Gammaglobulin for primary immunodeficiency: when should it be used?

Antibodies are an essential component of the adaptative immune response and hold long-term memory of the immunological experiences throughout life. Antibody defects represent approximately half of the well-known primary immunodeficiencies requiring gammaglobulin replacement therapy. On the other hand this therapy can be used for some diseases that do not belong to this group, like hyper IgM syndrome, immunodeficiency with thymoma and severe combined immunodeficiency. This therapy is a safe procedure and induces dramatic improvement in the clinical outcome of patients, reducing the risks of death and complications.Anticorpos são componentes essenciais da resposta imunológica adaptativa e apresentam memória imunológica em longo prazo. Defeitos de anticorpos representam aproximadamente metade das imunodeficiências primárias conhecidas e requerem terapia de reposição de gamaglobulina. Por outro lado, esta modalidade terapêutica pode ser usada para algumas outras doenças que não pertencem a este grupo, como síndrome de hiper IgM, imunodeficiência com timoma e imunodeficiência combinada grave. Este tratamento é um procedimento seguro e acarreta em significativa melhora clínica dos pacientes, reduzindo os riscos de morte e complicações

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature

Introduction Since the frst description of gain of function (GOF) mutations in signal transducer and activator of transcrip tion (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefts in several reported cases, their indica tions, dosing, and monitoring remain to be established. Methods A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profle and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune defciency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p=0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions Our study supports the potentially benefcial use of JAKinibs in patients with STAT1 GOF, in line with previ ously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitor ing, as well as defning biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature.

Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries

First Report of the Hyper-IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: Novel Mutations, Unique Infections, and Outcomes

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Jeffrey Modell FoundationLatin American Advisory Board on Primary Immunodeficiencies initiativeUniv São Paulo, Inst Biomed Sci, Dept Immunol, BR-05508000 São Paulo, BrazilCtr Invest & Estudios, Dept Biomed Mol, Mexico City, DF, MexicoDr Ricardo Gutierrez Childrens Hosp, Buenos Aires, DF, ArgentinaHosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa RicaPediat Allergy & Immunol Clin, Caxias Do Sul, RS, BrazilAlbert Sabin Hosp, Fortaleza, Ceara, BrazilHosp Base Dist Fed, Brasilia, DF, BrazilIntegrated Ctr Pediat Specialties, Curitiba, PR, BrazilHosp Ninos VJ Vilela, Rosario, ArgentinaHosp Ninos Luis Calvo Mackenna, Santiago, ChileUniv Fed Parana, Dept Pediat, BR-80060000 Curitiba, Parana, BrazilUniv Estadual Campinas, Sch Med, Dept Pediat, Campinas, SP, BrazilConceicao Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Porto Alegre, RS, BrazilChildrens Hosp Lucidio Portela, Teresina, PI, BrazilPontificia Univ Catolica Chile, Div Pediat, Santiago, ChileUniv Estadual Campinas, Sch Med, Dept Med, Campinas, SP, BrazilUniv São Paulo, Ribeirao Preto Med Sch, BR-14049 Ribeirao Preto, SP, BrazilHosp Nacl Edgardo Rebagliati Martins Alergia & In, Lima, PeruUniv Fed Rio de Janeiro, Sch Med, Dept Pediat, Rio de Janeiro, BrazilInst Nacl Pediat, Unidad Invest Inmunodeficiencias, Mexico City, DF, MexicoIMSS, Unidad Med Alta Especialidad 25, Monterrey, Nuevo Leon, MexicoClin Montefiori, Unidad Inmunol, Lima, PeruUNAL, Univ Hosp, Monterrey, Nuevo Leon, MexicoFac Med ABC, Santo Andre, SP, BrazilChildrens Hosp, Dept Pediat, New Orleans, LA USAHop Necker Enfants Malad, INSERM, Unite U768, Paris, FranceUniv Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USASeattle Childrens Res Inst, Seattle, WA USAUniversidade Federal de São Paulo, Dept Pediat, Div Allergy Immunol & Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, Div Allergy Immunol & Rheumatol, São Paulo, BrazilFAPESP: 2012/50515-4FAPESP: 2006/57643-7FAPESP: 2012/51745-3Web of Scienc