The cysteinyl leukotrienes: where do they come from? What are they? Where are they going?

Cysteinyl leukotrienes are established mediators of bronchial asthma and have agonist roles analogous to those of histamine in allergic rhinitis. We now know that the substance originally termed slow-reacting substance of anaphylaxis was composed of three cysteinyl leukotrienes that act in the inflammatory response via receptors on smooth muscle and on bone marrow-derived inflammatory cells. K. Frank Austen describes the work culminating in the identification, biosynthesis and functional characterization of these moieties.

Neuromuscular blocking agents induced anaphylaxis: Results and trends of a French pharmacovigilance survey from 2000 to 2012.

BACKGROUND: Perioperative anaphylaxis mainly involves neuromuscular blocking agents (NMBAs) with an IgE-mediated mechanism. In France, this life-threatening condition is reported by anesthetists and allergologists, and two safety alerts concerning suxamethonium were raised in 2011 and 2012. This led to start a national survey over the 2000-2012 period which objectives were to provide a descriptive analysis, to estimate incidence rates, and to analyze the trends over this period. METHODS: The French pharmacovigilance database was retrospectively queried for all the available NMBAs. Anaphylaxis cases with elevated tryptase and positive skin tests were qualified as "confirmed cases." Subgroup analysis compared atracurium and cisatracurium vs suxamethonium and rocuronium. RESULTS: A total of 680 confirmed cases and 944 nonconfirmed cases were identified. Suxamethonium was the most implied NMBA (64%). Incidence rates (according to sales data) of suxamethonium and rocuronium were, respectively, 10- and 13-folds higher than those of the others NMBAs, regardless the confirmed/nonconfirmed status. Cisatracurium incidence rates remained stable over the period, while suxamethonium and atracurium increased and rocuronium first decreased but re-increased after 2006. Male patients were more frequent in the subgroup "atracurium-cisatracurium" (P = .019), whereas obesity and emergency setting were more frequent in the subgroup "rocuronium-suxamethonium." Shared characteristics were the poorly documented previous exposure to NMBA(s) and an insufficient adherence of patients to perform skin tests, showing the need to improve this procedure. CONCLUSION: Suxamethonium and rocuronium are markedly more involved in perioperative anaphylaxis than the other available NMBAs. Patients should be more informed about their perioperative anaphylaxis and its consequences.

Increases in anaphylaxis fatalities in Australia from 1997 to 2013.

BACKGROUND: Recent epidemiological studies indicate increases in Australian, UK and US hospital anaphylaxis admission rates. OBJECTIVES: The aim of this study was to determine whether Australian anaphylaxis fatalities are increasing in parallel and to examine the characteristics of fatalities recorded in the National Coronial Information System (NCIS). METHODS: Time trends in Australian anaphylaxis fatalities were examined using data derived from the Australian Bureau of Statistics (ABS) 1997-2013 and the NCIS 2000-2013, the latter providing additional information to verify cause and identify risk factors. RESULTS: The ABS recorded 324 anaphylaxis fatalities by cause: unspecified (n = 205); medication (n = 52); insect stings/tick bites (n = 41); food (n = 23); and blood products (n = 3). From 1997 to 2013, all-cause fatal anaphylaxis rates increased by 6.2%/year (95% CI: 3.8-8.6%, P < 0.0001) or from 0.054% to 0.099/10(5) population. Fatal food anaphylaxis increased by 9.7%/year (95% CI: 0.25-20%, P = 0.04) and unspecified anaphylaxis deaths by 7.8% (95% CI: 4.6-11.0, P < 0.0001). There was an insignificant change in medication-related fatalities (5.6% increase/year; 95% CI: 0.3% decrease to 11.8% increase, P = 0.06), and sting/bite fatalities remained unchanged. Hospital anaphylaxis admission rates for all-cause, food, unspecified and medication anaphylaxis increased at rates of 8%, 10%, 4.4% and 6.8%/year, respectively. A total of 147 verified NCIS deaths were examined in detail: medication- and sting/bite-related fatalities occurred predominantly in older individuals with multiple comorbidities. Upright posture after anaphylaxis was associated with risk of sudden death (all causes). Seafood (not nuts) was the most common trigger for food-related anaphylaxis deaths. CONCLUSIONS: Australian anaphylaxis fatality rates (most causes) have increased over the last 16 years, contrasting with UK- and US-based studies that describe overall lower and static overall anaphylaxis fatality rates (0.047-0.069/10(5) population).

A 17-year experience in perioperative anaphylaxis 1998-2015: harmonizing optimal detection of mast cell mediator release.

BACKGROUND: Sheffield NARCOS (National Adverse Reactions Advisory Service) investigates suspected perioperative anaesthetic reactions using serial tryptase, urinary methylhistamine (UMH) and clinical information. Further recommendations for additional allergy clinic assessment are provided. OBJECTIVE: To establish a robustly measurable protocol for identifying mast cell mediator (MMR) release in this cohort. To compare these thresholds with previously suggested thresholds and algorithms. METHOD: A review of 3455 NARCOS cases referred with a suspected perioperative allergic reaction. Tryptase, UMH and clinical details were analysed. A total of 1746 cases were graded using the Ring and Messmer scale. Reaction grade, tryptase and UMH changes were compared with statistical and graphical presentations appropriate to non-normally distributed measurements using Analyse-IT software. RESULTS: Sensitive strategies such as 3 µg/L or 20% are measurable and translatable and would substantially increase detection of potentially relevant changes in tryptases. Adequate quality assurance for low-level measurement is needed. An incremental threshold of 20% would identify potential MMR in an additional 14% of cases with peak tryptase (Tp) between 5 and 14 µg/L and a further 15% with Tp below 5 µg/L. Further work is required to establish the diagnostic performance characteristics of this more sensitive approach. UMH also identified up to 120 further cases of potential MMR in the absence of tryptase increments. CONCLUSIONS AND CLINICAL RELEVANCE: Future studies should establish and compare the predictive performance characteristics of each strategy against clinical phenotypes. A single agreed definition of positive serial tryptases is needed to enable robust evaluation of diagnostic strategies. This could serve as a harmonized standard for comparative studies of case series from different centres.

Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012.

BACKGROUND: The incidence of anaphylaxis might be increasing. Data for fatal anaphylaxis are limited because of the rarity of this outcome. OBJECTIVE: We sought to document trends in anaphylaxis admissions and fatalities by age, sex, and cause in England and Wales over a 20-year period. METHODS: We extracted data from national databases that record hospital admissions and fatalities caused by anaphylaxis in England and Wales (1992-2012) and crosschecked fatalities against a prospective fatal anaphylaxis registry. We examined time trends and age distribution for fatal anaphylaxis caused by food, drugs, and insect stings. RESULTS: Hospital admissions from all-cause anaphylaxis increased by 615% over the time period studied, but annual fatality rates remained stable at 0.047 cases (95% CI, 0.042-0.052 cases) per 100,000 population. Admission and fatality rates for drug- and insect sting-induced anaphylaxis were highest in the group aged 60 years and older. In contrast, admissions because of food-triggered anaphylaxis were most common in young people, with a marked peak in the incidence of fatal food reactions during the second and third decades of life. These findings are not explained by age-related differences in rates of hospitalization. CONCLUSIONS: Hospitalizations for anaphylaxis increased between 1992 and 2012, but the incidence of fatal anaphylaxis did not. This might be due to increasing awareness of the diagnosis, shifting patterns of behavior in patients and health care providers, or both. The age distribution of fatal anaphylaxis varies significantly according to the nature of the eliciting agent, which suggests a specific vulnerability to severe outcomes from food-induced allergic reactions in the second and third decades.

Increased incidence of admissions for anaphylaxis in Spain 1998-2011.

We report on trends in anaphylaxis admissions in the Spanish hospital system during the period 1998-2011. Data on admissions for anaphylaxis were obtained from the Spanish Information System for Hospital Data for the period 1998-2011. Patients were selected using the codes for anaphylaxis in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Poisson regression models were used to estimate incidence rate ratios. We recorded a 1.89-fold increase in admissions for anaphylaxis in Spanish hospitals during the study period, particularly in patients aged 0-14 years (1.65- to 3.22-fold until 2009 and 4.09- to 12.59-fold until 2011) and in food anaphylaxis in all age groups (2.78-fold until 2009 and 8.74-fold until 2011). The incidence of anaphylaxis is perceived as having increased in recent years, especially anaphylaxis caused by food and anaphylaxis affecting the pediatric population.

The history of the idea of allergy.

About 100 years ago, a young paediatrician understood that the function of the immune system should be rationalized not in terms of exemption of disease but in terms of change of reactivity. He coined a new word to represent such an idea: 'allergy': the first contact of the immune system with an antigen changes the reactivity of the individual; on the second and subsequent contacts, this change (or allergy) can induce a spectrum of responses from protective (literally, immune) to hypersensitivity ones. The idea was at first hardly understood by the scientific community because it undermined the essentially protective nature of the immune response as it was defined. Nevertheless, in the next years, the growing clinical evidence led to the acceptance of this new point of view, but not of the new word, at least not unconditionally. The original significance of the neologism 'allergy' became perverted and limited to describe hypersensitivity conditions. Perhaps because of the corruption of the term, today 'allergy' does not have a well-delimited significance among health professionals. Furthermore, the word has long ago escaped from physicians and gone to the streets, where it is popularly used also as synonymous with antipathy and rejection. This vulgarization of the term 'allergy' has significantly increased its imprecision.

Prevention of tetanus during the First World War.

The emergence of tetanus in wounded soldiers during the first months of the First World War (WWI) resulted from combat on richly manured fields in Belgium and Northern France, the use of modern explosives that produced deep tissue wounds and the intimate contact between the soldier and the soil upon which he fought. In response, routine prophylactic injections with anti-tetanus serum were given to wounded soldiers removed from the firing line. Subsequently, a steep fall in the incidence of tetanus was observed on both sides of the conflict. Because of fatal serum anaphylaxis associated with administration of serum at a time when purification methods still needed to be improved, it must be presumed that tens to hundreds of men might have died as a result of the routine administration of anti-tetanus serum during WWI. Yet anti-tetanus serum undoubtedly prevented life threatening tetanus among several hundred thousands of wounded men, making it one of the most successful preventive interventions in wartime medicine. After the abrupt fall in tetanus incidence in 1914 due to introduction of anti-tetanus serum, the incidence of the disease tended to become even lower as the war went on. This was probably due to earlier and more thorough surgical treatment, consisting of opening, cleaning, excision and drainage of wounds as early as possible. In this overview, recent battlefield findings from the Meuse-Argonne offensive in 1918 are used to illustrate common practices employed in the prevention of tetanus during WWI.

The History of IgE: From discovery to 2010.

The discovery of IgE and the role of IgE-mediated inflammation gave clinical allergy a scientific backbone, and as a result, the reputation of the specialty allergy has increased considerably over the years. Allergy diagnosis was improved by assays for in vitro determination of the presence and concentration of IgE antibodies, and clinical knowledge also broadened, allowing better service for the increasing number of allergic individuals. Access to immune assays for allergens finally allowed characterization and standardization of allergen preparations used for diagnosis and allergen-specific immunotherapy. Improved basic molecular technologies have further increased our knowledge about the complex component composition of an allergen extract, introduced IgE-specific immunotherapy, and allowed the allergist to better handle even severe allergic reactions such as anaphylaxis.

The early history of chemical immunosuppression: 1900-1965.

This is a short review on chemical immunosuppression following the discovery of anaphylaxis by Charles Richet. The paper discusses the role of serendipity in the advent of 6-mercapthopurine (6-MP) therapy and the productivity in the field through Nobel Prize recipients.

Charles Richet: medical scientist, innovator, peace thinker and savant.

This article looks at the life of Professor Charles Richet (1850-1935), a distinguished medical scientist who received the Nobel Prize in Physiology or Medicine in 1913 for his work on anaphylaxis. He was also an aeroplane engineer, an investigator of psychic phenomena, active in the medical and international peace movement as a member of the leading peace organisations of the time including the International Medical Association for the Suppression of War, and the French Peace League. He also promoted controversial views about eugenics and the means of constructing what he considered to be a strong and healthy society.

[Clemens Freiherr von Pirquet, developer of the concept of allergy]. / Revolutionär am Krankenbett.

The pediatrician and scientist, Clemens Freiherr von Pirquet (1874-1929) was the first to coin the term "allergy". His experiments with Behring's serum, which he administered to sick children, led him to an awareness of an interaction between the human organism and pathogens. In his article published in the Müncher Medizinischen Wochenschrift in 1906, he laid the foundation stone for modern allergology.

Biotherapies of chronic diseases in the inter-war period: from Witte's peptone to Penicillium extract.

In the inter-war period physicians elaborated numerous 'biotherapies' grounded in the complex interactions between physiology, bacteriology and immunology. The elaboration of these non-specific biological treatments was stimulated by the theory of generalized anaphylaxis that linked the violent reaction to a foreign protein to a broad array of chronic diseases, from asthma and urticaria to rheumatism or chronic colitis. Such diseases were perceived as the result of an 'abnormal reactivity' to a sensitisation of tissues and organs by bacteria and by foreign proteins, a view that provided an effective bridge between new concepts derived from bacteriology and immunology and the long-standing pathological tradition. Accordingly, physicians attempted to treat these conditions through specific desensitisation and non-specific biological therapies: peptone treatment, protein therapy, haemotherapy, 'antivirus' or 'opotherapy'. Therapies that attempted to neutralise the harmful effects of chronic infections through 'desensitisation' were not seen as marginal medical practices, but were promoted by leading advocates of the 'Pasteurian sciences', such as Richet, Widal, Vallery-Radot, Wright and Fleming. They also led to development of new products by the pharmaceutical industry.

History and classification of anaphylaxis.

Anaphylaxis is the maximal variant of an acute allergic reaction involving several organ systems. The phenomenon itself is old, but it was recognized and named at the beginning of the 20th century by Richet and Portier. The clinical symptoms of anaphylaxis affect various organs, most commonly starting in the skin and proceeding to the respiratory tract, to gastrointestinal involvement and to cardiovascular symptoms, and finally to cardiac and/or respiratory arrest. Anaphylaxis stricto sensu is an immunological reaction, mostly mediated by IgE antibodies, but also by IgG or IgM antibodies (immune complex anaphylaxis). There are cases with similar clinical symptomatology without detectable immunological sensitization which are called pseudo-allergic or anaphylactoid reactions. In the newer nomenclature, some authors tend to include these under the heading of 'anaphylaxis' which has then to be defined as an acute systemic hypersensitivity reaction. The most common elicitors of anaphylaxis include drugs, foods, additives, but also other allergens as well as physical factors (cold, heat, UV radiation). The clinical outcome--the intensity of the reaction--is not only influenced by the degree of sensitization, but also by concomitant other factors: sometimes, individuals only develop anaphylaxis after simultaneous exposure to the allergen and an infection, physical exercise, psychological stress or concomitant medication (e.g. beta blockers). The term 'summation anaphylaxis' has been proposed for this phenomenon which probably underlies many cases of so-called idiopathic anaphylaxis. In patients with insect venom anaphylaxis, decreased levels of plasma angiotensin have been measured in inverse correlation to the severity of the reaction. Certain differential diagnoses have to be distinguished from anaphylaxis. Every patient with a history of anaphylaxis should undergo allergy diagnosis with the aim to detect the eliciting agent, characterize the relevant pathomechanism (e.g. IgE-mediated reaction) and to offer a tolerable alternative (in food or drug allergy). In clear-cut IgE-mediated anaphylaxis, allergen-specific immunotherapy (hyposensitization) is the effective causal treatment, with success rates of 90% in insect venom anaphylaxis.

Charles Robert Richet and some milestones in the history of allergies.

French medicine in the second half of the 19th century includes the seminal contributions of Claude Bernard, Lasèque, Trousseau, Jaccoud and Charcot, and counted among the most notable representatives is Professor Charles Robert Richet, Nobel Prize Winner for Medicine and Physiology in 1913, for the discovery of anaphylaxis. With his versatile personality he was involved in many different fields. His investigative work included diverse themes such as respiration, digestion, epilepsy and the regulation of body heat. To him we owe three new words, and as such, three new concepts: anaphylaxis, polypnea and zoomotherapy. Richet also excelled as a bacteriologist, pathologist, medical statistician, poet, novelist, playwright, historian, psychologist, parapsychologist, pacifist, philosopher and bibliographer. Especially interested in telepathy, and in general, extrasensory perception phenomena, he contributed decisively to the creation of a new science, metapsychics.