A Registry Study of 240 Patients with X-Linked Agammaglobulinemia Living in the USA.

PURPOSE: To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry. METHODS: The USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton's tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality. RESULTS: Data compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1-52 years], 0.8 [r = birth-22.3 years], 2 [r = birth-29 years], and 10 [r = 1-56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3-56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died. CONCLUSIONS: Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood.

Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion Syndrome and Other Defects in Thymic Development.

Current practices vary widely regarding the immunological work-up and management of patients affected with defects in thymic development (DTD), which include chromosome 22q11.2 microdeletion syndrome (22q11.2del) and other causes of DiGeorge syndrome (DGS) and coloboma, heart defect, atresia choanae, retardation of growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome. Practice variations affect the initial and subsequent assessment of immune function, the terminology used to describe the condition and immune status, the accepted criteria for recommending live vaccines, and how often follow-up is needed based on the degree of immune compromise. The lack of consensus and widely varying practices highlight the need to establish updated immunological clinical practice guidelines. These guideline recommendations provide a comprehensive review for immunologists and other clinicians who manage immune aspects of this group of disorders.

Innovations in the treatment of anaphylaxis: A review of recent data.

PURPOSE OF REVIEW: The current standard of first-line emergency treatment of anaphylaxis is intramuscular (IM) epinephrine, mostly administered through epinephrine autoinjector (EAI) in the outpatient setting. However, undercarriage and underuse of EAIs are common, and delayed epinephrine use is associated with increased morbidity and mortality. Patients, caregivers, and healthcare professionals have expressed a strong desire for small, needle-free devices and products that would offer improved carriage, ease of use, and more convenient, less invasive routes of epinephrine administration. Novel mechanisms of epinephrine administration are under investigation to help address several recognized EAI limitations. This review explores innovative nasal and oral products under investigation for the outpatient emergency treatment of anaphylaxis. FINDINGS: Human studies of epinephrine administered through nasal epinephrine spray, a nasal powder spray, and a sublingual film have been conducted. Data from these studies indicate promising pharmacokinetic results comparable to those of the standard of outpatient emergency care (0.3-mg EAI) and syringe and needle IM epinephrine administration. Several products have shown maximum plasma concentration values higher than those of the 0.3-mg EAI and manual IM injection, although it remains unclear whether this has clinical relevancy in patient outcomes. Generally, these modalities show comparable time to maximum concentrations. Pharmacodynamic changes observed with these products are comparable to or more robust than those seen with EAI and manual IM injection. SUMMARY: Given comparable or superior pharmacokinetic and pharmacodynamic results and safety of innovative epinephrine therapies to those of current standards of care, US Food and Drug Administration approval of these products may help address numerous barriers that EAIs present. The ease of use and carriage and favorable safety profiles of needle-free treatments may make them an attractive alternative to patients and caregivers, potentially addressing injection fears, needle-based safety risks, and other reasons for lack of or delayed use.

Health-Related Quality of Life in 91 Patients with X-Linked Agammaglobulinemia.

PURPOSE: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency (PID) caused by a defect in the gene encoding for Bruton tyrosine kinase (BTK). In the absence of a functional BTK, patients have low or absent circulating B cells and low or absent serum immunoglobulin. Despite gammaglobulin replacement and prompt use of antimicrobial agents, patients with XLA continue to experience infectious and non-infectious complications throughout their lifetime. The purpose of this study was to understand self-perceived health status of US-based patients with XLA, and examine the associations amongst clinical characteristics, treatment experience, and quality of life (QoL). METHODS: A 46 and 68 question survey, developed by the Immune Deficiency Foundation (IDF) and a Short Form-12item v2® (SF-12v2®) for adults and SF-10™ for children to assess QoL, were mailed by IDF to patients in 2017 and 2018. Those that self-identified as having XLA or males with agammaglobulinemia were selected for analysis. Mean physical and mental composite scores (PCS and MCS) from SF-12v2® and mean physical health component (PHS) and psychological health summary (PSS) from SF-10™ scores were compared to the US normative data. RESULTS: Ninety-one patients completed the surveys: 58 (63.7%) adults and 33 (36.3%) children. For the combined surveys, the overall median age at time of the survey was 28.5 years (yrs); Inter-Quartile-Range (IQR) 13-49.5 yrs; the median age at diagnosis was 2 yrs (IQR = 0-4 yrs) and the median number of years with XLA diagnosis was 23 (IQR 10.75-40yrs). Amongst adult patients, physical scores were noted to be below the general adult population but did not reach statistical significance. In contrast, 2 or more chronic conditions impacted both physical and mental QoL (p < .001) and hospitalization was associated with significantly decreased physical health QoL (p < .001); three or more infections in the past 12 months exhibited impact on physical health although was not found to be statistically significant. Adult patients with public insurance fared worse in mental health domains compared to those with combined public and private or those with private alone (p = 0.001). Employment status did not impact QoL. None of these variables met statistical significance nor demonstrated impact within the pediatric population in either physical or mental domains of health. CONCLUSION: Our study provides further insight into what factors impact both physical and mental domains of health amongst patients with XLA. Early detection to prevent the development of associated morbidity, as well as vigilant care to prevent hospitalizations and infections, can limit the impact this disease may have on the overall well-being of XLA patients.

Peanut cross-contamination in randomly selected baked goods.

BACKGROUND: The current standard of care for managing peanut allergy includes avoidance of peanut and use of injectable epinephrine; however, strict avoidance is difficult and accidental ingestion is common with potentially serious consequences. Despite vigilance and efforts to minimize the risk of accidental exposure, peanut protein cross-contamination continues to occur in a variety of foods, including baked goods. OBJECTIVE: To assess and quantify the presence of peanut protein contamination in certain baked goods. METHODS: Randomly selected baked goods were collected from bakeries in the New York and Miami metropolitan areas that sold a variety of ethnic cuisines. A second set of samples from the same bakeries was collected at least 1 week after to evaluate between-batch variability. Samples were sent to the Food Allergy Research and Resource Program to analyze peanut contamination by enzyme-linked immunosorbent assay. Consumption estimates were based on 2003 to 2010 National Health and Nutrition Examination Survey survey data. RESULTS: Of 154 samples from 18 bakeries, 4 (2.6%) had detectable peanut contamination with peanut protein levels ranging from 0.1 mg/100 g to 650 mg/100 g. Consumption estimates for single occasion ingestion of a contaminated item ranged from 0.07 mg to 832 mg of peanut protein. CONCLUSION: In this study, unintended peanut protein was present in a small, but not insignificant, proportion of baked goods, with the potential to trigger a reaction in individuals with peanut allergy. Some products contained high levels of unintended peanut protein. The current data support the potential for accidental exposure to peanut protein with its associated risk.

Infant Anaphylaxis: A Diagnostic Challenge.

PURPOSE OF REVIEW: Infant anaphylaxis has been increasing in incidence; however, significant gaps in the literature remain. The aim of this article is to review the most recent literature pertaining to infant anaphylaxis and discuss recent findings related to epidemiology, diagnosis, management, and prevention. RECENT FINDINGS: There is no accurate report of the incidence and prevalence of anaphylaxis in infancy. Food is the most common trigger for infant anaphylaxis reported. The diagnosis of anaphylaxis in infants is often missed, and, even when the diagnosis is made, epinephrine continues to be under-utilized. An epinephrine autoinjector with a shorter needle and lower dose is now available for infants. Concise criteria specifically focusing on infant anaphylaxis is needed to streamline its diagnosis and management. Diagnosis is underrecognized in infants leading to improper treatment. When the diagnosis is made, epinephrine continues to be under-utilized and under-prescribed in infants.

Review of efficacy of ciclesonide for the treatment of asthma in children.

Background: Ciclesonide (CIC) is an inhaled corticosteroid (ICS) approved for the maintenance treatment of asthma in patients ages ≥ 12 years. The prodrug aspect of CIC is associated with a safety profile that may make it ideal for children. Objective: The objective was to summarize efficacy results from the eight phase III, randomized, double-blind, controlled trials in children with asthma conducted during CIC clinical development. Methods: Four trials compared CIC 40, 80, or 160 µg/day with placebo. Two trials compared CIC 160 µg/day with fluticasone propionate 200 µg/day, one trial compared CIC 80 or 160 µg/day with fluticasone 200 µg/day, and one trial compared CIC 160 µg/day with budesonide 400 µg/day. Results: The primary end point was met by at least two CIC doses versus placebo in the trials in which the primary end point was the change from baseline in lung function outcome (forced expiratory volume in 1 second [FEV1] % predicted or morning peak expiratory flow [PEF]). A trial that compared CIC with placebo did not meet the primary end point of superiority in time-to-first severe wheeze exacerbation or lack of improvement. The primary end point of noninferiority to the active control (fluticasone or budesonide) in the change from baseline in a lung function outcome (FEV1, morning PEF, evening PEF) was met with the CIC 160-µg dose in all active control trials. CIC generally demonstrated statistically significant improvements in forced expiratory flow at 25%-75% of forced vital capacity, asthma symptoms, rescue medication use, and asthma control when compared with placebo and noninferiority for these outcomes compared with fluticasone or budesonide. Conclusion: In children with asthma, once-daily CIC significantly improved large and small airway function, asthma symptoms, and asthma control, and reduced rescue medication use compared with placebo. CIC was comparable with other ICS used to treat asthma in children, which demonstrated its worth for the pediatric population.

Safety of ciclesonide in children with asthma: A review of randomized controlled trials.

Background: Parental concerns about the adverse effects of asthma medications can lead to nonadherence and uncontrolled asthma in children. Ciclesonide (CIC) is a prodrug, with low oropharyngeal deposition and bioavailability that may minimize the risk of local and systemic adverse effects. CIC is U.S. Food and Drug Administration approved for asthma in children ages ≥ 12 years. Objective: To summarize safety results from the 13 phase II or III randomized controlled trials conducted in children with asthma during CIC clinical development. Methods: Four 12- to 24-week trials compared the safety of once-daily CIC 40, 80, or 160 µg/day with placebo; four 12-week trials compared the safety of CIC 80 or 160 µg/day with either fluticasone or budesonide; one 12-month trial compared the long-term safety of CIC 40, 80, or 160 µg/day with fluticasone; one 12-month trial compared growth velocity of CIC 40 or 160 µg/day with placebo; and three cross-over trials compared short-term growth velocity and hypothalamic-pituitary-adrenal (HPA) axis effects of CIC 40, 80, or 160 µg/day with placebo or fluticasone. Results: In all, 4399 children were treated with CIC. The incidence of treatment-emergent adverse events (AE) was similar among the CIC doses and between CIC and placebo in short-term studies and between CIC and fluticasone in the long-term safety study. No CIC-related serious AEs were reported in any study. The incidence of treatment-related oral candidiasis was low and similar between CIC (≤0.5%) and placebo (≤0.7%) or active controls (≤0.5%) in the short-term studies. There was no clinically relevant HPA axis suppression or reduction in growth velocity associated with CIC. Conclusion: Data from 13 studies demonstrate that CIC is associated with low rates of oropharyngeal AEs, with no indication of clinically relevant systemic effects in children with asthma. The favorable safety profile and demonstrated improvements in asthma control make CIC an ideal inhaled corticosteroid for the treatment of asthma in children.

From the pages of AllergyWatch®: November 2020.

For this month's edition of "From the Pages of AllergyWatch," I have chosen reviews of articles of interest to the clinical allergist. The first study found that wheezing infants with atopic sensitization at the time of the first wheezing episode was strongly associated with bronchial reactivity in childhood. The next review, of an article published in the Annals of Allergy, Asthma & Immunology, investigated the complexity of atopic sensitization to foods in children with atopic dermatitis (AD). The final study confirms the determination of the US Environmental Protection Agency to the likely causal link between exposures to particulate matter and ozone and respiratory illness.

From the pages of AllergyWatch®: September 2020.

For the September edition of From the Pages of AllergyWatch, I have chosen reviews of articles focusing on topics that affect shared decision making. The first study examines the fact that perceived triggers of asthma can affect the quality of life (QoL). The next report studied the importance of school experience, particularly the interaction with teachers and staff to help children manage their asthma. The last summary reviews a study analyzing the influence of socioeconomic differences affecting the higher prevalence and exacerbation rate for asthma in African American patients (Stanley Fineman, MD, Editor in Chief, Allergy Watch.).

Allergy Watch.

A new Annals feature in 2018, "From the Pages of AllergyWatch" is devoted to publishing synopses of Allergy and Asthma literature relevant to a topic of emphasis. These unbiased synopses and comments by our Editors have been previously printed in the AllergyWatch bimonthly newsletter, and it is our hope that presenting carefully selected article summaries and comments in the Annals will serve as a valuable educational resource for practicing allergists.

From the Pages of Allergy Watch: February 2020.

A new Annals feature in 2018, "From the Pages of AllergyWatch" is devoted to publishing synopses of Allergy and Asthma literature relevant to a topic of emphasis. These unbiased synopses and comments by our Editors have been previously printed in the AllergyWatch bimonthly newsletter, and it is our hope that presenting carefully selected article summaries and comments in the Annals will serve as a valuable educational resource for practicing allergists.

From the Pages of Allergy Watch: November 2019.

A new Annals feature in 2018, "From the Pages of AllergyWatch" is devoted to publishing synopses of Allergy and Asthma literature relevant to a topic of emphasis. These unbiased synopses and comments by our Editors have been previously printed in the AllergyWatch bimonthly newsletter, and it is our hope that presenting carefully selected article summaries and comments in the Annals will serve as a valuable educational resource for practicing allergists.