Ana Fiandor

Incidence and natural history of challenge-proven cow's milk allergy in European children – EuroPrevall birth cohort

Cows milk allergy (CMA) is one of the most commonly reported childhood food problems. Community‐based incidence and prevalence estimates vary widely, due to possible misinterpretations of presumed reactions to milk and differences in study design, particularly diagnostic criteria.

Fish allergy in childhood

Fish and its derived products play an important role in human nutrition, but they may also be a potent food allergen. Fish can be an ingested, contact, and inhalant allergen. Gad c I, a Parvalbumin, the major allergen in codfish, is considered as fish and amphibian pan‐allergen. Prevalence of fish allergy appears to depend on the amount of fish eaten in the local diet. In Europe, the highest consumption occurs in Scandinavian countries, Spain and Portugal. In Spain, fish is the third most frequent allergen in children under 2 yr of age after egg and cow’s milk. An adverse reaction to fish may be of non‐allergic origin, due to food contamination or newly formed toxic products, but the most frequent type of adverse reactions to fish are immunologic‐mediated reactions (allergic reactions). Such allergic reactions may be both IgE‐mediated and non‐IgE‐mediated. Most cases are IgE‐mediated, due to ingestion or contact with fish or as a result of inhalation of cooking vapors. Some children develop non‐IgE‐mediated type allergies such as food protein induced enterocolitis syndrome. The clinical symptoms related to IgE‐mediated fish allergy are most frequently acute urticaria and angioedema as well as mild oral symptoms, worsening of atopic dermatitis, respiratory symptoms such as rhinitis or asthma, and gastrointestinal symptoms such as nausea and vomiting. Anaphylaxis may also occur. Among all the species studied, those from the Tunidae and Xiphiidae families appear to be the least allergenic.

Analysis of cross-reactivity between sunflower pollen and other pollens of the Compositae family

The sera of 20 patients with Compositae pollen allergy were investigated for the presence of IgE antibodies reacting against sunflower pollen by means of RAST and immunoblotting studies. Thirteen IgE-binding bands were detected with molecular weights ranging from 14.4 to 94 kd. Two of these bands, with molecular weights of 24 and 25 kd, contained major allergens that reacted strongly with 100% (24 kd) and 95% (25 kd) of the sera, respectively. Cross-reactivity between sunflower and other Compositae pollens (mugwort, marguerite, dandelion, golden rod, and short ragweed) was revealed by RAST and immunoblotting inhibition experiments. Mugwort pollen exhibited the greatest degree of allergenic homology (cross-reactivity) with sunflower pollen, whereas at the other end of the spectrum, short ragweed showed less cross-reactive epitopes.

Possible consequences of elimination diets in asymptomatic immediate hypersensitivity to fish

The natural history of IgE antibodies to food without related symptoms is unknown. We have followed the progress of 7 children with various atopic diseases and asymptomatic immediate hypersensitivity to fish, treated with elimination diet in spite of full alimentary tolerance. During the diet period, between 24 and 113 months, all 7 patients presented immediate symptoms upon accidental exposure to or challenge tests with fish (skin symptoms in all 7 cases, digestive in 5, respiratory in 4, and anaphylaxis in 2), which differed from those related to atopic diseases previously present. The levels offish‐specific IgE (prick test, RAST) remained unchanged or were increased. These findings suggest that during elimination diet, and perhaps due to minimal and hidden contact with the allergen, the patients’ degree of sensitization may increase, turning an asymptomatic into a symptomatic immediate hypersensitivity.

CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis

BACKGROUND Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe, bullous cutaneous diseases with uncertain pathogenesis, although cytotoxic T cells seem to be involved. Natural killer (NK)-like activity has been found in blister infiltrates. Cytotoxic T lymphocytes (CTLs) with NK-like activity (NK-CTLs) have been shown to express T-cell receptors restricted by the HLA-Ib molecule HLA-E. Alternatively, the HLA-E-specific activating receptor CD94/NKG2C can trigger T-cell receptor-independent cytotoxicity in CTLs. OBJECTIVE Our aim was to test whether HLA-E expression sensitizes keratinocytes to killing by CTLs with NK-like activity and to explore the expression of activating receptors specific for HLA-E in blister cytotoxic lymphocytes. METHODS We used flow cytometry and immunohistochemistry to analyze HLA-E expression in keratinocytes from affected skin in patients with SJS, TEN, and other less severe drug-induced exanthemas. The expression of CD94/NKG2C was analyzed by means of flow cytometry in PBMCs and blister cells from patients. PBMCs and blister cells were analyzed for their ability to kill HLA-E-expressing cells. Involvement of CD94/NKG2C in triggering degranulation of cytolytic cells was explored by means of CD107a mobilization assays and standard cytotoxicity chromium release assays. RESULTS We found that keratinocytes from affected skin expressed HLA-E and that cell-surface HLA-E sensitizes keratinocytes to killing by CD94/NKG2C(+) CTLs. Frequencies of CD94/NKG2C(+) peripheral blood T and NK cells were increased in patients with SJS and TEN during the acute phase. Moreover, activated blister T and NK lymphocytes expressed CD94/NKG2C and were able to degranulate in response to HLA-E(+) cells in an NKG2C-dependent manner. CONCLUSION CD94/NKG2C might be involved in triggering cytotoxic lymphocytes in patients with SJS and TEN.

Incidence and natural history of hen's egg allergy in the first 2 years of life – the EuroPrevall birth cohort study

BACKGROUND Parents and health staff perceive hens egg allergy (HEA) as a common food allergy in early childhood, but the true incidence is unclear because population-based studies with gold-standard diagnostic criteria are lacking. OBJECTIVE To establish the incidence and course of challenge-confirmed HEA in children, from birth until the age of 24 months, in different European regions. METHODS In the EuroPrevall birth cohort study, children with a suspected HEA and their age-matched controls were evaluated in 9 countries, using a standardized protocol including measurement of HE-specific immunoglobulin E-antibodies in serum, skin prick tests, and double-blind, placebo-controlled food challenges (DBPCFC). RESULTS Across Europe, 12 049 newborns were enrolled, and 9336 (77.5%) were followed up to 2 years of age. In 298 children, HEA was suspected and DBPCFC was offered. HEA by age two was confirmed in 86 of 172 challenged children (mean raw incidence 0.84%, 95% confidence interval (95% CI) 0.67-1.03). Adjusted mean incidence of HEA was 1.23% (95% CI 0.98-1.51) considering possible cases among eligible children who were not challenged. Centre-specific incidence ranged from United Kingdom (2.18%, 95% CI 1.27-3.47) to Greece (0.07%). Half of the HE-allergic children became tolerant to HE within 1 year after the initial diagnosis. CONCLUSIONS The largest multinational European birth cohort study on food allergy with gold-standard diagnostic methods showed that the mean adjusted incidence of HEA was considerably lower than previously documented, although differences in incidence rates among countries were noted. Half of the children with documented HEA gained tolerance within 1 year postdiagnosis.

Expression of α‐defensin 1–3 in T cells from severe cutaneous drug‐induced hypersensitivity reactions

To cite this article: Morel E, Álvarez L, Cabañas R, Fiandor A, Díaz R, Escamochero S, Prior N, Blanca M, Bellón T. Expression of α‐defensin 1–3 in T cells from severe cutaneous drug‐induced hypersensitivity reactions. Allergy 2011; 66: 360–367.

How should occupational anaphylaxis be investigated and managed

Purpose of reviewAnaphylaxis is a systemic allergic reaction that can be life-threatening or fatal and can result from work-related exposures. This review study focuses on the assessment, main triggers, and management of occupational anaphylaxis. Recent findingsExposed workers can be sensitized through inhalation and skin contact, and the risks increase with penetration of the allergen through the skin. The main eliciting agents of occupational anaphylaxis include stinging insects and animal bites, natural rubber latex and other vegetable allergens, food products, and drugs. Workers sensitized to occupational allergens may also develop anaphylaxis outside the work environment from exposure to the same or to cross-reacting allergens. Cofactors at work such as exercise may increase the risk. The relevant medical records and laboratory tests (e.g. tryptase) performed during the episode should be reviewed. SummaryIt is very important to confirm the diagnosis and to identify the specific trigger of anaphylaxis. Component-resolved diagnosis may help in the identification of primary sensitizers or cross-reactive allergens. Adrenaline must be administered to all patients experiencing anaphylaxis. Removal from exposure is mandatory to prevent further episodes. A written emergency management plan, health and safety education, and training and surveillance should be enforced in occupations at greater risk.

Allergy to several local anesthetics from the amide group

Local anesthetics (LAs) are classified into 2 groups: ester and amide compounds. Adverse reactions are frequent, but most of them are attributed to vasovagal reflexes or hemodynamic changes after the injection of LAs with epinephrine. Allergic reactions to LAs are uncommon. The preponderance of evidence suggests that there is no cross-reactivity between ester and amide LAs. Contact dermatitis (type IV) has been described, particularly induced by the ester group of anesthetics, and rarely to lidocaine in the amide group. Some isolated cases of immediate allergic reactions with mepivacaine or lidocaine have been previously reported. In most of those cases, tolerance to other amide anesthetics was demonstrated as a safe alternative. We present the case of a 41-year-old woman, previously diagnosed with endometriosis, who had a back nevus surgically removed. Three hours after the local administration of mepivacaine, she experienced an episode of pruritic maculopapular eruption and hives involving the upper side of the trunk, neck, and arms. She recovered completely 48 hours after the administration of intramuscular 6-methylprednisolone and dexchlorpheniramine maleate as well as oral antihistamines for 2 days. She denied any history of urticarial episodes or an adverse reaction to the ingestion of any food or medication. She reported no adverse reaction with the use of cosmetics or after the intake of foods or beverages containing sulphites. Skin prick testing results with (1) a standard panel of commercially available (ALK-Abelló, Madrid, Spain) allergen extracts (aeroallergens, foods, profilin, gliadin, latex, Anisakis simplex), (2) undiluted lidocaine (1%) (Normon, Madrid, Spain), mepivacaine (2%) (Scandinibsa, Inibsa, Barcelona, Spain), and bupivacaine (0.75%) (Inibsacain, Inibsa, Barcelona, Spain), (3) phenolated normal saline solution, and (4) histamine 0.1 mg/mL were all negative with the exception of the histamine control. Total serum IgE level was 11.1 kU/L (normal total serum IgE level range, <100 kU/L) (ImmunoCAP System, Thermo Fisher Scientific, Uppsala, Sweden), and total serum tryptase level was 3.9 mg/L (normal tryptase level range, <11.4 mg/L) (ImmunoCAP system). Complement factors (C3 and C4) and IgG, IgM, and IgA levels in serum were within the normal range. A single-blind subcutaneous challenge test with lidocaine was performed. Four hours after the administration of a cumulative dose of 1.5 mL, the patient experienced a similar but milder reaction affecting the same involved body area as occurred in the first reaction. Rather than pursuing further in vivo testing such as intradermal skin tests to evaluate hypersensitivity and given the very low rate of cross-reactivity among the amide group of LAs, we elected to proceed with another subcutaneous challenge test with bupivacaine 2 weeks later. Two hours after the administration of a cumulative dose of 0.5 mL, she again experienced pruritic exanthema on the torso and neck. She was treated with 60 mg of intravenous 6-methyl-prednisolone and 5 mg of dexchlorpheniramine maleate, with complete resolution of the reaction in 2 hours. In an attempt to clarify the underlying mechanism of this hypersensitivity reaction, a basophil activation test with bupivacaine, lidocaine, and mepivacaine (10, 5, and 0.5 mg/mL) was performed. Negative results (<3% activation) were obtained for all the drugs tested. A case report of elevated serum eosinophilic cationic protein (ECP) levels associated with a drug-induced perioperative hypersensitivity has been previously described. On this basis, we performed a novel in vitro test at the Clinical Laboratory of the Department of Immunology. One milliliter of heparinized whole blood was incubated with 5 mg/mL of mepivacaine, lidocaine, and bupivacaine for 16 hours at 37 C, 5% CO2. ECP was quantified with a Phadia 250 assay (Thermo Fisher Scientific) according to the manufacturer’s instructions. The Clinical Laboratory of the Department of Immunology meets ISO 9001:2008, and it is certified by the International Certification Network (IQNet). From baseline ECP levels of 18.4 mg/L, a significant rise in ECP levels was obtained with mepivacaine (38.7 mg/L), lidocaine (58.5 mg/L), and bupivacaine (25.2mg/L), whereas no significant changes were observed when the sample was incubated without drugs (20.4 mg/L). We described a patient who experienced a delayed cutaneous hypersensitivity reaction following the administration of mepivacaine during a surgical procedure and following positive subcutaneous challenge tests with bupivacaine and lidocaine. We have demonstrated a significant increase in ECP levels after the incubation of whole blood with these drugs in vitro. To our knowledge, this is the first reported case in which this procedure has been used to confirm a positive challenge test with these types of drugs. If further utilization of this novel in vitro methodology proves predictive of drug hypersensitivity, it would help avoid subsequent costly and untoward challenge procedures. Furthermore, the elevation in ECP level suggests a possible role of eosinophils in these hypersensitivity reactions, although the underlying mechanism of the reaction is not clear. A classical hypersensitivity mechanism appears unlikely due to the negative skin prick testing and basophil activation test results with the drugs involved. It has been recently suggested that meta-xylene, which is present in some amide and ester LAs as well as parabens, could play a role in certain cases of reactions to LAs. For this

Concurrent coxibs and anti-platelet therapy unmasks aspirin-exacerbated respiratory disease

To the Editor: Aspirin-exacerbated respiratory disease (AERD) is a clinical tetrad of chronic hypertrophic eosinophilic sinusitis, nasal polyps, asthma and sensitivity to any medication that inhibits cyclooxygenase (COX)-1, namely aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. The final metabolites of the degradation of arachidonic acid via COX-1 pathway are thromboxanes, prostacyclin and prostaglandins (PG); the most crucial ones are PGE2 and PGD2. According to the classical “cyclooxygenase” hypothesis, inhibition of COX-1, but not COX-2, triggers various mechanisms leading to asthmatic and/or nasal symptoms in AERD patients. The central mechanism was regarded as the deprivation of PGE2 as a consequence of COX-1 inhibition, which would lead to an even more increased local and systemic generation of cysteinyl leukotrienes (LT). The overproduction of cysteinyl LT, due to upregulation of LTC4 synthase and/or cysteinyl LT receptors in the airways, the hallmark of the disease, occurs at baseline as well, although at a much lower degree than after aspirin/NSAIDs intake [2]. After the introduction of the selective COX-2 inhibitors, casually referred to as coxibs, several well-designed studies reported the excellent safety profile of these new NSAIDs in patients with AERD [3, 4]. Nevertheless, shortly afterwards, as the use of coxibs extended, so did the number of case reports warning the clinicians that some AERD patients may not tolerate coxibs [5, 6]. In fact, all the position papers and updates on AERD evaluation and management recommend giving the first full dose of these …