Role of TNF-alpha polymorphism in patients with nickel allergy: a marker of susceptibility to contact polysensitization.

OBJECTIVE: Nickel allergy is the most frequent contact allergy in the industrialized country. In allergic contact dermatitis after the presentation of haptenated peptides by resident or newly recruited skin cells, activated CD8+ T cells release IFN-γ and TNF-α, these cytokines are potent activator of keratinocytes. The role of specific cytokines in nickel allergy is not yet fully elucidated. The adenine nucleotide at position -308 in the promoter region of the TNFA gene is associated with an increased production of TNF-α, that is a potent activator of keratinocytes. PATIENTS AND METHODS: To evaluate the expression of TNF-α polymorphism in patients with allergic contact dermatitis and in healthy people, 41 patients with allergic contact dermatitis to nickel and 40 healthy controls were enrolled. A total of 81 subjects (41 cases and 40 controls) underwent genotyping for the 308 genetic polymorphism in the TNFA gene. RESULTS: The distribution of TNF genotypes TNF-α 308 G/A polymorphism in cases didn't differ significantly in the controls group. The genotype GA was present in the 75% of the patients with polysensitization. In one patient was observed the rare genotype A/A. CONCLUSIONS: The carriage of the TNFA-308 A/A and GA genotype may act as a marker of enhanced susceptibility to contact polysensitization, indicating that TNF-α is a key regulator of the initiation of delayed-type hypersensitivity reactions, the polymorphism seems to be not enough for the development of nickel monosensitization.

Nickel free-diet enhances the Helicobacter pylori eradication rate: a pilot study.

BACKGROUND: The Helicobacter pylori eradication rate with standard triple therapy is very low. H. pylori is known to require the nickel-containing metalloenzymes urease and NiFe-hydrogenase to survive at the low pH environment in the stomach. AIM: To compare the H. pylori eradication rate of a nickel free-diet associated with standard triple therapy and standard triple therapy alone as the first-line regimen. METHODS: Fifty-two sex- and age-matched patients at the first diagnosis of H. pylori infection were randomized 1:1 into two different therapeutic schemes: (1) standard LCA (26 patients): lansoprazole 15 mg bid, clarithromycin 500 mg bid and amoxicillin 1,000 mg bid for 7 days with a common diet; (2) standard LCA plus a nickel free-diet (NFD-LCA) (26 patients). Patients followed 30 days of a nickel-free diet plus a week of lansoprazole 15 mg bid, clarithromycin 500 mg bid and amoxicillin 1,000 mg bid starting from day 15 of the diet. RESULTS: All patients completed the study. A significantly higher eradication rate was observed in the NFD-LCA group (22/26) versus LCA group (12/26) (p < 0.01). Only a few patients (9 of 52) reported the occurrence of mild therapy-related side effects, without any significant differences between the two groups. CONCLUSIONS: The addition of a nickel-free diet to standard triple therapy significantly increases the H. pylori eradication rate. The reduction of H. pylori urease activity due to the nickel-free diet could expose the bacterium to gastric acid and increase H. pylori's susceptibility to amoxicillin. Further studies are necessary to confirm this preliminary result.

Human basophils: a unique biological instrument to detect the allergenicity of food.

BACKGROUND: Labeling of major food allergens is mandatory for the safety of allergic consumers. Although enzyme-linked immunosorbent assay, polymerase chain reaction, and mass spectrometry are sensitive and specific instruments to detect trace amounts of food proteins, they cannot measure the ability of food constituents to trigger activation of mast cells or basophils. AIM: We evaluated the basophil activation test as an instrument to determine the allergenic potential of trace amounts of food allergens in complex matrices. Peanut (Arachis hypogaea) allergy was selected as a proof-of-concept model. METHODS: The study population comprised 5 severely peanut-allergic patients (3 males/2 females; median age, 12 years) all sensitized to 3 major peanut allergens (Ara h 1, Ara h 2, and Ara h 3) and 5 peanut-tolerant individuals (2 males/3 females; median age, 8 years). Basophils from patients and controls were stimulated with pure peanut extract and blank and peanut-spiked (0.1, 0.01, and 0.001 ppm) biscuits (baking time 11, 16, 21, 26 minutes) and chocolate extracts. RESULTS: Blank biscuits and chocolate did not induce cell activation in patients or controls. A comparison between patients and controls showed significantly higher activation of basophils after stimulation with 0.1 and 0.01 ppm of peanut-spiked biscuit at all baking times and peanut-spiked chocolate (P < .05). CONCLUSIONS: The basophil activation test is a highly sensitive and specific tool to detect traces of functionally active food allergens. For biscuits, its accuracy seems independent of baking time. Furthermore, it allows even the most sensitive patients to be included in study protocols.

Oral hyposensitization to nickel induces clinical improvement and a decrease in TH1 and TH2 cytokines in patients with systemic nickel allergy syndrome.

Some patients with nickel (Ni) allergic contact dermatitis suffer from systemic (intestinal or cutaneous) symptoms after ingestion of Ni-rich foods and experience symptoms reduction with low-Ni diet, a condition termed Systemic Ni Allergy Syndrome (SNAS). We aimed at evaluating whether oral administration of low nickel doses improved clinical conditions and modulated immunological aspects of SNAS, without significant side effects. Thirty-six SNAS patients were enrolled. Treatment started after 1-month of low-Ni diet and consisted in an incremental oral NiOH dose phase (0.3ng to 1.5 microg/week) followed by a 12-months maintenance phase (1.5 microg/week). Randomly, twenty-four patients added Ni therapy to low-Ni diet and 12 remained with diet alone. All patients were allowed rescue medications (antihistamines and topical steroids). After 4 months, Ni-rich foods were gradually reintroduced. In vitro allergen-driven IL13, IL5 and IFN-gamma release by peripheral blood mononuclear cells was evaluated before and after treatment. Twenty-three patients receiving NiOH and the 12 control patients completed the study. Evaluation of SNAS clinical severity (by VAS and drug consumption) showed a significant difference in favor of NiOH-treated patients compared to controls. Twenty of 23 patients in the NiOH group and none in the control group tolerated Ni-rich food reintroduction. Release of all studied cytokines in culture supernatants was significantly lower after NiOH treatment. In conclusion NiOH is effective in reducing symptoms and drug consumption in SNAS and is able to modulate inflammatory parameters.

Anaphylactic reactions during cesarean section.

Sensitization to latex seems to occur more frequently in women than in men. Obstetric and gynecological surgical procedures have recently been shown to be a common setting for latex anaphylaxis. We analyzed all the cases of anaphylactic reactions during 1240 cesarean sections in 2004; the patients were questioned for risk factors and underwent allergy testing for drugs and latex. Four patients had anaphylaxis under spinal anesthesia and in all cases it was due to latex allergy. Reported symptoms included facial edema, profuse sweating, itching, generalized erythematous rash and hypotension. Only one patient manifested a severe reaction which included bronchospasm, dyspnea, tachypnea and anaphylactic shock, requiring orotracheal intubation and epinephrine. Our data showed a high incidence (1:310) of intraoperative latex anaphylactic reactions in the one-year study period. This may be related to the very specific population (all women) in a very specific setting (obstetrics). To prevent anaphylactic reactions during obstetric surgery it is important to identify potential risk factors to include, for example atopy, adverse reactions to foods and latex items. If latex allergy is confirmed or strongly suspected, patients should be managed in a latex-safe environment. Premedication with antihistamines and steroids might be useful to further reduce the risk. After the delivery, specific desensitization may represent a good therapeutic option.

Sublingual desensitization in children with congenital malformations and latex allergy.

The frequency of latex allergy in children requiring multiple surgery ranges from 16.7% to 65%. The aim of this study was to investigate the safety and efficacy of latex desensitization in a group of 10 patients with a history of multiple surgical procedures and clinically manifested allergy to latex. We selected 10 children (female-male ratio = 5:5), aged 4-16 yr (mean +/- s.d.: 9 +/- 4), with a history of multiple surgical procedures, adverse reactions to latex and positive skin test to latex and/or specific immunoglobulin E (IgE). Latex allergy diagnosis was confirmed by specific provocation tests (cutaneous, sublingual, mucous, conjunctival tests). Rush (4-day) sublingual desensitization was performed with increasing doses of latex extract (ALK Abellò) under patients' tongue until the highest dose of 500 microg of latex. A maintenance therapy (10 drops of undiluted solution three times a week) was recommended. During the 2-yr follow-up mean values of specific IgG4 and IgE, eosinophilic cationic protein and total IgE did not show significant variations. Patients did not manifest any adverse effect during the rush phase and only two patients manifested mild local symptoms during the maintenance therapy. All the challenges showed a reduction in terms of percentage of positivity and mean scores. All the patients showed a reduction of the mean individual score (p < 0.001). Furthermore patients who needed dental examination or surgery underwent such procedures without the occurrence of symptoms. Our preliminary results show sublingual desensitization to latex can be an important therapeutic tool in the management of young allergic patients requiring multiple operations.

A clinical trial of oral hyposensitization in systemic allergy to nickel.

Nickel allergy is the most common contact allergy. Some nickel-sensitive patients present systemic (cutaneous and/or digestive) symptoms related to the ingestion of high nickel-content foods, which significantly improve after a specific low nickel-content diet. The etiopathogenetic role of nickel in the genesis of systemic disorders is, furthermore, demonstrated by the relapse of previous contact lesions, appearance of widespread eczema and generalized urticaria-like lesions after oral nickel challenge test. The aim of this study is to investigate the safety and efficacy of a specific oral hyposensitization to nickel in patients with both local contact disorders and systemic symptoms after the ingestion of nickel-containing foods. Inclusion criteria for the recruitment of these patients were (other than a positive patch test) a benefit higher than 80% from a low nickel-content diet and a positive oral challenge with nickel. Based on the previous experiences, our group adopted a therapeutic protocol by using increasing oral doses of nickel sulfate associated to an elimination diet. Results have been excellent: this treatment has been effective in inducing clinical tolerance to nickel-containing foods, with a low incidence of side effects (gastric pyrosis, itching erythema).

Amphotericin B and lysine acetylsalicylate in the combined treatment of nasal polyposis associated with mycotic infection.

BACKGROUND: Fungal infection may be secondary to nasal polyposis or represent a real etiopathogenic factor in the infection itself. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a combined treatment with lysine acetylsalicylate (LAS) and amphotericin B in preventing recurrence in patients with nasal polyposis with accompanying mycotic infection in comparison with a control group with nasal polyposis and fungal infection who did not receive antifungal therapy. PATIENTS AND METHODS: A total of 115 patients with nasal polyposis were randomly assigned to 4 different groups and treated as follows: (1) group A, 25 patients were first surgically treated and then treated with LAS; (2) group B, 25 patients received 40 mg of triamcinolone retard intramuscularly 3 times every 10 days (total dose 120 mg) and then they were treated with LAS; (3) group C, 16 patients were surgically treated and then treated with LAS and amphotericin B; (4) group D: 23 patients were treated with a medical polypectomy and steroids (as in the group B) and then with LAS and amphotericin B. RESULTS: We found no significant differences between groups C and D, groups C and A, or groups B and D. However, the recurrence of nasal polyps in the groups treated with amphotericin B plus LAS (C and D) was significantly lower (P = .018) than in the 2 groups treated only with LAS (A and B). CONCLUSION: Our results indicate that long term topical treatment with LAS and amphotericin B may be clinically effective in the treatment of patients with nasal polyposis associated with fungal infection.

Positive patch tests to Euro coins in nickel-sensitized patients.

BACKGROUND: Many efforts have been made to prevent nickel allergy, the most frequent contact allergy in industrialized countries, by identifying acceptable limits of exposure. Even though coins are not covered by the EU Nickel Directive, some authors suggest that nickel release from coins during handling may elicit contact dermatitis in nickel-allergic people. OBJECTIVES: To evaluate sensitivity to nickel released from coins in nickel-allergic patients and to verify whether nickel release from the new Euro coins may elicit stronger cutaneous reactivity than from old Italian lire coins. METHODS: Twenty-five nickel-allergic patients were patch tested with 1- and 2-Euro coins, 1-, 2- and 50-Euro cent coins, and 100 and 500 Italian lire coins. Ten healthy nonnickel-allergic control individuals were also tested. RESULTS: Nineteen patients had positive patch tests to 1- and 2-Euro coins. One was also positive to 1- and 2-Euro cent coins, four to 50-Euro cent coins, and 13 to the 500-lire coin. None had a positive patch test to the 100-lire coin. The number and degree of positive patch tests to coins were related to nickel content. CONCLUSIONS: Euro coins may be potentially more dangerous than old Italian coins. Coins containing little or no nickel should be chosen for coinage to prevent sensitization and to avoid exacerbation of contact dermatitis in nickel-allergic patients.

Allergic fungal sinusitis. A naso-sinusal specific hyperreactivity for an infectious disease?

Allergic fungal sinusitis (AFS) is a rare disease of naso-sinusal complex affecting mainly young, immunocompetent adults who complain of chronic rhinitis and/or recurrent nasal polyposis despite medical and/or surgical treatment. Aim of the study is to analyse, from an allergological and otorhinolaryngological point of view, patients affected by the so-called "allergic fungal sinusitis" in order to better define the relationship between fungi present in naso-sinusal secretions and the host's immunoreactivity. From February 2001 to January 2002, 24 selected patients (13 male 11 female) age range 25-65 years (mean 45), with chronic rhinosinusitis, with a positive fungal examination of nasal secretion, underwent allergological evaluation. All patients were positive for diagnostic criteria of allergic fungal sinusitis and, in all patients, nasal lavage was performed for microscopic examination by fluorescence. Samples were then cultured on Sabouraud growth media for identification of the fungus. Skin prick tests (SPT) were then performed with the 15 main inhalant allergens and twelve fungal allergens (Bracco). The total IgE serum level (PRIST), the specific fungal IgE and the eosinophilic cationic protein were then investigated by means of an immuno-fluorine enzymatic method. Finally, a nasal provocation test was carried out with diluted solutions (1/100, 1/10) and with a pure solution of fungal allergens, selected according to microbiological examination of nasal secretion of each subject. Prick tests were positive for seasonal and perennial allergens in 5 patients (21%), while prick tests with fungi were positive in only 4 patients (16.6%). Total IgE levels were higher than in normals (200 KU/l) in 6 patients (25%) (mean 364.74 KU/l). In another 18 patients, total IgE were normal. Specific IgE levels for the tested fungi and eosinophilic cationic protein levels were within normal range in all patients. Nasal provocation test was negative in all patients. Presence of fungi in nasal secretions of patients with AFS does not appear to be correlated with an allergic status to the isolated fungus. A role for IgE in either the aetiology or the pathophysiology of allergic fungal sinusitis in unlikely, and probably the diagnostic criteria for allergic fungal sinusitis should not include type I hypersensitivity, since no confirmed evidence exists that IgE-mediated type I hypersensitivity is involved in the pathophysiology of allergic fungal sinusitis.

Clinical usefulness of patch and challenge tests in the diagnosis of cell-mediated allergy to betalactams.

BACKGROUND: Literature reports dealing with cell-mediated allergy to betalactams have appeared with increasing frequency in the last years. OBJECTIVE: To evaluate patients with such reactions and to identify cross-reactivities among betalactams in order to provide safe guidelines for their further clinical management. METHODS: Thirty consecutive subjects with cell-mediated allergy to betalactams (history of adverse reactions to these antibiotics; serum total IgE within the normal range; absence of serum specific IgE antibodies to penicillin G and V, amoxicillin, and ampicillin; negative skin tests with a wide pattern of betalactam preparations; and positive patch-test to at least one betalactam antigenic determinant) were investigated. The subjects admitted to the study were patch tested with a wide variety of betalactam preparations in order to identify alternative molecules tolerated by the patient. To better evaluate the cross-reactivity pattern, tolerance challenges with patch-negative betalactams were also performed in each subject. RESULTS: Both specific IgE and skin tests were negative in all patients. The skin biopsies performed on the positive patch-tested area in four patients showed a clear T-lymphocyte, CD4+-type infiltrate, thus definitely proving the occurrence of a cell-mediated response. A total of 44 adverse reactions (mean: 1.47 episodes for each patient) were reported in history, with a mean interval of 15 hours after betalactam administration. The reported symptoms were mainly cutaneous (maculo-papular rash and urticaria) and the responsible drugs were chiefly aminopenicillins (86.4% of cases) and penicillin G (9.1%). We were able to identify three separate groups of patients on the basis of clinical history, patch-test, and tolerance challenge pattern: allergy to the side chain of aminopenicillins in 16 patients (53.3%); allergy to the thiazolidine ring in 3 patients (10.0%); undetermined specificity in the remainder 11 patients (36.7%). Cross-reactivity among different betalactam molecules (revealed by positive tolerance tests performed with patch-negative betalactams) was found in 4.8% of cases only (23.3% of all investigated patients). This fact demonstrates a very high (95.2%) predictive value of a negative patch-test in excluding the occurrence of a cross-reactivity. The mis-match between patch and tolerance tests was observed in 3 out of 178 cases only (1.7% of cases, 10.5% of patients) in groups A and B, and in as much as 12.2% of cases (45.5% of subjects) in group C (P < .05). CONCLUSIONS: Delayed allergy to betalactams (mainly to aminopenicillins) may be exerted by a cell-mediated response. Patch tests and tolerance challenges are extremely useful and safe for diagnosis and further clinical treatment of these patients, helping to identify safe alternative betalactam molecules that could be successfully tolerated by the allergic subjects.

Growth inhibition of fibroblasts from nasal polyps and normal skin by lysine acetylsalicylate.

Some authors have shown that lysine acetylsalicylate (LAS) may help prevent nasal polyp relapses. As some anti-inflammatory drugs have been found to regulate cell growth, we investigated the antiproliferative effect of LAS on fibroblasts derived from nasal polyps. Moreover, we studied the effect of LAS on the growth of fibroblasts derived from normal skin to determine whether the response was similar to that obtained in the above-mentioned cells. Fibroblasts were obtained from tissue samples of nasal polyps from two aspirin-tolerant and two aspirin-intolerant patients, and from the normal skin of a healthy donor. The cells were treated with LAS (20-2000 microg/ml of culture medium). Cell growth and viability were evaluated after 3 and 6 days of culture. LAS had a growth-inhibitory effect on cells independently of their derivation. A reduction in cell growth was seen at the concentrations of LAS tested, which correspond to those used in the local treatment of nasal polyposis.

Immunologic findings in Peyronie's disease: a controlled study.

OBJECTIVES: Recent literature suggests the hypothesis of an immune etiology of Peyronie's disease. In this controlled study, the immune response pattern of the disease is investigated. METHODS: Sixty-six patients with Peyronie's disease and 20 age-matched controls were studied. In all patients, skin test (multitest), in vitro lymphocyte transformation test (LTT), serum immunoglobulin (Ig) A, G, and M, anti-DNA, antinuclear and anti-smooth muscle cell antibodies, C3 and C4 complement fractions, antistreptolysin, and C-reactive protein titers were evaluated. RESULTS: A fair percentage (75.8%) of the patients with Peyronie's disease exhibited at least one abnormal immunologic test, in comparison to only 10% among controls (chi-square = 27.8, df = 1; P < 0.0001). Alterations of cell-mediated immunity (multitest, LTT) were observed in 48.5% of patients, alterations of humoral immunity (Ig) in 31.8%, and alterations of markers of autoimmune disorders (autoantibodies, complement activation) in 37.9% of the cases. CONCLUSIONS: Our results support the hypothesis that there is some involvement of the immune system in the pathogenesis of Peyronie's disease, although the available data still appear to be insufficient to formulate a definite pathogenetic hypothesis.

Nasal lavage cytometry in the diagnosis of nonallergic rhinitis with eosinophilia syndrome (NARES).

The nonallergic rhinitis with eosinophilia syndrome (NARES) is a type of chronic rhinitis, characterized by intense (> 20%) eosinophilia of the nasal secretions. In this study, screening for NARES in 81 patients with nonallergic chronic rhinitis was performed using a modified nasal lavage cytometric method. Twenty-one of the 81 investigated individuals (25.9%) showed nasal eosinophilia greater than 20%, therefore being diagnosed as having NARES. No statistical difference in total serum IgE concentration (Prist Pharmacia) was observed between the NARES subjects and those with other forms of chronic rhinitis, confirming the seemingly nonallergic nature of NARES. In 28.6% of these cases the presence of anosmia was detected: in 19.0% of cases with NARES (all subjects complaining of long-lasting symptoms and suffering from anosmia), nasal polyposis coexisted. Our results confirm that nasal lavage cytometry may represent a useful clinical tool in the diagnosis of chronic rhinitis.

Oral hyposensitization to nickel allergy: preliminary clinical results.

Fifty-one patients presenting a dermatological allergy (erythema, urticaria, angioedema, contact dermatitis) to nickel were treated over 3 years with oral doses of 0.1 ng nickel sulfate per day, following a low-nickel diet. Diagnostic tests comprised patch and oral provocation tests. In 7 cases, the treatment was interrupted because of symptom reactivation, and in 14 cases for other reasons. Among the 30 cases who went through the whole follow-up, symptomatology totally disappeared in 29 cases, and a partial alleviation was achieved in 1 case after 1 year of treatment. Oral provocation tests with these 30 patients showed an overall increase of tolerance. Patch tests showed no variation in 20 cases, a diminution in 5, and were negative in 5. Although the study was not conducted double blind, the results of this attempt to cure nickel allergy are statistically significant.

Rush desensitization in heparin hypersensitivity: a case report.

Among all the known drug intolerances, adverse reactions to heparin are not very common. No desensitization in patients with heparin hypersensitivity has ever been attempted. We report the case of a 55-year-old female patient with mitral stenosis and insufficiency, and tricuspid and aortic insufficiency. The patient underwent heparin treatment, and urticaria occurred with either s.c. calcium heparin or i.v. sodium heparin. Allergy testing (skin tests and patch tests) was negative. A pseudoallergic intolerance was diagnosed. Mitral valve replacement with the extracorporeal circulation method was necessary; therefore, heparin treatment was administered. A heparin rush desensitization together with antihistamine drugs (4 mg clorpheniramine maleate for 3 d) was started: 50 UI (0.5 mg) s.c. sodium heparin were first administered; within 4 d, 5000 UI (50 mg) sodium heparin was administered i.v. with no side-effects. A full-dosage heparin treatment was then administered and heart surgery was easily performed. During the postsurgical course, i.v. sodium heparin was smoothly replaced with s.c. calcium heparin (25,000 UI s.c. per day) and with oral anticoagulants (sodium warfarin).