F. Estelle R. Simons

World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis

The illustrated World Allergy Organization (WAO) Anaphylaxis Guidelines were created in response to absence of global guidelines for anaphylaxis. Uniquely, before they were developed, lack of worldwide availability of essentials for the diagnosis and treatment of anaphylaxis was documented. They incorporate contributions from more than 100 allergy/immunology specialists on 6 continents. Recommendations are based on the best evidence available, supported by references published to the end of December 2010.The Guidelines review patient risk factors for severe or fatal anaphylaxis, co-factors that amplify anaphylaxis, and anaphylaxis in vulnerable patients, including pregnant women, infants, the elderly, and those with cardiovascular disease. They focus on the supreme importance of making a prompt clinical diagnosis and on the basic initial treatment that is urgently needed and should be possible even in a low resource environment. This involves having a written emergency protocol and rehearsing it regularly; then, as soon as anaphylaxis is diagnosed, promptly and simultaneously calling for help, injecting epinephrine (adrenaline) intramuscularly, and placing the patient on the back or in a position of comfort with the lower extremities elevated. When indicated, additional critically important steps include administering supplemental oxygen and maintaining the airway, establishing intravenous access and giving fluid resuscitation, and initiating cardiopulmonary resuscitation with continuous chest compressions. Vital signs and cardiorespiratory status should be monitored frequently and regularly (preferably, continuously).The Guidelines briefly review management of anaphylaxis refractory to basic initial treatment. They also emphasize preparation of the patient for self-treatment of anaphylaxis recurrences in the community, confirmation of anaphylaxis triggers, and prevention of recurrences through trigger avoidance and immunomodulation. Novel strategies for dissemination and implementation are summarized. A global agenda for anaphylaxis research is proposed.

World Allergy Organization anaphylaxis guidelines: Summary

The uniqueWorld Allergy Organization (WAO) Guidelines for the Assessment and Management of Anaphylaxis were created in response to the absence of global guidelines for anaphylaxis. They were developed after documenting that essential medications, supplies, and equipment for assessment andmanagement of anaphylaxis are not universally available worldwide. Additionally, they were developed with the awareness that any health care professional might, at some time, have to assess and manage anaphylaxis in a low-resource environment, whether this be a country, a region, or a specific location, such as an aircraft cabin or a remote area. They incorporate contributions frommore than 100 allergy/immunology specialists on 6 continents received through the WAO member societies and the WAO Board of Directors. In order to transcend language barriers, the principles of anaphylaxis assessment and management set forth in the guidelines are summarized in 5 comprehensive illustrations. The guidelines review patients’ risk factors for severe or fatal anaphylaxis, cofactors that amplify anaphylaxis, and anaphylaxis in vulnerable patients, such as pregnant women, infants, and the

Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis.

BACKGROUND Platelet-activating factor (PAF) is an important mediator of anaphylaxis in animals, and interventions that block PAF prevent fatal anaphylaxis. The roles of PAF and PAF acetylhydrolase, the enzyme that inactivates PAF, in anaphylaxis in humans have not been reported. METHODS We measured serum PAF levels and PAF acetylhydrolase activity in 41 patients with anaphylaxis and in 23 control patients. Serum PAF acetylhydrolase activity was also measured in 9 patients with peanut allergy who had fatal anaphylaxis and compared with that in 26 nonallergic pediatric control patients, 49 nonallergic adult control patients, 63 children with mild peanut allergy, 24 patients with nonfatal anaphylaxis, 10 children who died of nonanaphylactic causes, 15 children with life-threatening asthma, and 19 children with non-life-threatening asthma. RESULTS Mean (+/-SD) serum PAF levels were significantly higher in patients with anaphylaxis (805+/-595 pg per milliliter) than in patients in the control groups (127+/-104 pg per milliliter, P<0.001 after log transformation) and were correlated with the severity of anaphylaxis. The proportion of subjects with elevated PAF levels increased from 4% in the control groups to 20% in the group with grade 1 anaphylaxis, 71% in the group with grade 2 anaphylaxis, and 100% in the group with grade 3 anaphylaxis (P<0.001). There was an inverse correlation between PAF levels and PAF acetylhydrolase activity (P<0.001). The proportion of patients with low PAF acetylhydrolase values increased with the severity of anaphylaxis (P<0.001 for all comparisons). Serum PAF acetylhydrolase activity was significantly lower in patients with fatal peanut anaphylaxis than in control patients (P values <0.001 for all comparisons). CONCLUSIONS Serum PAF levels were directly correlated and serum PAF acetylhydrolase activity was inversely correlated with the severity of anaphylaxis. PAF acetylhydrolase activity was significantly lower in patients with fatal anaphylactic reactions to peanuts than in patients in any of the control groups. Failure of PAF acetylhydrolase to inactivate PAF may contribute to the severity of anaphylaxis.

Epinephrine absorption in children with a history of anaphylaxis

BACKGROUND Prompt injection of epinephrine is the cornerstone of systemic anaphylaxis treatment. The rate of epinephrine absorption has not been reported previously in allergic children. OBJECTIVE Our objective was to study the clinical pharmacology of epinephrine in this population. METHODS We performed a prospective, randomized, blinded, parallel-group study in 17 children with a history of anaphylaxis to food, Hymenoptera venom, or other substances. We injected 0.01 ml/kg epinephrine solution (maximum 0.3 ml [0.3 mg]) subcutaneously, or 0.3 mg epinephrine intramuscularly from an autoinjector. Plasma epinephrine concentrations, heart rate, blood pressure, and adverse effects were monitored. RESULTS In nine children who received epinephrine subcutaneously, the mean maximum plasma epinephrine concentration (+/- SEM) was 1802 +/- 214 pg/ml, achieved at a mean time of 34 +/- 14 minutes (range, 5 to 120 minutes). Only two of the nine children achieved maximum plasma concentrations by 5 minutes. In eight children who received epinephrine intramuscularly, the mean maximum plasma concentration was 2136 +/- 351 pg/ml, achieved at a mean time of 8 +/- 2 minutes, which was significantly faster than the mean time at which maximum plasma concentrations were achieved after subcutaneous epinephrine injection (p < 0.05). Six of the eight children achieved maximum plasma concentrations by 5 minutes. The terminal elimination half-life was 43 +/- 15 minutes. No serious adverse effects were noted in any child. CONCLUSIONS In children, recommendations for subcutaneous epinephrine injection are based on anecdotal experience, and should be reevaluated in view of our finding of delayed epinephrine absorption when this route is used. This delay might have important clinical implications during an episode of systemic anaphylaxis. The intramuscular route of injection is preferable.

Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group.

OBJECTIVE To improve understanding of the epidemiology of anaphylaxis. DATA SOURCES We performed a qualitative review by hand of the major epidemiology studies of anaphylaxis. This review was restricted to articles in the English language. STUDY SELECTION Articles chosen were selected by the committee and dated back to 1968. There was no specific criterion used for selection except the determination of the members of the committee. RESULTS Data on anaphylaxis incidence and prevalence are sparse and often imprecise. Findings are based on diverse study designs and are not entirely comparable. These factors have contributed to widely varying estimates of the frequency of this important condition. The roundtable discussion led to an improved estimation of the frequency of anaphylaxis: approximately 50 to 2,000 episodes per 100,000 persons or a lifetime prevalence of 0.05% to 2.0%. The largest number of incident cases is among children and adolescents. In addition to underdiagnosis, we noted undertreatment, especially for those at highest risk (ie, those without immediate access to treatment with epinephrine). CONCLUSIONS Anaphylaxis is a relatively common problem, affecting up to 2% of the population. Further data on epinephrine dispensing could improve current estimates. Another way to improve current understanding would be through better population-based study designs in different geographic regions. A recurring theme was the importance of broader access to self-injectable epinephrine for high-risk populations. An improved epidemiologic understanding of this disorder would aid ongoing efforts to reduce morbidity and mortality from anaphylaxis and could provide important clues for primary prevention.

Histamine and H1-antihistamines: Celebrating a century of progress

In this review we celebrate a century of progress since the initial description of the physiologic and pathologic roles of histamine and 70 years of progress since the introduction of H(1)-antihistamines for clinical use. We discuss histamine and clinically relevant information about the molecular mechanisms of action of H(1)-antihistamines as inverse agonists (not antagonists or blockers) with immunoregulatory effects. Unlike first (old)-generation H(1)-antihistamines introduced from 1942 to the mid-1980s, most of the second (new)-generation H(1)-antihistamines introduced subsequently have been investigated extensively with regard to clinical pharmacology, efficacy, and safety; moreover, they are relatively free from adverse effects and not causally linked with fatalities after overdose. Important advances include improved nasal and ophthalmic H(1)-antihistamines with rapid onset of action (in minutes) for allergic rhinitis and allergic conjunctivitis treatment, respectively, and effective and safe use of high (up to 4-fold) doses of oral second-generation H(1)-antihistamines for chronic urticaria treatment. New H(1)-antihistamines introduced for clinical use include oral formulations (bilastine and rupatadine), and ophthalmic formulations (alcaftadine and bepotastine). Clinical studies of H(3)-antihistamines with enhanced decongestant effects have been conducted in patients with allergic rhinitis. Additional novel compounds being studied include H(4)-antihistamines with anti-inflammatory effects in allergic rhinitis, atopic dermatitis, and other diseases. Antihistamines have a storied past and a promising future.

International consensus on (ICON) anaphylaxis

ICON: Anaphylaxis provides a unique perspective on the principal evidence-based anaphylaxis guidelines developed and published independently from 2010 through 2014 by four allergy/immunology organizations. These guidelines concur with regard to the clinical features that indicate a likely diagnosis of anaphylaxis -- a life-threatening generalized or systemic allergic or hypersensitivity reaction.They also concur about prompt initial treatment with intramuscular injection of epinephrine (adrenaline) in the mid-outer thigh, positioning the patient supine (semi-reclining if dyspneic or vomiting), calling for help, and when indicated, providing supplemental oxygen, intravenous fluid resuscitation and cardiopulmonary resuscitation, along with concomitant monitoring of vital signs and oxygenation. Additionally, they concur that H1-antihistamines, H2-antihistamines, and glucocorticoids are not initial medications of choice.For self-management of patients at risk of anaphylaxis in community settings, they recommend carrying epinephrine auto-injectors and personalized emergency action plans, as well as follow-up with a physician (ideally an allergy/immunology specialist) to help prevent anaphylaxis recurrences.ICON: Anaphylaxis describes unmet needs in anaphylaxis, noting that although epinephrine in 1 mg/mL ampules is available worldwide, other essentials, including supplemental oxygen, intravenous fluid resuscitation, and epinephrine auto-injectors are not universally available.ICON: Anaphylaxis proposes a comprehensive international research agenda that calls for additional prospective studies of anaphylaxis epidemiology, patient risk factors and co-factors, triggers, clinical criteria for diagnosis, randomized controlled trials of therapeutic interventions, and measures to prevent anaphylaxis recurrences. It also calls for facilitation of global collaborations in anaphylaxis research.In addition to confirming the alignment of major anaphylaxis guidelines, ICON: Anaphylaxis adds value by including summary tables and citing 130 key references. It is published as an information resource about anaphylaxis for worldwide use by healthcare professionals, academics, policy-makers, patients, caregivers, and the public.

Anaphylaxis: Recent advances in assessment and treatment

The incidence rate of anaphylaxis is increasing, particularly during the first 2 decades of life. Common triggers include foods, medications, and insect stings. Clinical diagnosis is based on a meticulous history of an exposure or event preceding characteristic symptoms and signs, sometimes but not always supported by a laboratory test such as an elevated serum total tryptase level. Physician-initiated investigation of patients with anaphylaxis whose symptoms and signs are atypical sometimes leads to important insights into previously unrecognized triggers and mechanisms. In idiopathic anaphylaxis, in which no trigger can be confirmed by means of skin testing or measurement of specific IgE, the possibility of mastocytosis or a clonal mast cell disorder must be considered in addition to the possibility of a previously unrecognized trigger. Long-term risk reduction in patients with anaphylaxis focuses on optimal management of relevant comorbidities such as asthma and other respiratory diseases, cardiovascular disease, and mastocytosis or a clonal mast cell disorder; avoidance of the relevant confirmed allergen trigger; and relevant immunomodulation such as medication desensitization, venom immunotherapy, and possibly in the future, immunotherapy with food. Emergency preparedness for recurrence of anaphylaxis in community settings includes having epinephrine (adrenaline) autoinjectors available, knowing when and how to use them, and having a written, personalized anaphylaxis emergency action plan and up-to-date medical identification. Randomized controlled trials of the pharmacologic interventions used in an acute anaphylaxis episode are needed.

2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis.

Purpose of reviewThe World Allergy Organization (WAO) Guidelines for the assessment and management of anaphylaxis published in early 2011 provide a global perspective on patient risk factors, triggers, clinical diagnosis, treatment, and prevention of anaphylaxis. In this 2012 Update, subsequently published, clinically relevant research in these areas is reviewed. Recent findingsPatient risk factors and co-factors that amplify anaphylaxis have been documented in prospective studies. The global perspective on the triggers of anaphylaxis has expanded. The clinical criteria for the diagnosis of anaphylaxis that are promulgated in the Guidelines have been validated. Some aspects of anaphylaxis treatment have been prospectively studied. Novel investigations of self-injectable epinephrine for treatment of anaphylaxis recurrences in the community have been performed. Progress has been made with regard to measurement of specific IgE to allergen components (component-resolved testing) that might help to distinguish clinical risk of future anaphylactic episodes to an allergen from asymptomatic sensitization to the allergen. New strategies for immune modulation to prevent food-induced anaphylaxis and new insights into subcutaneous immunotherapy to prevent venom-induced anaphylaxis have been described. SummaryResearch highlighted in this Update strengthens the evidence-based recommendations for assessment, management, and prevention of anaphylaxis made in the WAO Anaphylaxis Guidelines.

Human IP-10 selectively promotes dominance of polyclonally activated and environmental antigen-driven IFN-γ over IL-4 responses

Human interferon‐inducible protein 10 (IP‐10) differs from most chemokines in its apparent specificity for activated T lymphocytes. We hypothesized that IP‐10 was relevant not only for recruiting T cells to inflammatory sites, but also for regulating cytokine synthesis patterns. We examined the effect of recombinant human IP‐10 (rhIP‐10) on human interferon γ (IFN‐γ) and interleukin 4 (IL‐4) production by fresh peripheral blood mononuclear cells. We demonstrate for the first time that this CXC chemokine selectively up‐regulates human T cell cytokine synthesis, with enhancement selectively targeted to promotion of Th1‐like dominance. Superantigen (TSST‐1), soluble anti‐CD3 mAb, and phytohemagglutinin were used to activate distinct intracellular signaling pathways, thereby inducing quantitatively different IFN‐γ:IL‐4 ratios. Selective enhancement of IFN‐γ responses was consistently observed, with median increases of 105–470%. Environmental antigens (Ag) were used to evaluate IP‐10s effect on CD4‐dependent, chloroquine‐sensitive cytokine synthesis. Ag‐driven IFN‐γ responses exhibited median 19‐ to 30‐fold increases in the presence of nanomolar concentrations of rhIP‐10. IL‐4 responses were neither enhanced nor inhibited under any of the conditions tested. These findings suggest a potential role for this T cell‐focused chemokine in maintenance of the default Th1‐like responses usually seen to environmental Ag and indicate a potential application in the modulation of Ag‐driven responses in vivo.—Gangur, V., Simons, F.E.R., Hayglass, K. T. Human IP‐10 selectively promotes dominance of polyclonally activated and environmental antigen‐driven IFN‐γ over IL‐4 responses. FASEB J. 12, 705–713 (1998)