Clinical reactivity to insect stings.

PURPOSE OF REVIEW: Allergy to insect stings remains a hazard worldwide and is the object of updated guidelines on management. This paper reviews the various clinical responses that may occur following an insect sting. RECENT FINDINGS: Although the general population is at slight risk, certain groups are more susceptible, including occasionally stung adult male agricultural workers, hobby honey beekeepers and family members of beekeepers. Individuals with systemic mastocytosis are especially reactive to stings. The body of evidence attesting to the marked beneficial effect that 3-5 years of venom immunotherapy has on the natural history of hymenoptera hypersensitivity is especially evident in children. Case reports indicate other consequences of hymenoptera sting, and these are discussed. SUMMARY: Hypersensitivity to insect stings is common and may be life threatening. Although most occur away from medical facilities, their diagnosis and management are important to a wide spectrum of health care professionals. Most reactions to stings are nonallergic manifestations of the venom's toxic effects, and present as erythema, pain and swelling about the sting site. Fire ants bite with their mandibles and pivot their head, inflicting multiple stings that usually result in a sterile pseudopustule at the site. Hypersensitivity responses to venom range from large local reactions (a late-phase response) to life-threatening anaphylaxis. Venom-specific immunotherapy is highly effective in the modification of subsequent reactions to hymenoptera stings, as is whole body extract for fire ant stings.

A four-way, double-blind, randomized, placebo controlled study to determine the efficacy and speed of azelastine nasal spray, versus loratadine, and cetirizine in adult subjects with allergen-induced seasonal allergic rhinitis.

BACKGROUND: Azelastine has been shown to be effective against seasonal allergic rhinitis (SAR). The Environmental Exposure Unit (EEU) is a validated model of experimental SAR. The objective of this double-blind, four-way crossover study was to evaluate the onset of action of azelastine nasal spray, versus the oral antihistamines loratadine 10 mg and cetirizine 10 mg in the relief of the symptoms of SAR. METHODS: 70 participants, aged 18-65, were randomized to receive azelastine nasal spray, cetirizine, loratadine, or placebo after controlled ragweed pollen exposure in the EEU. Symptoms were evaluated using the total nasal symptom score (TNSS). The primary efficacy parameter was the onset of action as measured by the change from baseline in TNSS. RESULTS: Azelastine displayed a statistically significant improvement in TNSS compared with placebo at all time points from 15 minutes through 6 hours post dose. Azelastine, cetirizine, and loratadine reduced TNSS compared to placebo with an onset of action of 15 (p < 0.001), 60 (p = 0.015), and 75 (p = 0.034) minutes, respectively. The overall assessment of efficacy was rated as good or very good by 46% of the participants for azelastine, 51% of the participants for cetirizine, and 30% of the participants for loratadine compared to 18% of the participants for placebo. CONCLUSIONS: Azelastine's onset of action for symptom relief was faster than that of cetirizine and loratadine. The overall participant satisfaction in treatment with azelastine is comparable to cetirizine and statistically superior to loratadine. These results suggest that azelastine may be preferential to oral antihistamines for the rapid relief of SAR symptoms.

Factors that affect the allergic rhinitis response to ragweed allergen exposure.

BACKGROUND: People with seasonal allergic rhinitis (SAR) respond to allergen exposure differently. OBJECTIVE: To determine the factors that affect the rate and degree of symptom development upon controlled allergen exposure. METHODS: Study participants underwent skin prick testing (SPT) to selected aeroallergens, completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and the 36-Item Short Form Health Survey, and provided a detailed allergy and exposure history. Nasal eosinophil counts and late-phase responses to SPT were measured. Eligible participants underwent a 3-hour ragweed pollen exposure in the Environmental Exposure Unit, rating rhinoconjunctivitis symptoms every 30 minutes. Data were analyzed using a mixed-effects model for repeated measures. RESULTS: One hundred twenty-three participants completed the study. Skin test reactivity to ragweed was not correlated with the rate of symptom development or with severity. Participants with positive SPT reactions to dust mite, dog, or grass and those with self-reported symptoms to dog or cat exposure tended to develop symptoms earlier and to a greater degree by 90 minutes. Self-report of SAR symptoms during the ragweed or grass season and RQLQ scores were positively associated with the rate and degree of symptom development. No other significant associations were detected. CONCLUSIONS: The rate of symptom development upon ragweed exposure was related to concomitant hypersensitivity to perennial allergens and grass pollen as determined by SPT and clinical history. The RQLQ was a powerful predictor of the priming response to ragweed, showing a dose-response-type association. These data suggest that a "prepriming" phenomenon is present in patients with SAR. No correlation was shown between symptomatic responses and degree of SPT reactivity.

Efficacy of loratadine-montelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit.

BACKGROUND: Nasal congestion is considered to be one of the most bothersome symptoms of allergic rhinitis (AR) and often the most difficult to treat. Oral therapies providing safe, effective, and reliable relief of AR symptoms, including nasal congestion, are limited. OBJECTIVE: To evaluate the efficacy of a single dose of loratadine-montelukast (10 mg/10 mg) vs placebo and phenylephrine (10 mg) in relieving nasal congestion over 6 hours after ragweed pollen exposure in the environmental exposure unit at the Kingston General Hospital. METHODS: After a screening visit and up to 6 priming visits, patients who met minimum symptom requirements during ragweed pollen exposure were randomized to receive loratadine-montelukast, phenylephrine, or placebo. Patients evaluated nasal congestion and other symptoms of AR and measured peak nasal inspiratory flow before dosing and at 20-minute intervals during the subsequent 8 hours of pollen exposure. RESULTS: During the first 6 hours after treatment (primary end point), loratadine-montelukast treatment resulted in greater improvement in the mean nasal congestion score vs placebo (P = .007) and phenylephrine (P < .001). Loratadine-montelukast was more effective than placebo (P < or = .02) and phenylephrine (P < or = .002) in relieving total symptoms, nasal symptoms, and nonnasal symptoms and in improving peak nasal inspiratory flow. There were no statistically significant differences between phenylephrine and placebo for any measures. Fewer patients in the loratadine-montelukast group (3.9%) reported adverse events than in the phenylephrine (7.9%) and placebo (7.1%) groups; most adverse events were mild or moderate. CONCLUSIONS: Loratadine-montelukast was more effective than placebo and phenylephrine in relieving nasal congestion and other nasal and nonnasal symptoms resulting from ragweed pollen exposure. There was no statistically significant difference between phenylephrine and placebo.

Onset of action of loratadine/montelukast in seasonal allergic rhinitis subjects exposed to ragweed pollen in the Environmental Exposure Unit.

Onset of action is recognized as an important pharmacologic property of allergic rhinitis (AR) medications. This study was designed to evaluate the onset of action of loratadine/montelukast (L/M; 10 mg/10 mg) versus placebo in subjects with ragweed-induced seasonal AR (SAR). A single-center, double-blind, parallel-group study of ragweed-sensitive AR subjects (n = 310) was performed in the Environmental Exposure Unit (EEU). Subjects were exposed to ragweed pollen in the EEU and symptoms were recorded at 30, 60, 90, and 120 minutes before a single dose of L/M or placebo. After dosing, symptoms were recorded for 4 hours, at 15-minute intervals for the first 2 hours and at 30-minute intervals for the final 2 hours. The primary end point was time to onset of action of L/M, defined as the first time point at which the mean change from baseline in total symptom score (TSS) for L/M became and remained significantly better than placebo. Secondary end points included nasal congestion scores and peak nasal inspiratory flow (PNIF). The onset of action of L/M for TSS was 1 hour and 15 minutes (p = 0.005 versus placebo). L/M reduced nasal congestion as indicated by significant improvements in both the nasal congestion score (p = 0.011) and the PNIF measurements (p = 0.007) within 1 hour and 15 minutes postdose. The incidence of treatment-emergent adverse events was similar between groups. The onset of action after treatment with L/M was 1 hour and 15 minutes for TSS, as well as nasal congestion. L/M was well tolerated.

Efficacy of levocetirizine compared with montelukast in subjects with ragweed-induced seasonal allergic rhinitis in the Environmental Exposure Unit.

Levocetirizine dihydrochloride, a potent H1-receptor antagonist, and montelukast sodium, a selective leukotriene receptor antagonist, have been approved for the treatment of seasonal allergic rhinitis (SAR), but target two different pathways that cause SAR symptoms. The study objective was to compare the efficacy of levocetirizine (LCTZ), 5 mg, and montelukast (MLKT), 10 mg, in reducing SAR symptoms in ragweed-sensitive adults exposed to ragweed pollen in the Environmental Exposure Unit (EEU). This randomized, double-blind, placebo-controlled, parallel-group study of 418 adult subjects with SAR to ragweed compared the efficacy of LCTZ, MLKT, and placebo administered once daily (11:00 A.M.) for 2 consecutive days in the EEU. There were three evaluation periods: period I, 0-5 hours after first dose; period II, 22.5-24 hours after first dose; and period III, 0-4.5 hours after second dose. The primary efficacy variable was the Major Symptom Complex (MSC) score (six symptoms) over period I. Both active drugs significantly improved the MSC score compared with placebo in all periods. The adjusted mean MSC score difference between LCTZ and MLKT was -0.93 (p = 0.100) in period I, -3.11 (p < 0.001) in period II, -2.42 (p < 0.001) in period III, and -1.88 (p < 0.001) over the total treatment period. The same trends were observed for the Total Symptom Complex score (10 symptoms) and most individual symptoms. Subject-reported global satisfaction was greater for LCTZ compared with MLKT and placebo. All treatments had a favorable safety profile. LCTZ, 5 mg, was more effective than MLKT, 10 mg, in subjects with SAR and had better subject-reported global satisfaction.

Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients.

BACKGROUND: Although it is known that anaphylaxis can follow a biphasic course, reports of its incidence are conflicting. Furthermore, little is known about predictors of biphasic reactivity. OBJECTIVE: To describe the incidence and characteristics of biphasic anaphylaxis occurring in a Canadian tertiary care center. METHODS: All patients with emergency department visits and inpatients given a diagnosis of "allergic reaction" or "anaphylaxis" during a 3-year period were evaluated. Patients were contacted within 72 hours to establish symptoms and determine the presence of biphasic reactivity. A full medical record review ensued, and uniphasic and biphasic cases were compared using the Mann-Whitney U test for continuous data and the chi2 and Fisher exact tests for ordinal data. RESULTS: A total of 134 patients with anaphylaxis were identified; complete follow-up was obtained for 103 patients. Twenty patients (19.4%) experienced confirmed biphasic reactivity. Average time to onset of the second phase was 10 hours (range, 2-38 hours); 8 patients (40.0%) had their second phase occur more than 10 hours after the initial reaction. The clinical presentations and histories of uniphasic and biphasic reactors were similar. Time to resolution of initial symptoms was significantly longer for biphasic reactors (112 vs 133 minutes; P = .03). Differences in management were noted: biphasic reactors received less epinephrine (P = .048) and tended to receive less corticosteroid (P = .06). CONCLUSIONS: Biphasic reactivity occurred with an incidence of 19.4%, consistent with first descriptions. The second-phase onset was 10 hours on average, but it occurred as late as 38 hours. Biphasic anaphylaxis may be related, in part, to undertreatment.

Experimental models for the evaluation of treatment of allergic rhinitis.

OBJECTIVE: To review the experimental models used for the clinical evaluation of treatments for allergic rhinitis. DATA SOURCES: Peer-reviewed clinical studies and review articles were selected from the PubMed database using the following relevant keywords: allergic rhinitis in combination with efficacy, wheal and flare, nasal challenge, park, cat room, or exposure unit. Regulatory guidance documents on allergic rhinitis were also included. STUDY SELECTION: The authors' knowledge of the field was used to limit references with emphasis on recent randomized and controlled studies. References of historical significance were also included. RESULTS: Traditional outpatient studies are universally accepted in the evaluation of treatment for allergic rhinitis. Experimental models provide ancillary information on efficacy at different stages of treatment development. Skin histamine and allergen challenge, as well as direct nasal challenge with histamine and allergen, are often used as early steps in assessing drug efficacy. Exposure units, park settings, and cat rooms better approximate real life by drawing on the natural mode of allergen exposure and delivering the sensitizing allergen to allergic individuals in the ambient air. Park studies make use of allergens in the outdoors, whereas cat rooms and exposure units present the sensitizing allergens indoors, with the latter providing consistent predetermined allergen levels. Exposure unit and park studies are acknowledged for the determination of onset of action and are also suited to the measurement of duration of effect and other measures of efficacy. Onset and duration of effect are 2 important pharmacodynamic properties of antihistamines and nasal corticosteroids as determined by the Allergic Rhinitis and Its Impact on Asthma and the European Academy of Allergology and Clinical Immunology workshop group. CONCLUSIONS: All challenge models serve as important instruments in the evaluation of antiallergic medications and provide additional information to complement traditional studies.

Comparative efficacy of cetirizine and fexofenadine for seasonal allergic rhinitis, 5-12 hours postdose, in the environmental exposure unit.

In a previous study, cetirizine and fexofenadine similarly relieved seasonal allergic rhinitis symptoms in the first 5 hours, but cetirizine was more effective at 21-24 hours postdose. This randomized, double-blind, placebo-controlled study compared the response to treatment between 5 and 12 hours. Eligible ragweed allergic subjects were exposed to pollen in the Environmental Exposure Unit and randomized (n = 599) to a single dose of cetirizine, 10 mg; fexofenadine, 180 mg; or placebo (2.5:2.5:1). The primary efficacy end point was the change from baseline in total symptom severity complex (TSSC) score at 12 hours postdose. TSSC score was the sum of self-rated scores (0 = absent to 3 = severe) for runny nose, sneezing, itchy nose/palate/throat, and itchy/watery eyes, recorded half-hourly. Mean baseline TSSC scores were similar: 9.2, cetirizine and fexofenadine; 8.9, placebo. Reductions in TSSC scores from baseline were 4.3 at 12 hours and 5.0 overall (i.e., average over 5-12 hours postdose) for cetirizine and 3.4 and 4.4, respectively, for fexofenadine. Cetirizine produced a 26% greater reduction in TSSC at 12 hours (p = 0.001) and 14% greater reduction in TSSC overall (p = 0.006) compared with fexofenadine. Cetirizine and fexofenadine reduced TSSC scores (p < 0.001) and individual symptoms (p < 0.05) more than placebo. However, cetirizine was more effective than fexofenadine (p < 0.05) for runny nose and sneezing (12 hours and overall), itchy/watery eyes (12 hours), and itchy nose/throat/palate (overall). Incidence of treatment-emergent adverse events and somnolence were similar among groups: cetirizine, 25.3 and 0.8%, respectively; fexofenadine, 29.6 and 0%, respectively; placebo, 35.0 and 0%, respectively. In conclusion, cetirizine produced greater relief of seasonal allergic rhinitis symptoms than fexofenadine at 12 hours postdose and over the 5- to 12-hour postdose period.

The role of epinephrine in the treatment of anaphylaxis.

Epinephrine is the cornerstone of anaphylaxis management. Its administration should be immediate upon evidence of the occurrence of anaphylaxis. Delays in administration may be fatal. The most appropriate administration is 0.3 to 0.5 mL of 1:1000 dilution intramuscularly for adults and 0.01 mg/kg for children, given in the lateral thigh. Patients with known anaphylactic reactivity should be prescribed an epinephrine auto-injector to be carried at all times for treatment of potential recurrences. Education of the patient or parent regarding the proper use of this tool is paramount.

Diagnosis and management of anaphylaxis.

Anaphylaxis is a severe systemic allergic reaction that is potentially fatal. It requires prompt recognition and immediate management. Anaphylaxis has a rapid onset with multiple organ-system involvement and is mostly caused by specific antigens in sensitized individuals. Reactions typically follow a uniphasic course, however, 20% will be biphasic in nature. The second phase usually occurs after an asymptomatic period of 1-8 hours, but there may be a 24-hour delay. Protracted anaphylaxis may persist beyond 24 hours. Concurrent beta-blocker therapy may adversely affect the response to management. Epinephrine is the treatment of choice and should be administered immediately. Secondary measures include circulatory support, H(1) and H(2) antagonists, corticosteroids and, occasionally, bronchodilators. Post-treatment observation of these patients is necessary, and they should remain within ready access of emergency care for the following 48 hours.

Levocetirizine: a new selective H1 receptor antagonist for use in allergic disorders.

Levocetirizine is the active R-enantiomer of cetirizine and represents a new second-generation histamine H(1) antagonist. It has a high affinity and selectivity for H(1) receptors. Comparative studies have shown evidence of superior H(1) receptor binding affinity over its racemate, cetirizine. Levocetirizine has a favorable pharmacokinetic profile; it is rapidly and extensively absorbed, minimally metabolized, and has a lower volume of distribution (V(d)) than some other second-generation antihistamines. A number of studies using the histamine-induced wheal and flare model have repeatedly demonstrated marked suppressive effects for levocetirizine. Levocetirizine has also been found to be effective in relieving symptoms of seasonal and perennial allergic rhinitis, including nasal congestion, and its side effects are minor.

Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis.

There is published evidence that cetirizine has a longer duration of effect than fexofenadine. This study compared duration of effect and other measures of efficacy of cetirizine, 10 mg; fexofenadine, 180 mg; and placebo in allergic subjects exposed to pollen in the Environmental Exposure Unit. Eligible subjects (n = 575) were exposed to ragweed pollen (day 1, 7 hours; day 2, 5 hours) and randomized in double-blind fashion to once-daily cetirizine, 10 mg; fexofenadine, 180 mg; or placebo. The total symptom severity complex (TSSC) score, the primary efficacy variable, was based on four rhinoconjunctivitis symptoms rated at 20-minute intervals. Treatment evaluation was divided into three periods: period 1 TSSC, average of 15 scores obtained 0-5 hours after the first dose; period 2 TSSC, average of 9 scores obtained 21-24 hours after the first dose; and period 3 TSSC, average of 6 scores obtained 0-2 hours after the second dose. The primary efficacy end point was the change from baseline TSSC at period 2. Baseline TSSC was the final pretreatment score on day 1 and was 9.7 for cetirizine, 9.8 for fexofenadine, and 9.7 for placebo. For the primary efficacy end point, the reduction in baseline TSSC at period 2 was greater for cetirizine (-3.6) compared with fexofenadine (-2.7; p < 0.001) and placebo (-2.0; p < 0.001), representing a 33% greater reduction for cetirizine versus fexofenadine. Cetirizine continued to reduce TSSC more than fexofenadine (-5.2 versus -4.6; p = 0.017) and placebo (-3.9; p < 0.001) (period 3). Similar efficacy was observed in period 1 for both active treatments. Treatment-related adverse events were similar in all groups with an incidence of somnolence of 1.3% for both active medications. In conclusion, cetirizine produced a 33% greater reduction in SAR symptoms over the 21- to 24-hour interval after the first dose and for 40 minutes after the second dose, indicating a superior and longer duration of effect, which is relevant because both are once-daily medications. Onset of action was comparable and both treatments were safe and well tolerated.

A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis.

BACKGROUND: Decrements in cognitive performance are associated with the use of sedating antihistamines. Most, but not all, second-generation antihistamines have been found to be nonsedating. OBJECTIVE: To examine the central nervous system (CNS) profile of a new second-generation antihistamine, desloratadine. METHODS: Subjects with ragweed-induced allergic rhinitis (aged 18-60 years) who demonstrated a predetermined severity of symptoms after priming with ragweed pollen in the Environmental Exposure Unit were randomized to receive a single dose of desloratadine, 5 mg; diphenhydramine, 50 mg; or placebo. A comprehensive battery of repeatable, automated neuropsychological tests was administered to subjects before treatment (symptomatic baseline) and 90 minutes after taking study medication. RESULTS: Both desloratadine (P = .04) and diphenhydramine (P < .01) alleviated the symptoms of allergic rhinitis compared with placebo, but treatment with diphenhydramine was associated with clinically meaningful decrements on all vigilance parameters (P < .05 for desloratadine-diphenhydramine contrasts). Also, subjects treated with diphenhydramine performed significantly worse than subjects given desloratadine or placebo across all cognitive domains evaluated. Most effect sizes for the mean desloratadine and diphenhydramine differences were between 0.4 and 0.8 (moderate to high). Stanford Sleepiness Scale scores also indicated significantly more somnolence with diphenhydramine vs desloratadine or placebo (P < .001). There were no significant differences on any of the cognitive parameters between subjects treated with desloratadine and those given placebo. CONCLUSIONS: Desloratadine improved ragweed-induced allergic rhinitis symptoms without adversely affecting performance. Diphenhydramine improved allergic rhinitis symptoms but caused significant decrements in vigilance and cognitive functioning. Thus, efficacy of antihistamine treatment must be balanced against the associated effects on CNS functioning.