Peanut (Arachis hypogaea) allergen powder-dnfp for the mitigation of allergic reactions to peanuts in children and adolescents.

INTRODUCTION: Peanut allergy can result in severe, sometimes fatal hypersensitivity reactions that place a considerable burden on the lives of patients. This article reviews the first approved immunotherapy for the mitigation of allergic reactions following accidental peanut exposure, peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Palforzia®, Aimmune Therapeutics). AREAS COVERED: This article highlights the unmet need for patients with peanut allergy, describes the therapeutic landscape, and reviews the development of and clinical data for PTAH. EXPERT OPINION: PTAH offers a standardized preparation of peanut allergen, with a tolerability and efficacy profile clearly defined through its robust clinical development and trial program. In children 4-17 years old, PTAH provides a standardized, approved product that many clinicians sought prior to initiating oral immunotherapy. PTAH reduced the likelihood of more severe reactions following exposure to peanut protein; although peanut avoidance remains essential, PTAH will enable more individuals with peanut allergy to participate in activities of daily life with less anxiety.

Peanut allergy is a serious, potentially fatal condition. It often starts in childhood, and the only treatment used to be emergency medicine after contact with peanuts. Children are recommended to avoid any contact with peanuts or products made with peanuts, which can be difficult and stressful, especially in social situations such as school.A treatment called oral immunotherapy, based on very small amounts of protein from peanut, was developed to help the body get used to coming into contact with peanuts without a dangerous reaction. PTAH (Peanut [Arachis hypogaea] allergen powder-dnfp) is a type of oral immunotherapy that doctors can prescribe for children with peanut allergy. It is the first medicine of its kind to be allowed and is prepared specially to make sure that the right amount of peanut is given to children.In controlled tests, children with peanut allergy were given increasing amounts of peanut to see how much they could eat before they had a bad reaction. Children who had been given PTAH for a few months could eat more peanut (without a bad reaction) than children who had been given a placebo. Although there are some side effects from PTAH, particularly tummy upsets, most children who took it in the trials were able to keep taking it.Although children with peanut allergy will still need to avoid peanuts, PTAH may allow them to lead a more normal life with less worry about accidentally coming into contact with peanuts.

Oral Immunotherapy for Peanut Allergy in Children 1 to Less Than 4 Years of Age.

BACKGROUND: Peanut allergy is a common childhood allergy, and the only approved treatment for children 4 to 17 years of age is peanut allergen powder-dnfp (PTAH) oral immunotherapy. METHODS: For this phase 3, randomized, double-blind, placebo-controlled trial, we enrolled peanut-allergic children 1 to <4 years of age who experienced dose-limiting symptoms from ≤300 mg peanut protein during a screening double-blind, placebo-controlled food challenge (DBPCFC). Participants received PTAH or placebo, randomized in a 2:1 ratio, for approximately 12 months. At the trial conclusion, all participants underwent an exit BDPCFC. The primary end point was desensitization (i.e., tolerating a ≥600-mg single dose of peanut protein with only mild allergy symptoms). RESULTS: In the PTAH-treated group (n=98), 73.5% of participants tolerated a single dose of ≥600 mg peanut protein at exit DBPCFC compared with 6.3% in the placebo group (n=48). Most participants experienced an adverse event (98.0% of PTAH-treated and 97.9% of placebo-treated participants), which was mild or moderate in grade for 93.2% of participants (92.9% in PTAH-treated and 93.8% in placebo-treated participants). Treatment-related adverse events, which were mild to moderate, were experienced by 75.5% of PTAH-treated and 58.3% of placebo-treated participants. Three treatment-related systemic allergic reactions, none of which were severe or serious in grade, were noted in two PTAH-treated participants (2%). CONCLUSIONS: In peanut-allergic children 1 to <4 years of age treated with PTAH for approximately 12 months, the majority tolerated all peanut protein dose levels assessed. PTAH-treated patients had more treatment-related adverse events, which were mild to moderate severity. (Funded by Aimmune Therapeutics; ClinicalTrials.gov number, NCT03736447.)

Understanding the asthmatic response to an experimental rhinovirus infection: Exploring the effects of blocking IgE.

BACKGROUND: Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear. OBJECTIVE: Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection. METHODS: Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection. RESULTS: Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P < .01 for upper respiratory symptom tract scores and P < .001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days. CONCLUSIONS: LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection.

Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma.

BACKGROUND: Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. METHODS: To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6-18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. RESULTS: From pre-/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. CONCLUSIONS: These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01748175 .

Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age.

BACKGROUND: The effect of age on asthma severity is poorly understood. OBJECTIVES: The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. METHODS: SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. RESULTS: Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. CONCLUSIONS: The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.

Mastocytosis in Children.

PURPOSE OF REVIEW: In this review, we examine the current understanding of the pathogenesis, clinical presentations, diagnostic tools, and treatment options of pediatric mastocytosis as well as the natural history of the disease. RECENT FINDINGS: We discuss the emerging concept of mast cell activation syndrome. Mastocytosis in children presents most commonly as isolated cutaneous lesions and is a relatively rare occurrence with excellent prognosis and spontaneous regression often occurring by adolescence. Systemic mastocytosis with organ system involvement is a more serious condition and is likely to persist into adulthood.

Future Prospects of Biologic Therapies for Immunologic Diseases.

This article presents an overview of future uses for biologic therapies in the treatment of immunologic and allergic conditions. Discussion is centered on the use of existing therapies outside of their current indication or on new therapies that are close to approval. This information may help familiarize practicing allergists and immunologists with therapies they may soon encounter in their practice as well as help identify conditions and treatments that will require further study in the near future.

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations.

RATIONALE: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined. OBJECTIVES: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. METHODS: Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP-1 + 2 cohort. MEASUREMENTS AND MAIN RESULTS: Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index units, and 1.2 [1.1-1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4-2.1] and 1.6 [1.3-2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP-1 + 2 multivariable model. CONCLUSIONS: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases.

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology.

Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice.

ADAM10, as the sheddase of the low affinity IgE receptor (CD23), promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J). While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone) WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J) compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT) is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone). C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease.

Management and Prevention of Anaphylaxis.

Anaphylaxis prevalence has increased within the last few years. This may be due to a marked increase in allergic sensitization to foods especially in the pediatric population, as well as to an increase in outdoor recreational habits and the availability of new biologic medications.  Furthermore, guidelines for the diagnosis of anaphylaxis have been published, thus facilitating the recognition of this disorder. Diagnosis of anaphylaxis is mainly based on history and clinical criteria of organ system involvement. The serum tryptase assay is now commercially available and may be a helpful diagnostic tool in certain clinical situations involving hypotension, but not in the context of food-induced anaphylaxis. Treatment of anaphylaxis mainly involves the use of epinephrine as a first line medication for severe manifestations followed by  symptomatic management of specific  symptoms, such as antihistamines for urticaria and albuterol for wheezing. Although commonly practiced, treatment with systemic corticosteroids  is not supported by evidence-based literature. Observation in a medical facility for 4-6 hours is recommended to monitor for late phase reactions, although these rarely occur. Education is an essential component of management of a patient with a previous history of anaphylaxis, emphasizing early use of epinephrine and providing a written action plan. Referral to a board-certified allergist/immunologist is recommended to determine  the cause of the anaphylaxis as well as to rule out other potential conditions. In this review, our main focus will be on the treatment and prevention of anaphylaxis while providing our readers with a brief introduction to the diagnosis of anaphylaxis, its prevalence and its most common causes.

Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells.

It has been shown recently that MCs are required for differential regulation of the immune response by granulocytic versus monocytic MDSCs. Granulocytic MDSCs promoted parasite clearance, whereas monocytic MDSCs enhanced tumor progression; both activities were abrogated in MC-deficient mice. Herein, we demonstrate that the lack of MCs also influences MDSC trafficking. Preferential trafficking to the liver was not seen in MC-deficient mice. In addition, evidence that the MC mediator histamine was important in MDSC trafficking and activation is also shown. MDSCs express HR1-3. Blockade of these receptors by HR1 or HR2 antagonists reversed the histamine enhancement of MDSC survival and proliferation observed in cell culture. In addition, histamine differentially influenced Arg1 and iNOS gene expression in MDSCs and greatly enhanced IL-4 and IL-13 message, especially in granulocytic MDSCs. Evidence that histamine influenced activity seen in vitro translated to in vivo when HR1 and HR2 antagonists blocked the effect of MDSCs on parasite expulsion and tumor metastasis. All of these data support the MDSC-mediated promotion of Th2 immunity, leading to the suggestion that allergic-prone individuals would have elevated MDSC levels. This was directly demonstrated by looking at the relative MDSC levels in allergic versus control patients. Monocytic MDSCs trended higher, whereas granulocytic MDSCs were increased significantly in allergic patients. Taken together, our studies indicate that MCs and MC-released histamine are critical for MDSC-mediated immune regulation, and this interaction should be taken into consideration for therapeutic interventions that target MDSCs.

Evaluation of a practice-based intervention to improve the management of pediatric asthma.

Pediatric asthma remains a significant burden upon patients, families, and the healthcare system. Despite the availability of evidence-based best practice asthma management guidelines for over a decade, published studies suggest that many primary care physicians do not follow them. This article describes the Provider Quality Improvement (PQI) intervention with six diverse community-based practices. A pediatrician and a nurse practitioner conducted the year-long intervention, which was part of a larger CDC-funded project, using problem-based learning within an academic detailing model. Process and outcome assessments included (1) pre- and post-intervention chart reviews to assess eight indicators of quality care, (2) post-intervention staff questionnaires to assess contact with the intervention team and awareness of practice changes, and (3) individual semi-structured interviews with physician and nurse champions in five of the six practices. The chart review indicated that all six practices met predefined performance improvement criteria for at least four of eight indicators of quality care, with two practices meeting improvement criteria for all eight indicators. The response rate for the staff questionnaires was high (72%) and generally consistent across practices, demonstrating high staff awareness of the intervention team, the practice "asthma champions," and changes in practice patterns. In the semi-structured interviews, several respondents attributed the intervention's acceptability and success to the expertise of the PQI team and expressed the belief that sustaining changes would be critically dependent on continued contact with the team. Despite significant limitations, this study demonstrated that interventions that are responsive to individual practice cultures can successfully change practice patterns.

A simple and rapid genotyping assay for simultaneous detection of two ADRB2 allelic variants using fluorescence resonance energy transfer probes and melting curve analysis.

Allelic variants at codons 16 and 27 of the beta(2)-adrenergic receptor gene (ADRB2) have shown clinical and pharmacological implications in asthma, hypertension, ischemic heart failure, diabetes, obesity, and cystic fibrosis. We have developed a simultaneous genotyping assay for the c.46A>G and c.79C>G allelic variants using hybridization probes and melting curve analysis. The assay was optimized on a panel of 30 DNA samples of known ADRB2 genotype as determined by sequencing with 100% concordance between the two techniques. Melting temperature (Tm) ranges for the different genotypes were obtained using data from three independent experiments. Single peaks for p.Arg16Arg (Tm = 57.76 degrees C +/- 0.10 degrees C) and p.Gly16Gly (Tm = 66.73 degrees C +/- 0.18 degrees C) and two melting peaks for p.Arg16Gly were obtained. Similarly, single peaks for p.Gln27Gln (Tm = 53.98 degrees C +/- 0.19 degrees C) and p.Glu27Glu (Tm = 64.93 degrees C +/- 0.16 degrees C) and two peaks for p.Gln27Glu were detected. Independent operators easily assigned genotypes in a sample set of 385 asthmatic patients. Haplotype and allele frequencies were in concordance with previously published data: Arg allele frequencies in children/adults were 0.34/0.30 in Caucasians and 0.45/0.52 in African Americans, and Gln allele frequencies were 0.58/0.52 in Caucasians and 0.82/0.84 in African Americans. Thus, the ADRB2 genotyping assay represents a highly reliable and rapid technique for routine clinical use in the simultaneous detection of ADRB2 variants.

Ocular mast cells and mediators.

Mast cells have long been recognized for their role in immediate hypersensitivity reactions, by virtue of the presence of high affinity receptors for IgE (FcepsilonRI) on their surface. More recently, mast cells have been postulated to be involved in a variety of chronic inflammatory disorders as numerous mediators released by activated mast cells are characterized. This article summarizes current information on mast cell mediators, heterogeneity, and differentiation, and it reviews studies of mast cells in the normal eye and various ocular disorders.

Structural and functional comparison of mast cells in the pregnant versus nonpregnant human uterus.

OBJECTIVE: To characterize uterine mast cells and investigate uterine muscle strips contractile responses to challenge with an allergen in nonpregnant and pregnant women. STUDY DESIGN: A double-antibody labeling technique was used to identify tryptase positive or chymase-tryptase-positive mast cells in uterine samples from term pregnant and nonpregnant women. Longitudinal myometrial strips were prepared from biopsies of hysterectomy specimens from patients undergoing procedures for benign indications and women who had elective cesarean sections. Responses to ragweed antigen were compared in uterine tissues from allergic and nonallergic patients and with passively sensitized tissues in the absence or presence of H1 receptor antagonist and a cyclooxygenase inhibitor. RESULTS: Tryptase-chymase-positive mast cells were predominant in nonpregnant myometrium, whereas tryptase-positive cells were dominant in pregnant myometrium. Mast cell density was significantly higher in tissue from pregnant women than those of nonpregnant women. Studies in tissues from patients with known allergy to ragweed, as well as in passively sensitized tissues, showed an immediate and substantial increase in the frequency and force of myometrial contraction after a challenge with ragweed antigen. A similar response was observed to histamine. There was no contractile response to antigen challenge in tissues from nonallergic patients. An H1 receptor antagonist partially inhibited the response to antigen, whereas a cyclooxygenase inhibitor had no effect. CONCLUSION: Sensitized isolated pregnant and nonpregnant human uterine tissue is capable of responding to antigen challenge with strong myometrial contractions. This ability, along with the increased density of mast cells in pregnant tissues as compared with nonpregnant tissues, indicates a possible role for mast cells in mediating uterine contractility in pregnancy.

The challenge of mild persistent asthma.

OBJECTIVE: To review the current data and treatment options for mild persistent asthma. DATA SOURCES: A MEDLINE search was performed for relevant articles. STUDY SELECTION: The expert opinion of the author was used to select studies for inclusion in this review. RESULTS: Current data suggest that asthma severity is determined early in life and that disease progression may not occur outside early childhood. Furthermore, no therapy has been demonstrated to clearly prevent or reverse structural airway changes in patients with persistent asthma. Thus, the primary goal of asthma therapy is to prevent disease exacerbations rather than to halt disease progress, at least in patients past early childhood. Published reports of severe exacerbations in patients with reported mild asthma may actually reflect inclusion of patients with more severe forms of the disease who were inappropriately classified in terms of asthma severity. CONCLUSION: Unlike the case for moderate and severe asthma, where regular therapy with inhaled corticosteroids is clearly the treatment of choice, clear guidelines for treating patients with mild persistent asthma have not been established. Patients with mild disease without severe exacerbations may require only the minimum therapy necessary for disease control.