Search

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.

WOS: 000393996800025, PubMed: 27577878, Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes., South-Eastern Norway Health Authority; American Women's club of Oslo; National Human Genome Research InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart, Lung, and BloodUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [U54HG006542]; Jeffrey Modell Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI-120989], Funding for the work performed in Oslo was provided by the South-Eastern Norway Health Authority, and A. S.-P. received research scholarship from the American Women's club of Oslo. The BHCMG is supported by the National Human Genome Research Institute and the National Heart, Lung, and Blood (U54HG006542). Funding was also provided by the Jeffrey Modell Foundation and NIH AI-120989 (to J.S.O.).

The hallmarks of X-linked Agammaglobulinemia (XLA) are panhypogammaglobulinemia, absent B-cells, and recurrent sinopulmonary and gastrointestinal infections starting at an early age, as well as other infections like cellulitis, meningitis, arthritis and sepsis. A number of non-infectious complications have been reported in these patients, including autoimmune diseases and malignancy, especially lymphomas. Here, we report the case of a 30-year old man who developed gastric adenocarcinoma in the context of XLA. Previous reports of, and hypotheses addressing the development of cancer in patients with XLA, are also summarized. Solid cancer in XLA affects mainly the gastrointestinal tract and seems to be related to chronic infection. A natural evolution can be traced back from gastric adenocarcinoma to megaloblastic anemia due to achlorhydria in the context of chronic infection; periodic endoscopy thus seems justified to detect and treat carcinoma in early stages.

Background Autoimmune manifestations in primary immunodeficiencies (PIDs) are not uncommon, and they are more frequently observed in defects affecting lymphocytes and their regulatory mechanisms. There is a wide variability in prevalence, ranging from immune defects in which autoimmunity defines the syndrome, others with a very high prevalence of autoimmune manifestations, defects with a moderate prevalence, and those in which autoimmunity is rather an exception than the rule. Objective We aimed to determine the prevalence of autoimmunity in children with PIDs from our hospital, to delineate their clinical features. Methods An internal register was consulted to identify autoimmune diseases in our patients with PIDs. Their clinical files were then reviewed for diagnostic workup, age of presentation and outcome. Results We identified a prevalence of 18.8% (47 out of 250 patients, 68.1% male patient), within a period of 40 years (1970–2010), with autoimmune manifestations in the context of PID. Of which most are still alive: 35 (74.5%); lost to follow-up: 3 (6.4%), Dead: 9. Known or probable consanguinity was reported in 25.4%, 36.2% had a positive family history. 12.8% also had an allergic disease; none had cancer. The most frequent AI type was Systemic Autoimmune disease (11 case, 23%), followed by Organ-specific autoimmunity (15 cases, 32%), cytopenias (8 cases, 17%), and just antibodies (6 cases, 13%). Other than Autoimmune lymphoproliferative syndrome (ALPS), in which autoimmunity is a case-defining feature, the group of well defined (Hyper-IgE Syndrome (HIES), and Wiskott-Aldrich Syndrome (WAS)) were the PIDs with more cases of autoimmune disease, followed by phagocytosis deficiencies and antibody deficiency. Discussion The overall prevalence of autoimmune disease is relatively high PID syndromes such as ALPS, moderate levels in HIES, WAS and defects of phagocytosis and antibody interestingly. Interestingly, most of our patients with HIES have an autosomal-recessive pattern of inheritance and no identified mutational diagnosis; nearly all of our patients with CGD are receiving chronic subcutaneous therapy with human recombinant interferon gamma. Regular follow-up visits are justified for surveillance for complications and frequent treatment adjustments, given the delicate balance between immunosuppression and infection prophylaxis that is required in the care of these patients.

Background X-linked agammaglobulinemia (XLA) is characterized by impaired B-cell differentiation caused by mutations in Bruton's tyrosine kinase (Btk) gen. Btk is expressed in myeloid cells and recent evidence support that it participates in Toll like receptor signaling, but results regarding its rol in XLA patients are contradictories. Objective To evaluate lipopolysaccharide (LPS)-induced pro-inflammatory cytokine response in peripheral blood mononuclear cells (PBMC) from XLA patients. Methods Thirteen patients with XLA were included in the study. PBMC LPS-induced TNF-α, IL-1β, IL-6, and IL-10 production was determined by ELISA and compared with that obtained from matched healthy controls. Cytokine production was correlated with the severity of the mutation, affected domain and clinical characteristics. Results In response to LPS, PBMC from XLA patients produced significantly higher amounts of pro-inflammatory cytokines and IL-10 compared with controls and this production is not influenced by the neither severity of mutation or the affected domain. PBMC from patients with a history of more hospital admissions before diagnosis and patients with lower expression of Btk in monocytes produced higher levels of TNF-α and IL-1β, respectively. PBMC from patients with lower IgA levels showed a higher production of TNF-α and IL-1β. Less severe (punctual) mutations in Btk gene were associated with higher IgG levels at diagnosis. Conclusions Our results demonstrated a predominantly inflammatory response in XLA patients after LPS stimuli and suggest a TLR signaling dysregulation in absence of Btk. This response may be influenced by environmental factors.