Differentiating the cellular and humoral components of neuromuscular blocking agent-induced anaphylactic reactions in patients undergoing anaesthesia.

BACKGROUND: The significance of IgE antibodies to neuromuscular blocking agent (NMBA)-induced anaphylactic reactions during anaesthesia is unclear. We investigated the relevance of IgE to rocuronium using an in vitro technique. METHODS: Serum samples from 61 patients with anaphylactic reactions during anaesthesia were investigated. On the basis of clinical history, allergy to NMBA was considered likely in 48 patients, further assessed using intradermal skin tests for several commonly used NMBAs, including rocuronium, vecuronium, and succinylcholine. To determine the presence of rocuronium IgE in human serum, a rocuronium-human serum albumin (rocHSA) conjugate was coupled to a solid phase and a radioallergosorbent test performed. The biological effects of patient serum NMBA-IgE on histamine release were investigated using in vitro sensitized basophils from healthy blood donors. RESULTS: IgE to rocuronium was found in 23 of 48 serum samples (48%) with NMBA allergy, although only two of these were able to sensitize basophils to release histamine in response to rocHSA. IgE-responsiveness in the basophil test was only observed with conjugated rocHSA and not with unconjugated rocuronium or the other NMBAs evaluated. However, unconjugated rocuronium inhibited the histamine release induced by rocHSA. Correlation between skin-test reactivity to rocuronium and IgE to rocHSA was low (P>0.1). In contrast, striking correlation between IgE to rocuronium and skin-test reactivity to succinylcholine was found (P<0.001). CONCLUSIONS: Our results indicate that NMBA-related anaphylaxis requires not only IgE NMBA reactivity, but also altered cellular reactivity in the patient. The latter may be demonstrable by testing basophils from the patient, a skin test with (steroidal) NMBA, or both.

[Safety of reintroducing platelet-inhibitory doses of aspirin in patients with urticaria or angioedema induced by anti-inflammatory doses]. / Réintroduction de l'aspirine à dose antiagrégante après urticaire ou angio-oedème induits par des doses anti-inflammatoires.

BACKGROUND: Aspirin is one of the most widely prescribed drugs in the world on account of its analgesic, antipyretic, and anti-inflammatory properties. Its effect on platelet aggregation makes it the first choice for prophylaxis in cardiovascular, neurological and obstetric diseases. However, a history of aspirin-induced urticaria and/or angioedema is usually a contraindication for further prescription of the drug. The aim of this article was to demonstrate that patients presenting aspirin-induced cutaneous reactions at anti-inflammatory doses can safely benefit from aspirin reintroduction at platelet-inhibitory doses. PATIENTS AND METHODS: Patients with a history of aspirin-induced urticaria and/or angioedema referred to our department between January 2000 and June 2008 for double-blind placebo-controlled reintroduction at platelet-inhibitory doses for a medical indication were enrolled in this study. RESULTS: Seventy patients with aspirin hypersensitivity as well as a medical indication for this therapy were referred to our department. Of these, 38 (54.3%) had a history of aspirin-induced urticaria and/or angioedema, including three laryngeal oedemas (7.9%). All subjects received platelet-inhibitory doses of aspirin (maximal total dose: 400mg/day) in double-blind placebo-controlled fashion during a one-day hospitalization period. None of the patients presented an immediate hypersensitivity reaction. Only one patient, who had received a cumulative dose of 200mg/day, reported diffuse urticaria and facial angioedema of no clinical significance the following day. He had a history of chronic urticaria. CONCLUSION: This article demonstrates the safety of reintroducing platelet-inhibitory doses of aspirin in patients in whom it is indicated and reporting aspirin-induced urticaria and/or angioedema with anti-inflammatory doses. However, patients with a history of chronic urticaria should undergo a challenge with the lowest platelet-inhibitory dose (75mg/day) in order to minimize the risk of aggravating their condition.

Comparison of two basophil activation markers CD63 and CD203c in the diagnosis of amoxicillin allergy.

BACKGROUND: To confirm allergy to beta-lactam (BL), a basophil activation test in flow cytometry based on CD63 up-regulation was described. CD203c is a more recent basophil activation marker and up to day there is no consensus about which marker is the more sensitive one. CD203c has not yet been evaluated in the diagnosis of BL allergy. OBJECTIVE: The aim of the study was to compare the reliability of CD203c to CD63 for the diagnosis of amoxicillin (AX) allergy, which is nowadays the most frequent BL allergy. METHODS: Twenty-seven patients with an immediate positive skin test (ST) to AX, 20 had had anaphylaxis with AX and 7 had urticaria and/or angioedema, were compared with 14 controls with no allergy to BL and to six patients with delayed positive ST to AX. RESULTS: In the anaphylaxis group, AX induced up-regulation of CD203c in the basophils of 12 patients out of 20 (60%) and of CD63 in four patients (20%) (P<0.02). Two patients out of seven with urticaria or angioedema had a positive result with CD203c and CD63. In patients who had anaphylaxis, ampicillin (AMP) induced CD203c up-regulation in eight out of 12 (67%) patients tested, and CD63 up-regulation in 4 out of 12 (33%) (all patients who had anaphylaxis could not be tested with AMP). False-positive results were observed with CD203c as well as CD63, and for 10 patients indeed this was confirmed by a negative drug provocation test. The origin of conflicting results between CD63 and CD203c might be at least the targeting of basophils based on anti-IgE labelling. Among IgE(+) gated cells, by means of CD33, a marker of monocytes, a contamination up to 50% by monocytes was detected. In contrast to CD63, CD203c is an activation marker specific of basophils with a basal low-level expression in resting basophils. Thus, IgE and CD203c double targeting of basophils avoids the contamination by monocytes. CONCLUSION: CD203c seems to be a more sensitive activation marker of basophils than CD63 for the diagnosis of amoxicillin allergy.

Purification of human IgG4 subclass with allergen-specific blocking activity.

Blocking antibodies (bAb) induced by allergen immunotherapy are restricted to the IgG1 and IgG4 subclasses, with IgG1 predominating early and IgG4 coming later. Study of IgG4 bAb has been limited, in part, by the absence of a method to purify IgG4. We describe a rapid immunoaffinity chromatographic method for the purification of that subclass from whole serum. Starting serum (TR) contained 90 micrograms/ml Dactylis glomerata (orchard grass) pollen (DGP)-specific IgG4, measured by indirect ELISA. The blocking activity of TR was assayed in vitro on IgE-sensitized human basophils. Immunoadsorption on a strong-binding anti-IgG4 monoclonal antibody (mAb) removed about 90% of the total and allergen-specific IgG4 and nearly all of the blocking activity from TR. An IgG4-rich fraction was then obtained by absorption of several small volumes of TR on a weak-binding anti-IgG4 mAb column at neutral pH followed by elution with glycine-HCl buffer. The pooled eluates contained 82% IgG4, amounting to a 65-fold purification of the serum IgG4; the yield was approximately 30%. Nearly all the DGP-specific antibody was in the IgG4 component of the eluate. The blocking activity of the eluate was approximately equal to that of TR. Immunoblot patterns with the eluate and with TR on SDS-PAGE of DGP were nearly identical. This method thus provides a fully active, relatively pure IgG4 blocking antibody. Moreover, the results reinforce the importance of using a well-chosen mAb when purifying proteins by immunoaffinity chromatography.

Acquired hemophilia due to factor VIII inhibitors in 34 patients.

BACKGROUND: Acquired hemophilia is a rare disease caused by the development of auto-antibodies against factor VIII. SUBJECTS AND METHODS: We studied the characteristics and outcomes of 34 patients (19 women and 15 men) with acquired hemophilia from 1980 to 1997. RESULTS: The mean age of the patients was 61 years (range, 22-93 years). An underlying disease was observed in 18 (53%) patients: 5 patients had cancer, 4 an autoimmune disorder, 2 a dermatologic disorder, 3 asthma, 3 were postpartum, and 1 had an adverse reaction to ampicillin. Factor VIII level was <5% in 30 (90%) patients; factor VIII antibodies were elevated (>10 Bethesda units) in 23 (69%) patients. Bleeding requiring transfusions was reported in 25 (75%) patients. Human factor VIII was given to 14 patients and porcine factor VIII to 5. Six patients received prothrombin complex concentrates and one desmopressin. Several immunosuppressive treatments were used, mainly corticosteroids, cyclophosphamide, and intravenous immunoglobulin. Bleeding stopped in all but one patient within 2 weeks. Most patients achieved complete remission, although two relapses were observed subsequently. CONCLUSION: This large study helps to clarify the presentation and clinical course of acquired hemophilia. Prospective studies are needed to determine the efficacy of treatment.

Comparison between formoterol 12 microg b.i.d. and on-demand salbutamol in moderate persistent asthma.

Inhalation of on-demand salbutamol (ODS) several times daily is sometimes the only beta2-agonist prescribed in moderate persistent asthma, whereas a long-acting beta2-agonist should be added. This trial aimed to compare the efficacy of formoterol dry-powder capsule 12 microg b.i.d. (Foradil) and ODS in patients with moderate persistent asthma treated with inhaled corticosteroids, in the conditions of real practice. Two hundred and fifty-nine patients were randomized (formoterol; 130; ODS: 129) in this open, parallel-group trial. The mean increases in morning peak expiratory flow (PEF primary variable) and evening PEF over the 3-month treatment period were statistically significantly higher with formoterol: +25.7 and +24.1 l min(-1), respectively vs. +4.5 and +0.5 l min(-1) respectively with ODS. The increase in FEV1 was statistically significantly higher with formoterol at months 1 and 3. Formoterol reduced the use of salbutamol as rescue medication by two-thirds. The percentages of symptom-free days and nights statistically significantly increased with formoterol (+20% and +33% respectively), but did not significantly change with ODS. Clinically relevant and statistically significant improvement in the mean total score of the St George's Hospital Respiratory Questionnaire was observed in the formoterol group. Adverse events were similar in the two groups. The results show that treatment with formoterol has significant advantages over ODS in patients with moderate persistent asthma.

Comparative therapeutic effect and safety of mizolastine and loratadine in chronic idiopathic urticaria. URTILOR study group.

Mizolastine, a new second-generation H1 receptor antagonist with additional anti-allergic properties, was compared with loratadine in 61 patients suffering from severe chronic idiopathic urticaria (CIU). In this double-blind study, patients were randomly allocated to receive either mizolastine 10 mg (n = 26) or loratadine 10 mg (n = 35) once-daily for 28 days. Both compounds were well tolerated, safe and efficacious. The reduction in the number of episodes per week (5. 6+/-16.3 and 6.4+/-12.4 for mizolastine and loratadine, respectively) and the reduction in the symptom severity score, measured using a Visual Analogue Scale (VAS), were comparable (30.2 +/- 39.0 mm and 30.5 +/- 28.5 mm for mizolastine and loratadine, respectively). Mizolastine had a positive effect on angioedema (85% CI 95% [0.69-1.00]) of patients improved compared with 75% (CI 95% [0.59-0.91]) of the loratadine group and the differential reduction of the mean total duration of episodes in the mizolastine group was higher when compared with the loratadine group (from 13.7 +/- 33.5 hours on day 0 to 5.1 +/- 9.0 hours over the treatment period and from 8.2 +/- 8.8 hours on day 0 to 5.1 +/- 7.8 hours over the treatment period for mizolastine and loratadine, respectively). Prick test analysis demonstrated that both drugs caused a significant decrease of histamine-induced wheal and flare with no development of tolerance, with a significant superiority of mizolastine over loratadine for some histamine concentrations. Mizolastine and loratadine both proved very efficacious and safe. In addition mizolastine demonstrated a superiority in prick tests, beneficial effects on angioedema and seemed to provide a faster onset of action.

Treatment of severe seasonal rhinoconjunctivitis by a combination of azelastine nasal spray and eye drops: a double-blind, double-placebo study.

BACKGROUND: Evaluation of combined azelastine nasal spray and eye drops treatment in patients with severe rhinoconjunctivitis. METHODS: Phase III, multicenter, randomized, double-blind study of patients with a history of grass pollen allergy, confirmed by skin testing/specific IgE, total symptom scores > or =6 (ocular) or > or =8 (nasal). Intent-to-treat analysis. RESULTS: 99 patients (azelastine = 53, placebo = 46) enrolled homogeneously from May to September 1997 in 7 venues in France. The efficacy of azelastine was significantly higher compared to placebo (49% vs. 28%, p = 0.04), considering response as a decrease of the total sum of ocular and nasal scores by at least 50% and no use of cetirizine by day 7. The decrease of total ocular and nasal scores by at least 50% at day 7, with cetirizine rescue <3 tablets was higher, but not significantly, in azelastine patients (43% vs. 30%). Cetirizine rescue was more frequent, from day 0 to 7, in the placebo patients (4.9 +/- 5.0 vs. 2.7 +/- 4.1, p = 0.02). Global efficacy was rated higher for azelastine by investigators (26% vs. 10%, p = 0.05) and patients (28% vs. 7%, p = 0.01). Adverse events were burning sensation, "red eyes," nasal irritation, bitter taste. No serious adverse events were reported. Tolerance of azelastine was "very good/good"/"satisfactory" in the majority (62%/82% assessed by investigators, or 55%/79% by patients, respectively). CONCLUSIONS: Combining azelastine eye drops and nasal spray is a safe and effective treatment of severe seasonal rhinoconjunctivitis.

Competitive immunoassay for antigenic latex protein measurement: rabbit antiserum-based assay compared to modified Lowry and human IgE-inhibition methods.

A new rabbit antiserum-based assay was designed and evaluated for the assessment of the allergen potency of latex medical gloves, since total protein measurement by modified Lowry method remains unsatisfactory and the human IgE-inhibition method is limited by the use of sera from type I allergic patients. Four rabbit sera against a nonammoniated latex extract were shown by immunoblotting to have similar binding patterns to those obtained by human IgE. One rabbit serum was used to develop a competitive immunoassay for antigenic latex proteins (CIALP). The same nonammoniated latex extract was used for coating and calibration. The lower detection limit of the method was 0.085 microgram/g of glove. Antigenic proteins measured by CIALP for 77 latex glove extracts (33 pairs of surgical gloves and 11 exam gloves) showed positive correlation with those of the modified Lowry method (r = 0.4; p < 0.001). For 36 extracts made from the right and the left hand of 18 out of the 33 surgical latex gloves tested, inhibition of human specific-IgE results did not correlate with the modified Lowry method but did with the CIALP results (r = 0.8, p < 0.0001). The CIALP, which is well correlated with the human IgE-inhibition test, enables the assessment of the allergenicity of latex medical gloves by measuring the antigenic proteins.

Hypersensitivity to azathioprine mimicking gastroenteritis. Absence of recurrence with 6-mercaptopurine.

Hypersensitivity mimicking gastroenteritis is a rare complication of azathioprine therapy for which the mechanism is unknown. We report a case of devastating diarrhoea and vomiting due to azathioprine treatment in which hypersensitivity to the imidazole moiety of azathioprine was demonstrated. This has important therapeutic implications: in this situation, 6-mercaptopurine, which is the portion of azathioprine responsible for the cytotoxic therapeutic effect, can be administered without recurrence of side-effects.

[Mast cells and basophils in asthma]. / Mastocytes et basophiles dans l'asthme.

Airway inflammation may contribute to the nonspecific bronchial hyperreactivity, which is a prominent feature in chronic asthma. Many stimuli such as allergens in allergic asthma, virus and irritants may induce an early reaction and in some cases a late reaction. An increase of nonspecific bronchial hyperreactivity is well demonstrated after this late reaction but no after the early one. Although a variety of inflammatory cells may be located within the respiratory tract, the late phase is generally considered as a direct consequence of the effects of mediators released from mast cells activated during the early reaction. Eosinophils and other inflammatory cells are attracted by chemotactic mediators such as PGD2. However the pathophysiology of chronic asthma remains uncertain because the heterogeneity of mast cells and the complexity of intercellular regulations. The role of basophils has been suggested mainly because their number increases during the late phase of allergic process. On the other hand, histamine and LTC4, but not PGD2, are found during the late phase: it is well established that basophils do not release PGD2. Two recent hypothesis have focused interest on basophils: the higher releasability property of basophils obtained from allergic and asthmatic patients, whatever their serum IgE and the presence of histamine releasing factors acting only on one kind of IgE (IgE+) which is apparently found in severe asthmatic patients. It may be probable that other cells, such as epithelial cells, play also a prominent role in chronic asthma.

[Why are some allergens enzymes?]. / Pourquoi certains allergènes sont-ils des enzymes?

In the last ten years, progress in the field of allergy research has led to the purification of some of the major allergens and to a better knowledge of their physico-chemical properties. A number of studies have shown that some allergens have enzymatic activities. Molecular biology has provided the means to clone and sequence genes encoding these allergens and to produce recombinant allergens in yeast and bacteria. Epitope mapping of natural and synthetic allergens, using polyclonal or monoclonal antibodies and cell-stimulation tests, has also contributed greatly to the understanding of their immunogenicity and allergenicity. Analysis of these new data allow us to explain why some allergens are enzymes.

[Practical aspects of leukotriene E4 determination in urine]. / Aspects pratiques du dosage du leucotriène E4 dans les urines.

Leukotrienes constitute a class of potent biological mediators of inflammation and anaphylaxis. However, their routine assay in various biological fluids is restricted by the complexity of the methodology. Previously this could only be performed by research laboratories with high pressure liquid chromatography and radioimmunological capabilities. The recent availability of kits for immunoenzymatic assay of leukotrienes offers a new tool for clinical laboratories provided the limitations of the method are understood. We suggest a simplified methodology for direct urinary LTE4 detection and outline a number of areas of concern encountered with this method.

[Reproducibility of intradermal tests after anaphylaxis caused by muscle relaxants]. / Reproductibilité des tests cutanés intradermiques après anaphylaxie aux myorelaxants.

Intradermal tests with 5 muscle relaxants were performed on two occasions in 56 patients who had experienced an adverse event during general anaesthesia: anaphylactoid reaction with at least one positive test 19.5 +/- 13.5 months previously in 50 cases; adverse reaction unrelated to muscle relaxants and with negative tests 21 +/- 6.4 months previously in 6 cases. Sixteen healthy subjects who had never been tested served as controls; their tests were all negative. The reproducibility of 244 assessable tests in the 56 patients reached 88.1%. Twenty-three (9.4%) of the tests previously positive had become negative and six (2.5%) of the tests previously negative had become positive. Tests performed with pancuronium or vecuronium had more often become negative (47% and 40% respectively) than those performed with the other 3 muscle relaxants tested (P less than 0.001). These results suggest that skin tests should be repeated prior to general anaesthesia in all patients who previously developed an anaphylactoid reaction to muscle relaxants.

[Predictive value of intradermal tests using muscle-relaxing drugs]. / Valeur prédictive des tests intradermiques aux curarisants.

A retrospective postal inquiry was carried out to find out a possible relation between the results of intradermal tests carried out for a previous anaesthetic and the course of a second anaesthetic performed afterwards. This study included 350 patients who have had an intradermal test to vecuronium, alcuronium, suxamethonium, gallamine, pancuronium, thiopentone, fentanyl and droperidol between March 1984 and November 1986. Eighty-nine did not reply (25.4%), 183 (52.3%) did not undergo new general anaesthetic since the skin tests, whilst 78 (22.3%) did. The inquiry was then sent to the 73 anaesthetists corresponding to the last group of patients. The 51 complete answers included 62 anaesthetics. Twenty-four patients had negative intradermal tests before the new anaesthetic, the other 27 having had a test positive to at least one muscle relaxant. Of these latter, 16 were given a muscle relaxant during their general anaesthetic, selected among those resulting in a negative intradermal test. Thirteen had undergone skin testing because of an anaphylactic reaction during induction. No new anaphylactic reaction was observed. Three anaesthetists only were not aware of the results of the intradermal tests at the time of the new anaesthetic. These data tend to demonstrate that a muscle relaxant could be injected in a patient who has had a previous anaphylactic reaction with positive intradermal tests, provided that the drug chosen for the new anaesthetic does not give a positive intradermal reaction.

[Intolerance to sulfonamides in HIV infected subjects. Toxic and allergic origin]. / Intolérance aux sulfamides chez les sujets infectés par le VIH. Origine toxique et allergique.

Intolerance to sulfonamides is very frequent in HIV-infected subjects and 10 times more common than in the general population. There are 2 types of intolerance to sulfonamides: early reactions with urticaria or angioedema, which are IgE-dependent, and late reactions with febrile rash, which occur between the 6th and 12th days of treatment and represent the vast majority of allergic manifestations in HIV-infected subjects. Clinically, these reactions resemble serum sickness, but all physiopathological hypotheses point to toxic process. The degradation of sulfonamides has two different pathways: the N-acetylation pathway which is genetically determined and saturable, and the cytochrome P450 pathway which produces toxic hydroxylamine metabolites "detoxified" by glutathione. In HIV-infected subjects detoxication is thought to be incomplete due to an acquired deficiency of glutathione and probably increased in the presence of a slow acetylation profile.

[Cutaneous reactions to heparin: immunological and clinical aspects]. / Réactions cutanées à l'héparine: aspects immunologiques et cliniques.

Skin reactions to heparin are rare, the most frequent manifestation being skin necrosis. Reactions occur either as an isolated manifestation or within a context of heparin-induced thrombopenia. Urticarious and eczematous reaction, either localized at injection sites or with a general distribution, have been recently reported. In all cases, it is mandatory to withdraw heparin therapy. Such accidents can be observed with all types of heparin (standard heparin and low-molecular weight heparin). Cross-reactions between two types of heparin are frequent. Skin tests can be used to guide heparintherapy.

[Skin tests and chymopapain-specific immunoglobulins E after chemonucleolysis]. / Tests cutanés et immunoglobulines E spécifiques à la chymopapaïne après chimionucléolyse.

Skin tests (prick tests) with chymopapain were performed on 3 groups of patients: 75 patients awaiting chemonucleolysis with chymopapain (group I), 42 of these 75 patients 2-3 weeks after chemonucleolysis (group II), and 60 atopic patients suffering from asthma and/or rhinitis with positive skin tests to at least one of the airborne allergens (group III). A positive skin test was found in one patient of group I (1.33%), one patient of group III (1.7%) and 11 patients of group II (26.2%). Thus, sensitization to chymopapain is not more frequent among atopic patients, and chemonucleolysis has a highly significant (P less than 0.001) sensitizing effect. Chymopapain-specific IgE's were found in one out of 75 patients (1.33%) before, and in 14 out of 45 patients (31%) after chemonucleolysis; the difference was significant (P less than 0.001). Concordance between skin tests and specific IgE's reached the 74% level. Our results are consistent with those of the literature. They show that prick tests with a 10 mg/ml solution of chymopapain constitute, for the time being, a simple, reliable and cheap method for detecting subjects at risk.

[Anaphylactic reactions to aprotinin: intradermal diagnostic tests] . / Réaction anaphylactique à l'aprotinine: intérêt diagnostique des tests intradermiques.

A 66-year-old patient, undergoing heart surgery, developed an anaphylactic reaction following the first administration of a test-dose of aprotinin. Skin tests were performed six months later. Prick-tests with 10(-2) and 10(-1) aprotinin dilutions were negative but intradermal reaction with a 10(-3) dilution was clearly positive. The level of aprotinin specific IgE was high, both in the serum obtained before surgery and in the one sampled on the day of the testing. As no reaction was observed during the tests, skin-testing and specific IgE appear to be an interesting alternative to a potentially dangerous test-dose, but they both need further evaluation.

[Anisakis simplex and immediate hypersensitivity reactions]. / Anisakis simplex et réactions d'hypersensibilité immédiate.

BACKGROUND: Anisakis simplex is one of the nematode worms that parasitize sea mammals. When its larvae are accidentally ingested by humans, they can infect the host, resulting in anisakiasis manifested by digestive symptoms, or they may cause an allergic reaction, which in some cases may be severe. CASE REPORTS: We report three cases of acute urticaria associated with abdominal pain, and hypotension in two of them, starting two to six hours after ingestion of raw fish. The diagnosis of an allergic reaction caused by Anisakis simplex was based on the clinical histories and positive tests for anisakis-specific IgE. DISCUSSION: In patients with acute urticaria associated with abdominal symptoms, a history of ingestion of raw fish in the preceeding hours is evocative of gastro-allergic anisakiasis. In association with symptomatic treatment, gastrointestinal endoscopy allows the larvae to be visualized and removed, which may relieve the symptoms and provide a diagnosis before the results of skin testing and serological assay are known.