Search

Tryptase is the most abundant endopeptidase released by mast cells degranulation, involved in many pro and anti-inflammatory processes. Normal serum tryptase range is 0-11.4 μg/L. Tryptase is a useful diagnostic tool for anaphylaxis, systemic mastocytosis (SM) and mast cell activation syndrome (MCAS), where specific threshold values must be used. SM diagnosis criteria include evidence of dense mast cell infiltrate either in the bone marrow or the affected organ (such as skin), presence of KIT D816V mutation and elevated serum tryptase level (20 μg/L). In SM, tryptase level is correlated with the burden of mast cells in bone marrow. MCAS should be considered in case of severe and recurrent typical clinical signs of systemic mast cell activation involving at least two organs, associated with an increase in serum tryptase level of 20% + 2 μg/L from the individual's baseline. Anaphylaxis is the most severe among hypersensitivity reactions. A clonal mast cell disorder is a central question in anaphylaxis and appropriate explorations should be conducted in these patients. Triggers for anaphylactic reactions vary significantly in the general population and in patients with MS or MCAS. Finally, physicians must be aware of the many pathological and physiological situations that affect tryptase levels.

Introduction > L'anaphylaxie est une urgence allergique dont la fréquence augmente dans tous les pays depuis les années 2000. Son management repose sur l'administration d'adrénaline et la coordination entre urgentistes et allergologues. L'objectif de l'étude était de déterminer l'incidence de l'anaphylaxie en 2015, d'en décrire les principales caractéristiques et d'évaluer les pratiques en Lorraine pour cette même année. Méthodes > Quatre centres hospitaliers lorrains ont été sélectionnés pour participer à l'étude. Pour chacun, les dossiers médicaux informatiques des patients admis aux urgences adultes ou pédiatriques entre le 1er janvier et le 31 décembre 2015 ont été interrogés sur leurs motif de recours et code diagnostique. Les dossiers dont le codage était susceptible de correspondre à une réaction anaphylactique (95 codes sélectionnés) étaient revus individuellement par un investigateur allergologue, puis inclus en cas de confirmation. Un questionnaire standardisé a permis de recueillir les données épidémiologiques et caractéristiques cliniques des anaphylaxies, et d'évaluer leur prise en charge et orientation. Résultats > L'anaphylaxie représente 0,16 % des passages aux urgences des centres participants pour l'année 2015 ; l'incidence estimée est de 34 pour 100 000 personnes-année en Lorraine. La présentation clinique est influencée significativement par l'âge, le facteur étiologique, certains cofacteurs (asthme, comorbidité cardiovasculaire, médications), et la gravité de la réaction. En cas d'anaphylaxie sévère (grade ≥ 3), le recours à l'adrénaline n'était que de 32,4 % (48/148), et 4 fois sur 10 la durée de surveillance hospitalière était inférieure à 6 heures. Une orientation vers l'allergologue était proposée chez 57,9 % (187/323) des patients. Conclusions > L'anaphylaxie est une cause non exceptionnelle d'admission aux urgences en Lorraine. Les recommandations sont encore trop peu appliquées, et une meilleure connaissance de la pathologie et de sa prise en charge est nécessaire pour les professionnels gérant l'urgence.

Systemic mastocytosis is characterised by abnormal proliferation of mast cells in various organs. We report an original case of systemic mastocytosis revealed by vulvar oedema.A 24-year-old patient was examined in the dermatology department for vulvar oedema appearing during sexual intercourse. She presented vasomotor dysfunction of the lower limbs, urticaria on the trunk on exertion, diarrhoea and bone pains. Laboratory tests showed serum tryptase of 29.7μg and plasma histamine at twice the normal value. Myelogram results showed infiltration by dysmorphic mast cells. Screening for c-kit D816V mutation was positive. Duodenal biopsies revealed mast-cell clusters with aggregation involving over 15 mast cells. CD2 staining was inconclusive and CD25 staining could not be done. Trabecular osteopenia was found, and we thus made a diagnosis of indolent systemic mastocytosis (ISM variant Ia) as per the WHO 2008 criteria. Symptomatic treatment was initiated (antiH1, H2, antileukotrienes) and clinical and laboratory follow-up was instituted.The cutaneous signs leading to diagnosis in this patient of systemic mastocytosis involving several organs were seemingly minimal signs associated with mastocyte degranulation. This is the third recorded case of mastocytosis revealed by vulvar oedema and the first case revealing systemic involvement. The two previously reported cases of vulvar oedema revealed cutaneous mastocytosis alone. Mastocytosis, whether systemic or cutaneous, must be included among the differential diagnoses considered in the presence of vulvar oedema.

"Iodine allergy" does not exist. The concept of "iodine allergy" should be abandoned since it may result in inappropriate measures such as drug, food or environmental eviction. Immediate or non-immediate allergic hypersensitivity to iodinated contrast media is not infrequent. The corresponding allergens have not been identified. Iodine is not involved. Immediate or non-immediate allergic hypersensitivity to povidone iodine is rare. The corresponding allergen is povidone in case of immediate hypersensitivity while nonoxynol might be involved during non-immediate hypersensitivity. Seafood allergens belong to a group of muscle proteins. Immediate drug hypersensitivity or food hypersensitivity is assessed by immediate-reading skin tests while non-immediate drug hypersensitivity is investigated by delayed-reading skin testing. Combined histamine and tryptase measurement is invaluable during the diagnostic approach of immediate hypersensitivity. Other biological tests are being evaluated. Allergic hypersensitivity to iodinated contrast agents does not contraindicate the use of other iodinated drugs.

Hypersensitivity or allergic reactions can occur after transfusion of any kind of blood products. They represent the second or third causes adverse events related to labile blood product administration. This review summarizes their physiopathology, and the current guidelines regarding their diagnosis and treatment.

Anaphylaxis is a severe, generalized, life-threatening reaction of rapid onset. We report the case of a patient presenting several systemic anaphylactic reactions over many years, initially ascribed to a cereals allergy but which finally proved to be due to systemic mastocytosis hidden for a long time.A 53-year-old man consulted for an eruption consisting of monomorphic pigmented maculopapular lesions on the trunk associated with itching and urticaria. He was a farmer and presented severe sensitivity to cereals, with anaphylaxis, which continued despite withdrawal of these allergens. Skin and bone marrow infiltration, abnormal mast cells, positivity for c-kit 816 mutation and the persistent elevation of serum tryptase enabled a diagnosis of indolent systemic mastocytosis to be made.In systemic mastocytosis anaphylaxis is an expected complication relating to the proliferation of mast cells and a massive increase in mediator release (non-immunological mechanism). All patients with severe and recurrent anaphylaxis should be analyzed for underlying mastocytosis by careful physical examination and assay of baseline tryptase.

Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in individuals with asthma following the ingestion of aspirin. AERD affects up to 20 % of adults with asthma. At present, no reliable in vitro test is available to confirm the diagnosis. The confirmation of the diagnosis of AERD therefore depends on the response to challenge testing with aspirin. The pathogenesis of AERD is linked to abnormalities in arachidonic acid metabolism. Prior to exposure to aspirin, respiratory mucosal inflammation is the result of a cell infiltration, an overproduction of leukotrienes, prostaglandins D2, 5-oxo-eicosatetraenoic acid and an underproduction of lipoxins. After aspirin ingestion, patients with AERD synthesize excessive amounts of cysteinyl leukotrienes and prostaglandin metabolites involved in bronchoconstriction. New hypotheses concerning AERD pathogenesis have been added to the initial cyclooxygenase theory. These propose that AERD may be linked to the complement system, adenosine metabolism or angiotensin converting enzyme gene and IgE receptor gene polymorphisms.

Mast cell disorders are defined by the accumulation of mast cells in one or more organ systems. Cutaneous forms are mainly observed in children whereas systemic forms are predominant in adults. Mast cells cause symptoms by the release of proinflammatory mediators or by infiltration of various organs. The measurement of serum tryptase has opened the possibility of screening for mastocytosis, which must be taken into consideration in case of severe anaphylactic reactions. Definite diagnosis is established based on a biopsy of skin or bone marrow. An activating mutation of stem cell factor receptor c-kit is often found. Treatment is based on control of the symptoms triggered by mast cell degranulation. Moreover, novel treatment options targeting mast cell proliferation become available for clinical use.

Mastocytosis are characterized by an accumulation of abnormal mast cells in various tissues. Their incidence is estimated at 1/150,000 patients. Pure cutaneous mastocytosis which are mainly observed during childhood may resolve spontaneously during adolescence, whereas systemic mastocytosis involving one or more organs or tissues are more observed in adults. The initial event leading to mastocytosis is believed to be related to activating mutations in c-kit receptor, thus resulting in increased proliferation of mast cells precursors, migration in various tissues and degranulation leading to clinical signs. This nosologic entity does not belong to allergic diseases. Their perioperative management involves a multidisciplinary approach. The degranulation of mast cells with subsequent clinical symptoms can be triggered by psychological, chemical, traumatic, physical (rubbing, extreme temperatures...) agents. Avoiding these triggers should be realized whenever possible according to each patient. The premedication has not proven its efficiency. Tryptase measurement is part of the preoperative biological assessment. The clinical signs severity is related to the cardiovascular homeostasis disturbances (arterial hypotension, cardiovascular collapse, cardiac arrest). The cardiovascular symptoms do not correlate to the cutaneous versus systemic description of the disease. The drug of choice for the treatment of the severe cardiovascular signs is epinephrine associated to vascular loading. The aim of this literature review is to suggest the different modalities of perioperative care of patients with mastocytosis.

Selective ewe's or goat's milk allergy without cow's milk allergy often presents as a severe picture. Diagnosis and follow-up are facilitated by the use of laboratory tests. Serum tryptase is elevated after mast cell degranulation. Combined determination of serum tryptase and immunoglobulin-E levels are particularly useful in the work-up of anaphylaxis, should it have been fatal. A case of ewe's milk allergy without cow's milk allergy and its laboratory work-up are reported.

Type I hypersensitivity is a major problem in public health, often requiring numerous investigations which aim to diagnose atopy and identify the causative allergen. Among these investigations, several blood tests, mostly using immunoenzymatic methods, can be performed to measure total and specific IgE levels. Type I hypersensitivity can also be investigated with assays which quantitate several mediators released after cellular activation induced by allergens.

Systemic mastocytosis is characterized by abnormal mast cell proliferation in different organs. The 2001 consensus classification distinguishes in separate categories indolent systemic mastocytosis, systemic mastocytosis with concomitant blood disease, aggressive systemic mastocytosis and mast cell leukemia. Clinical manifestations are caused by tissue infiltration by proliferating mastocytes and by release of mediators. The principal organs affected are the skin, bones, digestive tract, liver, spleen and lymph nodes. Diagnosis of mastocytosis is based on appropriate stains (Giemsa, toluidine blue) and immunophenotype features (tryptase, CD117, also known as c-KIT and stem cell factor receptor). Serum tryptase levels reflect the total mast cell burden. Treatment must prevent release of mast cell mediators (histamine antagonists, cromolyn sodium, corticosteroids, or leukotriene-receptor inhibitors), limit bone involvement (bisphosphonates) and reduce the number of circulating mast cells (interferon, cladribine, or tyrosine kinase inhibitors). Enhanced understanding of the pathogenic mechanisms (mutation of c-kit and platelet-derived growth factor receptor alpha has led to the development of targeted treatments, including new inhibitors of tyrosine kinase and of nuclear factor Kappa B.

Hypersensitivity reactions IgE-mediated (anaphylaxis) or non-IgE-mediated (anaphylactoid) reactions occurring during anaesthesia remain a major cause of concern for anaesthesiologists, since these reactions remain usually unpredictable, may be potentially life-threatening even when appropriately treated. The authors report the results of the last 2-year survey (2001, 2002) of such reactions conducted in France by the GERAP (groupe d'etude des reactions anaphylactoides peranesthesiques), and compare these results with their previous published surveys.Between January 1, 2001 to December 31, 2002, 712 patients who experienced immune-mediated (anaphylaxis) or non-immune-mediated (anaphylactoid) reactions were referred to one of the 40 allergo-anaesthesia centres members of the GERAP. Anaphylaxis was diagnosed on the basis of clinical history, tryptase measurements during the adverse reaction, and skin tests and/or specific IgE assay.Anaphylactic and anaphylactoid reactions were diagnosed in 491 cases (69%) and 221 cases (31%), respectively. The most common causes of anaphylaxis were neuromuscular blocking agents (NMBA) (n=271, 55%), latex (n=112, 22.3%), and antibiotics (n=74, 14.7%). Succinylcholine (n=102, 37.6%) and rocuronium (n=71, 26.2%) were the most frequently incriminated NMBAs. Cross-reactivity between NMBAs was observed in 63.4 % of cases of anaphylaxis to a NMBA. No difference was observed between anaphylactoid and anaphylactic reactions when the incidences of atopy, food, or drug intolerance were compared. However atopy, asthma and food allergy were significantly more frequent in case of latex allergy, when compared with NMBA allergy. Clinical manifestations were more severe in anaphylaxis. The positive predictive value of tryptase measurement for the diagnosis of anaphylaxis was 95.3%, the negative predictive value 49%. The diagnostic value of specific neuromuscular blocking agent IgE assays was confirmed.Our results further corroborate the need for systematic screening in case of immediate hypersensitivity reaction during anaesthesia and for the constitution of allergo-anaesthesia centres to provide expert advice to anaesthesiologists and allergologists.

A 28-year-old woman, G3P3, who was otherwise healthy and had taken no medication and had no known allergy, was admitted to our hospital for delivery after a normal pregnancy. An epidural catheter was inserted for analgesia and labour was induced with oxytocin. Two hours later, she suffered a sudden cardiac arrest. She was immediately treated and, since a normal cardiac rhythm and a blood pressure of 90 mmHg has been obtained 30 minutes later, a 3750 g child was delivered by caesarean section. Soon after delivery, a life-threatening uterine haemorrhage appeared, due to DIC. Evolution was favourable, after bilateral uterine arteries embolization had been performed. The diagnosis of amniotic fluid embolism was established by the clinical course, the absence of local cause and the presence of a large number of amniotic cells in the mother's peripheral blood. Tryptase blood concentration was normal in the mother's blood.

A 56-year-old patient was scheduled for coronary artery bypass surgery, because of a severe coronary artery disease. Soon after induction of anaesthesia, he rapidly developed a cardiovascular collapse with bronchospasm and rash. Specific immunoglobulin E and tryptase measurements supported the diagnosis of grade III anaphylactic shock due to rocuronium bromide. A few days later, a general anaesthesia was administered without muscle relaxant and was uneventful.

Drug allergy is the most difficult area in Allergology because: Clinical polymorphism and specially physiopathology (IgE-dependent hypersensibility reaction, cyclo-oxygenase inhibitor, etc.). Feeble specificity and sensitivity in the basic immunoallergic investigation (Skin tests, specific IgE). Very frequently his necessitates recourse to REALISTIC TESTS of drug re-introduction under clinical and biological surveillance (HSI mediators: histamine/tryptase/urinary methyl histamine) to produce a diagnosis.

The biological exploration of the anaphylactoid reaction is based on tryptase and plasma histamine determinations. As this reaction may be considered as a particular case of the acute inflammatory reaction, we have compared, on 25 subjects having presented a drug induces anaphylactoid reaction grade 1 to 3 the plasma level of tryptase, histamine and interleukin 6 (IL6) at 30 and 90 min. On a population of patients having presented an increase of plasma histamine and/or tryptase (n = 14), we have shown that the concentrations of tryptase, histamine and IL6 respectively plateaued (63.9 +/- 70 micrograms/l et 74 +/- 102 micrograms/l), decreased (82.5 +/- 102 mmole/l et 20.5 +/- 27 mmole/l), or greatly increased (19.5 +/- 25.3 ng/l et 320 +/- 745 ng/l) at 30 and 90 min. Correlation between IL6 and the two parameters was only significant for tryptase at 30 and 90 min. Due to the longer lasting kinetic of IL6 (48 h) as compared to histamine and tryptase, IL6 could have a place in the immediate exploration of the anaphylactoid reactions, these results having to be completed by studies on a longer delay and on groups of well defined clinical reactions.

A protocol has been produced for the study of anaphylactic accidents that occur post-operatively that allows definition of the anaphylactic origin, and so reactions that are mediated by IgE in post-operative accidents. This protocol occurs in two stages, the first is done in the minutes and hours that follow the anaphylactic accident, and the second a month or 6 weeks afterwards. At first, we evaluate the sequential study of the liberation of the mediators of anaphylaxis, plasma histamine, serum tryptase, urinary methylhistamine and, more recently, leucotriene E4. The second study is devoted to reactions that are mediated by IgE, essentially, specific serum IgE, tests of activation of basophils by flow cytometry, measurement of leucotriene C4 and skin tests. A study on 16 subjects has evaluated and validated the protocol and shown a significant level of correspondence of results between the sequential measurement of mediators on one hand and on the other the search for IgE-mediated reactions every time that there was an anaphylactic reaction.

Post-anesthesia anaphylactic reactions or those seen during drug provocation tests with a systemic clinical reaction may be confirmed by the sequential release into blood of plasma histamine, tryptase and leukotriene C4 and into urine of urinary methylhistamine and leukotriene E4.

When peri-anaesthesia anaphylactic and/or anaphylactoid reactions occur, anaesthetist is the first investigator: the quality of immuno-allergological investigations depends on these initial investigational procedures. We have used sample kits for several years in order to make easier the immediate investigation. From retrospective analysis of the allergic complications which happened in 1997, the importance of these sample kits as well as the anaesthetist's part in the immuno-allergological management are examined. Nine observations were itemized (0.047%): 3 generalized erythema observations (grade I), in which atracurium was incriminated twice, and propacetamol once; 2 observations of grade II, in which vecuronium (elevated tryptase) and atracurium were incriminated; 4 anaphylactic shocks, in which three neuromuscular blocking drugs (suxamethonium, vecuronium and pancuronium), and one antibiotic (cloxacilline) were incriminated. The use of sample kits allowed an early diagnosis approach, confirmed by skin tests. Diagnosis should be thought closely between anaesthetists and immunologists for investigations.

Allergy to the gelatin used as a plasma filler product has not been recognised until now. Methods used have not been validated but are composed of specific serum IgE, skin tests and histamine release by leucotrienes. The clinical observation that we report has the merit of showing the reality of an allergy that is dependent on plasma filler products due to development of a protocol which includes firstly, during anaphylactic shock, measurement of the mediators of immediate hypersensitivity and secondly, after the clinical accident, test of the activation of basophils by flow cytometry (TAB) and measurement of leucotrienes.

The measurement of Tryptase by the Fluoro-Immuno-Enzymatic (FEIA) method is nowadays possible on the Pharmacia CAP system (automatic UniCAP). This measurement is more comprehensive as it measures the release of serum tryptase from both the tissue mastocytes (MCTC) as well as the mucosal mastocytes (MCM). Technically the measurements are comparable with those made by the method of radio-immunology (RIA), are absolutely reproducible and surprisingly at 100%. It has also been possible to evaluate the two techniques of FEIA and RIA on negative and positive pools. This new FEIA technique for serum tryptase is applicable: to anaphylactic and/or anaphylactoid accidents at the time of induction of anesthesia, in general conditions such as haemorrhagic recto colitis (RCH), Crohn's disease, and mastocytosis. Finally these measurements can be used during nasal and bronchial provocation tests, as the measurements may be made on nasal and bronchial lavage liquids. The sensitivity and the very good reproducibility of this new technique of FEIA for tryptase is of very great interest and avoids use of radio-active isotopes.

Histamine and tryptase, released during anaphylactoid reactions in anaesthesia, can be measured out by radioimmunoassay, provided that their own pharmacokinetic is respected. For two years, we have used sample kits in order to realize the measuring out of these mediators. The aim of this study was to evaluate the interest of these mediators within investigational procedures for anaphylactoid reactions. Eleven anaphylactoid reactions were observed (0,03%). The early blood samples (the first ten minutes following onset of the reaction) were made only in 36% of the cases. Within the serious reactions (grade III), the raising of tryptase indicates the involvement of mast-cell activation. Within minor clinical reactions (grade I), plasma histamine and urinary methylhistamine were the only mediators detected. In an anaphylactic reaction of grade II, which happened after the administering of vecuronium, tryptase was not detected. Therefore, these mediators give the anaesthetists the possibility to prove quickly the severity of the reactions and to direct the investigations very early towards the right way.

Objective improvement in the diagnosis of immuno-allergology can only be obtained by application of reliable and reproducible immuno-biological methods, but until now, only measurements of total and specific IgE can be used and this has certain limitations. Presence of specific serum IgE, correlated with skin tests, favours a sensitization and implies nothing about the responsibility of the allergens. This is why we must consider if a definite improvement of diagnostic methods can be obtained by measurement of mediators. From an observation of food allergy to pork meat, we now show that it is possible to use sequential measurements of the mediators plasma histamine and urinary methylhistamine, ECP and serum tryptase to refine the diagnosis and provide proof of the responsibility of the food allergen. We report here a didactic observation which is characterised by reproducibility and specificity of the measurements. It illustrates the progress in diagnostic methods in allergy: we give a statistical diagnosis by measurement of antibodies and a dynamic diagnosis by measurement of mediators.

Tryptase (T), chymase (C), carboxypeptidase A, cathepsin G-like constituent of preformed mediators contained in mastocyte granules, are a group of neutral proteases with proteolytic activity. These enzymes gives differentiation of two groups of mastocytes, MCTC and MCT as a function of the richness of enzymes. Although the functions of these molecules are becoming better and better understood, their exact roles as well as that of their inhibitors, still remain to be explored in urticaria.

Drug allergy is still a region where diagnosis remains difficult. It relies on clinical history, sometimes skin tests and lymphoblast transformation tests, though only when the antigen is soluble. Provocation tests may, if there is a doubt, prove the involvement of the drug. It may be made objective by the measurement of mediators: ECD and tryptase, thus showing the involvement of eosinophils and mastocytes. Should change in these mediators be associated with a syndromic reaction or is it on its own, a diagnostic factor? A complementary study with a reference group, on a sufficient number of patients has allowed, with the assistance of a statistical analysis, better objectivity from the results.

Three markers of in vivo histamine release, i.e. plasma histamine and tryptase, and urinary methylhistamine, were assessed using sensitive radioimmunoassays in 18 patients who had experienced an adverse reaction to an anaesthetic agent. Controls were obtained from 35 patients following a general anaesthetic, which included a muscle relaxant, and who remained free from any adverse reaction. A first blood sample was obtained from all 18 patients a mean 25 +/- 26 min after the reaction, and a second one in thirteen a mean 120 +/- 65 min after the reaction. Ten patients had had a life-threatening reaction. Plasma histamine levels were increased in all these cases, and tryptase concentrations in 9 out of 10. Urinary methylhistamine rarely reached pathological levels (4 out of 10). Skin tests were positive in the four tested patients. Plasma histamine concentration was still high in 8 cases thirty minutes after the reaction, and remained increased for more than 2 h in two patients. Among the other eight patients with a moderate reaction, 3 had high histamine levels, with normal or weakly increased tryptase concentrations, and normal urinary methylhistamine. Two of these patients had positive skin tests. There were no abnormal findings in any of the investigations carried out in the other five patients, except for a slightly positive skin test to atracurium in one patient. Plasma histamine had a higher sensitivity than tryptase levels. Methylhistamine concentrations were only rarely of interest. There were no false positives with the three investigated markers.(ABSTRACT TRUNCATED AT 250 WORDS)