Erythema multiforme during cytomegalovirus infection and oral therapy with terbinafine: a virus-drug interaction.

The authors report a case of erythema multiforme in a 32-year-old woman who was also taking oral terbinafine for an onychomycosis. The patient data analysis showed serological positivity for cytomegalovirus (IgM and IgG) and hepatitis C virus and serological titre of antinuclear antibody was elevated. After a brief review of the literature the authors propose the possibility of virus-drug interaction as a model of adverse drug reactions.

Acute generalized exanthematous pustulosis in cystic echinococcosis: immunological characterization.

We report the first case, to the best of our knowledge, of a woman suffering from cystic echinococcosis of the liver, who consequently developed urticaria and acute generalized exanthematous pustolosis (AGEP). Serum immunoglobulin (Ig)E and IgG4 specific to Echinococcus granulosus antigens were detected by immunoblotting. Furthermore, the intracellular cytokine analysis revealed a prevalent T-helper 2 polarization. It can be reasoned that, while the presence of IgE specific to various E. granulosus allergens may be responsible for the chronic urticarial manifestations, the detection of IgG4 specific for E. granulosus antigens, forming immunocomplexes, may be related to the development of the AGEP.

Cutaneous response to irritants.

We evaluated the role of pre-existing dermatitis in the response to irritants by patch testing the skin of 40 healthy volunteers and the uninvolved skin of 480 subjects for 2 days. These latter were affected by active atopic dermatitis, psoriasis, eczema with positive and negative patch test reactions, urticaria and generalized pruritus. A first panel containing 15 micro L of aq. solutions of disodium laureth sulfosuccinate (NaLSS) 5% and 10%, potassium cocoate (KCC) 5%, potassium oleate (KOL) 5%, zinc coleth sulphate (ZnCS) 5%, sodium mireth sulphate (NaMS) 5%, sodium cocoamphoacetate (NaCCAA) 3% and 5%, was simultaneously applied to 1 site on the upper back. The results, scored by visual assessment, were compared to those observed when testing on the opposite side a second panel containing 15 micro L of aq. solutions of 3 well-known irritants, benzalkonium chloride (BAK) 1%, sodium lauryl sulphate (SLS) 1%, and dimethylsulphoxide (DMSO) 10%. Whilst the substances of the first panel and DMSO gave, on the whole, a scarce number of positive responses in all the tested groups, more evident differences in number, percent and mean intensity of the positive responses to BAK and SLS were found between the different groups. Although some of them seemed statistically significant, when the same values were evaluated by means of chi2 and Student t-test, they did not differ in a statistically significant way from the values found in healthy subjects. The results of this study seem to indicate that the substances of the first panel have a chemical structure that makes them quite safe in real-life conditions. In contrast, BAK and SLS have chemical properties that condition the number and intensity of the responses, making the role exerted by the pre-existing dermatosis quite marginal. In particular, there is no proof that the healthy skin of active atopic subjects is the most susceptible to the irritating effects of the tested substances.

Levels of enzymatic antioxidants activities in mononuclear cells and skin reactivity to sodium dodecyl sulphate.

Chemical irritants are able to produce several biological modifications of the skin, including the direct or indirect production of cytokines and reactive oxygen species leading to an inflammatory reaction. This report examines the existence of a possible correlation between the skin sensitivity to the irritant sodium dodecyl sulphate (SDS) and the activity of the enzymatic antioxidants. In twenty-three healthy subjects the evaluation of the epidermal and peripheral blood mononuclear cells (PBMCs) activities of Superoxide Dismutase (SOD) and Catalase (Cat) demonstrate a significant correlation (r= 0,85 and p< 0,005 for SOD, and r= 0,87 and p< 0,0001 for Cat). Based on this result, on a further group of normal subjects (n=13) we studied the link between the threshold dose of skin reactivity to SDS and the activities of the enzymatic antioxidants in PBMCs. The degree of skin modification induced by SDS, applied at different concentrations for 24 hrs, was determined by means of Trans Epidermal Water Loss (TEWL), Erythemal Index or by Visual Score (VS). The minimal dose of the irritant capable of inducing skin modifications, was significantly correlated with SOD (r=0,77) and Cat (r=0,81) activities in PBMCs, and the modification of TEWL or EI were inversely correlated with levels of antioxidants in PBMCs (r=-0,62 for SOD and r=-0,66 for Cat). Our results indicate that the skin reactivity to irritants can be modulated by the levels of antioxidants, and suggest a possible therapeutical approach in preventing irritant contact dermatitis.

IgE-mediated allergy to corn: a 50 kDa protein, belonging to the Reduced Soluble Proteins, is a major allergen.

BACKGROUND: Although corn is often cited as an allergenic food, very few studies have been devoted to the identification of corn allergens and corn allergy has been rarely confirmed by double-blind, placebo-controlled food challenge (DBPCFC). Recently, Pastorello et al. (1) identified some salt-soluble IgE-binding proteins of corn flour as potential allergens. One of these, corresponding to corn Lipid Transfer Protein (LTP), appeared to be the major one. The aim of this study was to verify the clinical significance of the skin prick test (SPT) and CAP-FEIA CAP-System IgE fluozoenzyme immunosorbent assay (Pharmacia Diagnostic, Uppsala, Sweden) positivities to corn and to identify the presence of IgE-binding proteins in the corn flour salt-insoluble protein fractions (comprising up to 96% of the total protein) using sera of patients with DBPCFC-documented food allergy to corn. In addition the effect of cooking and proteolytic digestion on the corn allergens was investigated. METHODS: Sixteen subjects with SPT and CAP-FEIA positivities to corn flour were examined. Only six of them complained of suffering from urticaria and/or other symptoms after ingestion of corn-based foods. The patients were food challenged with cooked corn flour (polenta). IgE-binding proteins were detected by immunoblotting. The digestibility of the IgE-binding proteins was examined during a pepsin attack followed by a pancreatin digestion performed on a cooked corn flour sample. RESULTS: Oral challenge was positive only for six patients with symptoms after ingestion of corn. A 50 kDa protein, belonging to the corn Reduced Soluble Protein (RSP) fraction was recognized by the serum IgE of all the DBPCFC-positive subjects and resulted to be resistant to both heating and peptic/pancreatic digestion. SPT with the purified RSP fraction gave positive results for all of the DBPCFC-positive patients examined. CONCLUSIONS: SPT and CAP-FEIA positivities to corn flour had no clinical significance for most of the patients and food allergy to corn has to be proved by DBPCFC. A salt-unextractable protein of 50 kDa, belonging to the RSP fraction, represents a potential allergen in food hypersensitivity to corn because of its stability to cooking and digestion.

IgE binding to soluble and insoluble wheat flour proteins in atopic and non-atopic patients suffering from gastrointestinal symptoms after wheat ingestion.

BACKGROUND: The involvement of IgE-mediated hypersensitivity reactions in the genesis of gastrointestinal symptoms after ingestion of foods containing wheat has been rarely reported. OBJECTIVE: To detect IgE specifically binding to wheat proteins in the sera of atopic and non-atopic patients suffering from gastrointestinal symptoms after ingestion of wheat and to evaluate the reliability of skin prick test and CAP in the diagnosis of food allergy to wheat. METHODS: The sera of patients (10 atopic and 10 non-atopic) previously diagnosed as suffering from irritable bowel syndrome and complaining of symptoms after wheat ingestion were analysed by immunoblotting for IgE binding to water/salt-soluble and insoluble wheat flour proteins. RESULTS: All the atopic patients and only one of the non-atopic patients were positive to wheat CAP. For the patients tested, skin prick test was positive for all the atopic patients and for only one of the non-atopic patients. However, immunoblotting experiments showed the presence of specific IgE to wheat proteins in all the patients. Ten out of 11 of the wheat CAP-positive patients had IgE binding to a soluble 16-kDa band, but the same band was recognized, in a slighter way, by only two out of nine of the wheat CAP-negative patients. Moreover, although almost all of the patients were negative in CAP testing with gluten, 19 out of 20 recognized protein bands belonging to the prolamin fraction. CONCLUSIONS: For the atopic patients the positivity to skin prick test and CAP to wheat was in accordance with the immunoblotting results and a food allergy to wheat could be diagnosed. In these patients a major allergen was a 16-kDa band corresponding to members of the cereal alpha-amylase/trypsin inhibitors protein family, the major allergens involved in baker's asthma. In the non-atopic patients the positive immunoblotting results contrasted with the responses of the allergologic tests, indicating that the allergenic wheat protein preparations currently used are of limited value in detecting specific IgE to wheat and that the fraction of irritable bowel syndrome (IBS) patients with food allergy may be larger than believed.

Multicentre study of allergic contact cheilitis from toothpastes.

The present work reports the results of a multicentre study of toothpaste allergic contact cheilitis (TACC) conducted by GIRDCA (Gruppo Italiano Ricerca Dermatiti da Contatto e Ambientali). The study examined 54 patients with eczematous lesions on the lips, the possible cause of which was suspected to be the use of toothpastes. Patch tests were conducted with a standard series, a specially-targeted series (toothpaste cheilitis series, TCS), and with suspected toothpaste(s). A stop-restart test (SRT) was carried out with these, together with a use test to identify possible alternative products. The TCS produced 17 positive reactions in 13 patients, the most frequent being to spearmint oil. Of the 54 patients, 5 displayed positive reactions only to the TCS. The patch tests with toothpaste produced positive reactions in 11/32 patients, the SRT a positive response in 10/12 cases. The diagnosis of TACC was confirmed in 15/54 patients. Alternative products were identified for 5 patients. In conclusion, the allergens most frequently responsible for TACC were the flavourings, and the additional series proved to be useful in many cases (together with patch tests with toothpastes and the SRT) for correct diagnosis and to initiate effective prevention.

Expression of metallothioneins-I and -II isoforms at positive patch-test sites.

The expression and the distribution of metallothioneins (MT)-I and II isoforms were evaluated in 5 healthy volunteers and in 16 subjects with positive patch test reactions to various compounds. Skin specimens taken both from the healthy skin of the back and at positive patch test sites (at 48 h), were treated using a 3-step indirect immunoperoxidase procedure with a mouse monoclonal IgG1 antibody reactive against I and II isoforms of human, rat and horse MT. MT were expressed in the basal layer of the healthy skin of both controls and sensitive subjects, without any significant difference. At positive patch test sites, there was an overexpression of MT in basal and suprabasal layers of the epidermis. Overexpression of MT, related to the degree of the inflammatory reactions elicited by the penetrating compounds was observed in the dermis. The cells expressing MT in the dermis were mostly T lymphocytes and cells with dendritic morphology which positively stained in part for CD34 and in part for XIIIa markers and negatively for KP1, S100 and HLA-DR. Taken together, these results seem to indicate that MT represent a constitutive mechanism of defence expressed by different types of cells in the skin, which is triggered by contact with both metallic and non-metallic compounds. The biological significance of MT in the skin remains to be elucidated. Our preliminary findings do not permit evaluation of whether these nearly ubiquitous proteins exert their cytoprotective effects in the skin acting simultaneously as antioxidant, metal binding or zinc suppliers, or if they display these activities mainly depending on the nature of the penetrating substances.

Platinum in the environment: frequency of reactions to platinum-group elements in patients with dermatitis and urticaria.

The aim of the present paper is to evaluate whether increasing environmental exposure increases the frequency of the positive prick and patch test reactions to certain chlorinated platinum salts in patients with dermatitis and urticaria. 800 consecutive subjects with contact dermatitis (n=749) and urticaria (n=51) were variously patch and prick tested with 30 haptens of a standard series, with aqueous solutions of, respectively, hexachloroplatinic acid (H2[PtCl6]), potassium tetrachloroplatinate (K2[PtCl4]), sodium hexachloroplatinate (Na2[PtCl6]), iridium chloride (IrCl3), rhodium chloride (RhCl3) and palladium chloride (PdCl2), and with 16 common inhalants. 153 workers, variably exposed in a platinum refinery, were patch and prick tested only with solutions containing platinum-group elements at various concentrations and with 16 common inhalants. Platinum-group elements did not elicit positive patch or prick test reactions in non-occupationally exposed subjects. In contrast, in exposed workers, positive patch test reactions at day 2 and at 25 min, respectively, were found in 2 subjects with hand dermatitis and in 2 with urticaria and asthma. 22 out of the 153 workers, 18 of whom had rhinitis, asthma, and urticaria, gave positive prick test reactions to 1 or more salts. Furthermore, on patch and prick testing, 4 cross-reactions between platinum, palladium, iridium and rhodium were demonstrated. In conclusion, the test results demonstrate that the present concentration in the environment does not increase the incidence of reactions to platinum salts in patients with dermatitis and/or urticaria. However, if the average level of environmental platinum exposure approaches those existing in industrial settings in the future, we are going to observe more frequent health effects.

Urticaria from beer: an immediate hypersensitivity reaction due to a 10-kDa protein derived from barley.

BACKGROUND: Urticaria from beer has been reported in atopic patients. In these subjects, the skin-prick test positivity to and presence of specific serum immunoglobulin (Ig)E for barley malt, the basic ingredient used in brewing, suggested a type I hypersensitivity to barley component(s). OBJECTIVE: To identify the beer allergen(s) and to investigate the presence of related proteins in barley. METHODS: Three patients with urticaria from beer and other atopic people, some of them suffering from baker's asthma, were examined for both prick test sensitivity to and the occurrence of serum-specific IgE for partially purified proteins from beer. Allergen identification in beer, malt and barley was performed by immunoblotting. RESULTS: Skin-prick tests and detection of specific IgE by both solid-phase (RAST) and liquid-phase (AlaSTAT) assays demonstrated that the 5-20-kDa beer protein fraction contained the allergen. Immunoblot analysis with sera of patients with urticaria from beer showed that IgE bound only the 10-kDa protein band in beer and malt, whereas a main 16-kDa protein was revealed in barley in addition to a very faint 10-kDa band. With the serum of a patient suffering from baker's asthma no IgE binding bands were observed in beer, whereas specific IgE binding to several proteins, including a major 16-kDa component, were detected for both malt and barley. CONCLUSIONS: Urticaria from beer is an IgE-mediated hypersensitivity reaction induced by a protein component of approximately 10 kDa deriving from barley. This allergen does not seem to be related to the major barley 16-kDa allergen responsible for baker's asthma. Because of the severity of the allergic manifestations to beer we recommend testing atopic patients positive to malt/barley and/or who exhibit urticarial reactions after drinking beer for their sensitivity to this beverage.

Thimerosal positivities: patch testing to methylmercury chloride in subjects sensitive to ethylmercury chloride.

The aim of this paper was to evaluate whether methylmercury chloride (MeHgCl) aq., when patch tested in a group of thimerosal-positive subjects reacting to ethylmercury chloride (EtHgCl), might be a reliable model for the better understanding of interactions between alkylmercury compounds and the skin. 19 out of 21 consecutive patients who previously had given positive patch-test reactions to both ethylmercury chloride 0.0165% eth.(EtHgCl, 0.615 mM) and MeHgCl 0.031% aq.(1.23 mM), and negative reactions to thiosalicylic acid 0.05% (3.24 mM) aq./eth. 50/50, were repatch tested to 8 microl of MeHgCl 0.031% aq. and to 8 microl of aq. solutions containing MeHgCl mixed with cysteine, glutathione, ZnSO4, MgSO4, MnSO4, ZnCl2, MgCl2 and MnCl2, respectively. The results showed that cysteine, glutathione and Zn(II) salts were able to abolish the positive reactions, demonstrating the rôle played by both thiol groups and Zn(II) itself. Patch tests concomitantly carried out in 16 out of 19 patients to 8 microl of aqueous MeHgCl and to 8 microl of aqueous solutions containing MeHgCl and MeHgCl mixed to fragment 56-61 of metallothionein I (MT I), MT I and MT II-Zn, respectively, revealed that all the MTs tested were able to reduce or to inhibit the reactions, demonstrating the effect of the thiol groups. Due to the close chemical similarities to EtHgCl and to its water solubility, MeHgCl seems to be a suitable model for evaluating the reactivity of alkylmercury compounds in the skin. We speculate that both EtHg- and MeHg-derivatives are xenobiotics with similar reactivity. However, the lack of clinical relevance of the reactions to both alkyl compounds lead us to conclude that, since environmental exposure does not seem to play a pivotal rôle, they probably have mostly to do with compounds included in in the standard series, and are elicited by reduced function of physiological SH chelators.

Thimerosal positivities: the rôle of SH groups and divalent ions.

For a better understanding of the mechanistic details of the interactions of organomercury compounds inside the skin, 32 subjects who previously had given positive patch-test reactions to thimerosal (TH) and negative reactions to thiosalicylic acid, were divided into 2 groups. 16 subjects were repatch tested to ethylmercury chloride (EtHgCl) and to solutions containing EtHgCl mixed with L-cysteine and glutathione, respectively. The remaining 16 were repatch tested to EtHgCl and to solutions containing EtHgCl mixed with chlorides of Zn, Mg, and Mn, respectively. The results showed that whilst L-cysteine, glutathione and ZnCl2 were able to abolish or to reduce the positive reactions to EtHgCl, chlorides of Mg and Mn were unable to do so. Patch tests revealed that in causing positive reactions to TH, EtHg probably interacted with thiol groups and with Zn ions, as in biological systems when causing toxic effects. The limited number of TH reactions in the general population, the constant presence of concomitant positive reactions to EtHgCl and MeHgCl, and the lack of cross-reactivity with other organic or inorganic mercury compounds, lead us to speculate that reactions to TH are due to organomercury alkyl compounds, and that positive subjects have a constitutively reduced capability to metabolize organomercury compounds, rather than to reveal previous exposure.

The influence exerted by cutaneous ligands in subjects reacting to nickel sulfate alone and in those reacting to more transition metals.

To study the influence exerted by cutaneous ligands in nickel reactions we have evaluated the patch tests responses to 4 aqueous nickel salts (sulfate, chloride, nitrate, acetate) able to form different complexes with different geometry. Two groups of respectively 71 subjects who previously reacted only to nickel sulfate 5% petrolatum (pet) and of 30 subjects who previously reacted to nickel sulfate 5% pet and to at least 1 other transition metal, were simultaneously repatch-tested to 200 microg of Ni++ contained in nickel sulfate in pet and to 47 microg of Ni++ contained in 4 different aqueous nickel salts. Another 2 groups of 25 subjects with the same characteristics were simultaneously repatch tested to 200 microg of Ni++ in pet and to 12 microg of aq Ni++ as in the first 2 groups. Visual score, total score, and mean value of the reactions were utilized in evaluating the degree of the responses. On testing to 200 microg of Ni++ in pet all the subjects were able to give positive responses. Whilst a higher percentage of the responses of 2+ degrees was found in subjects reacting to nickel sulfate 5% pet alone, a higher percentage of responses of 3+ degrees was observed in subjects reacting to more transition metals. On testing to 47 and 12 microg of aqueous Ni++ a large variability of responses to the single salts was observed in all the subjects. However, in subjects reacting to more metals there were either a greater number of multiple responses to 3 or 4 salts or responses stronger than those found in subjects reacting to nickel sulfate alone. Although patch testing cannot give us complete information about the degree of previous exposure, the results arising from the tests seem to demonstrate that the subjects allergic to nickel and other transition metals are more reactive than the subjects allergic only to nickel to the application of the same amounts of Ni++ contained in different salts. When considering the QSAR model, the difference in the sensitizing potential of the metal at the same penetration properties can depend on the possibility of combining with specific ligands. Therefore, it is likely that in subjects reacting to more metals there is a more uniform availability of cutaneous ligands which conditions the formation of complexes more immunogenic. The arising inflammatory reaction in these cases leads to a stronger but less specific response.

Thimerosal positivities: the role of organomercury alkyl compounds.

Contact allergy to thimerosal (TH) has not been considered a marker for mercury allergy, since there is a low degree of cross-sensitivity to inorganic as well as to organic mercury salts. 40 subjects, who previously gave a positive patch test reaction only to thimerosal 0.1% pet. (Hermal), when simultaneously repatch-tested to solutions containing TH, mersalyl acid, p-amino-phenylmercuric acid, mercuric acetate and thiosalicylic acid, respectively, gave positive reactions only to TH. 36 out of 40 subjects were divided into 2 groups of 18 subjects and simultaneously repatch-tested to solutions containing TH, methylmercury chloride (MeHgCl), thiosalicylic acid, and, ethylmercury chloride (EtHgCl), respectively. EtHgCl was tested in the 1st group at 0.031% and in the 2nd group at 0.015%. The results showed that all subjects gave concomitant positive reactions to TH, EtHgCl and MeHgCl. EtHgCl 0.031% gave a higher number of reactions than EtHgCl 0.015%, underlining the rôle of the solvent in these reactions. Patch test results in 300 consecutive patients to a standard series, to which MeHgCl was added, showed that MeHgCl and TH were never able to give isolated positive reactions, and that the concomitant positive reactions occurred in only 3.6% of subjects. In conclusion, our data seem to suggest that the positive reactions to TH found in our patients were due to EtHgCl, and that the structural similarities with MeHgCl were so close that the skin reacted against each as if they were identical.

Multiple sensitivities to transition metals: the nickel palladium reactions.

Patch test data of 1000 consecutive patients sensitive to at least 1 substance of our standard series showed that transition metals gave associated reactions amongst themselves more frequently than they did with the remaining substances. The responses to transition metals were largely variable and seemed dependent not only upon the associated exposure to different metals or the concomitant responses of the T cell clones, as reported by others, but also upon the chemical properties of the metals and the consequent interactions inside the skin. Concomitant reactions to nickel sulfate and palladium chloride were the most frequently found associated positivities and occurred in a minority of nickel-sulfate-sensitive subjects. In 43 out of 45 of these subjects, patch tests to mixed solutions containing nickel sulfate, plus sulfates of magnesium, zinc, and manganese at higher doses, were not able to reduce the nickel sulfate reactions. This behaviour contrasted with that found in the majority of subjects sensitive only to nickel sulfate. These findings seem to demonstrate that, whilst in subjects with positive reactions to nickel sulfate alone antigen formation involves biomolecules containing ions, in those with concomitant reactions to palladium chloride, other structures are involved.

Nickel chloride/chlorides of divalent metal interactions in nickel-sensitive subjects.

To verify if the counter-ion Cl- permits the same interactions between nickel and divalent metals with physicochemical similarities as the counter-ion SO4- does, 50 sensitive subjects to nickel sulfate 5% pet. who previously gave positive patch test reactions either to 8 mu 1 of aq. nickel sulfate 0.1 M or to 8 mu 1 of aq. nickel chloride 0.1 M, or to both, were patch retested simultaneously to 8 mu 1 of, respectively, aq. nickel sulfate 0.1 M and aq. nickel chloride 0.1 M, and to 8 mu 1 of aq. mixed solutions containing, respectively, nickel chloride 0.1 M+magnesium chloride 0.3 M, nickel chloride 0.1 M+zinc chloride 0.3 M, nickel chloride 0.1 M+zinc chloride 0.5 M, nickel chloride 0.1 M+manganese chloride 0.3 M, and nickel chloride 0.1 M+manganese chloride O.5 M. Whilst 4 subjects gave a positive patch test response to only nickel sulphate, 8 gave a positive response to nickel chloride alone and the remaining 38 gave a concomitant positive response to both. In all subjects who gave positive responses to nickel chloride, the chlorides of divalent metals were not able to inhibit or reduce the positive reaction. 25 healthy subjects patch tested to both single salts and mixed solutions, and all gave negative responses. 9 of the 50 subjects, 4 who previously gave positive reactions to only nickel chloride 0.1 M, and 5 with concomitant reactions of equal intensity to both nickel chloride and nickel sulfate 0.1 M, were patch retested simultaneously to 8 mu 1 of, respectively, aq. nickel sulfate 0.1 M, aq. nickel chloride 0.1 M and aq. mixed solutions containing nickel sulfate (0.1 M) mixed with sulfates (0.3 M) and nickel chloride (0.1 M) mixed with chlorides of Mg, Zn, Mn (0.3 M). Whilst the mixed sulfate solutions were able to reduce nickel sulfate, 0.1 M patch test positive reactions, those containing chlorides, at all concentrations tested, did not inhibit the nickel chloride reactions in any of the subjects. The results of the tests to chlorides, compared to those reached on testing to sulfates of the same metals, lead us to hypothesize that the anion probably affects the uptake and local tissue distribution of the metal, modulating in this way, together with the individual cutaneous ligands, its effects.