F. Berard

Usefulness of basophil activation tests for the diagnosis of IgE-mediated allergy to quinolones

vidual (5). Food Standards Code has not eliminated two significant problems, dealing with the use by manufacturers of ‘may contain’ statements, as well as complex terminology which are still extensive. These reveal that the guidance is insufficient and limited to stating, which allergenic substances should be declared on a label. This study reveals consumers’ confusion on ingredients contained in commercial food products. There is profound need to state exact terms for use for each food allergen and allow only limited use of ‘may contain’ statements to avoid misleading labelling.

Methylprednisolone‐induced anaphylaxis: diagnosis by skin test and basophil activation test

Although corticosteroids are broadly used to treat asthma and allergic disorders, steroids themselves, however, can induce hypersensitivity reactions (IHS) (1). We present the first case of anaphylactic shock reaction due to intravenous methylprednisolone (MP) that occurred during anaesthesia, with positive skin tests and positive basophil activation test (BAT). In July 2007, an 18-year-old female patient experienced anaphylactic shock during general anaesthesia for a dental extraction [tryptase: 38 (N < 15 lg/l) and histamine 359 nmol/l (N < 10 nmol/l)], which was rapidly reversed by epinephrin. The drugs used during anaesthesia were: diazepam, sufentanil, mepivacaine, MP and amoxicillin. The skin tests (prick and intradermal tests – IDT) carried out in January 2008 were negative for latex and every other drug used, but were positive for MP according to the prick test (10 mg/ml) and the IDT (positive at 100 and 10 lg/ml). The BAT analyses, by flow cytometry, the percentage of polynuclear basophils expressing CD203c after in vitro MP re-stimulation compared with the percentage of basophils expressing CD203c without re-stimulation. The patient’s BAT was positive at 71% (control 2%). The BAT was negative in two healthy volunteers. We performed a corticoid battery of skin tests and found a positive cross-reaction with hydrocortisone, while the prick and IDT tests were negative for prednisone, betamethasone, prednisolone and beclomethasone. The BAT with prednisone was negative. Carboxymethylcellulose (CMC) was not tested in our case. In June 2008, the patient was challenged with prednisone in intensive care unit without allergic reaction. Severe IgE mediated anaphylaxis after intra-venous corticosteroids injection occurs in 0.1% of the patients (2). Corticosteroids have been classified in four reactivity groups (A, B, C and D) based on their structural and clinical characteristics. Our observation suggests that skin tests could be useful for the diagnosis of MP IHS. Carboxymethylcellulose is a carbohydrate widely used as an additive in tablets, cosmetics, some injectable hormone formulations and food. Anaphylaxis to CMC in corticosteroid preparations has been reported (3). However, in our case, there was a cross reactivity with hydrocortisone, which does not contain CMC and excluded a CMC immediate hypersensitivity. Skin tests sensibility for MP anaphylaxis is unknown, but several observations have shown that they could be of interest (2). We have found cross reactivity between MP and hydrocortisone, and two drugs belonging to the A group of corticosteroids, which are frequently involved in corticosteroids IHS. Nevertheless, our patient did tolerate prednisolone, another group A steroid, as previously described (4). Interestingly, the BAT was also positive confirming the patient IgE mediated MP hypersensitivity. An increasing number of studies have demonstrated that flow cytometry is a reliable tool for monitoring basophil activation upon allergen challenge by detecting membrane expression of degranulation/activation markers (CD63 or CD203c) (5). BAT seems to be a reliable tool for the diagnosis of IgE mediated allergy to betalactams or muscles relaxants (curare) (6). To our knowledge, BAT has not been yet described as a diagnosis tool for corticosteroids anaphylaxis. Our present case suggests that the BAT could be a sensitive in vitro assay for the diagnosis of MP allergy.

Physiopathologie de l’urticaire

Resume L’urticaire est un œdeme dermique resultant de la dilatation vasculaire et une fuite de liquide dans la peau en reponse a des molecules liberees par les mastocytes. Le principal mediateur responsable de l’urticaire est l’histamine. Cependant, la diversite des differentes formes d’urticaire suggere que d’autres molecules, y compris les leucotrienes, les prostaglandines, differentes cytokines et chimiokines, produites et liberees apres l’activation des mastocytes contribuent au polymorphisme de ce symptome et l’evolution variable des lesions. Il est classique de distinguer l’urticaire immunologique et l’urticaire non immunologique. L’urticaire immunologique est une reaction d’hypersensibilite mediee par des anticorps et/ou des lymphocytes T qui se traduit par l’activation des mastocytes. Bien que les immunoglobulines (Ig) E, responsables de l’hypersensibilite (HS) de type I, ont ete longtemps considerees comme la principale cause immunologique responsable de l’activation des mastocytes, cette voie est en fait rare. Il est maintenant bien etabli que l’urticaire puisse resulter frequemment de la liaison d’auto-anticorps IgG anti-IgE et/ou au recepteur des IgE presents sur les mastocytes (reaction d’HS de type II). Ces urticaires auto-immunes representent jusqu’a 50 % des patients atteints d’urticaire chronique. L’activation des mastocytes peut egalement resulter mecanismes d’HS de type III par la liaison de complexes immuns circulants a des Fc-recepteurs pour les IgG, qui sont des recepteurs activateurs des mastocytes. Enfin, dans certains cas, les lymphocytes T peuvent induire l’activation des mastocytes, ainsi que la liberation d’histamine (type IV HS). Les urticaires non immunologiques resultent de l’activation des mastocytes par l’intermediaire de recepteurs membranaires impliques dans l’immunite innee (recepteurs aux fractions du complement, recepteurs de type Toll, recepteurs aux cytokines/chimiokines, recepteurs aux opioides), voire par toxicite directe des xenobiotiques (haptenes, medicaments). En conclusion, l’urticaire peut donc resulter de differents mecanismes physiopathologiques qui expliquent la grande heterogeneite des symptomes cliniques et les reponses variables au traitement.

Severe hypocalcemia and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome under deferasirox therapy for myelodysplasic syndrome

To the editor: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare life-threatening adverse drug reaction. The culprit drugs are dominated by Allopurinol and anticonvulsants [1]. The efficiency of deferasirox (DFX) has been reported in the treatment of iron overload secondary to myelodysplastic syndrome (MS) management [2]. We report the first case of DRESS during DFX treatment, associated with severe hypocalcemia. In 2010, a 75-year-old woman, followed for MS since 2004, was admitted in ICU, for exanthema associated with skin necrosis aeras, facial edema, and fever, 15 days after starting DFX therapy. Blood tests revealed no eosinophilia, leukocytosis (13,5 3 10 L (N < 10)), atypical lymphocytes, increased liver enzymes (ALAT until 10 N), prothrombin time at 30% (N > 70%), disseminated intravascular coagulation (DIC) signs (low fibrinogen 0.5 g L (N > 1.8), thrombopenia until 17 3 10 L), and severe hypocalcemia (ionized calcemia at 0.92 mmol L (N > 1.4 mmol L). Ferritin level was high (12,546 lg L (n < 322)), and triglycerides were normal. Serum calcium concentration before DFX therapy was normal. Bone marrow biopsy revealed eosinophils infiltrate (20%) and iron overload. without any sign of hemophagocytic syndrome, leukemia, or MS. VIH,VHB, VHC, HHV6, CMV, and EBV serology and blood polymerase chain reaction were negative. Repeated blood cultures and mycoplasma pneumoniae serology were negative. The evolution was complicated rapidly by cardiac arrest without any etiology except severe hypocalcemia. The vitamin D level (1.25OH D3) was low (<10 ng mL (N > 50)). Parathormone level was normal. Histologic analysis of skin and necrosis areas biopsy revealed perivascular lymphocytes infiltrates with eosinophils, compatible with DRESS and intracapillary thrombosis, compatible with cutaneous lesions of DIC. The diagnosis score, according to criteria published by Kardaun et al. [3], was calculated at 6 and confirm the diagnosis of probable DRESS. At admission, DFX was immediately stopped and systemic intravenous corticosteroid treatment by methylprednisolone 60 mg day and calcium supplementation, without antibiotics, were started. Under this therapy, the cutaneous rash, necrosis, and visceral involvement slowly improved. Nevertheless, electroencephalogram assay revealed the diagnosis of definitive chronic vegetative state probably secondary to cardiac arrest. DRESS is characterized by clinical criterias such as later onset, skin rash, multiorgan involvement, atypical lymphocytes, and eosinophilia [1]. DRESS is a lethal disease with an estimated mortality of 10%. Nevertheless, eosinophilia is often absent or delayed for 1 to 2 weeks, as reported by Chen et al. [4] with only 50% of eosinophilia or atypical lymphocytes in 60 DRESS cases. In our case, corticosteroids were started immediately before admission, which could also rapidly decrease or hide blood anomalies. Furthermore, even if eosinophils level were not high in blood, they could infiltrate other organs, such as the skin or bone marrow, as in our case. Only two cases of DFX allergic reactions have been reported including acute renal failure and delayed hypersensitivity syndrome [5]. DRESS is not well known as being responsible for profound hypocalcemia. Furthermore, hypocalcemia under DFX therapy with recurrence after re-exposure have been reported and suggest that DFX could be a risk factor of hypocalcemia in this case [6]. The suspected pathophysiology is an ‘‘hungry bone syndrome.’’ Under DFX, iron chelation in bone’s patient lead to an increase of bones calcium uptake and in consequence to serum calcium anomalies. In conclusion, clinicians should be aware of the risk of (i) severe hypocalcemia during DFX therapy and (ii) potentially lethal DRESS under DFX therapy, which is being more and more prescribed.

Severe sporotrichoid fishtank granuloma following infliximab therapy for Crohn's disease

To the Editor: Cutaneous adverse reactions of anti-TNFa biotherapies are varied and present frequently as eczematiform reactions, paradoxical psoriasis, or more rarely, infections. We report here a rare form of severe sporotrichoid fishtank granuloma following infliximab therapy that developed in a patient whose hobby was aquariophilia. A 63-year-old man with an otherwise unremarkable past medical history had been treated for Crohn’s disease since 2005 with infliximab, administered intravenously every other month. Steroid treatment was initially administered concomitantly but was discontinued in 2006. In June 2008 the patient presented with 3 nodules of 2 months’ duration that showed a linear arrangement; 2 of them were located on the right thumb (bulb and base of the first metatarsal) and the third one on the inner face of the forearm (Fig. 1). Laboratory work-up revealed raised C-reactive protein (CRP) titers (34 mg/L, N <5 mg/L). Neither lymphopenia nor kidney or liver dysfunctions were found. The diagnosis of sporotrichoid fishtank granuloma was considered clinically and was supported by the patient’s history, as he owned an aquarium and had cleaned it out around the time of the appearance of the nodules. Histological examination showed a moderately dense, diffuse dermal infiltrate made of lymphocytes and occasional histiocytes. Histochemical stains (PAS, Ziehl-Neelsen) failed to show microorganisms. The diagnosis of Mycobacterium marinum infection was confirmed by positive cultures of the microorganism. Infliximab was discontinued and the patient was given minocyclin (20 g/d). After 2 months the lesions had considerably regressed, leaving a residual hyperpigmentation; they healed completely after an additional 2 month’s treatment that was well tolerated. Infliximab was reintroduced in August because of worsening of Crohn’s disease, with no adverse effects to date. The patient mentioned that the skin disease was unknown to his aquariophilic friends and did not seem to be mentioned in specialized magazines. The risk of mycobacterial infections, especially tuberculosis, seems to be higher under TNFa inhibitors. Nevertheless, few atypical mycobacterium infections have been reported affecting the lungs, liver, or the skin. As a matter of fact, TNFa plays an essential role in the defense against infectious agents, namely, mycobacteria, by favoring the recruitment of inflammatory cells participating in the formation of tuberculous granulomas. However, it does not seem involved in granuloma formation but rather in its persistence, by preventing the necrosis of macrophages. To the best of our knowledge, only 3 cases of M. marinum infections have been so far reported under antiTNFa treatment. Confirmation of the diagnosis, which may initially be difficult in the absence of granuloma histologically, was only possible thanks to bacteriological examination in 2 cases, of which ours is the first occurring in an aquarium enthusiast. Remarkably, multiplicity of lesions and a sporotrichoid arrangement were noted in all cases, probably because of the iatrogenic immunosuppression. The treatment of M. marinum infections is a challenge. Single lesions can be excised surgically. First-line treatment for limited forms includes monotherapy with clarithromycin, trimethoprim sulfamethoxazole, minocyclin, or doxycyclin. The treatment must be continued for 2 months after clinical healing. In disseminated forms bitherapy is recommended, with various combinations of clarithromycin (1 g/d), rifampicin (10 mg/kg), minocyclin, and doxycyclin (200 mg/d). In vitro resistance, however, is frequent with ethambutol. When this fails, photodynamic therapy seems to be an interesting option. The choice of treatment, however, remains empirical since no randomized studies have been carried out.

Évolution du remboursement des anticancéreux inscrits sur la liste en sus : impact financier au sein d’un centre hospitalo-universitaire

INTRODUCTIONnIn the context of health expenses control, reimbursement of high-cost medicines with a minor or nonexistent improvement in actual health benefit evaluated by the Haute Autorité de santé is revised by the decree of March 24, 2016 related to the procedure and terms of registration of high-cost pharmaceutical drugs. This study aims to set up the economic impact of this measure.nnnMETHODnA six months retrospective study was conducted within a French university hospital from July 1, 2015 to December 31, 2015. For each injectable high-cost anticancer drug prescribed to a patient with cancer, the therapeutic indication, its status in relation to the marketing authorization and the associated improvement in actual health benefit were examined. The total costs of these treatments, the cost per type of indication and, in the case of marketing authorization indications, the cost per improvement in actual health benefit were evaluated considering that all drugs affected by the decree would be struck off.nnnRESULTSnOver six months, 4416 high-cost injectable anticancer drugs were prescribed for a total cost of 4.2 million euros. The costs of drugs with a minor or nonexistent improvement in actual benefit and which comparator is not onerous amount 557,564 euros.nnnDISCUSSIONnThe reform of modalities of inscription on the list of onerous drugs represents a significant additional cost for health institutions (1.1 million euros for our hospital) and raises the question of the accessibility to these treatments for cancer patients.

Syndrome de Gianotti–Crosti post-vaccinal : une manifestation d’hypersensibilité retardée aux vaccins

Introduction Nous decrivons un cas de syndrome de Gianotti et Crosti survenu apres une vaccination par ROR (PRIORIX®, vaccin rougeole, oreillons et rubeole). Methodes Une femme de 27 ans nous etait adressee en consultation pour hypersensibilite au vaccin PRIORIX®. Elle avait presente en juin 2017, 5xa0jours apres sa premiere injection de PRIORIX®, un prurit des jambes, suivi de l’apparition de lesions erythematopapuleuses. Quelques jours plus tard, l’eruption s’etendait aux 4xa0membres. Un traitement par dermocorticoides locaux a permis la regression de l’eruption en 7xa0jours. Discussion Le syndrome de Gianotti et Crosti est une eruption rencontree principalement chez l’enfant, plus rarement chez l’adulte jeune. Ce syndrome a ete decrit en association avec le virus de l’hepatite B, mais est associe a des etiologies virales variees (EBV, CMV, coksackies, parvovirus B19, VRS). Des formes post-vaccinales sont rapportees (vaccins contre l’hepatite B et A, poliomyelite, ROR). Il s’agit d’une eruption monomorphe, tantot sous forme de multiples papules planes erythemateuses ou couleur chair, tantot de forme papulovesiculeuses. Elle touche surtout les faces d’extension des membres. Les lesions peuvent persister plusieurs semaines et sont prurigineuses. Dans les formes typiques, le diagnostic est clinique. En l’absence d’orientation etiologique ou dans les formes de l’adulte, un bilan minimal comportant un hemogramme, des transaminases et des serologies virales (VHB, VHC, VIH) est suffisant. Le traitement est symptomatique (anti-histaminiques oraux et dermocorticoides) ( Fig. 1 ). Conclusion Nous rapportons un cas de syndrome de Gianotti et Crosti post-vaccinal. Il s’agit d’un diagnostic d’hypersensibilite retarde aux vaccins auquel les allergologues peuvent etre confrontes. Sa survenue ne contre-indique pas les vaccinations ulterieures.

Hypersensibilité retardée aux héparines : faible sensibilité des tests cutanés et nécessité des tests sous-cutanés de réintroduction

Introduction Les heparines peuvent entrainer des reactions d’hypersensibilite retardees allergiques (HSRA), se manifestant par des lesions nodulaires ou eczematiformes aux points d’injection, prurigineuses. Le bilan allergologique comprend classiquement la realisation de patch test (PT) et intradermoreaction (IDR), mais souvent seul le test de reintroduction permet de faire le diagnostic. Nous presentons un cas d’HSRA a une heparine de bas poids moleculaire (HBPM) chez lequel les tests cutanes etaient negatifs, alors que les tests sous-cutanes (SC) ont permis de poser le diagnostic. Cas clinique Une patiente de 64xa0ans, debute un traitement par tinzaparine et fluindione pour une phlebite profonde. Au deuxieme jour, des lesions nodulaires maculopapuleuses prurigineuses apparaissent aux points d’injection, s’etendant secondairement. Les traitements sont stoppes, avec un relais par apixaban. Initialement, l’eruption regresse sans desquamation, mais recidive apres 5xa0jours de traitement par apixaban. Ce tableau clinique nous evoque une HSRA. Un bilan allergologique est realisexa0: –xa0IDR de Tinzaparine (14xa0500xa0UantiXa/mL) d’enoxaparine (4000xa0UantiXa/mL) et de calciparine (12xa0500xa0UI/mL) diluees au centiemexa0; –xa0SC de 0,1xa0mL de ces 3xa0HBPM puresxa0; –xa0PT d’apixaban pur. Resultats Les tests sont lus a 72xa0heuresxa0: le PT et les IDR sont negatifs, en revanche les SC sont positives pour toutes les molecules. Le fondaparinux et le danaparoide sont testes comme alternatives. Les IDR et SC sont negativesxa0; ces deux molecules sont reintroduites avec une bonne tolerance. Discussion Ce cas montre que les IDR sont insuffisamment sensibles pour faire le diagnostic d’HSRA. Nous n’avons pas pose de PT aux heparines car ils sont peu sensibles et les IDR sont a preferer, selon la litterature. Des SC pures de petits volumes (0,1xa0mL) realisees en meme temps que les tests ont permis dexa0: (i) confirmer le diagnostic d’HSRAxa0; (ii) caracteriser les HBPM responsables des reactionsxa0; (iii) identifier les molecules denuees de reactivite croisee.

Hypersensibilité retardée aux produits de contraste iodés

Introduction Identifier la nature des reactions d’hypersensibilites retardees (HSR) aux produits de contraste iodes (PCI) est parfois un defi diagnostique. Nous rapportons un cas de multiples HSR aux PCI dont la prise en charge a fait appel aux tests cutanes, aux tests microbiologiques et a la reintroduction medicamenteuse. Resultats La pose d’un TAVI (Transcatheter Aortic Valve Implantation) et une angioplastie coronarienne ont ete necessaires chez un patient de 70xa0ans. Il a presente des reactions d’HSR de gravite croissante a trois PCI de basse osmolalite (monomere non ioniquexa0: IOPAMIRON, OPTIRAY et dimere non ioniquexa0: VISIPAQUE). Les prick-tests et intradermoreactions lus a 72xa0h etaient positifs pour OPTIRAY et VISIPAQUE. Le Iopamiron reste negatif n’a pas ete reintroduit du fait de la severite de la reaction. D’autres molecules alternatives ont alors ete testeesxa0: monomere non ionique de basse osmolalite (IOMERON, XENETIC et ULTRAVIST), de haute osmolalite (TELEBRIX) et un excipientxa0(ALCAPHOR). Les tests cutanes ont ete negatifs pour le IOMERON, ULTRAVIST et TELEBRIX. Une reintroduction de IOMERON a induit un exantheme diffus isole. Celle du TELEBRIX a ete bien toleree. Le seul PCI de basse osmolalite negatif en tests cutanes a ete l’ULTRAVIST. Devant un test de transformation lymphocytaire et un ELLISPOT negatifs a cette molecule, une reintroduction prochaine est prevue. Discussion De multiples reactivites aux PCI sont possibles par reactivites croisees ou co-sensibilisation. La difference entre ces deux phenomenes est difficile a etablir du fait du biais de memoire des patients et par l’absence de test permettant de les differencier. Conclusion Dans notre cas, de multiples reactivites ont ete retrouvees dans les differentes classes de PCI. Il est donc difficile de se baser uniquement sur la classification actuelle pour definir une alternative therapeutique. Seule la reintroduction de PCI testee negativement permet d’eliminer une reactivite en cas d’HSR aux PCI.

Hypersensibilité immédiate aux antibiotiques : développement d’un score de dépistage diagnostique pour l’allergie

Introduction L’hypersensibilite immediate (HSI) aux antibiotiques est frequente, de nature allergique (HSIA) ou non (HSINA). Son diagnostic repose sur un interrogatoire precis et des tests allergologiques en milieu hospitalier. Or l’acces a ces explorations est restreint. Afin d’ameliorer le parcours des patients ayant une HSI aux antibiotiques, nous postulons que la nature des HSI peut etre suspectee des l’interrogatoire grâce a un score clinique simple et sensible. Methodes Etablir un score de depistage pour differencier des l’interrogatoire les HSIA des HSINA. Les donnees d’interrogatoire de 877xa0patients HSI ont ete comparees aux resultats des tests allergologiques. Les donnees les plus sensibles ont ete determinees. Deux scores de depistage ont ensuite ete elabores en associant ces donnees, pour obtenir la meilleure valeur predictive negative (VPN). Resultats Les donnees «xa0delai d’apparition des symptomesxa0 Conclusion Le score 2, appele IHSCOR associant les deux criteres cliniques simples, permet de suspecter des l’interrogatoire la nature d’une HSI aux antibiotiques. Un IHSCOR nul caracterise par une reaction d’HSI survenant plus d’une heure apres la premiere prise et de grade de severite a 1, avait 99,3xa0% a 99,7xa0% de probabilite d’avoir une HSINA a cet antibiotique. Apres calcul, sur 1000xa0HSI a un antibiotique, 439xa0a 462xa0patients auraient un HISCOR nul, soit une forte probabilite d’avoir une HSINA, selon une prevalence d’HSI estimee de 5xa0a 10xa0%. Cet outil a pour ambition de faciliter l’orientation des patients vers la structure medicale adaptee.