Christopher W. Calabria

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.

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 patients 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.

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 patients palm), large local reactions (LLRs; larger than the patients 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.

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 patients 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.

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.

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.

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.

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.

Current Evidence on Safety and Practical Considerations for Administration of Sublingual Allergen Immunotherapy (SLIT) in the United States

Liquid sublingual allergen immunotherapy (SLIT) has been used off-label for decades, and Food and Drug Administration (FDA)-approved grass and ragweed SLIT tablets have been available in the United States since 2014. Potentially life-threatening events from SLIT do occur, although they appear to be very rare, especially for FDA-approved products. Practice guidelines that incorporate safety precautions regarding the use of SLIT in the United States are needed. This clinical commentary attempts to address unresolved issues including controversy regarding the FDA mandate for the prescription of epinephrine autoinjectors for patients on SLIT; how to approach polysensitized patients; optimal timing and duration of SLIT administration; how to address gaps in therapy; whether antihistamines can prevent local reactions, if certain patient populations (such as persistent asthmatics) should not receive SLIT; and when to instruct patients to self-administer epinephrine. Key points are that physicians should focus on educating patients regarding: (1) when not to administer SLIT; (2) how to recognize a potentially serious allergic reaction to SLIT; and (3) when to administer epinephrine and seek emergency care.