Dal convegno "Novità diagnostico-terapeutiche in Allergologia e Immunologia Clinica" dell'11 Novembre 2017, Torino

1. L’allergia non IgE mediata al latte vaccino
11.11.2017
Alberto Martelli
UOC Pediatria - Ospedale G.Salvini
Garbagnate Milanese

2. La classificazione dell’EAACI/WAO
Johansson SGO et al. A revised nomenclature for allergy. Allergy
2001;56:813-24

3. APLV non IgE mediate
I- Cutaneous Atopic dermatitis
II - GI GERD
Allergic Eosinophil Esophagitis
Cow’s Milk Protein-Induced Gastroenteropathy
Constipation
Severe Irritability (Colic)
FPIES
III-respiratory Milk-Induced Chronic Pulmonary Disease
(Heiner’s Syndrome)
Fiocchi A, Schunemann H. Diagnosis and Rationale for Action against Cow’s Milk
Allergy. The WAO DRACMA guideline. WAO Journal & Pediatr Allergy Immunol 2010;
S1,1-105.

4. L’attore principale

5. Rosenberg HF et al. Eosinophils: changing perspectives in health and disease. Nat Rev
Immunol. 2013;13:9-22.

6. Il danno tissutale è indotto da un gran
numero di mediatori degranulati dagli
eosinofili nella sede della flogosi: una
vera macchina da guerra

7. I sospetti

8. APLV GI non IgE mediate: come
sospettarle
1) Relazione temporale più ampia rispetto IgE mediate
2) Esclusione di patologie infettive, malformative,
metaboliche e altre cause infiammatorie
3) Mancata risposta a terapie convenzionali mirate a
cause anatomiche, funzionali, metaboliche o infettive
4) Risultati di esami coerenti con una causa allergica
(ad esempio, eosinofilia)
5) Conferma di correlazione tra ingestione di PLV e
segni/sintomi in challenge clinici o ripetute esposizioni
6) Associazione con altre patologie atopiche
7) Miglioramento dei segni/sintomi con l’eliminazione
delle PLV e successiva ripresa con la reintroduzione
8) Mancanza di altre spiegazioni per la reazione clinica
Adapted to Sampson HA. J Pediatr Gastroenterol Nutr 2000;30:S87–S94

9. Solo in pochi casi è lecito
sospettare un’APLV nella DA
1) Nelle DA severe
2) Nelle DA con esordio molto precoce
3) Nelle DA poco responsive alle comuni terapie
topiche
4) Nelle DA dove sono già presenti altri segni di allergia
(orticaria, disturbi gastro-intestinali, deficit di
crescita…)
5) Molte volte si tratta solo di sensibilizzazione al prick
by prick con latte fresco senza reattività clinica
all’esposizione dell’allergene

10. I sintomi e segni nell’EoE
Liacouras CA et al. Eosinophilic esophagitis: updated consensus recommendations for
children and adults. J Allergy Clin Immunol. 2011;128:3-20.e6;

11. Segni e sintomi nell’EoE: bambini e adulti
Dellon ES et al. Clinical, endoscopic, and histologic findings distinguish eosinophilic
esophagitis from gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2009;
7:1305-13;

12. Noel RJ et al. Eosinophilic esophagitis. N Engl J Med. 2004;351:940-1.
Incidenza di segni atopici nell’EoE

13. EEo anche nei piccoli
• Di 558 bambini con EEo, 127 (22.8%) avevano età
< 5 anni (età media 2.5 anni).
• Sintomatologia di RGE (90.1%)
• vomito (86.2%)
• diarrea (55.3%)
• disfagia per i liquidi (52.0%) più rappresentata nei
piccoli (P = .0101)
• stipsi (50.0%)
• segni di impatto alimentare (1.6%) rari.
Sun RW et al. Eosinophilic esophagitis in children under the age of 5 years:
Clinical characteristics. Laryngoscope. 2017 Sep 2.

14. I più comuni allergeni alimentari e
ambientali rappresentati
• Albume (39.7%)
• LV (36.5%)
• Arachidi (34.9%)
• Pelo di animale (15.1%)
• Pollini (11.1%).
Sun RW et al. Eosinophilic esophagitis in children under the age of 5 years:
Clinical characteristics. Laryngoscope. 2017 Sep 2.

17. FPIES acuta: clinica e diagnosi differenziale
Michelet M et al. Food protein-induced enterocolitis syndrome - a review of the
literature with focus on clinical management. J Asthma Allergy. 2017;10:197-
207.

18. FPIES cronica: criteri diagnostici
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

19. Alimenti trigger nei vari Paesi: rosso più comuni
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.
ItaliaSpagna
Sud
Corea
IsraeleUKAUUSA
LV
Soia
Riso
Pesce

20. Selezione degli alimenti in FPIES
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

21. Presentazione di sospetta APLV non IgE nel I anno
Venter C et al. Better recognition, diagnosis and management of non-IgE-mediated
cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk
Allergy in Primary Care) guideline. Clin Transl Allergy. 2017;23;7:26.

22. APLV lieve e moderata non IgE mediata
Venter C et al. Better recognition, diagnosis and management of non-IgE-mediated
cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk
Allergy in Primary Care) guideline. Clin Transl Allergy. 2017;23;7:26.

23. Come confermare le
APLV non IgE mediate

24. Trillo Belizón C et al. Faecal calprotectin as an aid to the diagnosis of non-IgE
mediated cow's milk protein allergy. An Pediatr (Barc). 2015 Sep 2.
Faecal calprotectin and diagnosis

25. Hochwallner H, et al. Patients suffering from non-IgE-mediated cow's milk
protein intolerance cannot be diagnosed based on IgG subclass or IgA
responses to milk allergens. Allergy. 2011;66:1201-7.
Diagnosi: né sottoclassi IgG, né IgA

26. The low sensitivity for APT
Soares-Weiser K et al. EAACI Food Allergy and Anaphylaxis Guidelines Group. The
diagnosis of food allergy: a systematic review and meta-analysis. Allergy 2014;69:76-86.

28. Practice parameters: APT sì per EE
• Summary Statement 35
Although routine use of atopy patch tests for
diagnosis of food allergy is not recommended,
the use of food atopy patch tests in patients with
pediatric eosinophilic esophagitis (EoE) have
been demonstrated to be valuable in assessing
potential food triggers. [Strength of
recommendation: Moderate; C Evidence]
Sampson HA et al. Food allergy: A practice parameter update-2014. J Allergy Clin
Immunol. 2014;134:1016-25.

29. Review più recente: APT nì per EE
Lin SK et al. A review of the evidence linking eosinophilic esophagitis and food
allergy. Allergy Asthma Proc. 2015 ;36:26-33.
Although several
studies in children and
adults support
considering EoE a form
of food allergy, the
usefulness of skin-prick
testing and atopy patch
testing for food allergies
and the optimal
elimination diet for
disease management
are still uncertain.

30. Segni radiologici ed endoscopici in EoE
Liacouras CA et al. Eosinophilic esophagitis: updated consensus recommendations for
children and adults. J Allergy Clin Immunol. 2011;128:3-20.e6;

32. Istologia nell’EoE
Liacouras CA et al. Eosinophilic esophagitis: updated consensus recommendations for
children and adults. J Allergy Clin Immunol. 2011;128:3-20.e6;

33. Mehta P et al. Eosinophils in Gastrointestinal Disorders: Eosinophilic Gastrointestinal
Diseases, Celiac Disease, Inflammatory Bowel Diseases, and Parasitic Infections.
Immunol Allergy Clin North Am. 2015 ;35:413-37.
Ma quanti devono essere gli eosinofili?

34. L’evoluzione é verso la stenosi: EoE é una malattia progressiva
Dellon ES et al. A phenotypic analysis shows that eosinophilic esophagitis is a
progressive fibrostenotic disease. Gastrointest Endosc. 2014 ;79:577-85.

35. Numero normale di eosinofili

36. L’eosinofilia periferica è presente
ma non dirimente. La diagnosi si
pone con il referto di una
dettagliata conta degli eosinofili o
per distretto esofageo o GI

37. APLV in due neonati e massivo sangue nelle feci
Hirose R et al. Pediatr Surg Int 2006;22:935-8.

38. Ipotesi: e se la gastroenterite
eosinofila precedesse le MICI?
Mutalib M et al. Eosinophilic gastrointestinal disease and inflammatory bowel
disease in children: is it a disease continuum? Eur J Gastroenterol Hepatol.
2015;27:20-3.
Infiammazione eosinofila del colon Malattia di Crohn

39. Anche nei neonati e nei lattanti
possono verificarsi disordini
eosinofili gastrointestinali

40. Patogenesi della FPIES
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

41. Diagnosi differenziale
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

42. FPIES acuta: criteri diagnostici: 1+ 3
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

43. Tpo: criteri diagnostici
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

44. Come comportarsi a casa
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

45. FPIES e allergie concomitanti
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

46. Come scegliere il latte nelle
APLV non IgE mediate

47. Milk intolerance: risks of inappropriate diet
• Malnutrition
• High cost to the family and society
• Anxiety in the family
• Overprotection of the child
• Alteration of family dynamics
social isolation of the family
• Anguish

48. Non bevono latte ma assumono formaggi
• The study found that 22.2% (260 of 1173) of responders from
Campania do not drink milk, and 18.1% (213 of 1173) drink
lactose-free milk, mainly because of gastrointestinal symptoms.
• The vast majority of the sample population chose to avoid
consuming milk without undergoing the breath test for lactose
intolerance or consulting a doctor.
• The population sample does not avoid dairy products; rather,
they seem to be consumed quite frequently.
• The data support the need for mandatory implementation of a
nutritional campaign to increase understanding regarding, for
example, unnecessary avoidance of milk and excessive
consumption of cheese.
Zingone F et al. Consumption of milk and dairy products: Facts and figures. Nutrition.
2017;33:322-325.

49. Meyer R et al. The impact on quality of life on families of children on an
elimination diet for Non-immunoglobulin E mediated gastrointestinal food
allergies. World Allergy Organ J. 2017;10:8.
Patient demographics

50. Meyer R et al. The impact on quality of life on families of children on an
elimination diet for Non-immunoglobulin E mediated gastrointestinal food
allergies. World Allergy Organ J. 2017;10:8.
Family Impact Module (FIM)

51. Diagnosi corrette: palatabilità delle formule
Miraglia Del Giudice M et al. Flavor, relative palatability and components of cow's milk
hydrolysed formulas and amino acid-based formula. Ital J Pediatr 2015;41:42.

52. Maslin K et al. Cows’ milk exclusion diet during infancy: Is there a long-term effect on children’s
eating behaviour and food preferences?. Pediatr Allergy Immunol. 2016;27:141-6.
Proseguono evitando cibi nuovi

53. Fiocchi A, Schunemann
H. Diagnosis and
Rationale for Action
against Cow’s Milk
Allergy. The WAO
DRACMA guideline.
WAO Journal & Pediatr
Allergy Immunol 2010;
S1, 1-105.

54. Specie negli adolescenti, è molto
difficile la compliance alimentare per
la dietoterapia di esclusione

55. Henderson CJ, et al. Comparative dietary therapy effectiveness in remission of
pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2012;129:1570-8.

56. Conclusioni
• La QoL dei bambini con APLV non IgE mediata é peggio di
quanto si pensi
• La diagnosi viene condotta con l’eliminazione delle PLV, con il
miglioramento/risoluzione della sintomatologia e con la ripresa
degli stessi segni/sintomi con la reintroduzione delle PLV
• APT confinato a scopi di ricerca
• Non eliminare mai PLV solo sulla scorta di APT+
• Per la diagnosi di FPIES acuta basta 1 segno clinico maggiore
e 3 minori
• La diagnosi di Esofagite eosinofila si pone con il riscontro, in
corso di EGDS, di > 15 eosinofili/HPF nei 3 tratti dell’esofago
• Per la terapia sostitutiva fare riferimento alle linee guida
DRACMA, elaborate con il GRADE, che saranno aggiornate a
breve

57. I criteri diagnostici
• The diagnosis of FPIES requires that a patient meets the major criterion
and at least 3 minor criteria.
• If only a single episode has occurred, a diagnostic oral food challenge
should be strongly considered to confirm the diagnosis, especially since
viral gastroenteritis is so common in this age group.
• Further, while not a criterion for diagnosis, it is important to recognize that
acute FPIES reactions will typically completely resolve over a matter of
hours, compared to with the usual several-day course required for
resolution of gastroenteritis.
• The patient should be asymptomatic and growing normally when the
offending food is eliminated from the diet.
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

58. Terapia degli episodi acuti
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

59. Morita H et al. Food protein-induced enterocolitis syndromes with and without
bloody stool have distinct clinicopathological features. J Allergy Clin Immunol.
2017 Jun 16.
FPIES: cambia se è presente ematochezia

60.  98 pazienti con EoE (≤ 21 anni)
 No steroidi orali o topici (spray)
 2 consecutive EGDS per
monitorare dietoterapia
 3 dietoterapie per EoE
– 49 Dieta Elementare
– 26 Six food elimination diet
– 23 dieta in base ai test di
sensibilizzazione allergica
Henderson CJ, et al. Comparative dietary therapy effectiveness in remission of
pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2012;129:1570-8.
EGDS: conta degli eosinofili pre e post dieta. Le 3 diete
più prescritte: bene tutte e 3. Significativa solo la prima

62. Alimenti trigger nei vari Paesi: rosso più comuni
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.

63. > 15 eosinofili/CM a tre livelli
dell’esofago
Papadopoulou A et al. ESPGHAN Eosinophilic Esophagitis Working Group and the
Gastroenterology Committee. Management guidelines of eosinophilic esophagitis in
childhood. J Pediatr Gastroenterol Nutr. 2014 ;58:107-18.

64. I criteri diagnostici della FPIES
Michelet M et al. Food protein-induced enterocolitis syndrome - a review of the
literature with focus on clinical management. J Asthma Allergy. 2017;10:197-
207.

65. FPIES: fenotipi acuti e cronici
Nowak-Węgrzyn A. et al. Food Protein-Induced Enterocolitis Syndrome. J
Investig Allergol Clin Immunol. 2017;27:1-18.