Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Egg OIT in clinical practice (SEICAP II): Maintenance patterns and desensitization state after normalizing the diet.

BACKGROUND: It is unknown which are the most suitable maintenance pattern and egg consumption to maintain the desensitization state after ending the oral immunotherapy (OIT). This multicenter, randomized, controlled trial compared two OIT maintenance patterns with pasteurized egg white (PEW), evaluating the egg consumption effect on the desensitization state after ending the OIT. METHODS: One hundred and one children with confirmed egg allergy were randomized: 25 to an egg-free diet (CG) and 76 to an OIT year with PEW and two maintenance patterns, 38 patients to daily 3.3 g proteins (AG) and 38 to every two days (BG). PEW challenge (DBPCFC), adverse reactions, and immune markers were assessed at baseline, at the end of the OIT, and at 6 and 12 months later on ad libitum egg consumption (T0, T12, T18, and T24). A questionnaire evaluated the egg consumption at T18. RESULTS: At T12, 64 of 76 (84.21%) OIT patients had reached total desensitization (32 AG and 32 BG) vs 4 of 25 (16.00%) CG who passed the PEW DBPCFC. Thirty (93.75%) AG vs 25 (78.12%) BG patients completed an OIT year. At T18, 27 of 29 (93.1%) AG vs 20 of 24 (83.3%) BG passed the PEW DBPCFC, 96% consuming at least two egg servings/week. At T24, 97.43% OIT patients passed the challenge. Most patients had adverse reactions, more frequent in the BG patients; frequency and severity of reactions decreased through the study. PEW skin prick test wheal and sIgE antibody serum levels similarly decreased in AG or BG, but AG patients had greater increase in PEW sIgG4 (P < 0.05). CONCLUSIONS: Daily OIT maintenance achieves better adherence, effectiveness, and safety. Two egg servings/week ensure maintained desensitization after the end of an OIT year.

Egg oral immunotherapy in children (SEICAP I): Daily or weekly desensitization pattern.

BACKGROUND: Studies are required before incorporating egg oral immunotherapy (OIT) into clinical practice. The Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology (SEICAP) conducted a multicenter, randomized controlled study assessing the effectiveness and safety of the OIT using pasteurized egg white (PEW) in egg-allergic children. METHODS: One hundred and one egg-allergic children (6-9 years) were randomized for 1 year: 25 to an egg-free-diet (CG) and 76 to OIT (target dose 3.3 g PEW proteins), PI (30% weekly plus 5% daily increments) or PII (only 30% weekly increments) buildup patterns. Egg skin prick test, sIgE and sIgG4 serum levels, PEW double-blind placebo-controlled food challenge (DBPCFC), and dosing adverse reactions (DARs) were evaluated in all patients from inclusion (T0) until completing 1 year of follow-up (T12). At T12, egg-allergic control patients could start OIT. The effectiveness and safety of OIT and the effect of the buildup pattern were analyzed. RESULTS: At T12, 4/25 (16.0%) CG patients passed the PEW DBPCFC vs 64/76 (84.2%) OIT that reached total desensitization (P = 0.000); 12 egg-allergic control patients started OIT. Finally, 72/88 (81.81%) patients reached total desensitization, 96.15% PI vs 75.80% on PII (P = 0.01). Induction period (121.12 ± 91.43, median 98.00 days) was longer in patients on PII buildup pattern, and those with allergic asthma, minor threshold dose, or higher egg sIgE (P < 0.05). Most patients (89.06%) developed DARs: 74.53% were mild; 21.90% moderate; and 3.5% requiring adrenaline-treatment. Moderate reactions and those requiring adrenaline were more frequent in patients with allergic asthma, PII pattern, or higher egg sIgE serum antibody levels (P < 0.05). CONCLUSIONS: PEW OIT is an effective treatment for children with persistent egg allergy. A 30% weekly plus 5% daily increment pattern could be more effective and safer than one with only 30% weekly increments.

Non-Hodgkin lymphoma in pediatric patients with common variable immunodeficiency.

UNLABELLED: Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency associated with an increased risk of malignancy in adulthood, with lymphoma as one of the major causes of death. The aim of this study is to describe those malignancies detected in our cohort of pediatric CVID patients. We reviewed the clinical and laboratory data and the treatments and their outcomes in all pediatric CVID patients from our institution that developed a neoplasia. Four malignancies were diagnosed in three out of 27 pediatric CVID patients. Three malignancies were non-Hodgkin lymphoma (NHL) of B cell origin (mean age at diagnosis: 8 years old), and the remaining was a low-grade astrocytoma. Among NHL, two were mucosa-associated lymphoid tissue (MALT) lymphomas and one was associated with Epstein-Barr virus infection. NHL developed before CVID diagnosis in two patients. CVID patients showed different clinical phenotypes and belonged to different groups according Euroclass and Pediatric classification criteria. CONCLUSIONS: Malignancies, especially lymphoma, may develop in pediatric CVID patients with no previous signs of lymphoid hyperplasia and even before CVID diagnosis. Consequently, strategies for cancer prevention and/or early diagnosis are required in pediatric CVID patients.

Protocol per a l’administració d’immunoteràpia específica amb al·lèrgens en l’atenció primària / Protocol for the administration of allergen-specific immunotherapy in primary care

OBJECTIUS FORMATIUS1. Què és la immunoteràpia específica ambal·lèrgens? Definir les indicacions.2.Conèixer les pautes i els mètodes d’administració.3.Recursos necessaris per a l’administració de laimmunoteràpia. On i com s’ha d’administrar.4.Quines són les possibles reaccions adverses?Com reconèixer-les i tractar-les.IntroduccióL’Organització Mundial de la Salut defineix clínicament la immunoteràpia amb al·èrgens (ITA) coml’administració gradual de quantitats creixents d’unavacuna al·lergènica a un subjecte al·lèrgic fins arribara una dosi que sigui eficaç, millorant els símptomes associats a l’exposició posterior a l’al·lergen causant. (AU)

Primary immunodeficiencies and B-cell lymphomas.

INTRODUCTION: In primary immunodeficiencies there is a failure in the anti-tumor defense. Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies characterized by an alteration in the differentiation of B lymphocytes (BL). Epstein-Barr virus (EBV) is an ubiquitous virus that selectively infects the BL. In patients with immunodeficiency, uncontrolled proliferation of infected BL and the action of viral proteins promote the development of lymphomas. CLINICAL CASES: At the University Hospital Sant Joan de Deu, Barcelona, 28 patients were diagnosed with CVID from 2000 to 2013. This paper describes four patients who developed non-Hodgkin's lymphoma (NHL). The lymphoma was associated with EBV in two of the cases. Patients were<18 years old, diagnosed with lymphoma between 4 and 13 years old. Two patients were treated with rituximab as monotherapy and achieved complete remission. Two patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and radiotherapy or rituximab and achieved complete remission. CONCLUSIONS: Early detection of EBV infections and NHL in all patients diagnosed with CVID is recommended, regardless of age at diagnosis.

¿Están seguros los niños alérgicos en nuestros colegios y comedores escolares? / Are allergic children safe in our schools and school canteens?

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Primary immunodeficiencies and B-cell lymphomas / Inmunodeficiencias primarias y linfomas de células B

Abstract Introduction: In primary immunodeficiencies there is a failure in the anti-tumor defense. Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies characterized by an alteration in the differentiation of B lymphocytes (BL). Epstein-Barr virus (EBV) is an ubiquitous virus that selectively infects the BL. In patients with immunodeficiency, uncontrolled proliferation of infected BL and the action of viral proteins promote the development of lymphomas. Clinical cases: At the University Hospital Sant Joan de Deu, Barcelona, 28 patients were diagnosed with CVID from 2000 to 2013. This paper describes four patients who developed non-Hodgkin's lymphoma (NHL). The lymphoma was associated with EBV in two of the cases. Patients were < 18 years old, diagnosed with lymphoma between 4 and 13 years old. Two patients were treated with rituximab as monotherapy and achieved complete remission. Two patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and radiotherapy or rituximab and achieved complete remission. Conclusions: Early detection of EBV infections and NHL in all patients diagnosed with CVID is recommended, regardless of age at diagnosis.

Resumen Introducción: En las inmunodeficiencias primarias existe un fallo en la defensa antitumoral. La inmunodeficiencia variable común (IDVC) es una de las inmunodeficiencias primarias más frecuentes. Se caracteriza por una alteración en la diferenciación de linfocitos B (LB). El virus de Epstein-Barr (EBV) es un virus ubicuo que infecta de manera selectiva los LB. En pacientes con inmunodeficiencias, la proliferación incontrolada de LB infectados y la acción de proteínas virales promueve la aparición de linfomas. Casos clínicos: En el Hospital Universitario Sant Joan de Déu, Barcelona, se han diagnosticado 28 pacientes con IDVC del 2000 al 2013. En este trabajo se describen cuatro que desarrollaron linfoma no Hodgkin (NHL). El linfoma fue asociado a EBV en dos de ellos. Los pacientes eran menores de 18 años, con el linfoma diagnosticado entre los 4 y 13 años de edad. Dos de los pacientes fueron tratados con rituximab como monoterapia, y lograron la remisión completa. Dos fueron tratados con CHOP (ciclofosfamida, doxorrubicina, vincristina y prednisolona) y radioterapia o rituximab y también alcanzaron la remisión completa. Conclusiones: Se recomienda realizar la detección precoz de las infecciones por EBV y los NHL en todos los pacientes con diagnóstico de IDVC, independientemente de la edad del diagnóstico.