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Purpose of Review: B cell disorders result in decreased levels or function of immunoglobulins in an individual. Genetic mutations have been reported in a variety of B cell disorders. This review, in follow-up to a previous review, describes some rare B cell disorders as well as their known underlying genetic etiologies., Recent Findings: Genetic studies identify and permit precise classification of an increasing number of B cell disorders, leading to a greater understanding of B cell development and function. The B cell disorders are rare diseases. While clinicians are most familiar with X-linked agammaglobulinemia and so-called common variable immunodeficiency (CVID), there are many causes of hypogammaglobulinemia. Genetic testing provides a specific diagnosis, offers useful information for genetic counseling, and can identify previously unrecognized B cell disorders.

Purpose of Review: The advent of enhanced genetic testing has allowed for the discovery of gene defects underlying two broad categories of antibody deficiency in children: agammaglobulinemia and common variable immunodeficiency (CVID). This review describes the underlying gene defects and the clinical manifestations., Recent Findings: Because novel monogenetic defects have been discovered in both categories, a strict dichotomous classification of B cell disorders as either X-linked agammaglobulinemia or common variable immunodeficiency is no longer appropriate. Advances in genetic testing technology and the decreasing cost of such testing permit more precise diagnosis of B cell disorders, more helpful information for genetic counselors, and a better understanding of the complex process of B cell development and function. More disorders await discovery.

Purpose: Allergic rhinitis (AR) is a highly prevalent disease, affecting the quality of life of millions of Americans. Intranasal corticosteroids (INCs) are widely recommended as first-line therapy for moderate to severe AR. Although these drugs exhibit similar safety and efficacy, a potentially differentiating factor within this class is the varying sensory attributes associated with each INC. The objective of this literature review was to evaluate product characteristics, sensory attributes, and patient preferences of fluticasone furoate intranasal spray (FFNS) compared with other INCs., Methods: A narrative literature search for studies evaluating FFNS was performed in MEDLINE and Google Scholar. Key terms included "allergic rhinitis," "anti-allergic agents," "intranasal administration," "fluticasone furoate," and "patient preference." Studies published from 2007 to present were included. Nine trials met the search criteria, each evaluating FFNS versus placebo or other INCs for efficacy, safety, and/or preference, and were included. Approximately 2400 patients with AR were enrolled across varying study protocols., Findings: In 4 placebo-controlled trials, FFNS showed significant efficacy in relieving symptoms of AR and a tolerable safety profile. Three trials evaluating FFNS and fluticasone propionate nasal spray (FPNS) found that FFNS was significantly preferred over FPNS regarding scent, aftertaste, and leakage down the throat/nose. The results of 2 trials found that FFNS was preferred overall over mometasone furoate nasal spray (MFNS)., Implications: INCs are effective first-line treatments for AR and show significant reduction in nasal and ocular symptoms. Patients preferred the scent, aftertaste, and mist gentleness of FFNS ∼2:1 over the same sensory attributes of FPNS. Patients experienced less negative sensory characteristics with FFNS compared with MFNS, preferring FFNS to MFNS overall. Selecting an INC with favorable attributes in accordance with patient preferences could potentially improve adherence, therapeutic outcomes, and health care costs., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Many genetic conditions predispose affected individuals to opportunistic infections. A number of immunodeficiency diseases, including genetic defects termed Mendelian susceptibility to mycobacterial disease (MSMD), permit infection from many different strains of mycobacteria that would otherwise not cause disease. These include tuberculous and nontuberculous mycobacteria, and bacille Calmette-Guérin vaccine (BCG). Patients may present with infections from other organisms that depend on macrophage function for containment. Defects in multiple genes in the IL-12 and NFKB signaling pathways can cause the MSMD phenotype, some of which include IL12RB1, IL12B, IKBKG, ISG15, IFNGR1, IFNGR2, CYBB, TYK2, IRF8, and STAT1., Recent Findings: Multiple autosomal recessive and dominant, and 2 X-linked recessive gene defects resulting in the MSMD phenotype have been reported, and others await discovery. This review presents the known gene defects and describes clinical findings that result from the mutations. If MSMD is suspected, a careful clinical history and examination and basic immunodeficiency screening tests will narrow the differential diagnosis. A specific diagnosis requires more sophisticated laboratory investigation. Genetic testing permits a definitive diagnosis, permitting genetic counseling. Mild cases respond well to appropriate antibiotic therapy, whereas severe disease may require hematopoietic stem cell transplantation.

Purpose: Allergic rhinitis is a highly prevalent disease affecting the quality of life of millions of North Americans. The management of allergic rhinitis includes allergen avoidance, pharmacotherapy, and immunotherapy. Current pharmacologic options include oral and intranasal antihistamines, intranasal corticosteroids, oral and intranasal decongestants, oral and intranasal anticholinergics, and leukotriene receptor antagonists. Second-generation oral antihistamines and intranasal corticosteroids are the mainstays of treatment, with practice guidelines recommending intranasal corticosteroids as first-line treatment for moderate to severe allergic rhinitis., Methods: Clinical trials studying a widely used intranasal corticosteroid, fluticasone propionate, in comparison with second-generation oral antihistamines, cetirizine, loratadine, or montelukast, were selected to support the comparative review of the efficacy and tolerability of these 2 classes of medications. Studies evaluating the combination of fluticasone propionate with an oral antihistamine were also included to review the efficacy and tolerability of combination therapy to treat allergic rhinitis., Findings: Studies comparing fluticasone propionate with cetirizine had mixed findings; fluticasone propionate was found to have equal or greater efficacy in reducing nasal symptom scores. Combination therapy of fluticasone propionate and the oral antihistamine, loratadine, was found to have efficacy comparable with that of intranasal corticosteroid alone., Implications: Many of these medications are available over the counter in the pharmacy, and the community pharmacist plays an important role as part of the patient's health care team in managing this disease. Pharmacotherapy is patient-specific, based on type, duration, and severity of symptoms, comorbidities, prior treatment, and patient preference. This article aims to provide an overview of the pathophysiology, available treatment options, guideline recommendations, and role of the pharmacist for this disease., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Healthy children may develop candidal infections as the result of exposure to antibiotics or corticosteroids, but chronic candidiasis in children after the newborn period is unusual. Chronic mucocutaneous candidiasis (CMC) refers to a group of conditions characterized by recurrent or persistent infections with Candida species, particularly Candida albicans. CMC is a phenotype observed in a spectrum of immunologic disorders, some with endocrinologic and autoimmune features., Recent Findings: CMC can arise secondary to inherited or acquired T cell deficiencies, but in children is largely due to inborn errors impairing the dectin pathway and IL-17 immunity. We review the current understanding of the pathogenesis of chronic mucocutaneous candidiasis and discuss the immunologic pathways by which the immune system handles Candida. We highlight the historical and recent knowledge of CMC in children, emphasizing recent insights into basic science aspects of the dectin pathway, IL-17 signaling, consequences of AIRE gene defects, and clinical aspects of inheritance, and features that distinguish the different syndromes. The clinical phenotype of CMC has many underlying genetic causes. Genetic testing is required for definitive diagnosis.

A recreational scuba diver wore a second scuba regulator against his face during a scuba dive, attached by an elastic rubber cord necklace. After surfacing, the diver's left face became swollen. Through a process of elimination all other items of scuba equipment were excluded as potential causes. A dive with the same equipment minus the necklace confirmed the involvement of the necklace in the pathogenesis of the hypersensitive reaction. In vitro ImmunoCap IgE assay was positive to latex (1.30 kUa/L), subsequent patch testing for contact dermatitis provoked a reaction for benzophenone-4, (a UV stabalizer) and Fourier Transform Infra Red spectroscopy identified the elastic as ethylene propylene rubber, containing additional unidentified compounds. Allergy to natural rubber latex occurs in as many as 6% of Americans and Australians. Around three million American residents are thought to scuba dive each year. Recreational divers are, therefore, advised to check such necklaces, which are typically worn around the throat, for frayed ends and exposed rubber filaments., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The ability to perceive the onset and severity of symptoms of worsening asthma is important, not only for initial diagnosis but also for early identification of an asthma exacerbation and prompt management. There are subjective and objective methods for identifying symptoms. Symptom perception is affected by multiple mechanisms, and not all patients can accurately perceive symptoms of airflow limitation. Hyperperceivers will report substantial discomfort in the face of minimal bronchoconstriction, and poor perceivers will report no symptoms even in the presence of severe obstruction. The use of objective measures of airflow limitation is essential for such patients. Regimens for training perception in children and adults have been studied and are available.

Background: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells., Methods: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates., Results: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients., Conclusions: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies., (Copyright © 2012 S. Karger AG, Basel.)

Objective: To review major milestones in the development of subcutaneous allergen immunotherapy in 20-year segments., Data Sources: Review of the literature available in textbooks and journals., Study Selection: Articles and books addressing major achievements in the development of subcutaneous allergy immunotherapy were selected for inclusion in this review., Results: Immunotherapy administration has improved the lives of possibly millions of patients with hay fever. Asthmatic symptoms have been relieved if not ablated in millions as well. Insect venom hypersensitivity became treatable and highly effective. In the beginning years of immunotherapy, it was clear that immunotherapy worked; in the later years, the mechanisms for this efficacy were discovered. In this case, the therapy preceded its validation. Methods, materials, and safety have vastly improved. Postulated mechanisms explain much but not everything., Conclusions: There is still research to be accomplished, improvements to be made, and, of course, patients to be made well., (Copyright © 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The links between asthma and rhinitis are well characterized. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines stress the importance of these links and provide guidance for their prevention and treatment. Despite effective treatments being available, too few patients receive appropriate medical care for both diseases. Most patients with rhinitis and asthma consult primary care physicians and therefore these physicians are encouraged to understand and use ARIA guidelines. Patients should also be informed about these guidelines to raise their awareness of optimal care and increase control of the two related diseases. To apply these guidelines, clinicians and patients need to understand how and why the recommendations were made. The goal of the ARIA guidelines is to provide recommendations about the best management options for most patients in most situations. These recommendations should be based on the best available evidence. Making recommendations requires the assessment of the quality of available evidence, deciding on the balance between benefits and downsides, consideration of patients’ values and preferences, and, if applicable, resource implications. Guidelines must be updated as new management options become available or important new evidence emerges. Transparent reporting of guidelines facilitates understanding and acceptance, but implementation strategies need to be improved.

Allergic Aspergillus sinusitis is a type of allergic fungal sinusitis (AFS), a form of chronic rhinosinusitis with pathological findings similar to those seen in allergic bronchopulmonary aspergillosis (ABPA). There are no evidence-based criteria for diagnosis or management, and the pathogenesis is unknown. Known risk factors are underlying chronic rhinitis, exposure to Aspergillus fumigatus, and the ability to make an IgE-mediated allergic response to that organism. While many individuals meet these conditions, it is not known why only some go on to develop allergic Aspergillus sinusitis. Speculative risk factors are unknown conditions permitting fungal growth, concomitant superantigen responses, and HLA associations.

Although some older antihistamines have a relatively slow onset of action, modern agents indicate an efficacy between 1 and 3 hours of administration. For patients who use antihistamines regularly, a short onset of action is relatively unimportant. When antihistamines are used as needed, either because of poor compliance or in accordance with emerging therapeutic guidelines, antihistamines with a short onset of action are preferable.

Background: Familial cold autoinflammatory syndrome (FCAS), formerly known as familial cold urticaria, is a rare condition characterized by fever, rash, and arthralgias elicited by exposure to cold. Recently, mutations responsible for FCAS were identified in a novel gene (CIAS1), making it possible to confirm the diagnosis in most patients., Objective: We present a summary of clinical data from a large family with FCAS to further define the characteristics of the disorder and to validate previously proposed clinical criteria., Methods: A total of 73 participants were evaluated by interview and questionnaire, including 36 affected individuals. Responses from the questionnaire were analyzed and comparisons of proportions were made using the Z test. DNA was isolated and genotyping was performed on all subjects. Affected haplotypes (genotype patterns) were identified and used to confirm the diagnosis. Sequencing of the CIAS1 gene was performed in selected patients to confirm the mutation., Results: The prevalence of rash, fever/chills, joint complaints, nausea, headache, and thirst were not significantly different from previously reported proportions. There was statistically significant differences in conjunctivitis, sweating, and drowsiness with alpha = 0.01. The mean temperature required to produce symptoms was 22 degrees C, and the average earliest onset of symptoms after exposure was 1.5 hours., Conclusions: Applying the proposed clinical criteria, 41% of affected subjects met all six criteria, 90% met five criteria, and 100% met four criteria for FCAS. None of the unaffected subjects met more than two criteria. Using a threshold of 4 of 6 clinical criteria, the data support the diagnostic validity of the proposed clinical criteria.

Background: Allergic bronchopulmonary mycosis is primarily caused by Aspergillus fumigatus. Despite similarities, allergic fungal sinusitis (AFS) is thought to be caused by various fungi., Objective: Identify fungal elements in AFS allergic mucin and determine the prevalence of specific immunoglobulin (Ig)E to recombinant A. fumigatus allergens (rAsp) in AFS patients., Methods: Allergic mucin from 17 definitive and 10 probable AFS patients were histologically examined for fungal elements. Sera from 18 definitive AFS patients, 10 probable AFS patients, 6 chronic sinusitis patients, and 5 A. fumigatus-allergic patients were tested for specific IgE to A. fumigatus and five rAsps., Results: Ten of the 17 definitive cases had hyphae morphologically resembling Aspergillus or Fusarium spp. One probable AFS patient had similar findings. Of definitive patients, 94% (17 of 18) showed A. fumigatus-specific IgE (> or = 0.35 kUa/L), and 67% were positive to one or more rAsp. Four of 10 probable patients demonstrated A. fumigatus-specific IgE, and 2 had IgE to one or more rAsp. The definitive group had greater mean A. fumigatus IgE (P < 0.05) versus the probable and chronic sinusitis groups. The definitive group's rate of IgE to the rAsps was statistically greater. All definitive patients with Aspergillus or Fusarium spp. in situ had A. fumigatus-specific IgE, and 7 of 10 had IgE to at least one rAsp., Conclusions: Most definitive AFS patients have A. fumigatus-specific IgE and many have specific IgE to rAsps. Many also demonstrate Aspergillus spp. or Fusarium spp. in situ. Findings suggests that A. fumigatus is an important causative agent in AFS in the southeast United States.

Although several methods for estimating avidity of antigen-antibody reactions are available, most are impractical for the study of human IgE antibodies because of a requirement for pure allergen and antibody in relatively large amounts. To determine the relative avidity of specific IgE antibodies for Dermatophagoides pteronyssinus allergens, seven concentrations of the chaotropic thiocyanate ion were used to disrupt epitope-antibody binding in a specific IgE immunoassay system, using sera from 16 allergic patients with marked skin test reactivity to a standardized D. pteronyssinus extract. Relative avidity, the molarity of thiocyanate required to produce a 50% decrement in binding, ranged from 0.29-3.1. Within assay coefficient of variation (CV) was 9.9% and between assay CV was 13%. D. pteronyssinus specific IgE levels ranged from 0.66-141 kUa/L, not correlating with relative avidity (rho = -0.12). Thiocyanate elution appears to be a useful method for estimating relative avidity of specific IgE antibodies for the myriad epitopes of the allergenic proteins in an allergen extract. It could be used to study the immunochemistry of specific IgE assays; avidity maturation in allergen immunotherapy and in asymptomatic but sensitized patients; and preseasonal versus postseasonal changes in avidity within individuals. With a suitable solid phase, it could be modified to examine avidity at the epitope level.

Background: Patients with allergic fungal sinusitis demonstrate skin test reactivity to many fungal extracts. Various fungi have been isolated from the characteristic allergic mucin., Objective: This study was designed to identify allergens in allergic mucin and to compare them to those found in commercial fungal extracts., Methods: Allergic mucin was collected during functional endoscopic sinus surgery from 11 patients meeting strict diagnostic criteria for allergic fungal sinusitis and from three allergic rhinitis patients with chronic sinusitis. A portion was solubilized in saline and centrifuged. To identify allergens, proteins in allergic mucin and fungal extracts were separated by SDS-polyacrylamide gel electrophoresis, transferred to nitrocellulose and immunostained using patient sera and enzyme-labeled anti-human IgE., Results: All patient sera recognized numerous bands ranging from 18 to 90 kD. In mucin, bands were consistently found in the 35 to 50 kD range. Corresponding bands in fungal extracts were found in only 1/11 patients with allergic fungal sinusitis. Sera from 4/11 patients detected an 18-kD protein in allergic mucin, but sera from all patients with allergic fungal sinusitis recognized an 18-kD protein in commercial fungal extracts. Sera from selected patients with allergic fungal sinusitis detected human epithelial proteins in the 35 to 50 kD range., Conclusions: Fungal allergens were not detected in allergic mucin of all patients with allergic fungal sinusitis. The 18-kD allergen appears to be shared by many fungi, and may be a fungal panallergen. The source of the apparent allergens in the 3550-kD range warrants further study.

Background: In allergic fungal sinusitis diagnostic and monitoring criteria are not firmly established, and the role of eosinophils in pathogenesis is not clear., Objective: To determine whether assessment of eosinophil activation by measurement of eosinophil cationic protein in serum or allergic mucin would be useful in distinguishing patients with allergic fungal sinusitis from patients with chronic sinusitis of other etiologies., Methods: Thirteen patients referred for possible allergic fungal sinusitis were evaluated and given a definite allergic fungal sinusitis diagnosis if they met five of the following six criteria: (1) history and physical not suggesting another etiology, (2) sinus computed tomography consistent with allergic fungal sinusitis, (3) typical allergic mucin, (4) fungus isolated from allergic mucin, (5) presence of fungal-specific IgE, and (6) elevated total IgE. Eosinophil cationic protein, a marker of eosinophil activation, was measured in serum and allergic mucin., Results: Nine patients met criteria for allergic fungal sinusitis. All patients had nasal polyps and were atopic. Eight of the patients had allergic rhinitis and three had asthma. Mean total IgE at surgery was 1,385 IU/mL. A fungus was isolated from allergic mucin of eight patients. All patients demonstrated fungal-specific IgE. Mean allergic mucin eosinophil cationic protein levels obtained at surgery were significantly higher in patients with allergic fungal sinusitis than in four patients not meeting strict diagnostic criteria, and in 16 control patients having sinus surgery for other indications. There was no significant difference in serum eosinophil cationic protein levels between the three groups. Serial allergic mucin eosinophil cationic protein levels appeared to correspond with disease activity in some allergic fungal sinusitis patients., Conclusions: Eosinophils in allergic mucin are activated. Measuring eosinophil cationic protein may be useful in diagnosis of allergic fungal sinusitis and in monitoring response to therapy.

Background: Eosinophilic inflammation plays a central role in the pathogenesis of asthma. Striking inflammatory changes are present in the airways of patients with all levels of disease severity. The degree of airway inflammation correlates with airway hyperresponsiveness, the primary physiologic abnormality of asthma. Inflammation is typically initiated by immunologic events (including allergy) and is driven by mediators released by various cells of the immune system, particularly eosinophils, monocytes and macrophages, lymphocytes, and mast cells., Methods: Literature on asthma and the inflammatory response was drawn from recent articles presented and reviewed in journal clubs and from selected articles from the National Library of Medicine., Results and Conclusions: The inflammatory process can be divided into six steps: triggering, signaling, migration, inflammatory cell activation, tissue damage, and resolution. Recognition of the importance of inflammation in the pathogenesis of asthma and the progression of the disease has shifted research efforts and the development of new therapeutic agents toward reduction of airway inflammation. Anti-inflammatory therapy, which can be directed against specific steps in the inflammatory process, actually reduces bronchial hyperresponsiveness. Although anti-inflammatory management has assumed a primary role in asthma therapy, short acting beta 2-adrenergic receptor agonists are needed for treatment of acute symptoms, and some patients require regular beta 2-agonist therapy despite apparently adequate anti-inflammatory therapy.

Objective: To review the classification of fungal sinusitis as well as discuss current approaches to diagnosis and management., Data Sources: A MEDLINE literature search was performed using the index terms sinus infection, fungal, diagnosis, radiology, microbiology, and treatment. The search was restricted to the English language and human subjects. With one exception the references were restricted to the last 10 years. Clinical data from studies performed at our institution were also included., Results: Fungal sinusitis can be divided into four primary categories: (1) acute/fulminant (invasive), (2) chronic/indolent (invasive), (3) fungus ball, and (4) allergic fungal sinusitis. Each subtype has unique immunologic, pathologic, and clinical features. Allergic fungal sinusitis is the most recently described and most common form. The treatment and prognosis of fungal sinusitis varies significantly among the four different categories., Conclusion: Recent advances in endoscopy and computed tomography have enhanced the understanding of fungal sinusitis; however, they remain diseases surrounded by controversy. New insights into the etiology and pathogenesis of these diseases along with advances in diagnosis and treatment will lead to improved medical therapy.

Background: In vitro testing for fire ant sensitization would be useful for research purposes and in special clinical situations., Methods: Laboratory performance of a commercial assay (Pharmacia CAP System, [PCS]), for specific IgE to Solenopsis invicta whole body extract was studied in 46 persons. Assay results were compared with those of venom skin testing, RAST, and ELISA. The manufacturer's global cutoffs were compared with cutoffs set by using methods derived from analytical detection limit theory., Results: Thirty-two study subjects had positive skin test results, and 14 had negative results. Raw PCS data demonstrated a high level of correlation with RAST (rho = 0.941) and ELISA (rho = 0.931), and showed good correlation with skin testing (rho = -0.769). Analysis of binormal receiver operating characteristic curves, using skin test results as the reference standard, demonstrated no difference in performance among the three assays. The fixed global quantitative cutoff of 0.35 kUa/L was relatively insensitive. Use of the manufacturer's qualitative alternate scoring method cutoff substantially increased sensitivity without loss of specificity, as did lower limit of detection set by use of diluent., Conclusions: In situations in which skin testing for fire ant sensitization is not feasible, PCS appears to be an acceptable in vitro alternative method for determination of fire ant allergen-specific IgE.

One of the major sources of uncertainty and controversy in allergy testing is the definition and clinical significance of a positive test result in the low assay range. Use of analytical detection limit theory can guide the diagnostic allergy laboratory director in setting a lower assay cutoff and in the evaluation of the recommended cutoff by the manufacturer of the assay. Several methods for calculating lower limit of detection are applicable to specific IgE assay methods. Receiver operating characteristic (ROC) curves illustrate the relationship between statistical sensitivity and specificity as cutoffs are adjusted, and statistical analysis of ROC curves is an invaluable aspect of the comparative performance evaluation of two or more assays relative to an independent standard such as skin testing.

The beta 2 adrenoceptor has been cloned and sequenced, and details of how agonist stimulation ultimately results in clinically evident effects are now known. Receptor desensitization by agonist is an almost universal process that can be prevented and reversed by corticosteroids. Although immunologic mechanisms appear to prevail in asthma, beta 2 receptor dysfunction may be important in some circumstances. Many receptor agonists are available for asthma therapy, including a new generation of long acting agents (such as salmeterol) with duration of action of 12 hours or more. Statistical links between beta agonist use and asthma mortality or morbidity warrant careful examination for clinical relevance, but may not be dismissed. Beta agonists are relatively safe and clearly effective in asthma, but anti-inflammatory management (including allergen avoidance and immunotherapy when appropriate) is indicated in patients who require chronic therapy.

Pollen patterns were compared between Vail, CO (8,200 feet elevation), Aspen, CO (7,900 feet) and Denver, CO (5,280 feet) from 1984 through 1988. Counts were obtained at all sites with a volumetric intermittent cycling rotating impaction sampler. Aspen and Denver were compared in 1984, and Vail and Denver from 1985 through 1988. While counts were generally lower in the mountain sites than Denver, certain pollens, especially trees, were quite high. Ragweed was essentially absent from Aspen and Vail, and chenopod-amaranth counts were very low. Cedar, pine, and aspen frequently pollinated despite active snowfall.

The allergen-specific backgrounds of a paper disk radioimmunoassay (RIA) system and a cellulose sponge fluorescent enzyme immunoassay (FEIA) system were evaluated using three inhalants, timothy, short ragweed, and cat, with reagents obtained from the same manufacturer. Radioimmunoassay was performed with Phadebas RAST reagents by the modified RAST method, and FEIA by the Pharmacia CAP System. Horse serum, 5% HSA, assay diluent, and serum pools from nonallergic and allergic patients, were assayed. The lower limit of detection (LLD) was defined using both the Z distribution (as is conventional) and the t distribution. The solid phases, analytes, and assays differed (p less than .001) in background results. For RIA, background was lowest for timothy and highest for cat; for FEIA, background was lowest for cat and highest for short ragweed. For RIA, background assessed with the allergic serum pool was higher than the other analytes; for FEIA, responses of the five analytes did not differ. For timothy and short ragweed, background of RIA was lower than FEIA. For FEIA, the highest LLD calculated using the Z distribution was 11 SD lower than the manufacturer's recommended quantitative cutoff; for RIA, the highest LLD calculated was 2.5 SD higher than the recommended analytic cutoff. The analytic false positive rate for RIA may differ between allergic and nonallergic patient populations. Laboratories reporting results near either assay's background should set LLD based on assay of allergen-specific negative controls in each assay run.

Interest in immunoassay standardization has prompted development of specific IgE assays reporting results related to the international IgE reference. To examine the single point calibration curve employed in the modified RAST assay (MRT) to convert MRT counts to IgE units, independent dilutions of a 25 kU/L total IgE reference and nine allergic sera (three each for short ragweed, cat, and timothy) were made in horse serum and assayed. In a log-log plot, the single point curve was, by definition, linear over its entire range; the dilution curve was curvilinear because of reagent system saturation, which was at 7 kU/L. Curves were not parallel (P less than .001). Allergen-specific dilution curves showed saturation points at values similar to or less than the total IgE system. The linear portions of these curves paralleled the total IgE dilution curve but not the single point curve. This lack of parallelism would have resulted in varying magnitudes of error in estimation of IgE antibody levels in the upper and lower assay ranges, and would imply a lower detection limit for IgE than that which the assay actually has. Modified RAST assay is not appropriate in research or a clinical situation in which accurate quantitative results are needed. Modified RAST assay would furthermore be an inappropriate means of assigning units to proposed reference preparations for standardization.

The histamine content of 108 inhalant, food, and venom extracts from four commercial sources was measured by chemical (glass fiber-based) and immunologic (competitive RIA) methods. Histamine was present in 64 of 76 inhalant extracts (range, 0.005 to 7.4 micrograms/ml), 20 of 26 food extracts (range, 0.16 to 23 micrograms/ml), and six of six venoms, 100 micrograms/ml (range, 1.0 to 38 micrograms/ml). Histamine was removed by treatment with diamine oxidase or dialysis of an extract. Repeat assay of selected extracts after addition of known amounts of histamine in the glass fiber-based method produced additive results, and glycerin- or phenol-extract preservatives did not affect assay performance. Timed extractions of dried-pollen grains demonstrated maximal histamine content at 30 seconds, suggesting that histamine is an inherent component of at least some pollens. Histamine found in some allergen extracts could, under extreme circumstances, produce false-positive results in skin testing and in basophil histamine release assays, and could affect the result of research that uses intact pollen or allergen extracts.