Title: Assessment of sIgE to rLep d 2 for DetectingLepidoglyphus destructor SensitizationConclusion: The novel recombinant allergen rLep d 2 exhibits excellent specificity, although its sensitivity is lower compared to specific IgE tests and skin prick tests using Lepidoglyphus destructor . Its additional diagnostic utility for respiratory allergies related to L. destructor is minimal.To the Editor:Recently, rLep d 2 has been introduced to diagnose IgE-mediated allergy to Lepidoglyphus destructor. We aimed to analyze the sensitivity, specificity, and likelihood ratios of sIgE against rLep d 2.We retrospectively analyzed 95 sera of patients previously diagnosed with respiratory allergy to L destructor , to whom an IgE determination of L destructor had been requested. The protocol was approved by the Hospital Ethics Committee for Clinical Research (PI 2023/09/1425). Material and methods are specified in Supplementary material.Statistically significant differences were found between patients sensitized and not sensitized to L destructor . Patients with a sIgE positive to L destructor were younger, had a higher percentage of asthma and moderate/severe persistent rhinitis, and had higher levels of total IgE and sIgE to rLep d 2 and rDer p 2 than non-sensitized patients. (Table 1).There was a high correlation between L destructor and rLep d 2 (R=0.940, p<0.001), although no correlation was observed between L. destructor and r Der p 2 (R= 0.117, p= 0.260) (Figure S1).The sensitivity of sIgE to rLep d 2 was 71.64% (95% CI, 59.31-81.99), and specificity was 96.43% (95% CI, 81.65-99.91). PLR was 20.06 (95%CI, 2.91-138.28) and NLR 0.29 (95% CI, 0.20-0.43). The Receiver Operating Characteristic (ROC) curve for sIgE to rLep d 2 had an area under the curve of 0.931 (Figure S2). The results of the patients’ test are summarized in Figure 1.This is the first study to examine the accuracy of the commercially available major allergen rLep d 2 in a population of patients allergic and non-allergic to L destructor with rhinitis and/or asthma. Good sensitivity (71.64%), excellent specificity (96.43%), remarkable PLR (20.06) and NRL (0.29), and a noteworthy ROC result (0.931) were observed.Data analysis showed a high correlation between sIgE to rLep d 2 and sIgE to L destructor (0.94) (Figure S1A), much higher than that previously obtained by Johansson et al. (1), who used a non-commercial recombinant extract of Lep d 2, finding a correlation coefficient of 0.70. Additionally, the lack of correlation between sIgE to rDer p 2 and sIgE to L destructor , with a correlation coefficient of 0.117 (Figure S1B), agrees with the lack of cross-reactivity between group 2 allergens of L destructor andD pteronyssinus (2). Therefore, most patients who test positive for rLep d 2 and rDer p 2 can be considered co-sensitized.The sensitivity and specificity data for sIgE to rLep d 2 indicate that a positive result suggests sensitization to L. destructor . In contrast, a negative result does not necessarily rule out sensitization, as almost 30% of patients can still be sensitized to L destructor . The PLR of 20.06 provides robust evidence for L destructor allergy when rLep d 2 values are ≥0.35 kU/L. However, it is noteworthy that the ability to exclude L destructor allergy is weaker when rLep d 2 values fall below that threshold.Patients’ test results (Figure 1) suggest that both SPT and sIgE should be used when evaluating a patient with suspected allergy to L destructor . In addition, 19 patients had sIgE positive to L destructor but negative sIgE to rLep d 2. It could happen that some patients may have been sensitized to allergens other than Lep d 2. Accordingly, rLep d 2 should not be initially used when evaluating a patient with a suspected allergy to L destructor . Notwithstanding, sIgE against Lep d 2 might be helpful before initiating specific immunotherapy with L destructor (3).To conclude, despite an excellent specificity, determining sIgE to rLep d 2 does not seem to offer additional diagnostic value when compared SPTs and/or sIgE to L destructor .REFERENCESJohansson E, Eriksson TLJ, Olsson S, et al. Evaluation of Specific IgE to the Recombinant Group 2 Mite Allergens Lep d 2 and Tyr p 2 in the Pharmacia CAP System. Int Arch Allergy Immunol. 1999;120(1):43-49.Parvaneh S, Johansson E, Elfman LH, et al. An ELISA for recombinant Lepidoglyphus destructor, Lep d 2, and the monitoring of exposure to dust mite allergens in farming households. Clin Exp Allergy. 2002 Jan;32(1):80-6Ansotegui IJ, Melioli G, Canonica GW, et al. IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper. World Allergy Organ J. 2020 Feb 25;13(2):100080.

ANAPHYLAXIS TO PANTOPRAZOLE IN A CHILDArriba-Méndez S2,3 MD PhD, Martin-Valbuena J2 MD, Sanz-Rueda L2 MD, Sobrino-García M1,3 MD PhD, Gallardo-Higueras A1 MD, Castillo-Loja R1 MD, Macías E,1,3 MD PhD Martín C1,3 MD PhD, Moreno E1,3,4 MD PhD, Muñoz-Bellido FJ1,3 MD PhD, Gracia-Bara MT1,3 MD, Laffond E1,3 MD PhD, Dávila I1,3,4MD PhD.Department of Allergy, University Hospital of Salamanca, Salamanca, SpainDepartment of Pediatrics, University Hospital of Salamanca, Salamanca, SpainInstitute for Biomedical Research of Salamanca, IBSAL, Salamanca, SpainAsthma, Allergic and Adverse Reactions (ARADyAL) Network for Cooperative Research in Health of Instituto de Salud Carlos III, Hospital Universitario de Salamanca, Salamanca, España.Key words: Proton pump inhibitors. Pantoprazole. Hypersensitivity. Child. Anaphylaxis.To the Editor,Pantoprazole and its analogs (omeprazole, esomeprazole, lansoprazole, rabeprazole) are potent proton pump inhibitors (PPIs), whose use is increasing in the pediatric population (1). They are prescribed for several gastrointestinal pathologies (2), particularly gastroesophageal reflux disease (GERD), but also duodenal ulcers, non-steroidal anti-inflammatory-induced ulcer-related prophylaxis, Helicobacter pylori infection, eosinophilic esophagitis, and other diseases. In general, they have an excellent safety profile, and adverse effects are mild and infrequent (1-3% of patients)(1).Hypersensitivity reactions to PPIs are mainly IgE-mediated, but non-IgE-mediated [contact dermatitis, toxic epidermal necrolysis, leukocytoclastic vasculitis or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)] have been described. In children, immediate hypersensitivity reactions have only been exceptionally reported (3).We introduce the case of a five-year-old girl with a medulloblastoma diagnosed at the age of 3 years, undergoing radiotherapy treatment (last session ten days ago) who was referred to our Allergology Service after suffering an episode of anaphylaxis. Previously to each session, she received premedication with ondansetron plus pantoprazole. In the last session, she had just received ondansetron intravenously and a few minutes after starting the pantoprazole infusion, a generalized diffuse erythematous exanthema suddenly erupted. The event was followed by coughing, severe dyspnea, and inspiratory stridor. No consciousness decrease was reported, neither vomiting nor other gastrointestinal symptoms. Acute anaphylaxis was diagnosed, and the patient was treated with intramuscular epinephrine (0.01mg/kg), intravenous systemic corticosteroids (1mg/kg), and dexchlorpheniramine with gradual resolution in half an hour. The patient had previously received ondansetron and pantoprazole without presenting any adverse reaction. There was neither family nor personal background of hypersensitivity reactions or atopic disease.Skin prick-tests with solutions of non-irritating concentrations (4) of ondansetron (2mg/ml), pantoprazole (40mg/ml), omeprazole (40mg/ml) and lansoprazole (30 mg/ml) were all negative, i.e., the wheal maximum diameter was less than 3 mm over the saline control. Intradermal tests (IDTs) with ondansetron (0.002mg/ml and 0.01 mg/ml) were negative, but IDTs with pantoprazole (4mg/ml) and omeprazole (4 mg/ml) were positive. A single-blind placebo-controlled oral challenge test with ondansetron was performed, showing tolerance of a 3mg dose.A diagnosis of anaphylaxis for pantoprazole was established. Tolerance to lansoprazole was not considered, due to the previous life-threatening reaction, but, it could be considered in the future if required. All proton pumps inhibitors were formally contraindicated.Despite the increase in PPI prescription in pediatric patients, a rise in immune-mediated reactions has not been detected, but there are few studies evaluating PPI allergy in children (5). To date, three cases of PPI anaphylaxis have been described in the pediatric population. One of them was an adolescent studied at 16 who had had anaphylaxis with omeprazole three years earlier. Prick and intradermal tests with omeprazole (0.4 and 4 mg/ml), pantoprazole (0.4 and 4 mg/ml) were negative, but she had a positive challenge with pantoprazole, reproducing anaphylaxis (6).That same year, probable anaphylaxis due to omeprazole and esomeprazole was also described in a 4-month-old infant who presented several episodes of respiratory distress, alongside facial edema in some of them, after using these drugs; however, no allergy study was performed (7). The final described case (8) is a 14-year-old male that had anaphylaxis with omeprazole. Skin prick test were negative, but intradermal tests with omeprazole and lansoprazole were positive. The authors did not perform skin tests with pantoprazole.Ours is the fourth published case of PPI anaphylaxis in children, being the youngest reported patient in which intradermal tests demonstrated an IgE-mediated hypersensitivity reaction. In the literature, cross-reactivity patterns among PPIs have described (9): selective sensitization to a single PPI, whole-group hypersensitivity, omeprazole-esomeprazole-pantoprazole hypersensitivity, and lansoprazole-rabeprazole hypersensitivity. In addition, there are published cases that do not fit those patterns (10). Any case, in PPI-mediated IgE allergy, skin tests have proven useful for diagnosis as they have high specificity and positive predictive value, although low sensitivity (10).In a suspected allergy to a PPI, preventive withdrawal of all PPIs can be appropriate in managing these patients, but we consider that skin tests should always be performed. If negative, controlled oral provocation tests with the PPIs that displayed negative results should always be considered, acknowledging the risk-benefit ratio and possible cross-reactivity patterns.

Title: Real-life study in non-atopic severe asthma patients achieving disease control by omalizumab treatmentTo the Editor,Severe asthma is defined as asthma requiring treatment with guidelines-suggested medications for Global Initiative for Asthma (GINA) steps 4 or 5 or systemic corticosteroids for ≥50% of the previous year to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy.1 Up to 34%–50% of severe asthmatic patients have non-atopic (also called non-allergic) asthma. 2 A significant proportion of these patients have severe uncontrolled asthma, which requires high doses of inhaled corticosteroids (ICS) or even oral corticosteroids (OCS).2 Until the advent of biologics, treatment options in these patients have been very limited. For many years, both the pathogenesis knowledge and the results of clinical trials supported the view that anti-IgE treatment is specifically effective in allergic asthma. Interestingly, recent molecular and clinical evidence suggests that anti-IgE treatment might also be effective in patients with non-allergic asthma.2 Omalizumab (Xolair®) is an anti-IgE monoclonal antibody that selectively binds to human IgE and prevents the binding of IgE to its receptors. Although omalizumab is indicated in Europe in patients with severe persistent allergic asthma, several case reports and short series have provided data on the value of omalizumab in patients with non-atopic asthma.3,4The observational, multicenter, retrospective, real-life FENOMA study specifically evaluated patients who achieved full asthma control after one year of treatment with omalizumab.5 The study included 345 patients, 80 (23.2%) of whom had non-atopic asthma. The present post-hoc sub-analysis aims to describe the clinical improvement of patients with non-atopic asthma. Socio-demographic and asthma-related characteristics were collected at baseline. Outcomes analyzed at baseline and after one year of treatment were those included in the definition of asthma control by GEMA guidelines.5 Medical records were reviewed between February 2015 and June 2016. For statistical comparisons, the 2-sided Wilcoxon signed-rank test was used. A P-value of <0.05 was considered to be statistically significant. All analyses were performed with the SAS statistical package (version 9.4; SAS Institute, Cary, NC).The primary outcome of this post-hoc sub-analysis was to describe the baseline characteristics and clinical improvement of non-atopic asthma patients who achieved full disease control after one-year of treatment with omalizumab through i) frequency of daytime symptoms, ii) changes in use of ICS or OCS iii) need for rescue therapy, iv) pulmonary function (forced expiratory volume in 1 second [FEV1]), v) number of non-severe exacerbations and vi) use of healthcare resources, i.e. unplanned visits to primary care or specialists and the number of days of school or workplace absenteeism due to asthma worsening. Non-severe asthma exacerbations were defined as those that did not require OCS, emergency assistance or hospitalization. Secondary outcomes include an assessment of the percentage of eosinophil blood count and exhaled nitric oxide fraction (FeNO) before and after treatment.Demographic, clinical characteristics and asthma history (before starting treatment with omalizumab) are shown in Table 1 . Mean (SD) age of patients was 58.7 (12.2) years and 65% were female. Almost all patients had daytime symptoms, 92% of patients needed rescue medication, and the mean (SD) initial dose of omalizumab was 338.7 (153.1) mg.After one year of treatment with omalizumab 50.0% (n=40) of patients had no daytime symptoms, while 37.5% (n=30) and 12.5% (n=10) had symptoms 1 and 2 days per week, respectively. Forty-one (51.2%) of the 54 patients who were receiving OCS at entry, stopped treatment (P<0.0001). Of those continuing on OCS, the average reduction of the daily dose was not statistically significant (P=0.2132). More than half of patients (53.7%, n=43) needed no rescue medication. Median FEV1 increase was 15% and there was a reduction in the number of non-severe asthma exacerbations. After one year of treatment with omalizumab, a great reduction in unplanned visits and absenteeism from school or workplace (P<0.0001; Table 2 ) was observed.Of note, the effectiveness of omalizumab was previously assessed in a Spanish multicenter registry, which evaluated 29 non-atopic severe asthma patients over 2 years.6 However, our series is the most extensive study in patients with non-atopic asthma published to date in Spain, and provides data on full disease control. There have been several potential suggestions to explain the effectiveness of omalizumab in non-atopic patients.7 In a proof-of-concept study in non-atopic asthma patients, treatment with omalizumab resulted – as per in atopic patients – in a significant reduction of high-affinity IgE receptor (FcεRI) expression on blood basophils and plasmacytoid dendritic cells (pDC2), which hampered IgE binding and the subsequent production on proinflammatory mediators.8 Additionally, omalizumab treatment was associated with an increase in FEV1 with a positive trend in some relevant clinical endpoints, such as asthma exacerbations.8 In another proof-of-concept trial, omalizumab therapy (but not placebo) reduced IgE expression and IgE sensitization of target cells within the bronchial mucosa, and increased FEV1 versus baseline despite withdrawal of conventional therapy.9 Interestingly, it has been hypothesized that patients labelled as ‘non-allergic’ might in fact have a localized allergy to an unrecognized allergen, with elevated concentrations of allergen-specific IgE antibodies in the airways.7Our study has several limitations. Its single-arm retrospective nature relies on the accuracy and completeness of the information entered into the clinical records. This has especially affected predictors of response such as FeNO and the level of eosinophils, which were not routinely assessed in the clinical practice at the time of the study. The benefits of omalizumab presented here are those observed in the population of non-atopic patients who achieved disease control after one year of treatment with omalizumab. It is unknown how many other patients classified as non-atopic in the clinical practice did not benefit from this treatment.In summary, in the population of patients with non-atopic severe asthma who achieved full disease control after one year of treatment with omalizumab, the clinical and pulmonary benefits were remarkable and similar to those described for atopic patients. A reduction in the use of healthcare resources was also documented. Large randomized controlled trials are warranted to confirm the value of omalizumab in this population of patients.

Background: There is a lack of tools to holistically quantify the response to monoclonal antibodies (mAbs) in severe uncontrolled asthma (SUA) patients. The aim of this study was to develop a valid score to assist specialists in this clinical context. Methods: The score was developed in 4 subsequent phases: (1) elaboration of the theoretical model of the construct intended to be measured (response to mAbs); (2) definition and selection of items and measurement instruments by Delphi survey; (3) weight assignment of the selected items by multicriteria decision analysis (MCDA) using the Potentially All Pairwise RanKings of all possible Alternatives (PAPRIKA) methodology via the 1000Minds software; and (4) face validity assessment of the obtained score. Results: Four core items, with different levels of response for each of them, were selected: “severe exacerbations”, “oral corticosteroid use”, “symptoms” (evaluated by Asthma Control Test: ACT) and “bronchial obstruction” (assessed by FEV1 % theoretical). “Severe exacerbations” and “oral corticosteroid maintenance dose” were weighted most heavily (38% each), followed by “symptoms” (13%) and “FEV1” (11%). Higher scores in the weighted system indicate better response and the range of responses runs from 0 (worsening) to 100 (best possible response). Face validity was high (intraclass correlation coefficient: 0.86). Conclusions: The FEOS score (FEV1, Exacerbations, Oral corticosteroids, Symptoms) allows clinicians to quantify response in SUA patients who are being treated with mAbs.