Identification of 22 novel BTK gene variants in B cell deficiency with hypogammaglobulinemia.

X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by pathogenic variants in the BTK gene, resulting in impaired B cell differentiation and maturation. Over 900 variants have already been described in this gene, however, new pathogenic variants continue to be identified. In this report, we describe 22 novel variants in BTK, associated with B cell deficiency with hypo- or agammaglobulinemia in male patients or in asymptomatic female carriers. Genetic data was correlated with BTK protein expression by flow cytometry, and clinical and family history to obtain a comprehensive assessment of the clinico-pathologic significance of these new variants in the BTK gene. For one novel missense variant, p.Cys502Tyr, site-directed mutagenesis was performed to determine the impact of the sequence change on protein expression and stability. Genetic data should be correlated with protein and/or clinical and immunological data, whenever possible, to determine the clinical significance of the gene sequence alteration.

Adverse reactions to infliximab and the outcome of desensitization.

BACKGROUND: Infliximab is a highly effective monoclonal antibody against tumor necrosis factor, which is a major inflammatory mediator in certain gastrointestinal, rheumatic, and skin diseases. In some patients, infliximab infusion causes systemic adverse reactions that often lead to discontinuation of therapy even in responsive patients. OBJECTIVE: To investigate the frequency and characteristics of adverse reactions to infliximab at the authors' institution and the outcome of their management, including desensitization. METHODS: This was a single-center retrospective study of patients who were treated with infliximab, primarily for inflammatory bowel disease, from January 1, 2000 to March 31, 2014. Data included age, sex, underlying disease, infliximab therapy duration before the first reaction, manifestation of reaction, onset, and management. RESULTS: There were 336 patients with inflammatory bowel disease who were treated with infliximab during the study period. Thirty patients (8.9%) developed a systemic adverse reaction to infliximab, which was discontinued in 15 patients (50%) and was continued in 3 patients after premedication and/or decreased infusion rate. Twelve patients (40%) underwent infliximab desensitization with gradually increasing doses starting at a dilution of 0.1 mg/mL to reach the full treatment dose over approximately 4 to 6 hours. It was successful in all 12 patients, who continued to receive up to 26 infliximab infusions, mostly without premedication. CONCLUSION: Infliximab can trigger systemic reactions that hinder its administration. The present desensitization protocol appears to be safe and effective and it can be considered in patients whose inflammatory bowel disease responds well to infliximab but who develop systemic adverse reactions.

Infections in DNA Repair Defects.

DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. Consequently, the characteristics of the infections may vary from mild upper respiratory tract infections to severe, opportunistic, and even fatal infections with bacteria, viruses, or fungi. Here, infections in 15 rare and sporadic DNA repair defects that are associated with immunodeficiencies are discussed. Because of the rarity of some of these conditions, limited information is available regarding infectious complications.

Should newborns be screened for immunodeficiency?: lessons learned from infants with recurrent otitis media.

Recurrent otitis media in children is considered one of the warning signs of primary immunodeficiencies (PIDs), particularly antibody deficiencies. Infants who have the most serious and potentially lethal form of PID, severe combined immunodeficiency (SCID), sometimes present with recurrent otitis media. Most of the time, because of the severity of the immune defect, they develop more serious and systemic infections. SCID is distinct among the PIDs and considered a pediatric emergency. Diagnosing SCID during the newborn period is crucial because survival completely depends on early diagnosis and treatment. Mortality declines significantly if immune reconstitution is established before 3.5 months of age, particularly before severe infections have occurred. However, most patients are diagnosed after they have suffered chronic or recurrent infections and developed permanent sequelae. Without institution of population-based newborn screening, most infants will miss the opportunity to live a healthy life.

Interleukin-2 treatment for persistent cryptococcal meningitis in a child with idiopathic CD4(+) T lymphocytopenia.

We report a 16-year-old male patient who presented with headache, behavior changes, and fever. His cerebral spinal fluid and blood cultures grew Cryptococcus neoformans. His laboratory evaluation was negative for human immunodeficiency virus infection but flow cytometry revealed low CD4(+) count of 39 cells/mm(3) and CD4:CD8 ratio of 0.43. He was initially treated with antifungal agents with only partial clinical improvement, and he was discharged to home on oral fluconazole and prophylactic co-trimoxazole. After discharge, he continued to have persistent headache and recurrent episodes of vomiting. He was readmitted several times because of worsening of meningitis symptoms and received prolonged courses of multiple antifungal therapy, with clearance of infection from the central nervous system. He was subsequently placed on prophylactic therapy with fluconazole. His peripheral CD4(+) cell count remained low after resolution of his meningitis. Eight months after the initial diagnosis, recombinant IL-2 therapy was initiated and within a few months, his CD4(+) cell count started to increase. Treatment with rIL-2 and prophylactic antifungal therapy continued and he has been asymptomatic for almost 20 months so far. This case is the first reported pediatric idiopathic CD4(+) T-lymphocytopenia case with cryptococcal meningitis that was successfully treated by the addition of rIL-2 therapy to antifungal therapy.