A non-synonymous polymorphism in galectin-3 lectin domain is associated with allergic reactions to beta-lactam antibiotics.

Genetic predictors of beta-lactam (BL) allergy are mostly related to Immunoglobulin E (IgE) synthesis and atopy. Despite this context, little attention has been devoted to genes of IgE/FcɛRI pathway, such as galectin-3, a ß-galactoside-binding lectin, which binds to IgE. We evaluated the association of LGALS3 polymorphisms with BL allergy in 395 Spanish and 198 Italian cases, compared with 310- and 339-matched controls, respectively. The rs11125 predicted BL allergy with an odds ratio of 4.0 in Spanish population (P<0.0001). This association was replicated with an odds ratio of 5.1 in Italian population (P<0.0001); rs11125 predicted also increased serum level of total IgE in Spanish controls. These data are consistent with the predicted deleterious influence of Gln>His substitution produced by rs11125 on galactose-binding activity of galectin-3. In conclusion, LGALS3 is the strongest genetic predictor of BL allergy reported so far. This association reflects the influence of genes of IgE/FcɛRI pathway in this pathology.

Quality-of-life issues in survivors to anaphylactic reactions to drugs.

The aim of this cross-sectional observational study was to explore quality of life and well-being in patients with drug-induced anaphylaxis. Two validated tools were used: the Drug Hypersensitivity Quality-of-Life Questionnaire (DrHy-Q) and the Psychological General Well-Being Index (PGWBI). Sixty-five patients (13 males) underwent data analysis. The mean DrHy-Q score was 62.82 ± 12.1. Mean PGWBI score was 64.03 ± 17.66. DrHy-Q score was significantly correlated with PGWBI total score (r = -0.314; P = 0.011) and with the following domains: Anxiety (r = -0.260; P = 0.036), Depressed mood (r = -0.406; P = 0.001), Positive well-being (r = -0.251; P = 0.004), and General Health (r = -0.352; P = 0.004). Compared with the Italian reference population, patients had a significantly reduced PGWBI total and domain score. Our results highlight for the first time how impaired HRQoL and distress commonly feature in survivors to anaphylactic reactions to drug.

Natural evolution of skin-test sensitivity in patients with IgE-mediated hypersensitivity to cephalosporins.

There are studies demonstrating that skin-test sensitivity to penicillins can decrease over time and that allergic patients may lose sensitivity if the responsible compounds are avoided. With regard to subjects with IgE-mediated hypersensitivity to cephalosporins, however, such studies are lacking. We evaluated prospectively in a 5-year follow-up 72 cephalosporin-allergic patients. After the first evaluation, patients were classified into two groups according to their patterns of allergologic-test positivity: to both penicillins and cephalosporins (group A), or only to cephalosporins (group B). Skin tests and serum-specific IgE assays were repeated 1 year later and, in case of persistent positivity, 3 and 5 years after the first allergologic examination. Seven (43.7%) of the 16 subjects of group A and 38 (67.8%) of the 56 patients of group B became negative; one was lost to follow-up. Patients of group B became negative sooner and more frequently than group A subjects.

Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins.

Studies performed on subjects with IgE-mediated hypersensitivity to penicillins have demonstrated a 1% rate of cross-reactivity between penicillins and both imipenem and meropenem, while a single study found a 5.5% rate of cross-reactivity with imipenem/cilastatin in subjects with T-cell-mediated hypersensitivity to ß-lactams, mostly penicillins. We studied 204 consecutive subjects with a well-demonstrated T-cell-mediated hypersensitivity to assess the cross-reactivity with carbapenems and the tolerability of such alternative ß-lactams. All 204 subjects underwent skin tests with imipenem/cilastatin and meropenem; 130 of them were skin-tested also with ertapenem. Subjects with negative test results were challenged with these carbapenems. All subjects displayed negative skin tests to carbapenems and tolerated challenges. These data demonstrate the absence of clinically significant T-cell-mediated cross-reactivity between penicillins and carbapenems. Negative delayed-reading skin testing with carbapenems in individuals with documented T-cell-mediated hypersensitivity to penicillins correlates well with subsequent clinical tolerance of therapeutic doses of carbapenems.

Allergy to betalactams and nucleotide-binding oligomerization domain (NOD) gene polymorphisms.

BACKGROUND: Polymorphisms of interleukin genes related to IgE production and inflammation are predictors of hypersensitivity to betalactam, but nothing is known on the influence of NOD genes, despite their association with inflammation and atopy. OBJECTIVE: To evaluate the association of NOD2 and NOD1 polymorphisms with betalactam allergy. METHOD: We genotyped 3 polymorphisms of NOD2 and 1 of NOD1 in 368 Italian and 387 Spanish patients, compared with 368 and 326 controls, respectively. RESULTS: CT/TT genotypes of rs2066845 of NOD2 predicted a lower risk in Italy (P = 0.003), while WT/insC genotype of rs5743293 (also in leucine-rich repeat domain) predicted a higher risk in Spain (P = 0.007). G allele of rs2066845 was associated with a higher level of IgE in the Italian population. CONCLUSION: The mirrored influence of these NOD2 polymorphisms on betalactam allergy in two populations suggests a link with pathways of inflammation and/or atopy through mechanisms, which need to be clarified.

Lipid transfer proteins: the most frequent sensitizer in Italian subjects with food-dependent exercise-induced anaphylaxis.

BACKGROUND: Specific food-dependent exercise-induced anaphylaxis (S-FDEIAn) is a distinct form of food allergy in which symptoms are elicited by exercise performed after ingesting food to which the patient has become sensitised. Non-specific FDEIAn (NS-FDEIAn) is a syndrome provoked by exercise performed after ingesting any food. OBJECTIVE: We sought to identify the culprit allergenic molecules in patients with FDEIAn, combining 'classic' allergy testing with an allergenic molecule-based microarray approach for IgE detection. METHODS: All subjects were evaluated who reported at least one episode of anaphylaxis in association with physical exercise performed within 4 h after a meal. We performed skin prick tests (SPT) with commercial food extracts, prick plus prick tests (P + P) with fresh foods (P + P), and serum specific IgE assays by means of both the ImmunoCAP (CAP) and the ISAC 89 microarray system (ISAC). RESULTS: Among our 82 FDEIAn patients, the most frequent suspected foods were tomato, cereals, and peanut. SPT, P + P, and CAP displayed different degrees of sensitivity. Each test disclosed some positivities not discovered by others. Seventy-nine subjects were positive to at least one food (49 to more than 20), whereas three were negative. All suspected foods were positive to at least one of SPT, P + P, and CAP. When tested using the ISAC, 64 (78%) subjects were positive to Pru p 3 [peach lipid transfer protein (LTP)], 13 were positive to other food allergen molecules, and five displayed negative results to all food allergenic molecules. Overall, 79 patients probably had S-FDEIAn and the other 3 NS-FDEIAn. CONCLUSIONS: Multiple food hypersensitivity represents a clinical hallmark of a large percentage of FDEIAn patients. The very high prevalence of IgE to the LTP suggests a role of this allergen group in causing S-FDEIAn.

Assessing potential determinants of positive provocation tests in subjects with NSAID hypersensitivity.

BACKGROUND: Provocation tests (PTs) with the suspected compounds are considered the 'gold standard' for establishing or excluding a diagnosis of hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs). However, only a few studies have evaluated the potential determinants of positive responses to PTs. OBJECTIVE: The aims of this study are to assess the reliability of clinical histories as indicators of NSAID hypersensitivity, as well as the risk factors for a positive PT. METHODS: Two hundred and seventy-five subjects with an unequivocal history of NSAID hypersensitivity reactions underwent PTs with the suspected drugs. To establish the potential determinants of positive PTs, we examined the following variables: gender, age at the time of reaction (<40 or ≥40 years), family and personal histories of atopy, patients who had reacted to one or more NSAIDs, time interval between drug intake and symptom onset (immediate or non-immediate reactions), time interval between the last drug reaction and the allergologic examination (≤12 or >12 months), and inclusion in a category of the Stevenson et al. classification. RESULTS: Two hundred and fourteen (77.8%) subjects tolerated the suspected drugs and 61 (22.2%) reacted. Age <40 years, male gender, immediate reactions, and time interval ≤12 months were significant risk factors for a positive PT. CONCLUSIONS AND CLINICAL RELEVANCE: Our study confirms that clinical histories are not reliable tools for diagnosing NSAID hypersensitivity. Therefore, we recommend that suspected cases should undergo drug PTs. However, further studies on large samples of NSAID-sensitive patients are necessary to establish the risk factors that allow the number of candidates for PTs to be reduced.

The very limited usefulness of skin testing with penicilloyl-polylysine and the minor determinant mixture in evaluating nonimmediate reactions to penicillins.

BACKGROUND: The contribution of skin testing with penicilloyl-polylysine (PPL) and the minor determinant mixture (MDM) to the diagnosis of hypersensitivity reactions to penicillins differs greatly according to the type of reaction: immediate (occurring within 1 h after the last drug administration) or nonimmediate (occurring more than 1 h after the last drug administration). OBJECTIVE: To assess the contribution of skin testing with PPL and MDM to the diagnosis of nonimmediate reactions to penicillins. METHODS: We evaluated 162 adults who had had 232 nonimmediate reactions to penicillins, mostly aminopenicillins, and presented positive skin and/or patch tests to one or more penicillin reagents: PPL, MDM, benzylpenicillin, ampicillin, and amoxicillin, as well as any responsible penicillins. RESULTS: A total of 157 subjects (96.9%) displayed patch-test and/or delayed-reading intradermal-test positivity to penicillin reagents, which indicates a cell-mediated hypersensitivity; six of them also presented immediate-reading skin-test positivities. All 157 patients with a cell-mediated hypersensitivity were positive to the responsible penicillins (parent drugs); 16 of them also displayed delayed-reading intradermal-test positivity to MDM. Five (3.1%) of the 162 patients displayed only immediate-reading skin-test positivity (four to PPL and one to amoxicillin). Overall, 158 subjects (97.5%) presented positive responses to the responsible penicillins, while only 9 (5.5%) and 17 (10.5%) were positive to PPL and MDM, respectively. CONCLUSIONS: The contribution of skin testing with PPL and MDM in diagnosing nonimmediate hypersensitivity reactions to penicillins, especially cell-mediated ones, is very limited. This finding could be useful at a time when PPL and MDM are not available in all countries.

Determining the negative predictive value of provocation tests with beta-lactams.

BACKGROUND: The beta-lactam allergic work-up is mostly standardized. However, the negative predictive value of drug provocation tests is not yet well established. METHOD: A historical-prospective multicentre cohort study was conducted in four centres (one in France, one in Portugal, two in Italy) to assess the negative predictive value of provocation tests with beta-lactams in patients initially tested for a suspicion of drug allergy/hypersensitivity. Patients were contacted at least 6 months after the work-up, between 2003 and 2007. A new allergic work-up was proposed to reacting patients. RESULTS: Among the 457 patients included, 365 (79.9%) were followed up (159 [79.1%] from France, 153 [82.7%] from Italy and 53 [74.6%] from Portugal). Only 118 (25.8%) were re-exposed to the negatively tested beta-lactam. Nine (7.6%) reported a non-immediate (occurring more than 1 h after drug administration) reaction: five urticaria, three exanthema and one undefined cutaneous reaction. None were severe. Only four accepted a re-challenge, negative in two cases and positive in the two others. The negative predictive value was 94.1% (89.8-98.3) (111 out of 118 patients). CONCLUSION: Although the negative predictive value of drug provocation tests may not be 100%, none of the false negative patients experienced a life-threatening reaction. This should reassure doctors who might hesitate to prescribe beta-lactams, even in patients with negative allergic work-ups.

Cross-species comparisons of the pharmacokinetics of ibudilast.

To enable clinical development of ibudilast for new indications, its pharmacokinetics were characterized in mice, rats, rabbits, dogs, cynomolgus monkeys, and minipigs. Animal pharmacokinetics were compared with a separate study in healthy volunteers. Following oral dosing, the dose-normalized area under the curve (AUC) (DN-AUC(24h)) in humans is 896 ((ng*h ml(-1))/(mg kg(-1))), and in animals ranges from 0.3 to 87. The variability among species cannot be explained by intrinsic clearance, which in intravenous dosing experiments shows only moderate interspecies variation (13-41 l h(-1) m(-2)). A portal vein rat pharmacokinetics model suggested that differences in first-pass gut clearance may explain some of the interspecies variation in oral bioavailability. Ibudilast shows auto-induction of metabolism in some animals, but not in humans. Plasma protein binding in humans and some animals is greater than or equal to 95%. The primary metabolite 6,7-dihyrdodiol-ibudilast is measurable and has been quantitated in plasma from animals and humans. Finally, biodistribution studies show that ibudilast distributes rapidly, extensively, and reversibly to the central nervous system.

Benzylpenicillin skin testing is still important in diagnosing immediate hypersensitivity reactions to penicillins.

BACKGROUND: The fact that both Hollister-Stier and Allergopharma ceased the production of penicilloyl-polylysine (PPL) and minor determinant mixture (MDM) in 2004 is severely hampering the diagnosis of beta-lactam hypersensitivity and may produce negative consequences. OBJECTIVE: To assess the contribution of skin testing with benzylpenicillin to the diagnosis of immunoglobulin E-mediated hypersensitivity to penicillins, in order to determine how much such testing could compensate for PPL and MDM unavailability. METHODS: We selected patients with histories of immediate reactions to penicillins and positive results to skin tests for one or more penicillin reagents (PPL, MDM, or benzylpenicillin), one or more semi-synthetic penicillins (ampicillin, amoxicillin, or piperacillin), or both. RESULTS: A total of 300 patients were selected, 105 in the French center and 195 in the Italian centers. Amoxicillin and ampicillin were the main responsible drugs. The most common clinical manifestation was anaphylaxis. The reagents most frequently positive to skin tests were amoxicillin (188, 62.7%), ampicillin (151, 50.3%), and benzylpenicillin (111, 37.0%). Among the 300 subjects, 113 (37.7%) were positive only to semi-synthetic penicillins, 109 (36.3%) to both semi-synthetic penicillins and the classic penicillin reagents, and 78 (26.0%) only to the latter. In the last group, 64 (21.3% of the 300 subjects) were positive only to PPL and/or MDM and 14 (4.7%) to benzylpenicillin, of whom 8 (2.7%) were positive only to the latter. CONCLUSIONS: Skin testing with benzylpenicillin can partially compensate for PPL and MDM unavailability. Moreover, it can slightly increase the allergologic workup's sensitivity and therefore reduce the number of potentially dangerous challenges.

Las pruebas cutáneas con bencilpenicilina siguen siendo importantes en el diagnóstico de las reacciones inmediatas de hipersensibilidad a las penicilinas / Benzylpenicillin skin testing is still important in diagnosing immediate hypersensitivity reactions to penicillins

Antecedentes. El hecho de que tanto Hollister-Stier como Allergopharma haya cesado la producción de penicilil-polilisina (PPL) y la mezcla de determinantes menores (MDM) en 2004, es un obstáculo importante en el diagnóstico de la hipersensibilidad a los ß-lactámicos y puede producir consecuencias negativas. Objetivo. Evaluar la contribución de las pruebas cutáneas con bencilpenicilina para el diagnóstico de la hipersensibilidad a penicilina mediada por IgE, con el fin de determinar cuánto podría compensar esta prueba cutánea la falta de disponibilidad de PPL y MDM. Métodos. Se seleccionaron pacientes con antecedentes de reacciones inmediatas a penicilina y test cutáneo para uno o más reactivos de penicilina (PPL, MDM o bencilpenicilina), una o más penicilinas semisintéticas (ampicilina, amoxicilina o piperacilina) o ambos. Resultados. Se seleccionaron en total 300 pacientes, 105 en el centro de Francia y 195 en los centros italianos. Las principales drogas responsables fueron la amoxicilina y ampicilina. La manifestación clínica más común fue la anafilaxia. Las pruebas cutáneas más frecuentemente positivas fueron con amoxicilina (188; 62,7%), ampicilina (151; 50,3%) y bencilpenicilina (111; 37,0%). Entre los 300 sujetos, 113 (37,7%) fueron positivos sólo para las penicilinas semisintéticas, 109 (36,3%) a ambas penicilinas semi-sintéticas y el clásico reactivo penicilina y 78 (26,0%) sólo a este último. En el último grupo, 64 (21,3% de los 300 sujetos) fueron positivos sólo a PPL y/o MDM y 14 (4,7%) a bencilpenicilina, de los cuales 8 (2,7%) fueron positivos sólo a este último Conclusiones. Las pruebas cutáneas con bencilpenicilina pueden compensar en parte la falta de PPL y de MDM. Por otra parte, puede aumentar ligeramente la sensibilidad del estudio diagnóstico alergológico y, por lo tanto, reducir el número de desafíos potencialmente peligrosos(AU)

Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins.

BACKGROUND: Administration of meropenem to penicillin-allergic patients who might benefit from this treatment is usually avoided because of a 47.4% rate of cross-reactivity to imipenem, the prototype of the carbapenem class of beta-lactam antibiotics, demonstrated in a single study on the basis of positive responses to skin tests with imipenem reagents. However, recent studies of ours have demonstrated a very low rate of cross-reactivity between penicillins and both meropenem and imipenem in adults. OBJECTIVE: To assess cross-reactivity and tolerability of meropenem in children with documented penicillin allergy. METHODS: One hundred and eight consecutive children who had suffered a total of 129 immediate reactions (120 urticarial and/or angioedematous manifestations and 9 anaphylactic shocks) to penicillins and had positive results to skin tests for at least one of the penicillin reagents tested underwent skin tests with meropenem and negative subjects were challenged with it. RESULTS: One subject (0.9%) displayed a positive intradermal test to meropenem. The remaining 107 subjects with negative skin tests to meropenem tolerated challenges. Challenges were not followed by full therapeutic courses. CONCLUSIONS: Our results demonstrate a low rate of cross-reactivity between penicillins and meropenem. Therefore, the practice of avoiding meropenem in children with immunoglobulin E-mediated hypersensitivity could be abandoned; in those who especially require meropenem treatment, prophylactic skin tests are advisable, because negative results indicate tolerability.

Association of tumor necrosis factor-alpha -308G>A polymorphism with IgE-mediated allergy to betalactams in an Italian population.

Tumor necrosis factor-alpha (TNF-alpha) is released from mast cells via an immunoglobulin E (IgE)-dependent mechanism. The variant G>A at -308 of TNFA is part of an extended haplotype HLA-A1-B8-DR3-DQ2 and influences the gene expression. We evaluated this variant in relation to IgE-mediated reactions to betalactams, in 427 subjects, including 167 cases and 260 age- and gender-paired controls. TNFA GG genotype was a significant independent predictor of the primary risk of betalactam allergy, concurrently with total IgE level, with an age- and sex-adjusted odds ratio estimated at 2.45 (95% confidence interval: 1.18-5.08, P=0.0163). Cases with -308AA genotype had a higher serum level of specific IgE than those with -308GA/GG genotype, with median levels (relative units) of 4.6 (inter-quartiles: 3.9-10.6) and 2.2 (1.4-4.3), respectively (P=0.0046). In conclusion, our results suggest an ambivalent influence of a genetic determinant of pro-inflammatory pathways on IgE-mediated hypersensitivity to betalactams.

Nonisothermal reactors for the production of pure water from peritoneal dialysis waste waters.

The diffusion of peritoneal dialysis (PD) at home is somewhat restricted by the difficulty of transport and storage of a large amount of dialytic solutions. This problem is exacerbated in the case of hemodialysis. With the aim of producing pure water to be used in preparing the solution for peritoneal dialysis, or for hemodialysis in general, as one example, we purified the spent dialysate solution from PD. Experiments were carried out with 24 dialysate solutions taken from 8 patients. Pure water was obtained by means of a thermodialysis process in a hollow fiber reactor operating under nonisothermal conditions. Results show that the yield of the nonisothermal process is dependent on the temperature difference applied across the hydrophobic membranes. The production of pure water per square meter of membrane and per hour was equal to 0.55 or 1.2 or 2.0 liters, with a temperature difference of 11 degrees C or 21 degrees C or 28 degrees C, respectively. These results encourage the use of the thermodialysis process in the production of pure water for clinical uses.

A comparison of the performance of two penicillin reagent kits in the diagnosis of beta-lactam hypersensitivity.

BACKGROUND: Skin testing with penicilloyl polylysine (PPL) and minor determinant mixture (MDM) represents the first-line method for diagnosing beta-lactam hypersensitivity. However, in 2004, Allergopharma and Hollister-Stier announced their decision to stop the production of penicillin reagents (Allergopen and PrePen, respectively) within 1 year. Therefore, we decided to compare PPL and MDM from Allergopharma (Allergopen) with those from Diater (DAP). METHODS: We skin-tested 195 subjects with both Allergopen and DAP reagents, as well as with other beta-lactams; 74 (group A) had had immediate reactions to beta-lactams and 74 (group B) nonimmediate reactions, while 47 (group C) underwent prophylactic tests. RESULTS: One hundred two patients (52.3%) had positive skin tests; 29 (14.9%) were positive to PPL and/or MDM. Of the 102 skin-test-positive patients, 44 belonged to group A, 57 to B and 1 to C; the last was positive only to Allergopen PPL (PPL-A) and tolerated the benzylpenicillin challenge. Minor determinant mixture reagents produced identical results in the 148 patients of groups A and B, 22 (14.9%) of which were positive. Both PPL reagents produced negative results in 139 of these 148 patients and positive ones in 5; one subject was positive to DAP PPL (PPL-D) and negative to PPL-A, while three patients were positive to PPL-A and negative to PPL-D; two of the latter tolerated benzylpenicillin challenges. CONCLUSIONS: Minor determinant mixture reagents produced identical results in all 195 patients. Results of skin testing with PPL reagents were concordant in 190 (97.4%) of them. Therefore, DAP reagents are a reliable alternative to Allergopen ones.