X-linked agammaglobulinemia: report on a United States registry of 201 patients.

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies.

Long-Term Follow-Up and Outcome of a Large Cohort of Patients with Common Variable Immunodeficiency

On 29 March 2005 a 41 year old journalist died of sepsis six days after a minor surgical procedure; she had consulted eight doctors over the intervening Easter bank holiday weekend. Whereas the national press focused on the political question relating to the provision of out of hours medical services in the United Kingdom, the coroner pointed out that “non-recognition of the seriousness of her condition contributed [to her death].” With an estimated annual mortality of between 30 and 50 deaths per 100 000 population,1 2 this condition ranks in the top 10 causes of death,3 affects all ages, and occurs in the community, in long term care facilities, and among patients admitted to hospital under the care of any, and every, medical specialty.

#### Summary points

Systemic illness caused by microbial invasion of normally sterile parts of the body is referred to as “sepsis.” This is a term that specifically serves to differentiate an illness of microbial origin from an identical clinical syndrome that can arise in several non-microbial conditions, of which pancreatitis is the archetype. The similarity in clinical picture is explained by the pathophysiological role …

https://www.bmj.com/content/bmj/335/7625/879.full.pdf

Sepsis: definition, epidemiology, and diagnosis

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.

Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity

Sophisticated genetic tools have made possible the identification of the genes responsible for most well-described immunodeficiencies in the past 15 years. Mutations in Btk, components of the pre-B cell and B cell receptor (lambda5, Igalpha, Igbeta), or the scaffold protein BLNK account for approximately 90% of patients with defects in early B cell development. Hyper-IgM syndromes result from mutations in CD40 ligand, CD40, AID, or UNG in 70-80% of affected patients. Rare defects in ICOS or CD19 can result in a clinical picture that is consistent with common variable immunodeficiency, and as many as 10% of patients with this disorder have heterozygous amino acid substitutions in TACI. For all these disorders, there is considerable clinical heterogeneity in patients with the same mutation. Identifying the genetic and environmental factors that influence the clinical phenotype may enhance patient care and our understanding of normal B cell development.

Grazia Dell'Erba

Papers

Clinical, Immunological, and Molecular Analysis in a Large Cohort of Patients with X-Linked Agammaglobulinemia: An Italian Multicenter Study