Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Measurement of Typhi Vi antibodies can be used to assess adaptive immunity in patients with immunodeficiency.

Vaccine-specific antibody responses are essential in the diagnosis of antibody deficiencies. Responses to Pneumovax II are used to assess the response to polysaccharide antigens, but interpretation may be complicated. Typhim Vi® , a polysaccharide vaccine for Salmonella typhoid fever, may be an additional option for assessing humoral responses in patients suspected of having an immunodeficiency. Here we report a UK multi-centre study describing the analytical and clinical performance of a Typhi Vi immunoglobulin (Ig)G enzyme-linked immunosorbent assay (ELISA) calibrated to an affinity-purified Typhi Vi IgG preparation. Intra- and interassay imprecision was low and the assay was linear, between 7·4 and 574 U/ml (slope = 0·99-1·00; R2  > 0·99); 71% of blood donors had undetectable Typhi Vi IgG antibody concentrations. Of those with antibody concentrations  > 7·4 U/ml, the concentration range was 7·7-167 U/ml. In antibody-deficient patients receiving antibody replacement therapy the median Typhi Vi IgG antibody concentrations were  < 25 U/ml. In vaccinated normal healthy volunteers, the median concentration post-vaccination was 107 U/ml (range 31-542 U/ml). Eight of eight patients (100%) had post-vaccination concentration increases of at least threefold and six of eight (75%) of at least 10-fold. In an antibody-deficient population (n = 23), only 30% had post-vaccination concentration increases of at least threefold and 10% of at least 10-fold. The antibody responses to Pneumovax II and Typhim Vi® correlated. We conclude that IgG responses to Typhim Vi® vaccination can be measured using the VaccZyme Salmonella typhi Vi IgG ELISA, and that measurement of these antibodies maybe a useful additional test to accompany Pneumovax II responses for the assessment of antibody deficiencies.

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.

Validation of international consensus equation for acute serum total tryptase in mast cell activation: A perioperative perspective.

There is no standardized method for assessing serum total mast cell tryptase (MCT) in anaphylaxis. The consensus equation (peak MCT should be>1.2× baseline tryptase+2 mg/L) has been proposed to interpret acute MCT in mast cell activation syndrome (MCAS). To validate consensus equation in a perioperative setting analyses of cases of suspected perioperative anaphylaxis during general anaesthesia (GA) were performed. Anaphylaxis was defined as per World Allergy Organisation (WAO) criteria. Timed serial MCT measurements were mapped against the consensus equation and receiver operating characteristic (ROC) curves produced. A total of 82 patients (60 females, mean age 56.5 years±SD17.2) underwent investigation. Sixty (73%) patients fulfilled WAO criteria for anaphylaxis, and 22 patients did not. Aetiology included 59% IgE-mediated anaphylaxis, 2% non-IgE-mediated anaphylaxis, 12% anaphylaxis of unknown cause and 27% deemed non-anaphylaxis. IgE-mediated anaphylaxis included the following: NMBA (35%), antibiotics (46%), chlorhexidine (8%), patent blue dye (8%) and others (8%). An acute MCT with a comparable baseline was available in 71 of 82 (87%) patients (60 anaphylaxis and 11 controls). The median interquartile range (IQR) time from reaction to peak MCT was 1.34 (0.82-2.51) hours. Analyses confirmed that a rise in acute MCT greater than that defined by the equation had a sensitivity, specificity, positive predictive value (PPV) and negative (N) PV of 78%, 91%, 98% and 44%, respectively. The magnitude of increase in acute MCT above the threshold predicted by consensus equation was higher in the anaphylaxis group compared to controls (P=.0001). This equation has a high specificity, PPV with a moderate NPV and sensitivity in perioperative anaphylaxis.

Is there a role for telemedicine in adult allergy services?

Telemedicine refers to the application of telecommunication and information technology (IT) in the delivery of health and clinical care at a distance or remotely and can be broadly considered in two modalities: store-and-forward and real-time interactive services. Preliminary studies have shown promising results in radiology, dermatology, intensive care, diabetes, rheumatology and primary care. However, the evidence is limited and hampered by small sample sizes, paucity of randomized control studies and lack of data relating to cost-effectiveness, health-related quality of life and patient and clinician satisfaction. This review appraises the evidence from studies that have employed telemedicine tools in other disciplines and makes suggestions for its potential applications in specific clinical scenarios in adult allergy services. Possible examples include: triaging patients to determine the need for allergy tests; pre-assessment for specialized treatments such as allergen immunotherapy, follow-up to assess treatment response and side effects; and education in self-management plan including training updates for self-injectable adrenaline and nasal spray use. This approach might improve access for those with limited mobility or living far away from regional centres, as well as bringing convenience and cost savings for the patient and service provider. These potential benefits need to be carefully weighed against evidence of service safety and quality. Keys to success include delineation of appropriate clinical scenarios, patient selection, training, IT support and robust information governance framework. Well-designed prospective studies are needed to evaluate its role.

Anaphylaxis and ethnicity: higher incidence in British South Asians.

BACKGROUND: The incidence of anaphylaxis in South Asians (Indian, Pakistani and Bangladeshi ethnicity) is unknown. Birmingham is a British city with a disproportionately large population of South Asians (22.5%) compared with the rest of the UK (4.9%). The main aims of this study were to determine the incidence and severity of anaphylaxis in this population and to investigate the differences between the South Asian and White populations. METHODS: A retrospective electronic search of emergency department attendances at three hospitals in Birmingham during 2012 was carried out. Wide search terms were used, medical notes were scrutinized, and the World Allergy Organization diagnostic criteria for anaphylaxis were applied. Patients' age, sex, ethnicity and home postal code were collected, reactions were graded by severity, and other relevant details including specialist assessment were extracted. Multivariate analysis was undertaken using 2011 UK census data. RESULTS: Age-, sex- and ethnicity-standardized incidence rate of anaphylaxis was 34.5 per 100 000 person-years. Multivariate logistic regression which controlled for the confounders of age, sex and level of socioeconomic deprivation showed that incidence was higher in the South Asian population (OR 1.48, P = 0.005). Incidence rate in the South Asian population was 58.3 cases per 100 000 person-years compared to 31.5 in the White population. South Asian children were more likely to present with severe anaphylaxis (OR 5.31, P = 0.002). CONCLUSIONS: Incidence of anaphylaxis is significantly higher in British South Asians compared to the white population. British South Asian children are at a greater risk of severe anaphylaxis than White children.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

Retrospective case series analysis of penicillin allergy testing in a UK specialist regional allergy clinic.

INTRODUCTION: Penicillin allergy is the most common drug allergy. Skin testing for the major (PPL) and minor determinants (MDMs) of penicillin offers increased sensitivity and specificity over in vitro testing alone. Following a worldwide absence of reagents, a new kit was licensed in the UK in 2008 (Diater, Spain) and this report evaluates its use in a UK specialist allergy clinic. METHODS: Prospective data on 50 consecutive patients tested with the new reagents were collected. The departmental protocol is adapted from the 2003 EAACI position paper. RESULTS: 14% (7/50) and 12% (6/50) of patients were diagnosed with immediate and non-immediate reactions respectively. The negative predictive value of the PPL and MDM reagents at the neat concentration for an immediate reaction was 93% (true negatives 37, false negatives 3). Two patients experienced systemic reactions to DPT in the absence of demonstrable specific IgE. None of the patients were diagnosed using skin prick testing alone or at lower concentrations of IDT. Five patients were diagnosed at the IDT stage and two at the DPT stage in the absence of demonstrable specific IgE. Six patients were diagnosed with non-immediate reactions, two on IDT alone and four following IDT and DPT. CONCLUSION: The new PPL and MDM determinants offer enhanced sensitivity when evaluating ß-lactam hypersensitivity; however, there are limitations to the current testing regimens. The UK would benefit from local guidelines, which incorporate the new reagents and acknowledge the high amoxicillin prescription rate and the relatively lower specialist-to-patient ratio in this country.

Clinical immunology review series: an approach to desensitization.

Allergen immunotherapy describes the treatment of allergic disease through administration of gradually increasing doses of allergen. This form of immune tolerance induction is now safer, more reliably efficacious and better understood than when it was first formally described in 1911. In this paper the authors aim to summarize the current state of the art in immunotherapy in the treatment of inhalant, venom and drug allergies, with specific reference to its practice in the United Kingdom. A practical approach has been taken, with reference to current evidence and guidelines, including illustrative protocols and vaccine schedules. A number of novel approaches and techniques are likely to change considerably the way in which we select and treat allergy patients in the coming decade, and these advances are previewed.

Wheat dependent exercise induced anaphylaxis: is this an appropriate terminology?

BACKGROUND: The presentation of wheat dependent exercise induced anaphylaxis (WDEIA) can be variable. A high index of clinical suspicion is required to initiate the investigation pathway. Double blind placebo controlled food-exercise challenge is the gold standard investigation but the practicality of this test limits its application. AIM: To critically analyse the symptoms of WDEIA and their correlation with serum specific IgE (sIgE) to romega-5-gliadin. METHODS: 17 patients were tested for serum sIgE to romega-5-gliadin. The clinical response to a diet/exercise intervention protocol was used to assess specificity of a positive sIgE to romega-5-gliadin. Length of time to diagnosis, clinical likelihood scores, exercise intensity involved and the severity of allergic reactions were examined retrospectively. RESULT: 8/10 patients with positive sIgE to romega-5-gliadin had a confirmed diagnosis of WDEIA. Half of the WDEIA patients had a prolonged time lag to diagnosis (32-62 months) and were initially diagnosed with idiopathic anaphylaxis or chronic idiopathic urticaria and angioedema. Only three patients had experienced life threatening symptoms (Mueller grading 4). A close association was observed between requirements of lower exercise intensity to provoke a reaction and diagnostic delay. CONCLUSION: Specific IgE to romega-5-gliadin can provide supportive evidence for WDEIA without the need of a food-exercise challenge. The wheat-exercise association is not obvious in many patients, highlighting the need to consider WDEIA in the differential diagnosis of all patients presenting with idiopathic systemic reactions. The term anaphylaxis may be inappropriate and it is therefore worth considering an alternative terminology such as 'activity dependent wheat allergy' to describe this condition.

Practice of venom immunotherapy in the United Kingdom: a national audit and review of literature.

BACKGROUND: Venom immunotherapy (VIT) is the only effective treatment for prevention of serious allergic reactions to bee and wasp stings in sensitized individuals. However, controversies exist relating to diagnosis, indications for treatment and treatment schedules. We audited current practice of VIT in the United Kingdom to evaluate adherence to international guidelines. METHODS: An online questionnaire was sent to all clinicians practising immunotherapy identified on the British Society of Allergy and Clinical Immunology website. Eighty-six questionnaires were sent and 53 responses (61.6%) were received. Of these, 48 (85%) carried out VIT at their centre. RESULTS: Skin prick tests (SPT) and serum venom-specific IgE (SSIgE) were equally preferred as first-line investigation. Fifty percent of the respondents perform intradermal tests if both SPT and SSIgE are negative. While 8% of respondents commence VIT in patients with negative SSIgE and a history of severe reaction, 57% prefer to repeat the tests in 6-12 months if serum tryptase is elevated. If the insect responsible is uncertain and SSIgE is detected against bee and wasp venoms, 22% of the respondents will desensitize to both while 32% initiate treatment against the venom with the higher SSIgE. A protocol of weekly up-dosing for 12 weeks is preferred for induction and only 25% of respondents have ever used rush or ultra-rush protocols. Three years is thought to be optimum duration of VIT by most (56%). Eleven percent perform sting challenges at the end of treatment. Although 47% measure SSIgE at the end of treatment, only 3% use these results as a basis for discontinuing VIT. CONCLUSION: Currently there is considerable variation in the diagnosis and management of hymenoptera venom allergy in the United Kingdom. This audit has demonstrated that the current international guidelines for the diagnosis and management of hymenoptera venom allergy are not being followed by UK allergy practitioners.

Loss of cytomegalovirus-specific immunological memory in a patient with thymoma.

Cytomegalovirus (CMV) retinitis is a re-activation infection associated with severely impaired T cell-mediated immunity. We describe a patient with long-standing Crohn's disease and thymoma who developed severe CMV retinitis. While thymoma can be associated with impaired humoral immunity and a quantitative CD4+ T helper cell deficiency, these were not evident in our patient. However, more detailed investigation of anti-CMV responses showed absence of specific T cell responses to CMV antigen. Normal CMV seropositive controls have detectable proliferation and interferon-gamma production by T cells in response to stimulation with CMV antigen, but this was absent in this patient both during the acute infection and in convalescence. Other measures of T cell function were normal. Since CMV retinitis is due to reactivation of latent CMV infection, it appears that selective loss of CMV-specific immunity had occurred, perhaps secondary to a thymoma. The causes of thymoma-associated immune impairment are not understood, but this case demonstrates that selective defects can occur in the absence of global T cell impairment. Opportunistic infections should therefore be suspected in patients with thymoma even in the absence of quantitative immune deficiencies.

Investigation for immunodeficiency in patients with recurrent ENT infections.

Patients suffering with primary immunodeficiency frequently present to ear, nose, and throat (ENT) clinics, but the diagnosis is rarely made at this time. Early diagnosis of these patients would help to prevent morbidity and even mortality. Normal results from a simple panel of blood tests will exclude the commonest immune deficiencies. An abnormal result from these tests, or a strong suspicion despite normal initial testing, should prompt discussion with an immunologist.