A novel treatment in X-linked agammaglobulinaemia - hyperbaric oxygen therapy in refractory chronic wounds.

Chronic wounds are a rare complication of X-linked agammaglobulinaemia (XLA). Fastidious organisms such as helicobacter bills have been reported in XLA with chronic wounds but sterile chronic wounds also occur. Hyperbaric Oxygen Therapy has been used in chronic wounds but has not previously been reported in primary antibody deficiencies. We present a case of a chronic wound in a patient with XLA refractory to antimicrobial therapy that made a remarkable recovery following Hyperbaric Oxygen Therapy.

A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency.

X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012.

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

Natural killer cell cytotoxicity in patients with recurrent herpes infections: diagnostic utility of a flow cytometric assay.

BACKGROUND: Primary immune deficiencies of natural killer (NK) cells have been described in patients with a susceptibility to herpes infections. AIMS: To assess the diagnostic utility of measurement of NK cytotoxicity in patients with recurrent oral herpes infections. METHODS: A retrospective audit was carried out on results obtained over an 18-month period, from 28 NK cell cytotoxicity assays (24 patients; all with a history of recurrent oral herpes infections), and 24 control samples (three healthy donors). Percentage specific cytotoxicity (PSC) was determined by measurement of the percentage of K562 target cells lysed by NK cells after incubation, using the NK TEST. Comparison of PSC was made with reference ranges provided. RESULTS: No patient with absent NK/NKT cells or NK cell cytotoxicity was identified (95% CI 0 to 14.8%). Two patients had persistently low PSC. Two patients with reduced PSC showed PSC within the normal reference range on repeat testing. Patient and control samples were seen both above and below the reference ranges. A relationship was expected between NK cell percentage and PSC; however this correlation was not significant (r(s)=0.29, p=0.18, 95% CI -0.14 to 0.63). CONCLUSIONS: A deficiency of NK cell cytotoxicity has not been identified in this cohort. An apparent reduction in cytotoxicity may be due to normal interpersonal and intersample variability in NK cytotoxicity. Without reference ranges established from a large population of control samples to account for this, a reduction in PSC is difficult to define. Further studies are required to identify if a correlation exists between the percentage of NK cells and PSC.

An unusual case of sinusitis.

BACKGROUND: Common Variable Immunodeficiency (CVID) is the commonest form of severe antibody deficiency. It is characterized by reduced levels of IgG (<400 mg/dL) and low IgA and/or IgM levels, recurrent bacterial infections, impaired antibody responses despite the presence of B Cells and normal or near normal T immunity in 60% of patients. There is a high mortality from infections without treatment. The main stay treatment is to replace the immunoglobulins. CASE PRESENTATION: We describe a British soldier with a 10 year history of recurrent chest infections, sinusitis and otitis media. He repeatedly presented 2 to 3 times a year complaining of either a green nasal discharge or a cough productive of yellow/green sputum. He presented three years ago with severe sinusitis which resulted in investigations highlighting hypogammaglobulinaemia. Subsequently he was started on immunoglobulin therapy with Flebogamma 40 g three weekly. RECOMMENDATIONS: Despite being a relatively rare condition, CVID when diagnosed, can be easily treated and improve patients' prognosis. Medical Officers should be aware of the condition as a differential diagnosis for individuals presenting with recurrent infections.

T cell immunodeficiency.

T cell immunodeficiency can occur as one of a group of primary disorders or develop secondary to chronic infection, illness or drug therapy. Primary T cell disorders are rare, accounting for approximately 11% of reported primary immunodeficiencies, and generally present in infancy or early childhood. Early recognition is very important as many of these patients will require bone marrow transplantation prior to the onset of severe infection or other complications. Because of their rarity, these infants usually present to clinicians who have little or no prior experience of these conditions, and therefore laboratory-based clinicians with knowledge of the key laboratory/pathological abnormalities and clinical features have a valuable role in identifying the possibility of immunodeficiency. Secondary T cell deficiency is a cardinal feature of HIV infection and the specific susceptibility to infectious micro-organisms is highlighted. The possibility of T cell immunodeficiency should be considered in any patient presenting with unusual or severe viral, fungal or protozoal infection.

Eczema and X-linked agammaglobulinaemia.

An 8-year-old boy presented with eczematous skin lesions, recurrent otitis media and unexplained pyrexias. X-linked agammaglobulinaemia was diagnosed and treatment commenced with intravenous immunoglobulin replacement therapy. X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency syndrome associated with a deficiency of B lymphocytes, caused by a defect in the expression of Bruton's tyrosine kinase. It affects only boys and usually presents before the age of 2 years with recurrent bacterial sinopulmonary infections. IgG levels are usually <2 g/L (normal range 5.4-16.1) and IgM and IgA are usually undetectable. The commonest cutaneous features of XLA are pyogenic skin infections; however, eczema can occur with increased frequency. We report a child who presented with multiple discrete eczematous lesions who subsequently developed eczematous exacerbations several days after administration of intravenous immunoglobulin (IVIg) replacement therapy.

Inactivation of the Fas gene by Alu insertion: retrotransposition in an intron causing splicing variation and autoimmune lymphoproliferative syndrome.

Mutations in the Fas (apo-1, CD95) gene result in autoimmune lymphoproliferative syndrome (ALPS). These mutations are dominated by small deletions and point mutations that result in splicing errors or missense changes. We report here a novel mutation caused by retrotransposon insertion, which results in loss of exon 8 and ALPS. A father and son suffering from recurrent lymphadenopathy were examined for resistance to Fas-mediated apoptosis. A functional defect was detected and RT-PCR analysis revealed two different copies of Fas mRNA, one normal and a second shorter version lacking exon 8. DNA analysis of the genomic region between exons seven and nine in the longer copy revealed two PCR products, one being 331 base pairs (bp) longer than expected. Sequencing revealed that intron 7 had undergone an insertion event with an Alu element (99.31% homology with Alu-Sb1) of 331 bp. This element included a 34-bp Poly A tract that was flanked on each side by a perfect 17 bp direct duplication of the target site. Both patients were heterozygous for the mutated allele that produced Fas mRNA lacking exon 8, although not due to loss of a splice junction. The structure of the insertion suggests that the Alu element may have integrated by retrotransposition, and represents the first report of a retrotransposon causing ALPS.