Evidence-based dosing of maintenance subcutaneous immunotherapy: a contemporary review of state-of-the-art practice.

BACKGROUND: Subcutaneous immunotherapy is an effective allergy treatment only if properly dosed. In this article we review the data on the probable effective dose range for subcutaneous immunotherapy and convert the recommended doses into a clinically relevant format. METHODS: A comprehensive literature search of dose-response subcutaneous immunotherapy studies was done of EBM databases, Medline database, PreMedline, and the National Guideline Clearinghouse for the period 1980-2016. Recommended doses were converted to the volume of allergen extract that should be added to a 5-mL maintenance vial. RESULTS: A safe and effective dose for subcutaneous immunotherapy is likely 5-20 µg of major allergen per injection. A 0.5-mL injection from a 5-mL maintenance vial containing 0.2 mL of manufacturer's extract of each allergen should reach the lower end of the probable effective dose range for most allergens. A larger volume of extract is required to reach that range when treatment includes cat, dog, or only 1 dust mite. Increasing beyond the commonly prescribed 0.2 mL of manufacturer's extract added to a 5-mL treatment vial is reasonable for nearly all allergens to achieve a maintenance dose higher in the probable effective dose range. CONCLUSION: Current otolaryngic allergy practice usually escalates patients to 0.5-mL injections from 5-mL maintenance vials containing 0.2 mL of manufacturer's extract of each allergen. With the main exceptions of cat and dog, those injections administered 1 or 2 times per month likely provide an efficacious dose of allergen and are consistent with published guidelines. A larger volume of extract should be considered in certain clinical situations.

Allergen stability of testing/treatment boards and immunotherapy vials with various diluents.

BACKGROUND: Otolaryngologists commonly use glycerin and normal saline with phenol (NSP) in diluting solutions to help preserve allergenicity in immunotherapy vials. Studies have shown that diluting with human serum albumin (HSA) may provide better allergen stability. The purpose of this study was to assess the ability of various diluents to preserve allergen content in testing/treatment boards (TTBs) and immunotherapy treatment vials (ITVs) at multiple time points. METHODS: TTBs with 4 allergens were prepared with HSA, NSP, 10% glycerin, and 50% glycerin. The major allergen content of the TTBs was measured at creation (time 0), 3 days, 8 weeks, and 18 weeks. Multiallergen ITVs containing the 4 allergens were prepared from the NSP board (diluted to 10% glycerin) and the HSA board (diluted in HSA) at the time of making the freshly prepared TTBs and again 8 weeks later, simulating the creation of ITVs from a "new" and an "old" TTB. The major allergen content of these ITVs was determined at creation and at interval time points thereafter. RESULTS: TTBs and ITVs showed a substantial loss of allergen at day 3. The loss of allergen was more pronounced in the more dilute (#4, #5, and #6) vials. HSA and 50% glycerin showed superior allergen preservation compared to NSP and 10% glycerin in TTBs. HSA showed superior allergen preservation compared to 10% glycerin-NSP in ITVs. CONCLUSION: The use of HSA as a diluent in TTBs and ITVs showed superior allergen preservation compared to NSP and 10% glycerin, particularly for more dilute vials.

Dosing of sublingual immunotherapy for allergic rhinitis: evidence-based review with recommendations.

BACKGROUND: Since the mid 1980s, the clinical use of sublingual immunotherapy (SLIT) has dramatically increased. However, 1 of the primary barriers to providing SLIT is lack of a published dosing recommendations. The purpose of this work is to provide a range of effective SLIT dosing based upon a rigorous review of the existing evidence base. An appendix with SLIT dosing recommendations is also included. METHODS: A comprehensive search of the past 25 years of the medical literature using PubMed was performed for specific antigens. Inclusion criteria for articles included: randomized, placebo-controlled studies of SLIT, studies with clinical allergic rhinitis outcomes, and dosing units available to determine the micrograms per month of major allergen administered. The extracted data was used to compile a range of effective SLIT dosing for individual antigens. RESULTS: Seventy-five articles met the inclusion criteria, providing a range of effective dosing for some allergens. There was commonly a wide range in doses for particular antigens between the individual studies. For some antigens, there was significant overlap in dosage amount between studies showing efficacy and lack of efficacy. Clinical trials meeting inclusion criteria are not available for many allergens. CONCLUSION: This study provided a comprehensive review of the published sublingual dosing ranges for specific antigens. The review provided a range of effective sublingual doses for some allergens, whereas for other allergens there was insufficient published data to determine specific doses. Recommendations for SLIT dosing were produced based on the data revealed in the review and expert opinion.

Anaphylaxis in the allergy practice.

BACKGROUND: Otolaryngologists managing patients with allergic rhinitis are faced with the possibility of anaphylactic reactions in the office, especially when providing allergen immunotherapy. METHODS: Literature review was performed and recent published articles on anaphylaxis were examined. Details on pathophysiology, incidence, signs/symptoms, and treatment of anaphylaxis are included in this review article. RESULTS: Although anaphylaxis is a rare event with allergy testing and immunotherapy, it can result in fatal consequences. Clinical manifestations of anaphylaxis are rapid, and the upper and lower airways, skin, conjunctiva, and gastrointestinal and cardiovascular systems are often affected, individually or in combination. Treatment of anaphylaxis in the office begins with proper preparation in advance. The most important drug in the treatment of anaphylaxis is epinephrine, which should be administered early during an anaphylactic reaction. Recognition of the risks factors for anaphylaxis, such as uncontrolled asthma, may be helpful in order to prevent anaphylaxis. CONCLUSION: Fortunately, Anaphylaxis is a rare occurrence in the allergy office if strict attention is paid to proper testing and treatment principles. Maintaining a high level of vigilance and preparedness is important to increase the chances of a favorable outcome should an anaphylactic episode occur.

The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) survey: provider practices and beliefs about allergen immunotherapy.

BACKGROUND: The practices and beliefs of the provider specialties that treat allergic rhinoconjunctivitis (ARC) with allergen immunotherapy (AIT) may vary. METHODS: A telephone survey of 500 randomly selected health care practitioners in 7 specialties, conducted in 2012. RESULTS: AIT was provided as a subcutaneous injection (SCIT) by 91% of allergist/immunologists, 54% of otolaryngologists, and 18% to 24% of other specialties. Otolaryngologists were the most frequent providers of sublingual drops of AIT (SLIT; 33%), compared to 2% to 10% of other specialties. AIT was recommended for adults with allergic rhinoconjunctivitis by 100% of allergist/immunologists vs 62% to 84% of the other specialties (p < 0.001). The primary reason for recommending AIT for adults (52%) or children (46%) was that other therapies did not work. Between 48% (nurse practitioners/physician assistants) and 93% (allergist/immunologists) of practitioners always or often decreased symptomatic medications over the course of AIT treatment. Most practitioners in all specialties (82-100%) thought that AIT was appropriate for patients with severe allergy symptoms. Significantly more allergist/immunologists and otolaryngologists than other specialists thought AIT was appropriate for mild allergy symptoms (p < 0.001 and p = 0.004, respectively, vs other specialties). Significantly more allergist/immunologists than other specialists thought that AIT was more effective than symptomatic medications (p < 0.001), could reduce the further development of allergies (p = 0.03), and could prevent the development of asthma. CONCLUSION: SCIT was more frequently provided than SLIT by all the specialties. Otolaryngologists were the most likely to offer SLIT, while very few allergist/immunologists offered SLIT. Allergist/immunologists differed from other specialties in some beliefs about the effectiveness of AIT.

Current practice trends in allergy: results of a united states survey of otolaryngologists, allergist-immunologists, and primary care physicians.

BACKGROUND: Clinical practices for the diagnosis and treatment of allergic disease evolve over time in response to a variety of forces. The techniques used by various physician specialties are not clearly defined and may vary from published descriptions or recommendations in the literature. METHODS: This work is a Web-based survey enrolling 250 U.S. physicians in the following specialties: otolaryngology (ENT), allergy-immunology (A/I), and primary care (PCP). RESULTS: Respondents reported that skin-prick testing is the most common diagnostic testing method, followed by in vitro specific immunoglobulin E (IgE) testing. ENTs were more likely to use intradermal testing compared to other specialties (p = 0.0003 vs A/I; p < 0.0001 vs PCP). Respondents reported a wide distribution in number of allergens tested, regardless of testing method (range, 11 to >60). Significant use of home immunotherapy injections (defined as >10% of immunotherapy patients) ranged from 27% to 36% of physicians, with no statistically significant difference noted based upon specialty. PCPs reported greater use of sublingual immunotherapy (PCP, 68%; A/I, 45%; otolaryngology, 35%; A/I vs PCP, p = 0.005; ENT vs PCP p < 0.001)). CONCLUSION: A variety of allergy testing and treatment methods are employed by U.S. physicians, with some differences noted based upon specialty. Home immunotherapy continues to be employed in allergy practices, and sublingual immunotherapy is a common form of delivery, especially in primary care practices.

Ocular and nasal allergy symptom burden in America: the Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) surveys.

Previous nationwide surveys of allergies in the United States have focused on nasal symptoms, but ocular symptoms are also relevant. This study determines the effects of ocular and nasal allergies on patients' lives. Telephone surveys of randomly selected U.S. households (the patient survey) and health care providers (provider survey) were conducted in the United States in 2012. Study participants were 2765 people ≥5 years of age who had ever been diagnosed with nasal or ocular allergies and 500 health care providers in seven specialties. Respondents to the patient survey reported a bimodal seasonal distribution of allergy symptoms, with peaks in March to May and September. Nasal congestion was the most common of the symptoms rated as "extremely bothersome" (39% of respondents), followed by red, itchy eyes (34%; p = 0.84 for difference in extreme bothersomeness of nasal and ocular symptoms). Twenty-nine percent of respondents reported that their or their child's daily life was impacted "a lot" when allergy symptoms were at their worst. Workers rated their mean productivity at 29% lower when allergy symptoms were at their worst (p < 0.001 compared with no symptoms). Providers reported that itchy eyes was the symptom causing most patients to seek medical treatment by pediatricians (73%), ophthalmologist/optometrists (72%), and nurse practitioners or physician assistants (62%), whereas nasal congestion was the symptom causing most patients to seek treatment from otolaryngologists (85%), allergist/immunologists (79%), and family medicine practitioners (64%). Ocular and nasal allergy symptoms substantially affected patients' lives and were comparable in their impact.

The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) survey: patients' experience with allergen immunotherapy.

Allergen immunotherapy (AIT) is used for the treatment of allergic rhinoconjunctivitis as a subcutaneous injection (subcutaneous immunotherapy [SCIT]). Extracts used for SCIT are also used off-label to formulate a liquid delivered as sublingual drops (sublingual immunotherapy [SLIT]). This study was designed to survey patients' experiences and beliefs regarding SCIT and SLIT. People who had ever been diagnosed with nasal and/or ocular allergies were identified in a 2012 telephone survey of U.S. households. Respondents were asked questions about their or their child's use of SCIT and SLIT and their beliefs about AIT. Of 2765 respondents, 46.5% had ever heard of AIT and 22.7% had ever initiated it: 20.9% with SCIT and 1.8% with SLIT (p < 0.0001). The most frequently cited reason for beginning AIT was that symptoms were unresolved with other medications (SCIT, 32.1%; SLIT, 14.0%). Some or full symptom relief was reported by 74.9% of respondents treated with SCIT and 66.0% of those treated with SLIT (p = 0.17 for SCIT versus SLIT). Approximately one-third of respondents who had ever heard of or had been treated with AIT said "don't know" when asked if immunotherapy controls allergy symptoms for years (33.6%), is a very safe treatment (29.3%), or can cure allergy symptoms (27.5%). Effective relief of allergy symptoms was cited most often as the primary benefit of SCIT (37.8%) and convenience was the primary benefit of SLIT (14%). Only one-fifth of respondents had ever been treated with AIT, largely with SCIT. More than one-half of respondents had never heard of AIT and respondents' beliefs indicated a need for educational efforts.

Diagnosis and treatment of nasal and ocular allergies: the Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) surveys.

BACKGROUND: Allergic rhinoconjunctivitis (ARC) is managed by a number of health care professional specialties, whose practice styles may vary. OBJECTIVE: To survey patients and health care professionals about the diagnosis and treatment of ARC. METHODS: The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) surveys were telephone surveys of randomly selected patients and health care professionals in the United States in 2012. Participants were 2,765 people ever diagnosed as having nasal and/or ocular allergies and 500 practitioners in 7 specialties who were treating ARC. RESULTS: Adult respondents to the patient survey reported that their allergies had been diagnosed most often by physicians in family practice (46%) rather than by allergists/immunologists (17%) or otolaryngologists (11%). Children's allergies had been diagnosed most often by pediatricians (41%) and family practitioners (22%). Most respondents with conditions diagnosed by an allergist/immunologist (94.9%) or otolaryngologist (62.7%) had been given an allergy test, but the test was not given to most patients with conditions diagnosed by family practitioners (61.3%) or pediatricians (64.9%). Most patients (75.8%) were treating their allergies with over-the-counter medications, and 53.5% were taking prescription medications. Allergen immunotherapy was being used by 33% (adult) or 28% (child) patients of allergist/immunologists, 25% (adult) or 24% (child) patients of otolaryngologists, and 8% and 10% of patients of family practitioners and pediatricians, respectively. CONCLUSION: Most patients took nonprescription medications for their allergy symptoms or were treated by general practitioners, who did not use allergy testing when diagnosing ARC. Most patients seen by allergist/immunologists and otolaryngologists were evaluated with allergy tests, and most allergen immunotherapy was provided by allergy specialists.

Sublingual immunotherapy.

Sublingual immunotherapy (SLIT) has been shown to be safe and efficacious in treating allergic rhinitis. It has been used in Europe for more than 20 years, and interest in the United States is increasing. SLIT has been shown to elicit immunologic changes similar to subcutaneous injection immunotherapy. SLIT may prevent new sensitizations, improve asthma control, and decrease asthma development in allergic individuals. Although differences in antigen quantification and standardization make European dosing schemes difficult to translate in the United States, several new studies suggest the range for effective dosing. Further studies will help clarify optimal dosing.

Allergen immunotherapy and health care cost benefits for children with allergic rhinitis: a large-scale, retrospective, matched cohort study.

BACKGROUND: Children with allergic rhinitis (AR) often experience significant impairment in quality of life and health, which increases health care utilization. OBJECTIVE: To determine whether allergen immunotherapy reduces health care utilization and costs in children newly diagnosed as having AR using a retrospective matched cohort design. METHODS: Among children (age <18 years) with a Florida Medicaid paid claim between 1997 and 2007, immunotherapy-treated patients were selected who had newly diagnosed AR, who had not received immunotherapy before their first (index) AR diagnosis, who had received at least 2 immunotherapy administrations after their index AR diagnosis, and who had at least 18 months of data after their first immunotherapy administration. A control group of patients with newly diagnosed AR who had not received immunotherapy either before or subsequent to their index AR diagnosis also were identified, and up to 5 were matched with each immunotherapy-treated patient by age at first AR diagnosis, sex, race/ethnicity, and diagnosis of asthma, conjunctivitis, or atopic dermatitis. RESULTS: Immunotherapy-treated patients had significantly lower 18-month median per-patient total health care costs ($3,247 vs $4,872), outpatient costs exclusive of immunotherapy-related care ($1,107 vs $2,626), and pharmacy costs ($1,108 vs $1,316) compared with matched controls (P < .001 for all). The significant difference in total health care costs was evident 3 months after initiating immunotherapy and increased through study end. CONCLUSIONS: This study demonstrates the potential for early and significant cost savings in children with AR treated with immunotherapy. Greater use of this treatment in children could significantly reduce AR-related morbidity and its economic burden.

Injection and sublingual immunotherapy in the management of allergies affecting the unified airway.

The spectrum of allergic disease involves both the upper and lower airways. Immunotherapy has been shown to produce immunologic changes that can result in the improvement of allergic diseases. Numerous clinical trials have demonstrated the effectiveness of injection and sublingual immunotherapy in the treatment of rhinitis and asthma. Recent data suggest that immunotherapy may have a role in preventing the development of new sensitizations or in decreasing the progression of allergic disease from rhinitis to asthma. Models of immunotherapy may therefore transition from symptom-relieving treatments to preventive methodologies for the management of allergic disease.

Sublingual Immunotherapy: Past, present, paradigm for the future? A review of the literature.

Since the early 1900s, allergen immunotherapy has been recognized as an effective treatment option for patients with inhalant allergies. Subcutaneous injection has traditionally been the main route of antigen delivery for immunotherapy in the United States. Over the past 15 years, sublingual administration of allergen extract has become a widely used method of immunotherapy in other countries, particularly in Europe. Although sublingual immunotherapy (SLIT) has been used by some physicians in the United States, this technique has not found widespread utilization. A growing interest in SLIT use in this country is developing. SLIT offers several potential advantages, including excellent safety and tolerability, increased access to immunotherapy, and improved method of antigen delivery to children. This paper reviews the basic and clinical science data available in the literature concerning the immunology, efficacy, and safety of SLIT. It is written to serve as a springboard for future discussions and clinical investigations regarding the potential expanded use of SLIT in the United States.

The use of demineralized bone matrix for mastoid cavity obliteration.

OBJECTIVE: To evaluate the use of demineralized bone matrix as a graft material for mastoid cavity obliteration in the treatment and prevention of problematic mastoid cavities. STUDY DESIGN: The study is a retrospective review of patients identified using a computerized otology database. SETTING: Tertiary care referral center. PATIENTS: Patients were included in this study if they underwent mastoid obliteration using demineralized bone matrix. INTERVENTION: Mastoid obliteration was performed for revision of a problematic mastoid cavity (n = 8) or primarily after canal wall down mastoidectomy for recurrent cholesteatoma (n = 3). MAIN OUTCOME MEASURES: Data were collected to evaluate the ability to achieve a dry ear canal. Postoperative healing time and hearing results were also assessed. RESULTS: A dry ear canal was achieved in all patients with a follow-up of 6 to 20 months (average, 14.5 mo). Eight patients (73%) had a well-healed, dry ear canal by their first postoperative visit (9 wk). One patient required 12.5 weeks to heal. Two patients (18%) had more prolonged granulation at the ear canal incision, which resolved in 17 and 28 weeks, respectively. The average preoperative pure-tone average air-bone gap was 47 +/- 14.9 dB (mean +/- SD), compared with postoperative values of 27.6 +/- 12.8 dB (p = 0.0033; paired t test). This represents an average pure-tone average air-bone gap closure of 20 dB. CONCLUSION: The use of demineralized bone matrix as a graft extender in mastoid obliteration allowed creation of a dry, smooth-contoured canal in all patients studied. A significant improvement in hearing was also obtained. Demineralized bone matrix is an acceptable graft alternative for mastoid obliteration.

Bioactive glass ceramic particles as an alternative for mastoid obliteration: results in an animal model.

HYPOTHESIS: This study was conducted to evaluate the use of the bioactive glass ceramic particulate NovaBone Bioglass as a graft material for mastoid cavity obliteration in an animal model. BACKGROUND: Canal wall down procedures in otologic surgery may result in a problematic mastoid cavity. Mastoid cavity obliteration can potentially prevent or correct this problem. Many techniques and implant materials have been used for mastoid obliteration, but no single graft material has proved to be ideal. METHODS: Mongolian gerbils received tympanic bulla obliteration using the NovaBone Bioglass particulate. Nine weeks after implantation, the animals were killed, and histologic sections were prepared. Histologic evaluation was performed to evaluate new bone formation within the implant. RESULTS: Wound healing occurred without complication. Mature trabecular bone was observed throughout the entire thickness of the implant material. Extensive neovascularity was observed within the graft material. There was no histologic evidence of inflammatory reaction or short-term resorption. CONCLUSIONS: The extensive new bone formation obtained with bioactive glass ceramic particles in this study makes this material a potential alternative resource as a graft material for mastoid obliteration.