Iride Dello Iacono Unità Operativa di Pediatria ed Allergologia Crescere sani: diagnosi e terapia nelle allergie alimentari Iride Dello Iacono Unità Operativa di Pediatria ed Allergologia Ospedale Fatebenefratelli Benevento

Diagnosi Allergologica Iter diagnostico Test di provocazione Dieta di eliminazione diagnostica IgE s SPT Esame obiettivo Anamnesi accurata 2

IgE-mediated reactions The clinical presentation of food allergy involves a large spectrum of symptoms IgE-mediated reactions IgE-mediated symptoms develop within minutes to 1 to 2 hours of ingesting the food.

The clinical presentation of food allergy involves a large spectrum of symptoms Non IgE-mediated reactions Predominantly abdominal symptoms (vomiting, diarrhea, pain, and bloody stools) that develop several hours after ingestion of the food.

Diagnosis Patient’s clinical history and examination Although the medical history often provides evidence for the type of food-induced allergic reaction and the potential causative food or foods involved, neither medical history nor physical examination alone is diagnostic of food allergy. Sampson 2014

Diagnosi Allergologica IgE-mediated reactions Test di provocazione Dieta di eliminazione diagnostica IgE s SPT Esame obiettivo Anamnesi accurata IgE-mediated reactions 6

E’ realmente allergico o no? SENSIBILIZZAZIONE NON EQUIVALE AD ALLERGIA SENSIBILIZZAZIONE NON EQUIVALE AD ALLERGIA E’ realmente allergico o no?

NON EFFETTUARE SKIN PRICK TEST VERSO ALIMENTI CHE IL BAMBINO ASSUME SENZA ALCUN PROBLEMA

Diagnosi Allergologica Iter diagnostico Test di provocazione Dieta di eliminazione diagnostica IgE s SPT Esame obiettivo Anamnesi accurata 9

ECCEZIONE: ANAFILASSI ELIMINATION DIET The duration of the avoidance should be no longer than necessary to achieve a significant relief of symptoms, usually 2–4 weeks for IgE-mediated symptoms and longer for non-IgE ones [e.g., up to 6 weeks for eosinophilic esophagitis (EoE)]. ECCEZIONE: ANAFILASSI

Diagnosi Allergologica Iter diagnostico Test di provocazione Dieta di eliminazione diagnostica IgE s SPT Esame obiettivo Anamnesi accurata 11

Diagnosi Allergologica Iter diagnostico Test di provocazione Dieta di eliminazione diagnostica IgE s Cut-off ? SPT Esame obiettivo Anamnesi accurata 12

TEST DIAGNOSTICO NEGATIVO TEST DIAGNOSTICO POSITIVO SE PARLIAMO DI CUT OFF …… SANI TEST DIAGNOSTICO NEGATIVO MALATI TEST DIAGNOSTICO POSITIVO Ops…. Test! Carmen Verga

Optimal cut-off: è il valore di positività che permette di combinare la maggiore sensibilità (probabilità che un malato risulti positivo al test diagnostico) con la migliore specificità (probabilità che un sano risulti negativo al test diagnostico). E’ la migliore combinazione possibile tra sensibilità e specificità e serve a valutare l’accuratezza di un test. Carmen Verga

QUALE TEST ? … e COME ? Sensibilità e Specificità Caratteristiche operative stabilite dai test di validazione Sensibilità e Specificità Solo una Specificità > 95% garantisce una efficienza diagnostica, in positivo, indipendentemente dalla frequenza della patologia nella popolazione Se la Specificità è > 95% , possiamo considerare che i falsi positivi sono < 5%. Nel nostro caso, quindi, utilizzando un test con Spec > 95%, meno del 5% dei pazienti positivi al test sarà considerato allergico senza esserlo e sarà messo a dieta inutilmente Bergamini

QUALE TEST ? … e COME ? Caratteristiche operative dipendenti dalla frequenza della malattia nella popolazione Valore Predittivo Positivo (VPP) e Valore Predittivo Negativo (VPN) Anche con un test con VPP > 95% i falsi positivi sono < 5%, quindi meno del 5% dei pazienti positivi al test sarà considerato allergico senza esserlo e sarà messo a dieta inutilmente. Ma ciò vale solo per la popolazione sulla quale il test è stato validato e per popolazioni (settings) con uguale prevalenza di malattia. Il VPP non è trasferibile a popolazioni (settings) con diversa prevalenza. Bergamini

In alcuni pazienti è possibile evitare il Test di Provocazione Orale? Specificità … ≥ 95% (indipendente dalla prevalenza) Prick tests IgE specifiche Valore Predittivo Positivo ≥ 95% (dipende dalla prevalenza) Carmen Verga

IL PROBLEMA DEI CUT-OFFs ATTRAVERSO LA LETTURA DELLE LINEE GUIDA E DELLE REVISIONI SISTEMATICHE

2010 The diagnosis of cows milk allergy (CMA) starts with suspicion and ends with an oral food challenge (OFC)

2014 Specific IgE and SPT tests are good to confirm or rule out the involvement of IgE in (self-)reported food hypersensitivity………… However, they are often unable to differentiate between clinically relevant allergy and tolerance and oral challenges are therefore required.

Valore non dipendente dalla prevalenza della patologia ed applicabile in tutti i settings, ma dovrebbe essere confermato almeno da un 2° studio indipendente con adeguata numerosità campionaria It has been suggested that weal sizes of ≥ 8 mm (≥ 6 mm in infants < 2 years) are 100% specific for positive challenge and that there is no need to undertake oral challenge to confirm diagnosis in these Cases (Du Toit et al. 2009)

Several studies showed that cutoff values might vary with the degree of cooking of the egg used for the oral food challenge, with age, and with the type of allergen used to perform SPTs (commercial extract, raw egg, or heated egg). Thus, in the present review, we grouped studies according to these three factors.

Further and better-designed studies are needed to determine the SPT ≥ 10 mm SPT ≥ 4 mm SPT ≥ 14 mm IgEs >1,7 KUA/l IgEs >7,3 KUA/l Further and better-designed studies are needed to determine the remaining diagnostic cutoff of specific IgE and SPT for heated and baked egg allergy.

Diagnosi di Allergia Alimentare: E’ possibile evitare il Test di Provocazione Orale? Allo stato attuale delle conoscenze, non esiste un cut-off validato per tutte le realtà allergologiche. Ogni centro allergologico potrebbe/dovrebbe calcolare cut-offs validi per la propria popolazione di studio che potrebbero orientare sugli esiti del Test di Provocazione Orale. Il dato che nessun cut-off sia ancora in grado di sostituire il gold-standard, ossia il Test di Provocazione Orale, implica, comunque, che la conferma diagnostica di AA deve passare attraverso l’esecuzione di quest’ultimo.

Diagnosi Allergologica Iter diagnostico Test di provocazione Dieta di eliminazione diagnostica IgE s SPT Esame obiettivo Anamnesi accurata 25

LA TERAPIA DELL’ AA 2010 2011 2014

J Allergy Clin Immunol 2012 *The primary therapy for food allergy is strict avoidance of the causal food or foods. *This is true for IgE-mediated, non–IgEmediated,and mixed IgE- and non–IgE-mediated food allergy syndromes.

GRADE 2010

APLV IgE-mediata: fenotipi clinici WAO Journal - April 2010

2010 APLV non-IgE mediata: fenotipi clinici eHF APLV IgE/non-IgE: fenotipi clinici AAF/eHF 2010

CLINICAL RECOMMEMDATIONS 2011 CLINICAL RECOMMEMDATIONS Treatment with CMA replacement formulas In its therapeutic guidelines DRACMA recommended a milk-free diet for cases of IgE-mediated CMA and the use of appropriate alternative formulas up to at least 2 years of age to meet the nutritional needs of these very young children (Table 1). The complete recommendation set is available at http://www.worldallergy.org/publications/ WAO_DRACMA_guidelines.pdf. According to these recommendations, when a substitute formula is needed a milk-based extensively hydrolyzed formula (eHF) is the first choice except in case of anaphylaxis or eosinophilic esophagitis, where AAF is recommended. eHFs should be tested on an outpatient basis before being used at home and new formulas should be monitored for adverse reactions when first administered. eHFs are preferred over soy formulas (SF) to avoid untoward reactions to soy. Conversely, eHF is preferred over extensively hydrolyzed rice formula (eHRF) because more commonly available on the market. Where readily available as in Italy, eHRF can adequately replace eHF. Further studies are required to confirm the benefits of rice protein over SFs.

2014 Extensively hydrolyzed cow’s milk formulas are the first choice as an alternative to cow’s milk. However, amino acid-based formulas are the only completely nonallergenic formula and they can be effective in patients not responding to extensively hydrolyzed formulas and in subgroups of children. 2014

Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson. JACI 2011

500°F 3’ 350°F 30’ età media di 7,5 anni (range 2.1 – 17.3)

Heather Lemon-Mulè et al Immunologic changes in children with egg allergy ingesting extensively heated egg JACI 2008 La conclusione degli AA è che sia possibile che l’ingestione di uovo cotto, in dosi gradualmente crescenti, possa influenzare la storia naturale dell’allergia all’uovo. 25 no TPO “regolare” per IgE altamente predittive (14) o storia convincente recente (7) o rifiuto (4) 64/91 (70%) allergici all’ uovo (dubbio sui 25 di cui sopra) hanno tollerato l’ uovo molto cotto

J Allergy Clin Immunol. 2011 Jul;128(1):125-131.e2. Epub 2011 May 23 M. Bergamini

J Allergy Clin Immunol. 2011 Jul;128(1):125-131.e2. Epub 2011 May 23 M. Bergamini

Conclusions: 58% of patients clinically reactive to CM tolerated PLoS ONE | www.plosone.org July 2012 | Volume 7 | Issue 7 | e40945 Conclusions: 58% of patients clinically reactive to CM tolerated fully maturated PR. The preliminary digestion of CAS induced by PR maturation process, facilitating a further loss of allergenic reactivity during gut digestion, might explain the tolerance.

Allergy Asthma Immunol Res. 2013 January;5(1):42-47. Conclusions: This study showed that the antigenic activity of ovomucoid can be reduced by baking EW with wheat flour. The decrease in ovomucoid antigenicity in the baked mixture of EW and wheat flour was dependent on the time of heat treatment, indicating that heating should be prolonged to achieve a reduction in ovomucoid antigenic activity.

Our data support initiation of home reintroduction of well-cooked egg from 2 to 3 years of age in children with previous mild reactions and no asthma.

Although a strict avoidance diet of all allergic foods is typically recommended, recent studies indicate that regular exposure of heat-modified egg and milk protein in allergic patients is not only well tolerated in up to 70% of allergic patients but might be clinically beneficial. Sampson HA et al, J Allergy Clin Immunol 2014; 134: 1016.25

Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson. JACI 2011

IC tutti contenuti nella parte dx del forest plot, a favore del trattamento (Verga ) Nessuna eterogeneità tra gli studi, alta significatività statistica dei risultati (Verga)

RR= 9.98 La percentuale di pazienti che acquisiscono la tolleranza totale è, nei trattati, 10 volte superiore rispetto ai controlli (Verga)

Gli studi sono tra loro eterogenei (I2= 75%) e gli intervalli di confidenza sono ampi, espressione di una variabilità di risultati anche tra i pazienti di uno stesso studio. Ma se la dimensione dell’effetto (maggiore o minore efficacia) è variabile, la direzione dell’effetto (a favore o contro il trattamento) è decisamente a favore del trattamento (tutto l’intervallo di confidenza contenuto a sinistra del forest plot) (Verga ) RR = 21% La OIT, complessivamente, comporterebbe un beneficio modesto, ma la metanalisi accorpa studi con alta eterogeneità, su OIT per alimenti diversi, su pazienti con diversi gradi di gravità della malattia e con diversa validità del disegno e della conduzione (Verga ) Differenza statisticamente significativa Alta eterogeneità tra gli studi Nurmatov 2014

La percentuale di pazienti che acquisiscono la tolleranza totale è, nei trattati, 5.73 volte superiore rispetto ai controlli (Verga )

Volume 12 Number 3 June 2012

Specific Immunotherapy Food allergen-specific immunotherapy for primary food allergy is a promising immune-modulatory treatment approach , but it is associated with risk of adverse reactions, including anaphylaxis ; it is therefore not at present recommended for routine clinical use. In light of its potential benefit, it should be performed only in highly specialized centres (combining staff with high expertise and adequate equipment) and according to a clinical protocol approved by the local ethics committee

Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson. JACI 2011

Considering its efficacy in reducing serum IgE levels and downregulating the cell surface expression of FceRI, omalizumab has been explored for other IgE-associated conditions, such as IgE-mediated food allergy and food induced anaphylaxis A. Licari et al. 2014

J Allergy Clin Immunol. 2011 June ; 127(6): 1622–1624. We conducted a pilot phase I study in 11 children (age, 7-17 years) with cow’s milk allergy by using omalizumab (anti-IgE mAb; Xolair) in combination with relatively rapid oral milk desensitization The limitations of our study include the small sample size, the lack of a placebo group, and lack of a baseline oral food challenge.

J Allergy Clin Immunol 2013;132:1368-74. We performed oral peanut desensitization in peanut allergic children at high risk for developing significant peanut-induced allergic reactions. Omalizumab was administered prior to and during oral peanut desensitization We enrolled 13 children (median age, 10 years), with a median peanut-specific IgE of 229 kUA/L and a median total serum IgE of 621 kU/L, who failed an initial double-blind placebo controlled food challenge at doses 100 mg peanut flour Among children with high-risk peanut allergy, treatment with omalizumab may facilitate rapid oral desensitization, and qualitatively improve the desensitization process.

Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson Future therapies for food allergies A Nowak-Wegrzyn and H. A. Sampson. JACI 2011

Molecular Immunology 65 (2015) 104–112 Use of recombinant proteins for immunotherapy has been beneficial due to the purity of the recombinant proteins compared to natural proteins. In this study, we produced IgE reactive recombinant egg white proteins that can be used for future immunotherapy. Using E. coli as an expression system, we successfully produced recombinant versions of Gal d 1, 2 and 3, that were IgE reactive when tested against a pool of egg allergic patients’ sera.

Sempre di piu’ verso l’exposure

Breast milk. Breast milk is suitable for most infants with cow’s milk allergy. Cow’s milk protein b-lactoglobulin can be detected in the breast milk of most lactating women although in concentrations that will be of no consequence to most cow’s milk allergic infants. Mothers should therefore be encouraged to continue breastfeeding and usually do not require dietary dairy restrictions unless the infant has symptoms whilst being breastfed.

BENEVENTO IX GIORNATA DI ALLERGOLOGIA ED IMMUNOLOGIA PEDIATRICA 15-16 Gennaio 2016 58