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 RESULTS: Corticosteroids could be withdrawn and mepolizumab dose interval was spared up to 10 wk with no disease relapse.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.

Angioedema Due to Acquired Deficiency of C1-Inhibitor: A Cohort Study in Spain and a Comparison With Other Series.

BACKGROUND: Data on acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) from 4 European countries (France, Italy, Germany, and Hungary) were recently published. OBJECTIVE: To report data from a group of 50 patients with acquired C1-INH deficiency from Spain, of whom 46 had angioedema, and compare them with other European series. METHODS: We performed a retrospective observational study of 46 patients with C1-INH-AAE and 4 asymptomatic patients. Clinical and biological characteristics and associated diseases were assessed and compared with other European series. RESULTS: Women accounted for 73.9% of cases. The prevalence of C1-INH-AAE related to hereditary forms was 1/10.1. Overall, 8.7% patients were aged <40 years. Diagnostic delay was 1.1 years. Angioedema mainly affected the face (91.3%), followed by the oropharynx (63%), extremities (50%), and abdomen (37%). Only 1 patient underwent orotracheal intubation. Erythema marginatum was present in 1 patient. A hematologic disorder was recorded in 50% of patients. Angioedema preceded all benign conditions, mostly monoclonal gammopathy of undetermined significance, but appeared very close to or after malignant hematologic diseases (median, 2.2 and 0.29 years). Autoimmune diseases were associated in 50% (autoimmune thyroiditis, 21.5%; systemic lupus erythematosus, 10.9%). Half of them coexisted with hematologic disorders. Anti-C1-INH antibodies were found in 67% of tested patients and were not related to the associated disease. Long-term prophylaxis was necessary in 52.2%, most of whom responded to tranexamic acid. CONCLUSIONS: This study emphasizes the possibility of C1-INH-AAE in patients younger than 40 and in autoimmune diseases other than systemic lupus erythematosus such as autoimmune thyroiditis.

Eosinophilic Esophagitis: Review and Update.

Background: Eosinophilic esophagitis (EoE) was first described in the 1990s, showing an increasing incidence and prevalence since then, being the leading cause of food impaction and the major cause of dysphagia. Probably, in a few years, EoE may no longer be considered a rare disease. Methods: This article discusses new aspects of the pathogenesis, symptoms, diagnosis, and treatment of EoE according to the last published guidelines. Results: The epidemiological studies indicate a multifactorial origin for EoE, where environmental and genetic factors take part. EoE affects both children and adults and it is frequently associated with atopic disease and IgE-mediated food allergies. In patients undergoing oral immunotherapy for desensitization from IgE-mediated food allergy the risk of developing EoE is 2.72%. Barrier dysfunction and T-helper 2 inflammation is considered to be pathogenetically important factors. There are different patterns of clinical presentation varying with age and can be masked by adaptation habits. Besides, symptoms do not usually correlate with histologic disease activity. The diagnostic criteria for EoE has evolved but mainly requires symptoms of esophageal dysfunction with histologic evidence of a peak value of at least 15 eosinophils per high-power field. Endoscopies have to be repeated in order to diagnose, monitor, and treat EoE. Treatment of EoE can be started either by drugs (PPIs and topical corticosteroids) or elimination diets. The multistage step-up elimination diet management approach of EoE is promising. Endoscopic dilation is used for patients with severe dysphagia/food impaction with inadequate response to anti-inflammatory treatment. Conclusions: Research in recent years has contributed to a better understanding of EoE's pathogenesis, genetic background, natural history, allergy workup, standardization in assessment of disease activity, evaluation of minimally invasive diagnostic tools, and new therapeutic approaches. However, several unmet needs are to be solved urgently, as finding a non-invasive disease-monitoring methods and biomarkers for routine practice, the development or new therapies, novel food allergy testing to detect triggering foods, drug, and doses required for initial therapy and safety issues with long-term maintenance therapy, amongst others. Besides, multidisciplinary management units of EoE, involving gastroenterologists, pediatricians, allergists, pathologists, dietitians, and ENT specialists are needed.

Helicobacter pylori infection does not protect against eosinophilic esophagitis: results from a large multicenter case-control study.

OBJECTIVES: Rising trends in eosinophilic esophagitis (EoE) have been repeatedly linked to declining Helicobacter pylori (H. pylori) infection, mostly in retrospective studies. We aimed to prospectively evaluate this inverse association. METHODS: Prospective case-control study conducted in 23 centers. Children and adults naïve to eradication therapy for H. pylori were included. Cases were EoE patients, whereas controls were defined by esophageal symptoms and <5 eos/HPF on esophageal biopsies. H. pylori status was diagnosed by non-invasive (excluding serology) or invasive testing off proton pump inhibitor (PPI) therapy for 2 weeks. Atopy was defined by the presence of IgE-mediated conditions diagnosed by an allergist. RESULTS: 808 individuals, including 404 cases and 404 controls (170 children) were enrolled. Overall H. pylori prevalence was 38% (45% children vs. 37% adults, p 0.009) and was not different between cases and controls (37% vs. 40%, p 0.3; odds ratio (OR) 0.97; 95% confidence interval (CI) 0.73-1.30), neither in children (42% vs. 46%, p 0.1) nor in adults (36% vs. 38%, p 0.4). Atopy (OR 0.85; 95%CI 0.75-0.98) and allergic rhinitis (OR 0.81; 95%CI 0.68-0.98) showed a borderline inverse association with H. pylori infection in EoE patients. This trend was not confirmed for asthma or food allergy. CONCLUSIONS: H. pylori infection was not inversely associated with EoE, neither in children nor in adults. A borderline inverse association was confirmed for atopy and allergic rhinitis, but not asthma of food allergy. Our findings question a true protective role of H. pylori infection against allergic disorders, including EoE.

Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 study.

BACKGROUND: Numerous dietary restrictions and endoscopies limit the implementation of empiric elimination diets in patients with eosinophilic esophagitis (EoE). Milk and wheat/gluten are the most common food triggers. OBJECTIVE: We sought to assess the effectiveness of a step-up dietary strategy for EoE. METHODS: We performed a prospective study conducted in 14 centers. Patients underwent a 6-week 2-food-group elimination diet (TFGED; milk and gluten-containing cereals). Remission was defined by symptom improvement and less than 15 eosinophils/high-power field. Nonresponders were gradually offered a 4-food-group elimination diet (FFGED; TFGED plus egg and legumes) and a 6-food-group elimination diet (SFGED; FFGED plus nuts and fish/seafood). In responders eliminated food groups were reintroduced individually, followed by endoscopy. RESULTS: One hundred thirty patients (25 pediatric patients) were enrolled, with 97 completing all phases of the study. A TFGED achieved EoE remission in 56 (43%) patients, with no differences between ages. Food triggers in TFGED responders were milk (52%), gluten-containing grains (16%), and both (28%). EoE induced only by milk was present in 18% and 33% of adults and children, respectively. Remission rates with FFGEDs and SFGEDs were 60% and 79%, with increasing food triggers, especially after an SFGED. Overall, 55 (91.6%) of 60 of the TFGED/FFGED responders had 1 or 2 food triggers. Compared with the initial SFGED, a step-up strategy reduced endoscopic procedures and diagnostic process time by 20%. CONCLUSIONS: A TFGED diet achieves EoE remission in 43% of children and adults. A step-up approach results in early identification of a majority of responders to an empiric diet with few food triggers, avoiding unnecessary dietary restrictions, saving endoscopies, and shortening the diagnostic process.

Immediate reactions to iodinated contrast media.

BACKGROUND: Immediate hypersensitivity reactions (IHRs) to iodinated contrast media (ICMs) remain a common clinical concern. Positive skin test and basophil activation test results suggest a specific IgE-mediated mechanism in some cases. Skin test and controlled challenge test (CCT) are useful to manage these patients. OBJECTIVE: To study clinical and allergologic features of IHRs to ICMs in a Spanish tertiary hospital during a 7-year period. METHODS: Demographic and clinical data concerning the reaction were recorded. Patients treated at the Allergy Department of Hospital General Universitario Gregorio Marañón, Madrid, Spain, underwent skin tests. In those with positive results, CCTs with an alternative skin-test-negative ICM was performed. Global reaction rate was calculated and compared for each ICM. RESULTS: A total of 342 reactions occurred in 329 patients. Cutaneous symptoms were the most common (87.7%). A total of 196 patients underwent an allergy workup, 15 (7.6%) of whom had positive skin test results. Reactions were more severe in patients with positive vs negative skin test results (grade 1, 46.7% vs 73.6%; grade 2, 33.3% vs 20.9%; grade 3, 20% vs 5.46%; P < .05). Three patients had cross-reactivity to 3 ICMs, all including ioversol and iomeprol. Six patients allergic to iopamidol tolerated ioversol and 1 tolerated iomeprol. Four patients allergic to ioversol and 1 allergic to iomeprol tolerated iopamidol. The global reaction rate was 0.2%, differing for each ICM (iopamidol, 0.14%; ioversol, 0.2%; and iomeprol, 0.4%; P < .001). Positive skin test results were found in a low percentage of patients in whom skin test-based CCT identified an alternative non-cross-reactive ICM. Low-grade cross-reactivity was found, especially between iopamidol and ioversol. Reactions were more severe in patients with positive skin test results. The reaction rate was greater for iomeprol compared with iopamidol (reaction rate, 2.8%) and ioversol (reaction rate, 2%). CONCLUSION: This study identified a possible underlying specific IgE-mediated mechanism by positive skin test result in a low percentage of patients with IHRs to ICMs. In these patients, the CCT based on skin test results was useful for identifying an alternative non-cross-reactive ICM. More studies are needed to investigate the underlying mechanism in patients with IHRs and negative skin test results.

[Not Available]. / Ingesta dietética de pacientes adultos con esofagitis eosinofílica que siguen una dieta de exclusión de seis grupos de alimentos.

Introducción: la esofagitis eosinofílica (EEo) es una enfermedad inmunoalérgica crónica emergente en adultos. Surge como respuesta disfuncional frente a los antígenos de los alimentos y se caracteriza por síntomas recurrentes de disfunción esofágica e inflamación. El tratamiento farmacológico y dietético se basa en su patogénesis y debe ser individualizado. Uno de los posibles abordajes dietéticos se basa en la eliminación empírica de alimentos que con mayor frecuencia causan EEo.Objetivo: evaluar la ingesta dietética de los pacientes con EEo que siguen la dieta de exclusión de los seis grupos de alimentos (DESGA) y conocer sus posibles carencias nutricionales.Métodos: estudio transversal descriptivo en un grupo de pacientes con EEo que inició tratamiento con DESGA durante el periodo de marzo de 2013 hasta marzo de 2015. Se evaluó la ingesta mediante registro de 72 horas. Se compararon los resultados con las referencias para población adulta sana española (23). Para el análisis estadístico se usaron los test de Mann-Whitney, Krhuskall-Wallis y Chi-cuadrado. Significación p < 0,05.Resultados: se incluyeron en el estudio 14 pacientes. En algunos de ellos, la ingesta dietética siguiendo DESGA fue deficitaria en energía, proteínas y fibra. Tampoco consiguieron cubrir las ingestas de micronutrientes de calcio, zinc, magnesio, ácido fólico, niacina y vitaminas B2 y D, teniendo en cuenta edad y sexo, el 60% de la muestra.Conclusiones: el abordaje terapéutico mediante DESGA, teniendo en cuenta las características de la dieta, debe acompañarse de una evaluación periódica del estado nutricional, que incluya micronutrientes y una pauta de suplementación específica.

Mast cell-restricted tetramer-forming tryptases and their beneficial roles in hemostasis and blood coagulation.

Tetramer-forming tryptase (hTryptase-ß) was recently discovered to have a prominent role in preventing the internal accumulation of life-threatening fibrin deposits and fibrin-platelet clots. The anticoagulant activity of hTryptase-ß is an explanation for the presence of hemorrhagic disorders in some patients with anaphylaxis or mastocytosis. The fragments of hFibrinogen formed by the proteolysis of this prominent protein by hTryptase-ß could be used as biomarkers in the blood and/or urine for the identification and monitoring of patients with mast cell-dependent disorders. Recombinant hTryptase-ß has potential to be used in clinical settings where it is desirable to inhibit blood coagulation.

Management of angioedema without urticaria in the emergency department.

Angioedema refers to a localized, transient swelling of the deep skin layers or the upper respiratory or gastrointestinal mucosa. It develops as a result of mainly two different vasoactive peptides, histamine or bradykinin. Pathophysiology, as well as treatment, is different in each case; nevertheless, the resulting signs and symptoms may be similar and difficult to distinguish. Angioedema may occur at any location. When the affected area involves the upper respiratory tract, both forms of angioedema can lead to an imminent upper airway obstruction and a life-threatening emergency. Emergency physicians must have a basic understanding of the pathophysiology underlying this process. Angioedema evaluation in the emergency department (ED) should aim to distinguish between histamine- and bradykinin-induced angioedema, in order to provide appropriate treatment to patients. However, diagnostic methods are not available at the ED setting, neither to confirm one mechanism or the other, nor to identify a cause. For this reason, the management of angioedema should rely on clinical data depending on the particular features of the episode and the patient in each case. The history-taking should be addressed to identify a possible etiology or triggering agent, recording complete information for an ulterior diagnostic study in the outpatient clinic. It is mandatory quickly to recognize and treat a potential life-threatening upper airway obstruction or anaphylaxis. This review focuses on the underlying mechanisms and management of histamine- and bradykinin-induced angioedema at the emergency department and provides an update on the currently available treatments.

Mast cell restricted mouse and human tryptase·heparin complexes hinder thrombin-induced coagulation of plasma and the generation of fibrin by proteolytically destroying fibrinogen.

The mouse and human TPSB2 and TPSAB1 genes encode tetramer-forming tryptases stored in the secretory granules of mast cells (MCs) ionically bound to heparin-containing serglycin proteoglycans. In mice these genes encode mouse MC protease-6 (mMCP-6) and mMCP-7. The corresponding human genes encode a family of serine proteases that collectively are called hTryptase-ß. We previously showed that the α chain of fibrinogen is a preferred substrate of mMCP-7. We now show that this plasma protein also is highly susceptible to degradation by hTryptase-ß· and mMCP-6·heparin complexes and that Lys(575) is a preferred cleavage site in the protein α chain. Because cutaneous mouse MCs store substantial amounts of mMCP-6·heparin complexes in their secretory granules, the passive cutaneous anaphylaxis reaction was induced in the skin of mMCP-6(+)/mMCP-7(-) and mMCP-6(-)/mMCP-7(-) C57BL/6 mice. In support of the in vitro data, fibrin deposits were markedly increased in the skin of the double-deficient mice 6 h after IgE-sensitized animals were given the relevant antigen. Fibrinogen is a major constituent of the edema fluid that accumulates in tissues when MCs degranulate. Our discovery that mouse and human tetramer-forming tryptases destroy fibrinogen before this circulating protein can be converted to fibrin changes the paradigm of how MCs hinder fibrin deposition and blood coagulation internally. Because of the adverse consequences of fibrin deposits in tissues, our data explain why mice and humans lack a circulating protease inhibitor that rapidly inactivates MC tryptases and why mammals have two genes that encode tetramer-forming serine proteases that preferentially degrade fibrinogen.

Autoimmune progesterone dermatitis: clinical presentation and management with progesterone desensitization for successful in vitro fertilization.

OBJECTIVE: To report clinical cases of autoimmune progesterone (P) dermatitis, its relationship to IVF, and the potential for P desensitization to treat these cases to achieve viable pregnancies. DESIGN: Clinical description. SETTING: Institutional hospitalary practice. Allergy Division. PATIENT(S): Six patients from the Allergy Clinic consulting for cyclic rashes or anaphylaxis related to the luteal phase of the menstrual cycle. Three of the conditions were related to IVF. INTERVENTION(S): Skin tests were performed with P. For IVF, rapid 8- and 10-step P desensitization protocols were performed, with increasing doses administered every 20 minutes via intravaginal suppositories. A rapid oral desensitization protocol was performed in one patient who required an oral contraceptive for uterine bleeding. MAIN OUTCOME MEASURE(S): Progesterone skin test results. Tolerance to P desensitization. Achievement of viable pregnancies. RESULT(S): Skin tests were positive in all patients and negative in 10 controls. Desensitization was successful in four patients: three patients for IVF, resulting in viable pregnancies. Another patient achieved tolerance to oral contraceptives. CONCLUSION(S): Women with autoimmune P dermatitis can be desensitized successfully to P. We provide the first evidence of successful P desensitization in patients requiring IVF culminating in successful pregnancies.