Leptomeningeal disease from melanoma-Poor prognosis despite new therapeutic modalities.

OBJECTIVE: The development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients. METHODS: We performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019. RESULTS: In total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0-91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7-4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4-4.9). CONCLUSIONS: Systemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor.

Outcome of repeat anaesthesia after investigation for perioperative anaphylaxis.

BACKGROUND: Perioperative anaphylaxis (POA) is infrequent, but remains an important and potentially life-threatening complication of general anaesthesia. The diagnostic uncertainty surrounding the investigation of anaesthetic allergy poses numerous challenges. We aimed to inform practice by auditing the outcomes of repeat anaesthesia, after an investigation for previous POA. METHODS: One-hundred and seventy-four subjects were investigated after suspected POA between December 2002 and August 2015. Outcome data were obtained for a total of 70 patients who underwent repeat anaesthesia after investigation in the drug-allergy clinic. RESULTS: Sixty-seven out of the 70 patients studied underwent repeat anaesthesia without further complications. Three individuals experienced a further episode of anaphylaxis. In two cases, incomplete referral information led to the offending drugs being omitted from initial testing. The third was found to have underlying systemic mastocytosis (SM). CONCLUSIONS: In our cohort, the incidence of repeat anaphylaxis after a comprehensive assessment in the drug-allergy clinic for suspected POA was 4%. Important risk factors include the completeness of referral information provided to the assessor and the role of exacerbating disorders, particularly SM.

Enhancing antibiotic stewardship by tackling "spurious" penicillin allergy.

Approximately 90-99% of patients with a label of penicillin allergy (PenA) are not allergic when comprehensively investigated. An inaccurate label of PenA has major public health implications-longer hospital stay, more frequent hospital admissions, greater use of fluoroquinolones, glycopeptides, cephalosporins and other expensive antibiotics resulting in significantly higher costs to the health service and predisposing to Clostridium difficile, methicillin-resistant Staphylococcus aureus infections and vancomycin-resistant enterococcus. We describe lessons learnt from recent studies regarding possible reasons contributing to an inaccurate label of PenA as well as propose a concerted multidisciplinary approach to address this important public health problem. Given the unmet need for allergy services in the UK and several other countries and knowledge gaps regarding PenA amongst healthcare professionals, we describe the potential role for a computerized clinical decision support system to enable non-specialists rapidly identify and de-label "low-risk" hospitalized patients with a label of PenA thereby obviating the need for allergy tests. This approach however needs rigorous evaluation for feasibility, safety, patient and physician acceptability, cost-effectiveness and its compatibility with information technology systems currently employed in the health service.

Progressive multi-focal leucoencephalopathy - driven from rarity to clinical mainstream by iatrogenic immunodeficiency.

Advances in immune-mediated targeted therapies have proved to be a double-edged sword for patients by highlighting the risk of iatrogenic infective complications. This has been exemplified by progressive multi-focal leucoencephalopathy (PML), a hitherto rare devastating viral infection of the brain caused by the neurotrophic JC polyoma virus. While PML achieved prominence during the first two decades of the HIV epidemic, effective anti-retroviral treatment and restitution of T cell function has led to PML being less prominent in this population. HIV infection as a predisposing factor has now been supplanted by T cell immunodeficiency induced by a range of immune-mediated therapies as a major cause of PML. This review focuses on PML in the context of therapeutic immunosuppression and encompasses therapeutic monoclonal antibodies, novel immunomodulatory agents such as Fingolimod and dimethyl fumarate, as well as emerging data on PML in primary immune deficiency.

Three difficult cases: the challenge of autoimmunity, immunodeficiency and recurrent infections in patients with Good syndrome.

Good syndrome (GS) is a rare, adult-acquired primary combined immunodeficiency syndrome arising in the context of previous or current thymoma. Patients with GS frequently develop recurrent sinopulmonary infections and are also at high risk of autoimmune manifestations, including skin conditions such as lichen planus. We report three middle-aged patients with GS complicated by multiple autoimmune and infectious manifestations. The combination of immunodeficiency, autoimmunity and recurrent infections seen in patients with GS continues to present a management challenge, particularly in patients with oral mucosal disease and recurrent candidiasis. Clinicians should be prompted to investigate an underlying immunodeficiency in patients with multiple autoimmune conditions and recurrent sinopulmonary infections.

Intravenous immunoglobulin-induced haemolysis: a case report and review of the literature.

OBJECTIVES: To review the incidence and clinical features of intravenous immunoglobulin (IVIg)-induced haemolysis. BACKGROUND: Haemolysis can be a severe complication of IVIg administration. It is due to the passive transfer of blood group antibodies and may result in significant anaemia and renal failure. METHODS: We report a case of severe IVIg-induced haemolysis; review the data reported to vigilance groups (The Medicines and Healthcare Products Regulatory Agency, European Union Drug Regulatory Authorities, Food and Drug Administration and the Canada Vigilance Centre) between January 1998 and May 2012; and systematically review IVIg-induced haemolysis case reports (between January 1948 and January 2013). RESULTS: Nine hundred-twenty five cases of IVIg-induced haemolysis were identified from a review of cases reported to vigilance groups; 62 case reports were included in the systematic review. The majority of these were due to administration of doses of at least 2 g kg(-1) of IVIg (97%). IVIg-induced haemolysis was reported most commonly for patients with blood group A (65%) or AB (26%). One case report noted that in two patients with IVIg-induced haemolysis both received IVIg from the same batch. CONCLUSION: We make the following recommendations for the management of suspected cases of IVIg-induced haemolysis: Stop IVIg infusion and perform tests for haemolysis. Check titres of anti-blood group antibodies in IVIg. Provide supportive management for patient with fluid and/or red blood cell transfusions if necessary. Consider quarantine of the IVIg batch if found to be high titre for anti-A/B. Report reaction to regulatory/vigilance body.

Impact of national guidelines on reporting anaphylaxis during anaesthesia -- an outcome audit.

AIMS: Anaphylaxis during anaesthesia is a rare and potentially fatal event. Adequate reporting and investigation of anaphylaxis associated with anaesthesia results in improved patient safety and outcomes. Guidelines from the Association of Anaesthetists of Great Britain and Ireland (AAGBI) designed to improve this process were first issued in 1990 and updated in 1995, 2003 and 2008. In a setting where no formal guideline was previously in place, we compared the reporting and investigation of anaphylaxis in a large hospital before and after the introduction of the 2008 guideline. METHODS: A retrospective outcome audit was conducted to compare data from 12 patients referred from April 2006 to May 2008 prior to release of the 2008 AAGBI guidance, with 53 patients referred from 2008 until April 2011. Data were collected using the AAGBI Anaphylaxis Referral Form. RESULTS: There was an increase in the number of referrals for suspected anaphylaxis following implementation of the AAGBI guidance. The clinical features observed in patients were consistent with previous studies. There was improved documentation of referral to local and national databases. Most cases resulted in cancellation of surgery, and there were no patient deaths. A substantial increase in the number of patients with amoxicillin allergy was noted in the second time period, which was linked to a change in the local perioperative antibiotic policy. CONCLUSIONS: Implementation of the AAGBI guidelines locally in a large hospital in 2008 resulted in an improved awareness of the importance of reporting and investigation of suspected anaphylaxis under anaesthesia. This tool was implemented coincidentally with the change in hospital antibiotic prophylaxis and enabled the cases detected to be accurately recorded and investigated. This led to a change in the hospital antibiotic policy for surgical prophylaxis. Implementation of structured guidance from a national anaesthesia organisation enhances recognition of the clinical features of anaphylaxis, increases number and completeness of referrals and more thorough immunological investigation, leading to improved patient safety during anaesthesia.

Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of dysregulated lymphocyte homeostasis. Biomarkers including elevated CD3+TCRαß+CD4-CD8- double negative T cells (TCRαß+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate between ALPS and common variable immunodeficiency (CVID) patients with an overlapping clinical phenotype. We investigated the utility of ALPS biomarkers in 13 CVID patients with lymphoproliferation and/or autoimmune cytopaenia with comparison to 33 healthy controls. Vitamin B12 (P < 0.01) and IL-10 (P < 0.0001), but not sCD95L or TCRαß+ DNT, were increased in CVID compared to controls. The 95th percentile for TCRαß+ DNT in healthy controls was used to define a normal range up to 2.3% of total lymphocytes or 3.4% of T cells. These frequencies lie markedly beyond the cut offs used in current ALPS diagnostic criteria (≥ 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes), suggesting these limits may have poor specificity for ALPS.

IgE-mediated allergy to local anaesthetics: separating fact from perception: a UK perspective.

Local anaesthetic (LA) agents have been routinely used in dentistry, ophthalmology, minor surgery, and obstetrics since the late nineteenth century. Reports relating to adverse reactions and LA allergy have appeared in the published literature for several years. However, the incidence of true, IgE-mediated LA allergy remains uncertain and is presumed to be very low. We critically reviewed the English language literature on suspected LA allergy and its investigation with the aim of estimating the reported prevalence and analysing the role of different tests currently used to identify and confirm LA allergy. Twenty-three case series involving 2978 patients were identified and analysed. Twenty-nine of these patients had true IgE-mediated allergy to LA, thus confirming the reported prevalence of LA allergy in large series to be <1% (0.97%). The protocols used in the investigation of these patients have also been discussed. Evidence from this review confirms the rarity of IgE-mediated allergy to LA and supports an investigation strategy based on using the clinical history to select patients for skin testing and challenge. We believe that such a triage process would alleviate pressures on allergy services without compromising patient safety.

Recommended indications for the administration of polyclonal immunoglobulin preparations.

The following recommendations, which aim at standardising and rationalising the clinical indications for administering polyclonal immunoglobulins in Belgium, were drawn up by a working group of the Superior Health Council. To this end, the Superior Health Council organised an expert meeting devoted to"Guidelines for the use of immunoglobulins". The experts discussed the indications for immunoglobulin use, the'ideal'immunoglobulin preparation, its mechanisms of action, the practical issues involved in administering immunoglobulins and their potential side effects. The recommendations formulated by the experts were validated by the Superior Health Council working group with the purpose of harmonising immunoglobulin use in Belgium

Bringing immunoglobulin knowledge up to date: how should we treat today?

Immunoglobulin (Ig) therapy is constantly evolving. Advances in the basic and clinical science of immunoglobulins have provided new perspectives in using polyclonal IgG to treat patients with primary immunodeficiencies. Recent meta-analyses of patient data and outcomes, optimization of IgG administration and better understanding of the IgG receptor variability and clinical effect are new concepts which practising immunologists can use in tailoring their approach to treating patients with primary immunodeficiencies. This manuscript presents the proceedings of a satellite symposium, held in conjunction with the European Society for Immunodeficiencies (ESID) 2010 meeting, to inform attendees about new scientific concepts in IgG therapy, with the goal of empowering expert level evaluation of what optimal IgG therapy is today.

Common filaggrin null alleles are not associated with hymenoptera venom allergy in Europeans.

The association of filaggrin mutations with atopic eczema (atopic dermatitis, AD) is well established and it is thought that filaggrin dysfunction impairs the skin's barrier function allowing allergen penetration and subsequent cutaneous sensitisation and inflammation. However, as most forms of barrier dysfunction are not associated with allergic sensitisation to common allergens, the possibility that filaggrin itself is involved in Th1/Th2 polarisation remains. We tested the hypothesis that allergen delivered to the skin independently of the stratum corneum is not associated with filaggrin mutations. Wasp stings bypass the stratum corneum and deliver antigen to the dermis. We found that European individuals with AD (n = 32) have an increased frequency of the 2 commonest filaggrin null mutations (R501X and 2282del4) compared to those with vespid allergy (n = 56) and healthy controls (n = 30). Thus, filaggrin does not appear to have a downstream effect on the development of allergic disease, and it is indeed filaggrin's role in the epithelial function that is likely to determine the link between filaggrin mutations and allergic sensitisation.

Does a gating policy for ANCA overlook patients with ANCA associated vasculitis? An audit of 263 patients.

BACKGROUND: Antineutrophil cytoplasm antibodies (ANCA) are used as diagnostic markers for small-vessel vasculitis of the Wegener Granulomatosis-microscopic polyangiitis (WG-MPA) spectrum, but if testing is applied indiscriminately, its value is diminished. The authors measured the effect of a targeted ANCA testing policy introduced in our institution in an attempt to improve the diagnostic value of testing in patients with suspected vasculitis. METHODS: The authors measured the rate of ANCA requests at a single regional centre in the year prior to and following the introduction of clinical guidelines to ensure appropriate test usage. The authors also audited clinical outcomes in patients in whom ANCA testing was declined. RESULT: Following implementation of the antineutrophil cytoplasm antibodies (ANCA) gating policy, the number of monthly ANCA tests carried out fell from 287+/-30 to 143+/-18 (p<0.0001) and was associated with an increased rate of positivity, from 18.5% (95% CI 17.0 to 20.1%) to 30.3% (27.5 to 33.1%; p<0.0001). The authors undertook a careful review of the case records from 263 patients in whom testing was declined according to the gating policy over an 8-month period. After 6 months' follow-up, no diagnoses of small-vessel vasculitis of the WG-MPA spectrum were reached. CONCLUSIONS: The rational use of ANCA testing to aid in the diagnosis of vasculitis should include a clinical gating policy to improve diagnostic performance. Adherence to a gating policy for ANCA testing coupled with close liaison between clinician and laboratory does not result in either a missed or delayed diagnosis of small-vessel vasculitis belonging to the WG-MPA spectrum.

Lipoprotein-associated phospholipase A2 mass is significantly reduced in dyslipidemic patients treated with lifestyle modification and combination lipid-modifying drug therapy.

Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil, extended-release niacin, colesevelam hydrochloride, and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin. The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol.

An approach to the diagnosis and management of systemic vasculitis.

The systemic vasculitides are a complex and often serious group of disorders which, while uncommon, require careful management in order to ensure optimal outcome. In most cases there is no known cause. Multi-system disease is likely to be fatal without judicious use of immunosuppression. A prompt diagnosis is necessary to preserve organ function. Comprehensive and repeated disease assessment is a necessary basis for planning therapy and modification of treatment protocols according to response. Therapies typically include glucocorticoids and, especially for small and medium vessel vasculitis, an effective immunosuppressive agent. Cyclophosphamide is currently the standard therapy for small vessel multi-system vasculitis, but other agents are now being evaluated in large randomized trials. Comorbidity is common in patients with vasculitis, including the cumulative effects of potentially toxic therapy. Long-term evaluation of patients is important in order to detect and manage relapses.

Efficacy of combination drug pulse therapy in maintaining lipid levels in patients intolerant of daily statin use.

The objective of this study was to evaluate the efficacy of combination drug pulse therapy in maintaining lipid levels in patients intolerant of a daily dose of statins. Twenty-three patients, previously receiving aggressive statin therapy, were treated twice weekly with rosuvastatin or atorvastatin in different dosages along with ezetimibe as well as daily doses of bile acid sequestrant for a mean period of 4.5 months. The recommended National Cholesterol Education Program Adult Treatment Panel III goals had already been achieved in 78% of patients (n=18) before starting combination pulse therapy. This combination therapy significantly increased high-density lipoprotein cholesterol values by 5.82% (t=2.138, P=.044), while the increases in total cholesterol, low-density lipoprotein cholesterol, triglyceride, and apolipoprotein B levels compared with baseline were not statistically significant. Overall, 3 of 23 patients (13%) discontinued the combination therapy because of muscle-related symptoms over a mean course of 4.5 months of treatment.

Subcutaneous immunoglobulin: opportunities and outlook.

Immunoglobulin (Ig) administration via the subcutaneous (s.c.) route has become increasingly popular in recent years. The method does not require venous access, is associated with few systemic side effects and has been reported to improve patients' quality of life. One current limitation to its use is the large volumes which need to be administered. Due to the inability of tissue to accept such large volumes, frequent administration at multiple sites is necessary. Most studies conducted to date have investigated the use of subcutaneous immunoglobulin (SCIg) in patients treated previously with the intravenous (i.v.) formulation. New data now support the use of s.c. administration in previously untreated patients with primary immunodeficiencies. SCIg treatment may further be beneficial in the treatment of autoimmune neurological conditions, such as multi-focal motor neuropathy; however, controlled trials directly comparing the s.c. and i.v. routes are still to be performed for this indication. New developments may further improve and facilitate the s.c. administration route. For example, hyaluronidase-facilitated administration increases the bioavailability of SCIg, and may allow for the administration of larger volumes at a single site. Alternatively, more concentrated formulations may reduce the volume required for administration, and a rapid-push technique may allow for shorter administration times. As these developments translate into clinical practice, more physicians and patients may choose the s.c. administration route in the future.

An 'n-of-1' placebo-controlled crossover trial of intravenous immunoglobulin as adjuvant therapy in refractory pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is an organ-specific autoimmune blistering mucocutaneous disorder that is potentially fatal. High-dose intravenous immunoglobulin (IVIg) is increasingly used in the treatment of autoimmune diseases and it has been reported that it may also be effective in PV. OBJECTIVES: To evaluate prospectively the efficacy of IVIg for PV using an 'n-of-1' placebo-controlled trial. METHODS: A randomized, placebo-controlled, crossover trial of IVIg was conducted in a single patient with severe PV, comprising two phases of six consecutive months of either IVIg or placebo infusion. Before the commencement of the trial, the patient had received 18 months of IVIg but concerns about the continuing therapeutic efficacy of IVIg led to the double-blind placebo-controlled 'n-of-1' trial of IVIg. RESULTS: Pemphigus autoantibody titres were significantly higher when on placebo compared with IVIg treatment (median 1 : 80 vs. 1 : 20, P = 0.007), desmoglein 3 (126 vs. 79, P = 0.004) and desmoglein 1 antibody levels (126 vs. 94, P = 0.004). There was a significant improvement in subjective disease activity scores while on IVIg compared with placebo (mean overall score 11.6 vs. 20.6, P < 0.0001). CONCLUSIONS: The results of this study confirm a beneficial effect of IVIg in the management of refractory PV.