Les réactions allergiques et pseudoallergiques aux antalgiques,antipyrétiques et anti-inflammatoires non stéroïdiens

Antalgics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, but suspected allergic reactions to these drugs are rare, especially in children. Most frequent reactions are cutaneous (urticaria, angioedema) and respiratory (rhinitis, asthma). Other reactions (anaphylaxis or anaphylactoid reactions, potentially harmful toxidermias) are rare. In a few patients, reactions may result from a specific (allergic) hypersensitivity (HS), with positive responses in prick and intradermal tests (anaphylaxis, immediate urticaria and/or angioedema) and in intradermal and patch tests (non-immediate reactions). However, most reactions result from a non-specific (non-allergic) HS (intolerance), with a frequent cross-reactivity between the various families of antalgics, antipyretics and NSAIDs, including acetaminophen (paracetamol). Based on a convincing clinical history and/or positive responses in challenge tests, intolerance to antalgics, antipyretics and NSAIDs has been diagnosed in 13 to 50% of the patients with allergic-like reactions to these drugs. Risk factors for HS to antalgics, antipyretics and NSAIDs are a personal atopy and age. In our experience, 50% of the children with allergic-like reactions to antipyretics, antalgics and NSAIDs were diagnosed intolerant to these drugs. Risk was high in children reporting reactions to NSAIDs (aspirin, ibuprofen) and lower in children reporting reactions to paracetamol. All the children intolerant to paracetamol were also intolerant to NSAIDs. In contrast, most children with NSAID intolerance were tolerant to paracetamol. A personal history of atopy and a mean age ≥ 8 years were significant risk factors for intolerance to antalgics, antipyretics and NSAIDs.     

Valeurs diagnostique et prédictive des tests cutanés aux médicaments et substances biologiques

Immediate-reading skin tests (pricks and intradermal tests) are indicated in patients reporting symtoms suggesting immediate-type hypersensitivity reactions. The diagnostic and/or predictive value of these tests is good with betalactams, latex and myorelaxants, and several other substances such as corticosteroids, dyes, antiseptics, vaccines, etc. Non irritant concentrations have been determined for several substances (betalactams, myorelaxants, etc.), but are unknown for numerous other substances. For other substances, non irritant concentrations in skin tests should be evaluated in control patients, in parralel with skin tests performed in patients. The diagnostic value of nonimmediate-reading skin tests is highly variable, and depends on the drug and the nature of the symptoms. Although the sensitivity and the specificity of nonimmediate-reading skin tests are not perfect, these tests are useful in the diagnosis of mild to moderately severe toxidermias, such as nonimmediate urticarias and angio-oedemas, fixed drug eruptions, maculopapular rashes, and acute generalized exanthematic pustulosis. In contrast, their diagnostic value is low in potentially severe toxidermias. The diagnostic value of responses in intradermal tests is usually higher than in patch-tests. However, patch-tests may be positive in few patients with negative intradermal tests. Ideally, skin tests should be performed between 6 weeks and 1 to 2 years after the clinical reaction. However, most nonimmediate drug sensitizations can be diagnosed several years later.     

Avantages et limites des tests sanguins in vitro lymphocytes T/interféron gamma comparativement au test intradermique à la tuberculine pour le diagnostic de tuberculose

The development of in vitro blood tests that measure the delayed hypersensitivity reaction developed after contact with Mycobacterium tuberculosis will change progressively the diagnosis of M. tuberculosis infection. These blood assays (Quantiferon TB Gold^TM, Cellestis, Australia; T-SPOT.TB^TM, Oxford Immunotec, United Kingdom) use specific, complex M. tuberculosis antigens (ESAT-6 and CFP-10), whereas the intradermal Mantoux test is done with tuberculin, a complex mixture of more than 200 antigens. ESAT-6 and CFP-10 are absent from all the BCG vaccine strains used throughout the world. Significant improvement in the specificity with equivalent or increased sensitivity of the in vitro tests compared to the Mantoux test will lead eventually to replacement of the latter.     

Reproducibility and use of low-concentration skin prick test.

We aimed to evaluate the reproducibility of the skin prick test performed with serial 1:4 dilutions of commercial standardized extracts in comparison with serum-specific IgE and the undiluted commercial extract. Twenty-four subjects sensitized to one (17 cases) or two (seven cases) inhalant allergens were selected and submitted to duplicate skin prick tests with concentrated commercial allergenic extracts or with serial 1:4 dilutions of the same extracts in two different examinations 7 days apart. Blood samples were obtained from 17 of the 24 patients for specific IgE determination. No statistically significant within-patient variations in the area of the wheal in skin prick tests done 1 week apart were found up to the eighth dilution (1:256) of the commercial allergen. On a patient-by-patient basis, only some dilutions showed a statistically significant correlation between allergen-specific IgE and the wheal area elicited by the same allergen, and a significant correlation was found between the wheal elicited by 10 mg/ml histamine and both the concentrated and diluted allergens (up to the sixth dilution). In polysensitized patients, the allergen producing the largest wheal when used in concentrated form did not produce the same result when diluted. The skin prick test with low-potency allergens was reproducible in individual patients even after a 7-day interval up to a 1:256 dilution of the commercial extract, although there was no clear correlation with allergen-specific IgE concentration. In polysensitized patients, the use of high-potency or low-potency allergens for skin prick tests can lead to different conclusions regarding the relative importance of each allergen.     

Excellente tolérance du prick-test dans l’exploration des allergies médicamenteuses en milieu de type hospitalier

Introduction

The diagnosis of drug allergy is based on clinical history and skin tests. Although medical literature reports a risk of allergic reactions during skin tests, our experience, based upon several thousands of patients since 1998, strongly suggests that skin tests with drugs are well tolerated.

Patients and methods

In this prospective study, we analysed the adverse effects observed during skin testing of 183 patients explored for suspected drug-induced immediate hypersensitivity, such as urticaria, angioedema, bronchospasm, and anaphylactic shock, between November 2004 and March 2005. Patients were first tested with prick-tests, and with intradermal tests (IDT) at 1/1000 and 1/100 dilutions of the prick solution only when the prick-tests were negative.

Results

One hundred and seventy-nine prick-tests and 169 IDT were realised with drugs diluted by the hospital's chemist. Nine of the 183 patients (5.0%) were diagnosed as having drug-induced immediate-type hypersensitivity, based on a severe suggestive initial reaction and immediate responses in prick or IDT. No reaction was observed during prick testing. IDT induced a non-severe reaction, with less severe symptoms than the initial accident, in one patient only.

Conclusion

Our results confirm the excellent tolerance of prick-tests. Also, they strongly suggest that it is important to investigate drug hypersensitivity with a well-defined protocol, in a hospital setting, starting with pricks and using low concentrations of drugs in IDT.     

Immediate systemic hypersensitivity reaction associated with topical application of Australian tea tree oil.

Australian tea tree oil has been used as a veterinary antiseptic for many years and, more recently, has been extended into human use. There have been many reports of allergic contact dermatitis and toxicity reactions, but it has never been implicated in immediate systemic hypersensitivity reactions. A 38-year-old man experienced immediate flushing, pruritus, throat constriction, and lightheadedness after topical application of tea tree oil. Our purpose was to determine whether this represented an immunoglobulin E (IgE)--mediated reaction. Skin-prick and intradermal testing was performed, as well as enzyme-linked immunosorbent assays for specific IgG and IgE against tea tree oil. The patient had a positive wheal and flare reaction on intradermal testing with tea tree oil. All five patient controls were negative on skin testing. No specific IgG or IgE was detected. We present the first reported case of an immediate systemic hypersensitivity reaction occurring after topical application of Australian tea tree oil, confirmed by positive wheal and flare reaction on skin testing.     

A case received pre-exposure immunization against rabies by intradermal injection of rabies vaccine because of allergic reaction to the component of the vaccine]

A female, 25 years of age, came to our clinic to receive pre-exposure immunization against rabies. In another hospital she was tested to find out whether she was allergic to the components of rabies vaccine (PCEC) manufactured by the Chemo-Sero-Theraptic Research Institute (Kaketsuken) by cutaneous reaction using a 2,000-fold diluted PCEC. She showed a positive reaction. In our clinic she was again examined by skin test using 0.1 ml of 10-fold diluted PCEC. She showed wheal and flare reaction. Further we tested using 0.05 ml and 0.1 ml of non-diluted PCEC. Her skin reaction did not increase by several mm in diameter. So we decided to immunized her against rabies with intradermal injections of PCEC instead of subcutaneous injections that is indicated by the manufacturer. The second intradermal injections were done to right and left forearms a week later. Then the third shot was given 4 weeks after the second. At 2 weeks after the third injection her blood sample was taken to measure anti-rabies antibody titer by ELISA method with Platelia rabies kit (Diagnostic Pasteur, France). She had 6.7 U/ml of anti-rabies ELISA antibody that was much higher than the protective level (0.5 IU/ml) officially recognized by WHO. Therefore, it is concluded that she had produced sufficiently high level of anti-rabies antibody with intradermal injection of PCEC. It is reasonably recommended to investigate further if the intradermal injection of PCEC will be an effective method as a pre-exposure immunization against rabies.     

Les urticaires au cours d'un traitement anti-infectieux : le médicament est-il vraiment souvent en cause ?

Hypersensitivity drug reactions, including immediate allergic reactions, are one of many types of adverse drug reactions. While urticaria is one of the most frequent clinical forms of drug allergy, other manifestations may also occur. To determine that the cause of an urticarial reaction is drug-induced is important, although in most cases this diagnosis is not established. Diagnosis is based on immediate skin test reactions and drug provocation testing. These tests are not without danger, which is why a complete clinical history and the patient's responses to the ENDA (European Network for Drug Allergy) questionnaire, as well as careful attention to necessary precautions, are important. The Drug Allergy and Hypersensitivity Database (DAHD) includes 1,267 reports of urticaria possibly due to drugs; β-lactams were the most frequently involved (35.6%). However, a drug allergy work-up demonstrated that only 15.4% of these reactions were actually due to a drug; 44.6% were diagnosed by means of skin tests, the rest by provocation tests. Of the positive tests, 41.2% were positive within the first hour and 16.6% only after 24 hours. Urticaria may be induced by drugs, especially antibiotics, but drugs are not the main cause of urticaria. The diagnosis of drug allergy requires confirmation by relevant tests.     

Anaphylactic reaction to drugs commonly used for gastrointestinal system diseases: 3 case reports and review of the literature.

Proton pump inhibitors and H2 receptor antagonists, which are commonly used to treat peptic ulcer and gastroesophageal reflux diseases, are associated with a low incidence of adverse reactions. We report 3 cases of anaphylactic reactions induced by lansoprazole or ranitidine diagnosed in a population of 8304 first-referral patients over a 13-year period. Cutaneous sensitivity to famotidine, ranitidine, omeprazole, pantoprazole, and lansoprazole was evaluated by skin prick tests with a concentration of 10 mg/mL (at 1:1000, 1:100, 1:10 and 1:1 dilutions), and if they were negative, intradermal skin tests were performed with the same dilutions of the extracts. Single-blind, placebo-controlled oral provocation tests were performed with lansoprazole, omeprazole, famotidine, and ranitidine in 2 cases. One case involved anaphylaxis during an oral provocation test with lansoprazole, and 2 cases were anaphylactic reactions to ranitidine. In both cases the skin test was positive for ranitidine and in 1 case an oral provocation test was also positive. The second patient refused that test. Cross reactivity to other H2 receptor antagonists was not demonstrated and a safe alternative drug was found for all 3 patients. Although incidences of anaphylactic reactions induced by proton pump inhibitors or H2 reactions are rare, they can be life threatening.     

Limitations of the intradermal test for schistosomiasis mansoni: experience from epidemiologic studies in a Puerto Rican community

The intradermal reaction with Schistosoma mansoni adult-worm antigen (35-40 microgram/ml nitrogen) was evaluated as an edpidemiologic tool in an endemic Puerto Rican community where the prevalence of S. mansoni infection was 36% and the geometric-mean egg count was 17.6 eggs/g. Subcutaneous injections of antigen were made in forearms, and stool specimens were examined for S. mansoni eggs by a formol-ether concentration method. Of 296 persons tested, 43% had positive intradermal reactions (greater than or equal to 1.0 cm 2 at least twice the area of the control wheal), compared to 48% positive stool examinations. However, sensitivity was low at 36% for children 14 yr old or less, and only 73% to 79% for adults. The test results were very specific for children (96%), but 32% of stool negative adults were positive. Mean wheal area was not directly related to intensity of infection as determined by egg counts in either children or adults, but did increase directly with age. Mean wheal areas were greater for males than females (both children and adults) at all intensities of infection. Because of unsatisfactory sensitivity and specificity the intradermal test may overestimate the prevalence of infection when rates are low, and underestimate prevalence of infection when rates are high. For its proper interpretation, complementary parasitologic data from stool surveys are required.     

Ragweed skin test responsiveness correlates with specific immunoglobulin E levels.

Evaluation for allergic rhinitis requires an objective measure of atopy. Serum eosinophils, total and specific immunoglobulin E (IgE), and skin testing have been used as this measure. The objective of our study was to examine the relationship between in vitro allergy tests and in vivo responsiveness. We compared eosinophil counts, total IgE, and the specific IgE radioallergosorbent test (RAST) measurements to end point skin test titrations with ragweed. Forty subjects > or = 18 years of age with at least a 2-year history of moderate to severe ragweed-allergic rhinitis and a positive skin-prick test to ragweed participated in this study with 33 subjects having data for all measurements. End point skin tests were performed by intradermal injection of 0.03 mL of threefold dilutions of standardized short ragweed extract into the forearm. Ragweed-specific IgE was significantly correlated to end point wheal and erythema concentrations. The results were similar whether the endpoint wheal (r = -0.714; p < 0.001) or erythema (r = 0.862; p < 0.001) concentration was used, and the correlation between these two values was significant (r = 0.97; p < 0.001). However, 8 of 33 subjects had a negative specific IgE RAST value for ragweed. There was a significant relationship between ragweed-specific IgE and total IgE (r = 0.72; p < 0.01). No significant correlations were found between blood eosinophils and either total IgE, ragweed-specific IgE, and end point wheal or erythema concentrations. Skin test responsiveness to ragweed correlated with in vitro ragweed-specific IgE levels, but these tests are not equivalent indicators of the degree of IgE-mediated sensitivity.     

L'allergie au tournesol et à son huile : rôles du contact,de l'ingestion et de l'inhalation

We report the case of a 5-years old girl with food allergy to sunflower oil. Sensitivity to sunflower oil and seeds was demonstrated by skin tests whereas assays of serum for sunflower-specific IgE were negative. An oral challenge test with 54 ml of sunflower oil was positive. The patient also reacted to cutaneous contact and inhalation of sunflower seeds. Depending on the route of contact –– skin contact, ingestion or inhalation –– sunflower oil and seeds can trigger symptoms such as urticaria, erythema, vomiting, dyspnea or fatigue.     

Anaphylaxis to oral furosemide

Furosemide, one of the most used diuretic drugs, rarely induces type-1 allergic reactions It is included in the non-aromatic sulfonamides but a cross-reactivity mechanism between this group and the sulfonamides antibiotics, has not been clearly demonstrated. A 24-year-old woman, 10 minutes after the intake of one pill of Seguril 40mg experienced oral itching, generalized urticaria, facial angioedema, dyspnea and hypotension. She recovered after the administration of parental adrenaline, methyl-prednisolone and dyphenhydramine. An skin prick test with furosemide (10 mg/ml) was negative. The intradermal skin tests were positive to furosemide (1 %) as well as sulfamethoxazole (0.03 mg/ml), with 10 atopic and non-atopic negative controls. The patient rejected the performance of an oral challenge test with sulfamethoxazole. IgE-mediated reactions to furosemide are infrequent, but it could be the cause of life-threatening reactions. We have reported a case of anaphylaxis after the oral administration of furosemide with a demonstrated hypersensitivity mechanism through the positive intradermal skin test. The previous administration of the drug could probably the mechanism of sensitization, but the positive intradermal test to sulfamethoxazole would open the hypothesis of a cross-reactivity between non-aromatic and antimicrobial sulfonamides. It could be necessary an oral challenge test with furosemide in allergic patients to sulfamides.     

Asthme et rhinite d’origine professionnelle causés par le séné

The authors report a case of occupational allergy by senna: a 28-year-old female developped an IgE-mediated asthma and rhinitis caused by senna in a phytopharmaceutical factory: the skin prick test gave a 12-mm wheal reaction, the CAP-RAST Phadia with senna was positive (2.9 kU/L) and in the bronchial challenge test, she exhibited a strong reduction of FEV1 (48 %).     

Anaphylaxis to muscle relaxants: rational for skin tests

IgE-dependent allergy to muscle relaxants (MR) has an estimated prevalence of 1 out of 6500 General Anesthesias (GA). 62% of anaphylaxis during surgery are due to MR anaphylaxis. All the molecules are divalent, carrying two NH4+ epitopes (quaternary ammonium ions), either structurally or after rapid in vivo protonization (vecuronium). The excellent overall performance of skin test makes them the golden standard for the diagnosis of anaphylactoid reactions. Techniques include intradermal tests and prick-tests. The current localizations are the forearm and the back. Positivity criteria are 3 mm for prick-tests. For IDTs, the criterium is the doubling of the size of the injection papula, when 0.02 to 0.04 ml is injected: 8 mm. The recommended concentrations are not falsely negative. Commercial concentrations can be tested by prick tests, except for mivacurium and atracurium tested of 1:10 dilution. A scale of concentrations is advised for IDT starting with 1:10,000, up to a normally non reactive concentration that is: 100 micrograms/ml (succinylcholine), 200 micrograms/ml (gallamine), 10 micrograms/ml (atracurium), 2 micrograms/ml (mivacurium), 200 micrograms/ml (pancuronium), 400 micrograms/ml (vecuronium), 1,000 micrograms/ml (rocuronium), 200 micrograms/ml (cis atracurium). The specificity and sensitivity of the skin tests to MRs are greater than 95%. The reproducibility over years is 88%. The overall concordance of PT and IDR is 97%. Both types of tests can be used for the diagnosis. IDT have to be carried out for the search of the cross sensitization. 84% of patients do have cross sensitization to MRs but only 16% react to all MRs. The further use of MRs selected by negative IDTs has been proved to be safe.     

Choc anaphylactique à l'Augmentin chez une patiente présentant des tests cutanés et un test de provocation négatifs à l'amoxicilline

Mme M. was seen in consultation with a history of possible allergy to penicillin. The patient reported that three months earlier she had experienced the sudden onset of a generalized but not very severe urticarial reaction, which included swelling of the face, beginning four days after taking amoxicillin, but not any other medication. She was not aware of any previous reaction associated with taking any drug, including penicillin. Skin tests with major and minor penicillin determinants, and then with amoxicillin, up to a concentration of 20 mg/ml intradermally were negative. It was then elected to do an oral provocation test with amoxicillin. She tolerated a single 1 g oral dose perfectly well. Eighteen months later, she was seen again following an episode of anaphylactic shock that had begun immediately after taking 1 g of amoxicillin associated with clavulanic acid (Augmentin^®). Between the two consultations, the patient had received no betalactamines, whereas she had tolerated two courses of treatment with macrolides. At the second consultation, skin tests with penicilloyl-polylysine and amoxicillin were definitely positive. This observation suggests two hypotheses, which are not however mutually exclusive: 1) The low predictive value of skin and provocation tests in patients weakly sensitized (Could such patients continue treatment with amoxicillin for several more days?); 2) the possibility that an initially weak sensitization was potentiated by the skin and provocation tests (Is it advisable to systematically do a second allergy workup several weeks after the first one to exclude the possibility of sensitization in this type of patient?).     

Hypersensibilité immédiate aux cosmétiques et aux médicaments topiques

Numerous molecules can induce contact urticaria (CU) either involving a specific IgE dependent immune reaction or through a non-immunological mechanism. Systemic manifestations (rhinitis, conjunctivitis, bronchospasm, and anaphylaxis) sometimes occur with CU. A number of topical medicines can cause CU: chlorohexidine applied on mucus membranes, for example, can induce severe CU with anaphylaxis; iodinated povidone, alcohol and Emla^® cream rarely do. Among cosmetics, those used in beauty parlors, for example paraphenylenediamine, ammonium persulfate and Crotein Q, are the most frequent cause of CU. Some cases of CU associated with the use of cosmetics containing plant proteins, such as wheat or sesame, will be described. Diagnosis of CU entails open tests and prick tests, occasionally intradermal tests. Testing must nevertheless be done with caution, first using very dilute solutions because of the risk of anaphylaxis.     

Skin tests in patients with history of anaphylactic reaction to penicillin]

Skin tests including immediate patch test (IPT), skin prick test (SPT), or intradermal test (IT) with penicillin G(PenG) and SPT with benzylpenicilloyl human serum albumin (BPO) were done in 54 patients with history of anaphylactic reaction to penicillin or shock of unknown cause. 26 patients with penicillin allergy were diagnosed. BPO specific IgE measured with ELISA gave a lower positive rate in detecting penicillin allergy as compared with the tests mentioned above. The results of skin tests in 26 patients showed that IPT with 500 IU/ml of PenG was not only accurate but also safe. Because no skin injury occurred and PenG residue could be washed out, the amount of PenG penetrated into skin is very small, thus, adverse reactions were very few. It is recommended that IPT with PenG in 500 IU/ml concentration is performed at the beginning of skin tests. If negative, SPT and then IT both with a solution of 500 IU/ml concentration are carried out, until a positive reaction occurs. This procedure is relatively accurate, simple and safe.     

Mesure des aérosols fongiques dans l'air : utilisation de l'ergostérol

The aim of this study was to develop a method to evaluate the level of airborne indoor fungal exposure. To this end, we have adapted and applied a biomass assay method. Using liquid phase chromatography (HPLC), a specific component of the fungal cell membranes (ergosterol) was measured. This method allowed us to identify this substance and to detect it to a limit of 40 ng/ml (n = 33, σ = 5). When used in association with a rotating foam air sampler, it was possible to measure the airborne fungal contamination with a detection limit of 0.4 ng/m³, corresponding to a theoretical value of 150 spores/m³. Measurement of ergosterol carried out at different indoor sites showed that this method can be used to evaluate different types of exposure of individuals to airborne fungal contamination.     

Allergie aux corticostéroïdes

Corticosteroids are widely used for their anti-inflammatory and immunosuppressive properties in the treatment of respiratory, allergic and autoimmune diseases. Their adverse effects are well known, but allergic reactions to these drugs are relatively rare although they are sometimes severe. While the route of administration was different in the two cases reported here - one oral, the other by inhalation - the adverse reactions began soon after administration and presented the same symptoms, namely, cough, dyspnea and wheezing. Skin tests and/or provocation tests are essential to confirm the diagnosis. They require tests with different groups of molecules. For our young asthmatic patient, the results were positive for only one group of corticosteroids, which allowed us to prescribe an alternative treatment.