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

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.

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.

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.

Achievement of immune tolerance in a patient with haemophilia B and inhibitory antibodies, complicated by an anaphylactoid reaction.

We describe a young boy with severe haemophilia B who developed inhibitory antibodies and an anaphylactoid reaction to factor IX. Immune tolerance was achieved by desensitisation with escalating doses of factor IX followed by the Malmö regimen.

Is minocycline therapy in acne associated with antineutrophil cytoplasmic antibody positivity? A cross-sectional study.

BACKGROUND: Minocycline (MN), one of the commonly prescribed therapies for acne, is known to be associated with autoimmune disorders including drug-induced lupus. However, data are sparse regarding the prevalence of autoimmune disease in acne or in patients with acne treated with MN. OBJECTIVES: To establish the prevalence of antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA) and new autoimmune syndromes in an MN-exposed and unexposed population with acne. METHODS: In a cross-sectional study, 252 patients with acne vulgaris were assessed. Sixty-nine per cent had been exposed to MN at some point or were taking the drug at the time of the interview. Data recorded included duration of disease (acne) and drug history as well as possible side-effects of drugs, in particular joint symptoms (pain and swelling). In addition, blood was taken for ANA, ANCA, liver function tests and HLA analysis. RESULTS: There was no statistical difference in the prevalence of ANA positivity between patients exposed (13%) or not exposed (11%) to MN. However, higher titres of ANA (1/160 or higher) were found in the MN-exposed group (45% compared with 12% in the unexposed group). ANCA positivity was found in 7% of the MN-exposed group but no positivity was found in the unexposed cohort (P = 0.022). In 58% of cases, the ANCA detected were of the perinuclear pattern (p-ANCA) with myeloperoxidase specificity, and this finding was associated with clinical symptoms in the majority of cases. Two p-ANCA-positive patients were thought in retrospect to have developed a drug-induced lupus syndrome. CONCLUSIONS: ANA positivity is seen in patients with acne irrespective of exposure to MN; however, p-ANCA appear to be a serological marker for developing autoimmune disease in patients receiving MN.

Defining the T cell antigen proteome of wasp venom.

BACKGROUND: While modulation of T cell function is believed to be important in the successful acquisition of clinical tolerance during venom immunotherapy, little is known of the role of wasp venom specific T cell antigens. OBJECTIVE: We sought comprehensively to characterize the T cell proteome for wasp venom to facilitate the future development of T cell-based immunotherapeutic approaches. METHODS: Using peripheral blood mononuclear cells from wasp venom-allergic individuals and IL-4 ELISPOT analysis, we characterized T cell responses to whole venom and gel filtration/ion exchange-fractionated venom. Reactive fractions were purified and identified using highly sensitive electrospray ion-trap mass spectrometry. RESULTS: Wasp venom-allergic individuals have detectable whole wasp venom-specific T cells directly ex vivo, which show rapid IL-4 effector function. T cell responses to gel filtration/ion exchange fractionated venom were dominated by responses to phospholipase A(1), hyaluronidase and antigen 5. CONCLUSION: Although it is likely that there are many T cell antigens within wasp venom, the main responses are to proteins coincident with the known IgE-binding proteins.

Survey of clinical allergy services provided by clinical immunologists in the UK.

BACKGROUND: The UK National Health Service is failing to meet the need for diagnosis and treatment of allergic disorders, which are common and increasing in prevalence. The House of Commons select committee report on allergy services highlighted the inequalities and urgent need for investment. AIM: To survey the allergy workload provided by clinical immunologists to inform service planning and resource allocation. METHODS: The allergy services performed by clinical immunologists during a 12 month period from 1 April 2003 to 31 March 2004 were surveyed by means of a questionnaire via supra-regional audit groups. RESULTS: The immunology centres surveyed serve 32 million people and offer almost the complete repertoire of a specialised allergy service. There were large variations in clinic capacity, new referrals, appointment duration, and service configuration. Services were largely consultant delivered, but availability of joint clinics with paediatricians and anaesthetists was locally variable. Novel service delivery models utilising nurses and clinical assistants have been developed and merit further investigation. CONCLUSION: Consultant immunologists and trainees currently make a major contribution to the development and provision of specialised allergy services. Consultant immunologists will probably remain key providers of tertiary level allergy care in the UK in the long term (in line with other countries) and will be pivotal in supporting and developing the provision of equitable national access to specialist allergy services in a timely manner. Rapid progress in developing the new specialty of allergy and securing better access to services for patients in the short term will be best served by strengthening the collaborative relationship between allergists and clinical immunologists.