolaryngol Clin North Am 1998;31:69-82. 5. Mabry RL, ed. American Academy of Otolaryngic Allergy: skin endpoint titration. New York: Thieme; 1992. 6. Danielsson J, Jensen M. The natural course of allergic rhinitis during 12 years of follow-up. Allergy 1997;52:331-4. 7. Flynn S, Andrist D, McCready L, et al. Most frequent indications and positive reactions from allergy skin testing from Minnesota [abstract]. J Allergy Clin Immunol 1999;103:S7. 8. Savolainen S. Allergy in patients with viral acute maxillary sinusitis. Allergy 1989;44:116-22. 9. Van Dishoek HAE, Fraussen MGC. The incidence and correlation of allergy and chronic maxillary sinusitis. Pract Otolaryngol 1957;19:502-8. 10. Joks R, Taningco G, Tuysuzoglu G, et al. Allergy skin test results from Brooklyn: new insights into inner city sensitivities. J Allergy Clin Immunol 1999;103:S27. 11. Najib NM, Chowdrhy IA, Silverman BA, et al. Skin sensitivity to common aeroallergens in perennial allergic rhinitis [abstract]. J Allergy Clin Immunol 1999;103:S24. 12. Price GW, Bonini LV, Spoto AP, et al. Survey of skin tests in a central Florida practice [abstract]. J Allergy Clin Immunol 1996;97:388. 13. Donahue JG, Greineder DK, Connor-Lacke L, et al. Utilization and cost of immunotherapy for allergic asthma and rhinitis. Ann Allergy Asthma Immunol 1999;82:339-47. 14. Rhodes BJ. Patient dropouts before completion of optimal dose, multiple allergen immunotherapy. Ann Allergy Asthma Immunol 1999;82:281-6. 15. Naclerio RM, Proud D, Moylan B, et al. A double-blind study of the discontinuation of ragweed immunotherapy. J Allergy Clin Immunol 1997;100:293-300. 16. Durham SR, Walker SM, Varga E, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468-75.
OBJECTIVE: Allergic disease plays a central role in the clinical practice of otolaryngology. The purpose of this study was to review the 20-year experience of an allergy clinic integrated within an otolaryngology practice at a major academic institution. STUDY DESIGN: We performed a retrospective database review of over 3300 otolaryngology patients referred for allergy skin testing between 1979 and 1999. RESULTS: Approximately 80% of patients referred for allergy testing in our clinic had positive test results, of which 75.7% went on to undergo desensitization. The most common allergen was house dust, with allergies to mites, ragweed, and grass also prevalent. Among current allergy immunotherapy patients, 30.8% have undergone nasal septal, turbinate, and/or endoscopic sinus procedures in addition to allergy management. Nasal obstruction was the symptom most frequently persistent despite immunotherapy and the one most frequently reported to be improved by surgery. CONCLUSIONS: The otolaryngologist–head and neck surgeon is uniquely qualified to perform comprehensive medical and surgical management for patients with complex disease processes involving a component of allergy. We believe that an integrated approach to allergy within an otolaryngology practice optimizes the treatment of such patients. (Otolaryngol Head Neck Surg 2001;124:9-15.)
A
llergy, as it pertains to the head and neck, is a core component of the specialty of otolaryngology–head and neck surgery and a required area of education for all
From the Division of Otolaryngology–Head and Neck Surgery, The University of North Carolina School of Medicine. Presented at the Annual Meeting of the American Academy of Otolaryngic Allergy, New Orleans, LA, September 23-25, 1999. Reprint requests: Andrew P. Lane, MD, Division of Otolaryngology– Head and Neck Surgery, Department of Surgery, The University of North Carolina School of Medicine, 610 Burnett-Womack Building, CB# 7070, Chapel Hill, NC 27599-7070. Copyright © 2001 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2001/$35.00 + 0 23/1/111602 doi:10.1067/mhn.2001.111602
training programs receiving accreditation. It has been estimated that 50% of patient complaints encountered in an otolaryngology clinic have some component of allergic disease.1 Inhalant allergy is particularly prevalent, with between 14% and 22% of all Americans affected by allergic rhinitis and rhinosinusitis.2-4 A key element in the diagnosis and treatment of inhalant allergy is the use of skin testing. At this time, however, the majority of academic otolaryngology clinics do not directly provide this service. To date, no significant review of allergy testing and immunotherapy has been reported from an academic otolaryngology department. As specialists of the head and neck, otolaryngologists are uniquely qualified to give comprehensive care for a vast array of conditions in which allergy is an underlying or contributing element. The experience gained in the primary diagnosis and management of otolaryngic allergy is critical to the training of residents, as well as in defining the future role of otolaryngologists in the care of patients with head and neck manifestations of allergy. The well-trained otolaryngologist must be proficient in the available techniques of testing for allergy and must understand the treatment options. Since 1983, the American Academy of Otolaryngic Allergy has promoted a standardized protocol for the skin endpoint titration (SET) method of allergy testing.5 This technique both serves to identify allergic patients and to guide dosing for subsequent immunotherapy. It is simple to perform in the office setting and rapidly yields valuable clinical information. Although a positive SET test result for aeroallergens is an indication for immunotherapy, the goal is to control the allergic symptoms quickly and effectively whether by avoidance, pharmacotherapy, or immunotherapy. Additionally, as surgeons, otolaryngologists are in the position to treat anatomic or infectious problems that may be acting in concert with allergy to cause the patient’s specific complaints. Ultimately, the appropriate form of therapy must be individualized to a given patient and supported by personal or institutional experience with large numbers of patients. For more than 20 years, an integrated allergy clinic has existed within the otolaryngology clinic at the University of North Carolina (UNC) Hospitals. The clinic is staffed by an attending otolaryngologist and 2 allergy nurses. Referrals for allergy testing are made through resident and attending clinics and are generally 9
10
Otolaryngology– Head and Neck Surgery January 2001
LANE et al
Table 1. Patient symptoms at time of presentation: Effects of immunotherapy and surgical intervention
Symptom
Patients reporting symptom (n = 273)
Symptom improved with immunotherapy (n = 228)
Symptom not improved with immunotherapy (n = 212)
Symptom improved with surgery (n = 74)
Symptom not improved with surgery (n = 69)
78.8 68.9 66.7 60.8 60.8 41.4
30.3 32.0 38.6 33.3 31.1 5.3
27.4 9.4 20.8 24.5 10.8 11.3
74.3 27.0 20.2 5.4 0 4.1
18.8 24.6 15.4 21.7 7.2 14.5
Blockage (%) Recurrent infections (%) Headache-pressure (%) Rhinorrhea (%) Sneezing (%) Other (%)
Surgical intervention subjectively improved nasal blockage in 74.3% of allergy clinic patients who underwent surgery. This is compared with 30.3% of allergy clinic patients who reported improvement in nasal congestion after immunotherapy alone. Other symptoms of allergy, including recurrent sinus infections and headache or pressure, were reported to be improved by both surgery and immunotherapy, although more so with immunotherapy. Nonobstructive symptoms of allergy, such as rhinorrhea and sneezing, were seldom reported to be improved with surgery; however, one third of the allergy clinic patients believed these symptoms were improved by immunotherapy alone.
performed either the same day or scheduled in conjunction with the return visit with the referring physician. In the UNC experience over 3300 patients have been skin tested for allergy, and approximately 630 patients are currently undergoing immunotherapy. In 1 year, there are between 9000 and 10,000 allergy clinic visits and about 325 new allergy tests performed. In this article the results of allergy testing for the population of patients seen at UNC between 1979 and 1999 are reviewed, and the experiences of current immunotherapy patients are surveyed. METHODS AND MATERIAL Allergy records from 3329 patients tested between 1979 and 1999 in the otolaryngology clinic at the UNC Hospitals were reviewed retrospectively. For each patient, the age, sex, dates of testing, and results of SET were recorded into a database by using Microsoft Access software. Where available, other information concerning patient symptoms, duration of therapy, and in vitro testing were also entered. Patients undergoing allergy testing in our clinic were referred from within the general otolaryngology clinic, where they were being seen for otolaryngologic complaints. Indications for allergy testing vary somewhat from physician to physician but usually are based on a history and physical examination suggestive of allergy as a factor in the patient’s complaints. Before testing, a complete head and neck examination was performed by the referring otolaryngologist to identify nonallergic causes. Any patient tested in the allergy clinic stopped taking all medications that might affect the skin test results. For the patients currently undergoing immunotherapy, a questionnaire was used to obtain further information about symptoms, surgical history, and effectiveness of therapy. In addition, the UNC Hospitals electronic medical record was used to review surgical procedures and outpatient clinic notes in this patient group. The questionnaire specifically asked the patients to rate the effectiveness of immunotherapy on a 1 to
5 scale, with 5 being most effective. Also, patients were asked to list the symptoms that were most and least helped by immunotherapy and, when applicable, by surgery. The number of symptoms listed was variable, and some patients did not offer responses to these questions at all. The data from the questionnaires were compiled in Microsoft Access and transferred to Microsoft Excel for statistical analysis with unpaired t tests, Spearman correlations, and analysis of variance. Intradermal SET was performed in a standard fashion with a panel of aeroallergens diluted serially in 5-fold decreasing concentrations.5 Antigens were purchased from Hollister-Stier. All patients were tested for epidermals; mold mix; Trichophyton, Candida, and Epidermophyton (TOE) species; cotton; house dust mixture (without mite antigens); mite (Der f 1); ragweed; weed mix; grass mix; tree mix; and fescue. The mold mix (MMP) contained the following species: Aspergillus, Dematiaciae, Penicillin, Thycomycetes, Fusarim, Chaetomium, Botytiscinis, Monilia, Mycogone, and Paecilomyces. The house dust extract was supplied as a mixture that did not contain any mite antigens. A subset of patients with exposure to pets was also tested for cat and dog antigens. In general, the starting dose of antigen for desensitization was derived from the endpoint concentration. Mixes were used for desensitization, although this is not recommended under the current American Academy of Otolaryngic Allergy policy. Patients were treated twice weekly for 2.5 weeks, then weekly for 2 weeks, and then every 2 weeks after that with an escalating dose until the maintenance level was reached. This dose was altered if symptoms persisted or if systemic or large local reactions occurred. There are no specific criteria for the cessation of immunotherapy, although the decision is ideally reached jointly between the patient and otolaryngologist on the basis of a perceived control of symptoms or a failure of therapy. RESULTS
Allergy clinic records for 3329 patients undergoing SET testing between 1979 and 1999 were entered into
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11
Table 2. Percentage of positive SETs by allergens tested Endpoint dilution ≥4
Positive skin test responses
Allergen
Dust mix Mite Ragweed Grass mix Tree mix Fescue MMP Weed mix TOE Cotton Epidermals Cat *Positive
Patients with positive SETs* (% of all patients tested)
Positive SET at lowest dilution (2) only (% of all positive skin test responses)
81.0 61.6 55.3 55.0 54.7 52.6 52.3 52.0 50.8 36.6 45.3 20.9
36.9 51.5 56.3 52.2 59.1 53.4 62.4 61.0 53.0 77.7 49.3 56.5
Patients with positive SETs at dilution ≥4 (% of all patients tested)
30.5 14.2 17.5 18.4 11.8 19.6 7.6 11.5 10.3 2.4 8.5 6.4
SET is defined as a skin response at any dilution of allergen.
the database. Of this group, 637 patients were currently undergoing immunotherapy, 297 of whom were treated in the UNC clinic and another 340 who were desensitized elsewhere. The remainder of patients had either completed or never started immunotherapy. The average age was 45.2 ± 14.5 years. There were 2653 (79.7%) patients with positive skin test responses, as defined by 3 or more 2+ reactions or 1 or more 3+ reactions. Of these patients, 2008 (75.7%) went on to have desensitization performed (60.3% of the total patients referred for testing). The average duration of therapy was 24.65 months (SD, 25.84 months) for those who have completed therapy. For the group being treated currently, 28% have been treated for less than a year, 45% for less than 3 years, and 67% for less than 5 years. Fifty-eight percent of the patients tested were female. A slightly lower percentage of women had negative skin test responses than did men (20.8% vs 23.9%), and more women with positive test responses began immunotherapy than did men (73% vs 67.9%). Neither of these differences achieved statistical significance. The most common presenting symptom was nasal congestion (71.5%). The other most common symptoms are listed in Table 1. Of patients currently being desensitized, the greatest improvement reported was in headache or pressure, with fewer noting relief of rhinorrhea or congestion. The symptom most often cited as not improving with therapy was congestion, with rhinorrhea following closely. On a 1- to 5-point scale of overall effectiveness of immunotherapy, the average rating was 3.9. Among patients who reported no improvement in nasal congestion, the average rating was significantly lower at 3.57 (P = 0.015). This level of dissatisfaction associated with continued congestion was
greater than that observed with other symptoms, such as headache, sneezing, and rhinorrhea (Fig 1). The most prevalent allergen in the population tested was dust, with 81.2% having a skin endpoint of 2+ or greater and 30.6% having an endpoint of 4+ or greater. The next most common allergen causing a 2+ or greater endpoint was mite; however, fewer than 25% of these responses had an endpoint of 4+ or greater. Ragweed, grass mix, and tree mix were the next most common allergens, followed closely by MMP, fescue, weed mix, and TOE. Of these, fescue and grass mix had the greatest proportion of 4+ or greater endpoints. A summary of the allergens tested and the associated skin test results appears in Table 2. For most allergens, 75% to 85% of patients with 4+ endpoints went on to be treated with desensitization. Although cat allergy was not prevalent, greater than 94% of patients with a 4+ or greater endpoint were treated. Very few patients were allergic to weed mix, tree mix, or fescue without being allergic to multiple antigens. In contrast, among the patients with allergies isolated to one or two antigens, 73.5% were sensitive to dust, ragweed, or TOE. A subset of 275 patients who are currently undergoing therapy returned surveys and had medical information available for review on the electronic medical record. Of this group, 84 (30.5%) have a documented history of nasal or sinus surgery. Surgery was performed after starting desensitization in 57.8% of these patients and before desensitization in 35.6%, and 6% had surgery at approximately the same time that immunotherapy was started. The period of time elapsed between surgery and immunotherapy was variable. When surgery came first, the mean interval was 9.5 years, with an SD of 10.5 years. The mean interval
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A Fig 1. Effectiveness of immunotherapy as rated by patients with a 1- to 5-point visual analogue scale, where 5 is most effective. Recurrent sinus infection was defined as recurrent purulent nasal discharge, usually with pain, fever, or both, requiring antibiotic therapy by a physician. Error bars represent SEM. Comparisons between groups were made by using unpaired t tests. A, The subset of patients reporting improvement in any presenting symptom after immunotherapy tended to rate the effectiveness of their immunotherapy higher than the group as a whole (P = 0.06). Statistical significance was reached only in the group of patients reporting improvement in recurrent sinus infections (mean rating, 4.12 vs 3.57; P = 0.04).
when immunotherapy preceded surgery was 5.3 years, with an SD of 8.6 years. The types of procedures and their frequencies are depicted in Fig 2. The symptom most often reported to be improved with surgery was congestion (74.3%), and the most frequent persistent complaint after surgery was recurrent sinus infection (24.6%). The mean rating for the overall effectiveness of immunotherapy was not significantly different between the groups of patients who had and had not undergone surgery. DISCUSSION
In the UNC experience, the predominant complaints that bring patients with sinonasal disease to the otolaryngology clinic include congestion, rhinorrhea, sinus pressure or headache, irritation-sneezing, and recurrent infections. Allergic rhinosinusitis, which is prevalent in the US population, is frequently suggested by the history and physical examination. The presence of an integrated allergy clinic within the otolaryngology clinic allows for
prompt allergy testing, which greatly facilitates the diagnosis and ultimate management of the patient’s symptoms. It is important to recognize that allergy may be only one component in the overall disease process and that the complete care of the patient may involve modalities other than allergy therapy. In our experience over 30% of patients being treated with immunotherapy for allergy have also undergone nasal or sinus surgery at some point in their treatment. This finding suggests that sinonasal disease in allergic patients often requires both medical and surgical approaches and underlines the important role of the otolaryngologist in the management of rhinosinusitis with allergic manifestations. The symptom of nasal obstruction particularly illustrates the importance of a comprehensive approach to sinonasal disease. Nasal blockage is often reported to be the most common complaint of patients with allergic rhinitis.6,7 Among patients referred to the UNC allergy clinic, more than 78% had a chief complaint of nasal
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B Fig 1. Con’t. B, Patients with persistent complaints of nasal congestion despite immunotherapy gave a mean rating of their immunotherapy that was significantly lower than that of the group as a whole (3.57 vs 3.9, P = 0.015). No other persistent symptom had a significant effect on the mean ratings of immunotherapy.
obstruction. Interestingly, although congestion is frequently improved by immunotherapy, it was the symptom most often reported to be unimproved with immunotherapy in our survey. If immunotherapy was not effective for congestion, patients felt significantly less positive about the overall benefit of desensitization. No other symptom affected the allergy patient’s overall perception this strongly. When surgery has been performed, nasal obstruction is, by a wide margin, the symptom most often reported to be improved. Nasal obstruction certainly has the potential to be multifactorial and can be improved surgically when related to anatomic problems, such as septal deformity, turbinate hypertrophy, or polyp disease. About 85% of the surgical procedures that allergy patients had undergone involved septoplasty, turbinate reduction, or both. Additional procedures reported as sinus surgery may also have involved removal of polyps and therefore, in effect, also addressed congestion. Clearly, although immunotherapy reduces allergic inflammation enough to provide relief of obstruction in many patients, a surgical approach is often needed to achieve complete resolution of this bothersome complaint.
The interrelationship between allergy and sinusitis has long been known and described in the literature.8,9 Failure to address allergy when it is a contributing factor to sinus disease diminishes the probability of a successful surgical intervention. Among allergy patients at UNC with a history of recurrent sinusitis, those who felt helped by immunotherapy in this regard rated their treatment significantly more positively than the group as a whole. About half of the patients who underwent sinus surgery believed that the surgery alone was not sufficient to completely resolve the recurrent episodes of infection. Again, medical and surgical management must often be blended to achieve optimal patient treatment outcomes. The patient population served by UNC Hospitals is largely derived from the rural and suburban southeastern United States. As might be expected, ragweed, grass, and trees are common allergens, seen in about 50% of patients referred for SET. The even greater percentage of patients with sensitivities to dust and mite antigens is somewhat surprising. However, several recent reports have also demonstrated similar findings in both urban and rural populations.10-12 In the UNC allergy clinic population this may also reflect a tenden-
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Fig 2. Venn diagram representing distribution of surgical procedures performed on patients currently undergoing immunotherapy. Fifty-eight percent of procedures were performed after starting immunotherapy, 36% before immunotherapy, and 6% approximately concurrent with the beginning of immunotherapy.
cy to refer patients with perennial symptoms for testing and immunotherapy more than those with seasonal allergies. It should be realized that allergens generating positive SET responses might not necessarily represent clinically relevant allergies, especially when the response occurs only at the lowest dilutions. For example, very few of the positive responses to molds, cotton, and mites were greater than 3+, whereas over one third of responses to dust, fescue, and grass mix were 4+ or greater. Of the more than 300 UNC otolaryngology clinic patients per year referred for allergy testing, approximately 80% have positive test responses, as defined by 3 or more 2+ reactions or at least one 3+ reaction. This high rate of positive skin test response speaks to the fact that patients are first screened with a complete history and head and neck examination by an otolaryngologist. At our institution, over 75% of patients with positive test responses proceed to undergo immunotherapy. This can be seen as a high proportion, considering that approximately 2% of patients with asthma or rhinitis diagnoses received immunotherapy in a recent study of health maintenance organization patients in Boston.13 There are at least 2 plausible reasons for our large percentage. First, many patients with an obvious clinical presentation of allergy are tested specifically to guide dosing for anticipated immunotherapy. Second, the subset of
patients who are willing to undergo skin testing are likely to be those who would consider immunotherapy as a mode of treatment. Large numbers of patients with allergy symptoms do not elect to undergo intradermal testing and therefore undergo in vitro testing or are treated empirically with avoidance, pharmacotherapy, or both. Once a patient is started on immunotherapy, the eventual duration of therapy is variable. Several factors may contribute to the length of treatment, such as concurrent medical problems, noncompliance, change of residence, inconvenience, and allergic reactions.14 The mean treatment period of 2 years in the UNC experience is lower than the recommended 3 to 5 years but is comparable with that described elsewhere in the literature.14 The SD of 25 months, however, reflects the wide range of treatment duration in our allergy clinic. The UNC medical record usually does not provide the reason for discontinuation of therapy. A survey of patients who have completed immunotherapy or a prospective study would be needed to further investigate this issue. It is not known how the duration of therapy affects the long-term effectiveness of immunotherapy. Naclerio et al15 observed a partial recrudescence of immediate sensitivity to ragweed within 1 year of discontinuation of immunotherapy given for greater than 3 years. A recent study by Durham et al16 reported prolonged clinical remissions in
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patients undergoing 3 to 4 years of immunotherapy for grass pollen. Further study would again be needed to address the efficacy of immunotherapy over the range of treatment durations seen in our clinic population. In summary, the data presented in this article reviews a 20-year experience of successful otolaryngic allergy diagnosis and therapy at UNC. Because head and neck manifestations of allergy are prevalent and encountered daily in clinical otolaryngology, it is critical that otolaryngologists be experts in this area. Otolaryngologists are uniquely qualified to provide complete and comprehensive management of medical and surgical problems of the upper aerodigestive tract. The ability to perform the necessary diagnostic and therapeutic procedures without outside referral or consultation should be included in an otolaryngologist’s armamentarium. The presence of integrated allergy clinics within academic otolaryngology practices provides important benefits with respect to patient care, residency training, and the establishment of expertise in allergy management within the specialty. We thank our allergy nurses, Libby Drake and Judy Miles, for their excellent patient care and their assistance in accumulating and sorting the large amount of data reviewed in this article. This work is dedicated to the late Dr Paul W. Biggers, without whom there would not have been an allergy clinic at Chapel Hill. His specific interest and expertise in otolaryngic allergy was ahead of its time and kept the allergy clinic at the forefront of the field. His tireless dedication to student and resident education at UNC Chapel Hill enriched the otolaryngology experience of all that had the opportunity to learn from him.
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REFERENCES 1. Hadley JA. Evaluation and management of allergic rhinitis. Med Clin North Am 1999;83:13-25. 2. Nathan RA, Meltzer EO, Selner JC, et al. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol 1997;99:S808-13. 3. NIAD. Task force report: asthma and other allergic diseases. Bethesda (MD): National Institutes of Health; 1979. Publication No. 79-387. 4. Hadley JA. Overview of otolaryngic allergy management: an eclectic and cost-effective approach. Otolaryngol Clin North Am 1998;31:69-82. 5. Mabry RL, ed. American Academy of Otolaryngic Allergy: skin endpoint titration. New York: Thieme; 1992. 6. Danielsson J, Jensen M. The natural course of allergic rhinitis during 12 years of follow-up. Allergy 1997;52:331-4. 7. Flynn S, Andrist D, McCready L, et al. Most frequent indications and positive reactions from allergy skin testing from Minnesota [abstract]. J Allergy Clin Immunol 1999;103:S7. 8. Savolainen S. Allergy in patients with viral acute maxillary sinusitis. Allergy 1989;44:116-22. 9. Van Dishoek HAE, Fraussen MGC. The incidence and correlation of allergy and chronic maxillary sinusitis. Pract Otolaryngol 1957;19:502-8. 10. Joks R, Taningco G, Tuysuzoglu G, et al. Allergy skin test results from Brooklyn: new insights into inner city sensitivities. J Allergy Clin Immunol 1999;103:S27. 11. Najib NM, Chowdrhy IA, Silverman BA, et al. Skin sensitivity to common aeroallergens in perennial allergic rhinitis [abstract]. J Allergy Clin Immunol 1999;103:S24. 12. Price GW, Bonini LV, Spoto AP, et al. Survey of skin tests in a central Florida practice [abstract]. J Allergy Clin Immunol 1996;97:388. 13. Donahue JG, Greineder DK, Connor-Lacke L, et al. Utilization and cost of immunotherapy for allergic asthma and rhinitis. Ann Allergy Asthma Immunol 1999;82:339-47. 14. Rhodes BJ. Patient dropouts before completion of optimal dose, multiple allergen immunotherapy. Ann Allergy Asthma Immunol 1999;82:281-6. 15. Naclerio RM, Proud D, Moylan B, et al. A double-blind study of the discontinuation of ragweed immunotherapy. J Allergy Clin Immunol 1997;100:293-300. 16. Durham SR, Walker SM, Varga E, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468-75.