Luigi Macchia

Italian real-life experience of omalizumab

Omalizumab is a humanized murine monoclonal antibody directed toward a portion of the IgE indicated in Europe for the treatment of severe persistent allergic asthma, inadequately controlled despite high-dose of ICS (mean BDP equivalent dose of inhaled corticosteroid 2224.68microg/die) in association with long-acting beta(2) agonists. Our aim was to describe the experience, efficacy and safety in a cohort of Italian patients treated with omalizumab in a real-life clinical setting. One hundred and forty two patients from 13 Italian Centers were observed and analysed. The dosage of omalizumab was established according to the labelling indication, with a median dose of IgE of 297.38IU/ml or kU/l. During the previous year, all patients experienced frequent exacerbations (mean=4.87), emergency visits (mean=4.45) and hospitalisation (mean=1.53). Following treatment with omalizumab, the annual rate of exacerbations, emergency visits and hospitalisation decreased by 79%, 88% and 95%, respectively. The proportion of patients without exacerbation, not needing emergency visits and hospitalization increased by 610%, 154% and 28%, respectively. The response to omalizumab measured with the GETE (global evaluation of treatment effectiveness) scale rated as good to excellent in 77% of patients. Overall, 9.6% (n=9) of the patients experienced one single adverse effect. Only one patient reported a serious adverse event (local reaction at the site of injection) leading to interruption of treatment. The observed reduction of asthma-related events in particularly poorly controlled patients in this Italian real-life setting is consistent with the results of other observational studies.

Human mast cells express two leukotriene C4 synthase isoenzymes and the CysLT1 receptor

Cysteinyl-leukotrienes (cys-LTs) are potent smooth muscle contracting agents, especially in the respiratory tract and microcirculation, and play a key role in inflammatory and allergic diseases. The final step in the biosynthesis of LTC(4), the parent compound of cys-LTs, is catalyzed by a specific GSH transferase termed LTC(4) synthase, which is typically expressed in certain bone marrow-derived cells such as eosinophils and mast cells. Here we report that the human mast cell line HMC-1 as well as human mast cells derived from cord blood (CBMC) express a second enzyme capable of synthesizing leukotriene C(4), i.e., microsomal GSH transferase type 2. Furthermore, these cells abundantly express CysLT(1) receptors that are mostly located at the surface of both types of mast cells, as judged by immunohistochemistry. In addition, stimulation of CBMC with LTC(4) and LTD(4) elicits an immediate and dose-dependent (10(-7)-10(-11) M) mobilization of intracellular Ca(2+), which can be blocked with specific CysLT(1) receptor antagonists. Taken together, our data suggest that human mast cells are equipped with two enzymes that can catalyze the committed step in the biosynthesis of cys-LTs. Moreover, the expression of the cognate receptor CysLT(1) suggests that these lipid mediators may be involved in autocrine signaling pathways regulating mast cell functions.

Beauvericin: Chemistry, Biology and Significance

Mycotoxin contamination of cereal crops is of a worldwide concern since about 35% of cereal crop products contain measurable amount ofmycotoxins. Beauvericin is one toxic metabolite recently reported as product of some important phytopathogenic Fusarium species. We have described in this multidisciplinary and collaborative report the chemistry, the biological toxicity, the natural occurrence as contaminant of cereals and the main Fusarium species involved in their production. This chapter strongly addresses that a great attention should be directed to this toxin and that studies on its synergistic effects with other food-toxins should be carried out.

Purification and fine characterization of a major allergen from Olea europaea pollen extract

Olea europaea (olive) pollen extract was prepared by aqueous extraction and characterized by biochemical and immunochemical methods. Two components, displaying respective mol. wt. of 17000 and 19000, were the most reactive allergens, being the doublet (designated Ole e I) recognized by most sera tested. The 19000 mol. wt. component, purified by conventional biochemical procedure and lectin‐affinity chromatography from the Ole e I doublet, was deglycosylated and analyzed by SDS–PAGE and by ELISA inhibition. The results obtained suggest that the 19000 mol. wt. component represents the glycosylated form of the 17000 component.

Efficacy of allergen immunotherapy in reducing the likelihood of developing new allergen sensitizations: a systematic review

Guidelines and position papers indicate that allergen immunotherapy (AIT) is the only disease‐modifying treatment, including prevention of the onset of new allergen sensitizations. However, this preventive effect was shown by only a few observational studies. Our aim was to systematically review the efficacy of AIT in preventing the onset of new allergen sensitizations.

KIR2DL3 and the KIR ligand groups HLA-A-Bw4 and HLA-C2 predict the outcome of hepatitis B virus infection

Killer immunoglobulin‐like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA‐KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty‐seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA‐A‐Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA‐C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA‐A‐Bw4 and HLA‐C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.

Changes in skin reactivity, specific IgE and IgG levels after one year of immunotherapy in olive pollinosis

Changes in specific skin reactivity, specific IgE and specific IgG after immunotherapy (IT) were investigated in olive pollinosis. Thirty patients, receiving IT with commercial extracts, were studied in comparison with a control group of seven patients, receiving only drug therapy. Skin reactivity, IgE and IgG were assessed before starting IT and 1 year later. Definite changes in the three considered parameters occurred in patients given IT with Olea europaea extracts; no variation was observed in the control group. The specific skin reactivity, evaluated by means of quantitative skin prick tests, significantly decreased (Skin Index geometrical mean from 2.73 to 0.88, P<0.001); the specific IgE, measured by RAST, were surprisingly decreased (from 7.76 to 4.74 PRU/ml, P < 0.001); the specific IgG, measured by ELISA, in basic conditions were detectable only in nine patients of 30, while, after IT, they were found in almost all patients with a remarkable increase (from 5.48 to 266.89 AU/ml, P < 0.001). No correlation was found among the changes in the considered parameters, suggesting that, at least in olive pollinosis, specific skin reactivity, specific IgE and specific IgG are three variables depending on IT but reciprocally independent.

Long-term treatment of refractory severe chronic urticaria by omalizumab: analysis of two cases

Omalizumab is a recombinant humanized monoclonal antibody raised against the Cɛ3 domain of human IgE, whose efficacy and safety in the treatment of moderate to severe asthma has been demonstrated [1–3]. Several other possible indications for this innovative drug have been considered, including severe idiopathic urticaria [4–6].

Fig and mulberry cross-allergy

BACKGROUND Hypersensitivity reactions to ingestion of figs (Ficus carica) and mulberries (Morus nigra and Morus alba) are considered uncommon and have never been reported as occurring in the same patient. OBJECTIVE To determine whether hypersensitivity to figs and mulberries can induce cross-allergy. METHODS We describe 3 cases of associated fig and mulberry allergy in 3 patients with multiple sensitizations to food allergens (mostly fruit) and airborne allergens. The presence of specific IgE was investigated by skin prick tests and radioallergosorbent tests. RESULTS The 3 patients had a convincing clinical history of food allergy caused by eating fresh figs, and in all 3 cases clinical and/or laboratory evidence of sensitization to mulberries was also collected. CONCLUSIONS We reason that Ficus and Morus are closely related genera of the Moraceae family and speculate that hypersensitivity to figs and mulberries might be associated as the result of allergen cross-reactivity rather than mere coincidence.

General adverse reaction to aspirin administered by transdermal iontophoresis.

Sir: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed pharmaceutical products worldwide. These powerful cyclooxygenase inhibitors, however, may cause severe side effects and, in susceptible individuals, allergylike adverse reactions [1]. To minimize the risk of both kinds of event, when possible, these drugs are administered topically. Transdermal administration of sodium salicylate, aspirin, and other NSAIDs by iontophoresis has been widely employed in the treatment of a number of rheumatic, orthopedic, and posttraumatic conditions [2, 3, 4, 5]. Here we report an unusual, moderate to severe systemic reaction to iontophoresis administration of lysine acetylsalicylate. An 18-year-old man had been prescribed a short course of daily lysine acetylsalicylate transdermal administrations (1 g) by anodic iontophoresis, in relation to knee pain, inflammation, and functional impairment of possible postsurgical origin. A few days into the treatment, approx. 3 h after receiving the daily iontophoresis treatment, the patient complained of generalized cutaneous eruption, with small, nonconfluent erythematous-pomphoid lesions and pruritus, lip angioedema, nasal obstruction, and a sense of constriction in the chest. Symptoms receded spontaneously in 5–6 h except lip swelling, which lasted for approx. 12 h. Notably the patient had used and tolerated aspirin and other NSAIDs previously and had never suffered from asthma before. Skin prick tests for airborne allergens revealed sensitization to grass pollen, olive pollen, cypress pollen, and house dust mites. However, none of these allergic sensitizations was related to the clinical history, which was negative for both pollenand miteassociated allergic conditions. Aspirin oral challenge was performed, according to a single-blind schedule: doses of 15, 30, 65, 140, 250, and 500 mg lysine acetylsalicylate were administered sequentially, with an increase every 30 min. Three hours after the end of the challenge procedure the patient exhibited lip angioedema. As a consequence he received prompt medication, consisting of 1 g hydrocortisone intravenously and 10 mg loratadine orally. In spite of this treatment he experienced acute respiratory symptoms (cough and shortness of breath) during the following night, approx. 12 h after the challenge. NSAIDs, including aspirin but not salicylates in general, can induce allergylike symptoms in susceptible individuals. Thus approx. 1% of the treated subjects may experience urticaria and angioedema (more severe drug-related skin disorders, from erythema multiforme to toxic epidermal necrolysis, are fortunately much less common), and approx. 0.5% of them develop rhinosinusitis and asthma [1]. In addition to the oral and parenteral routes of administration, which account for the vast majority of prescriptions, in a not negligible number of cases NSAIDs are administered transdermally, with the purpose of minimizing the risk of side effects and allergylike adverse reactions. In particular, transdermal iontophoresis has been successfully employed for the topical delivery of these drugs in the treatment of localized musculoskeletal disorders [2, 3, 4, 5]. General adverse reactions to aspirin and NSAIDs administered locally (in the absence of physical modalities for delivery enhancement, such as iontophoresis and phonophoresis) are considered rare and primarily consist in gastrointestinal adverse reactions [6]. A comprehensive study published in 1994 found only 98 reports, out of 18,348 reports of NSAIDs-related adverse reactions, in which the adverse event was attributable to NSAIDs administered topically. Moreover, only 5 of Eur J Clin Pharmacol (2002) 58: 641–642 DOI 10.1007/s00228-002-0533-7