Adverse drug reactions with an immunological basis: from clinical practice to basic research.
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Drug Hypersensitivity↗
Biomedical subjects
C Mayorga
Publications and source records attributed to C Mayorga.
Monoclonal antibodies to amoxicillin express different idiotypes determined by anti-idiotype antibodies production.
Penicillins are beta-lactam antibiotics able to generate several antigenic determinants that are recognized by the immune system. To study the differences in the antigen binding site of two monoclonal antibodies (Mab) specific to amoxicillin, polyclonal rabbit anti-idiotypic antibodies were produced. One Mab, AO3.2 (IgG2a), specific to a structure formed by the acyl-side chain structure and a part of the nuclear region of amoxicillin. The second one, AO6.2 (IgE), is specific to the side chain of amoxicillin, although it also recognizes the side chain of other penicillins (penicillin G and ampicillin). These antibodies were used to immunize rabbits in order to produce polyclonal anti-idiotypic antibodies, which were purified in several steps by affinity chromatography. The specificity and cross-reactivity studies were made by ELISA and ELISA inhibition. The results suggest that the anti-Id antibodies produced are the internal image of the antigen, since the binding to their specific idiotype is blocked mainly by the original hapten (amoxicillin): in 98% of the cases with anti-id-1 (induced against AO3.2) and in 59% with anti-id-2 (induced against AO6.2). The absence of cross-reactivity of each anti-idiotypic antibody with the different Mabs specific to amoxicillin shows that the idiotypes induced by the same hapten have differences that are reflected by the nonrecognition of these anti-idiotypes. We conclude that such a small molecule as amoxicillin can present several antigenic determinants that induce a panel of antibody specificities especially directed against the side chain.
Amoxicillin↗
Controlled administration of penicillin to patients with a positive history but negative skin and specific serum IgE tests.
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Adolescent↗
Side-chain-specific reactions to betalactams: 14 years later.
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Anti-Bacterial Agents↗
Study of binding and neutralising antibodies to interferon-beta in two groups of relapsing-remitting multiple sclerosis patients.
Interferon (IFN)-beta is generally considered an effective treatment for multiple sclerosis (MS); however, some patients do not respond to this therapy, possibly due to the production of neutralising antibodies (NAB) which can prevent the biological effect of IFN-beta. We compared the two types of IFN-beta, the glycosylated IFN-beta1a and the non-glycosylated IFN-beta1b, as their chemical differences may entail differing immunogenic capacities. We studied 22 relapsing-remitting MS patients treated with IFN-beta1a and 31 treated with IFN-beta1b for 1 year, using the same assay and criteria, to compare the two types of IFN-beta in their ability to induce binding and neutralising antibodies and examined the correlation of the findings with the clinical data. Binding antibodies to IFN-beta1a and IFN-beta1b were determined by enzyme-linked immunosorbent assay. A bioassay was used to detect and quantify the NABs to IFN-beta, measuring the capacity of NABs to block the antiviral resistance induced by IFNs. Binding antibodies were found in 32 % of those treated with IFN-beta1a and in 52 % of those treated with IFN-beta1b; NABs were found in 14% and 24 %, respectively. Both groups showed a significant decrease in relapse rate during the first year of treatment. These results demonstrate that the IFN-beta1b molecule is more immunogenic than the IFN-beta1a molecule. This may be due to the non-glycosylated, chemical structure of the former, which can produce aggregates and enhance antibody production. No association was found between the presence of NABs and the clinical status of the patients.
Adult↗
In vitro T-cell responses to beta-lactam drugs in immediate and nonimmediate allergic reactions.
BACKGROUND: beta-Lactam drugs may induce both cellular and humoral allergic reactions, and there is evidence that T cells play an important role in the pathogenesis of these reactions. The aim of this work was to assess the sensitivity and specificity of the lymphocyte transformation test (LTT) as an in vitro diagnostic tool, in patients with either an immediate or a nonimmediate reaction to penicillin G and/or amoxicillin. METHODS: Fifty patients with a well-documented history of allergic reactions to beta-lactams (31 immediate and 19 nonimmediate) were studied by means of skin tests (prick and intradermal), radioallergosorbent test (RAST), and, when necessary, controlled administration of the drug. Twenty-eight healthy subjects with good tolerance to penicillins served as controls. LTT was performed in all subjects. RESULTS: Skin tests were positive in 77.4% of the patients with immediate reactions and in 36.8% of those with nonimmediate reactions. The overall sensitivity of LTT in the allergic patients was 62%, but, when analyzed separately, sensitivity was 64.5% for the immediate group and 57.9% for the nonimmediate group. The LTT specificity was 92.8%. CONCLUSION: The LTT should be considered a useful in vitro diagnostic tool to identify subjects allergic to penicillins, especially patients with nonimmediate reactions where the LTT has a better diagnostic value than skin tests. Interestingly, positive T-cell proliferative responses can be observed 10 or more years after the occurrence of the reaction without further exposure to the drug.
Adult↗
Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing.
BACKGROUND: Penicillin is no longer the most commonly prescribed beta-lactam, and the pattern of reactions has changed. We studied the diagnostic value of skin testing in penicillin-allergic subjects from a population where benzylpenicillin is not now the most frequently used beta-lactam. METHODS: Patients with a history of immediate allergic reactions to penicillins were studied with: skin tests with major and minor determinants of benzylpenicillin (BPO/MDM), amoxicillin, and ampicillin; in vitro determination of specific IgE; and controlled administration for those with a positive history but negative skin and in vitro tests. A reaction was considered immediate when symptoms appeared within a maximum of 1 h after drug intake. RESULTS: After testing, 290 patients (71% having anaphylaxis and 29% having urticaria) proved to be allergic. Amoxicillin was involved in 64.8% and benzylpenicillin in 2.8% of the patients. Skin test positivity to at least one determinant appeared in 70% of cases, amoxicillin being the most frequent. The overall sensitivity decreased markedly when only BPO and MDM were considered. In 13.1% of patients, the diagnosis was established by in vitro test and in 16.9% by controlled administration. Of the 290 patients, 42.1% were positive to determinants generated from benzylpenicillin and 57.9% were selective responders. CONCLUSIONS: Sensitivity of skin tests to BPO was lower than reported, being partly replaced by minor determinants, mostly amoxicillin. The incorporation of additional reagents and the development of new tests are required, and these will probably change as the patterns of consumption vary.
Amoxicillin↗
Clinical evaluation of Pharmacia CAP System RAST FEIA amoxicilloyl and benzylpenicilloyl in patients with penicillin allergy.
BACKGROUND: The diagnosis of IgE-mediated immediate reactions to penicillins can be supported by in vivo or in vitro tests using classical benzylpenicillin determinants. The wide variety of beta-lactams and the description of new specificities requires a re-evaluation of the different tests available. The objective was to evaluate the diagnostic capacity of Pharmacia CAP System RAST FEIA amoxicilloyl c6 (AXO) and benzylpenicilloyl c1 (BPO) in patients with a documented IgE-mediated penicillin allergy. METHODS: We studied 129 patients in five groups. Groups 1, 2, and 3 had developed an immediate reaction after penicillin treatment. Group 1 (n=19) were skin test positive to amoxicillin (AX) and/or BPO and/or minor determinant mixture (MDM); group 2 (n=29) were skin test positive to AX but negative to BPO and MDM; and group 3 (n=26) were skin test negative to all determinants, the diagnosis being confirmed by a previous repetitive history or controlled administration. Two control groups, one with nonimmediate reactions -- group 4 (n=25) -- and one with good tolerance to penicillin -- group 5 (n=30) -- were included. All samples were analyzed in vitro for AXO and BPO, and the results compared to the in vivo diagnosis. RESULTS: AX was the drug most often involved. In group 1, 53% were in vitro positive for AXO and 68% for BPO, but 74% had at least one positive test result. In group 2, only 10% had a positive in vitro test to BPO compared to 41% to AXO. In group 3, 42% had positive BPO and/or AXO in vitro tests. In the control groups 4 and 5, the negative in vitro results for AXO were 96% and 100%, and for BPO 100% and 97%, respectively. A positive correlation between specific IgE levels and the time interval from the reaction to the evaluation was found only for group 3. CONCLUSIONS: This in vitro assay is beneficial for evaluating subjects allergic to beta-lactams. It is necessary to test for specific IgE to AXO in addition to BPO in patients with immediate allergic reactions after AX. The combination of in vivo and in vitro tests for estimating IgE antibodies to penicillins is important because of the existence of patients with a positive history but negative skin test.
Adolescent↗
Allergy to two drugs in a patient.
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Ampicillin↗
Expression of the skin-homing receptor in peripheral blood lymphocytes from subjects with nonimmediate cutaneous allergic drug reactions.
BACKGROUND: In nonimmediate cutaneous reactions to drugs, the skin is the organ most frequently involved, and T cells may play a relevant role. T cells related to skin immune responses express the cutaneous lymphocyte-associated antigen (CLA), the skin-homing receptor. METHODS: We studied the expression of the CLA in peripheral blood T cells from nine subjects with exanthematous reactions induced by beta-lactams (4), phenytoin (2), propyphenazone (1), spiramycin plus metronidazol (1), and captopril plus tiazide (1). The cutaneous symptoms appeared at least 6 h after drug intake. CLA expression was evaluated by flow cytometry at the time of the reaction (T1) and 1 month later (T2). HLA-DR activation marker expression was also evaluated at T1. In four patients, it was necessary to readminister the culprit drug to establish a causal relationship, and sequential estimation of the markers was performed. Two control groups were included: healthy controls and subjects exposed to the culprit drugs with good tolerance. Values were compared by nonparametric statistics. RESULTS: The expression of circulating CLA + T cells at T1 was increased compared to healthy controls (median = 20.4 vs 9.4) (P < 0.001), and the patients also expressed increased levels of HLA-DR (median = 3.8) (P < 0.005). Comparison between T1 and T2 (median = 11.2) also showed differences in levels of CLA+ T cells (P < 0.01). The patients re-exposed to the culprit drug showed an increase followed by a decrease of circulating CLA+ T cells (P < 0.05) and CLA+ HLA-DR+ (P < 0.05) paralleling the symptoms. CONCLUSIONS: These data support the immunologic nature of delayed skin reactions to drugs, and suggest that these CLA+ T cells parallel the disease evolution and may participate in the pathophysiologic mechanisms.
Adult↗
Immediate allergic reactions to cephalosporins: cross-reactivity and selective responses.
BACKGROUND: After penicillins, cephalosporins are the most important beta-lactams inducing IgE-mediated reactions. Responses may be selective or cross-reactive with common beta-lactam determinants. Unlike determinants derived from benzylpenicillin, cephalosporin allergenic determinants have not been properly identified, even though a wide variety of these beta-lactams is currently used. OBJECTIVE: We sought to evaluate the IgE response in subjects with immediate allergic reactions to injectable cephalosporins and to assess their reactivity to different penicillins and cephalosporins. METHODS: We studied 30 subjects with immediate reactions to one or more of the following cephalosporins: ceftriaxone, cefotaxime, ceftazidime, and cefuroxime. Skin tests and in vitro-specific IgE antibody assays were performed for major and minor determinants of penicillin G, amoxicillin, and ampicillin, as well as for the culprit cephalosporins. Responses to cephalosporins other than the culprit ones were also studied by using skin testing. RESULTS: Twenty-six patients (group A, 86.7%) displayed skin test and RAST negativity to penicillin determinants and skin test positivity to cephalosporins, with RAST confirmation in 9 patients. Four subjects (group B, 13.3%) had a positive response to penicillin determinants. In group A two patterns of reactivity were observed: one characterized by a response only to the culprit cephalosporin (n = 15, 57.7%) and the other by positive responses to different cephalosporins, including the responsible cephalosporins (n = 11, 42. 3%). CONCLUSION: Most patients with a history of immediate reactions to cephalosporins are sensitized to determinants generated only by cephalosporins (group A), although a small percentage react to penicillin determinants (group B). Some patients from group A responded only to the culprit cephalosporin, but others reacted to different cephalosporins. These findings can be explained in terms of either selective response to unique determinants or cross-reactivity.
Adolescent↗
Natural evolution of skin test sensitivity in patients allergic to beta-lactam antibiotics.
BACKGROUND: Subjects with immediate reactions to penicillins and positive skin test responses may lose sensitivity if penicillin is avoided. The longer the interval between the reaction and the skin test, the greater the likelihood of having a negative result. OBJECTIVE: We sought to study prospectively the evolution of skin test sensitivity in a group of subjects allergic to penicillin with positive skin test responses to different penicillin determinants. METHODS: Skin tests were performed with major and minor determinants of benzylpenicillin (BPO/MDM), amoxicillin (AX), and ampicillin at the initial evaluation and repeated 1, 3, and 5 years later if the responses were still positive. Subjects were divided into 2 groups. Group A consisted of patients with a positive skin test response to benzylpenicilloyl or minor determinant mixture, and group B consisted of those with a selective response to amoxicillin and good tolerance to benzylpenicillin. RESULTS: In group A (n = 31) after 1 year, 25 patients continued to have positive responses and 6 began to have negative responses; after 3 years, 18 continued to have positive responses, 5 began to have negative responses, and 2 were lost to follow-up; and after 5 years, 12 continued to have positive responses, 5 began to have negative responses, and 1 was lost to follow-up. In group B (n = 24) 12 had positive responses, and 12 had negative responses after 1 year; 6 had positive responses, 5 had negative responses, and 1 was lost to follow-up after 3 years; and no patients had positive responses, 5 had negative responses, and 1 was lost to follow-up after 5 years. Survival analysis showed significant differences between groups (log-rank test = 12.8; P <. 0003). CONCLUSION: Patients with a selective response to amoxicillin tended to lose sensitivity faster than those who responded to several penicillin determinants, supporting the existence of at least 2 distinct types of IgE response in patients allergic to beta-lactam.
Adult↗
Immunologic response to different determinants of benzylpenicillin, amoxicillin, and ampicillin. Comparison between urticaria and anaphylactic shock.
BACKGROUND: Subjects with IgE-mediated allergic reactions to penicillins can develop urticaria or anaphylactic shock. Urticaria is mainly associated with positivity to the major determinant of benzylpenicillin (BPO), and anaphylactic shock with minor determinants (MDM). The presence of IgG antibodies to BPO is thought to be mainly associated with urticaria, possibly protecting from anaphylactic shock. We aimed to study the skin test response to BPO and MDM, amoxicillin (AX), and ampicillin (AMP) in a group of subjects allergic to penicillins, and to evaluate the role of specific IgG. METHODS: We studied a group of patients with immediate allergic reactions to penicillins, comparing urticaria and anaphylactic shock. Skin tests were done with BPO, MDM, AX, and AMP. Specific IgE and IgG antibodies to benzylpenicilloyl-poly-L-lysine (BPO-PLL) and amoxicilloyl-poly-L-lysine (AXO-PLL) were determined by RAST and ELISA, respectively. RESULTS: Fifty-nine patients were studied (30 with anaphylactic shock and 29 with urticaria). Skin test positivity to BPO was associated with urticaria (P<0.001), and positivity to MDM, AX, and AMP with anaphylactic shock (P=0.006, P<0.001, and P=0.002, respectively). Specific anti-BPO-PLL and AXO-PLL IgG values were higher in patients than controls (P<0.001), but no differences were observed between urticaria and anaphylactic shock. CONCLUSIONS: Positivity to minor determinants of penicillins is associated more with anaphylactic shock than urticaria, but the role of IgG antibodies in helping to prevent the development of anaphylactic shock could not be confirmed.
Adult↗
In vitro methods for quantifying IgE antibodies to betalactams.
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Antibodies↗
Selective type-1 hypersensitivity to cefuroxime.
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Cefuroxime↗
Epidemiology of invasive pneumococcal infections in infants and young children in Metropolitan Santiago, Chile, a newly industrializing country.
AIM: To study the epidemiology of invasive pneumococcal infections in infants and young children in Santiago, Chile, as a representative pediatric population in a newly industrializing country where pneumococcal conjugate vaccines may be used in the future. METHODS: A 5-year retrospective laboratory-based review (1989 to 1993) was followed by a 3-year prospective laboratory and hospital surveillance study in two of the six health administrative areas of Santiago to detect all hospitalized cases of invasive pneumococcal disease (defined as Streptococcus pneumoniae isolated from blood, cerebrospinal fluid or another normally sterile site) among infants and children (0 to 23 months of age in the retrospective and 0 to 59 months of age in the prospective study). RESULTS: During the 5-year retrospective survey the incidence of invasive pneumococcal disease was 90.6 cases per 10(5) infants 0 to 11 months old and 18.5 cases per 10(5) toddlers 12 to 23 months old. Similar rates (60.2 per 10(5) infants and 18.1 per 10(5) toddlers) were recorded during the 3 years of prospective surveillance. Among the 110 cases in children 0 to 59 months of age detected during the 3-year prospective surveillance, 2 clinical forms, pneumonia and meningitis, accounted for 87.2% of all cases; 13 of the 49 pneumonia patients (26%) had empyema as a complication. Notably 40 of the 110 cases (36.4%) occurred before 6 months of age (63.4% of the 63 infant cases). Serotypes 1, 14, 5 and 6B were the most prevalent. Overall 76 and 69%, respectively, of S. pneumoniae isolates were antigenic types that would be covered by the 11- or 9-valent conjugate vaccines under development. CONCLUSIONS: Invasive pneumococcal infections in Santiago, Chile, exhibit an epidemiologic pattern intermediate between that of developing and industrialized countries. The high burden of disease in early infancy dictates that an accelerated immunization schedule (beginning in the perinatal period) or maternal immunization with pneumococcal vaccines should be explored.
Age Factors↗
New aspects in betalactam recognition.
The data presented in this review confirm that penicillin continues to be the most well defined model for studying drug allergy. The identification of new specificities has improved the understanding of allergy to penicillins, and different well defined subgroups now exist. The capacity of humans to respond to unique penicillin determinants has shown that although penicillin is a very small molecule it can be recognized in different ways by different IgE antibodies. These well defined models have left open the possibility that other betalactams can also induce specific reactions which implies that for diagnostic purposes, in addition to classical determinants, others are required for in vitro and/or in vivo evaluation. When the different subgroups now recognized are compared, not only are there differences in the manner of hapten recognition but also in the evolution of the natural sensitivity and in the capacity for recognizing other structures. The recognition of betalactams by T cells is also important and a number of studies have shown that subjects respond specifically to some aminopenicillins or cephalosporins with good tolerance to benzylpenicillin. The confirmation that these responses can be a T-cell-mediated reaction have been reported not only in vitro by the generation of T cell lines and T cell clones but also in vivo doing skin biopsies in subjects who have developed different types of delayed cutaneous reactions [44]. More studies are needed to determine the structure of T cell epitopes and this will help for a better understanding of both the IgE and IgG-mediated reactions.
Animals↗
Determination of IgE antibodies to the benzylpenicilloyl determinant: a comparison of the sensitivity and specificity of three radio allergo sorbent test methods.
The quantitation of in vitro IgE antibodies to the benzylpenicilloyl determinant (BPO) is a useful tool for evaluating suspected penicillin allergic subjects. Although many different methods have been employed, few studies have compared their diagnostic specificity and sensitivity. In this study, the sensitivity and specificity of three different radio allergo sorbent test (RAST) methods for quantitating specific IgE antibodies to the BPO determinant were compared. Thirty positive control sera (serum samples from penicillin allergic subjects with a positive clinical history and a positive penicillin skin test) and 30 negative control sera (sera from subjects with no history of penicillin allergy and negative skin tests) were tested for BPO-specific IgE antibodies by RAST using three different conjugates coupled to the solid phase: benzylpenicillin conjugated to polylysine (BPO-PLL), benzylpenicillin conjugated to human serum albumin (BPO-HSA), and benzylpenicillin conjugated to an aminospacer (BPO-SP). Receiver operator control curves (ROC analysis) were carried out by determining different cut-off points between positive and negative values. Contingence tables were constructed and sensitivity, specificity, negative predictive values (PV-), and positive predictive values (PV+) were calculated. Pearson correlation coefficients (r) and intraclass correlation coefficients (ICC) were determined and the differences between methods were compared by chi 2 analysis. Analysis of the areas defined by the ROC curves showed statistical differences among the three methods. When cut-off points for optimal sensitivity and specificity were chosen, the BPO-HSA assay was less sensitive and less specific and had a lower PV- and PV+ than the BPO-PLL and BPO-SP assays. Assessment of r and ICC indicated that the correlation was very high, but the concordance between the PLL and SP methods was higher than between the PLL and HSA or SP and HSA methods. We conclude that for quantitating IgE antibodies by RAST to the BPO determinant, BPO-SP or BPO-PLL conjugates offer advantages in sensitivity and specificity compared with BPO-HSA. These results support and extend previous in vitro studies by our group and highlight the importance of the carrier for RAST assays.
Adult↗