Inmaculada Sánchez-Machín

T cell activity in successful treatment of chronic urticaria with omalizumab

Omalizumab, a humanized monoclonal anti-IgE antibody has the potential to alter allergen processing. Recently, it has been postulated the assessment of PHA-stimulated adenosine triphosphate (ATP) activity as maker of CD4+ T cells activity in peripheral blood cells. We present the case report of a 35-year-old woman with a history of chronic idiopathic urticaria and angioedema of 8 years of development with poor response to treatment. The patient was partially controlled with cyclosporine at doses of 100 mg/12 h. However, she was still developing hives daily. Finally treatment with omalizumab was started at dose of 300 mg every 2 weeks. The patient experienced a decrease in urticarial lesions 2 days after starting therapy. We also evaluated the effects of omalizumab therapy on the activity of peripheral blood CD4+ T cells from the patient, in order to determine the potential modification of anti-IgE therapy on the process of antigen presentation-recognition. Activity of CD4+ cells by ATP release was clearly increased demonstrating an enlarged CD4 activity. Omalizumab may be useful in the treatment of severe chronic urticaria. ATP activity of peripheral blood CD4+ T cells might be a non-subjective method to assess Omalizumab activity.

Importance of repeat testing in the diagnosis of penicillin allergy

SIR, In the May 2005 issue of this Journal Lammintausta and Kortekangas-Savolainen presented an interesting article about the usefulness of skin tests in determining drug hypersensitivity. We have found the results to be very helpful as there are only few reported works about the prevalence of positive skin tests in the context of allergic reactions. However, we have some points of contention. Although both patch tests (PTs) and intradermal tests (IDTs) are used for the diagnosis of nonimmediate reactions to aminopenicillins, and both tests appear to be valuable, delayed-reading IDTs appear to be somewhat more sensitive than PTs, but also less specific. In the report by Lammintausta and Kortekangas-Savolainen, beta-lactam antibiotics were the drugs more often suspected and tested. However, IDTs with major and minor determinants were carried out only in 31 of 342 patients with suspected penicillin allergy and none of them elicited a positive reaction. The European Network for Drug Allergy (ENDA) recommends testing in most patients in whom penicillin allergy is suspected. In fact, most diagnoses of penicillin allergy have recently been reported to be obtained by means of the IDT. Between January 2002 and June 2005 we evaluated 604 patients with suspected betalactam allergy. In all of them, after written informed consent, skin prick tests and IDTs were performed with benzylpenicilloyl polylysine (PPL), minor determinants mixture (MDM; including benzylpenicillin, benzylpenicilloic acid and sodium benzylpenicilloate), penicillin G and the suspect drug if it was other than penicillin. PPL and MDM were purchased from two different companies (Allergopen ; Allergopharma, Reinbeck, Germany and Diater SA, Madrid, Spain). If the skin tests were negative, controlled drug challenge was performed under strict supervision. After 15 days the skin tests and drug challenge were repeated, as recommended by ENDA. After completing the study, 66 patients were diagnosed with beta-lactam allergy, 60 by skin testing and 10 of those in the repeat tests. From 1108 challenges with beta-lactams in 554 patients, there were only six positives following a previously negative skin test. In the report by Lammintausta and Kortekangas-Savolainen, repeat testing was not carried out. ENDA describes that the natural history of allergy to penicillin is such that patients may lose sensitivity or become negative in skin testing. Because of that, repeat testing has been recommended in patients with a positive history and negative skin and in vitro tests, even in those showing a good tolerance after drug provocation testing. ENDA recommends that repeat testing should follow the same protocol and be performed between 2 weeks and 1 month after the first tests. Our results showed that 16% of subjects (10 of 60) who showed tolerance to beta-lactams in the first challenge were diagnosed as sensitive after repeat testing. In one patient with an unequivocal history of allergy to penicillin a third evaluation was necessary to produce a positive skin test. Although penicillin allergy has been vastly overdiagnosed, and too many people are incorrectly labelled as allergic to penicillin, misdiagnosis is also a risk to consider, as a considerable percentage of patients was able to lose sensitivity or was negative in the first evaluation. Repeat testing, which could be considered as a booster, and the determination of specific IgE levels, will help to obtain an accurate diagnosis of beta-lactam allergy, although the majority of the penicillin-allergic donors failed to produce penicillin-specific IgE in vitro, when their lymphocytes were cultured in the presence of allergen.

Oral mite anaphylaxis by Thyreophagus entomophagus in a child: a case report.

Sensitization to Thyreophagus entomophagus, a storage mite, is uncommon and might produce occupational respiratory disorders in farmers. We present the first case of a child suffering anaphylaxis produced by ingestion of contaminated flour with Thyreophagus entomophagus.

Assessing the Validity of Asthma Associations for Eight Candidate Genes and Age at Diagnosis Effects

Background Before the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis. Methodology/Principal Findings We systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R. Conclusions/Significance Our results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.

Evaluating the Usefulness of Retesting for Beta-Lactam Allergy in Children.

Many children with adverse reactions to beta-lactams are labeled as allergic without performing an allergy study to confirm it. In this retrospective study of 10 years, we detected only 3.3% positive cases. Although international guidelines recommend a second allergy workup in patients with a negative study, we found from our results a low profitability of retesting.

Beta-lactam allergy in children.

Editor, We read the paper of Atanaskovic-Markovic et al. recently published in Pediatric Allergy and Immunology (1). This study set the alarm bells ringing, not least among pediatricians and general practicioners as the authors reported a high percentage (58.3%) of beta-lactam-positive allergy in a group of 1170 pediatric patients. The results are surprising as most of the studies have reported a prevalence of around 10–20% (2, 3) of positive results. The authors claim that their results cannot be compared with the literature because they studied only the pediatric population. However, different groups have reported a low rate of prevalence (around 4–10%) in the pediatric population (4–7). Some foods and additives have the ability to trigger an allergic reaction (8). Similarly, skin reactions can be associated with viral infections. These types of symptoms can be wrongly diagnosed as drug allergy. In a study of patients categorized according to clinical history, 14.1% in the group with a convincing history of allergy, 6.7% in the group with a vague history, and 0% in patients with an unacceptable history were skin test (ST) positive (9). We studied 4to 6-yr-old children (n 1⁄4 91) suspected of beta-lactam allergy (10). After obtaining written informed consent, skin prick tests (SPT) were performed with major and minor determinants, penicillin G and the suspected drug if it was other than penicillin, (11). In patients older than 12 or those with a very convincing history, we performed intradermal tests. If the ST results were negative, a controlled oral challenge with the suspected drug was performed. After 15 days, ST and drug challenges were performed again, following the recommendations of the European Network for Drug Allergy (12). We foundonly onepositive result, according for<2% of our study population. In the study of Atanaskovic-Markovic et al. essential data about ST are lacking. Information about the commercial brand, minor determinants used in the study, and specific concentration of each drug for SPT and intradermal tests is unknown. A second re-evaluation was not performed either (13). It is surprising that almost 87% of diagnoses were made by SPT, as diagnosis is usually made by intradermal tests (7, 11), even in populations with high positive results (14). Furthermore, results of intradermal testing were not shown. Most practicians retrain from intradermal testing in children under 12 yr, except under special circumstances (4, 12). SPT and intradermal tests were performed in 100 children without penicillin allergy as controls without informed consent. This is, at least, unethical. On the other hand, the authors talk about selective sensitization as a positive reaction to a culprit drug with good tolerance to all other drugs. It can be coincided that in patients with positive ST to a single drug, they performed oral challenge with the other drugs, but they failed to mention it. It is more likely that they are mentioning only the results of ST. Similarly, the authors report a 26.3% selective sensitization to benzilpenicillin (BP) determinants. No mechanism of BP sensitization with aminopenicillin tolerance is known; therefore we think that they are again referring only to the results of ST. In addition, they admit that they found an almost 100% reactivity between BP and other penicillins. If only ST was evaluated, without oral challenge, one cannot be sure of real selective sensitizations. Overdiagnosis of penicillin allergy in the pediatric population is a cause for concern, with the accompanying increases in heath costs and harm. Bearing this in mind, the result of AtanaskovicMarkovic et al. should be interpreted with caution. Further studies are needed to confirm or refute these data. Pediatr Allergy Immunol 2006: 17: 236–237

Downregulation of Angiogenesis Factors, VEGF and PDGF, after Rapid IgE Desensitization and Oral Immunotherapy in Children with Food Allergy

Background. Angiogenesis has a key role in several conditions and is regulated by several factors such as the platelet-derived growth factor (PDGF) or the vascular endothelial growth factor (VEGF). The goal of this study was to investigate the possible role of PDGF and VEGF in a group of patients with severe food allergy. Methods. We design a prospective longitudinal study (n = 30) with patients with persistent cows milk proteins (CMP) allergy. After achieving a CMP rush desensitization protocol, a clinical followup including SPT and blood samples to determine sIgE, protein levels, PDGF, and VEGF-A and a panel of the most representative Th1, Th2, Treg, and Th17 cytokines were also monitored. Results. Baseline levels of PDGF and VEGF in the CMP allergic patients (1170 pg/mL and 253 pg/mL) were different compared to those nonallergic CMP control subjects (501 pg/mL and 108 pg/mL). Both PDGF and VEGF were significantly downregulated (P < 0.05) 6 months after completion of the CMP desensitization process and remained significantly decreased 12 months later. Conclusion. The present study shows a significant increase of PDGF and VEGF in anaphylaxis suffering children compared to a control group. Interestingly, both VEGF and PDGF were significantly downregulated after completing a full CMP rush IgE desensitization.

Accuracy in diagnosis of allergy to β-lactams

There are a large number of patients labelled as allergic to drugs commonly used in clinical practice without having been studied and based only on clinical history. This creates a major health resource problem, having to use alternative treatments, in many cases with higher cost.

IP-10 In Pediatric Celiac Disease and Food Allergy.

physicians and pharmaceutical companies that PML could occur. Th is brings us to the topic of the biological plausibility of the rare event of PML in association with anti-adhesion therapies. We off er as a cautionary example the unexpected immunologic eff ect of serum antibodies to Abciximab. Th is monoclonal antibody therapy was designed to bind to the activated form of platelet glycoprotein IIb / IIIa (aka integrin α IIb β 3 ), and prevent clotting during endovascular procedures without an excess of clinically important bleeding in most patients. However, some patients developed antibodies against the abciximab / platelet complex, which reduced the specifi city of this interaction ( 3 ). When one of these rare patients is treated with abciximab, severe thrombocytopenia occurs, and rapid bleeding from all mucosal surfaces ensues. Although it is unlikely that a similar mechanism might reduce the specifi city of other antiintegrin monoclonal therapies, it is not impossible. Th at this has previously occurred in patients treated with another anti-integrin monoclonal antibody, and that patients with infl ammatory bowel disease (IBD) are prone to autoimmune reactions, makes it unlikely but possible that an unforeseen mechanism in rare patients could reduce the specifi city of an antiα 4 β 7 monoclonal therapy ( Figure 1 ). Suffi cient sample size can change a very rare event to a reasonably likely event. We would like to reiterate that the rule of 3 s provides the upper limit of the 95 % confi dence interval, not the actual estimate of the risk of an event. We agree with the letter writers that PML cases associated with vedolizumab, if they occur at all, will be rare events, and that there are many factors that could aff ect an estimate of the frequency of rare events, including biological plausibility, latency, and other risk factors. We are hopeful that anti-adhesion therapies will prove benefi cial to millions of patients with IBD worldwide, but we should be prepared for the possibility of rare events, including PML. We hope that if PML does occur in the future in association with the newer anti-adhesion therapies, gastroenterologists, the Food and Drug Administration, and the general public will thoughtfully consider the frequency of rare events and embrace the richness of human diversity. To paraphrase Miranda in Shakespeare ’ s Th e Tempest (V,i), O brave new world, that has such biologic processes in it! To dismiss the past (abciximab) and deny the possibility of rare risks in the future would make us ill-prepared for an important potential complication. As vedolizumab leaves the island of clinical trials for the wider world of clinical practice, rare events might occur, but we should not panic or overreact to them. Instead, we should thoughtfully consider the frequency and magnitude of benefi ts in relation to the frequency and magnitude of rare risks .

Safety of Modified Dust Mite Subcutaneous Immunotherapy in Severe Allergic Asthma

U E S D A Y 730 CC10 A38G Polymorphism (rs3741240) Is Associated with Asthma Susceptibility and Bronchial Hyperresponsiveness Mediated by the Eosinophilic Inflammation in Korean Children Kyungmo Hong, Hyun-Kyung Kim, Mi-Jin Kang, MS, Ho-Sung Yu, BS, Byoung-Ju Kim, MD, PhD, Young Ho Jung, MD, Jinho Yu, MD, PhD, Soo-Jong Hong, MD, PhD; Goucher College, Baltimore, USA, Childhood Asthma Atopy Center, Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, South Korea, Department of Pediatrics, Hae-undae Paik Hospital, Inje University College of Medicine, Busan, South Korea, Childhood Asthma Atopy Center, Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, Research Center for Standardization of Allergic Disease, Seoul, South Korea. RATIONALE: Clara cell secretory protein (CC10) or uteroglobin (secretoglobin, family 1A, member 1 (SCGB1A1)) is produced by nonciliated Clara cells in the respiratory tract. CC10 is believed to function in reducing inflammation, inhibiting phospholipase A2. We investigated the association of the CC10 A38G polymorphism with asthma in Korean children, and to assess the effect of these variants on intermediate phenotypes of asthma. METHODS: Asthmatic children (N5930) and control children (N5578) were evaluated for asthma phenotypes and intermediate phenotype such as IgE, pulmonary function test, and BHR to methacholine. Polymorphism of CC10 (rs3741240) was genotyped by using TaqMan assay. RESULTS: In children with asthma and atopic asthma, the frequencies of the AA genotype were higher than normal controls (aOR 1.60, 1.68; 95% confidence interval (CI) 1.18-2.16, 1.23-2.29, respectively). The AA genotype was associated with higher logECP (p50.031) in children with atopic asthma, and lower PC20 (aOR 1.61; 95% CI 1.05-2.46) values in children with asthma compared to the GG + AG genotypes. CONCLUSIONS: The CC16 A38G polymorphism is associated with the development of asthma and intermediate asthma phenotypes in Korea children. Atopic asthmatic children with AA genotype were associated with higher log ECP level and asthmatic children were also associated with lower PC20 values. Therefore, the AA genotype may be related with an increased risk of asthma and BHR inKorean childrenmediated by airway eosinophilic inflammation. This study was supported by a grant from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare, Republic of Korea (A092076)