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Heiner Syndrome and Milk Hypersensitivity: an Updated Overview on the Current Evidence

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Heiner Syndrome and Milk Hypersensitivity: an Updated Overview on the Current Evidence nutrients Review Heiner Syndrome and Milk Hypersensitivity: An Updated Overview on the Current Evidence Stefania Arasi 1,*,†,‡ , Carla Mastrorilli 2,†,‡ , Luca Pecoraro 3,4,‡, Mattia Giovannini 5,‡, Francesca Mori 5,‡, Simona Barni 5,‡, Lucia Caminiti 6,‡, Riccardo Castagnoli 7,‡ , Lucia Liotti 8,‡ , Francesca Saretta 9,‡, Gian Luigi Marseglia 7,‡ and Elio Novembre 10,‡ 1 Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio, 4, 00165 Rome, Italy 2 Pediatric Unit and Emergency, University Hospital Consortium Corporation Polyclinic of Bari, Pediatric Hospital Giovanni XXIII, 70126 Bari, Italy; [email protected] 3 Department of Medicine, University of Verona, 37129 Verona, Italy; [email protected] 4 Pediatric Unit, ASST Mantua, 46100 Mantua, Italy 5 Allergy Unit, Department of Pediatrics, Meyer Children’s University Hospital, 50139 Florence, Italy; mattia.giovannini@unifi.it (M.G.); [email protected] (F.M.); [email protected] (S.B.) 6 Department of Human Pathology in Adult and Development Age “Gaetano Barresi”, Allergy Unit, Department of Pediatrics, AOU Policlinico Gaetano Martino, 98158 Messina, Italy; [email protected] 7 Department of Pediatrics, Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy; [email protected] (R.C.); [email protected] (G.L.M.) 8 Department of Pediatrics, AOU Ospedali Riuniti Ancona, Presidio Ospedaliero di Alta Specializzazione “G. Salesi”, 60126 Ancona, Italy; [email protected] 9 Pediatric Department, Latisana-Palmanova Hospital, Azienda Sanitaria Universitaria Friuli Centrale, 33100 Udine, Italy; [email protected] 10 Department of Health Science, University of Florence, 70126 Florence, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-06-68593570 Citation: Arasi, S.; Mastrorilli, C.; † These authors contributed equally to this work. Pecoraro, L.; Giovannini, M.; Mori, F.; ‡ From the Rare Allergic Diseases Commission of the Italian Society of Pediatric Allergy and Immunology. Barni, S.; Caminiti, L.; Castagnoli, R.; Liotti, L.; Saretta, F.; et al. Heiner Abstract: Infants affected by Heiner syndrome (HS) display chronic upper or lower respiratory tract Syndrome and Milk Hypersensitivity: infections, including otitis media or pneumonia. Clinically, gastrointestinal signs and symptoms, ane- An Updated Overview on the Current mia, recurrent fever and failure to thrive can be also present. Chest X-rays can show patchy infiltrates Evidence. Nutrients 2021, 13, 1710. miming pneumonia. Clinical manifestations usually disappear after a milk-free diet. The patho- https://doi.org/10.3390/nu13051710 genetic mechanism underlying HS remains unexplained, but the formation of immune complexes Academic Editor: Yvan Vandenplas and the cell-mediated reaction have been proposed. Patients usually outgrow this hypersensitivity within a few years. The aim of this review is to provide an updated overview on the current evidence Received: 8 April 2021 on HS in children, with a critical approach on the still undefined points of this interesting disease. Accepted: 17 May 2021 Finally, we propose the first structured diagnostic approach for HS. Published: 18 May 2021 Keywords: allergy; anemia; cow’s milk; children; immunology; non-IgE-mediated food allergy; Publisher’s Note: MDPI stays neutral pneumonia; pulmonary hemosiderosis; pulmonary infiltrates with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Heiner syndrome (HS) is a rare food-induced hypersensitivity disease characterized by chronic respiratory symptoms with X-ray (XR) infiltrates, and the resolution of signs Copyright: © 2021 by the authors. and symptoms after the removal of milk proteins. Other clinical manifestations include Licensee MDPI, Basel, Switzerland. poor growth, gastrointestinal signs and symptoms, iron deficiency anemia and pulmonary This article is an open access article hemosiderosis (PH). Precipitins to cow’s milk (CM) were also considered a useful aid in distributed under the terms and recognizing hypersensitivity to CM [1]. The literature concerning HS is restricted to a few conditions of the Creative Commons case reports or series, although the disease has always been described at infant or pediatric Attribution (CC BY) license (https:// age [2]. The definition of the disease is lacking and the diagnosis is often delayed, since creativecommons.org/licenses/by/ its presentation is uncommon with dissimilar manifestations. In the present review we 4.0/). Nutrients 2021, 13, 1710. https://doi.org/10.3390/nu13051710 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 14 Nutrients 2021, 13, 1710 2 of 12 or pediatric age [2]. The definition of the disease is lacking and the diagnosis is often de- layed, since its presentation is uncommon with dissimilar manifestations. In the present review we aimed at presenting clinical, diagnostic and therapeutic characteristics of HS, startingaimed at from presenting current clinical, evidence. diagnostic and therapeutic characteristics of HS, starting from current evidence. 2. Search Methodology and Results 2. Search Methodology and Results We carried out a non-systematic review including the most relevant studies on “Hei- We carried out a non-systematic review including the most relevant studies on “Heiner ner Syndrome” (HS) present on databases including PubMed Syndrome” (HS) present on databases including PubMed (https://www.ncbi.nlm.nih. (https://www.ncbi.nlm.nih.gov/pubmed/ accessed on 26 March 2021), MEDLINE, The gov/pubmed/ accessed on 26 March 2021), MEDLINE, The Cochrane Library, from their Cochraneinception Library, to 26 March from 2021.their inception The searched to 26 termsMarch were2021. “HeinerThe searched Syndrome” terms were [all fields];“Hei- ner“pulmonary Syndrome” hemosiderosis” [all fields]; “pulmonary and “children” hemosiderosis” [all fields]; “pulmonaryand “children” hemosiderosis” [all fields]; “pul- and monary“cow’s milk”hemosiderosis” [all fields]; and “pulmonary “cow’s milk” hemosiderosis” [all fields]; and“pulmonary “hypersensitivity” hemosiderosis” [all fields]. and “hypersensitivity”We found 16 studies. [all Theyfields]. were We allfound clinical 16 studie casess. or They consecutive were allcase clinical series, cases involving or consec- an utiveoverall case pool series, of 61 involving patients. an Findings overall were pool summarized of 61 patients. narratively Findings belowwere summarized for each study nar- as rativelywell as inbelow Table for1. each study as well as in Table 1. InIn order order to better stratifystratify thethe levellevel of of evidence evidence for for the the diagnosis, diagnosis, we we are are herein herein propos- pro- posinging the the first first structured structured diagnostic diagnostic criteria criteria for for HS HS to to our our best best knowledge. knowledge. This This diagnostic diagnos- ticapproach approach consists consists of theof the following following criteria: criteria: (A)(A) PulmonaryPulmonary symptoms symptoms and and XR XR infiltrates infiltrates or or pulmonary pulmonary hemosiderosis hemosiderosis (PH); (PH); (B)(B) ResolutionResolution after after milk milk removal; removal; (C)(C) RecurrenceRecurrence after after milk milk reintroduction. reintroduction. HSHS diagnosis diagnosis (HSD): (HSD): (A) + (B) (B) = = probable probable disease; disease; (A) + (B) (B) + + (C) (C) = = convincing convincing disease disease (Figure(Figure 11).). Figure 1. Proposed approach for Heiner syndrome diagnosis. Figure 1. Proposed approach for Heiner syndrome diagnosis. Nutrients 2021, 13, 1710 3 of 12 Table 1. Characteristics of the included studies of Heiner syndrome. Allergic Improvement Recurrence Upon Authors, n. Age at Onset Lung Pulmonary Hemosiderosis Milk Delayed Country Signs/Symptoms Sensitization to Milk [sIgE and/or Upon Milk Milk Year Cases (Months) Radiologic Infiltrates Hemosiderosis Diagnosis Precipitins Hypersensitivity skin prick test (SPT)] Avoidance Reintroduction chronic cough (7/7); wheezing (7/7); chronic gastric or bronchial intradermal test rhinitis (7/7); frequent fever (7/7); frequent yes, aspirates (4/7); 1 Heiner, 1960 USA 7 1–17 yes (5/7) yes (ID) late response ID +ve (7/7) yes (6/6) yes (2/6) earache (6/7); recurrent pulmonary needle pos (4/7) diarrhea (6/7); vomiting (5/7); hemoptysis (4/7) biopsy (1/7) respiratory disease; failure to thrive (FTT); Holland, yes (22/24 on 2 USA 22 4–12 anemia; splenomegaly; non specified (NS) NS NS yes NS NS NS 1962 milk-free diet) hepatomegaly doubtful, based on FTT ; 3 Chang, 1969 USA 1 9 yes NS NS yes NS NS yes clinical history anemia; chronic recurrent lung disease (CH) iron-deficiency anemia; lethargy; pallor; bloody doubtful, based on 4 Archer, 1971 England 1 13 vomit; severe cardiac yes yes needle biopsy no NS SPT –ve yes CH failure; hemoptysis idiopathic chronic or recurrent pulmonary disease; upper respiratory symptoms; FTT (3/6); gastric frequent regurgitation and watery stools (1/6). washing or 4 ID delayed yes (5/6); 1/6 5 Boat, 1975 USA 6 7–48 yes (6/6) yes (5/6) yes (6/6) total IgE –ve (6/6); SPT +ve (5/6) yes (1/6) SOF (1/6): Iron deficiency (5/6); Anemia (4/6); bronchoalveolar response loss of data Eosinophilia (4/6); right ventricular hypertrophy lavage (BAL) (3/6); adenoid hypertrophy (3/6) wheezing (5/9); chronic rhinitis (3/9); large gastric washing
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