Immunotherapy with a ragweed vaccine.
Explore the source record for details and available documents.
Allergens↗
Biomedical subjects
F Estelle R Simons
Publications and source records attributed to F Estelle R Simons.
Diphenhydramine in infants.
Explore the source record for details and available documents.
Central Nervous System↗
Human subjects without peanut allergy demonstrate T cell-dependent, TH2-biased, peanut-specific cytokine and chemokine responses independent of TH1 expression.
BACKGROUND: Peanut allergy is a major cause of anaphylaxis. Regulation of immune responses to peanut allergen, particularly why sensitization does not usually progress to allergic reactions, is not well investigated. Most studies focus exclusively on serologic responses and individuals with peanut allergy. OBJECTIVE: We sought to determine the existence, prevalence, and nature of peanut-specific, T cell-dependent cytokine and chemokine responses of adults who eat peanut without having symptoms. METHODS: We developed systems to examine specific immunity in peanut-tolerant individuals who had (1) negative histories and negative peanut skin test responses, (2) negative histories and positive peanut skin test responses, and (3) clinically apparent peanut allergy. After primary culture of PBMCs restimulated with whole peanut extract, we quantified responses characteristic of TH1 (IFN-gamma and CXCL10) and TH2-like immunity (IL-5, IL-13, CCL17, and CCL22) using ultrasensitive ELISAs. Antigen-presenting cell costimulatory requirements (CD4, HLA-DR, CD80/86, and cytotoxic T lymphocyte-associated antigen 4 [CTLA4] Ig) were determined. RESULTS: T cell-dependent, peanut-specific IL-5, IL-13, and CCL22 were common in peanut-tolerant individuals, regardless of whether they had positive or negative skin test responses. These were blocked by anti-CD4 and were dependent on CD28/CD86 costimulation. None of the 70 individuals studied had demonstrable IFN-gamma or CXCL10 responses to peanut. All demonstrated TH1 and TH2 responses to the ubiquitous recall antigen streptokinase. CONCLUSIONS: Qualitatively similar and quantitatively increasing peanut-specific TH2 responses in the consistent absence of putatively protective TH1 immunity were found in both peanut-tolerant individuals and those with peanut allergy. CLINICAL IMPLICATIONS: The continuum of responses between individuals with negative and individuals with positive skin test results, rather than TH1 versus TH2 bias, might be important in peanut allergy.
Adolescent↗
Human metapneumovirus elicits weak IFN-gamma memory responses compared with respiratory syncytial virus.
Human metapneumovirus (MPV) is a recently discovered pathogen that causes repeated lower respiratory tract infections beginning in infancy. The prevalence, nature and control of human regulatory responses to MPV are unknown. In this study, we develop and optimize systems to evaluate MPV-driven cytokine responses. Using primary culture of human PBMC from previously exposed adults, MPV-stimulated responses were directly compared with those elicited by genetically and clinically similar respiratory syncytial virus (RSV). Intense IL-6 production was evident following culture with infectious or inactivated RSV. MPV elicited IL-6 responses averaging 3.5-fold more intense (p < 0.001). Virus-dependent expression of IL-11, IL-12, IFN-alpha, and other innate immunity cytokines differed little between MPV and RSV. When examining adaptive immunity, RSV infection elicited strong IFN-gamma responses by all 60 adults. In marked contrast, MPV elicited IFN-gamma in a lower frequency of adults (p < 0.002) and at levels averaging 6-fold weaker (p < 0.001). These Th1-dominated responses were CD4, CD8, CD86 dependent, and were closely paralleled by strong virus-driven IL-10 and CCL5 production. For MPV and RSV, Th2 (IL-5, IL-13) responses were sporadic, occurring in 10-40% of the population. Thus, MPV and RSV, although both ubiquitous and leading to very high levels of infection, seroconversion, and clinically similar presentation in the population, evoke distinct innate and adaptive T cell-dependent cytokine responses. Although both viruses yield Th1-dominated responses with strong IL-10 and CCL5 production, MPV restimulation results in markedly more robust IL-6 and significantly weaker adaptive cytokine responses, in both prevalence and intensity, than does RSV.
Adolescent↗
Fast-disintegrating sublingual tablets: effect of epinephrine load on tablet characteristics.
The aim of this study was to evaluate the effect of increasing epinephrine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anaphylaxis. Four tablet formulations, A, B, C, and D, containing 0%, 6%, 12%, and 24% of epinephrine bitartrate, respectively, and microcrystalline cellulose:low-substituted hydroxypropyl cellulose (9:1), were prepared by direct compression, at a range of compression forces. Tablet weight variation, content uniformity, hardness, disintegration time, wetting time, and friability were measured for each formulation at each compression force. All 4 tablet formulations at each compression force were within the United States Pharmacopeia (USP) limits for weight variation and content uniformity. A linear increase in compression force resulted in an exponential increase in hardness for all formulations, a linear increase in disintegration and wetting times of A, and an exponential increase in disintegration and wetting times of B, C, and D. At a mean +/- SD hardness of > or = 2.3 +/- 0.2 kg, all tablet formulations passed the USP friability test. At a mean +/- SD hardness of < or = 3.1 +/- 0.2 kg, all tablet formulations resulted in disintegration and wetting times of <10 seconds and <30 seconds, respectively. Tablets with drug loads from 0% to 24% epinephrine can be formulated with hardness, disintegration times, and wetting times suitable for sublingual administration.
Administration, Oral↗
Histamine receptors are hot in immunopharmacology.
In addition to its well-characterized effects in the acute allergic inflammatory responses, histamine has been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. Histamine can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and other functions leading to chronic inflammation. Histamine also regulates dendritic cells, T cells and B cells, as well as related antibody isotype responses. In addition, acting through its receptor 2, histamine positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. The diverse effects of histamine on immune regulation appear to be due to differential expression and regulation of 4 types of histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors for histamine is highly decisive for the biological effects of histamine and drugs that target histamine receptors. This article highlights recent discoveries in histamine immunobiology and discusses their relevance in allergic inflammation.
Animals↗
Epinephrine for the treatment of anaphylaxis: do all 40 mg sublingual epinephrine tablet formulations with similar in vitro characteristics have the same bioavailability?
Epinephrine autoinjectors are underutilized in the first aid emergency treatment of anaphylaxis in the community; so non-invasive sublingual epinephrine administration is being proposed. In order to determine the effect of changing excipients on the bioavailability of sublingual epinephrine, four distinct fast-disintegrating epinephrine 40 mg tablet formulations, A, B, C and D, were manufactured using direct compression. All formulations were evaluated for tablet hardness (H), disintegration time (DT) and wetting time (WT). In a prospective 5-way crossover study, four sublingual formulations and epinephrine 0.3 mg i.m. as a control were tested sequentially in a validated rabbit model. Blood samples were collected before dosing and at intervals afterwards. Epinephrine plasma concentrations were measured using HPLC-EC. All tablet formulations met USP standards for weight variation and content uniformity, and resulted in similar mean H, DT and WT (n=6). The area under the curve (AUC), maximum concentration (C(max)) and time at which C(max) was achieved (T(max)) did not differ significantly after the sublingual administration of formulation A and epinephrine 0.3 mg i.m. The AUC after B, C and D were significantly lower (p<0.05) than after epinephrine 0.3 mg i.m. These results suggest that the selection of excipients used in these tablet formulations can affect the bioavailability of sublingually administered epinephrine.
Administration, Sublingual↗
Anaphylaxis, killer allergy: long-term management in the community.
Traditionally, physicians are trained to diagnose and treat anaphylaxis as an acute emergency in a health care setting. In addition to this crucial and time-honored role, we should be cognizant of our wider responsibility to (1) provide a risk assessment for individuals with anaphylaxis, (2) prevent future anaphylaxis episodes by developing long-term personalized risk reduction strategies for affected individuals, and (3) emphasize anaphylaxis education. Risk assessment should include verification of the trigger factor or factors for the anaphylaxis episode by obtaining a comprehensive history and performing relevant investigations, including allergen skin tests and measurement of allergen-specific IgE in serum. In addition, the potential effect of comorbidities and concurrently administered medications on the recognition and emergency treatment of subsequent episodes should be determined. Risk reduction strategies should be personalized to include information about avoidance of specific triggers and initiation of relevant specific preventive treatment (eg, venom immunotherapy). At-risk individuals should be coached in the use of self-injectable epinephrine and equipped with an anaphylaxis emergency action plan and with accurate medical identification. Anaphylaxis education should be provided for these individuals, their families and caregivers, health care professionals, and the general public. Further development of an optimal diagnostic test for anaphylaxis and of tests and algorithms to predict future risk and prevent fatality are urgently needed.
Anaphylaxis↗
Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
There is no universal agreement on the definition of anaphylaxis or the criteria for diagnosis. In July 2005, the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network convened a second meeting on anaphylaxis, which included representatives from 16 different organizations or government bodies, including representatives from North America, Europe, and Australia, to continue working toward a universally accepted definition of anaphylaxis, establish clinical criteria that would accurately identify cases of anaphylaxis with high precision, further review the evidence on the most appropriate management of anaphylaxis, and outline the research needs in this area.
Anaphylaxis↗
The allergy archives: pioneers and milestones.
Explore the source record for details and available documents.
Allergy and Immunology↗
Sublingual epinephrine tablets versus intramuscular injection of epinephrine: dose equivalence for potential treatment of anaphylaxis.
BACKGROUND: Epinephrine autoinjectors are underused in the emergency treatment of anaphylaxis in the community, perhaps in part because of fear of needles. OBJECTIVES: To determine the sublingual epinephrine dose from a novel fast-disintegrating tablet required to achieve epinephrine plasma concentrations (EPPCs) similar to those obtained after epinephrine 0.3 mg intramuscular injection. METHODS: In a prospective 5-way crossover study, sublingual tablets containing epinephrine 0, 10, 20, and 40 mg, and epinephrine 0.3 mg intramuscular in the thigh (EpiPen) were compared in a validated rabbit model. Blood samples were collected before dosing and 5, 10, 15, 20, 30, 40, 60, 90, 120, 150, and 180 minutes afterward. EPPCs were measured by using high-performance liquid chromatography-electrochemical detection. Pharmacokinetic parameters were calculated by using WinNonlin. RESULTS: The area under the curve (AUC), maximum concentration (C(max)), and time at which C(max) was achieved (T(max)) did not differ significantly (P > .05) after epinephrine 40 mg (AUC = 1861 +/- 537 ng/mL/min, C(max) = 31.0 +/- 13.1 ng/mL, and T(max) = 9 +/- 2 minutes) and epinephrine 0.3 mg intramuscular (AUC = 2431 +/- 386 ng/mL/min, C(max) = 50.3 +/- 17.1 ng/mL, and T(max) = 21 +/- 5 minutes). The AUC after tablets containing epinephrine 0 mg (AUC = 472 +/- 126 ng/mL/min), epinephrine 10 mg (AUC = 335 +/- 152 ng/mL/min), and epinephrine 20 mg (AUC = 801 +/- 160 ng/mL/min) did not differ significantly from each other, but were significantly lower (P < .05) than the AUC after epinephrine 0.3 mg intramuscularly. CONCLUSION: Sublingual administration of epinephrine 40 mg from this tablet formulation resulted in EPPCs similar to those obtained after epinephrine 0.3 mg intramuscular injection in the thigh. CLINICAL IMPLICATIONS: For treatment of anaphylaxis in the community, self-injectable epinephrine is underused. This novel, fast-disintegrating epinephrine tablet formulation for sublingual administration is a feasible alternative that warrants further development.
Administration, Sublingual↗
Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report.
There are remarkable differences in the diagnostic and therapeutic management of atopic dermatitis practiced by dermatologists and pediatricians in different countries. Therefore, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams who were given the task of finding a consensus to serve as a guideline for clinical practice in Europe as well as in North America. The consensus report is part of the PRACTALL initiative, which is endorsed by both academies.
Adult↗
Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group.
OBJECTIVE: To improve understanding of the epidemiology of anaphylaxis. DATA SOURCES: We performed a qualitative review by hand of the major epidemiology studies of anaphylaxis. This review was restricted to articles in the English language. STUDY SELECTION: Articles chosen were selected by the committee and dated back to 1968. There was no specific criterion used for selection except the determination of the members of the committee. RESULTS: Data on anaphylaxis incidence and prevalence are sparse and often imprecise. Findings are based on diverse study designs and are not entirely comparable. These factors have contributed to widely varying estimates of the frequency of this important condition. The roundtable discussion led to an improved estimation of the frequency of anaphylaxis: approximately 50 to 2,000 episodes per 100,000 persons or a lifetime prevalence of 0.05% to 2.0%. The largest number of incident cases is among children and adolescents. In addition to underdiagnosis, we noted undertreatment, especially for those at highest risk (ie, those without immediate access to treatment with epinephrine). CONCLUSIONS: Anaphylaxis is a relatively common problem, affecting up to 2% of the population. Further data on epinephrine dispensing could improve current estimates. Another way to improve current understanding would be through better population-based study designs in different geographic regions. A recurring theme was the importance of broader access to self-injectable epinephrine for high-risk populations. An improved epidemiologic understanding of this disorder would aid ongoing efforts to reduce morbidity and mortality from anaphylaxis and could provide important clues for primary prevention.
Anaphylaxis↗
Concerns about intranasal corticosteroids for over-the-counter use: position statement of the Joint Task Force for the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology.
The Joint Task Force for the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology was charged with formulating a position paper regarding the potential release of intranasal corticosteroids for over-the-counter use. We took the position that safety issues regarding this proposal would be our sole concern. We reviewed the literature to evaluate the frequency and severity of potential adverse events related to the administration of intranasal corticosteroids. We limited this review to 5 areas: (1) effects on growth, (2) ocular effects, (3) effects on bone, (4) effects on the hypothalamic-pituitary-adrenal axis, and (5) local adverse effects. After review of the available data, we concluded that intranasal corticosteroids should remain prescription-only drugs. Patients receiving an intranasal corticosteroid should be instructed in its use and that use should be monitored by a physician or an appropriately trained medical provider (eg, nurse practitioner or physician assistant) under the direct supervision of a physician. This conclusion was reached based on the evidence that corticosteroids administered by any route, including the intranasal route, have the potential to cause adverse effects in all the areas noted herein. Our conclusion was strengthened by the fact that these adverse effects can be insidious and therefore not evident for many years; there is the potential for overuse; patients could also have access to other forms of topically administered corticosteroids, thus increasing their total dose; and individuals vary in their susceptibility to corticosteroid-induced adverse effects. We were also influenced to take this position knowing that generally reassuring data regarding the use of respiratory tract-administered corticosteroids are based on mean data and that all such studies have shown outliers in whom adverse effects were evident. Thus, as stated, we recommend that intranasal corticosteroids remain prescription-only drugs.
Administration, Inhalation↗
Clinical outcomes and adverse effect monitoring in allergic rhinitis.
The subjective recording in diary cards of symptoms of itch, sneeze, nose running, and blockage, with the use of a rating scale to indicate the level of severity, is usual for clinical trials in allergic rhinitis. The primary outcome measure is usually a composite score that enables a single total symptoms score endpoint. It is appreciated, however, that rhinitis has a greater effect on the individual than is reflected purely by the recording of anterior nasal symptoms. Nasal obstruction is troublesome and may lead to sleep disturbance in addition to impaired daytime concentration and daytime sleepiness. These impairments affect school and work performance. Individuals with rhinitis find it socially embarrassing to be seen sneezing, sniffing, or blowing their nose. To capture these and other aspects of the disease-specific health-related quality of life, questionnaires such as the Rhinoconjunctivitis Quality of Life Questionnaire have been developed and validated for clinical trial use. The adoption of health-related quality of life questionnaires into clinical trials broadens the information obtained regarding the effect of the therapeutic intervention and helps focus on issues relevant to the individual patient. It must be appreciated that it is not only the disease that may adversely affect health-related quality of life; administered therapy, although intended to be beneficial, may also cause health impairment. Adverse-event monitoring is thus essential in clinical trials. The first-generation H 1 -histamines, because of their effect on central H 1 -receptors, are classically associated with central nervous system (CNS) effects such as sedation. Although this is not always perceived by the patient, it is clearly evident with objective performance testing, and positron emission tomography scanning has directly demonstrated the central H 1 -receptor occupancy. The second-generation H 1 -antihistamines have reduced central H 1 -receptor occupancy and considerably reduced or absent CNS sedative effects. Therefore, the CNS effects are entirely avoidable, and the first-generation H 1 -antihistamines should no longer be used in the management of allergic rhinitis. The considerably rarer but potentially very serious cardiac arrhythmogenic effects of H 1 -antihistamines are appreciated to be molecule-specific rather than class-specific. The in vitro screening of new compounds to eliminate the further development of those with cardiotoxicity ideally will lead to this adverse effect being historic. The incorporation of electrocardiogram recording in clinical trials provides direct information relating to prolongation of QT interval corrected for heart rate. Although administered at low doses, intranasal steroids still have the potential for systemic absorption and adverse consequences. However, it is appreciated that meaningful differences exist in the bioavailability of different steroid molecules, and although a small but statistically significant effect on growth in children has been identified with the long-term use of intranasal beclomethasone when administered twice daily for 1 year, this is not evident with all intranasal steroids. In addition, twice-daily intranasal steroid administration may have more effect--from the endocrinologic perspective--than once-daily administration in the morning, which coincides better with the natural diurnal variation in cortisol. Thus, once-daily intranasal steroid administration is preferable, and when used in studies in children, measurement of height change during the study period is an important outcome variable together with other indices of systemic steroid bioavailability (eg, tests of hypothalamic-pituitary-adrenal axis function). These considerations have even greater relevance if children are concurrently also receiving inhaled steroids for asthma, because the total steroid load will be greater.
Anti-Allergic Agents↗
Quandaries in prescribing an emergency action plan and self-injectable epinephrine for first-aid management of anaphylaxis in the community.
Anaphylaxis often occurs in the community in the absence of a health care professional. Prompt administration of self-injectable epinephrine as first-aid treatment in the context of a personalized emergency action plan is the key to survival. There is little argument that physicians should prescribe self-injectable epinephrine for individuals who have already experienced anaphylaxis involving respiratory distress or shock triggered by allergens that might be encountered in the community. A quandary faced by physicians is that additional individuals with identified allergy who have no recognized prior history of anaphylaxis or who have a history of mild symptoms after exposure to a known trigger might also be at risk for subsequent life-threatening anaphylaxis and might also warrant prescription of self-injectable epinephrine. Prescribing for the latter individuals requires considerable clinical judgment and has led to controversy regarding possible overprescription or underprescription of self-injectable epinephrine. A second quandary for physicians occurs with regard to the advice they should give to at-risk individuals about actual use of their self-injectable epinephrine. It is difficult for health care professionals, let alone persons with no health care training, to predict whether anaphylaxis symptoms will occur in an at-risk individual after exposure to a known trigger. Moreover, at the onset of an acute allergic reaction, it is difficult to predict the symptoms that will ultimately develop. We examine these 2 common quandaries and provide examples of clinical scenarios and potential pitfalls in the management of persons identified as being at risk for anaphylaxis in the community. Additional studies of the recognition and treatment of anaphylaxis in the community are needed to develop comprehensive, evidence-based recommendations for its management in this setting.
Anaphylaxis↗
Apparent lack of response to epinephrine in anaphylaxis.
Explore the source record for details and available documents.
Adrenergic Agonists↗
Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.
BACKGROUND: The pharmacokinetics and pharmacodynamics of medications may differ between children and adults, necessitating different dose regimens for different age groups. Levocetirizine, the active enantiomer of cetirizine, is used in the treatment of allergic rhinitis and chronic urticaria in Europe. Its pharmacokinetics and pharmacodynamics have not yet been studied prospectively in school-age children. OBJECTIVES: This study was performed to investigate levocetirizine pharmacokinetic disposition and pharmacodynamics in relation to skin reactivity to histamine in children aged 6 to 11 years. METHODS: Blood samples were obtained at predose baseline and at defined intervals up to and including 28 hours after a 5-mg levocetirizine dose. Concurrently, epicutaneous tests with histamine phosphate, 1 mg/mL, were performed. Wheals and flares were traced at 10 minutes, and the areas were measured with a computerized digitizing system. RESULTS: In children aged 8.6 +/- 0.4 years (+/- SEM), the peak levocetirizine concentration was 450 +/- 37 ng/mL, and the time at which peak concentrations occurred was 1.2 +/- 0.2 hours. The terminal elimination half-life was 5.7 +/- 0.2 hours, the oral clearance was 0.82 +/- 0.05 mL/min/kg, and the volume of distribution was 0.4 +/- 0.02 L/kg. Compared with predose areas, the wheals and flares produced by histamine phosphate were significantly decreased from 1 to 28 hours, inclusive (P < .05). Mean maximum inhibition of wheals and flares occurred from 2 to 10 hours (97% +/- 1%) and from 2 to 24 hours (93% +/- 1%), respectively. CONCLUSIONS: Levocetirizine had an onset of action within 1 hour and provided significant peripheral antihistaminic activity for 28 hours after a single dose. Once-daily dosing may be optimal in children aged 6 to 11 years, as it is in adults.
Cetirizine↗