Gianfranco Calogiuri

Alternative glucocorticoids for use in cases of adverse reaction to systemic glucocorticoids: a study on 10 patients.

Background  Reactions to systemically administered corticosteroids are rare, despite their widespread use.

Drug-induced aseptic meningitis.

Aseptic meningitis is a rare but well-recognized complication of drug therapy. The clinical presentation of drug-induced aseptic meningitis (DIAM) is distinct. Symptoms typically include fever, neck stiffness, headache, confusion, nausea and vomiting. The major categories of causative agents are non-steroidal anti-inflammatory drugs, antimicrobials and also intravenous immunoglobulins, monoclonal antibodies and vaccines. These drugs most commonly implicated as causes of aseptic meningitis act more likely through an immunological mechanisms. However, the exact pathogenetic mechanism of DIAM is still unknown. The diagnosis of drug-induced aseptic meningitis is difficult and infectious etiologies must be excluded. In some cases the diagnosis has been confirmed by rechallenging the patient with the suspected agent. In this case, informed written consent is necessary and rechallenge must be medically supervised both to document the response and to offer medical care and advice, if required. The outcome of DIAM is generally good, usually without long term sequelae.

Anaphylaxis to hydrocortisone hemisuccinate with cross-sensitivity to related compounds in a paediatric patient

SIR, In the literature, different reports describe allergic reactions and allergy-like reactions to glucocorticoids in paediatric patients. A 9-year-old female patient was admitted with bronchospasm, facial angio-oedema, an urticarial rash and hypotension after the injection of hydrocortisone hemisuccinate (Solu-Cortef, Pharmacia), 200 mg intramuscularly. During hospitalization, she was treated with intravenous adrenaline, aminophylline and chlorpheniramine, a high dosage of inhaled beclomethasone and oxygen ventilation after she took and tolerated oral prednisone at a low to medium dose (15 mg daily). The clinical history of the patient was characterized by an allergic asthma associated with a nonsteroidal anti-inflammatory drug hypersensitivity. Previously the bronchospasm had been treated with short courses of methylprednisolone succinate intravenously. After a month, the patient had specific allergy tests to glucocorticoids. Percutaneous and intradermal skin tests were performed according to the scheme of Freedman et al. with hydrocortisone hemisuccinate (Solu-Cortef, Pharmacia-Upjohn Company, Milan), methylprednisolone succinate (Solu-Medrol, Pharmacia Upjohn Company), prednisolone succinate (Soluda-Cortin, Bracco Company, Milan, Italy), dexamethasone sodium phosphate (Soldesam, Pharma-Milano Company) and betamethasone sodium phosphate (Bentelan, Glaxo-SmithKline Company, Verona). Skin prick tests were positive at a concentration of 10 mg mL to hydrocortisone hemisuccinate and intradermal tests were positive to both methylprednisolone succinate and prednisolone succinate at 1 and 0Æ1 mg mL, while intradermal tests to dexamethasone and betamethasone at 1, 2 and 4 mg mL gave negative results when they were read 30 min later. An incremental challenge test with oral betamethasone carried out 2 days later at the following dosages: 0Æ5 mg, 1 mg, 2 mg, 4 mg with a delay interval of 1 h after any administration was negative. We have obtained the tolerance to fluorinated glucocorticoids in 10 patients affected by immediate-type reactions to succinate esters of hydrocortisone or methylprednisolone. Recently IgE specific to glucocorticoid molecules has been shown in some reports. Hydrocortisone is a hapten which must bind irreversibly to a protein to become a complete antigen. Bundgaard proposed that cortisol in aqueous solution degrades to steroid-glyoxal, with an aldehyde group in the C21 position, able to bind covalently the guanidine groups of the protein, thus establishing a potentially immunogenic steroid-protein compound as shown in Figure 1. At the same time, Freedman et al. postulated that the high affinity of succinate esters to serum proteins could favour the immunogenic role of succinates, the glucocorticoids most used in emergency situations because of their good water solubility. The disposition of corticosteroid succinate esters, like the steroid-glyoxal (Fig. 2), could promote an IgEmediated reaction. Burgdorf et al. isolated IgE specific to methylprednisolone succinate from the serum of a patient who had anaphylactic shock after a bolus of methylprednisolone succinate. It should be mentioned that the patient tolerated 60 mg of oral prednisone during an incremental challenge test. On the contrary, Polosa et al. described a patient affected by a suspected IgE reaction to oral prednisone who tolerated intravenous administration of methylprednisolone succinate or hydrocortisone hemisuccinate, as shown by intravenous challenge tests. An ultrastructural analysis of interaction between the cortisol hapten and an antisteroid monoclonal antibody (mAb) showed how the position of the link to the carrier protein affects the specificity of the antisteroid mAb. The comparison of the affinity constants of prednisone or prednisolone and hydrocortisone for albumin and transcortin demonstrated that prednisolone binds approximately 2Æ5 times stronger to transcortin and more than 300 times stronger to the albumin molecule. These differences in binding affinity suggest that the presence of the C1–C2 double bond in the A ring sterically favours the binding of prednisolone to each of those serum proteins. As a consequence the D ring and C21 are oriented towards the paratope of specific IgE, which does not recognize the steroid

Allopurinol Hypersensitivity Reactions: Desensitization Strategies and New Therapeutic Alternative Molecules

Allopurinol, an analog of hypoxanthine has been worldwide used for the treatment of hyperuricemia and gout for over 40 years. Unfortunately some patients assuming this medication have developed hypersensitivity reactions ranging from mild cutaneous eruption to more severe clinical manifestations such as allopurinol hypersensitivity syndrome or Steven-Johnson syndrome and lethal toxic epidermal necrolysis. Various strategies of slow desensitization have been elaborated to reintroduce allopurinol in a part of these patients, mainly patients affected by mild skin reactions as fixed drug eruption or exanthema. However, several new uricosuric therapies have been recently introduced. Actually drugs as recombinant urate oxidase and febuxostat are under post-marketing surveillance to control potential adverse effects related to their immunogenicity even.

The Employment of Leukotriene Antagonists in Cutaneous Diseases Belonging to Allergological Field

Leukotrienes (LTs) are potent biological proinflammatory mediators. LTC4, LTD4, and LTE4 are more frequently involved in chronic inflammatory responses and exert their actions binding to a cysteinyl-LT 1 (CysLT1) receptor and a cysteinyl-LT 2 (CysLT2) receptor. LTs receptor antagonists available for clinical use demonstrate high-affinity binding to the CysLT1 receptor. In this paper the employment of anti-LTs in allergic cutaneous diseases is analyzed showing that several studies have recently reported a beneficial effects of these agents (montelukast and zafirlukast as well as zileuton) for the treatment of some allergic cutaneous related diseases-like chronic urticaria and atopic eczema although their proper application remains to be established.

Delayed-type hypersensitivity to bupivacaine.

Local anesthetics are classified according to their chemical structure. The two main groups are the ester type anesthetics which are all derivatives of para-amino benzoic acid (i.e. benzocaine) and the amides which include the amino acylamides (lidocaine, mepivacaine), amino alkylamides (i.e. procainamide) and the quinoline derivative dibucaine. Delayed allergy to local anesthetics of the ester type such as tetracaine has previously been reported (1). So far, there have been few reports of type IV hypersensitivity to amides (2), in particular bupivacaine. We present a patient who developed an eczematous reaction after continuous epidural analgesia with bupivacaine 0.075% infusion. The patient was a 33-year-old woman with no history of atopy, parturient at 39-week gestation. During the active phase of labor, to relieve the pain and allow a comfortable delivery, the patient underwent continuous epidural analgesia, after giving informed consent. The epidural administration technique consisted of placing the catheter in the L3–4 interspace under sterile conditions. Then, a loading dose of bupivacaine 0.075% was administered to ensure a diminished pinprick sensation caudal to the T10 dermatome. The epidural infusion continued up to delivery, that occurred without any complications. About 3 days later, the patient developed an itchy, vesicular, eczematous reaction on the back and trunk up to the neckline. She was treated with topical steroids and the lesions disappeared within 10 days. About 4 months afterwards, on completion resolution of the lesions, the patient was referred to the Allergy Clinic of BariUniversityHospital, where, in view of her history, we decided to perform cutaneous tests. The patient was patch tested to a rubber additive series, to natural rubber latex, to the SIDAPA (Società Italiana di Dermatologia e Allergologia Professionale e Ambientale) standard series and bupivacaine (0.5% aq). Patch testing was conducted with Finn Chambers (Epitest, Tuusula, Finland), which were applied on the back using Scanpor tape (Norgesplaster, Vennesla, Norway) and removed after 2 days. Readings were made at day (D) 2 and D4. Reactions were evaluated according to International Contact Dermatitis Research Group recommendations (3). Doubtful or irritant reactions were considered negative. On completion of readings on D4, each positive result was assessed in relation to the patient s occupation and clinical history. To carry out the latex patch test, a commercial nonammoniated latex (Chemotechnique Diagnostics AB, Malmö, Sweden) was applied using IQ chambers. A positive reaction was observed only to bupivacaine (+++), while all the other patch tests were negative. To find an alternative local anesthetic to be administered when necessary, we performed an Incremental Challenge Test (ICT) with mepivacaine free of adrenaline and preservatives (Carbocaina 3%, 2 ml vials; Astra farmaceutici, Milan, Italy) (4). The test was started with an undiluted drug prick test; then, because the finding was negative, an intradermal test followed after 15 min, with the drug diluted 1/100; because this was negative too, the subject received s.c. administrations at 15-min intervals of 0.1 ml of a 1/10-dilution and 0.1, 1, and 2 ml of undiluted drug. However, 2 days after the test, eczematous reactions, with erythema and papules, appeared on the patient s arms where the test had been performed. Hence, about 15 days after, we performed ICT with articaine (Citocartin 1 : 200 000, 1.7 ml vials; Molteni dental, Florence, Italy), as described above. The drug was tolerated and no reaction appeared either at the time of testing or during the following days. Based on these results, the patient was advised to inform physicians that only articaine could be administered to her as a local anesthetic. This is the first report of a delayed hypersensitive reaction to bupivacaine. To find a replacement local anesthetic for the patient, we chose to test mepivacaine, as the patient had used this drug previously during dental procedures (information requested and given by her dentist), up to 2 years before the adverse reaction, without any problems. In addition, as reported by other authors, there is no cross reactivity (referred to type IV hypersensitivity) between mepivacaine and bupivacaine (5). Unfortunately, in our case, the patient did react to mepivacaine, although the reaction was delayed; the type of reaction was the same as those that appeared after the use of bupivacaine, showing the same mechanisms. In this case, the sensitization to bupivacaine is most likely the expression of cross-reactivity with mepivacaine (in fact, there was no evidence that bupivacaine had ever been used in this patient). On the basis of this result, we decided to test articaine that is an amide, but has a substitute thiophen ring, whereas all amino acylamides have a methylated phenyl ring. This difference may explain the lack of cross reactivity of articaine. With this report we wish to warn of the possibility of a delayed hypersensitive reaction to bupivacaine. If this occurs, a valid local anesthetic to be used as an alternative is articaine (nevertheless, to be administered only after previous ICT).

Allergic reactions to henna-based temporary tattoos and their components

Temporary henna-based tattoos, particularly popular among western tourists holidaying in exotic places, can expose to the risk to develop allergic reactions. Although hypersensitivity to henna is extremely rare, para-phenylenediamine, which is sometimes added to henna to obtain a dark, blackish color, is a frequent contact sensitizer. The purpose of this article is to review the literature about allergic reactions to temporary henna tattoos and outline the causes, clinical aspects and complications of this practice that should not be regarded as innocuous and risk-free.

Tolerance to etoricoxib in 37 patients with urticaria and angioedema induced by nonsteroidal anti-inflammatory drugs

BACKGROUND The use of cyclooxygenase-2 inhibitors, a new class of analgesic drugs, is suggested in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE To evaluate tolerance to etoricoxib, a new cyclooxygenase-2 inhibitor, in NSAID-sensitive patients with urticaria-type adverse reactions. PATIENTS Thirty-seven patients with adverse reactions to NSAIDs. METHODS Single-blind, placebo-controlled oral challenge with increasing doses of etoricoxib. RESULTS Thirty-four patients tolerated etoricoxib treatment without adverse reactions, but a generalized urticarial rash developed in 3 patients (8%). CONCLUSIONS Etoricoxib, like other cyclooxygenase-2 inhibitors, is a well-tolerated drug in most NSAID-sensitive patients. However, according to our experience, a previous challenge test in a safe environment may be necessary before prescribing the drug to such patients.

Contact Allergy to Topical Corticosteroids: Update and Review on Cross- Sensitization

Contact allergy to topical corticosteroids (TCs) is an emerging problem, whose diagnosis can be complex owing to the peculiar characteristics of steroid allergens and the possible inadequacy of current diagnostic methods, including concentration and vehicle used in patch testing. The occurrence of cross-reactions among different TCs is not rare, but prediction of these is not sufficiently reliable. Moreover, the distinction between true cross-reactivity and concomitant sensitization may be difficult. The original classification proposed by Coopman et al. has been distinguished corticosteroids into four groups according to their molecular structure. These authors hypothesized that allergic contact reactions were more frequent with corticosteroids belonging to the same group. However, the clinical practice has evidenced that cross reactivity exists also among corticosteroids belonging to different groups. The potential to cross-react among corticosteroids is thought to be related not only to the structural homology but also to the stereoisomerism and metabolism of these drugs. Recent evidence suggests that mechanisms responsible for cross-reactivity may occur at T lymphocyte level during antigen presentation. Further investigations are needed to gain a more complete understanding of this important topic. This article also reviews some patents related to the treatment of contact dermatitis and other inflammatory skin diseases.

The safety of a novel sublingual rush induction phase for latex desensitization

Abstract Objectives: In latex allergic individuals the avoidance of all exposure to natural rubber latex products is recommended. Sublingual immunotherapy against latex has recently been proposed. The aim of the study is to evaluate the tolerability of sublingual immunotherapy with latex extract, by a double-blind, placebo-controlled study, according to a three-day build-up phase rush protocol in a population of patients with latex-induced contact urticaria without a professional exposure to latex. Methods: Twenty-one patients with latex-induced urticaria were randomized to receive sublingual immunotherapy (SLIT) with latex extract or placebo. Rush (3-day) induction protocol of latex sublingual immunotherapy was performed with increasing doses of ALK-Abelló latex extract at three concentrations of latex proteins (5, 50 and 500 μgmL−1). Any side-effects that might be related to immunotherapy, the corresponding dose and treatment were registered. Results: Among the 21 patients, 12 were treated with latex sublingual immunotherapy (9 women and 3 men) and 9 with placebo (8 women and one man). All patients ended the rush protocol. Four patients (19.0%) [one in the SLIT group (8.3%) and three in the placebo group (33.3%)] developed adverse reactions. One SLIT patient reported mouth itching and burning of the tongue. In the placebo group, one patient presented gastrointestinal complaints while two patients reported unspecific symptoms. All these side-effects regressed spontaneously. No statistically significant differences were found between the proportions of adverse events in the two examined groups. Conclusion: This study supports the safety of SLIT against latex conducted in adult patients with latex-induced contact urticaria according to a 3-day build-up phase rush protocol. The proposed 3-day induction phase for latex sublingual immunotherapy should be conducted under medical supervision, although in patients with only latex-induced contact urticaria the registered adverse reactions were so slight that it could be argued that patients could start safely our tested rush protocol at home.