Jean-Christoph Roger J-P Caubet

The role of penicillin in benign skin rashes in childhood: A prospective study based on drug rechallenge

Background Delayed-onset urticarial or maculopapular rashes are frequently observed in children treated with β-lactams. Many are labeled “allergic” without reliable testing. Objective Determine the etiology of these rashes by exploring both infectious and allergic causes. Methods Children presenting to the emergency department with delayed-onset urticarial or maculopapular rashes were enrolled. Acute and convalescent sera were obtained for viral screening along with a throat swab. Subjects underwent intradermal and patch skin testing for β-lactams 2 months after presentation. Anti–β-lactam blood allergy tests were also obtained. All subjects underwent an oral challenge test (OCT) with the culprit antibiotic. Results Eighty-eight children were enrolled between 2006 and 2008. There were 11 (12.5%) positive intradermal and no positive patch tests. There were 2 (2.3%) positive blood allergy tests. There were 6 (6.8%) subjects with a positive OCT, 2 were intradermal-negative, and 4 were intradermal-positive. No OCT reactions were more severe than the index event. Most subjects had at least 1 positive viral study, 54 (65.9%) in the OCT negative group. Conclusion In this situation, β-lactam allergy is clearly overdiagnosed because the skin rash is only rarely reproducible (6.8%) by a subsequent challenge. Viral infections may be an important factor in many of these rashes. OCTs were positive in a minority of intradermal skin test–positive subjects. Patch testing and blood allergy testing provided no useful information. OCTs should be considered in all children who develop a delayed-onset urticarial or maculopapular rash during treatment with a β-lactam.

Clinical features and resolution of food protein–induced enterocolitis syndrome: 10-year experience

BACKGROUND Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. FPIES diagnosis is frequently delayed because of the absence of classic allergic symptoms and lack of biomarkers. OBJECTIVE We sought to characterize the clinical features and resolution of FPIES in patients evaluated in our practice. METHODS Subjects 6 months to 45 years of age with FPIES were prospectively recruited for oral food challenges (OFCs). Medical records were searched to identify the subjects who did not participate in OFCs. RESULTS Among 160 subjects, 54% were male; median age at diagnosis was 15 months. We performed 180 OFCs to 15 foods in 82 subjects; 30% of the study population had FPIES confirmed based on OFC results. The most common foods were cows milk (44%), soy (41%), rice (22.5%), and oat (16%). The majority (65%) reacted to 1 food, 26% reacted to 2 foods, and 9% reacted to 3 or more foods. The majority were atopic, and 39% had IgE sensitization to another food. Thirty-nine (24%) subjects had positive specific IgE levels to the food inducing FPIES. Among children with specific IgE to cows milk, 41% changed from a milk FPIES to an IgE-mediated phenotype over time. The median age when tolerance was established was 4.7 years for rice, 4 years for oat, and 6.7 years for soy. Median age when milk tolerance was established for subjects with undetectable milk-specific IgE levels was 5.1 years, whereas none of the subjects with detectable milk-specific IgE became tolerant to milk during the study (P = .003). CONCLUSION FPIES typically resolves by age 5 years. Milk FPIES, especially with detectable food-specific IgE, can have a protracted course and eventually transition to acute reactions.

Utility of casein-specific IgE levels in predicting reactivity to baked milk

Based on data from a large cohort of milk allergic children, our results show that measurement of casein-specific IgE is a helpful diagnostic indicator for predicting reactivity to baked milk, showing the greatest area under the receiver operating characteristic curve of parameters tested.

Current understanding of the immune mechanisms of food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized and frequently misdiagnosed non-IgE-mediated food hypersensitivity disorder, characterized by severe vomiting and/or diarrhea. Despite the potential severity of acute reactions, FPIES can be considered self-limiting as avoidance of the incriminating allergen(s) leads to resolution of symptoms. Symptoms typically begin in the first month of life in association with failure to thrive and may progress to acidemia and shock. Although FPIES is well established as a distinct clinical entity, its pathophysiology has not yet been clearly defined and requires further characterization. Several immunologic alterations have been reported in FPIES, suggesting the involvement of antigen-specific T cells and their production of proinflammatory cytokines that regulate the permeability of the intestinal barrier. Humoral immune responses may also be involved in the pathomechanism of FPIES. The aim of this article is to delineate the immunological characteristics of this disorder based on the existing reports and to review the possible pathophysiologic basis of this disease.

Continuing food-avoidance diets after negative food challenges

Negative food challenges for follow‐up in patients previously diagnosed with food allergy should logically be followed by a normal diet. However, all patients do not reintroduce the food. The aims of the study were to define the proportion of negative food challenge not followed by a normal diet, and to identify possible reasons for not reintroducing the food. Patients with a negative food challenge were sent a questionnaire by mail. Items in the questionnaire included the symptoms at diagnosis, the duration of the diet, the fear of an accidental reaction during the avoidance diet and how it influenced the social life. Patients were also asked if the food was reintroduced after the negative food challenge, and if not, for which reasons. In 25.4% of the questionnaires (18/71) respondents reported that the food was not reintroduced. Patients with a previous diagnosis of peanut allergy tended to reintroduce the food less frequently than patients allergic to other foods. Girls were found to significantly less frequently reintroduce the food than boys. However, neither the severity of the initial reaction, the anxiety of an accidental reaction during the avoidance diet, nor a prolonged avoidance diet did influence the decision to reintroduce the food. Among other reasons listed, fears of persistence of allergies, with recurrent pruritus or non‐specific skin rashes after eating the food, were reported in 12.7% of the total number of questionnaires. Patients who reintroduced the food reported that their social life generally improved. One quarter of previously allergic patients continue a food avoidance diet despite a negative challenge. We suggest reassessing food consumption in all patients after a negative food challenge, and in those still avoiding the specific food to consider a repeated challenge test.

Baked Milk- and Egg-Containing Diet in the Management of Milk and Egg Allergy

Cows milk (CM) and hens egg allergies are among the most common food allergies in children. With evidence of increasing food allergy prevalence and more persistent disease, it has become vital to improve the management of CM and egg allergies. The ability to tolerate baked milk or egg, such as in a cake or muffin, has been associated with an increased chance of tolerance development. Studies report that about 70% of CM- and egg-allergic children can tolerate baked milk or egg and that incorporating baked milk or egg into the diet is well tolerated. Being able to add baked milk or egg into the diet can also increase quality of life by expanding the diet, boosting nutrition, and promoting inclusion in social activities. There is some debate over how baked milk and egg should be introduced, at home or in a supervised setting. Anaphylaxis and treatment with epinephrine during baked milk or egg challenges have been reported. Study of potential biomarkers to predict tolerability of baked milk and egg, such as serum specific IgE levels and skin prick test wheal diameters, is ongoing. Many parents can reliably report that their CM- or egg-allergic child is already consuming baked goods without symptoms. However, for those who cannot report such tolerance, the most prudent approach is to perform a supervised oral food challenge to determine the tolerability of baked milk and egg. The purpose of this article was to review the pathophysiology, clinical data, and safety of baked milk and egg and provide a practical guide to managing CM allergy and/or egg allergy. Recipes for baked milk and egg challenges and guidance on how to add baked milk and egg if tolerated to the childs regular diet are provided.

Molecular diagnosis of egg allergy.

Purpose of reviewAllergy to hens egg is common in infancy and childhood. Oral food challenges are often required to diagnose egg allergy, because of the limitation in the diagnostic accuracy of skin test and specific IgE to egg white. New molecular diagnostic technologies have been recently introduced into allergological research. In this article, we will review the recent literature regarding the potential value of these tests for the clinical management of egg-allergic patients. Recent findingsComponent-resolved diagnosis that can be combined with the microarray technology is promising as measurement of specific IgE antibodies to individual egg white components has been shown to predict different clinical patterns of egg allergy. Specific IgE to ovomucoid has been identified as a risk factor for persistent allergy and could indicate reactivity to heated egg. Ovomucoid and ovalbumin IgE and IgG4-binding epitope profiling could also help distinguish different clinical phenotypes of egg allergy. Particularly, egg-allergic patients with IgE antibodies reacting against sequential epitopes tend to have more persistent allergy. SummaryUsing recombinant allergens, IgE-binding epitopes, and microarrays, molecular-based technologies show promising results. However, none of these tests is ready to be used in clinical practice and oral food challenge remains the standard for the diagnosis of egg allergy.

In vitro tests for drug hypersensitivity reactions : an ENDA/EAACI Drug Allergy Interest Group position paper

Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time‐consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well‐controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well‐characterized patients with DHR and to develop new tests for diagnosis.

Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group

When questioned, about 10% of the parents report suspected hypersensitivity to at least one drug in their children. However, only a few of these reactions can be confirmed as allergic after a diagnostic workup. There is still a lack of knowledge on drug hypersensitivity (DH) epidemiology, clinical spectrum, and appropriate diagnostic methods particularly in children. Meanwhile, the tools used for DH management in adults are applied also for children. Whereas this appears generally acceptable, some aspects of DH and management differ with age. Most reactions in children are still attributed to betalactams. Some manifestations, such as nonsteroidal anti‐inflammatory drug‐associated angioedema and serum sickness‐like reactions, are more frequent among young patients as compared to adults. Risk factors such as viral infections are particularly frequent in children, making the diagnosis challenging. The practicability and validity of skin test and other diagnostic procedures need further assessment in children. This study presents an up‐to‐date review on epidemiology, clinical spectrum, diagnostic tools, and current management of DH in children. A new general algorithm for the study of these reactions in children is proposed. Data are presented focusing on reported differences between pediatric and adult patients, also identifying unmet needs to be addressed in further research.

Poor utility of atopy patch test in predicting tolerance development in food protein-induced enterocolitis syndrome

Diagnostic tests are lacking in food protein-induced enterocolitis (FPIES), a non–immunoglobulin E, presumably T cell–mediated food allergy disorder. FPIES typically presents in infancy with profuse vomiting and diarrhea 2 to 4 hours after ingestion of the allergen, combined with a left-shift in peripheral blood leukocytes, occasionally causing profound dehydration, hypotension, and lethargy.1 Chronic exposure results in failure to thrive and hypoalbuminemia.1 FPIES is elicited commonly by milk and soy protein,1 oat, rice, and other foods.2 Oral food challenge (OFC) is performed to follow tolerance development in FPIES, but protracted emesis and dehydration necessitate fluid resuscitation in up to 50% of reactive challenges. Therefore, OFC to confirm the diagnosis of FPIES can be associated with high risk. The atopy patch test (APT) has been suggested as a promising diagnostic test for FPIES3 based on the potential involvement of allergen-specific T lymphocytes, which have been cloned from APT biopsy specimens,4 in FPIES pathophysiology.5 Furthermore, it was recently shown that cutaneous exposure to food antigens can reprogram gut-homing effector T cells in lymph nodes to express skin-homing receptors, eliciting skin lesions on cutaneous food allergen contact.6 We performed APT in children with FPIES before OFC performed to monitor tolerance development. All these children had a history of reaction suggestive of “typical” FPIES as proposed by Sicherer et al1 (acute onset of severe, repetitive emesis within 1–4 hours of ingestion) to at least 1 of the following foods: milk, soy, oat, or rice. The study was approved by the Institutional Review Board. Informed consent was obtained from parents and assent from children when appropriate. A standard APT panel of cow milk, soybean, rice, and oat was performed on each patient within a week before OFC as described previously.3 Briefly, a thick paste of nonfat dried milk powder or soy, rice, or oat flour in normal saline was applied into Finn Chambers placed on the back with Scanpore tape (Allerderm Laboratories, Inc., Petaluma, California). Vanicream (Pharmaceutical Specialities Inc, Rochester, Minnesota) was used as a negative control. Patches were removed after 48 hours; reactions were blindly scored by a study physician at 72 hours. Erythema alone was considered “irritation” (negative); positive reactions included erythema with infiltration (+), or with few papules (++), several papules (+++), and vesicles (++++).7 Inpatient OFCs were performed by administering food in 3 equal doses over a 45-min interval with a peripheral intravenous line in place. The total amount of challenge food was calculated as (0.15–) 0.6 g food protein (or 17.6 mL liquid milk, 20.3 mL liquid soy milk, 9 g infant rice cereal, or 4.5 g infant oat cereal) per kilogram body weight. Positive challenges comprised symptoms and laboratory findings as described previously.8 We performed 38 nonblinded challenges in 25 subjects (15 males, 10 females) at median age of 3.3 years (range, 1.5–16.8 years) (Table 1). Their most recent FPIES reaction had occurred a median of 24.5 months (range, 14.5–79 months) before the OFC. Of the 38 OFCs, 16 (42%) were positive and included vomiting and sometimes other symptoms (Table 1), within a median of 2.5 hours (range, 2–6.2 hours) from the start of the challenge to a total dose in all the patients; only 2 subjects had a positive APT. Among the 23 negative OFCs, 2 subjects had a positive APT. The median age was comparable between those with a positive and negative OFC. The APT had sensitivity of 11.8%, specificity 85.7%, positive predictive value 40%, and negative predictive value 54.5%. A total of 102 tests were done as part of the APT panel to foods other than the offending food; 5 were positive. In 3, food was tolerated; in 2, food had not yet been introduced. Table 1 Characteristics of the study population and test results according to the trigger fooda The discrepancy compared with the report by Fogg et al (sensitivity of 100%, specificity 71%, positive predictive value 75%, negative predictive value 100%)3 may be attributable to the fact that we considered only palpable infiltration as a positive reaction, as recommended by the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network.7 The median age in the study by Fogg et al3 was younger, and the median time since the most recent reaction was shorter (12 months, range 4–29 months), which could represent a group of children with more “active” disease. However, their reaction rate was not significantly higher than ours (48.5% vs 42%). It is possible that the activation capacity of responsible T cells diminishes over time resulting in a negative APT. However, this was not the case in the gut mucosa during a positive OFC. In conclusion, APTs to common food allergens have poor utility in the follow-up prediction of outgrowing FPIES in children.