Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency.

The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype.

Meeting the challenges of wound care in Danish home care.

OBJECTIVE: To evaluate a community-based educational intervention to improve wound-care practice, and thereby reduce the costs of care, in four communities in Denmark. METHOD: Annual wound care audits recorded patients' ages, the number and types of wounds being treated, wound duration (days unhealed), frequency of dressing changes and nurse time per dressing change. Data were available at year 1 and year 3 post-intervention. A statistical analysis was performed, testing for changes in a range of variables between these years. RESULTS: In the post-intervention period, significant reductions were found in the proportion of chronic wounds, the proportion of wounds requiring a daily dressing change, mean frequency of dressing change, mean nurse time spent in wound care per week, and the total cost of wound care per week. CONCLUSION: These results suggest that it is possible to improve wound-care practice and reduce the resource costs of wound care through a systematic programme of education and training, tailored to suit the needs of local communities.

Gut inflammation in CVID: causes and consequences.

INTRODUCTION: There is a wide spectrum of noninfectious gastrointestinal pathology, causing considerable morbidity and mortality in CVID, where both etiology and effective therapy are under debate. AREAS COVERED: This review will focus on the noninfectious inflammation in the GI tract in CVID patients, covering the both the upper and lower GI tract inflammation, including the liver. The controversy of the CVID enteropathy definition and that of gluten-free diet for celiac-like disease in CVID will be discussed. Furthermore, the review will cover the link between GI inflammation and GI cancer. Finally, the role of gut microbiota, IgA, and genetics and its relationship with CVID enteropathy is scrutinized. The authors reviewed literature from PubMed. EXPERT OPINION: The heterogeneity and the unknown mechanism behind CVID enteropathy, and thereby the lack of effective treatment, is one of the key challenges in the field of CVID. Celiac-like disease in CVID is due to immune dysregulation, and a gluten-free diet is therefore not indicated. Gut microbial dysbiosis and mucosal IgA can initiate systemic and local inflammation and is involved in the immune dysregulation in CVID. Considering the heterogeneity of CVID enteropathy, personalized medicine is probably the future for these patients.

Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency.

Common variable immunodeficiency (CVID) patients have reduced gut microbial diversity compared to healthy controls. The reduced diversity is associated with gut leakage, increased systemic inflammation and ten "key" bacteria that capture the gut dysbiosis (dysbiosis index) in CVID. Rifaximin is a broad-spectrum non-absorbable antibiotic known to reduce gut leakage (lipopolysaccharides, LPS) in liver disease. In this study, we explored as a 'proof of concept' that altering gut microbial composition could reduce systemic inflammation, using CVID as a disease model. Forty adult CVID patients were randomized, (1:1) to twice-daily oral rifaximin 550 mg versus no treatment for 2 weeks in an open-label, single-centre study. Primary endpoints were reduction in plasma/serum levels of soluble (s) CD14, sCD25, sCD163, neopterin, CRP, TNF, LPS and selected cytokines measured at 0, 2 and 8 weeks. Secondary endpoint was changes in intra-individual bacterial diversity in stool samples. Rifaximin-use did not significantly change any of the inflammation or gut leakage markers, but decreased gut microbial diversity compared with no treatment (p = 0.002). Importantly, the gut bacteria in the CVID dysbiosis index were not changed by rifaximin. The results suggest that modulating gut microbiota by rifaximin is not the chosen intervention to affect systemic inflammation, at least not in CVID.

Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.