Long-term use of mepolizumab in a case of chronic eosinophilic pneumonia: extending interval dosing.

INTRODUCTION: Mepolizumab, a humanized anti IL-5 monoclonal antibody, has been used off-label for chronic eosinophilic pneumonia (CEP), inducing disease remission and saving systemic corticosteroids. CASE STUDY: We present a case of CEP, requiring long-term corticosteroids therapy due to relapse upon withdrawal. Mepolizumab was started and maintained for 2 years and 6 months. RESULTS: Corticosteroids could be withdrawn and mepolizumab dose interval was spared up to 10 wk with no disease relapse. CONCLUSION: Mepolizumab is shown to be useful for chronic eosinophilic pneumonia, allowing corticosteroid withdrawal. Dose interval may be individualized under close monitoring, for a more efficient treatment, reducing medical costs while improving patients' quality of life.

Oral Immunotherapy and Risk of Eosinophilic Esophagitis in Children: 15 Years' Experience.

OBJECTIVES: Oral immunotherapy (OIT) is an effective treatment for children with persistent food allergy, and has concerns about its safety, including eosinophilic esophagitis (EoE). The aim of this study was to evaluate the prevalence of EoE in a large cohort of children who underwent OIT in our center, and to determine if there were any clinical, endoscopic, or histologic differences depending on the food employed for the OIT. METHODS: A retrospective study was performed over a 15-year period (2005-2020). Children who underwent cow's milk (CM), egg, and/or peanut OIT and developed EoE were included. RESULTS: Six hundred and seven OIT were carried out (277 CM-OIT, 322 egg-OIT, and 8 peanut-OIT). Seventeen patients (2.8%) had a confirmed histologic diagnosis of EoE with a higher prevalence for patients who underwent CM-OIT (3.9%) than egg-OIT (2.2%). Symptoms suggestive of EoE and a confirmed diagnosis occurred at median times of 25 and 36 months, respectively, after the build-up phase of the OIT was completed. Choking, abdominal pain, and dysphagia were the most frequent symptoms and lamina propria fibrosis was observed in 41.2% of patients. No significant differences in clinical symptoms, endoscopic, or histologic findings between patients under CM or egg-OIT were found. One-third of patients reported mild symptoms suggestive of EoE before the OIT. CONCLUSIONS: EoE appears to be a rare but important adverse event that can occur even years after OIT. Validated questionnaires to screen EoE before the OIT and in the follow-up of these patients may be the main tool for an early diagnosis.

The Natural Course of Adult-Onset Food Protein-Induced Enterocolitis Syndrome.

BACKGROUND: Adult-onset food protein-induced enterocolitis syndrome (FPIES) has been increasingly recognized in recent years. Adult FPIES differs from pediatric FPIES in terms of dietary triggers and symptoms, thus further broadening the clinical phenotypes of the disease. The natural history of FPIES in adulthood is poorly characterized. OBJECTIVE: To evaluate the natural course of FPIES in adults. METHODS: We performed an ambispective study of adults diagnosed with acute FPIES during 2016-2021. Data on age, sex, symptoms, implicated food, and oral food challenge (OFC) outcomes at baseline and during follow-up were analyzed. RESULTS: Forty-two adults were included (83.3% female; median age at diagnosis, 40 years). The predominant symptoms were diarrhea (92.9%) and abdominal cramps (71.4%); vomiting was reported by 59% of patients. The most common triggers were shellfish (n = 19, 45.2%) and fish (n = 19, 45.2%). The mean number of reactions before diagnosis was 6.3 (2-15). Twenty-one OFCs were carried out with the offending food in 15 patients. Six patients achieved tolerance (40%) after a mean of 17.8 months (range, 6-36 months). Twelve of all OFCs performed were positive (57.1%). The absolute leukocyte and neutrophil counts measured before and 1 to 2 hours after the positive challenge showed a mean increase of 3045 and 2736 cells/µL, respectively. Serum tryptase, C-reactive protein, and eosinophil and platelet values did not change significantly after the OFC. CONCLUSION: Some patients may outgrow adult-onset FPIES.

The applications of eHealth technologies in the management of asthma and allergic diseases.

Portable devices, such as smartphones and mobile Internet access have become ubiquitous in the last decades. The term 'eHealth' stands for electronic health. The tools included in the eHealth concept utilize phones, computers and the Internet and related applications to improve the health care industry. Implementation of eHealth technologies has been documented for the management of different chronic diseases, including asthma and allergic conditions. Clinicians and patients have gained opportunity to communicate in new ways, which could be used cost-effectively to improve disease control and quality of life of those affected. Additionally, these innovations bring new opportunities to academic researchers. For example, eHealth has allowed researchers to compile data points that were previously unavailable or difficult to access, and analyse them using novel tools, collectively described as 'big data'. The role of eHealth become more important since early 2020, due to the physical distancing rules and the restrictions on mobility that have been applied worldwide as a response to the coronavirus disease 2019 pandemic. In this review, we summarize the most recent developments in various eHealth platforms and their relevance to the speciality of allergy and immunology, from the point of view of three major stakeholders: clinicians, patients and researchers.

Efficacy and safety of oral immunotherapy with AR101 in European children with a peanut allergy (ARTEMIS): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Peanut allergy is the leading cause of food-related anaphylaxis. Current management options can negatively affect food allergy-related quality of life. We aimed to investigate the efficacy of an investigational oral biologic drug (AR101). METHODS: The AR101 Trial in Europe Measuring Oral Immunotherapy Success in peanut-allergic children (ARTEMIS) trial was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial done at 18 hospitals in Ireland, France, Germany, Italy, Spain, Sweden, and the UK. Children and adolescents with peanut allergy, aged 4-17 years, who developed dose-limiting symptoms to 300 mg or less peanut protein (equivalent to approximately one peanut kernel) during a double-blind placebo-controlled food challenge test at study entry were enrolled. Participants were randomly assigned (3:1) to receive daily doses of either AR101 oral immunotherapy (AR101 group) or a taste-masked placebo (placebo group). All participants, investigators, and care providers were masked to treatment allocation until the study was completed. Doses were increased every 2 weeks over 6 months until a dose of 300 mg was reached and maintained for 3 months. The primary endpoint was the proportion of participants in the intention-to-treat or safety population (defined as those participants who had been randomly assigned and had received at least one dose of the assigned drug) who could consume a single dose of 1000 mg (cumulative dose 2043 mg) peanut protein without developing dose-limiting allergic symptoms at an exit double-blind placebo-controlled food challenge after 9 months of treatment. Additional endpoints included safety (ie, the frequency and severity of adverse events) and changes in food allergy-related quality of life, assessed by use of age-appropriate Food Allergy Quality of Life Questionnaires (FAQLQs) and the Food Allergy Independent Measure (FAIM). The study is registered with ClinicalTrials.gov, NCT03201003, and is completed. FINDINGS: Between June 12, 2017, and Feb 15, 2018, 227 patients were screened, of whom 175 were randomly assigned to the AR101 group (n=132) and the placebo group (n=43). All primary and secondary endpoints were met. 77 (58%) of 132 participants in the AR101 group tolerated 1000 mg peanut protein at the exit food challenge versus one (2%) of 43 participants in the placebo group (AR101-placebo treatment difference 56·0% [95% CI 44·1-65·2], p<0·0001). Adverse events were reported by almost all participants. The maximum severity of adverse events reported was mild or moderate for most participants who received AR101 (mild, 66 [50%] of 132 participants; moderate, 63 [48%]; and severe, one [1%]) or placebo (mild, 24 [56%] of 43 participants; moderate, 18 [42%]; severe, none). Participants aged 8-12 years in the AR101 group reported improvements that exceeded the minimum clinically important difference between the two groups across all FAQLQ domains. Additionally, participants in the AR101 group and their caregivers reported improvements that exceeded the minimum clinically important difference in FAIM domains related to the perceived likelihood and outcomes of a severe allergic reaction. INTERPRETATION: AR101 oral immunotherapy treatment led to rapid desensitisation to peanut protein, with a predictable safety profile that improved with treatment, and an associated improvement in self-reported and caregiver-reported food allergy-related quality of life. These patient-oriented outcomes provide invaluable data to help physicians, patients, and caregivers make informed, shared decisions on the management of peanut allergy. FUNDING: Aimmune Therapeutics.

Oral Food Challenge in Food Protein-Induced Enterocolitis Syndrome by Fish: Is There Any Room for Improvement?

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity usually due to cow's milk or soy. Among the solid foods, rice is one of the most causative foods worldwide, but it varies depending on the geographic area. In the Mediterranean countries, fish is one of the most important triggers of FPIES. There is not a specific biological marker for the disease that allows us to confirm the diagnosis or to predict when tolerance to the offending food has been achieved, so all patients with a FPIES diagnosis undergo an oral food challenge (OFC) at least once. The OFC is a risky procedure and many patients develop severe symptoms. OBJECTIVE: We sought to evaluate the safety of a new OFC protocol in children with fish-FPIES. METHODS: A retrospective study was performed over a 22-year period (1996-2018). We compared two methodologies used in the OFC: Method 1 that consisted in giving several doses during the same day versus Method 2 that consisted in giving a unique dose per day on 2 or three non-consecutive days. RESULTS: A total of 75 positive OFC with fish done in 40 children were included. Forty-three (57.3%) OFC were performed following Method 1 and 32 (42.7%) with Method 2.The severity of the symptoms of the OFC done with Method 1 was mostly moderate (41.9%) followed by severe (39.5%) and mild (18.6%). The adverse reactions with Method 2 were mostly mild (68.8%) and only 18.8 and 12.5% presented moderate or severe symptoms, respectively. CONCLUSIONS: OFC performed in children with fish-FPIES are risky and many patients develop moderate or severe symptoms after this procedure. We propose a new protocol that has demonstrated to improve safety.

Efficacy and Safety of Omalizumab (Xolair) for Cholinergic Urticaria in Patients Unresponsive to a Double Dose of Antihistamines: A Randomized Mixed Double-Blind and Open-Label Placebo-Controlled Clinical Trial.

BACKGROUND: Cholinergic urticaria (UCOL) is a highly disabling inducible urticaria triggered by an increase in core body temperature. OBJECTIVE: To explore the safety and efficacy of omalizumab in controlling UCOL. METHODS: We conducted a multicenter randomized mixed double-blind and open-label (first 4 months blinded followed by 8 months open-label) placebo-controlled clinical trial in 22 patients suffering from UCOL who were unresponsive to a double dose of antihistamines. We performed an exercise challenge test during each visit as our main outcome variable. RESULTS: The overall rate of exercise challenge test negative at week 48 was 31.3%, with an average increase in exercise challenge test negative rate of 2.9% points (95% CI, 1.5-4.2) per visit. Statistically significant differences in the negative exercise challenge test rate between the placebo and active intervention groups were not observed during the blinded period (first 4 months of the study). However, from the fourth dose, a progressive improvement was observed. When comparing before and after treatment, statistically significant improvements in all secondary outcome measures were noted after 4 doses (UCOL score: P = .0015; visual analog scale score: P = .0108; days with symptoms: P = .0125) and after 8 doses (UCOL score: P = .0005; chronic urticaria quality of life questionnaire: P = .0105; visual analog scale score: P = .0008; and days with symptoms: P = .0144). In the follow-up visit after the cessation of treatment, the symptoms reappeared, with positive exercise challenge test result and significant increases in all variables. Only 4 of 22 patients remained asymptomatic after 3 months of no treatment. No adverse effects were reported. CONCLUSIONS: This randomized mixed double-blind and open-label placebo-controlled trial showed evidence of the safety and potential efficacy of omalizumab in patients with UCOL.

Comparative study of adjuvants for allergen-specific immunotherapy in a murine model.

AIM: To compare the immunological and clinical changes induced by allergen-specific immunotherapy (AIT) using different adjuvants. MATERIALS & METHODS: Olea europaea pollen-sensitized mice were treated with olea plus aluminum hydroxide, calcium phosphate, monophosphoryl lipid A (MPL) or immunostimulatory sequences (ISS). RESULTS: Aluminum hydroxide seems to drive initially to a Th2-type response. Bacteria-derived adjuvants (MPL and ISS) skew the immune response toward Th1 and Treg pathways. Specific-IgE production was lower after AIT with MPL and ISS. Moreover, IgG2a production significantly increased in ISS-treated mice. Bacteria-derived adjuvants also improved the Th1 cytokine response due to IFN-γ higher secretion. In addition, they improved bronchial hyper-reactivity and lung inflammation. CONCLUSION: Bacteria-derived adjuvants may enhance the efficacy of AIT.

Differences in the Anaphylactic Response between C3H/HeOuJ and BALB/c Mice.

BACKGROUND: Anaphylaxis is a severe and potentially lethal allergic reaction whose incidence is increasing. Murine models can elucidate the underlying mechanisms and pave the way for appropriate therapeutic options. However, differences in strains and protocols hamper comparisons of data between researchers. We performed a parallel study of clinical and immune responses with 2 strains of mice, BALB/c and C3H/HeOuJ, in an allergen-induced systemic anaphylaxis protocol. Both strains have been widely used in allergy models, although they have not been compared in an intraperitoneal systemic model. METHODS: Groups of 5-week-old female BALB/c and C3H/HeOuJ mice were intraperitoneally sensitized with peanut in the presence of adjuvants. Specific immunoglobulin (sIg) G1, sIgG2a, sIgE, total IgE, histamine release, and specific stimulated splenocyte cytokines, interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, and interferon (IFN)-γ, were assessed. At week 6, mice were intraperitoneally challenged with peanut. Anaphylaxis was evaluated by recognition of clinical symptoms and changes in body temperature. RESULTS: All peanut-sensitized mice induced sIg and developed anaphylactic symptoms upon challenge. Nonetheless, the C3H/HeOuJ strain demonstrated earlier and persistently higher sIgG1 and sIgG2a production, elevated sIgE, and more severe clinical symptoms and histamine release than the BALB/c strain. In contrast, BALB/c exhibited higher release of IL-4, IL-5, IL-10, IL-13, and IFN-γ. CONCLUSIONS: Both models are suitable for studying anaphylaxis. Consequently, they could be used in research on the pathogenesis and therapy of anaphylaxis. However, according to the type of study performed, differences in the specific clinical, humoral, and cellular responses to antigens have to be considered.

Anaphylaxis in the Pediatric Emergency Department: Analysis of 133 Cases After an Allergy Workup.

BACKGROUND: Data on the incidence and characteristics of pediatric anaphylaxis are scarce. Reported causes of anaphylaxis are mostly those suspected by the physician in the emergency department (ED), which may not coincide with the real triggers. OBJECTIVES: To investigate the incidence, management, and etiology of pediatric anaphylaxis in the ED of a Spanish tertiary hospital and to determine the concordance between the suspected etiology in the ED and diagnosis after the allergy workup. METHODS: We performed an observational, descriptive study of all patients with anaphylaxis attended in the pediatric ED from 2012 to 2014. Cases were considered anaphylaxis based on National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria. We recorded data on clinical characteristics, management, etiology suspected by the ED physician and patient (or relatives), and the workup performed in the allergy department. RESULTS: We recorded 133 cases of anaphylaxis (incidence, 0.12%), with 20 cases (15%) recorded in children younger than 12 months. Anaphylaxis was correctly diagnosed in the ED in 70 cases (53%). Food allergy was the cause of anaphylaxis in 106 out of 118 studied in the allergy department (AD) (90%). The final etiology differed from the etiology initially suspected in the ED in 42 cases (39%). After the study, the frequency of patients with unidentified triggers decreased by 75%. CONCLUSIONS: The incidence of anaphylaxis is higher in children than previously reported in adults from the same center, and food is the trigger in most cases. To prevent erroneous diagnoses, the etiology of anaphylaxis should be established after an appropriate workup.

Automatic quantification of histological studies in allergic asthma.

The evaluation of new therapies to treat allergic asthma makes frequent use of histological studies. Some of them are based on microscope observation of stained paraffin lung sections to quantify cellular infiltrate, an effect directly related to allergic processes. Currently, there is no software tool available for doing this quantification automatically. This paper presents a methodology and a software tool for the quantification of cellular infiltrate in lung tissue images in an allergic asthma mouse model. The image is divided into regions of equal size, which are then classified by means of a segmentation algorithm based on texture analysis. The classification uses three discriminant functions, built from parameters derived from the histogram and the co-occurrence matrix. These functions were calculated by means of a stepwise discriminant analysis on 79 samples from a training set. Results provided a correct classification of 96.8% on an independent test set of 251 samples labeled manually. Regression analysis showed a good agreement between automatic and manual methods. A reliable and easy to implement method has been developed to provide an automatic method for quantifying microscopy images of lung histological studies. Results showed similar accuracy to that provided by an expert, while allowing analyzing a much larger number of fields in a repeatable way.

Immunology of anaphylaxis: lessons from murine models.

The use of animal models is increasing, and mice are suitable animals to use in exploring systemic anaphylaxis based on the similarity between human and mouse immune systems. Two anaphylaxis pathways have been characterized in mice, which may help in understanding some of the discrepancies found in humans. In addition, cytokine studies are raising new concepts that may put together some of the puzzling mechanisms described in this disease. Finally, the study of the mechanisms that parasitic infections use to evade the human immune system and the scene in which a parasite induces clinical anaphylaxis are opening new insights in the immunology pathways and new strategies to fight against this exclusive disease.