American Academy of Asthma, Allergy & Immunology membership experience with venom immunotherapy in chronic medical conditions and pregnancy, and in young children.

BACKGROUND: Few data exist regarding the use of venom immunotherapy (VIT) in specific high-risk chronic medical conditions and pregnancy, and in young children. METHODS: A Web-based survey was sent to American Academy of Asthma Allergy & Immunology members to explore their VIT experience in potential high-risk medical conditions and pregnancy, and in young children. Major problems were defined as "activation of underlying disease and/or VIT not well tolerated (systemic adverse events) and/or VIT discontinued for medical reasons." Results were expressed descriptively. RESULTS: A total of 697 of 5123 surveys (14%) were completed: 87% of the respondents were based in the United States, and 28% worked in an academic setting. Most respondents (71%) believed that pregnancy was a contraindication for starting VIT. Most were comfortable continuing VIT (51%) if the woman became pregnant after starting therapy. Of the allergists who treated children, many would give VIT down to age 5 years (42%) or younger, ages 1-4 years (35%). The following list is of the specific medical condition, the number of allergists who used VIT in patients with this condition, and the percentage who reported major problems: severe asthma, 212 (4.2%); hypertension, 287 (1.1%); coronary artery disease, 222 (3.6%); arrhythmias, 136 (3.4%); cerebrovascular disease, 104 (5.1%); cancer in remission, 166 (0%); cancer stable but still under treatment, 44 (7.2%); a history of bone marrow transplantation, 15 (4.9%); a history of solid organ transplantation, 29 (3.6%); human immunodeficiency virus, 53 (1.4%); acquired immunodeficiency syndrome, 24 (6.2%); stable autoimmune disease, 164 (2.8%); mastocytosis, 66 (18.4%); elevated serum tryptase, 101 (10.8%); immunodeficiency 59 (2.5%). CONCLUSION: Many allergists were comfortable using VIT in young children and continuing but not starting pregnant women on VIT. VIT was commonly used in patients with hypertension, coronary artery disease, arrhythmias, cancer in remission, and stable autoimmune disease. Major problems were most frequently reported in use with mastocytosis, elevated tryptase, and cancer still under treatment.

American Academy of Allergy, Asthma & Immunology membership experience with allergen immunotherapy safety in patients with specific medical conditions.

BACKGROUND: Little data in the literature exist concerning patients with certain underlying medical conditions who receive allergen subcutaneous immunotherapy (SCIT). OBJECTIVE: To survey allergists' experience with SCIT in patients with medical conditions considered to impose an elevated risk for untoward outcomes. METHODS: A Web-based survey was conducted among members of the American Academy of Allergy, Asthma & Immunology to query about their experience with SCIT in patients with certain medical conditions. RESULTS: There were 1085 replies (21% response), of whom, 86% were U.S. based, 51% were suburban, 31% were academic, 42% were medium-sized practices, and 54% had >15 years' experience. In responders' opinion, SCIT was "contraindicated" in patients with the following: acquired immune deficiency syndrome (AIDS) (48%), cancer (and still receiving active treatment) (33%), severe asthma (32%), and a history of transplantation (30%). Even so, survey responders collectively gave SCIT to >2400 patients for each of these conditions: severe asthma, coronary artery disease, cancer in remission, and autoimmune disorders; and to ≥5400 patients with hypertension and ≥4100 women who became pregnant. The experience of colleagues with these patients rarely resulted in major problems (i.e., activation of underlying disease, systemic reactions to SCIT, or SCIT discontinuation), with the exception of severe asthma (12.5%), initiation of SCIT during pregnancy (5.4%), and AIDS (4.2%). For most other conditions, it was ≤1.5% (e.g., continue during pregnancy, cancer in remission, history of transplantation, positive human immunodeficiency virus and no AIDS). CONCLUSION: According to the experience of a large group of practicing allergists, the American Academy of Allergy, Asthma & Immunology members, few medical conditions seemed to pose an elevated risk for untoward outcomes from SCIT. Because these are survey results, prospective research might yield even more solid data.

Accelerated immunotherapy schedules.

Rush and cluster immunotherapy schedules are accelerated immunotherapy build-up schedules. A cluster immunotherapy schedule involves the patient receiving several allergen injections (generally 2-4) sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is generally reached in 4-8 weeks. In rush immunotherapy protocols, higher doses are administered at 15- to 60-min intervals over a 1- to 3-day period until the maintenance dose is achieved. This review will serve as an update for accelerated immunotherapy schedules. The review will include recent investigations demonstrating the safety of cluster schedules in atopic dermatitis, pediatric patients, and inhalant allergen mixtures and an accelerated protocol utilizing an infusion pump for allergen delivery. There has also been further elucidation on the immunological changes which occur during accelerated immunotherapy. Finally, new studies analyzing systemic reaction risk factors are discussed.

Is immunotherapy safe for treatment of severe asthma.

PURPOSE OF REVIEW: The benefits of allergen immunotherapy (AIT), including subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT), for IgE-mediated asthma are well established, especially for dust mite. This review will explore whether the benefits of AIT outweigh the risks in severe asthmatic patients. RECENT FINDINGS: Studies have mostly included mild and moderate asthmatic patients, but at least a few studies do show improvements in asthma symptoms and medication use in severe asthmatic patients. Asthma, and especially uncontrolled asthma, is a major risk factor for severe and fatal systemic reactions from SCIT. Uncontrolled asthma is an absolute contraindication for SCIT. It is less clear whether the benefits of SCIT and SLIT may outweigh the risks in well controlled, severe asthmatic patients, and further study is needed in this area. Asthma biologics, especially Omalizumab, may improve outcomes in severe, controlled asthmatic patients on SCIT, but further data are needed regarding timing of initiation and duration of treatment. SUMMARY: Although severe asthmatic patients may benefit from AIT, significant risks exist, especially in those with uncontrolled asthma. Further study is needed regarding optimal strategies to minimize risks.

The REPEAT study: recognizing and evaluating periodic local reactions in allergen immunotherapy and associated systemic reactions.

BACKGROUND: prior studies have demonstrated that large local reactions (LLRs) to subcutaneous immunotherapy do not predict systemic reactions (SRs). However, a recent study demonstrated an increase in LLRs among systemic reactors in practices using routine local reaction dose adjustments. OBJECTIVE: to investigate the association between LLRs and SRs within a practice that does not dose adjust for LLRs. METHODS: we performed a retrospective analysis of an electronic immunotherapy database during a 12-month period at a single site that does not dose adjust for LLRs. An LLR was defined as larger than the size of the patient's palm measured at 30 minutes. Logistic regression was performed to investigate the association between SRs and LLRs after controlling for variable numbers of injections and visits among patients. RESULTS: three hundred sixty patients received a total of 9,679 injections (6,609 visits). Twenty-four patients (6.7% of patients) experienced 38 LLRs (0.4% of injections, 0.6% of visits), whereas 46 patients (12.7% of patients) experienced 51 SRs (0.5% of injections, 0.77% of visits). Only 10 patients (2.8%) experienced both LLRs and SRs, and 36 of 46 SR patients (78.3%) never had an LLR. Among the 24 LLR patients, the SR rate was 1.3% (12/932) of injections and 2.0% (12/611) of visits compared with the 336 non-LLR patients for whom the SR rate was 0.4% (39/8,747) of injections and 0.7% (39/5998) of visits. Of these 24 LLR patients, 10 (41.7%) experienced at least 1 SR vs 36 of 336 non-LLR patients (10.7%). After controlling for number of injections and 1 vs 2 injections per visit, a subgroup of LLR patients were more likely to have an SR during their subcutaneous immunotherapy course (odds ratio, 4.7; 95% confidence interval, 1.9-11.7). Recurrent LLR patients (n = 10) were not more likely to experience an SR (0.4% per injection). CONCLUSIONS: although LLRs do not predict SRs, a subgroup (41.7%) of LLR patients experience a higher frequency of SRs during their immunotherapy course. In light of a similar previous study, this association occurs irrespective of whether a dose adjustment protocol is used for LLRs.

Imported fire ant field reaction and immunotherapy safety characteristics: the IFACS study.

BACKGROUND: Imported fire ants (IFAs) are endemic in the southeastern United States, including Texas; can sting multiple times; and are a well-known cause of anaphylaxis. There are few data available on how many stings typically lead to systemic reactions (SRs). Likewise, there are no reports currently in the literature that characterize the safety of IFA subcutaneous immunotherapy (SCIT). OBJECTIVE: We sought to analyze a case-cohort sample of patients for IFA SCIT risk factors and to characterize the index field reactions of these patients. METHODS: A case-cohort study based on a 3-year retrospective chart review (2005-2008) at a single institution was performed for patients receiving IFA SCIT. Field reactions leading to initiation of IFA SCIT were also reviewed. RESULTS: Seventy-seven patients (40 female patients; mean age, 34 years) received 1,887 injections, and 7 patients experienced 8 SRs, for a rate of 0.4% per injection and 9.1% per patient. SRs were mild. Having an SR to skin testing was associated with increased odds of having an SR to IFA SCIT (odds ratio, 4.75; 95% CI, 1.13-20.0), as were large local reactions (odds ratio, 34.5; 95% CI, 6.52-182). No other risk factors were identified. Of the index field reactions leading to IFA SCIT, 59% were the result of 1 sting, and 87% of subjects experienced only 1 SR before initiation of IFA SCIT. Two of 4 patients who experienced loss of consciousness during the index field reaction required an increased maintenance dose for optimal response. CONCLUSIONS: IFA SCIT is safe; however, having an SR to skin testing or the presence of large local reactions increases the odds of having an SR to IFA SCIT. The majority of SRs to IFA field stings resulted from 1 sting.

Assessing the safety of subcutaneous immunotherapy dose adjustments.

BACKGROUND: Subcutaneous immunotherapy injections are often dose adjusted owing to late injections, for newly mixed vials after refills, or after systemic reactions (SRs) to reduce the subsequent SR risk. This practice is not strongly evidence based. OBJECTIVES: To analyze the safety of the Wilford Hall Medical Center dose-adjustment schedule. METHODS: A retrospective cohort analysis of a standardized dose-adjustment schedule across 4 years and covering 12,895 injections was performed to analyze the SR rate immediately after dose adjustments for late reactions (1 dose for each week late starting after 2 weeks), for newly mixed vials (a 50% dose reduction), or after a SR (a 10-fold dilution). RESULTS: Male patients (odds ratio [OR], 1.15; P <. 005), pediatric patients (OR, 1.19; P <. 01), and maintenance stage injections (OR, 2.14; P <.001) required more dose adjustments for late injections. Maintenance stage injections also experienced more dose adjustments for newly mixed vials (OR, 10.78; P <. 001). Pediatric patients (OR, 2.15; P <. 002) and buildup stage injections (OR, 2.38; P <. 005) were associated with an increased SR frequency and, as a result, required more post-SR dose adjustments. In each scenario, following the dose-adjustment schedule included in this article did not cause an increase in subsequent SRs. CONCLUSIONS: Multiple unique characteristics were found to be associated with the requirement for subcutaneous immunotherapy dose adjustment, and this sample dose-adjustment protocol was not associated with an increased risk of a subsequent SR. The safety of this proposed dose-adjustment protocol should be confirmed in future prospective studies.

The LOCAL Study: Local reactions do not predict local reactions in allergen immunotherapy.

BACKGROUND: Although previous immunotherapy studies have demonstrated that a local reaction does not predict a systemic reaction, no study has investigated whether a local reaction predicts a local reaction. OBJECTIVE: To determine whether a local reaction predicts a local reaction at the next immunotherapy injection. METHODS: A retrospective analysis of an electronic immunotherapy database over a 12-month period was performed at a single site that did not dose-adjust for local reactions. Total injections, small local reactions (less than or equal to the size of patient's palm), large local reactions (LLRs; larger than the patient's palm), systemic reactions, and whether a local reaction was followed by a local reaction were recorded. RESULTS: Between August 2005 and July 2006, 360 patients received a total of 9678 injections. Of all patients, 78.3% had at least 1 local reaction, and 7.5% had an LLR. The total local reaction rate was 16.3% (1574/9678), the small local reaction rate was 15.9% (1536/9678), and the LLR rate was 0.4% (38/9678). Of all local reactions followed by another injection, 27.2% were followed by a local reaction. The sensitivity and positive predictive value for a local reaction predicting a local reaction at the next injection were 26.2% and 27.2%, respectively. In contrast, the specificity for the absence of a local reaction predicting the absence of a subsequent local reaction was 85.5%. For LLRs, only 6.0% were followed by another LLR; the sensitivity, positive predictive value, and specificity were 5.2%, 6.0%, and 99.6%, respectively. CONCLUSION: In a clinic that does not dose-adjust for local reactions, local reactions do not predict local reactions at the next immunotherapy injection.

Comparison of serum-specific IgE (ImmunoCAP) and skin-prick test results for 53 inhalant allergens in patients with chronic rhinitis.

Prior studies comparing skin testing to serum-specific IgE testing for inhalant allergy focused on older technologies or small numbers of allergens. The purpose of this study was to compare ImmunoCAP (CAP) testing to skin prick testing (ST) for 53 inhalant allergens. Subjects > or =18 years old with chronic rhinitis and who had at least 1 positive ST to a 53 inhalant allergen panel underwent testing to an analogous CAP panel. ST was performed with the Quintip device. Using ST as a clinical gold standard, the sensitivity, specificity, positive, and negative predictive values (PPV, NPV) were calculated for CAP for each allergen. Percent agreement between testing methods was also evaluated, and the results were analyzed in association with the subjects' total IgE levels. Two-hundred fifty patients (96 male, 154 female, mean 37.1 years) were enrolled. Mean number of positive ST and CAP results were similar. The ST was more often positive for 69.8% of allergens, and 64% of patients had more positive ST than CAP. Overall, the specificity and NPV (generally 80-90%) of CAP were higher than the sensitivity and PPV. The overall agreement between tests was 80.6%, with 11.7% ST+CAP- results and 7.7% CAP+ST- results. In patients with a total IgE level > or = 200 IU/L, the percentage of positive CAP results for 52/53 allergens was significantly higher with more CAP+ST- results. The performance characteristics of CAP compared to ST vary among 53 inhalant allergens. CAP should be considered complementary, not equivalent, to ST. Total IgE levels should be obtained with serum-specific IgE testing.

The GILL study: glycerin-induced local reactions in immunotherapy.

BACKGROUND: The mechanism of local reactions is not well defined. Glycerin, an excellent preservative used commonly in immunotherapy extracts, is a recognized irritant. OBJECTIVE: This study was undertaken to examine whether higher glycerin concentration in immunotherapy extracts is associated with an increase in local reaction rates during immunotherapy. METHODS: A retrospective analysis of electronic immunotherapy records over a 12-month period was performed from a single site. A small local reaction was defined as induration and/or erythema at the injection site smaller than or equal to the size of the patient's palm. A large local reaction was defined as a reaction larger than the patient's palm. RESULTS: Over the 12-month period, 360 patients received a total of 9678 immunotherapy injections. For all injections, the total local reaction rate was 16.3% (1574/9678), the small local reaction rate was 15.9% (1536/9678), and the large local reaction rate was 0.4% (38/9678). For aeroallergens, small local reaction rates increased significantly with increasing allergen concentrations, from 7.3% (1:1000 vol/vol) to 23.0% (1:1 vol/vol; P < .001). The small local reaction rate was higher with increasing allergen content but not higher glycerin concentration. Large local reactions were infrequent and did not significantly increase with allergen or glycerin concentration. CONCLUSIONS: Small local, but not large local, reaction rates increase with higher allergen concentration, number, and volume. Higher glycerin concentrations (even 50%) are not associated with significantly higher small or large local reaction rates.

Accelerated immunotherapy schedules and premedication.

Subcutaneous immunotherapy is divided into a buildup and a maintenance phase. Accelerated immunotherapy has the advantage of a reduced number of office visits. Rush and cluster immunotherapy schedules are the most common accelerated schedules used in the United States. A cluster immunotherapy schedule involves the patient receiving several allergen injections sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is reached in 4 to 8 weeks. In rush immunotherapy protocols, higher doses are administered at intervals of 15 to 60 minutes in a period of 1 to 3 days until the maintenance dose is achieved.

Local production of IgE in the respiratory mucosa and the concept of entopy: does allergy exist in nonallergic rhinitis?

OBJECTIVE: To review research regarding locally produced IgE and its impact on patients with chronic rhinitis. DATA SOURCES: PubMed search with the following keywords: entopy, local IgE, nonallergic rhinitis, idiopathic rhinitis, vasomotor rhinitis, and allergic rhinitis. STUDY SELECTION: Articles were selected based on their relevance to entopy and locally produced IgE and its clinical effect and relationship to idiopathic rhinitis (IR). RESULTS: Local IgE has been found in a variety of tissues, including nasal and bronchial mucosa. IgE is produced in these local tissues and not simply the product of migration to the tissue from regional lymphoid tissue or blood. Local IgE has been identified in most of both atopic and nonatopic asthmatic patients and allergic rhinitis patients. Up to 40% of patients with IR and a positive nasal provocation test result have evidence of locally produced IgE, which has been coined entopy. Although patients with allergic rhinitis and IR show similar inflammatory patterns with increased activated mast cells, eosinophils, and T-cell subsets in some studies, other studies on IR patients are conflicting with regard to both inflammation and allergen-specific nasal provocation test results. CONCLUSION: The concept of local allergy in IR patients is both intriguing and controversial. Studies have reported conflicting results, and currently there is no single best test to evaluate for entopy. It is known that there are a large number of IR patients for whom current treatment regimens are suboptimal. Therefore, further research elucidating the mechanisms of IR and the concept of localized IgE are needed to optimally diagnose this condition and treat this group of patients.

A case of severe refractory chronic urticaria: a novel method for evaluation and treatment.

With cholinergic urticaria (ChU), the ultimate diagnosis often depends on the demonstration of characteristic urticaria by appropriate provocation. Several treatment options may be helpful but traditional options (antihistamines, leukotriene inhibitors, and immunosuppressives) may be exhausted by the refractory ChU patient. Here, we describe such a case. Demonstration of immediate hypersensitivity to autologous sweat skin testing (ASwST) may provide a rationale for use of omalizumab (Xolair, Genentech Novartis, South San Francisco, CA). Patients with severe ChU may have difficulty producing sufficient quantities of sweat for ASwST given that the very effort that produces the sample exacerbates ChU. Generation of sweat by iontophoresis with pilocarpine nitrate can be performed at many large medical centers. The procedure is simple, safe, and produces varying amounts of sweat depending on the individual. This sweat can then be used for ASwST. Our patient had a positive ASwST with appropriate positive and negative controls. Our testing methods were validated by negative ASwST, saline control, and positive histamine control in a nonatopic, nonurticarial control patient. By the patient's second injection of omalizumab, her quality of life score was significantly improved, as were her daily medication scores and exercise tolerance. We describe the first case of a patient with severe refractory ChU who had a positive ASwST by a novel collection method who has been successfully treated with omalizumab. We present a novel tool for the evaluation and demonstration of sweat-specific IgE in ChU patients who are unable to provide sweat by more traditional means.

T-cell epitopes of aeroallergens.

OBJECTIVE: To describe the current knowledge of the T-cell epitopes of common aeroallergens, how they were discovered, and implications for future therapy. DATA SOURCES: PubMed search of English-language articles without date limits pertaining to T-cell epitopes of aeroallergens included on a standard skin test panel. STUDY SELECTION: A total of 127 articles were screened based on the results of the PubMed search and cross-indexed as needed. The highest quality and most clinically relevant articles were included for discussion. RESULTS: Of the 47 allergen extracts included on the standard skin test panel at our instittition, T-cell epitopes have been described for 13. Immunodominant epitopes have been used for peptide immunotherapy trials. CONCLUSIONS: T-cell epitopes have been characterized for a minority of common aeroallergens. However, knowledge is rapidly expanding and can lay the groundwork for therapies that specifically target T cells.

The role of intradermal skin testing in inhalant allergy.

OBJECTIVE: To provide an overview of the role of intradermal skin testing (IDST) in inhalant allergy. DATA SOURCES: A literature search was conducted in MEDLINE to identify peer-reviewed articles related to IDST using the following keywords: skin testing, intradermal, intracutaneous, aeroallergen, and inhalant allergen. In addition, references cited within these articles were also reviewed. STUDY SELECTION: Articles were selected based on their relevance to the topic. RESULTS: The use of IDST for inhalant allergy varies widely among allergists. When performed, it is necessary to use a 100- to 1,000-fold dilution from the stock allergen extract. IDST is used routinely in the standardization of extracts in the United States. With a negative skin prick test result, a positive IDST result has low agreement with in vitro and challenge results and generally adds little to the diagnostic evaluation. In contrast, a negative IDST result generally has a high negative predictive value. Only a few inhalant allergens have been evaluated with challenge models for IDST. A summary of the data is also presented in tabular form. CONCLUSIONS: Most of the literature suggests that with a negative skin prick test result, a positive IDST result adds little to the diagnostic evaluation of inhalant allergy. However, additional studies are necessary using challenge models for less potent and nonstandardized inhalant allergens (molds, trees, dog, weeds).

Aeroallergen sensitization rates in military children with rhinitis symptoms.

BACKGROUND: Childhood sensitization rates for many aeroallergens are underreported. OBJECTIVES: To examine aeroallergen sensitization rates in military children undergoing skin testing for rhinitis and investigate the timing of atopic development for perennial and seasonal allergens. METHODS: A skin testing database was retrospectively analyzed. Children 18 years and younger referred for rhinitis underwent skin prick testing to either a screening panel of 8 tests or a standard panel of 51 allergens. RESULTS: A total of 209 patients underwent skin testing to the 8-test panel. Of these patients, 35.4% had at least 1 positive result. Atopy increased with age, from 6.3% in those younger than 1 year to 58.8% in those 5 years old. The most common allergens were mold mix (16.3%), cat (13.2%), dust mite mix (11.4%), tree mix (9.4%), and grass mix (9.4%). Only 4.0% were sensitized to seasonal aeroallergens before the age of 3 years. A total of 345 children underwent testing to a 51-allergen panel. A total of 80.3% had at least 1 positive test result, and the average number of positive test results was 11.4. Both the percentage of atopy and the average number of positive skin test results increased with age. The most common allergens were grasses, Alternaria, and cottonwood. Thirty-two of 51 allergens were positive in 20% or more children. Rates for many underreported allergens are presented. CONCLUSIONS: In children, aeroallergen sensitization rates are high and increase with age. Perennial allergens predominate up to the age of 3 years. Rates for many underreported allergens are presented. Although performed in a military population, these results should be applicable to many practices.

Prevalence of positive skin test responses to 53 allergens in patients with rhinitis symptoms.

Prior studies looking at allergic sensitization have focused on narrow age ranges or small numbers of allergens. This study is the first to examine the prevalence of positive skin test responses in a symptomatic military population with a wide age range of patients and large number of allergens. This study was a retrospective analysis of our skin test database. We included 1137 patients aged 4-79 years old who underwent our standard skin-prick testing panel of 53 aeroallergens and 2 controls using the Quintest device (Hollister-Stier, Spokane, WA). Results indicated that 81.6% of patients had at least one positive skin test. Rates of atopy were similar between male and female patients; 9.2% of patients were monosensitized. The average number of positive skin tests peaked in the 10- to 19-year age group at 13.1 and declined in older age groups. The prevalence of atopy peaked in the 30- to 39-year age group at 85.5% and decreased in older age groups. The most common allergens were grasses, mountain cedar, and dust mites. Sensitization rates for many underreported allergens, including mouse and rat, are presented. This study shows that 81.6% of patients in a symptomatic military population were atopic. These rates are high, even when compared with other allergic populations. Atopy peaked in young adulthood and declined in older age groups. Grasses, mountain cedar, and dust mites were the most common allergens. Although performed in a military population, these results should be applicable to many allergy practices.