Chlorhexidine allergy in four specialist allergy centres in the United Kingdom, 2009-13: clinical features and diagnostic tests.

We describe an observational survey of diagnostic pathways in 104 patients attending four specialist allergy clinics in the United Kingdom following perioperative hypersensitivity reactions to chlorhexidine reactions. The majority were life-threatening. Men undergoing urological or cardiothoracic surgery predominated. Skin prick testing and specific immunoglobulin (sIg)E testing were the most common tests used for diagnosis. Fifty-three per cent of diagnoses were made on the basis of a single positive test. Where multiple tests were performed the sensitivity of intradermal, basophil activation and skin prick testing was 68% (50-86%), 50% (10-90%) and 35% (17-55%), respectively. Seven per cent were negative on screening tests initially, and 12 cases were only positive for a single test despite multiple testing. Intradermal tests appeared most sensitive in this context. Additional sensitization to other substances used perioperatively, particularly neuromuscular blocking agents (NMBA), was found in 28 patients, emphasizing the need to test for possible allergy to all drugs to which the patient was exposed even where chlorhexidine is positive.

No evidence of asymptomatic variant CJD infection in immunodeficiency patients treated with UK-sourced immunoglobulin.

Surveillance of 75 immunodeficiency patients exposed to UK-sourced immunoglobulin, including batches derived from donors who went on to develop vCJD, has not detected any clinical cases of vCJD, or of asymptomatic infection in 15 patients with available tissue samples of sufficient quality for testing.

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.

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.

A UK national audit of hereditary and acquired angioedema.

Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life-threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.

Maternal deaths in women with lupus nephritis: a review of published evidence.

BACKGROUND AND OBJECTIVES: Pregnancies in women with systemic lupus erythematosus (SLE) and lupus nephritis are considered high-risk due to high rates of maternal and fetal complications. However, there has not been a formal analysis addressing the issue of maternal deaths in these women. The aim of this study was to perform a literature review of the maternal deaths in women with SLE and lupus nephritis to: (1) identify the main causes of death and (2) discuss possible reasons for these causes, and strategies that may improve patient care and outcomes. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENT: We performed an extensive electronic literature search from 1962 to 2009 using online databases (PubMed, Embase, Lilacs, Cochrane Controlled Trials Register, Medline, and Science Citation Index). Studies were included if they reported pregnancies in patients with SLE and lupus nephritis with at least one reported maternal death. RESULTS: We identified 13 studies that reported a total of 17 deaths in the 6 week post-partum period that were attributable to SLE and lupus nephritis. In all cases, death occurred in the setting of active disease, and was attributed either to infection in 41.2% (n = 7), or disease activity in 29.4% (n = 5). The remaining deaths were due to pulmonary embolus in 11.8% (n = 2), pregnancy-associated cardiomyopathy in 5.9% (n = 1), adrenal failure due to abrupt steroid withdrawal in 5.9% (n = 1), and undefined in 5.9% (n = 1). CONCLUSIONS: All maternal deaths in patients with SLE and lupus nephritis occurred in those with active disease, with disease activity/complications and infections (mainly opportunistic) being the two major causes. The presented evidence further supports timing of pregnancy relative to SLE activity, and the judicious use of immunosuppressive agents in pregnant patients.

Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register.

OBJECTIVES: To evaluate the risk of septic arthritis (SA) in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. METHODS: Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, the authors compared the risk of SA between 11 881 anti-TNF-treated and 3673 non-biological disease-modifying antirheumatic drug (nbDMARD)-treated patients. RESULTS: 199 patients had at least one episode of SA (anti-TNF: 179, nbDMARD: 20). Incidence rates were: anti-TNF 4.2/1000 patient years (pyrs) follow-up (95% CI 3.6 to 4.8), nbDMARD 1.8/1000 pyrs (95% CI 1.1 to 2.7). The adjusted HR for SA in the anti-TNF cohort was 2.3 (95% CI 1.2 to 4.4). The risk did not differ significantly between the three agents: adalimumab, etanercept and infliximab. The risk was highest in the early months of therapy. The patterns of reported organisms differed in the anti-TNF cohort. Prior joint replacement surgery was a risk factor for SA in all patients. The rate of postoperative joint infection (within 90 days of surgery) was 0.7%. This risk was not significantly influenced by anti-TNF therapy. CONCLUSIONS: Anti-TNF therapy use in RA is associated with a doubling in the risk of SA. Physicians and surgeons assessing the RA patient should be aware of this potentially life-threatening complication.

Fluctuations of haemoglobinaemia in chronic haemodialysis patients.

In March 2008 and June 2009, an ad hoc working group of nephrologists discussed the status of anaemia therapy with erythropoiesis-stimulating agents [ESA] in patients on chronic haemodialysis, the phenomenon of fluctuations of haemoglobinaemia, and the need for individualisation of ESA treatment. The working group put together the following statements: (1) ESAs increase the haemoglobin concentration and adaptations of the ESA dose adjust the response according to a negative-feedback loop. The long lag time between an ESA dose change and its effect on erythropoiesis is cumbersome. The optimal haemoglobin target concentration is different for every haemodialysis patient; the lowest haemoglobin concentration upon which one could consistently demonstrate a positive subjective and objective clinical benefit in chronic dialysis is 11 g/dL, in contrast to the lowest haemoglobin concentration of 10 g/dL recommended in the current EMEA label for ESAs. (2) Intra-individual fluctuation of haemoglobinaemia over time is unavoidable, not only due to the ESA dose/haemoglobin response interaction, but also, and more importantly, due to the occurrence of acute illnesses and exacerbations of co-morbid conditions. Many different methodologies to characterise haemoglobin variability have been described but there is currently no universally applied definition of the phenomenon. (3) An impact of the haemoglobin level and the amplitude of the haemoglobin fluctuations on patient outcome has been observed. Without disclosing any causal relationship, worse outcomes were associated with haemoglobin fluctuations around the lower target level, but later on, more simply linked to the relative time spent below the haemoglobin concentration of 11 g/dL and to the administration of inappropriately high ESA doses in order to achieve the recommended haemoglobin target range. A plausible mechanism might be that acute illnesses blunt the patients' basal ESA sensitivity; this leads to subnormal and/or varying haemoglobin levels, currently initiating an ESA dose increase. The longer it takes the patient to recover from the acute illness, the more the prolongation of the clinically poor condition is to some extent maintained by the persistence of low haemoglobinaemia and/or by the administration of high ESA doses, and, as such, on their turn possibly contributing to an ultimate poor outcome. In the absence of clinical trials, recommendations should be offered how to proceed with the administration of ESAs as optimal as possible in periods of clinical instability.

Rupture of the ureter mimicking acute renal infarction: case report and review of the literature.

We describe a case of acute rupture of the left proximal ureter as a result of lithiasis. The patient presented with a clinical picture of renal infarction: unilateral flank pain, more than 500 red blood cells per microliter urine and increased serum LDH levels. Abdominal ultrasound as well as a CT scan showed no abnormalities. Only CT angiography of the kidneys was able to demonstrate an acute rupture of the left proximal ureter with extravasation of contrast. Intravenous pyelogram confirmed this rupture with leaking of the contrast. One day after admission the patient urinated a 2 mm large calciumoxalate-monohydrate stone, the likely cause of the rupture. The rupture healed spontaneously. A review of the literature is given.

Immunodeficiencies.

Primary immunodeficiencies (PIDs) are uncommon, chronic and severe disorders of the immune system in which patients cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The treatment of choice for PID patients with predominant antibody deficiency is intravenous immunoglobulin (Ig) replacement therapy. Despite major advances over the last 20 years in the molecular characterization of PIDs, many patients remain undiagnosed or are diagnosed too late, with severe consequences. Various strategies to ensure timely diagnosis of PIDs are in place, and novel approaches are being developed. In recent years, several patient registries have been established. Such registries shed light on the pathology and natural history of these varied disorders. Analyses of the registry data may also reveal which patients are likely to respond well to higher Ig infusion rates and may help to determine the optimal dosing of Ig products. Faster infusion rates may lead to improved convenience for patients and thus increase patient compliance, and may reduce nursing time and the need for hospital resources. Data from two recent studies suggest that Gamunex and Privigen are well tolerated at high infusion rates. Nevertheless, careful selection of patients for high infusion rates, based on co-morbid conditions and tolerance of the current infusion rate, is advisable. Based on the available data, intravenous Ig offers broad protection against encapsulated organisms. As vaccine trends change, careful monitoring of specific antibody levels in the general population, such as those against pneumococcal and meningococcal bacteria, should be implemented.

6th International Immunoglobulin Symposium: poster presentations.

The posters presented at the 6th International Immunoglobulin Symposium covered a wide range of fields and included both basic science and clinical research. From the abstracts accepted for poster presentation, 12 abstracts were selected for oral presentations in three parallel sessions on immunodeficiencies, autoimmunity and basic research. The immunodeficiency presentations dealt with novel, rare class-switch recombination (CSR) deficiencies, attenuation of adverse events following IVIg treatment, association of immunoglobulin (Ig)G trough levels and protection against acute infection in patients with X-linked agammaglobulinaemia (XLA) and common variable immunodeficiency (CVID), and the reduction of class-switched memory B cells in patients with specific antibody deficiency (SAD). The impact of intravenous immunoglobulin on fetal alloimmune thrombocytopenia, pregnancy and postpartum-related relapses in multiple sclerosis and refractory myositis, as well as experiences with subcutaneous immunoglobulin in patients with multi-focal motor neuropathy, were the topics presented in the autoimmunity session. The interaction of dendritic cell (DC)-SIGN and alpha2,6-sialylated IgG Fc and its impact on human DCs, the enrichment of sialylated IgG in plasma-derived IgG, as wells as prion surveillance and monitoring of anti-measles titres in immunoglobulin products, were covered in the basic science session. In summary, the presentations illustrated the breadth of immunoglobulin therapy usage and highlighted the progress that is being made in diverse areas of basic and clinical research, extending our understanding of the mechanisms of immunoglobulin action and contributing to improved patient care.

Failure of antibody response to polysaccharide antigen in treated panhypopituitary adults.

Although pituitary hormones are known to affect immune function, treated hypopituitarism is not a recognized cause of immune deficiency in humans. We set out to assess integrity of baseline and stimulated immune function in severely hypopituitary adults. Twenty-one panhypopituitary adults (group 1), on stable pituitary replacement including growth hormone, and 12 healthy volunteers (group 2) were studied. Lymphocyte subsets, pneumococcal antibody levels pre- and 1 month after polysaccharide vaccination, T cell numbers and in-vitro interferon (IFN)-gamma response were studied. There were no significant differences in T cell numbers or IFN-gamma secretion. B cell numbers were lower in group 1, especially those with low prolactin levels. Independent of this finding, nine of 21 patients in this group had low antibody response to polysaccharide antigen. This was most striking in those with low insulin-like growth factor 1 levels and appeared to be independent of the use of anti-convulsants or corticosteroid replacement. Significant humoral immune deficiency is seen in panhypopituitarism and may contribute to morbidity.

Angioedema of the airway: an unusual case.

We report a case of angioedema caused by angiotensin-converting enzyme inhibitor and topical lignocaine spray, administered during nasendoscopy. Angioedema induced by angiotensin-converting enzyme inhibitors is a rare but well known entity. Allergy to topical lignocaine has been acknowledged as a rare phenomenon when used for dental surgery and for skin anaesthesia, but it has not previously been reported after topical administration prior to nasendoscopy. In the reported case, our patient was unfortunate enough to be allergic to both lisinopril and lignocaine. The result was life-threatening airway obstruction, and the continued use of lignocaine spray sustained the laryngeal oedema. We advise that patients are asked about any and every allergy--specifically, any previous problems with dental procedures--before administration of local anaesthetic spray to the upper aerodigestive tract.

Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients.

Mycophenolate mofetil (MMF) is one of the new immunosuppressive drugs used in renal transplantation. MMF inhibits the de novo purine synthesis. Since this purine synthesis in lymphocytes entirely depends on the de novo pathway, MMF is considered to cause a selective inhibition of T- and B lymphocytes. Recently, 4 transplant patients out of 30 developed a severe anemia in the early post-transplantation period. Their immediate post-transplantation immunosuppression consisted of corticosteroids, cyclosporine and MMF. They all received anti-T-lymphocyte globulin (ATG) as induction treatment or because of rejection. In all 4 patients, iron supplementation and a treatment with erythropoietin were started. Blood loss, deficiencies, hemolysis, drug interactions or viral infections were excluded as causes of the anemia. Bone marrow biopsies were carried out, showing pure red cell aplasia that was ascribed to the use of MMF. Cessation or reduction of MMF was followed by a hematological improvement after 5-9 days. We hypothesized that MMF has a broader antiproliferative effect than its proposed lymphocyte-specific effect.

Anti-D immunoglobulin treatment for thrombocytopenia associated with primary antibody deficiency.

AIMS: To review our experience of anti-D immunoglobulin for immune thrombocytopenia (ITP) in patients with primary antibody deficiency. METHODS/PATIENTS: A retrospective case notes review of four Rhesus positive patients with ITP and primary antibody deficiency, treated with anti-D. Patients were refractory to steroids and high dose intravenous immunoglobulin (IVIG). Two patients were previously splenectomised. RESULTS: All patients responded to anti-D immunoglobulin. Improved platelet counts were sustained for at least three months. Side effects included a fall in haemoglobin in all cases; one patient required red blood cell transfusion. Two patients had transient neutropenia (< 1 x 10(9)/litre). CONCLUSION: Anti-D immunoglobulin may be an effective treatment for antibody deficiency associated thrombocytopenia, even after splenectomy. Anti-D immunoglobulin may have considerable clinical advantages in this group of patients, where treatments resulting in further immunosuppression are relatively contraindicated.

Optimising testing for phospholipid antibodies.

AIM: To compare anticardiolipin (ACL) and anti-beta2 glycoprotein 1 (beta2gp1) enzyme linked immunosorbent assays (ELISAs) in the diagnosis of antiphospholipid syndrome (APS) and to incorporate these results into a meta-analysis of published data. METHOD: Three representative commercial ACL ELISAs and an in house beta2gp1 assay were optimised and then assessed on 124 sera from normal donors, patients with infection, or patients with APS. A Medline search was screened for papers meeting defined criteria to conduct a meta-analysis. The performance of the assays used in this study was included. RESULTS: A non-quantitative ACL assay performed at least as well as the anti-beta2gp1 assay in the diagnosis of APS. Meta-analysis confirmed that neither assay is perfect, although the anti-beta2gp1 assay had a higher specificity and lower sensitivity than the ACL assay. CONCLUSIONS: The pooled data suggest that the ACL assay is used to investigate thrombosis without overt underlying pathology and that the improved specificity of the anti-beta2gp1 assay is exploited where infection, connective tissue disease, or atheroma are present.

Flow cytometric immunodissection of the human distal tubule and cortical collecting duct system.

BACKGROUND: In recent years, considerable efforts were drawn to isolate human distal tubule (DT) and collecting duct (CD) cells with more or less success. Here, we present a procedure for isolating human DT cells [thick ascending limb (TAL)/distal convoluted tubule (DCT)] and CD system cells (connecting tubule/initial CD) as separate populations within the same kidney specimen, applying monoclonal antibodies in fluorescence-activated cell sorting (FACS) and culturing them. METHODS: We tested antibodies directed against the DT/CD system antigens, epithelial membrane antigen (EMA) and L1-cell adhesion molecule (L1-CAM). Segmental and subsegmental expressions were first assessed by using morphologic and histotopographic criteria, and by comparing sections with adjacent sections stained for expression of well-defined distal subsegment-specific markers. Immunoreactive cells were further characterized by dual immunostaining using cell type-specific markers. As a second step, cells obtained by collagenase digestion of normal renal cortical tissue were flow sorted following labeling with aforementioned antibodies and cultured. RESULTS: EMA expression was found on all cells present in the DT and in the CD system. Its expression was most abundant in TAL and from thereon decreased gradually along the course of the DT and CD system. Flow sorting of all EMA-expressing cells resulted in identification/isolation of DT and CD system cells as a heterogeneous mixture. Flow sorting of only the most strongly EMA-positive cells allowed purification of DT cells only, mainly TAL cells as shown by Tamm-Horsfall protein expression on> 80% of sorted cells. L1-CAM was expressed in only the CD system, and sorting of all L1-CAM-positive cells allowed> 95% purification of CD system cells (connecting tubule/cortical CD). Primary cultures of DT and CD system cells rapidly developed into confluent monolayers, and retained antigenic and functional properties inherent to their segments of origin. CONCLUSION: Our study presents a procedure for isolating and culturing pure populations of human DT cells and CD system cells as separate populations, using antibodies to the best available markers in FACS.