Simon G. A. Brown

Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation

Objectives: To assess a protocol for treatment of sting anaphylaxis. Design: Prospective assessment of treatment with oxygen, intravenous infusion of adrenaline (epinephrine), and volume resuscitation with normal saline. Setting: Sub-study of a venom immunotherapy trial. Participants: 21 otherwise healthy adults with systemic allergic reactions to diagnostic sting challenge. Main outcome measures: Response to treatment, total adrenaline dose and infusion duration, recurrence of symptoms after stopping the infusion, and additional volume resuscitation. Results: 19 participants required intervention according to the protocol. All received adrenaline, and five received volume resuscitation. In nine cases, physical signs of anaphylaxis recurred after initial attempts at stopping adrenaline but resolved after recommencing the infusion. The median total dose and infusion duration were 590 μg and 115 minutes respectively, but were significantly higher for eight patients who had hypotensive reactions (762 μg and 169 minutes respectively). Hypotension was always accompanied by a relative bradycardia, which was severe and treated with atropine in two patients. Widespread T wave inversion occurred, before starting treatment with adrenaline, in one person with an otherwise mild reaction. All patients fully recovered and were fit for same day discharge, apart from the person with ECG changes who was observed overnight and discharged the following day. Conclusions: Carefully titrated intravenous adrenaline combined with volume resuscitation is an effective strategy for treating sting anaphylaxis, however severe bradycardia may benefit from additional treatment with atropine. Cardiac effects of anaphylaxis, perhaps including neurocardiogenic mechanisms, may be an important factor in some lethal reactions.

2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines

The World Allergy Organization (WAO) Guidelines for the assessment and management of anaphylaxis provide a unique global perspective on this increasingly common, potentially life-threatening disease. Recommendations made in the original WAO Anaphylaxis Guidelines remain clinically valid and relevant, and are a widely accessed and frequently cited resource. In this 2015 update of the evidence supporting recommendations in the Guidelines, new information based on anaphylaxis publications from January 2014 through mid- 2015 is summarized. Advances in epidemiology, diagnosis, and management in healthcare and community settings are highlighted. Additionally, new information about patient factors that increase the risk of severe and/or fatal anaphylaxis and patient co-factors that amplify anaphylactic episodes is presented and new information about anaphylaxis triggers and confirmation of triggers to facilitate specific trigger avoidance and immunomodulation is reviewed. The update includes tables summarizing important advances in anaphylaxis research.

H1‐antihistamines for the treatment of anaphylaxis: Cochrane systematic review

Background:  Anaphylaxis is an acute systemic allergic reaction, which can be life‐threatening. H1‐antihistamines are commonly used as an adjuvant therapy in the treatment of anaphylaxis. We sought to assess the benefits and harm of H1‐antihistamines in the treatment of anaphylaxis.

Adrenaline for the treatment of anaphylaxis: cochrane systematic review

Background:  Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Adrenaline is recommended as the initial treatment of choice for anaphylaxis.

Cardiovascular aspects of anaphylaxis: implications for treatment and diagnosis.

Purpose of reviewAnaphylactic cardiovascular collapse can be resistant to treatment with epinephrine (adrenaline) and, in some cases, diagnostic uncertainty compromises follow-up care. The purpose of this review is to examine recent studies relevant to the management and diagnosis of this condition. Recent findingsNausea, vomiting, incontinence, diaphoresis, dyspnoea, hypoxia, dizziness and collapse are associated with hypotension. Relative bradycardia (falling heart rate despite hypotension) is a consistent feature of hypotensive insect sting anaphylaxis and may represent a non-specific physiological response to severe hypovolaemia in conscious individuals. Upright posture has been found to be associated with death from anaphylaxis. Animal studies have found the intramuscular route for epinephrine is ineffective, intravenous boluses temporarily effective, but intravenous infusions of epinephrine are able to reverse anaphylactic shock. In one animal model, antihistamines were found to be harmful. A prospective human study provides evidence for the efficacy of treatment with intravenous epinephrine infusion and fluid (volume) resuscitation. Case reports support the use of the vasoconstrictors metaraminol, methoxamine and vasopressin if adrenaline is ineffective. Repeated measurements of mast cell tryptase are more sensitive and specific than a single measurement for the diagnosis of anaphylaxis. SummaryCurrent evidence supports use of the supine/Trendelenburg position, epinephrine by intravenous infusion and aggressive volume resuscitation. If these fail, atropine should be considered for severe bradycardia and potent vasoconstrictors may be useful. To confirm the diagnosis of anaphylaxis, serial measurements of mast cell tryptase may be preferable to a single measurement.

Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study.

CONTEXT There are limited published data characterizing severe hypoglycemia complicating type 2 diabetes. OBJECTIVE The objective of the study was to determine the incidence and predictors of severe hypoglycemia in community-dwelling type 2 patients. DESIGN This was a longitudinal observational cohort study. SETTING This was a community-based study. PATIENTS There were 616 patients (mean age 67.0 yr, 52.3% males, median diabetes duration 7.7 yr) assessed in 1998 and followed up to the end of June 2006. MAIN OUTCOME MEASURES Severe hypoglycemia defined as that requiring ambulance attendance, emergency department services, and/or hospitalization. Cox proportional hazards modeling was used to determine predictors of first episode, and Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial regression models identified predictors of frequency. RESULTS Fifty-two (8.4%) experienced 66 episodes during 3953 patient-years (incidence 1.7 per 100 patient-years). Those experiencing severe hypoglycemia had one to four episodes. Significant independent predictors of time to first episode were duration of insulin treatment, estimated glomerular filtration rate less than 60 ml/min per 1.73 m(2), peripheral neuropathy, education beyond primary level, and past severe hypoglycemia. The zero-inflated negative binomial provided the best model of severe hypoglycemia frequency. Lower fasting serum glucose and higher glycosylated hemoglobin were significantly associated with frequency, whereas patients at minimal risk of repeated severe hypoglycemia were unlikely to use insulin or to have short-duration insulin treatment, to have renal impairment or peripheral neuropathy, or to be educated beyond primary level. CONCLUSIONS Duration of insulin treatment was confirmed as an independent risk factor for severe hypoglycemia. The novel association with educational attainment suggests knowledge-driven intensive glycemic self-management. The positive relationship between frequency and glycosylated hemoglobin may identify patients with unstable glycemic control.

Anaphylaxis: clinical patterns, mediator release, and severity.

BACKGROUND Prospective human studies of anaphylaxis and its mechanisms have been limited, with few severe cases or examining only 1 or 2 mediators. OBJECTIVES We wanted to define the clinical patterns of anaphylaxis and relationships between mediators and severity. METHODS Data were collected during treatment and before discharge. Serial blood samples were taken for assays of mast cell tryptase, histamine, anaphylatoxins (C3a, C4a, C5a), cytokines (IL-2, IL-6, IL-10), soluble tumor necrosis factor receptor I, and platelet activating factor acetyl hydrolase. Principal component analysis defined mediator patterns, and logistic regression identified risk factors and mediator patterns associated with reaction severity and delayed reactions. RESULTS Of 412 reactions in 402 people, 315 met the definition for anaphylaxis by the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network. Of 97 severe reactions 45 (46%) were hypotensive, 23 (24%) were hypoxemic, and 29 (30%) were mixed. One patient died. Severe reactions were associated with older age, pre-existing lung disease, and drug causation. Delayed deteriorations treated with epinephrine occurred in 29 of 315 anaphylaxis cases (9.2%) and were more common after hypotensive reactions and with pre-existing lung disease. Twenty-two of the 29 delayed deteriorations (76%) occurred within 4 hours of initial epinephrine treatment. Of the remaining 7 cases, 2 were severe and occurred after initially severe reactions, within 10 hours. All mediators were associated with severity, and 1 group (mast cell tryptase, histamine, IL-6, IL-10, and tumor necrosis factor receptor I) was also associated with delayed deteriorations. Low platelet activating factor acetyl hydrolase activity was associated with severe reactions. CONCLUSION The results suggest that multiple inflammatory pathways drive reaction severity and support recommendations for safe observation periods after initial treatment.

Ant venom immunotherapy: a double-blind, placebo-controlled, crossover trial

BACKGROUND The jack jumper ant Myrmecia pilosula is responsible for about 90% of ant venom anaphylaxis in southeastern Australia. We aimed to establish whether M pilosula venom immunotherapy (VIT) prevents lifethreatening sting anaphylaxis in otherwise healthy adults. METHODS We did a double-blind, placebo-controlled crossover trial of M pilosula VIT. Participants were randomly allocated either immunotherapy, in accordance with the semirush hyposensitisation regimen, or placebo. The primary endpoint was systemic reaction after a deliberate sting challenge. Analysis was per protocol. FINDINGS We randomly allocated 68 healthy volunteers (aged 20-63 years) who were allergic to M pilosula venom to placebo (33) and VIT (35). Four on placebo were stopped early and 12 on VIT had their treatment allocations revealed before the sting challenge, thus 29 on placebo and 23 on VIT were included in the primary analysis. Objectively defined systemic reactions to sting challenges arose in 21 of 29 participants (72%) on placebo (8 reactions were associated with hypotension) and none of 23 on VIT (p<0.0001). Of the remaining 12 on VIT who underwent sting challenges after treatment allocations were revealed, only one reacted to sting challenge with transient urticaria that did not require treatment. After crossover of the placebo group to VIT, one of 26 had a reaction to sting challenge (transient urticaria). In all patients who had VIT, we recorded objective systemic reactions in 22 of 64 (34%) during VIT; two of which were hypotensive. INTERPRETATION In well motivated, highly allergic, but otherwise healthy adults, VIT is highly effective in prevention of M pilosula sting anaphylaxis. The risk of systemic reactions during VIT means that treatment should be given where there is immediate access to resuscitation facilities.

Elevated serum cytokines during human anaphylaxis: Identification of potential mediators of acute allergic reactions

BACKGROUND Anaphylaxis is generally unanticipated and requires emergency management. Therefore, the biological mediators in human beings have been difficult to define. OBJECTIVE Our aim was to identify cytokines and chemokines whose concentrations increase during anaphylaxis in human beings and to determine how each correlates with severity. METHODS We measured the concentrations of potential mediators, including cytokines, chemokines, mast cell tryptase (MCT), and histamine, over 3 time points in 76 patients presenting to emergency departments with anaphylaxis and correlated these with a global severity scale, hypotension, and hypoxia. RESULTS IL-2, IL-6, IL-10, TNF receptor I, MCT, and histamine were significantly elevated in patients with severe reactions (n = 36) compared with moderate reactions (n = 40) and healthy controls. Histamine levels peaked at emergency department arrival, whereas other mediators peaked later. IL-4, IL-5, IL-13, IFN-gamma, and TNF-alpha were marginally elevated in severe reactions compared with healthy controls but did not correlate with reaction severity. Severe reactions tended to be either hypotensive (n = 19) or hypoxemic (n = 12). Levels of IL-6, IL-10, TNF receptor I, MCT, and histamine correlated with hypotension. No mediator correlated with hypoxemia or other respiratory features. CONCLUSION This study confirms that the concentrations of a number of cytokines are elevated in blood during anaphylaxis in human beings and that some correlate with the presence of hypotension. Others were only marginally elevated within a concentration range that available assays do not reliably detect. During respiratory reactions, mediators may be largely confined to the airways so that blood concentrations do not reflect activity.

Influenza vaccine effectiveness against hospitalisation with confirmed influenza in the 2010-11 seasons: a test-negative observational study.

Immunisation programs are designed to reduce serious morbidity and mortality from influenza, but most evidence supporting the effectiveness of this intervention has focused on disease in the community or in primary care settings. We aimed to examine the effectiveness of influenza vaccination against hospitalisation with confirmed influenza. We compared influenza vaccination status in patients hospitalised with PCR-confirmed influenza with patients hospitalised with influenza-negative respiratory infections in an Australian sentinel surveillance system. Vaccine effectiveness was estimated from the odds ratio of vaccination in cases and controls. We performed both simple multivariate regression and a stratified analysis based on propensity score of vaccination. Vaccination status was ascertained in 333 of 598 patients with confirmed influenza and 785 of 1384 test-negative patients. Overall estimated crude vaccine effectiveness was 57% (41%, 68%). After adjusting for age, chronic comorbidities and pregnancy status, the estimated vaccine effectiveness was 37% (95% CI: 12%, 55%). In an analysis accounting for a propensity score for vaccination, the estimated vaccine effectiveness was 48.3% (95% CI: 30.0, 61.8%). Influenza vaccination was moderately protective against hospitalisation with influenza in the 2010 and 2011 seasons.