Hypersensitivity reactions to proton pump inhibitors. An EAACI position paper.

Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1%-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Quality of life in patients with allergic and immunologic skin diseases: in the eye of the beholder.

Allergic and immunologic skin diseases negatively impact the quality of life (QoL) of affected patients with detrimental consequences. Nonetheless, in everyday clinical practice the evaluation of QoL is often overlooked. Considering the increasing prevalence of atopic dermatitis, allergic contact dermatitis, hereditary angioedema, cutaneous mastocytosis, and urticaria, it is essential to determine the effects of allergic and immunologic skin diseases on QoL. A joint meeting (GET TOGETHER 2021) of the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to summarize the features of the main QoL tools used in these diseases and to describe the extent of QoL impairment as well as the impact of treatments on QoL, particularly biologic therapies. The assessment of QoL in patients with allergic and immunologic skin diseases relies on generic, organ-specific and disease-specific questionnaires. While generic and organ-specific questionnaires allow comparison between different diseases, disease-specific questionnaires are designed and validated for specific cohorts: the QoL Index for Atopic Dermatitis (QoLIAD) and the Childhood Atopic Dermatitis Impact Scale (CADIS) in atopic dermatitis, the ACD-11 in allergic contact dermatitis, the Angioedema QoL Questionnaire (AE-QoL) and the Hereditary Angioedema QoL questionnaire (HAE-QoL) in hereditary angioedema, the Mastocytosis QoL Questionnaires (MCQoL e MQLQ) in cutaneous mastocytosis, and the Chronic Urticaria QoL questionnaire (CU-Q2oL) in urticaria. Among the many factors that variably contribute to QoL impairment, pruritus can represent the leading cause of patient discomfort. Biologic therapies significantly ameliorate QoL in atopic dermatitis, hereditary angioedema, mastocytosis and chronic urticaria. In general, adequate management strategies are essential for improving QoL in patients with allergic and immunologic skin diseases.

Efficacy of dupilumab in atopic comorbidities associated with moderate-to-severe adult atopic dermatitis.

BACKGROUND: Dupilumab is an anti-IL-4Rα antibody used in the treatment of patients with moderate-to-severe atopic dermatitis (msAD). This study explored the potential benefit of dupilumab in perennial allergic rhinoconjunctivitis (PAR) and perennial allergic asthma (PAA) caused by indoor allergens in adults with msAD. METHODS: This multicentric, prospective, observational, real-life study included adult patients with msAD who had been treated with dupilumab in 16 Italian care centres. Efficacy outcomes regarding AD, PAR and PAA were collected at baseline and 16 weeks. Safety was also assessed. RESULTS: We enrolled 123 patients with msAD. Between baseline and 16 weeks of treatment, the following measurements decreased statistically significantly: Eczema Area and Severity Index, SCOring AD, Patient-Oriented Eczema Measure, pruritus score, sleep score, Dermatology Life Quality Index and IgE. Dupilumab treatment in patients with comorbid PAR (n = 41) was associated with significant improvements in PAR disease control (measured using a Rhinitis Control Scoring System) and in PAR Quality of life (QoL) (measured using the Rhinoconjunctivitis QoL Questionnaire scores). In 32 patients with comorbid PAA, dupilumab significantly improved PAA control (measured using the Asthma Control Test and five-item Asthma Control Questionnaire scores) and disease-related QoL (measured using the Asthma QoL Questionnaire scores). Thirty-five patients (28.5%) developed conjunctivitis during the study period. CONCLUSION: These results support the benefits of dupilumab for adult patients with PAR and/or PAA associated with msAD.

Hymenoptera Allergy and Mast Cell Activation Syndromes.

Mast cell activation syndrome (MCAS) can be diagnosed in patients with recurrent, severe symptoms from mast cell (MC)-derived mediators, which are transiently increased in serum and are attenuated by mediator-targeting drugs. When KIT-mutated, clonal MC are detected in these patients, a diagnosis of primary MCAS can be made. Severe systemic reactions to hymenoptera venom (HV) represent the most common form of anaphylaxis in patients with mastocytosis. Patients with primary MCAS and HV anaphylaxis are predominantly males and do not have skin lesions in the majority of cases, and anaphylaxis is characterized by hypotension and syncope in the absence of urticaria and angioedema. A normal value of tryptase (≤11.4 ng/ml) in these patients does not exclude a diagnosis of mastocytosis. Patients with primary MCAS and HV anaphylaxis have to undergo lifelong venom immunotherapy, in order to prevent further potentially fatal severe reactions.

Clonal mast cell disorders in patients with severe Hymenoptera venom allergy and normal serum tryptase levels.

BACKGROUND: Systemic mastocytosis is a clonal mast cell (MC) disease that can lead to potentially fatal anaphylactic reactions caused by excessive MC mediator release. The prevalence of mastocytosis in patients with Hymenoptera venom allergy is high, and thus the disease should be suspected in patients with severe reactions caused by Hymenoptera stings and increased serum basal tryptase (SBT) levels. OBJECTIVE: We sought to evaluate the presence of clonal MC disorders in patients seen at our mastocytosis center with Hymenoptera sting-induced anaphylaxis, documented hypotension, absence of urticaria pigmentosa, and normal SBT levels. METHODS: Twenty-two patients with Hymenoptera sting-induced anaphylaxis, without skin lesions, and with tryptase levels of less than 11.4 ng/mL underwent bone marrow evaluation. Bone mineral density was assessed in those patients with ascertained mastocytosis. RESULTS: In 16 of 22 patients, a diagnosis of indolent mastocytosis could be established, and 1 patient had a monoclonal MC activation syndrome. Patients with mastocytosis had higher SBT levels (P = .03) but only rarely had angioedema/urticaria associated with hypotension (P = .004). CONCLUSIONS: The absence of urticaria or angioedema in severe reactions to Hymenoptera stings with hypotension might represent the most relevant factor in identifying patients with mastocytosis, regardless of their serum tryptase levels.

Hymenoptera Anaphylaxis and C-kit Mutations: An Unexpected Association.

Clinical manifestations of mastocytosis in adults comprise signs and symptoms linked to mast cell (MC) activation, including anaphylaxis. Depending on MC burden, adults can be diagnosed with systemic mastocytosis, when the WHO criteria are fulfilled, or with other clonal MC disorders, characterized by MC mediator symptoms and demonstration of activating KIT mutations and/or expression of CD25 on MCs. There is a specific link between mastocytosis and hymenoptera venom allergy (HVA): the reported frequency of HVA in mastocytosis is 20-50 % and raises to 60-80 % in patients affected by indolent systemic mastocytosis without skin lesions. The presentation of HVA characterized by severe hypotension in the absence of urticarial or angioedema is typical in patient with an underlying MC disorder, even in the presence of normal baseline serum tryptase levels.

Desensitization to thalidomide in a patient with multiple myeloma.

Cutaneous reactions to thalidomide have been noted in approximately 46% of patients treated with this drug. We describe a case of a 65-year-old woman with multiple myeloma who developed fever and a generalized, itchy maculopapular rash after a 2-day treatment with thalidomide 100 mg orally. Skin prick and patch test results with thalidomide were negative, while the oral provocation test results were positive. Because thalidomide was necessary for the patient, she underwent an oral desensitization protocol, and on the fifth day, she could tolerate 100 mg of oral thalidomide. To our knowledge, this is the first report in the literature regarding this topic.

The difficult management of anaphylaxis in the elderly.

PURPOSE OF REVIEW: In this article, an overview of the main characteristics of the anaphylaxis in the elderly, a subset of the population with particular clinical and physiological features that might influence the presentation and management of this entity, is performed. RECENT FINDINGS: Life expectancy of the population is increasing and so is the prevalence of allergic diseases in the elderly, including anaphylaxis. Older people present higher risk of fatalities after anaphylaxis, and some comorbidities and pharmacological treatments they may use might also increase that risk. SUMMARY: Recognition of the main triggers, the risk factors, and the wide variety of presenting symptoms of anaphylaxis is therefore helpful in its management, as well as a prompt initiation of the treatment and a complete follow-up.

Wasp venom allergy screening with recombinant allergen testing. Diagnostic performance of rPol d 5 and rVes v 5 for differentiating sensitization to Vespula and Polistes subspecies.

BACKGROUND: The appropriate therapeutic management of patients with wasp-induced allergic reactions necessitates an accurate allergologic workup, entailing differentiation between sensitization against Vespula or Polistes venoms. MATERIALS AND METHODS: We studied 52 consecutive adult subjects diagnosed with hypersensitivity to wasp venoms. Cap inhibition was performed using UniCAP Specific IgE. The concentration of serum IgE against two recombinant constituents of Antigen 5 (rVes v 5 and rPol d 5) was also measured using Immuno CAP 250. The ratio between values of specific IgE against recombinant allergens was calculated and a percentage difference >50% was considered significant for specific immunization against one of the two venoms. RESULTS: The diagnostic agreement between recombinant allergens testing and CAP inhibition was 54% (kappa statistics, 0.34; 95% CI, 0.18-0.50) in the whole study population. In the 24 patients with recombinant allergens ratio >50% and non dubious results of CAP inhibition assay the diagnostic agreement was perfect (100%; kappa of agreement, 1.00; 95% CI; 1.00-1.00). DISCUSSION: The results of this study show that the assessment of specific IgE against rVes v 5 and rPol d 5 may be regarded as a low-cost screening, providing valuable diagnostic information for differentiating the sensitization against Vespula or Polistes venoms. In patients with suggestive clinical history and ratio >50% between specific IgE against rVes v 5 and specific IgE against and rPol d 5, the CAP inhibition assay may be safely withheld, thus allowing to achieve an early diagnosis at lower cost.

Study on the Immunoreactivity of Triticum monococcum (Einkorn) Wheat in Patients with Wheat-Dependent Exercise-Induced Anaphylaxis for the Production of Hypoallergenic Foods.

Wheat [Triticum aestivum (T.a.)] ingestion can cause a specific allergic reaction, which is called wheat-dependent exercise-induced anaphylaxis (WDEIA). The major allergen involved is ω-5 gliadin, a gluten protein coded by genes located on the B genome. Our aim was to study the immunoreactivity of proteins in Triticum monococcum (einkorn, T.m.), a diploid ancestral wheat lacking B chromosomes, for possible use in the production of hypoallergenic foods. A total of 14 patients with a clear history of WDEIA and specific immunoglobulin E (IgE) to ω-5 gliadin were enrolled. Skin prick test (SPT) with a commercial wheat extract and an in-house T.a. gluten diagnostic solution tested positive for 43 and 100% of the cases, respectively. No reactivity in patients tested with solutions prepared from four T.m. accessions was observed. The immunoblotting of T.m. gluten proteins performed with the sera of patients showed different IgE-binding profiles with respect to T.a., confirming the absence of ω-5 gliadin. A general lower immunoreactivity of T.m. gluten proteins with scarce cross-reactivity to ω-5 gliadin epitopes was assessed by an enzyme-linked immunosorbent assay (ELISA). Given the absence of reactivity by SPT and the limited cross-reactivity with ω-5 gliadin, T.m. might represent a potential candidate in the production of hypoallergenic bakery products for patients sensitized to ω-5 gliadin. Further analyses need to be carried out regarding its safety.

Drug allergy in mastocytosis.

Drugs are known triggers of anaphylaxis in patients with mastocytosis even to the association between drug anaphylaxis and mastocytosis does not appear frequently appear. Nevertheless, mast cell disorders might be ruled out in cases of severe systemic reactions. Careful examination of the skin should accompany measurement of basal serum tryptase levels. The data published about drug anaphylaxis in patients with mast cell disorders are scarce, and it is not currently possible to provide clear recommendations. Most papers report cases of anaphylaxis during surgical procedures or radiocontrast media exposure. There are no specific recommendations to prevent severe reactions during such procedures, although some specialists suggest performing premedication with antihistamines and corticosteroids before anesthesia or radiocontrast media administration.

Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations.

BACKGROUND: A preferential association between systemic mastocytosis (SM) and hymenoptera allergy (HVA) has been observed. Patients with both diseases are at risk for more severe reactions, and venom immunotherapy (VIT) may represent a life-saving treatment, but the use of VIT in such patients raised concerns about its safety. OBJECTIVE: We evaluated a large population of patients with SM and HVA who received VIT. METHODS: This prospective study was performed in Italy and Spain. A diagnosis of SM and HVA and a VIT prescription were made according to international recommendations. The patients were carefully followed up during VIT, with special attention to field stings. RESULTS: A total of 84 patients (70 men, 14 women; mean age 52.1 years) were included, 81% with grade IV reaction, 91% with indolent SM. No difference was seen between the Italian and Spanish patients. There were 10 adverse reactions during the induction phase: 3 with the conventional induction and 7 with the rush-modified induction, none resulted in epinephrine administration and/or hospitalization. Fifty patients had one or more field re-sting (95 episodes), none during induction. The time elapsed from starting VIT and first re-sting was 2 months to 7 years, and the number of re-stings per patient was 1-6. Of the 50 patients who were re-stung, 43 (86%) resulted in being fully protected. Seven patients had reactions, and the maintenance dose was safely increased to 200 mcg. The maintenance dose interval was not different between patients with and those without reactions at re-stings. CONCLUSION: VIT is well tolerated, safe, and effective in patients with SM.

Allergy and psychologic evaluations of patients with multiple drug intolerance syndrome.

The multiple drug intolerance syndrome is a clinical entity characterized by adverse drug reactions to at least three drugs, chemically, pharmacologically and immunogenically unrelated, manifested upon three different occasions, and with negative allergy testing. Symptoms referred by the patients are often subjective, of neurovegetative origin. The aim of the study is to characterize patients suffering from the multiple drug intolerance syndrome from a psychological point of view, and to compare them to healthy subjects. We studied 30 women suffering from the multiple drug intolerance syndrome. All subjects underwent the following psychodiagnostic tests: (1) the State Trait Anxiety Inventory-Form Y, (2) the Zung Self-rating Anxiety Scale, (3) the Zung Self-rating Depression Scale, (4) the Quality of life enjoyment and satisfaction questionnaire, (5) the Minnesota Multiphasic Inventory-2, (6) the Toronto Alexithymia Scale. The study group was compared to 30 healthy women. When compared with the control group, our patients showed: a higher anxiety, a higher grade of depression, this difference was statistically significant (p < 0.01); a high difference (p < 0.01) between the two groups as regards somatic symptoms; a higher grade of alexithymia (p < 0.01); and a worse quality of life, in all the analyzed ambits. These findings clearly demonstrate the importance of psychological symptoms in patients with the multiple drug intolerance syndrome, and show that a complex allergy and psychological work-up is mandatory in the management of these patients.

'Empty sella syndrome': a case of a patient with sodium succinate hydrocortisone allergy.

OBJECTIVE: We present the case of a woman with 'empty sella syndrome' who experienced generalized urticaria after the administration of sodium succinate hydrocortisone in two episodes. METHODS: The patient underwent an allergological evaluation (prick, intradermal, and patch tests) with hydrocortisone sodium succinate, hydrocortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, methylprednisolone hemisuccinate, methylprednisolone, and preservatives held in the formulation of sodium succinate hydrocortisone (sodium phosphate and methyl-p-oxybenzoate). The basophil activation test (BAT) was also performed with hydrocortisone. The single-blind i.m. challenge test was performed with hydrocortisone sodium phosphate in 4 days. RESULTS: Skin test with hydrocortisone sodium succinate and methylprednisolone hemisuccinate was positive. On the contrary, allergological tests performed with other formulations of the same steroids and preservatives were negative. These results showed an immediate-type allergy to succinate ester. BAT was not helpful to improve our diagnostic work-up because our patient was a 'nonresponder.' Therefore, the patient underwent successfully to a challenge test with hydrocortisone sodium phosphate. CONCLUSIONS: Patients with succinate ester allergy can tolerate alternative corticosteroids without ester.

Food allergy and food intolerance: diagnosis and treatment.

Food allergy is a matter of concern because it affects about 0.5-3.8% of the paediatric population and 0.1-1% of adults, and as well may cause life-threatening reactions. Skin prick testing with food extracts and with fresh foods, the measurement of food-specific IgE, elimination diets and a double-blind, placebo-controlled food challenge are the main diagnostic procedures; many non-validated procedures are available, creating confusion among patients and physicians. The treatment of food allergy is still a matter of debate. Antihistamines, corticosteroids and, if necessary (in case of anaphylaxis), epinephrine, are the drugs of choice for the treatment of symptoms of food allergy. Sodium cromolyn may be used prophylactically even though there are no controlled studies certifying its efficacy. The only etiologic treatment of food allergy is specific desensitization. Sublingual-oral-specific desensitization has been used by our group for the treatment of food-allergic patients with a high percentage of success.

Multiple-drug intolerance syndrome: clinical findings and usefulness of challenge tests.

BACKGROUND: Multiple-drug intolerance syndrome (MDIS) is characterized by adverse reactions to several classes of chemically unrelated drugs. OBJECTIVE: To analyze all patients with a history of adverse reactions to at least 3 drugs at the Allergy Unit of Policlinico Gemelli in a 6-year period to better characterize patients with MDIS and to find safe alternative drugs. METHODS: We studied 480 patients (aged >16 years) with a history of adverse reactions to at least 3 unrelated drugs and with negative allergy test results. Patients who had experienced mild adverse reactions that remitted spontaneously underwent challenge tests without any premedication (group A). Patients with a clinical history of moderate reactions received sodium cromolyn, 500 mg, before the challenge (group B). Patients with a clinical history of severe reactions or undergoing parenteral challenges were given an antihistamine 30 minutes before the challenge (group C). RESULTS: In group A, 491 tolerance challenge tests were performed: 414 had negative results and 77 had positive results. In group B, 1,077 tolerance challenge tests were performed: 956 had negative results and 121 had positive results. In group C, 240 tolerance challenge tests were performed: 214 had negative results and 26 had positive results. Comparing the tolerance of alternative drugs in groups A and B, groups A and C, and groups B and C, no significant results were observed (P = .24, .14, and .44, respectively). CONCLUSIONS: Patients with MDIS can tolerate alternative drugs. Premedication with sodium cromolyn or oral H1-antihistamines may be useful in preventing adverse reactions.