-
J A Cornejo-García,
L R Jagemann,
N Blanca-López,
I Doña,
C Flores,
R M Guéant-Rodríguez,
M J Torres,
J Fernández,
J J Laguna,
A Rosado,
J A G Agúndez,
E García-Martín,
G Canto,
J-L Guéant,
M Blanca
[show abstract]
[hide abstract]
ABSTRACT: To date, genetic studies of hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) have been carried out mainly in aspirin-induced asthma and to a lesser extent in chronic urticaria, with no studies in patients with acute urticaria (AU), the most common entity induced by these drugs.
In this work, we analysed the association of common variants of 15 relevant genes encoding both enzymes and receptors from the arachidonic acid (AA) pathway with NSAID-induced AU.
Patients were recruited in several Allergy Services that are integrated into the Spanish network RIRAAF, and diagnosed of AU induced by cross-intolerance (CRI) to NSAIDs. Genotyping was carried out by TaqMan allelic discrimination assays.
A total of 486 patients with AU induced by CRI to NSAIDs and 536 unrelated controls were included in this large Spanish case-control study. Seven variants from 31 tested in six genes were associated in a discovery study population from Malaga (0.0003 ≤ p-value ≤ 0.041). A follow-up analysis in an independent sample from Madrid replicated three of the SNPs from the ALOX15 (rs7220870), PTGDR (rs8004654) and CYSLTR1 (rs320095) genes (1.055x10(-6) ≤meta-analysis p-value ≤ 0.003).
Genetic variants of the AA pathway may play an important role in NSAID-induced AU. These data may help understand the mechanism underlying this disease.
Clinical & Experimental Allergy 12/2012; 42(12):1772-81. · 5.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Betalactam (BL) immediate-type allergy is influenced by environmental and genetic determinants, as illustrated by differences in worldwide prevalence and ethnicity from a same area and by associations with genes related to atopy.
To evaluate the association of atopy with BL allergy.
We measured specific Immunoglobulin E (IgE) against prevalent allergens and genetic predictors of atopy, IL13, IL4, IL4RA, IL4, and TNFA, in 340 patients and 340 controls from South of Spain.
Total IgE and IgE against mites were at higher concentration in patients. Patients with high total IgE and IgE against prevalent allergens had a slower decrease in BL IgE than nonatopic patients. IL4RA I50V and Q551R were associated with IgE against prevalent allergens and total IgE, respectively, and were also predictors of BL allergy.
Interacting determinants of atopy, total IgE, IgE against prevalent allergens, and IL4RA polymorphisms, contribute to the high prevalence of BL allergy in South of Spain.
Allergy 07/2012; 67(9):1181-5. · 6.27 Impact Factor
-
I Doña,
N Blanca-López, J A Cornejo-García,
M J Torres,
J J Laguna,
J Fernández,
A Rosado,
C Rondón,
P Campo,
J A Agúndez,
M Blanca,
G Canto
[show abstract]
[hide abstract]
ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently involved groups of medicines in hypersensitivity drug reactions. Two mechanisms can induce the reaction: immunological (sensitization) due to a specific IgE or T cell response and pharmacological (cyclooxygenase inhibition). The contribution of each of these mechanisms to the reactions is not well known.
To analyse a large group of subjects with confirmed hypersensitivity reactions to NSAIDs.
The drugs involved, the clinical entities induced and the time interval between drug intake and appearance of the reaction were studied. In cases where the diagnosis was not confirmed, a drug provocation test was carried out. Atopy status was also assessed with prick test and total IgE in serum.
A total of 659 patients were finally considered to have had hypersensitivity reactions to NSAIDs; 76% had cross-intolerance (CI) and 24% were selective responders (SR). The most important drugs involved in CI were propionic acid derivatives, in most cases ibuprofen, and in SR pyrazolones. In CI, the most frequent clinical entity was urticaria and angio-oedema and to a lesser extent airway involvement. The skin and airways were both involved in an important proportion of cases. The most frequent entities in SR were urticaria and/or angio-oedema followed by anaphylaxis. Atopy was significantly associated in the CI group (P<0.005).
Cutaneous hypersensitivity reactions by CI to NSAIDs are the most frequent entities induced by these compounds. In addition to aspirin, other NSAIDs are taking on a predominant role. Atopy can be a predisposing factor in patients with CI.
Clinical & Experimental Allergy 01/2011; 41(1):86-95. · 5.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Drug allergy refers to a hypersensitivity reaction for which either an IgE or T-cell-mediated mechanism is demonstrated. The recognition of the drug by B and T cells is influenced by variants of HLA genes. The genetic factors involved in IgE-mediated mechanisms have been studied mainly in beta-lactam reactions, and they appear to be related to human leukocyte antigen presentation (HLA A2 and DRw52), TNFA -308G>A, class switching to IgE by B cells (variants of IL-13 and of IL-4RA), and expression of IgE receptors on target cells (variant of the FcepsilonRIbeta gene). Delayed T-cell-mediated reactions are also associated with HLA alleles. Studies have reported an association of HLA-B*1502 and HLA-B*5801 in patients with the Stevens-Johnson syndrome or toxic epidermal necrolysis provoked by carbamazepine, as well as of HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701 seems to be a strong predictor in whites, but not in Hispanics or Africans. Carbamazepine hypersensitivity is also influenced by gene variants of cytochrome P450 enzymes on the generation of reactive metabolites, while CYP2C9*2 and CYP2C9*3 polymorphisms influence the bioactivation of sulfamethoxazole in prohapten. Pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcepsilonRIalpha gene, and variants in genes of enzymes from the arachidonic acid pathway. In the future, identification of genetic predictors will benefit from genomewide association studies that also take ethnic differences into account. Ideally, predictors will help to prevent adverse reactions, as suggested by a recent study on the effectiveness of prospective HLA-B*5701 screening to prevent hypersensitivity reactions to abacavir in HIV patients.
Current pharmaceutical design 02/2008; 14(27):2770-7. · 4.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Immediate hypersensitivity reactions to betalactams are IgE mediated and constitute the most frequent allergic reactions mediated by specific immunological mechanisms. IgE responses to benzyl penicillin (BP), the first antibiotic producing the benzyl penicilloyl structure (BPO), are characterized by a quick release of inflammatory mediators, resulting in anaphylactic shock, urticaria and angioedema. With the progressive appearance of other structures, comprising cephalosporins, carbapenems, monobactams and clavulanic acid, IgE selective responses and cross-reactivity reactions were observed. The diagnosis of betalactam hypersensitivity, classically based on skin testing with major and minor determinants of benzyl penicillin or in vitro IgE antibodies to BP, has been modified by the inclusion of different determinants generated from these compounds, for which amoxicillin (AX) is the most relevant, followed by cephalosporins. Some subjects develop positive responses to several betalactams, mostly within the same family, but others develop a selective response. These are relevant for the appropriate selection of antimicrobial drugs in patients who have immediate hypersensitivity to betalactams.
Current pharmaceutical design 02/2006; 12(26):3327-33. · 4.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Basophil activation by allergens, including drugs, has been used to determine sensitivity and to study IgE recognition and cross-reactivity.
We sought to determine the sensitivity and specificity of a basophil activation test (Basotest) in patients with immediate allergic reactions to betalactams, with a later comparison between patients who were selective (those recognizing the culprit drug excluding benzylpenicillin (BP)) and cross-reactors (those recognizing several penicillin determinants including BP).
Basotest to different haptens was performed in 70 patients with immediate allergic reactions to betalactams, classified into three groups: (A) skin test positive independently of CAP/RAST immunoassay value, (B) skin test negative and CAP/RAST positive, and (C) skin test and CAP/RAST negative but drug provocation test positive. Basotest was carried out by flow cytometry following the manufacturer's instructions using different betalactam determinants and results expressed as a stimulation index.
Of the 70 patients, 34 (48.6%) were positive to Basotest (sensitivity: 48.6%), 31 (44.3%) to CAP/RAST and 46 (65.7%) to either one or the other. Considering the different groups, Basotest was positive in 50.9% of patients in Group A, 60% in Group B and 14.3% in Group C. The specificity was 91.3%. Positivity to the haptens was 28.6% to amoxicillin (AX), 21.7% to BP, 20% to benzylpenicilloyl-poly-l-lysine, 12.5% to ampicillin and 2.2% to minor determinant mixture. In patients with cephalosporin reactions, Basotest to the culprit cephalosporin was positive in 77.7%. There were differences between the two reactor groups in the sensitivity of Basotest (selective to AX=50%, cross-reactors=28.6%; chi(2)=10.809, P=0.004) and in the CAP/RAST (selective to AX=28.6%, cross-reactors=61.9%; chi(2)=8.944, P=0.011).
The sensitivity of Basotest is similar to immunoassays (CAP/RAST). Sensitivity is improved when used in combination. Although further studies are required, Basotest results for cephalosporin allergy seem very promising. This technique does not help differentiate between selective reactors and cross-reactors.
Clinical & Experimental Allergy 12/2004; 34(11):1768-75. · 5.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Atopic dermatitis (AD) is an inflammatory skin disease whose lesions can have two stages: acute and chronic. In skin biopsies a biphasic pattern of cytokine expression has been shown, Th2 in acute lesions and Th1 in chronic AD lesions.
We investigated the expression of an activation marker and a homing receptor, as well as cytokine production, in different peripheral blood T cell subpopulations from AD patients with chronic (Group A) and acute lesions (Group B) and controls.
We evaluated 26 adult AD patients (12 Group A, 14 Group B) and 14 non-atopic controls. IgE was measured by immunoassay. CD4, CD8, cutaneous-lymphocyte-associated antigen (CLA) and human leucocyte antigen (HLA)-DR expression, and cytokine production (IL-2, IL-13, IFN-gamma, TNF-alpha, IL-10, IL-4) were analysed in mononuclear cells by flow cytometry.
In Group B there was a significant increase in eosinophil levels and a non-significant increase in IgE. In Group A we found an increase in CLA(+)CD4(+) cells (8.19+/-1.84) compared with controls (4.83+/-0.53) (P<0.05) and CD4(+)HLA-DR(+) cells in the CLA(+) subpopulation (45.54+/-15.40) compared with controls (30.49+/-6.07) (P<0.05). In the CLA(+)CD4(+) subpopulation, there was a significant increase in IL-4, IL-13 and TNF-alpha production in Group B (12.46+/-7.7, 11.26+/-5.97, 43.92+/-15.55) compared with controls (5.34+/-3.50, 4.54+/-1.78, 19.29+/-9.97) with no differences in Group A.
Greater immunological differences were detected in peripheral blood from patients with acute compared with chronic lesions, especially in the circulating T cell-subset with skin tropism that preferentially responded to cutaneous allergens. This is the first demonstration of phenotypic changes in circulating CLA(+) T cells between AD patients with acute and chronic lesions.
Clinical & Experimental Allergy 04/2004; 34(4):559-66. · 5.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Nonimmediate reactions (NIR) to aminopenicillins (AP) are frequent. Although patch testing (PT) and intradermal testing (IT) are used for diagnosis, comparative results have never been adequately performed. We compared PT and IT in subjects with NIR to AP.
Twenty-one subjects with NIR to AP and positive IT were re-evaluated. Skin tests were performed with amoxicillin (AX) and ampicillin (AM) at different concentrations in petrolatum, 50, 25, and 5% w/w, for PT and in saline, 20, 2, and 0.2 mg/ml for both PT and IT. Skin biopsies from the site of the positive response were studied with haematoxylin-eosin and immunohistochemistry.
In the re-evaluation, one case was IT and PT negative and was excluded; 20 were IT positive and 18 PT positive for both AX and AM. Decreasing concentrations of AP induced a reduction in positivity in both methods when diluted in saline, but not when mixed in petrolatum (PT only). With both PT and IT, immunohistochemical studies showed a perivascular mononuclear infiltrate with CD4 and CD8 memory cells expressing perforin and granzyme B.
Both tests appear valuable for the diagnosis of NIR to AP. However, IT diagnosed more patients than PT. The vehicle (saline or petrolatum) had no influence on the response, although in the former the concentration was critical. The immunohistochemical analysis showed skin infiltrates compatible with a T-cell drug reaction.
Allergy 03/2004; 59(2):219-24. · 6.27 Impact Factor
-
Allergy 11/2002; 57(10):965. · 6.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although subjects with a positive history of immediate allergy to penicillin and negative skin test are traditionally considered to tolerate penicillin, current evidence indicates that they may develop an immediate reaction despite negative skin and serum specific IgE tests. It is thought that these patients require additional tests to confirm the diagnosis.
To assess in a large group of patients with a history of immediate allergy to penicillins but with both skin test and CAP-FEIA-negative to classical and side chain penicillin determinants, the role of controlled administration of betalactams as a diagnostic test.
A group of 330 patients with a history of immediate allergic reactions to penicillins was studied by two evaluators from the same allergy unit using the following protocol: skin tests with major and minor determinants of benzylpenicillin (benzylpenicilloyl-poly l-lysine and minor determinant mixture), amoxicillin and ampicillin, and determination of specific IgE antibodies to penicillins, by CAP-FEIA, in serum. If both tests proved negative, a controlled administration of the drug was then carried out.
A total of 89 (27%) patients were skin test and CAP-FEIA-negative and therefore required controlled administration of the drug. Of these, 49 developed an immediate response and were therefore considered allergic, and the remainder had good tolerance after administration of both benzylpenicillin and amoxicillin. The clinical characteristics of this group were similar to the other allergic patients who were skin test or CAP-FEIA-positive, except that they were younger (P < 0.01). Twenty-two (45%) developed a response to benzylpenicillin and 27 (55%) had a selective response to amoxicillin. Although all reactions appeared within 1 h, a positive correlation was found between the dose inducing the response and the time elapsed from drug administration, for both benzylpenicillin and amoxicillin (P < 0.001).
These data indicate that an important number of subjects are not correctly identified if only skin tests and/or CAP-FEIA are used and that this is particularly relevant for side chain-specific reactions and younger subjects. This suggests that new diagnostic tests are required so as to limit the use of controlled administration.
Clinical & Experimental Allergy 02/2002; 32(2):270-6. · 5.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Allergic drug reactions can be classified as immediate, accelerated or delayed. This classification usually correlates with the mechanism involved: immediate reactions are IgE mediated and delayed reactions are T cell dependent. We analyzed lymphocyte involvement in patients with these reactions by determining cell subpopulations, activation state and skin homing receptor expression (CLA) in blood and skin. Patients with immediate, accelerated and delayed reactions were evaluated during the acute phase and after resolution. Controls taking drugs were included. Phenotypic immunofluorescence analysis was done by flow cytometry in peripheral blood, and by immunohistochemistry in skin for delayed reactions. Forty-six patients were included, 17 with immediate reactions, 10 accelerated and 19 delayed. At the acute phase CLA was significantly increased in delayed reactions and HLA-DR in all three types of reaction. In the severest delayed reactions, Steven-Johnson/Lyell syndromes, the CD4 subsets were increased in peripheral blood and skin compared to maculopapular exanthemas and urticaria and HLA-DR when compared with urticaria. In maculopapular exanthemas CLA was significantly increased in peripheral blood and skin compared to urticaria and the severe reactions. We found that T-cells are implicated, besides delayed reactions, in immediate and accelerated reactions. In delayed reactions there is a parallelism between results found in skin and peripheral blood with a higher participation of CD4+ cells the more severe the reaction.
International journal of immunopathology and pharmacology 19(1):119-30. · 2.99 Impact Factor
