Maria Teresa Ventura

Non-specific immunity in aging: Deficiency of monocyte and polymorphonuclear cell-mediated functions

Peripheral blood monocytes obtained from 55 aged donors were evaluated for their chemotactic and phagocytic capacity. In the same subjects, polymorphonuclear cell-mediated functions were studied by chemotaxis, phagocytosis, nylon fiber adherence and nitroblue-tetrazolium reduction assay. Monocytes showed a normal chemotactic responsiveness to zymosan-activated serum, while the chemotactic activity induced by leukocyte-derived chemotactic factor and phagocytosis were rather depressed. A dramatic impairment of polymorphonuclear cell-mediated immune response was also observed. In fact, in spite of a normal nylon fiber adherence, chemotaxis, phagocytosis and nitroblue-tetrazolium reduction capacity were significantly depressed by the aging process. These data suggest that the deficiency of non-specific immunity may play an important role in the increased susceptibility to infections in aged donors.

Rhinitis and asthma in athletes: an ARIA document in collaboration with GA2LEN

This consensus document is aimed at reviewing evidence that the rhinits‐asthma links have peculiar features in athletes. Beside a review of epidemological data on the high prevalence of rhinitis and asthma in athletes, the effects on intense physical exercise on the immune system and repiratory functions are discussed, with special reference to the role of allergens and pollutants. In extending the Allergic Rhinitis and its Impact on Asthma (ARIA) recommendations to athletes, the issue is addressed of adapting diagnosis and management to criteria set by the International Olympic Committee (IOC) and regulations adopted by the World Anti‐Doping Agency (WADA).

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.

Patients with Hereditary Hemorrhagic Telangectasia (HHT) Exhibit a Deficit of Polymorphonuclear Cell and Monocyte Oxidative Burst and Phagocytosis: A Possible Correlation with Altered Adaptive Immune Responsiveness in HHT

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disease characterized by mutations occurring in the endoglin and ALK-1, two receptors of transforming growth factor-beta1. From a pathogenic point of view, a possible involvement of the immune system in HHT has been suggested since a mononuclear cell infiltrate was found around the area of telangiectases. Up until now, no information has been available about the role played by leukocytes in HHT and the mechanisms elicited by secretion of their mediators. However, the fact that a deficit of adaptive immunity in HHT has been reported in a companion paper in this issue will represent a great contribution to the understanding of HHT pathogenesis. The purpose of this study was to evaluate whether patients with HHT manifest also alterations in the innate immune response. Therefore, the phenotype of T, B and natural killer lymphocytes, serum immunoglobulin levels, phagocytosis and oxidative burst activity exerted by polymorphonuclear cells (PMN) and monocytes (MO) were analyzed in 22 patients. Twenty individuals demonstrated single or multiple deficits of PMN and MO functions, while the immunophenotype of lymphocytes and serum concentrations of immunoglobulins were normal. To the best of our knowledge, this is the first demonstration of a reduction in PMN and MO functions in HHT, thus suggesting a higher susceptibility to infectious complications in these patients. The relationship between innate immune deficits and T helper 1 and monocyte-derived cytokine dysfunction in HHT, as previously reported, is discussed.

Hypersensitivity to aromatic anticonvulsants : In vivo and in vitro cross-reactivity studies

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patients lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

Anisakis simplex Hypersensitivity Is Associated with Chronic Urticaria in Endemic Areas

Background: Chronic urticaria (CU) may affect up to 1% of the general population. Anisakis simplex hypersensitivity is frequent in areas where raw fish is consumed and A. simplex allergy represents a relevant cause of acute urticaria. We assessed the possible association between CU and A. simplex sensitization in an area where marinated fish is very frequently eaten. Methods: A thorough history of CU was sought in 919 adults seen at the Allergy Center, Bari. CU patients and 187 controls underwent skin-prick testing with a commercial extract of A. simplex, and reactors were recommended a 6-month raw-fish-free diet regimen. Responders were followed after a further 3 months. Results: Of 919 subjects, 213 (23%) met the criteria for CU and 106/213 (49.7%) were sensitized to A. simplex with a significant difference between patients aged >65 or <65 years (56 vs. 41%, respectively; p < 0.05). All patients hypersensitive to A. simplex were regular consumers of marinated fish. In a control population without CU, the prevalence of A. simplex sensitization was 16% (p < 0.001). The 6-month diet regimen led to the disappearance of urticaria in 82/106 cases (77%) versus 1/42 (2%) subjects who did not change their dietary habits (p < 0.001). All nonresponders were sensitized to house-dust mites. Of 75 responders who were followed-up after 3 months, CU relapsed in 88% of those who had reintroduced raw fish versus 14% of those who were still on the diet (p < 0.001). Conclusion: In areas where raw or marinated fish is frequently eaten, A. simplex hypersensitivity is a frequent cause of CU.

Allergic and non-allergic rhinitis in swimmers: clinical and cytological aspects

Background Rhinitis, either allergic or non-allergic, is frequent in athletes, particularly in swimmers. In this latter case, exposure to chlorine in swimming pools seems to play a relevant role, since it can exacerbate a pre-existing allergic rhinitis (AR) or produce a non-specific irritation. The aim of this study was to detail the clinical and cytological characteristics of rhinitis in swimmers, and to assess the possible role of chlorine-induced symptoms. Methods Elite swimmers with rhinitis symptoms underwent a complete diagnostic work-up, including allergy testing, nasal cytology and anterior rhinomanometry. Those evaluations were repeated after 1 month of use of a nasal clip during swimming. A matched group of asymptomatic swimmers was also studied. A total of 74 swimmers (54 symptomatic and 20 controls), with an age range of 9–21 years, were studied. In the control group, only mild and non-specific findings were observed, and only two had a positive skin test. Results In the symptomatic group, 24 (44%) had AR, and 19 (35%) had a predominant neutrophilic inflammation. The use of a nose clip reduced cellular infiltration and nasal resistances only in the subjects with neutrophilic rhinitis, whereas a clinical improvement was seen also in AR. Conclusion A neutrophilic rhinitis occurs in a large proportion of swimmers. This seems to be irritative in its nature and can be prevented by avoiding the direct contact with chlorinated water.

Hypersensitivity Reactions to Last Generation Chimeric, Umanized and Human Recombinant Monoclonal Antibodies for Therapeutic Use

A new class of drugs, produced with the hybridoma technique, has been introduced and employed to treat many immunological diseases. This class consists of recombinant monoclonal antibodies, which can be chimeric, humanized or human. Predictably, there has been a rise in adverse hypersensitivity reactions to these therapeutic agents, whose pathogenic mechanisms are not yet well understood. Specific IgE has been demonstrated in a very few cases, and only in some of these recombinant antibodies. Skin tests are not done as a clinical routine screening. In the present article the mechanisms underlying hypersensitivity reactions to these drugs are analyzed, also in the light of the personal experience and that reported in the literature, with the aim of identifying potential risk factors and means of prevention of these reactions. For some drugs, infusion reactions may be prevented thanks to the the use of premedication. Moreover, symptoms of acute hypersensitivity during infusion can be successfully managed in the majority of cases by slowing the speed of administration. All these findings seem to confirm that the pathogenesis is not related to a true immediate (IgE-mediated) hypersensitivity in most cases. When the substitution of the drug that has triggered a hypersensitivity reaction is required, this is only possible if such an alternative drug exists (i.e., replacement of a chimeric antibody with a humanized or human antibody sharing the same target). As an alternative, desensitization protocols have been employed to induce a state of temporary tolerance to the drug in some cases, yielding successful results for infliximab and trastuzumab.

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

Allergic and Pseudoallergic Reactions Induced by Glucocorticoids: A Review

Glucocorticoids (GCs) represent the most effective treatment for autoimmune and allergic diseases, even if collateral effects are not rare, especially endocrine and immunosuppressive manifestations. Moreover, these drugs can develop adverse immunological reactions of I, III or IV type. Though immediate adverse reactions caused by systemic therapy with GCs are not very frequent, the possible beginning of anaphylactic and pseudo-anaphylactic manifestations in patients undergoing therapy with these drugs has to be considered. It has been observed that immediate adverse reactions usually are happened in asthmatic patients and in patients obliged to assume GCs again and again because of their pathology (e.g, kidney transplant). Other risk factors resulted to be female sex and hypersensibility to acetylsalicylic acid (ASA). Both in the cases of pseudo-allergic and allergic reactions, the pharmacological principle is hardly the responsible agent for the reaction; instead the excipients in drugs are often implicated (succinate salt, sulphites and carboxy-methyl-cellulose). It is possible that the IgE-response is highly specific for a fixed GC molecule as well depending on the way of administration and its salification. Moreover, it has been hypothesized that in patients with a first type allergic reaction to GCs there is a fourth type, sensitization to GCs, which is not usually diagnosed and even comes before IgE sensitization. Third type hypersensibility reactions may occur, too. Since GCs are large-scale drugs, also in emergency medicine and reanimation, allergic sensitization towards them, although infrequent, gives many interventionist problems. In the light of this feature, it seems of crucial importance to verify the tolerance toward other GC molecules. And in particular, it has been noted that patients presenting immediate reactions to hydrocortisone (HC) and methylprednisolone (MP) could tolerate prednisone and prednisolone per os and second-generation GCs, such as desamathazone and betamethazone. Nevertheless, second-generation GCs must not be considered safe; in fact, the beginning of allergic manifestations has been pointed out even towards them.