Food-induced anaphylaxis during infancy is associated with later sleeping and eating disorders.

BACKGROUND: Accumulating evidence suggests that food-induced anaphylaxis (FIA) may induce different psychological disorders (PDs). In this study, we aimed to further evaluate the effect of FIA, specifically when occurring in early life, on subsequent PDs development. METHODS: We conducted a population-based, retrospective, matched-cohort study of pediatric patients (age ≤ 18 years) treated at the "Clalit" healthcare organization during the period 2001-2021. Children diagnosed with FIA were propensity score-matched with patients without any allergies (controls) of similar demographic parameters. Associations between FIA and different PDs were examined by multivariable regression models. RESULTS: The cohorts comprised 545 FIA patients and 4514 controls. Most patients were <3 years old [87.6% of controls (N = 3955) and 87.3% of the FIA cohort (N = 476)]. In this age group, the major food allergens were cow's milk (N = 258; 54.2%), eggs (N = 60; 12.6%), and peanuts (N = 20; 4.2%). The multivariable regression model identified an association between FIA and any PDs (p < .001), sleeping disorders (p < .001), and eating disorders (p = .050). Kaplan-Meier curves revealed that patients who experienced FIA before 3 years of age had an increased cumulative risk over the follow-up time of developing any PDs, sleeping disorders, and eating disorders. CONCLUSION: FIA during the first 3 years of life increases the risk of later developing eating and sleeping disorders, which can last into adulthood. Further attention should be focused on accurately diagnosing these children.

Dupilumab for cancer-associated refractory pruritus.

Background: Pruritus can be an intolerable symptom in patients with cancer. Type 2 inflammation, and specifically, the cytokines IL-4, IL-13, and IL-31, play major roles in the itching process. Dupilumab is an antibody against IL-4Rα, which is a common IL-4 and IL-13 receptor subunit. Blocking IL-4 and IL-13 activity reduces the synthesis of IL-31, the "itch cytokine," and receptors for these 3 cytokines are expressed on itch nerves. Dupilumab is approved for treating moderate-to-severe atopic dermatitis, of which itching is a significant symptom. Objective: The objective of this case study was to present the initial evidence of the safety and efficacy of dupilumab as a treatment for intractable malignancy-associated pruritus in 3 patients, thereby providing a basis for further investigation in a larger cohort. Methods: As a proof of concept, we used dupilumab in our center to treat 3 patients with intractable malignancy-associated pruritus. The first patient was a 73-year-old male with a history of prostate cancer, the second patient was a 75-year-old female with cutaneous T-cell lymphoma, and the third patient was a 32-year-old male with metastatic melanoma. All 3 patients experienced debilitating itching, which started at some stage after the malignancy had been diagnosed. Moreover, none of the 3 patients showed clinical evidence of atopic dermatitis or other causes of itching (eg, uremia or liver failure), and none of the 3 patients responded to conventional treatments for pruritus. Results: Biweekly treatment with dupilumab led to an immediate improvement in itching, which subsided entirely after a few doses without any significant adverse effects. Conclusion: We propose that dupilumab is a safe and effective treatment for intractable malignancy-associated pruritus, and we are currently testing it in a large cohort.

Administration of BNT162b2 mRNA COVID-19 vaccine to subjects with various allergic backgrounds.

Background: The mRNA-based COVID-19 vaccine was introduced to the general public in December 2020. Shortly thereafter, safety concerns were raised due to the reporting of allergic reactions. Allergy-related disorders were suspected to be significant risk factors and the excipient polyethylene glycol was suggested to be a robust allergen. Methods: This is a retrospective study analysis. Subjects with putative risk factors for severe allergic reactions to the Pfizer-BioNTech BNT162b2 vaccine were referred for vaccination under observation at the Unit of Allergy and Clinical Immunology. Data was collected for each subject, including demographic details, medical history and previous reactions to any allergen. When appropriate, skin tests were done prior to vaccination. Results: A total of 346 subjects received 623 vaccine doses under observation. The study included patients with various allergy-related disorders (n=290) and those with allergy to a previous COVID-19 vaccine dose (n=56). Both groups showed female predominance (78% and 88%, p=NS). Patients without reactions to previous doses reported more drug allergy (80% vs. 39%, p<0.001) and previous anaphylaxis (64% vs. 14%, p<0.001). There was no difference in sensitivity to other allergens, including polyethylene glycol. Under observation, mild allergic reactions were noted in 13 individuals characterized by female gender (100%), a history of anaphylaxis (69%) and drug allergy (62%). In 7 subjects, allergy was treated with antihistamines while others recovered spontaneously. Conclusion: Our study demonstrates that vaccination under specialist-supervision is a powerful tool for reducing over-diagnosis of systemic reactions and for rapid and reliable collection of vaccine safety data.

Fast Acting, Dry Powder, Needle-Free, Intranasal Epinephrine Spray: A Promising Future Treatment for Anaphylaxis.

BACKGROUND: Epinephrine intramuscular (IM) autoinjector is a life-saving drug for the emergency treatment of immediate-type allergic reactions (type I). Nevertheless, it is sometimes applied incorrectly or underused because of short shelf life, high costs, fear of use, or inconvenience of carrying. FMXIN002, a nasal powder spray of epinephrine, was developed as a needle-free alternative. OBJECTIVE: To compare epinephrine pharmacokinetics, pharmacodynamics, and safety after the administration of the FMXIN002 nasal spray versus autoinjector. METHODS: An open-label trial was performed in 12 adults with seasonal allergic rhinitis without asthma. Epinephrine pharmacokinetics, pharmacodynamics, and safety were compared between FMXIN002 (1.6 mg and 3.2 mg) administered intranasally with/without a nasal allergen challenge and IM (0.3 mg) EpiPen. RESULTS: FMXIN002 3.2 mg, administered after a nasal allergen challenge, displayed a shorter Tmax than EpiPen (median: 2.5 minutes vs 9.0 minutes, statistically nonsignificant [NS]) and a significantly shorter time when the measured analyte concentration is 100 pg/mL during the absorption phase pg/mL (median: 1.0 minutes vs 3.0 minutes for FMXIN002, P < .02). Moreover, FMXIN002 3.2 mg administered after the challenge test has resulted in a doubling of the maximal measured plasma analyte concentration over the sampling period (1110 vs 551 pg/mL, NS); area under the curve from 0 to 8 hours was 56% higher (672 vs 431 hours pg/mL, compared with EpiPen, NS). Pharmacodynamic response was comparable at all treatments. FMXIN002 was well tolerated, and treatment-emergent adverse events (AEs) were mild, local, and resolved spontaneously. No AEs were reported after the administration of EpiPen in our study. FMXIN002 was stable for 2 years at room temperature conditions. However, variability in the pharmacokinetics (expressed in coefficient of variation) is high. Having a prior nasal allergen challenge results in a substantial increase and speed of absorption. CONCLUSIONS: Intranasal absorption of dry powder epinephrine is faster than EpiPen offering a clinical advantage in the short therapeutic window for the treatment of anaphylaxis. The FMXIN002 product offers a needle-free, pocket-size, safe, user-friendly, and stable alternative to epinephrine autoinjectors.

Dark pigmentation and related low FMOD expression increase IL-3 and facilitateplasmacytoid dendritic cell maturation.

According to epidemiological research, skin autoimmune diseases are more prevalent among black Americans. We postulated that pigment-producing melanocytes may contribute to local immune regulation in the microenvironment. We examined murine epidermal melanocytes in vitro to determine the role of pigment production in immune responses mediated by dendritic cell (DC) activation. Our study revealed that darkly pigmented melanocytes produce more IL-3 and the pro-inflammatory cytokines, IL-6 and TNF-α, and consequently induce plasmacytoid DC (pDC) maturation. Additionally, we demonstrate that low pigment-associated fibromodulin (FMOD) interferes with cytokine secretion and subsequent pDC maturation.

Novel targeted inhibition of the IL-5 axis for drug reaction with eosinophilia and systemic symptoms syndrome.

Background: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe hypersensitivity reaction. Up-to-date treatment is based on withdrawal of medication, supportive care, and immunosuppression using high-dose corticosteroid (CS) therapy. However, evidence-based data are lacking regarding second-line therapy for steroid-resistant or steroid-dependent patients. Objectives: We hypothesize that the interleukin (IL)-5 axis plays a critical role in the pathophysiology of DRESS; hence, inhibition of this signaling pathway could offer a potential therapy for steroid-dependent and/or steroid-resistant cases, and it may offer an alternative to CS therapy in certain patients more prone to CS toxicity. Methods: Herein, we collected worldwide data on DRESS cases treated with biological agents targeting the IL-5 axis. We reviewed all cases indexed in PubMed up to October 2022 and performed a total analysis including our center experience with two additional novel cases. Results: A review of the literature yielded 14 patients with DRESS who were treated with biological agents targeting the IL-5 axis as well as our two new cases. Reported patients are characterized by a female-to-male ratio of 1:1 and a mean age of 51.8 (17-87) years. The DRESS-inducing drugs, as expected from the prospective RegiSCAR study, were mostly antibiotics (7/16), as follows: vancomycin, trimethoprim-sulfamethoxazole, ciprofloxacin, piperacillin-tazobactam, and cefepime. DRESS patients were treated with anti-IL-5 agents (mepolizumab and reslizumab) or anti-IL-5 receptor (IL-5R) biologics (benralizumab). All patients have clinically improved under anti-IL-5/IL-5R biologics. Multiple doses of mepolizumab were needed to achieve clinical resolution, whereas a single dose of benralizumab was often sufficient. Relapse was noted in one patient receiving benralizumab treatment. One patient receiving benralizumab had a fatal outcome, although mortality was probably related to massive bleeding and cardiac arrest due to coronavirus disease 2019 (COVID-19) infection. Conclusion: Current treatment guidelines for DRESS are based on case reports and expert opinion. Understanding the central role of eosinophils in DRESS pathogenicity emphasizes the need for future implementation of IL-5 axis blockade as steroid-sparing agents, potential therapy to steroid-resistant cases, and perhaps an alternative to CS treatment in certain DRESS patients more prone to CS toxicity.

Desensitization protocol to lenalidomide: An effective and safe treatment modality for delayed hypersensitivity-induced rash in patients with multiple myeloma.

INTRODUCTION AND OBJECTIVES: Lenalidomide is considered a standard of care in multiple myeloma (MM) Some MM patients will develop delayed hypersensitivity to lenalidomide, which can lead to treatment discontinuation. Desensitization to lenalidomide can help these patients to complete treatment courses. Here, we aimed to review lenalidomide-treated MM patients who developed delayed hypersensitivity-induced rash and were treated with desensitization. METHODS: A retrospective analysis of medical files of MM patients, who were desensitized to lenalidomide due to delayed hypersensitivity rash. Patients were treated between 2018 and 2022 at Hadassah Medical Center, Jerusalem, Israel. RESULTS: Search of patients yielded 16 patients that underwent desensitization to lenalidomide within the study period. The desensitization protocol consisted of a slow, 3-week-long protocol with lenalidomide's target doses of 10, 15, and 25 mg/day. Of the 16 patients, 10 (62.5%) succeeded to complete the protocol and thus were able to complete lenalidomide treatment cycles. One patient with unsuccessful desensitization was subsequently treated with first-generation IMiD thalidomide, with no rash appearing. None of the patients that were treated with desensitization had severe immune-mediated or non-dermatological adverse reactions. CONCLUSIONS: Desensitization to lenalidomide is safe and effective. Discontinuation of lenalidomide in MM patients with delayed hypersensitivity and no contraindication to desensitization should be discouraged. Collaboration between hematologists and allergists is needed.

B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies.

BACKGROUND: Much remains unknown regarding the response of the immune system to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination. METHODS: We employed circulating cell-free DNA (cfDNA) to assess the turnover of specific immune cell types following administration of the Pfizer/BioNTech vaccine. FINDINGS: The levels of B cell cfDNA after the primary dose correlated with development of neutralizing antibodies and memory B cells after the booster, revealing a link between early B cell turnover-potentially reflecting affinity maturation-and later development of effective humoral response. We also observed co-elevation of B cell, T cell, and monocyte cfDNA after the booster, underscoring the involvement of innate immune cell turnover in the development of humoral and cellular adaptive immunity. Actual cell counts remained largely stable following vaccination, other than a previously demonstrated temporary reduction in neutrophil and lymphocyte counts. CONCLUSIONS: Immune cfDNA dynamics reveal the crucial role of the primary SARS-CoV-2 vaccine in shaping responses of the immune system following the booster vaccine. FUNDING: This work was supported by a generous gift from Shlomo Kramer. Supported by grants from Human Islet Research Network (HIRN UC4DK116274 and UC4DK104216 to R.S. and Y.D.), Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust, Grail, and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center.

Allergic-like disorders and asthma in patients with common variable immunodeficiency: a multi-center experience.

OBJECTIVE: Common variable immune deficiency (CVID) encompasses a variety of diseases characterized by disturbed immunoglobulin (Ig) production and various immune dysregulations. Scarce data are available regarding relationships between CVID and allergic diseases. Here we examined possible associations between allergies and CVID. METHODS: For this multicenter study, we prospectively enrolled 79 adult CVID patients (≥18 years) who were diagnosed and treated between 2002-2017 at the Hadassah-Hebrew University and Shaare Zedek Medical Centers, Jerusalem, Israel. These patients were examined for allergic manifestations. Patient evaluation comprised medical history, physical examination, skin allergen testing, complete blood count, serum immunoglobulins, IgE levels, and pulmonary function tests. RESULTS: After implementing exclusion criteria, 29 patients were included in the final analysis. Allergic-like disorders were diagnosed in 65% of CVID patients with non-elevated serum IgE levels. Moreover, allergic CVID patients exhibited a higher prevalence of bronchiectasis on chest CT. Autoimmunity was diagnosed in 41.3% of CVID subjects. The type I allergy detected in our study was non-IgE mediated. CONCLUSIONS: Timely diagnosis and stratification of allergy in CVID patients is expected to improve their outcome and quality of life, as well as promote appropriate treatment and better management of pulmonary exacerbations.

Chronic Mucocutaneous Candidiasis in Early Life: Insights Into Immune Mechanisms and Novel Targeted Therapies.

Children with chronic mucocutaneous candidiasis (CMC) experience recurrent infections with Candida spp. Moreover, immune dysregulation in the early life of these patients induces various autoimmune diseases and affects normal growth and development. The adaptive and innate immune system components play a significant role in anti-fungal response. This response is mediated through IL-17 production by T helper cells. Inborn errors in IL-17-mediated pathways or Candida spp. sensing molecules are known to cause CMC. In this review, we describe underlying immune mechanisms of monogenic primary immune deficiency disorders known to cause CMC. We will explore insights into current management of these patients and novel available therapies.