Drug-induced enterocolitis syndrome with paracetamol (acetaminophen) in a 12-month-old-old boy B.Pascalab, B.Evrardac, E.Merlinbc, C.Egronb, B.Bonnetac, E.Michaudba Service d’immunologie, hôpital Gabriel Montpied, Clermont-ferrand, Franceb Service de pédiatrie générale, hôpital Estaing, Clermont-ferrand, Francec Université Clermont Auvergne, Clermont ferrand, FranceTo the Editor,Drug-induced enterocolitis syndrome (DIES) is a new clinical presentation similar to food protein-induced enterocolitis syndrome (FPIES). It was described for the first time in 2014 by Novembre et al.(1). More and more cases have been described since and clinical diagnostic criteria have recently been proposed. (2)A 12-month-old boy was referred to our Pediatric Allergy Unit for a suspected drug hypersensitivity. At age 10 months, he was admitted to the pediatric emergency room for vomiting and fever, previously treated with two intake of intrarectal paracetamol (15 mg/kg every 6 hours), the last one 4 hours before admission. He had no previous history (and no allergic history). During the initial examination, we observed asthenia, paleness, no fever (after antipyretics) and tachycardia, followed by four episodes of mucus vomiting without diarrhea. An occlusive syndrome was suspected. Given the hemodynamic disorders, continued fluid resuscitation was performed. Blood tests showed an isolated hyperleukocytosis with neutrophils (11.08 G/L). Eosinophils (0.210 G/L), lymphoid cells (7.25 G/L), the ionogramm and CRP (4.9 mg/L) were normal. Blood gas revealed a compensated respiratory alkalosis (lactates 2.2 mmol/L, methemoglobinemia 1.3%). No tryptase or specific IgE test was performed. Abdominal ultrasound was normal. Microbiological workup was negative. The next day, he was still irritable with several night vomiting episodes. He was discharged with some clinical improvement (diagnosed viral disease).By questioning the parents, they noticed that their child presented digestive disorders’ events at home since birth, which coincided with the 5 times intake of Paracetamol, twice orally and then intrarectally. The symptoms appeared systematically from the first intake. In the child’s medical history, we found no rhythmicity related to meals or other etiologies. His father has a well-known pollen and Penicillin allergies. By reviewing the emergency room observations (Figure 1), we noticed systematic digestive disorders approximately 3h to 6h after each paracetamol intake, explaining the moderate initial clinical improvement.Four months later, skin prick tests (10 mg/mL) and intradermal tests (0.1 mg/mL) were negative. The drug oral challenge (Table 1) was positive: repeated vomiting, marked pallor, lethargy, and crying without cutaneous or respiratory symptoms 2 hours after the last paracetamol intake. Rehydration and corticosteroid therapy brought a complete clinical recovery. No mast cell degranulation was observed (normal tryptase levels: 6.6 µg/L to 6.2 µg/L 1 hour after reaction). There was no infectious context or other confounding factors on the day of the challenge test.We inferred a drug-induced enterocolitis syndrome (DIES) caused by paracetamol, in the absence of other plausible causes. This child’s reaction met the various major and minor criteria described (3), independently of the dosage form, formally implicating paracetamol (Table 2). Therefore, the assay of specific immunoglobulins and the performance of a basophils activation test were not performed.Based on all these observations, we decided to propose an alternative treatment with ibuprofen, if the child had fever and eliminate cross allergy, confirmed by a negative challenge test. We will follow the child and perhaps propose another Paracetamol challenge test, in a few years, to assess possible cure of the syndrome. Since the provocation test, parents kept paracetamol excluded, the child no longer presented any digestive disorder. Prognosis of the DIES is actually unknown. Oral challenge seems to be indeed the only useful test to confirm or exclude DIES (3). In contrast, skin tests don’t provide conclusive evidence to diagnose DIES, as for FPIES.This is the first clinical presentation of DIES with paracetamol. Similar cases following antibiotic intakes (including amoxicillin) and only one for pantoprazole have been described, with similar clinical and biological manifestations (2). DIES is a clinical entity more frequent in a pediatric population, described with a minimum age of 2 years old, but adult cases are more and more reported in the literature. The patient is therefore younger than the cases described in the literature.Currently, it is considered in the literature that DIES is a syndrome equivalent to FPIES but with allergens of a different nature, respectively drug versus food. FPIES is a non-IgE mediated gastrointestinal food allergy (prevalence 1%), symptoms depend on the frequency of food exposure. FPIES affects infants and young children, diagnosis is clinical, and there are no specific biomarkers. In the literature, there were two kinds of FPIES being described: chronic FPIES occurs when food consumption is regular, symptoms (chronic diarrhea, vomiting, weight loss..) resolve with a period of avoidance, and acute FPIES occurs with occasional consumption of food and can have severe symptoms which may lead to shockSimilarly, DIES present specific criteria of non-IgE-mediated hypersensitivity, based only on the presence of typical symptoms (Table 2). However, to date, acute or chronic forms have not yet been described.Although its clinical manifestations can be severe and lead to hypovolemic shock, DIES pathophysiology is still not well understood. There is also no validated biomarker. According to Powell and al (4), neutrophilia has been recognized as a common finding in patients presenting with acute FPIES for a long time. The increase of the eosinophil cationic protein (ECP) in stool samples from 24 and 48 h after the reaction was also described. (5) Many cases of FPIES will be probably described in the coming years, maybe with new different drugs. This diagnosis should be considered in the event of a recurrent digestive disorder, at any age.To date, several unanswered questions need to be addressed. Clinicians must be known for example if DIES is a transient or persistent trouble. Further studies may allow to find the origin, evolution and treatment of DIES.In conclusion, we reported the first DIES induced by PARACETAMOL, with tolerance to IBUPROFEN, confirmed by oral challenge test. Until now, it is the youngest patient case report and the first for PARACETAMOL.Keywords: children; drug hypersensitivity reactions; drug-induced enterocolitis syndrome; drug allergy; antipyreticReferences1. Drug-Induced Enterocolitis Syndrome (DIES) Elio Novembre, Francesca Mori, Simona Barni, Neri Pucci,2. Mori F, Liccioli G, Fuchs O et al. Drug-induced enterocolitis syndrome: Similarities and differences compared with food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol. 2021 Mar 2.3. Van Thuijl AOJ, Landzaat LJ, Liem O, et al. Drug-induced enterocolitis syndrome (DIES): A clinical entity that deserves more awareness. Ann Allergy Asthma Immunol. 2019 May;122(5):538-539.4. G K Powell. Enterocolitis in low-birth-weight infants associated with milk and soy protein intolerance J Pediatr. 1976 May;88(5):840-4.5. Freundt Serpa NP, Sánchez-Morillas L, Jaqueti Moreno P, González-Gutiérrez ML, Cimarra M, Cerecedo I, Fernández-Rivas M. Drug-Induced Enterocolitis Syndrome Due to Amoxicillin-Clavulanic Acid With Good Tolerance to Penicillin. J Investig Allergol Clin Immunol. 2020;30(4):301-302. doi: 10.18176/jiaci.0500. Epub 2020 Feb 25. PMID: 32101171.

To the Editor, Precision medicine is increasingly used as an approach to the management of allergy and anaphylaxis, thanks to progress in diagnostic tests and biomarkers now allowing thorough characterization of a patient’s endotype1. Probability-based risk assessment and diagnostic algorithms have entered the allergists’ toolbox2-4. Allergy tests must therefore offer reliable, robust, and proficient results in each patient. Focusing onin vitro diagnostics, these requirements have led to the development of quality assurance (QA) programs for allergy laboratory assays and their implementation in virtually all clinical laboratories performing allergy assays. However, full performance targets for allergy assays have not yet been established, leaving allergists and clinical scientists without a common body of recommendations for the three routine assays, namely total serum IgE (tIgE), allergen-specific serum IgE (sIgE), and serum total tryptase. As an example, not only do recommendations on the acceptable bias and uncertainty of measurement (UM) of allergy assays miss from available literature, but there is also a complete lack of published recommendations on tryptase QA criteria. The multicentric French network of public clinical laboratories had previously documented a single-analyte QA strategy and recommendation for sIgE5. Hence, we set out to define QA criteria for intra- and interassay variation, analytical accuracy, and UM for sIgE, tryptase, and tIgE. QA data from 24 French centers were collected, analyzed, and compared to available literature, prior to issuing recommendations for QA management programs in allergy testing.Data were collected from 2016-2018 intralaboratory (internal) QA controls (IQA) and interlaboratory proficiency testing programs (external quality assurance, EQA) completed by the participant centers6. A literature search for English and French recommendations for allergy assays was performed, including scientific publications, statements of scientific societies, QA management schemes from independent QA organisms, and manufacturer documents. According to the regulated (tIgE) or nonregulated (sIgE, tryptase) analyte status7, the current work applies to any tIgE system, but for sIgE and total tryptase it is limited to the ImmunoCAP assay system, which is in use in all participant centers, is currently perceived as the reference in vitro diagnostic method for allergy2, and offers the only EU-cleared tryptase determination method. Briefly, IQA programs were performed with control samples provided by the manufacturer and with internal serum pools, particularly for tryptase determination. EQA programs were from UK NEQAS (UK National External Quality Assessment Services), Thermo Fisher Scientific (Uppsala, Sweden), ProBioQual (Lyon, France), and CTCB (Toulouse, France). All participant laboratories had subscribed to at least one EQA for each assay. Data analysis was performed stepwise: (1) definition of three concentration levels (low, medium, and high) within the dynamic range of each analyte and assignment of measurement results from each center to the corresponding level; (2) computation and analysis of intra- and interassay coefficient of variability (CV), bias from analytical accuracy, and UM for each analyte, concentration level, and participant; (3) comparison of assay performance of participant centers with extant recommendations, outlier identification and establishment of recommendations. Performance evaluation criteria were defined as follows: CV = 100xSD/mean (SD, standard deviation), bias = 100x[(participant result) – (peer group target result)]/(peer group target result), UM = √ [u2(IQA) + u2 (IQA)], with u2(IQA) denoting the variance (square SD) of all IQA results of the same concentration level, and u2(EQA) denoting the variance of corresponding EQA results8.Comparison of participant centers’ results and available recommendations (Table 1 ) revealed that actual tIgE assays outperformed most intra- and interassay CV recommendations, but were in line with bias recommendations. Actual sIgE assay performance for intra-and interassay CV matched the available non-manufacturer recommendations from CLSI (Clinical and Laboratory Standards Institute)9, but inconsistently attained UK NEQAS standards (Table 1 ). Intra-and interassay CV for total tryptase determination could only be compared to manufacturer recommendations, which appeared too stringent for inter-assay CV. Similarly, actual accuracy bias for tryptase determination was less performant than the available UK NEQAS standards, designed for low concentration levels (Table 1 ). For the three analytes and each concentration level, UM was calculated but due to a complete lack of available recommendations it could not be evaluated outside the peer group. Moreover, due to the lack of adequate EQA for each tryptase level, the UM for low (< 8 µg/L) and medium (8-20 µg/L) could only be computed for a combined low and medium concentration level up to 20 µg/L (Table 1 ).Analysis of data from participant centers and comparison with international standards (when available) allowed the establishment of recommended targets for performance evaluation, defined as the 95th percentile of the participants’ results (Table 2 ). It is noteworthy that UM, a performance criterion that should be considered whenever clinical interpretation and decision rely on quantitative results, needs improvement, both in terms of availability of adequate EQA samples spanning the whole range of analyte concentrations, and of results from participating centers. The first step to take is wider availability of IQA and EQA samples of paired concentration levels. As UM computation is based on the absolute value of variance, UM of low concentrations of an analyte is unfavorably impacted by the use of medium or high EQA sample results. In order to achieve the goal of using adequate pairs of EQA samples for each analyte level, in the absence of commercially available EQA programs, interlaboratory exchanges are a simple, cost-effective solution.In conclusion, we report here the first experience-based performance results for the most usual in vitro allergy and anaphylaxis assays, their comparison with available recommendations, and the establishment of the first recommendations for total tryptase assays and for the uncertainty of measurement of the three considered analytes: total serum IgE, allergen-specific serum IgE, and total serum tryptase. Conceived as a working tool for allergists and clinical scientists, our report aims at incentivizing further improvement and better use ofin vitro allergy assays for precision medicine.Anne Sarrat1, Rémy Couderc2, Marie-Alexandra Alyanakian3, Pol-André Apoil4, Céline Beauvillain5, Lionel Chollet6, Pascale Chrétien7, Arnaud Cirée8, Benoît Cypriani9, Erwan Dumontet10, Bertrand Evrard11, Lorna Garnier12, Angélique Grenier13, Valérie Guérin14, Caroline Hémont15, Anthony Léon16, Delphine Mariotte17, Pascale Nicaise-Roland18, Martine Pernollet19, Stéphanie Rogeau20, Thierry Tabary21, Béatrice Uring-Lambert22, Mylène Vivinus23, Julien Goret1, Joana Vitte24.1 Laboratoire d’Immunologie et Immunogénétique CHU Bordeaux, Hôpital Pellegrin, Bordeaux, France2 CHU Trousseau, Paris, France3 Laboratoire d’Immunologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France4 Institut Fédératif de Biologie, Hôpital Purpan, CHU Toulouse, Toulouse, France5 Laboratoire d’Immunologie, CHU Angers, France6 LBM CHI Toulon La Seyne sur Mer, Toulon, France7 Département d’Immunologie, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France8 Laboratoire d’Immunologie, CHRU Tours, Tours, France9 Laboratoire de biochimie CHRU Besançon, Besançon, France10 CHU Rennes, Pôle Biologie, Rennes, France11 Service d’Immunologie, CHU Clermont-Ferrand, Clermont-Ferrand, France12 Laboratoire d’Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France13 LBM Hôpital Robert Ballanger, CHI Aulnay, France14 Laboratoire d’Immunologie, Hôpital Robert Debré, AP-HP, Paris, France15 Laboratoire d’immunologie, CHU Nantes, Nantes, France16 LBM CH Emile Durkheim, Epinal, France17 Département d’Immunologie et Immunopathologie, CHU Caen, Caen, France18 Laboratoire d’immunologie, « Autoimmunité et Hypersensibilités », Hôpital Bichat-Claude Bernard, AP-HP, Paris, France19 Institut de Biologie et de Pathologie, Laboratoire d’Immunologie, CHU Grenoble Alpes, Grenoble, France20 CHRU de Lille, Institut d’Immunologie-HLA, Lille, France21 Laboratoire d’immunologie, CHU Reims, Reims, France22 Département d’Immunobiologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France23 Laboratoire d’Immunologie, Hôpital de l’Archet, CHU Nice, France24 Aix Marseille Univ, IRD, University Hospitals of Marseille, MEPHI, Marseille, France