Clinical and laboratory features of seventy-eight UK patients with Good's syndrome (thymoma and hypogammaglobulinaemia).

Good's syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK-Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy-eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy-four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB-type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren's syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good's syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia.

Bronchiectasis and deteriorating lung function in agammaglobulinaemia despite immunoglobulin replacement therapy.

Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinaemia. We hypothesized that despite regular immunoglobulin therapy, some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. One hundred and thirty-nine (70%) of 199 patients aged 1-80 years from nine cities in the United Kingdom with agammaglobulinaemia currently listed on the UK Primary Immune Deficiency (UKPID) registry were recruited into this retrospective case study and their clinical and laboratory features analysed; 94% were male, 78% of whom had Bruton tyrosine kinase (BTK) gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were 2 years old. Sixty per cent were also taking prophylactic oral antibiotics; 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 and 45 years. Multivariate analysis showed that three factors were associated significantly with bronchiectasis: reaching 18 years old [relative risk (RR) = 14·2, 95% confidence interval (CI) = 2·7-74·6], history of pneumonia (RR = 3·9, 95% CI = 1·1-13·8) and intravenous immunoglobulin (IVIG) rather than subcutaneous immunoglobulin (SCIG) = (RR = 3·5, 95% CI = 1·2-10·1), while starting immunoglobulin replacement after reaching 2 years of age, gender and recent serum IgG concentration were not associated significantly. Independent of age, patients with bronchiectasis had significantly poorer lung function [predicted forced expiratory volume in 1 s 74% (50-91)] than those without this complication [92% (84-101)] (P < 0·001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinaemia can develop chronic lung disease and progressive impairment of lung function.

The effect of increased fruit and vegetable consumption on selected macronutrient and micronutrient intakes in four randomised-controlled trials.

Fruit and vegetable (FV) intake is associated with reduced risk of a number of non-communicable diseases. Research tends to focus on antioxidants, flavonoids and polyphenols contained in FV as the main beneficial components to health; however, increasing FV may also alter overall diet profile. Extra FV may be substituted for foods thought to be less healthy, therefore altering the overall macronutrient and/or micronutrient content in the diet. This analysis merged dietary data from four intervention studies in participants with varying health conditions and examined the effect of increased FV consumption on diet profile. Dietary intake was assessed by either diet diaries or diet histories used in four FV randomised intervention studies. All food and drink intake recorded was analysed using WISP version 3.0, and FV portions were manually counted using household measures. Regression analysis revealed significant increases in intakes of energy (172 kJ (+41 kcal)), carbohydrate (+3·9 g/4184 kJ (1000 kcal)), total sugars (+6·0 g/4184 kJ (1000 kcal)) and fibre (+0·8 g/4184 kJ (1000 kcal)) and significant decreases in intakes of total fat (-1·4 g/4184 kJ (1000 kcal)), SFA (-0·6 g/4184 kJ (1000 kcal)), MUFA (-0·6 g/4184 kJ (1000 kcal)), PUFA (-0·1 g/4184 kJ (1000 kcal)) and starch (-2·1 g/4184 kJ (1000 kcal)) per one portion increase in FV. Significant percentage increases were also observed in vitamin C (+24 %) and -carotene (+20 %) intake, per one portion increase in FV. In conclusion, pooled analysis of four FV intervention studies, that used similar approaches to achieving dietary change, in participants with varying health conditions, demonstrated an increase in energy, total carbohydrate, sugars and fibre intake, and a decrease in fat intake alongside an expected increase in micronutrient intake.

Clinical and laboratory correlates of lung disease and cancer in adults with idiopathic hypogammaglobulinaemia.

Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype. This study used data from the national UK Primary Immune Deficiency (UKPID) registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. A total of 801 adults labelled with idiopathic hypogammaglobulinaemia and CVID aged 18-96 years from 10 UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leucocyte numbers and serum immunoglobulin concentrations) were collated and analysed using uni- and multivariate statistics. Low serum immunoglobulin (Ig)G pre-immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy [5 (range 1-13 years) versus 9 (range 2-24) years]. Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication [7 (range 2-22) years versus 5 (range 1-13) years]. Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinaemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both haematological and non-haematological, was associated with significantly lower absolute CD8(+) T cell but not natural killer (NK) cell numbers, raising the question as to what extent immune senescence, particularly of CD8(+) T cells, might contribute to the increased risk of cancers as individuals age.

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.

Effect of increased fruit and vegetable consumption on bone turnover in older adults: a randomised controlled trial.

UNLABELLED: Evidence suggests that increased fruit and vegetable (FV) intake may be associated with improved bone health, but there is limited evidence from intervention trials to support this. This 16-week study showed that increased FV consumption (five or more portions per day) does not have any effect on the markers of bone health in older adults. INTRODUCTION: Observational evidence suggests that increased FV consumption may be associated with improved bone health. However, there is lack of evidence from intervention trials to support this. This study examined the effect of increased FV consumption on bone markers among healthy, free-living older adults. METHODS: A randomised controlled trial was undertaken. Eighty-three participants aged 65-85 years, habitually consuming less than or equal to two portions of FV per day, were randomised to continue their normal diet or to consume five or more portions of FV per day for 16 weeks. FV were delivered to all participants each week, free of charge. Compliance was assessed at baseline and at 6, 12 and 16 weeks by diet histories and biomarkers of micronutrient status. Fasting serum bone markers (osteocalcin (OC) and C-terminal telopeptide of type 1 collagen (CTX)) were measured using enzyme-linked immunosorbent assay. RESULTS: Eighty-two participants completed the intervention. The five portions per day group showed a significantly greater change in daily FV consumption compared to the two portions per day group (p < 0.001), and this was reflected in significant increases in micronutrient status. No significant differences were evident in change in bone markers between the two portions per day group and the five portions per day group over the 16 weeks (geometric mean of week 16 to baseline ratio (95% confidence interval): OC-0.95 (0.89-1.02) and 1.04 (0.91-1.18), respectively, p = 0.25; CTX-1.06 (0.95-1.19) and 0.98 (0.90-1.06) respectively, p = 0.20). CONCLUSIONS: Increased FV consumption had no effect on bone markers in older adults. Larger intervention studies of longer duration are warranted to establish whether long-term FV consumption can benefit bone health.

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.

Design and experimental validation of a compact collimated Knudsen source.

In this paper, the design and performance of a collimated Knudsen source, which has the benefit of a simple design over recirculating sources, is discussed. Measurements of the flux, transverse velocity distribution, and brightness of the resulting rubidium beam at different source temperatures were conducted to evaluate the performance. The scaling of the flux and brightness with the source temperature follows the theoretical predictions. The transverse velocity distribution in the transparent operation regime also agrees with the simulated data. The source was tested up to a temperature of 433 K and was able to produce a flux in excess of 10(13) s(-1).

Suspended crystalline films of protein hydrophobin I (HFBI).

Protein interfaces play an essential role in both natural and man-made materials as stabilizers, sensors, catalysts, and selective channels for ions and small molecules. Probing the molecular arrangement within such interfaces is of prime importance to understand the relation between structure and functionality. Here we report on the preparation and characterization of large area suspended crystalline films of class II hydrophobin HFBI. This small, amphiphilic globular protein readily self-assembles at the air-water interface into a 2D hexagonal lattice which can be transferred onto a holey carbon electron microscopy grid yielding large areas of hundreds of square micrometers intact hydrophobin film spun across micron-sized holes. Fourier transform analysis of low-dose electron microscopy images and selected area electron diffraction profiles reveal a unit cell dimension a=5.6±0.1nm, in agreement with reported atomic force microscopy studies on solid substrates and grazing incidence X-ray scattering experiments at the air-water interface. These findings constitute the first step towards the utilization of large-area suspended crystalline hydrophobin films as membranes for ultrapurification and chiral separation or as biological substrates for ultrafast electron diffraction.

Acute exacerbation of vasculitis during interferon-alpha therapy for hepatitis C-associated cryoglobulinaemia.

A significant, previously unreported, adverse reaction to interferon-alpha therapy is reported. Immediately after the commencement of low dose therapy a man with hepatitis-C associated cryoglobulinaemia developed a purpuric rash and a severe, reversible impairment of renal function. This observation may elucidate the immunopathogenesis of vasculitis.

An association between ANCA positive renal disease and malignancy.

The detection of anti-neutrophil cytoplasmic antibodies (ANCA) is now a routine part of the evaluation of patients clinically suspected of suffering from small vessel vasculitis. The factor(s) that trigger the development of these autoantibodies and their role in the pathogenesis of vasculitis is still unclear. We describe four patients who presented to us since June 1990. All patients had positive ANCA serology and had clinical evidence of vasculitis. In all patients soon after the establishment of ANCA positivity, a carcinoma of either the respiratory or urinary tracts was diagnosed. We suggest that in some cases of ANCA-associated vasculitis, malignant disease may be a trigger for either the generation of these autoantibodies, or the development of vasculitis.

Acoustic measures of symptoms in abductor spasmodic dysphonia.

Speech of patients with abductor spasmodic dysphonia (ABSD) was analyzed using acoustic analyses to determine: (1) which acoustic measures differed from controls and were independent factors representing patients' voice control difficulties, and (2) whether acoustic measures related to blinded perceptual counts of the symptom frequency in the same patients. Patients' voice onset time for voiceless consonants in speech were significantly longer than the controls (p = 0.015). A principle components analysis identified three factors that accounted for 95% of the variance: the first factor included sentence and word duration, frequency shifts, and aperiodic instances; the second was phonatory breaks; and the third was voice onset time. Significant relationships with perceptual counts of symptoms were found for the measures of acoustic disruptions in sentences and sentence duration. Finally, a multiple regression demonstrated that the acoustic measures related well with the perceptual counts (r2 = 0.84) with word duration most highly related and none of the other measures contributing once the effect of word duration was partialed out. The results indicate that some of the voice motor control deficits, namely aperiodicity, phonatory breaks, and frequency shifts, which occur in patients with ABSD, are similar to those previously found in adductor spasmodic dysphonia. Results also indicate that acoustic measures of intermittent disruptions in speech, voice onset time, and speech duration are closely related to the perception of symptom frequency in the disorder.

Predictive value for coeliac disease of antibodies to gliadin, endomysium, and jejunum in patients attending for jejunal biopsy.

OBJECTIVE: To investigate the extent to which the detection of antibodies to gliadin, endomysium, and jejunum predicts the eventual diagnosis of coeliac disease according to the revised ESPGAN diagnostic criteria in a group of patients in whom there is a high suspicion of coeliac disease. DESIGN: Clinical assessment and laboratory analysis of patients with suspected coeliac disease. SETTING: Gastroenterology department of teaching hospital. PATIENTS: 96 adults with suspected coeliac disease attending for jejunal biopsy. MAIN OUTCOME MEASURES: Diagnosis of coeliac disease with the revised criteria of the European Society of Paediatric Gastroenterology and Nutrition in patients with and without antibodies associated with coeliac disease. RESULTS: 28 patients had a clinical diagnosis of coeliac disease, seven of other gastrointestinal diseases, and 12 of miscellaneous diseases; 49 had no diagnosis. Gliadin IgA detected by ELISA was found in all patients with coeliac disease and none of those without, giving a sensitivity, specificity, positive and negative predictive values, and predictive efficiency of 100% for diagnosing coeliac disease within the group. Endomysial IgA was found in 25 (89%) patients with coeliac disease and jejunal IgA in 21 (75%); neither IgA was found in patients without coeliac disease. CONCLUSION: Detection of gliadin IgA by ELISA and to a lesser extent the endomysial IgA should allow better selection of patients for jejunal biopsy and thus make diagnosing coeliac disease simpler and more efficient.

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.

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.

Neonatal infection does not affect the immunoreactive trypsinogen screening test for cystic fibrosis.

We aimed to discover whether neonatal infection affected levels of the immunoreactive trypsin (IRT) assay, which is used as a screening test for cystic fibrosis. Forty babies who had clinical features suggesting infection had blood spot specimens for IRT taken at the same time as blood for culture. Of 27 babies believed clinically to have infection, 19 had positive blood cultures and eight had negative culture. In retrospect, 13 were not thought to have infection. The mean (SD) IRT results in these three groups were 15 (8), 11 (4), and 16 (6) micrograms/L, respectively. The mean (SD; range) IRT result for all 40 babies was 14 (7; 10-39). Not only did no babies have elevated IRT results at routine neonatal screening, but none have presented with clinical features suggestive of cystic fibrosis since hospital discharge. Neonatal infection does not appear to cause elevated IRT levels and should therefore not cause false-positive results in mass neonatal screening.