Publications by authors named "Jacqueline A Pongracic"

83 Publications

Coconut allergy: Characteristics of reactions and diagnostic predictors in a pediatric tertiary care center.

Ann Allergy Asthma Immunol 2021 Feb 4. Epub 2021 Feb 4.

Department of Pediatric Allergy & Immunology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Background: Little is known on the clinical manifestations of coconut allergy. Our knowledge to date is mainly based on case reports.

Objective: To characterize the allergic reactions to coconut and suggest diagnostic cutoffs for specific immunoglobulin E (sIgE) and skin prick testing (SPT) to predict clinically reactive coconut allergy.

Methods: Methods include retrospective chart review at an urban tertiary care center of patients with positive testing result for coconut. Probability curves were computed by logistic regression for SPT and coconut sIgE.

Results: Of 275 records reviewed, 69 patients reported coconut reactions and 206 were sensitized only or nonallergic. The reactions occurred with breastfeeding (n = 2), contact (n = 10), or oral ingestion (n = 57). Approximately 50% of oral ingestion reactions were associated with mild/moderate anaphylaxis. Clinical reactivity vs sensitization was more common in topical coconut users (2-fold) (P = .02). Although not statistically significant, there was a trend toward more coconut allergy vs sensitization in Asian and African American patients. The probability of allergy with positive SPT result was approximately 50% and with sIgE was approximately 60%. At an SPT of 9 mm wheal or sIgE of 58 kU of allergen/L, there is a 95% probability of reaction. Cosensitization with tree nuts, legumes, and seeds was common. Macadamia nut had the strongest correlation with coconut (r = 0.81, P < .001, n = 101).

Conclusion: Although the rate of reactivity to coconut in sensitized individuals is low, half of the reactions from consumption met the criteria for anaphylaxis. Clinicians should be aware of the spectrum of reactions and diagnostic use of sIgE and SPT.
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http://dx.doi.org/10.1016/j.anai.2021.01.027DOI Listing
February 2021

African American Children Are More Likely to Be Allergic to Shellfish and Finfish: Findings from FORWARD, a Multisite Cohort Study.

J Allergy Clin Immunol Pract 2021 Jan 18. Epub 2021 Jan 18.

Center for Food Allergy and Asthma Research and Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Advanced General Pediatrics and Primary Care, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill.

Background: Despite major differences in health profiles and rates of health care utilization between African American (AA) and white children with food allergy (FA), the detailed phenotypic variables that can potentially impact these outcomes have not been thoroughly studied.

Objective: We aimed to characterize phenotypic differences such as allergies to different foods and allergic comorbidities between AA and white children with FA enrolled in the Food Allergy Outcomes Related to White and African American Racial Differences study.

Methods: Our active, prospective, multicenter cohort study is currently enrolling AA and white children aged 0 to 12 years diagnosed with FA and followed by allergy/immunology clinics at 4 urban tertiary centers in the United States. To evaluate associations between race and phenotypic variables, we used multivariable logistic regression, adjusting for important demographic and confounding factors, as well as potential household clustering.

Results: As of May 2020, there were 239 AAs and 425 whites with complete intake information enrolled in the study. In comparison with whites, we found that AAs had significantly higher adjusted odds of allergy to finfish (odds ratio [OR]: 2.54, P < .01) and shellfish (OR: 3.10, P < .001). AAs also had higher adjusted odds of asthma than whites (asthma prevalence of 60.5% in AAs and 27.2% in whites; OR: 2.70, P < .001). In addition, shellfish allergy was associated with asthma, after controlling for race.

Conclusion: Among a diverse cohort of children with physician-diagnosed FA, we observed that AA children had higher odds of allergy to shellfish and finfish, and higher rates of asthma. Interestingly, having asthma was independently associated with allergy to shellfish, after controlling for race.
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http://dx.doi.org/10.1016/j.jaip.2020.12.026DOI Listing
January 2021

Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation.

Contemp Clin Trials 2021 Jan 24;100:106228. Epub 2020 Nov 24.

Harvard Medical School, Boston, MA, United States of America; Brigham and Women's Hospital, Divisions of Pulmonary and Critical Care Medicine and Allergy and Immunology, Boston, MA, United States of America.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.
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http://dx.doi.org/10.1016/j.cct.2020.106228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887056PMC
January 2021

AAAAI Work Group Report: Trends in Oral Food Challenge Practices Among Allergists in the United States.

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3348-3355

Section of Allergy and Immunology, Children's Hospital Colorado, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colo.

The oral food challenge (OFC) is the criterion standard for diagnosing food allergy, but prior studies indicate many allergists may not be using OFCs for various reasons. To better understand current OFC trends, practices, and barriers, the American Academy of Allergy Asthma and Immunology (AAAAI) Adverse Reactions to Foods Committee subcommittee updated a 19-item survey (previously administered in 2009) and sent it to AAAAI and American College of Allergy, Asthma, and Immunology (ACAAI) membership. There were a total of 546 respondents who represented approximately a 10% response rate. Among the 546 respondents, compared with 2009, significantly more providers offer OFCs (95% vs 84.5%), offer >10 OFCs per month (17% vs 5.6%), obtain informed consent (82.2% vs 53.6%), and performed OFCs in fellowship (71% vs 45%) (all P < .001). Fellowship OFC training was limited, with 56% performing <10 OFCs in fellowship and 29% performing none. Although 94% see patients <12 months of age, 35.5% do not offer OFCs for early peanut introduction. Although 79% dedicate a supervising medical provider (MD, NP, PA) and 86% have a written OFC protocol, only 60% had a standardized reaction treatment protocol and 56% prepared emergency medications before OFC. Compared with 2009, there was significant worsening of perceived barriers to performing OFCs, including time (65.6% vs 55%), space (55.3% vs 27.1%), staffing (59.6% vs 44.3%), experience (16.9% vs 11.5%), and hospital proximity (10.9% vs 7.9%), though reimbursement as a barrier improved (45.9% vs 53.7%) (all P < .01). Compared with 2009, although more providers offer OFCs, multiple perceived barriers to performing OFCs have worsened. Hesitancy to challenge infants and emergency preparedness issues are emerging potential concerns.
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http://dx.doi.org/10.1016/j.jaip.2020.07.035DOI Listing
May 2020

Food allergy-related bullying and associated peer dynamics among Black and White children in the FORWARD study.

Ann Allergy Asthma Immunol 2021 03 4;126(3):255-263.e1. Epub 2020 Nov 4.

Center for Food Allergy and Asthma Research, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Stanford University School of Medicine, Stanford, California.

Background: The experiences of Black children with food allergy (FA) are not well characterized, particularly with respect to bullying victimization and other psychosocial outcomes.

Objective: To evaluate bullying experiences of Black and White children with FA, including associations with peer relationships, anxiety, and school policies.

Methods: Surveys were administered to parents of 252 children with physician-diagnosed FA enrolled in the multisite FORWARD cohort. The surveys assessed demographics, atopic disease, bullying victimization, and school FA management practices and policies. Descriptive statistics of bullying by race were compared by χ tests. Multiple logistic regression analyses adjusting for race, age, parental education, household income, child sex, and multi-FA compared adjusted probabilities of bullying victimization by school policies.

Results: Nearly 20% of school-aged children were bullied for FA with no substantial racial differences overall, though for children ages 11 years and up, White children reported higher rates of bullying. However, Black children experienced non-FA-related bullying twice as frequently as White children (38.6% vs 17.7%; P = .002). Most of the caregivers (85.7%) who intervened in their child's bullying reported that it was helpful. Among parents, 17.3% reported that they were teased or bullied owing to their child's FA. More than half of the respondents (54.8%) reported that some allergens are banned from their child's school, most typically peanut. In schools banning peanuts, FA-related bullying was less frequently reported by all students who have food allergy.

Conclusion: Bullying owing to FA is common, and caregivers, medical professionals, and school administrators can help reduce bullying by screening for bullying and supporting and educating school policies.
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http://dx.doi.org/10.1016/j.anai.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897313PMC
March 2021

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.

J Allergy Clin Immunol 2020 10 10;146(4):863-874. Epub 2020 Jul 10.

DBV Technologies, Montrouge, France; Division of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY.

Background: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg).

Objective: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study.

Methods: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment.

Results: Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%).

Conclusions: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.
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http://dx.doi.org/10.1016/j.jaci.2020.06.028DOI Listing
October 2020

Heterogeneity of Mild to Moderate Persistent Asthma in Children: Confirmation by Latent Class Analysis and Association with 1-Year Outcomes.

J Allergy Clin Immunol Pract 2020 09 7;8(8):2617-2627.e4. Epub 2020 Mar 7.

Department of Public Health Sciences, Penn State University, Hershey, Pa.

Background: Compared with adults, phenotypic characterization of children with asthma is still limited and it remains difficult to predict which children with asthma are at highest risk for poor outcomes.

Objective: To identify latent classes in a large population of treatment-adherent children with mild to moderate asthma enrolled in clinical trials and determine whether latent class assignment predicts future lung function abnormalities and exacerbation rate.

Methods: Latent class analysis was performed on 2593 children with mild to moderate asthma aged 5 18 years, with 19 variables encompassing demographic characteristics, medical history, symptoms, lung function, allergic sensitization, and type 2 inflammation. Outcomes included lung function and the annualized exacerbation rate at 12 months of follow-up.

Results: Five latent classes were identified with differing demographic features, asthma control, sensitization, type 2 inflammatory markers, and lung function. Exacerbation rates were 1.30 ± 0.12 for class 1 (multiple sensitization with partially reversible airflow limitation), 0.90 ± 0.05 for class 2 (multiple sensitization with reversible airflow limitation), 0.87 ± 0.08 for class 3 (lesser sensitization with reversible airflow limitation), 0.87 ± 0.05 for class 4 (multiple sensitization with normal lung function), and 0.71 ± 0.06 for class 5 (lesser sensitization with normal lung function). Lung function abnormalities persisted in class 1 at 12 months.

Conclusions: Children with mild to moderate asthma are a heterogeneous group. Allergic sensitization and lung function may be particularly useful in identifying children at the greatest risk for future exacerbation. Additional studies are needed to determine whether latent classes correspond to meaningful phenotypes for the purpose of personalized treatment.
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http://dx.doi.org/10.1016/j.jaip.2020.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483393PMC
September 2020

Food allergy: Diagnosis and treatment.

Allergy Asthma Proc 2019 11;40(6):446-449

Immunoglobulin E-mediated food reactions usually develop within minutes of food ingestion. Although most reactions are not life-threatening, fatalities do occur. Risk factors for fatal food-induced anaphylaxis include the presence of asthma (a risk factor for anaphylaxis in general), failure to use epinephrine autoinjectors promptly, a history of severe reactions, known food allergy, denial of symptoms, and adolescent and young adult age. The most commonly implicated foods are cow's milk, egg, peanut, soy, tree nuts, fish, shellfish, and wheat. Peanut, tree nuts, and seafood are the most common food allergens in adults, whereas cow's milk, peanut, egg, soy, and wheat are more common in children. The major food allergens are glycoproteins, which are generally water soluble and stable to the effects of heat, proteases, and acids. Recent studies showed that natural tolerance can be acquired at a later age than previously thought, even during adolescence. Allergies to peanut, tree nuts, and seafood are frequently life-long. Patients and their caregivers should be taught when and how to administer injectable epinephrine. In terms of primary prevention, there is evidence that early introduction, followed by ongoing regular consumption of peanut has a protective effect on the development of peanut allergy.
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http://dx.doi.org/10.2500/aap.2019.40.4268DOI Listing
November 2019

Hereditary and acquired angioedema.

Allergy Asthma Proc 2019 11;40(6):441-445

Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5-40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin β₂ receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.
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http://dx.doi.org/10.2500/aap.2019.40.4267DOI Listing
November 2019

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

N Engl J Med 2019 09;381(13):1227-1239

From National Jewish Health (M.E.W., R.C., J.T.O.), Denver, and University of Colorado School of Medicine (M.E.W., S.J.S., R.C., F.H., J.T.O.) and Children's Hospital Colorado (S.J.S.), Aurora - all in Colorado; Wake Forest School of Medicine (V.E.O., W.C.M., S.P.P.), Winston-Salem, North Carolina Clinical Research (C.F.L.), Raleigh, and Duke University Medical Center (N.L., L.Q.), Durham - all in North Carolina; Ann and Robert H. Lurie Children's Hospital of Chicago (J.A.P., R.G.R.), University of Illinois at Chicago (J.A.K., H.K.), Rush University Medical Center (J.M.), University of Chicago (E.N., J.S., S. White), and Northwestern University Feinberg School of Medicine (L.J.S.) - all in Chicago; Penn State University (V.C., S.J.K., D.M.), Hershey, and Allegheny General Hospital (D.G.) and University of Pittsburgh Medical Center (S. Wenzel), Pittsburgh - all in Pennsylvania; Nemours Children's Health System, Jacksonville (J.J.L., K.V.B., J.L.), and University of South Florida Morsani College of Medicine, Tampa (J.-C.C.) - both in Florida; University of Arizona Health Sciences, Tucson (E.R.B., M.K., F.M., D.A.M.); Washington University School of Medicine, St. Louis (L.B.B., A.B., M.C.); University of California, San Francisco (UCSF), San Francisco (M.B., M.D.C., S.C.L., D.L.) and UCSF Benioff Children's Hospital, Oakland (M.B., D.L.) - both in California; Brigham and Women's Hospital and Harvard Medical School (J.-C.C., N.G., E.I.) and Boston Children's Hospital (W.P., W.S.) - all in Boston; University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland (J.F.C., K.R.); University of Wisconsin-Madison, Madison (L.D., D.J.J., R.F.L., C.A.S.) and Aurora Sinai Medical Center, Milwaukee (L.S.-V.) - both in Wisconsin; Columbia University Irving Medical Center, New York, (E.D.); Emory University, Atlanta (A.M.F.); and University of New Mexico, Albuquerque (H.R.).

Background: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.

Methods: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry.

Results: When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age.

Conclusions: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).
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http://dx.doi.org/10.1056/NEJMoa1905560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026584PMC
September 2019

Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

N Engl J Med 2019 05 19;380(21):2009-2019. Epub 2019 May 19.

From the Division of Pulmonary and Critical Care Medicine and the Cardiovascular Research Institute (S.C.L., H.A.B., J.V.F., P.G.W.) and the Department of Pediatrics, Epidemiology, and Biostatistics (M.D.C.), University of California, San Francisco, San Francisco; the University of Illinois at Chicago (J.A.K.), the Department of Pediatrics, Rush University Medical Center (J.N.M.), Ann and Robert Lurie Children's Hospital of Chicago (J.A.P.), and Northwestern University, Feinberg School of Medicine (L.S.) - all in Chicago; the Department of Public Health Sciences, Penn State University, Hershey (T.S.K., V.M.C., D.T.M., A.-M.D.), and the University of Pittsburgh Asthma Institute (S.W., F.H.) and Allegheny General Hospital (D.G.), Pittsburgh - all in Pennsylvania; Nemours Children's Hospital, University of Central Florida College of Medicine, Orlando (J.E.L., K.V.B.), and Nemours Children's Health System, Jacksonville (J.E.L., K.V.B.) - both in Florida; the Department of Pediatrics and Medicine, National Jewish Health, Denver (R.C., S.J.S., M.E.W.), and Children's Hospital Colorado, Aurora (R.C., S.J.S., M.E.W.) - both in Colorado; Duke Allergy, Asthma, and Airway Center, Duke University School of Medicine, Durham (N.L., M.K., L.Q.), Wake Forest University School of Medicine, Winston-Salem (A.H., W.M., S.P.P.), and North Carolina Clinical Research, Raleigh (C.L.) - all in North Carolina; the Departments of Pediatrics and Medicine, Washington University in St. Louis School of Medicine, St. Louis (L.B.B., M.C.); Brigham and Women's Hospital and Harvard Medical School (J.C.C., E.I.) and Boston Children's Hospital (W.P.) - all in Boston; Rainbow Babies and Children's Hospital, Cleveland (J.C., R.M., K.R.); the University of Wisconsin, Madison (L.D., D.J., R.F.L., C.A.S.); Columbia University, New York (E.D.); the Department of Pediatrics, Emory University, Atlanta (A.M.F.); and the Arizona Respiratory Center, University of Arizona, Tucson (F.D.M., W.J.M.).

Background: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown.

Methods: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level.

Results: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%).

Conclusions: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).
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http://dx.doi.org/10.1056/NEJMoa1814917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711475PMC
May 2019

Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children.

Nat Immunol 2019 05 8;20(5):637-651. Epub 2019 Apr 8.

University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.
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http://dx.doi.org/10.1038/s41590-019-0347-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472965PMC
May 2019

Effect of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Ingestion Among Children With Peanut Allergy: The PEPITES Randomized Clinical Trial.

JAMA 2019 03;321(10):946-955

Massachusetts General Hospital, Boston.

Importance: There are currently no approved treatments for peanut allergy.

Objective: To assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children.

Design, Setting, And Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein.

Interventions: Daily treatment with peanut patch containing either 250 μg of peanut protein (n = 238) or placebo (n = 118) for 12 months.

Main Outcomes And Measures: The primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of 10 mg or less were responders if the posttreatment eliciting dose was 300 mg or more; participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs).

Results: Among 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group.

Conclusions And Relevance: Among peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-μg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined.

Trial Registration: ClinicalTrials.gov Identifier: NCT02636699.
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http://dx.doi.org/10.1001/jama.2019.1113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439674PMC
March 2019

A computerized decision support tool to implement asthma guidelines for children and adolescents.

J Allergy Clin Immunol 2019 05 5;143(5):1760-1768. Epub 2018 Dec 5.

Department of Medicine, Division of Allergy and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Background: Multicenter randomized controlled trials (RCTs) for asthma management that incorporate usual-care regimens could benefit from standardized application of evidence-based guidelines.

Objective: We sought to evaluate performance of a computerized decision support tool, the Asthma Control Evaluation and Treatment (ACET) Program, to standardize usual-care regimens for asthma management in RCTs.

Methods: Children and adolescents with persistent uncontrolled asthma living in urban census tracts were recruited into 3 multicenter RCTs (each with a usual-care arm) between 2004 and 2014. A computerized decision support tool scored asthma control and assigned an appropriate treatment step based on published guidelines. Control-level determinants (symptoms, rescue medication use, pulmonary function measure, and adherence estimates) were collected at visits and entered into the ACET Program. Changes in control levels and treatment steps were examined during the trials.

Results: At screening, more than half of the participants were rated as having symptoms that were not controlled or poorly controlled. The proportion of participants who gained good control between screening and randomization increased significantly in all 3 trials. Between 51% and 70% had symptoms that were well controlled by randomization. The proportion of well-controlled participants remained constant or improved slightly from randomization until the last posttreatment visit. Nighttime symptoms were the most common control-level determinant; there were few (<1%) instances of complete overlap of factors. FEV was the driver of control-level assignment in 30% of determinations.

Conclusion: The ACET Program decision support tool facilitated standardized asthma assessment and treatment in multicenter RCTs and was associated with attaining and maintaining good asthma control in most participants.
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http://dx.doi.org/10.1016/j.jaci.2018.10.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504600PMC
May 2019

AR101 Oral Immunotherapy for Peanut Allergy.

N Engl J Med 2018 Nov 18;379(21):1991-2001. Epub 2018 Nov 18.

Background: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.

Methods: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.

Results: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older.

Conclusions: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).
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http://dx.doi.org/10.1056/NEJMoa1812856DOI Listing
November 2018

Immunoglobulin E blockade during food allergen ingestion enhances the induction of inhibitory immunoglobulin G antibodies.

Ann Allergy Asthma Immunol 2019 02 4;122(2):213-215. Epub 2018 Nov 4.

Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2018.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360101PMC
February 2019

Multicenter, randomized, double-blind, placebo-controlled clinical trial of vital wheat gluten oral immunotherapy.

J Allergy Clin Immunol 2019 02 30;143(2):651-661.e9. Epub 2018 Oct 30.

Division of Allergy and Immunology, Department of Pediatrics, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, Kravis Children's Hospital, New York, NY. Electronic address:

Background: Wheat is a common food allergen that can cause anaphylaxis.

Objective: We sought to determine the efficacy and safety of vital wheat gluten (VWG) oral immunotherapy (OIT).

Methods: After baseline double-blind, placebo-controlled food challenge (DBPCFC), 46 patients with wheat allergy (median age, 8.7 years; range, 4.2-22.3 years) were randomized 1:1 to low-dose VWG OIT or placebo, with biweekly escalation to 1445 mg of wheat protein (WP). After a year 1 DBPCFC, active subjects continued low-dose VWG OIT for another year and underwent a year 2 DBPCFC and, if passed, a subsequent off-therapy DBPCFC. Placebo-treated subjects crossed over to high-dose VWG OIT (maximum, 2748 mg of WP).

Results: The median baseline successfully consumed dose (SCD) was 43 mg of WP in both groups. At year 1, 12 (52.2%) of 23 low-dose VWG OIT-treated and 0 (0%) of 23 placebo-treated subjects achieved the primary end point of an SCD of 4443 mg of WP or greater (P < .0001); median SCDs were 4443 and 143 mg, respectively. At year 2, 7 (30.4%) of 23 low-dose VWG OIT-treated subjects were desensitized to an SCD of 7443 mg of WP; 3 (13%) achieved sustained unresponsiveness 8 to 10 weeks off therapy. Among placebo-treated subjects who crossed over to high-dose VWG OIT, 12 (57.1%) of 21 were desensitized after 1 year (median SCD, 7443 mg of WP; nonsignificant vs low-dose VWG OIT). At year 1, skin prick test responses and wheat- and omega-5 gliadin-specific IgE levels did not differ between groups; the low-dose VWG OIT median specific IgG level was greater than placebo (wheat, P = .0005; omega-5 gliadin, P = .0001). Year 1 SCDs correlated with wheat-specific (rho = 0.55, P = .0003) and omega-5 gliadin-specific (rho = 0.51, P = .001) IgG levels in all subjects. Among 7822 low-dose VWG OIT doses in year 1, 15.4% were associated with adverse reactions: 0.04% were severe, and 0.08% subjects received epinephrine. Among 7921 placebo doses, 5.8% were associated with adverse reactions; none were severe.

Conclusions: Low- and high-dose VWG OIT induced desensitization in about one half of the subjects after 1 year of treatment. Two years of low-dose VWG OIT resulted in 30% desensitization, and 13% had sustained unresponsiveness.
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http://dx.doi.org/10.1016/j.jaci.2018.08.041DOI Listing
February 2019

Phenotypes of Recurrent Wheezing in Preschool Children: Identification by Latent Class Analysis and Utility in Prediction of Future Exacerbation.

J Allergy Clin Immunol Pract 2019 03 26;7(3):915-924.e7. Epub 2018 Sep 26.

Department of Statistics, Pennsylvania State University, Hershey, Pa.

Background: Recurrent preschool wheezing is a heterogeneous disorder with significant morbidity, yet little is known about phenotypic determinants and their impact on clinical outcomes.

Objective: Latent class analysis (LCA) was used to identify latent classes of recurrent preschool wheeze and their association with future exacerbations and inhaled corticosteroid (ICS) treatment response.

Methods: Data from 5 clinical trials of 1708 children aged 12 to 71 months with recurrent wheezing were merged. LCA was performed on 10 demographic, exposure, and sensitization variables to determine the optimal number of latent classes. The primary outcome was the annualized rate of wheezing exacerbations requiring systemic corticosteroids during the study intervention period; the secondary outcome was the time to first exacerbation. Exploratory analyses examined the effect of daily ICS treatment on exacerbation outcomes.

Results: Four latent classes of recurrent wheezing were identified; these were not distinguished by current symptoms or historical exacerbations but differed with regard to allergen sensitization and/or exposures. Annualized exacerbation rates (mean ± SEM/year) were 0.65 ± 0.06 for class 1 ("minimal sensitization"), 0.93 ± 0.10 for class 2 ("sensitization with indoor pet exposure"), 0.60 ± 0.07 for class 3 ("sensitization with tobacco smoke exposure"), and 0.81 ± 0.10 for class 4 ("multiple sensitization and eczema") (P < .001). In a research setting of high adherence, daily ICS treatment improved exacerbation rates in classes 2 and 4 but not the other groups.

Conclusions: Sensitization and exposure assessments are useful in the prediction of future exacerbation and may identify children most likely to respond favorably to daily ICS treatment.
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http://dx.doi.org/10.1016/j.jaip.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401237PMC
March 2019

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

N Engl J Med 2018 Mar 3;378(10):891-901. Epub 2018 Mar 3.

From the Department of Pediatrics, University of Wisconsin School of Medicine and Public Health (D.J.J., R.F.L.J.), and the University of Wisconsin-Madison (C.A.S.) - both in Madison; the Department of Pediatrics, Washington University in St. Louis School of Medicine and St. Louis Children's Hospital, St. Louis (L.B.B., A.B.); the Department of Public Health Sciences, Penn State University, Hershey (D.T.M., S.B.), and the University of Pittsburgh Asthma Institute at University of Pittsburgh Medical Center-University of Pittsburgh School of Medicine (F.H.) and the Department of Pediatrics, Allegheny General Hospital (D.A.G.), Pittsburgh - all in Pennsylvania; the Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland (J.F.C., R.E.M., K.R.); the Department of Pediatrics, Emory University, Atlanta (A.M.F.); the Divisions of Respiratory Diseases (J.M.G.) and Allergy-Immunology, Boston Children's Hospital (W.P., W.J.S., S.N.B.), Harvard Medical School, and Brigham and Women's Hospital, Harvard Medical School (E.I.) - all in Boston; the Arizona Respiratory Center, University of Arizona, Tucson (W.J.M., F.D.M.); Wake Forest University School of Medicine, Winston-Salem, NC (S.P.P.); the Departments of Pediatrics (M.D.C., N.L.), Epidemiology (M.D.C.), Biostatistics (M.D.C.), and Medicine (S.C.L.), University of California, San Francisco (UCSF), and UCSF Benioff Children's Hospital (M.D.C.) - both in San Francisco; Ann and Robert H. Lurie Children's Hospital of Chicago (J.A.P., R.G.R.), University of Illinois at Chicago (J.A.K., H.V.K.), and the Department of Pediatrics, Stroger Hospital of Cook County, Rush University Medical Center (J.N.M.) - all in Chicago; UCSF Benioff Children's Hospital Oakland, Oakland (M.B., D.L., J.M.); Nemours Children's Health System, Jacksonville (K.B., J.J.L.), and Nemours Children's Hospital, University of Central Florida College of Medicine, Orlando (J.E.L.) - both in Florida; the Department of Pediatrics, National Jewish Health, Denver (R.C., J.T.O.); and the Department of Pediatrics, University of New Mexico, Albuquerque (H.H.R.).

Background: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited.

Methods: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids.

Results: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06).

Conclusions: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).
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http://dx.doi.org/10.1056/NEJMoa1710988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972517PMC
March 2018

Genome-wide association study of maternal genetic effects and parent-of-origin effects on food allergy.

Medicine (Baltimore) 2018 Mar;97(9):e0043

Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China Mary Ann and J. Milburn Smith Child Health Research Program, Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago Department of Pediatrics Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL University of Chinese Academy of Sciences, Beijing, China Department of Population, Family and Reproductive Health, Center on the Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan Department of Public Health, China Medical University, Taichung, Taiwan Division of Neonatology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL Biostatistics Branch, NIEHS, NIH, DHHS, Research Triangle Park, NC Department of Bioinformatics, the University of Illinois at Chicago, Chicago, IL Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY Center for Intestinal and Liver Inflammation Research, Stanley Manne Children's Research Institute Division of Allergy and Immunology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL Department of Cardiovascular Internal Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Department of Epidemiology and Health Statistics, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA Division of General Pediatrics and Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.

Previous genetic studies of food allergy (FA) have mainly focused on inherited genotypic effects. The role of parental genotypic effects remains largely unexplored. Leveraging existing genome-wide association study (GWAS) data generated from the Chicago Food Allergy Study, we examined maternal genotypic and parent-of-origin (PO) effects using multinomial likelihood ratio tests in 588 complete and incomplete Caucasian FA trios. We identified 1 single nucleotide polymorphism with significant (P < 5×10) maternal effect on any FA (rs4235235), which is located in a noncoding RNA (LOC101927947) with unknown function. We also identified 3 suggestive (P < 5×10) loci with maternal genetic effects: 1 for any FA (rs976078, in a gene desert region on 13q31.1) and 2 for egg allergy (rs1343795 and rs4572450, in the ZNF652 gene, where genetic variants have been associated with atopic dermatitis). Three suggestive loci with PO effect were observed: 1 for peanut allergy (rs4896888 in the ADGB gene) and 2 for any FA in boys only (rs1036504 and rs2917750 in the IQCE gene). Findings from this family-based GWAS of FA provided some preliminary evidence on maternal genotypic or PO effects on FA. Additional family-based studies are needed to confirm our findings and gain new insight into maternal and paternal genetic contribution to FA.
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http://dx.doi.org/10.1097/MD.0000000000010043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851764PMC
March 2018

Short-term ibrutinib therapy suppresses skin test responses and eliminates IgE-mediated basophil activation in adults with peanut or tree nut allergy.

J Allergy Clin Immunol 2018 05 31;141(5):1914-1916.e7. Epub 2018 Jan 31.

Department of Medicine, Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.12.987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297295PMC
May 2018

Overweight/obesity status in preschool children associates with worse asthma but robust improvement on inhaled corticosteroids.

J Allergy Clin Immunol 2018 04 19;141(4):1459-1467.e2. Epub 2017 Dec 19.

Children's Hospital Colorado, The Breathing Institute, and University of Colorado School of Medicine, Aurora, Colo.

Background: Overweight/obesity (OW) is linked to worse asthma and poorer inhaled corticosteroid (ICS) response in older children and adults.

Objective: We sought to describe the relationships between OW and asthma severity and response to ICS in preschool children.

Methods: This post hoc study of 3 large multicenter trials involving 2- to 5-year-old children compared annualized asthma symptom days and exacerbations among normal weight (NW) (body mass index: 10th-84th percentiles) versus OW (body mass index: ≥85th percentile) participants. Participants had been randomized to daily ICS, intermittent ICS, or daily placebo. Simple and multivariable linear regression was used to compare body mass index groups.

Results: Within the group not treated with a daily controller, OW children had more asthma symptom days (90.7 vs 53.2, P = .020) and exacerbations (1.4 vs 0.8, P = .009) thanNW children did. Within the ICS-treated groups, OW and NW children had similar asthma symptom days (daily ICS: 47.2 vs 44.0 days, P = .44; short-term ICS: 61.8 vs 52.9 days, P = .46; as-needed ICS: 53.3 vs 47.3 days, P = .53), and similar exacerbations (daily ICS: 0.6 vs 0.8, P = .10; short-term ICS: 1.1 vs 0.8 days, P = .25; as-needed ICS: 1.0 vs 1.1, P = .72). Compared with placebo, daily ICS in OW led to fewer annualized asthma symptom days (90.7 vs 41.2, P = .004) and exacerbations (1.4 vs 0.6, P = .006), while similar protective ICS effects were less apparent among NW.

Conclusions: In preschool children off controller therapy, OW is associated with greater asthma impairment and exacerbations. However, unlike older asthmatic patients, OW preschool children do not demonstrate reduced responsiveness to ICS therapy.
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http://dx.doi.org/10.1016/j.jaci.2017.09.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675020PMC
April 2018

Obstruction phenotype as a predictor of asthma severity and instability in children.

J Allergy Clin Immunol 2018 10 14;142(4):1090-1099.e4. Epub 2017 Nov 14.

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Background: Small-airways instability resulting in premature airway closure has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small-airways dysfunction, a focus on the air-trapping component of obstruction might identify a risk factor for asthma instability.

Objective: We sought to use spirometric measurements to identify patterns of airway obstruction in children and define obstruction phenotypes that relate to asthma instability.

Methods: Prebronchodilation and postbronchodilation spirometric data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as a forced vital capacity (FVC) z score of less than -1.64 or an increase in FVC of 10% of predicted value or greater with bronchodilation. The airflow limitation phenotype (A Limit) had an FEV/FVC z score of less than -1.64 but not A Trpg. The no airflow limitation or air-trapping criteria (None) phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability.

Results: Patients with the A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study compared with those with the A Limit (P < .03) and None (P < .001) phenotypes. Patients with the A Trpg phenotype also had the highest Composite Asthma Severity Index score, the highest asthma treatment step, the greatest variability in FEV over time, and the greatest sensitivity to methacholine challenge.

Conclusions: A Trpg and A Limit patterns of obstruction, as defined by using routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability.
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http://dx.doi.org/10.1016/j.jaci.2017.09.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951738PMC
October 2018

Effect of Varying Doses of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Exposure Among Patients With Peanut Sensitivity: A Randomized Clinical Trial.

JAMA 2017 11;318(18):1798-1809

Hôpital Necker, Enfants Malades, Paris, France.

Importance: Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials.

Objective: To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment.

Design, Setting, And Participants: Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein.

Interventions: Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 μg (n = 53), 100 μg (n = 56), or 250 μg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose.

Main Outcomes And Measures: The primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs).

Results: Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-μg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-μg patch. Because of statistical testing hierarchical rules, the 50-μg patch was not compared with placebo. Interaction by age group was only significant for the 250-μg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-μg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-μg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-μg patch = 100%, 100-μg patch = 98.2%, 250-μg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%.

Conclusions And Relevance: In this dose-ranging trial of peanut-allergic patients, the 250-μg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial.

Trial Registration: clinicaltrials.gov Identifier: NCT01675882.
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http://dx.doi.org/10.1001/jama.2017.16591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820709PMC
November 2017

Reply.

J Allergy Clin Immunol 2017 04 22;139(4):1408-1409. Epub 2017 Feb 22.

University of Wisconsin School of Medicine and Public Health, Madison, Wis.

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http://dx.doi.org/10.1016/j.jaci.2016.12.962DOI Listing
April 2017

Hygiene factors associated with childhood food allergy and asthma.

Allergy Asthma Proc 2016 11;37(6):e140-e146

Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.

Background: Childhood food allergy and asthma rates are increasing. The hygiene hypothesis has been proposed as an explanation for the increased incidence of allergic disease.

Objective: To describe the association of childhood food allergy and asthma with hygiene factors, such as the number of siblings, antibiotic use, infection history, pet exposure, child care exposure, and maternalchild factors.

Methods: Children ages 021 years old (N = 1359) were recruited for a cross-sectional family-based study, including children with food allergy and children without food allergy, and their siblings. We assessed the associations between childhood food allergy and asthma with hygiene factors.

Results: Of the 1359 children, 832 (61.2%) had food allergy, and 406 (30%) had asthma. In the adjusted analysis, the prevalence of food allergy was increased if there was a history of skin infection (prevalence ratio [RRR] 1.12 [95% confidence interval {CI}, 1.011.24]) or eczema (RRR 1.89 [95% CI, 1.702.10]). The prevalence of asthma was increased with a history of respiratory syncytial virus infection (RRR 1.60 [95% CI, 1.341.90]) or eczema (RRR 1.54 [95% CI, 1.271.86]). A greater number of siblings were associated with a decreased prevalence of food allergy (RRR 0.79 [95% CI, 0.750.84]) and asthma (RRR 0.82 [95% CI, 0.740.91]).

Conclusion: Our findings supported the accumulating evidence of an association between skin infections and eczema with food allergy. Because these results could be subject to recall bias, additional prospective studies are needed to substantiate these findings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080537PMC
http://dx.doi.org/10.2500/aap.2016.37.3988DOI Listing
November 2016

Individualized therapy for persistent asthma in young children.

J Allergy Clin Immunol 2016 12 21;138(6):1608-1618.e12. Epub 2016 Oct 21.

Children's Hospital Colorado, The Breathing Institute, and University of Colorado School of Medicine, Aurora, CO.

Background: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications.

Methods: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response.

Results: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/μL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments.

Conclusions: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.
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http://dx.doi.org/10.1016/j.jaci.2016.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148729PMC
December 2016