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.

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.

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).

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.

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.

Landmarks in Allergy during the 19th Century.

There were remarkable achievements in the 19th century in our understanding of the cells of the allergic response, the clear descriptions of hay fever and asthma, as well as the role of pollen in seasonal rhinitis. Although allergy as a concept was not developed until well into the 20th century, the foundations of our present understanding of these diseases were laid in the 1800s. The outstanding physicians and scientists of this time included Paul Ehrlich (who described mast cells, eosinophils and basophils), John Bostock (who provided the first detailed account of hay fever), Charles Blackley (who showed that pollen was the cause of hay fever), Morrill Wyman (who demonstrated that autumnal catarrh was due to ragweed pollen), Henry Hide Salter (who made the first classic description of asthma) and Henri Laënnec (the inventor of the stethoscope).

Milestones in the 20th century.

From its very beginning, the 20th century represented the period of the main breakthrough for allergology as a clinical and scientific entity. The first years of this period were extraordinarily exciting because of the discovery of the anaphylactic reaction in 1902 and its clinical diagnosis as 'local anaphylaxis', 'serum sickness' (1903) or even as 'anaphylactic shock' (1907). The term 'allergy' was coined in 1906 and led to the recognition of allergic diseases as a pathogenetic entity. The first patient organization of hay fever sufferers was founded in Germany in 1900, the same year in which the very first report on immunotherapy was published in New York. In 1911 the era of actual immunotherapy started in London, becoming scientific with the first double-blind study in 1956, and still today being regarded as the backbone of allergology. In 1919 it was shown that allergy could be transferred by blood, in 1921 by serum (Prausnitz-Küstner test) and in 1966 the mystic 'reagins' were recognized as immunoglobulin (Ig) E. The development of the radioallergosorbent test for quantifying specific IgE antibody was a diagnostic landmark for allergists all over the world. The history of allergy diagnosis started with the introduction of a 'functional skin test', named the patch test in 1894. The scratch test was described in 1912 and the patch test in 1931. From 1908 the skin was tested by intracutaneous injections, and from 1930 by a 'puncture test' (a precursor of the prick test) which has been in worldwide use in modified variations since 1959. The rub test ('friction test') was added in 1961. Systematically applied provocation tests started with conjunctival provocation (1907), followed by nasal and bronchial provocation with allergens (1914 and 1925).

Anaphylaxis.

The term anaphylaxis was coined by Charles Richet and Paul Portier when they tried to immunize dogs with actinia extracts, but after a repeated injection of a small amount of the toxin the dog died within 25 min. The new term rapidly spread all over the world. The discovery of the phenomenon of anaphylaxis showed that by immunization not only protection but also harmful events could be induced. For this discovery Richet received the Nobel Prize in 1913, but he still believed the condition of anaphylaxis was a lack of protection to the poisonous effect of the substance. Already earlier similar clinical phenomena had been observed but not well described. A major breakthrough in understanding the pathophysiology came through the experiments of Dale and Laidlaw who showed that the newly discovered histamine was able to induce quite similar symptoms to anaphylaxis. For decades reactions mimicking anaphylaxis but without involvement of the immune systems were called 'anaphylactoid', 'allergy-like' or 'pseudo-allergic'. Since the new definition of the World Allergy Organization (WAO) anaphylaxis is defined on the basis of clinical symptoms independent of pathomechanisms involved: one distinguishes between allergic and non-immune anaphylaxis. Epinephrine (Adrenalin) was soon recognized as treatment of choice of this dramatic condition.

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.

History and classification of anaphylaxis.

Anaphylaxis as the maximal variant of an acute systemic hypersensitivity reaction can involve several organ systems, particularly the skin, respiratory tract, gastrointestinal tract and the cardiovascular system. The severity of anaphylactic reaction is variable and can be classified into severity grades I-IV. Some reactions are fatal. Most frequent elicitors of anaphylaxis are foods in childhood, later insect stings and drugs. The phenomenon itself has been described in ancient medical literature, but was actually recognized and named at the beginning of the 20th century by Charles Richet and Paul Portier. In the course of experiments starting on the yacht of the Prince of Monaco and continued in the laboratory in Paris, they tried to immunize dogs with extracts of Physalia species in an attempt to develop an antitoxin to the venom of the Portuguese man-of-war. While Charles Richet believed that anaphylaxis was a 'lack of protection', it has become clear that an exaggerated immune reaction, especially involving immunoglobulin E antibodies, is the underlying pathomechanism in allergic anaphylaxis besides immune complex reactions. Non-immunologically mediated reactions leading to similar clinical symptomatology have been called 'anaphylactoid' or 'pseudo-allergic'--especially by Paul Kallos--and are now called 'non-immune anaphylaxis' according to a consensus of the World Allergy Organization (WAO). The distinction of different pathophysiological processes is important since non-immune anaphylaxis cannot be detected by skin test or in vitro allergy diagnostic procedures. History and provocation tests are crucial. The intensity of the reaction is not only influenced by the degree of sensitization but also by concomitant other factors as age, simultaneous exposure to other allergens, underlying infection, physical exercise or psychological stress or concomitant medication (e.g. beta-blockers, NSAIDs); this phenomenon has been called augmentation or summation anaphylaxis.

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.

[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.