Development of a predictive model for pediatric atopic dermatitis: A retrospective cross-sectional nationwide database study.

BACKGROUND: The rise in prevalence of atopic dermatitis (AD) has been correlated with numerous elements of the exposome, modern-day lifestyle, and familial history. The combined analysis of familial history and other risk elements may allow us to understand the driving factors behind the development of AD. OBJECTIVE: To develop prediction models to assess the risk of developing AD using a large and diverse cohort (N = 77,525) and easily assessed risk factors. METHODS: We analyzed electronic medical record data from Leumit Health System. Documented predictive factors include sex, season of birth, environment (urban/rural), socioeconomic status, household smoking, diagnosed skin conditions, number of siblings, a paternal, maternal, or sibling history of an atopic condition, and antibiotic prescriptions during pregnancy or after birth. Predictive models were trained and validated on the data set. RESULTS: Medium (odds ratio [OR] 2.04, CI 1.92-2.17, P < .001) and high (OR 2.13, CI 1.95-2.34, P < .001) socioeconomic status, a previous diagnosis of contact dermatitis (OR 2.57, CI 2.37-2.78, P < .001), presence of siblings with an AD diagnosis (OR 2.21, CI 2.04-2.40, P < .001), and the percentage of siblings with any atopic condition (OR 2.58, CI 2.09-3.17, P < .001) drove risk for AD in a logistic regression model. A random forest prediction model with a sensitivity of 61% and a specificity of 84% was developed. Generalized mixed models accounting for the random effect of familial relationships boasted an area under the curve of 0.98. CONCLUSION: Predictive modeling using noninvasive and accessible inputs is a powerful tool to stratify risk for developing AD.

Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population.

Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin's disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.

Managing anaphylaxis: Epinephrine, antihistamines, and corticosteroids: More than 10 years of Cross-Canada Anaphylaxis REgistry data.

BACKGROUND: Epinephrine is the first-line treatment for anaphylaxis but is often replaced with antihistamines or corticosteroids. Delayed epinephrine administration is a risk factor for fatal anaphylaxis. Convincing data on the role of antihistamines and corticosteroids in anaphylaxis management are sparse. OBJECTIVE: To establish the impact of prehospital treatment with epinephrine, antihistamines, and/or corticosteroids on anaphylaxis management. METHODS: Patients presenting with anaphylaxis were recruited prospectively and retrospectively in 10 Canadian and 1 Israeli emergency departments (EDs) between April 2011 and August 2022, as part of the Cross-Canada Anaphylaxis REgistry. Data on anaphylaxis cases were collected using a standardized form. Primary outcomes were uncontrolled reactions (>2 doses of epinephrine in ED), no prehospital epinephrine use, use of intravenous fluids in ED, and hospital admission. Multivariate regression was used to identify factors associated with primary outcomes. RESULTS: Among 5364 reactions recorded, median age was 8.8 years (IQR, 3.78-16.9); 54.9% of the patients were males, and 52.5% had a known food allergy. In the prehospital setting, 37.9% received epinephrine; 44.3% received antihistamines, and 3.15% received corticosteroids. Uncontrolled reactions happened in 250 reactions. Patients treated with prehospital epinephrine were less likely to have uncontrolled reactions (adjusted odds ratio [aOR], 0.955 [95% CI, 0.943-0.967]), receive intravenous fluids in ED (aOR, 0.976 [95% CI, 0.959-0.992]), and to be admitted after the reaction (aOR, 0.964 [95% CI, 0.949-0.980]). Patients treated with prehospital antihistamines were less likely to have uncontrolled reactions (aOR, 0.978 [95% CI, 0.967-0.989]) and to be admitted after the reaction (aOR, 0.963 [95% CI, 0.949-0.977]). Patients who received prehospital corticosteroids were more likely to require intravenous fluids in ED (aOR, 1.059 [95% CI, 1.013-1.107]) and be admitted (aOR, 1.232 [95% CI, 1.181-1.286]). CONCLUSION: Our findings in this predominantly pediatric population support the early use of epinephrine and suggest a beneficial effect of antihistamines. Corticosteroid use in anaphylaxis should be revisited.

Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity.

BACKGROUND: In mid-December 2020, Israel started a nationwide mass vaccination campaign against coronavirus disease 2019 (COVID-19). In the first few weeks, medical personnel, elderly citizens, and patients with chronic diseases were prioritized. As such, patients with primary and secondary immunodeficiencies were encouraged to receive the vaccine. Although the efficacy of RNA-based COVID-19 vaccines has been demonstrated in the general population, little is known about their efficacy and safety in patients with inborn errors of immunity (IEI). OBJECTIVE: Our aim was to evaluate the humoral and cellular immune response to COVID-19 vaccine in a cohort of patients with IEI. METHODS: A total of 26 adult patients were enrolled, and plasma and peripheral blood mononuclear cells were collected from them 2 weeks following the second dose of Pfizer-BioNTech COVID-19 vaccine. Humoral response was evaluated by testing anti-SARS-CoV-2 spike (S) receptor-binding domain and antinucleocapsid antibody titers and evaluating neutralizing ability by inhibition of receptor-binding domain-angiotensin-converting enzyme 2 binding. Cellular immune response was evaluated by using ELISpot, estimating IL-2 and IFN-γ secretion in response to pooled SARS-CoV-2 S- or M-peptides. RESULTS: Our cohort included 18 patients with a predominantly antibody deficiency, 2 with combined immunodeficiency, 3 with immune dysregulation, and 3 with other genetically defined diagnoses. Twenty-two of them were receiving immunoglobulin replacement therapy. Of the 26 patients, 18 developed specific antibody response, and 19 showed S-peptide-specific T-cell response. None of the patients reported significant adverse events. CONCLUSION: Vaccinating patients with IEI is safe, and most patients were able to develop vaccine-specific antibody response, S-protein-specific cellular response, or both.

Respiratory effects of acute milk consumption among asthmatic and non-asthmatic children: a randomized controlled study.

BACKGROUND: A commonly held public belief is that cow's milk products increase mucus production and respiratory symptoms. Dietary milk elimination is often attempted despite lack of evidence. Our objective was to investigate whether a single exposure to cow's milk is associated with respiratory symptoms and changes in pulmonary functions in asthmatic and non-asthmatic children. METHODS: We conducted a prospective double blind, placebo-controlled trial on non-asthmatic and asthmatic children aged 6-18 years evaluated at a pediatric pulmonology unit. The children were randomly challenged with cow's milk or soy milk substitute. Symptoms, spirometry, fractional-exhaled nitric-oxide (FeNO), and pulse oximetry findings were obtained at baseline and at 30, 60, 90, and 120 min following challenge. A two-way ANCOVA (with repeated measures when required) was used to compare the performances of all groups and subgroups over time. The outcome measures of each participant were compared to his/her own variables over time and in relation to his/her baseline values. In case of missing data points, missingness analysis was performed using Little's missing completely at random (MCAR) test. RESULTS: Fifty non-asthmatic children (26 assigned to the cow's milk group and 24 to the soy substitute group), and 46 asthmatic children (22 in the cow's milk group and 24 in the soy substitute group) were enrolled. Age, gender, and body mass index Z-score were comparable between the two groups. No changes in symptoms, spirometry, FeNO, or oxygen saturation measurements were observed following challenge in any of the participants in both groups, at any time point compared to baseline. CONCLUSIONS: A single exposure to cow's milk is not associated with symptoms, bronchial inflammation, or bronchial constriction in both non-asthmatic and asthmatic children. Our findings do not support the strict elimination of dairy products from a child's diet for the prevention of respiratory symptoms. TRIAL REGISTRATION: This study was approved by the Tel Aviv Sourasky Medical Center Institutional Review Board and the Israeli Ministry of Health review board (Helsinki Committee, NIH #NCT02745899). Registered April 2016 https://clinicaltrials.gov/ct2/show/NCT02745899?cond=milk+asthma&rank=1 .

Efficacy of omalizumab treatment for pediatric chronic spontaneous urticaria: A multi-center retrospective case series.

BACKGROUND: Chronic urticaria is defined by the presence of itchy wheals, sometimes accompanied by angioedema, lasting for at least 6 weeks. In children, most cases occur without an eliciting factor and are defined as chronic spontaneous urticaria (CSU). CSU affects up to 0.75% of children with a negative impact on quality of life and school performance. CSU is treated in adults with second-generation antihistamines, increased up to four times normal doses for second-line treatment. Omalizumab (a monoclonal antibody to IgE) may be recommended as third-line therapy. A similar protocol is used in children, yet little is known of its efficacy and safety. OBJECTIVES: To summarize our multi-center experience in treating children with recalcitrant CSU with omalizumab. METHODS: A retrospective multi-center case series conducted in 5 tertiary care centers in Israel. Patients included were children <18 years old diagnosed with recalcitrant CSU who were treated with omalizumab. Patients were followed up throughout the duration of omalizumab therapy/symptom remission. Patients' electronic medical records were used to gather data. RESULTS: Nineteen participants (11 F; 8 M) presented with CSU between ages 6 and 16.9 years. Sixteen (84%) responded to omalizumab, including children <12 years old, although two became non-responsive after 6-12 months of therapy. Another three patients (16%) were resistant to treatment, achieving remission through fourth-line (Cyclosporine A) or other therapies. CONCLUSION: Children with recalcitrant CSU, even those <12 years old, respond well to standard-dose, third-line omalizumab therapy at rates similar to adults. Yet, some cases may become non-responsive with ongoing treatment.

Epicutaneous Exposure to Peanut Oil Induces Systemic and Pulmonary Allergic Reaction in Mice.

BACKGROUND: The prevalence of peanut allergy (PA) is constantly on the rise. Atopic dermatitis (AD) is a major risk factor for developing food allergy. Some bath oils and skin creams used for treating AD contain peanut oil, and it has been suggested that exposure to peanut allergens through a disrupted skin barrier is a potential cause of PA. Our aim was to investigate whether application of peanut oil to irritated skin causes a systemic or respiratory allergic response to peanuts in an animal model. METHODS: BALB/c mice underwent epicutaneous sensitization with either peanut oil (PM, n = 9) or phosphate buffered solution (controls, n = 9) daily for 5 consecutive days. Ten days after the last exposure the mice were challenged with intranasal peanut protein for 5 consecutive days. Bronchial alveolar lavage fluid was collected for cellular studies and measurement of cytokine levels. Sera were collected for immunoglobulin E (IgE) measurement. RESULTS: Epicutaneous peanut oil sensitization increased leukocyte and eosinophil counts and interleukin-13 levels (p = 0.003, p = 0.0006 and p = 0.03, respectively), in addition to increasing total serum IgE (p = 0.03). CONCLUSIONS: The results suggest that topical application of peanut oil may play a role in the etiology of PA.

Trends in the diagnosis and management of anaphylaxis in a tertiary care pediatric emergency department.

BACKGROUND: Underdiagnosis of anaphylaxis is a major concern in the pediatric emergency department (PED), leading to failure to administer and prescribe intramuscular epinephrine treatment. OBJECTIVE: To examine the clinical features, triggers, and management of anaphylaxis in the PED, with a special focus on the rate of cases diagnosed and treated correctly over time, and to compare correctly diagnosed and misdiagnosed cases. METHODS: All records of patients presenting to a tertiary care PED between 2013 and 2016 with a final diagnosis of anaphylaxis or allergic reaction were reviewed. RESULTS: The rate of anaphylaxis increased from 0.1% between 2013 and 2014 and 0.24% between 2015 and 2016. Symptoms such as breathing difficulties and wheezing were found significantly less among misdiagnosed patients compared with patients correctly diagnosed with anaphylaxis. Food was the most common causative agent in both of the study periods (88% in 2013-2014 and 91% in 2015-2016), with milk (20% in 2013-2014 and 28% in 2015-2016) and tree nuts (23.1% in 2013-2014 and 23.7% in 2015-2016 as the most prevalent identified triggers. Intramuscular epinephrine treatment in the prehospital and hospital settings and the automatic epinephrine injector prescription rate did not change significantly throughout the study. Referral to an allergist increased from 68% in 2013 to 2014 to 90% in 2015 to 2016. CONCLUSION: The rate of visits attributable to anaphylaxis in our PED doubled during the study period, with milk allergy as the most common trigger. Most cases of misdiagnosed and undertreated anaphylaxis had no respiratory signs and symptoms. Novel methods to improve recognition of anaphylaxis and adherence to treatment guidelines are needed.

Aging leads to impaired epicutaneous sensitization that causes attenuated allergy and pulmonary inflammation in mice.

Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)-mediated sensitization to environmental allergens. Yet, allergen-specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6-week-, 6-month-, and 18-month-old female BALB/c mice, underwent epicutaneous sensitization with ovalbumin (OVA) or phosphate buffered saline (PBS), followed by an inhaled OVA challenge. Blood OVA-specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids (BALF) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6-week-old (young) and 6-month-old (adult) groups. However, significantly decreased levels of systemic OVA IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18-month-old) mice compared to the other groups of mice. In addition, interleukin-10 (IL-10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA, possibly regulated by increased IL-10 levels.

Probiotic supplementation in mothers of very low birth weight infants.

OBJECTIVE: Oral probiotic supplementation reduces the risk of necrotizing enterocolitis (NEC) in preterm infants. Concerns about safety and purity of probiotic preparations have limited their use in preterm infants. The authors administered probiotic bacteria to mothers of preterm infants, thereby avoiding the risks of direct exposure of infants to probiotic bacteria. DESIGN: This prospective, randomized, double blind, placebo-controlled trial at the Tel Aviv Medical Center (June 2007-November 2009) examined the effects of maternal oral probiotic supplementation on the incidence of NEC, death, and sepsis in very low birth weight (VLBW) infants fed with maternal breast milk. Mothers were assigned to supplementation with Lactobacillus acidophilus and Bifidobacteria lactis 2 × 10(E) [DOSAGE ERROR CORRECTED] CFU/d or to placebo starting from 1 to 3 days postpartum. The primary outcome measures were NEC, sepsis, and death. RESULTS: In total 49 mothers of 58 VLBW infants were recruited. A total of 25 infants were in the probiotic group and 33 in the placebo group. The overall incidence of Bell stage II to III NEC was 12%, with an incidence of 4% in the infants of the probiotic group and 18.2% in the placebo group (p = 0.12), respectively. Sepsis and mortality rates were similar. CONCLUSION: Postpartum maternal supplementation with probiotic bacteria may decrease the incidence of NEC in breastfed infants.

Acute and chronic rapamycin use in patients with Fibrodysplasia Ossificans Progressiva: A report of two cases.

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP.

Ultrafine particle content in exhaled breath condensate in airways of asthmatic children.

Air pollution triggers and exacerbates airway inflammation. Particulate material (PM) in ambient is characterized as being coarse (PM 10, aerodynamic diameter range 2.5-10 µm), fine (PM 2.5, 2.5-0.1 µm) and ultrafine (UFP, nano-sized, <0.1 µm). It is known that smaller inhaled PM produced more inflammation than larger ones. Most data on human exposure to PM are based on environmental monitoring. We evaluated the effect of individual exposure to UFP on functional respiratory parameters and airway inflammation in 52 children aged 6-18 years referred to the Pulmonary and Allergic Diseases Laboratory due to respiratory symptoms. Spirometry, bronchial provocation challenge, induced sputum (IS), exhaled breath condensate (EBC) and franctional exhaled nitric oxide evaluations were performed by conventional methods. UFP content in EBC was analyzed by using a NanoSight Light Microscope LM20. The total EBC UFP content correlated with wheezing (r = 0.28, p = 0.04), breath symptom score (r = 0.3, p = 0.03), and sputum eosinophilia (R = 0.64, p = 0.005). The percent of EBC particles in the nano-sized range also correlated with wheezing (r = 0.36, p = 0.007), breath symptom score (r = 0.33, p ≤ 0.02), and sputum eosinophilia (r = 0.72, p = 0.001). Respiratory symptoms and airway inflammation positively correlated to UFP content in EBC of symptomatic children.