BSACI guideline for the management of chronic urticaria and angioedema.

This guidance for the management of patients with chronic urticaria and angioedema has been prepared by the Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is aimed at both adult physicians and paediatricians practising in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a Web-based system. Their comments and suggestions were carefully considered by the Standards of Care Committee. Where evidence was lacking, a consensus was reached by the experts on the committee. Included in this management guideline are clinical classification, aetiology, diagnosis, investigations, treatment guidance with special sections on children with urticaria and the use of antihistamines in women who are pregnant or breastfeeding. Finally, we have made recommendations for potential areas of future research.

A randomized controlled trial of postoperative analgesia following total knee replacement: transdermal Fentanyl patches versus patient controlled analgesia (PCA).

BACKGROUND: This randomized controlled trial compared a standard patient controlled analgesic (PCA) regime with a transdermal and oral Fentanyl regime for post-operative pain management in patients undergoing total knee replacement. METHODS: One hundred and ninety-six patients undergoing total knee replacement were recruited. Pre- and post-operatively Visual Analogue Score (VAS), Oxford Knee Score, Health Anxiety and Depression Score and Brief Pain Inventory Score were completed. According to the day 1, VAS score patients were randomly allocated to either a PCA regime or a Fentanyl transdermal/oral regime. Patient reported outcomes were measured until the patients were discharged. RESULTS: The results demonstrate that in terms of analgesic effect, day of discharge and side effect profile the two regimes are comparable. CONCLUSIONS: We conclude that a Fentanyl transdermal regime provides adequate analgesic effect comparable to a standard PCA regime in conjunction with a low side effect profile. Using a transdermal analgesic system provides efficient continuous delivery enabling a smooth transition from hospital to home within the first week. Transdermal Fentanyl provides an alternative analgesic regime that can provide an equivalent analgesic effect so as to enable a satisfactory outcome for the patient in terms of function and pain. LEVEL OF EVIDENCE: II.

NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders.

Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohn's disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence-specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild-type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.

Morphological study of tracheal shape in donkeys with and without tracheal obstruction.

REASON FOR PERFORMING STUDY: There is limited information on the gross tracheal morphology of donkeys with or without tracheal abnormalities. OBJECTIVES: To: 1) examine the morphology of tracheas of donkeys with and without clinical and/or post mortem evidence of tracheal obstruction; 2) record the cross-sectional dimensions and shapes of tracheal rings at fixed sites; and 3) document prevalence, sites and characteristics of detected tracheal abnormalities. METHODS: The tracheas of 75, predominantly aged (median age 30 years, range 7-48 years) donkeys that died or were subjected to euthanasia on humane grounds were examined. Five had severe dyspnoea due to tracheal obstruction (with intercurrent lung disease in 3), while 7 had post mortem evidence of severe tracheal airway obstruction. Every 5th tracheal ring was dissected free and the inner and outer vertical and transverse dimensions and cross sectional areas were measured. Each dissected ring was photographed and the shape of the trachea was classified as normal or, in one of 6 abnormal grades, according to the type and degree of structural abnormality present. RESULTS: The tracheas had a mean of 43 (range 34-50) tracheal rings that tended to be more oval in shape in the distal cervical region. Only 31.2% of rings examined had a circular to oval shape. Dorso-ventral flattening was present in 0.9% of tracheal rings, dorsal ligament separation in 24.4%, slight cartilage deformity in 26.0%, moderate cartilage deformity in 10.4%, marked cartilage deformity in 1.9% and miscellaneous other abnormalities in 4.9% of tracheal rings. The 12 donkeys with ante or post mortem evidence of tracheal obstruction had significantly increased tracheal abnormality grade in comparison to the remaining donkeys. CONCLUSIONS AND POTENTIAL RELEVANCE: Structural tracheal abnormalities are present in most old donkeys, but generally do not cause clinical problems in these sedentary animals unless intercurrent pulmonary disease is present.

Road traffic accidents and diabetes: insulin use does not determine risk.

AIMS: Progressive restrictions placed on insulin-treated patients with diabetes exclude them from driving group 2 and class C1 and D1 vehicles. This reflects an assumption that an increased risk of hypoglycaemia in these patients will cause road traffic accidents. These restrictions have been implemented without any consistent evidence that this is the case. The aim of the study was therefore to investigate whether the rate of road traffic collisions in insulin-treated patients was higher than that of the non-diabetic population using a population register-based study. METHODS: A historical cohort study combined information from the Devon and Cornwall Constabulary database on road traffic collisions with the district wide retinal screening database, to provide an anonymized matched database of road traffic collisions in the diabetic population. Accident rates were calculated in the diabetic population and compared to rates in the non-diabetic population using relative risks. RESULTS: The estimated overall annual accident rate for the non-diabetic population was 1469 per 100,000 vs. 856 per 100,000 for the diabetic population as a whole (Chi-squared, P < 0.001). On stratification of the groups by age, within the insulin-treated group there was no significant difference in the accident rate compared to the non-diabetic population, with relative risks between 0.51 [confidence interval (CI) 0.25-1.05] and 1.13 (CI 0.88-1.46). CONCLUSIONS: Our findings suggest that insulin-treated patients as a group do not pose an increased risk to road safety. They reiterate the need for an individualized risk-based assessment when considering driving restrictions.

The interarm blood pressure difference as predictor of cardiovascular events in patients with hypertension in primary care: cohort study.

Objectives of this study were to measure the prevalence of a difference in blood pressure (BP) between arms and determine whether a difference is associated with increased risk of cardiovascular events or death. A prospective cohort study of 247 patients with hypertension was undertaken in one rural general practice in England. The main outcome measures were mean difference in BP between arms and new episodes of myocardial infarction, cerebrovascular event, onset of angina or peripheral vascular disease or death. A total of 57/247 (23%) patients had a mean difference in systolic BP between arms of >or=10 mm Hg and 8/247 (3%) had a mean difference of >or=20 mm Hg. A total of 15/247 (6%) patients had a mean difference in diastolic BP between arms of >or=10 mm Hg. Survival analysis after 4.7 years (range 3.3-5.9) showed a shorter mean survival time without event or death for patients with a difference in systolic BP of >or=10 mm Hg compared with a difference of <10 mm Hg (3.7 (95% confidence interval, 3.2-4.2) versus 4.8 (4.6-5.1) years; P<0.001; hazard ratio 2.5 (1.5-4.2), P=0.001). Difference in systolic BP of >or=10 mm Hg between arms is common in this primary care population and is associated with a shorter survival time to death or new cardiovascular event. Detection of a difference between arms may identify hypertensive patients at increased risk of cardiovascular events. Such an approach would allow more effective targeting of resources in primary prevention strategies.

Tacrolimus immunosuppression in high-risk corneal grafts.

BACKGROUND: Unlike the immune privilege enjoyed by low-risk corneal grafts, high-risk corneal grafts experience rejection rates comparable to liver and kidney transplants. Systemic immunosuppression reduces the risk of rejection in high-risk corneal grafts. METHODS: Systemic tacrolimus, a specific T cell inhibitor, was used at a mean daily dose of 2.5 mg to immunosuppress 43 patients undergoing high-risk corneal transplantation. Immunosuppression was continued for a period of 18-24 months after the high-risk corneal graft. RESULTS: During a mean follow-up period of 33.7 months, clarity of the graft was maintained in 65% of patients. Eight patients experienced rejection episodes while on tacrolimus, and this led to graft failure in five patients. CONCLUSION: Tacrolimus is relatively safe and effective in reducing rejection and prolonging graft survival in patients with high-risk keratoplasty compared with other series where similar immunosuppression was not used.

Determinants of insulin concentrations in healthy 1-week-old babies in the community: applications of a bloodspot assay.

BACKGROUND: Epidemiological research into insulin secretion and insulin action would be helped by improved ability to measure insulin concentrations in large groups of healthy babies in the neonatal period. Such research is often restricted by the invasive nature of blood sampling. AIMS: We assessed the use of an assay that can measure insulin from bloodspots taken during routine Guthrie testing 7 days after delivery. STUDY DESIGN AND SUBJECTS: Insulin and glucose were measured in 366 seven-day-old infants from heel-prick bloodspots. Time since last feed and type of feed were recorded. RESULTS: Bloodspot insulin concentrations in normal 7-day-old infants were much lower (median (IQR): 15.4 pmol/l (<10-28.5)) than fasting insulin concentrations in adult males (44.3 pmol/l (30.6-72.6)) (p<0.001). Insulin and glucose concentrations were correlated (r=0.33, p<0.001). Insulin and glucose fell significantly with time from feed. Bottle fed infants had higher insulin concentrations but similar glucose concentrations compared to breast fed infants. Detailed analysis to account for confounders was limited due to the skewed distribution of time since feed and the lower limit of the assay leading to non-continuous insulin data. CONCLUSIONS: In the largest study of normal 7-day-old children to date we have shown insulin concentrations are low compared to adults and vary with glucose, time from feed, and type of feed. This validates the use of the bloodspot insulin assay as a potential research tool for large-scale epidemiological studies. However, careful study design would be required in future use to reduce the variation caused by timing and type of feeding and the problem of one third of values being at or below the lower limit of this assay.

The efficacy of sirolimus in the treatment of patients with refractory uveitis.

AIMS: To determine the efficacy of sirolimus in the treatment of patients with severe non-infectious uveitis. METHODS: Eight patients with severe non-infectious uveitis were recruited to an open study. Inclusion criteria were limited to patients whose disease was not controlled with at least two or more separate steroid sparing immunosuppressants (either because of unacceptable side effects or ineffectiveness of the drug) or who required regular doses of corticosteroids either as high dose systemic or orbital floor injections in order to control their disease. Intraocular inflammation, visual acuity, symptoms, corticosteroid burden, drug toxicity, and side effects were monitored. RESULTS: Sirolimus therapy was effective in five of the eight patients, all of whom had their dose of corticosteroids reduced or discontinued. Treatment in three patients was considered a failure as it caused intolerable side effects and/or failed to control the uveitis. Side effects were common and were typically gastrointestinal or cutaneous in nature. The severity of symptoms was dose dependent in most cases and occurred at trough blood levels above 25 ng/ml. CONCLUSION: Sirolimus is an effective and potent immunosuppressive treatment in the majority of patients with non-infectious uveitis and can reduce the need for long term supplementary corticosteroid therapy. Further studies are required to establish the long term efficacy and safety of sirolimus alone or in combination with other steroid sparing immunosuppressants.

Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family.

OBJECTIVE: To determine the clinical spectrum and natural history of the disease "familial Hibernian fever" (FHF). DESIGN: We ascertained the disease status in all 54 living members and 9 deceased members of the extended family and conducted a detailed study of those affected. MATERIAL AND METHODS: All family members with FHF were clinically assessed and investigated fully, including human leukocyte antigen (HLA) typing. Medical records were studied for relevant clinical features, drug therapy, and complications. All previously obtained histologic specimens were reviewed. Three typical case histories are presented. RESULTS: The updated family tree confirmed an autosomal dominant mode of inheritance in 16 living members with FHF. In addition to the febrile attacks, abdominal pain and localized myalgias were almost invariably present. Episodic erythematous patches, conjunctivitis, and unilateral periorbital edema were also notable features. Of 10 affected male family members, 8 had inguinal hernias (in comparison with 1 of 21 unaffected male family members). No association with HLA status was noted. Secondary amyloidosis was found in one affected member. CONCLUSION: The characteristic clinical features and natural history of FHF distinguish it from other periodic fever syndromes. The discovery of amyloidosis related to FHF alters the prognosis associated with this condition and emphasizes the need to search for effective treatment strategies. The high prevalence of inguinal herniation may provide clues about its pathogenesis.

Clinically useful monoclonal antibodies in treatment.

Monoclonal antibodies have been used in clinical diagnosis for many years but it is only now that these agents are being licensed for clinical treatments. This review will focus on UK licensed monoclonal antibodies highlighting their clinical benefits, limitations, and side effects.

Classical complement activation induced by pregnancy: implications for management of connective tissue diseases.

AIMS: To determine the effect of pregnancy on C4d concentrations and to assess whether C4d remains a useful disease activity marker in the management of connective tissue diseases during pregnancy. METHODS: Plasma C3, C4, and C4d concentrations were measured in 83 women at various stages of normal pregnancy and compared with those in 80 non-pregnant controls. RESULTS: C3 concentrations in the pregnant women were significantly raised (p = 0.0001) and the C4 concentrations were reduced (p = 0.0007), and accompanied by a significant increase in C4d (p = 0.0001). The C4d:C4 ratio was higher in the pregnant women (p = 0.0001). CONCLUSIONS: Pregnancy induces activation of the classical complement pathway. C4d concentrations cannot be used to monitor disease activity in patients with connective tissue diseases during pregnancy.

C3 degradation products (C3d) in normal pregnancy.

Plasma C3 degradation products (C3d) were measured in 65 normal pregnancies and compared with those of non-pregnant women. No significant difference was detected between the two groups, although a difference had been previously reported. Plasma C3d estimations give an indication of complement activation and may be used as an indicator of disease activity in patients with systemic lupus erythematosus (SLE), irrespective of pregnancy.

C reactive protein concentrations in neonates: determination by a latex enhanced immunoassay.

A latex enhanced immunoassay on a centrifugal fast analyser was used to compare serum C reactive protein concentrations in maternal and neonatal blood. In the neonate the C reactive protein concentration at birth was less than 1.0 mg/l; the concentration rose slightly during the first two weeks of life. There was no correlation between C reactive protein concentrations in maternal and neonatal sera. No significant difference was found between the C reactive protein concentrations in blood obtained by either heel prick or venepuncture.

Can the rapid semiquantitative estimation of serum C reactive protein be adapted for the management of bacterial infection?

Serum C reactive protein concentrations measured by a laboratory based assay were compared with the semiquantitative results obtained with a visual agglutination method (Well-cotest, CRP kit). Using this agglutination kit, diluting serum 1/10 and 1/20 gave C reactive protein results which could be of more clinical value than those obtained using the 1/2, 1/4, 1/8, and 1/16 dilutions recommended by the manufacturers. The kit was also used on the ward by junior medical staff, who showed that after minimal training reproducible serum C reactive protein results could be obtained.

Complement activation by cellulosic dialysis membranes.

AIMS: To assess the effect of cellulosic dialysis membranes on the production of complement degradation products to determine to the role of the classical pathway. METHOD: Complement activation was studied in 33 patients during a single haemodialysis session using cellulosic membranes. Pre- and post-dialysis plasma EDTA valves of C3, C4, C3dg, C4d and C reactive protein (CRP) were measured. Statistical analysis was done using the Wilcoxon signed rank test. RESULTS: Post-dialysis C4 (p = 0.0003), C3dg (p < 0.0001), and C4d (p = 0.003) concentrations were increased compared with pre-dialysis values. There was no significant change in C3 (p = 0.095) and CRP (p = 0.13) values. Post-dialysis C3dg and C4d concentrations correlated significantly (p = 0.007). IgG, an undialysed molecule, was quantified and post-dialysis valves were significantly higher than those before dialysis (p = 0.0002), indicating a degree of haemoconcentration. To remove this effect, the C3:IgG, C4:IgG, C3dg:IgG, C4d:IgG and CRP:IgG ratios were calculated. Compared with pre-dialysis values, post-dialysis C3dg:IgG and C4d:IgG ratios were increased and C3:IgG decreased significantly. No change was observed in C4:IgG and CRP:IgG ratios. CONCLUSION: This study confirms that significant complement activation takes place following dialysis with cellulosic membranes. This is denoted by an increase in C3dg. This was paralleled by a rise in C4d, implying a contributory role for the classical pathway. Concomitant post-dialysis increases in IgG and C4 indicate a degree of haemoconcentration; but removal of this effect shows that C3dg and C4d are increased following dialysis--suggesting classical, in addition to alternative, pathway activation.

The incidence of decreased red blood cell deformability in sepsis and the association with oxygen free radical damage and multiple-system organ failure.

We studied the incidence of decreased red blood cell deformability (RBCD) in sepsis and the association between decreased RBCD and oxygen free radical generation (as measured by malonyldialdehyde) and the occurrence of multiple-system organ failure (MSOF). Patients were divided into three groups: septic (n = 28), nonseptic (n = 15), and control (n = 5). Serial measurements of deformability index, malonyldialdehyde, and MSOF were made. The deformability index for the septic group (0.23 +/- 0.17) was significantly less than that for the nonseptic (1.12 +/- 0.48) and control (1.11 +/- 0.25) groups. The malonyldialdehyde levels for the septic group (4.5 +/- 1.0 nmol/mL) were significantly greater than those for the nonseptic (2.7 +/- 0.9 nmol/mL) and control (2.6 +/- 0.8 nmol/mL) groups. The MSOF index for the septic group (10.1 +/- 2.5) was significantly greater than that for the nonseptic (7.6 +/- 1.7) and control (6.0 +/- 0.0) groups. An inverse correlation existed between malonyldialdehyde and deformability index ( = .501, less than .001, n = 40) and between deformability index and MSOF index (= .350, less than .05, n = 61). We conclude that RBCD is decreased during human sepsis; free radicals generated during sepsis may play a role in the decrease in RBCD. Decreased RBCD may contribute to the MSOF that occurs during sepsis.

C3 nephritic factor and SLE: report of four cases and review of the literature.

We present four patients with C3 nephritic factor associated with partial lipodystrophy and/or mesangiocapillary glomerulonephritis type II. Each of these patients subsequently developed features of SLE, with an onset between 2 and 24 years after the development of the lipodystrophy or glomerulonephritis. All four patients had antinuclear antibodies and three of the four had anti-Ro antibodies. These patients bring to six the number of reported cases of this association. Possible explanations for the link between these two conditions are discussed.