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eosinophilic esophagitis ( ee ) is defined as a primary clinicopathologic disorder of the esophagus characterized by esophageal and/or upper gastrointestinal tract symptoms , whose clinical findings in adults include food impaction and dysphagia , whereas feeding intolerance and symptoms consistent with gastroesophageal reflux disease ( gerd ) are more frequently observed in children .
the key histological finding is an eosinophilic infiltration of the esophageal mucosa with more than 15 intraepithelial eosinophils / high - power field ( hpf ) in one or more biopsies , and a dense esophageal eosinophilia is often described in association with severe squamous epithelial hyperplasia , whereas the gastric and duodenal mucosae are spared .
moreover , a diagnostic requirement is the absence of gerd , which can be assessed with an esophageal ph monitoring study or after a high - dose proton pump inhibitor ( ppi ) treatment .
the correlation between ee , atopy , aeroallergen polysensitization and food allergens has been well documented ; indeed , a correlation between food allergens and ee was first demonstrated by kelly et al . who observed that an elemental diet improved clinical and histological findings in 10 children with ee .
these findings were subsequently confirmed by other authors . although an increasing number of children and adults are diagnosed as suffering from ee , only few controlled trials have been performed to guide clinical management ;
thus , clinical practice is largely based on limited data and experts ' opinions . here
we report the case of a 2-year - old child who was diagnosed with ee with an atypical clinical presentation and an unusual diagnostic course .
a 2-year - old child was referred to the pediatric surgical department of spedali civili of brescia complaining of dry cough with nocturnal exacerbations in the last 6 months , associated with retching and failure to thrive .
she had previously been diagnosed with atopic dermatitis and persistent rhinoconjunctivitis ; peripheral eosinophil count was normal .
due to a suspicion of gerd , 24-hour esophageal ph monitoring was performed resulting in a pathologic reflux index ( 12% ) , and a 3-month high - dose treatment with ppi ( esomeprazole 2 mg / kg / day ) was prescribed , without clinical improvement .
an esophagogastroduodenoscopy ( egds ) was carried out ; esophageal linear furrows were observed and an eosinophilic infiltration of the esophageal mucosa ( > 20 eosinophils / hpf ) was evident at histology ( fig .
1a - c ) , whereas gastric and duodenal findings were endoscopically and histologically normal . on these grounds
the possibility of ee was raised , and the patient was referred to the allergy unit of this hospital .
perennial and seasonal aeroallergens and food - specific serum ige ( cap system , phadia , uppsala , sweden ) were absent and skin prick tests for common aeroallergens were negative . since ee in children
is often associated with food allergy , and although in vitro tests with commercially available food extracts were negative , prick to prick skin tests with fresh foods were performed . however , only a very weak sensitization to tomato was detected and solanaceae exclusion from the diet did not result in any clinical improvement . nevertheless , since acute episodes appeared closely related to food intake and since milk and egg are reported among the main causative food in ee , a restricted dietary regimen was implemented , withdrawing milk and eggs .
after 2 weeks of dietary restriction the patient was accidentally exposed to milk proteins as she was fed with sliced carrots that had been prepared with a cheese grater .
after 1 month the patient gained weight and reported a steady and complete resolution of all symptoms , including cough .
egg intake was not followed by clinical relapse , whereas milk dietary reintroduction was no longer attempted . in order to confirm an etiopathogenetic correlation between cow 's milk sensitization and ee , patch tests with cow 's milk proteins
the tests were performed mixing 2% skin prick test commercial extract ( lofarma ) to vaseline .
after 48-hour occlusion , an infiltrated erythematous papula developed at the casein application site . as a result ,
two months later , with the patient completely asymptomatic , an egds with esophageal biopsies was repeated and showed normal - appearing mucosa ; the eosinophilic esophageal infiltration was no longer detectable ( fig .
after 4 months , the patients ate an ice cream made of cow 's milk and persistent intense coughing appeared 3 h later . on that occasion
a follow - up visit was performed 2 years after the diagnosis and the patient reported being completely asymptomatic .
dry cough with nocturnal exacerbations is a symptom described in gerd , usually defined as an atypical manifestation of the condition , but it is not generally found in ee patients , even though a particular subset of patients has emerged with airway manifestations .
the relationship between gerd and ee is not always still , as ee diagnosis requires exclusion of pathologic acid reflux with a ppi trial and/or a normal esophageal ph monitoring , but pathologic acid reflux in ee is described by some authors in a significant proportion of patients . on the other hand , eosinophilic infiltration of esophageal mucosa
is well described in gerd ; thus , the mere finding of a pathologic esophageal ph test can not rule out ee , and the mere presence of an eosinophilic infiltration is not diagnostic of ee .
the diagnostic guidelines developed by gastroenterologists are based on biopsy specimen findings of = 15 eosinophils / hpf , but the maximal number of eosinophils / hpf that is associated with gerd - related esophagitis is still under investigation .
.   underlined that the distinction between ee and gerd can not be reliably performed on histopathologic evidence alone in children with upper aerodigestive symptoms . in our patient the symptom and the result of the ph study led us to suspect gerd and to start treatment with ppi . after a 3-month trial without clinical improvement an egds was advised and ee detected . a possible explanation for the abnormal esophageal acid exposure could be due to a esophageal motility disorder and/or to lower esophageal sphincter incompetence , possibly associated to an inflammatory infiltration , but the literature is discordant about this topic .
we had a definite diagnosis only after a restricted dietary regimen with resolution of symptoms and of esophageal inflammatory infiltration . in gerd chronic cough
is considered the result of acid stimulation of esophageal chemoreceptors or the effect of direct acid irritation of laryngeal mucosa . in our patient acidity
we feel that esophageal eosinophilic inflammation was allergen - mediated ( milk protein ) rather than acid - mediated . in general
, eosinophils have proinflammatory effects , upregulating adhesion systems , mediating cell trafficking , and releasing cytokines , chemokines , lipid mediators and effector proteins .
more in depth , eosinophil cationic proteins participate in tissue damage eventually resulting in fibrosis .
eosinophil major basic protein , the predominant toxic protein found in eosinophilic granules , has been established as a critical cytotoxin in the pathophysiology of asthma and chronic rhinosinusitis .
this protein directly induces mast cell degranulation , airway reactivity and smooth muscle contraction , and increases smooth muscle responsiveness to agonist .
deposition of major basic protein in the esophageal mucosa in patients with ee has been described , although its role in the pathophysiology of this condition has not been explored . in our patient there
might have been an initial esophageal sensitization to milk proteins , with ee occurring on esophageal re - challenge with the same antigen . in this scenario
alternatively , mishra et al .   showed a link between allergic hypersensitivity response in the lung and the esophagus , but to our knowledge there are no previous studies showing a simultaneous esophageal and pulmonary eosinophilia due to food allergen exposure .
indeed , since most patients with ee display positive reactions to foods on skin prick test and/or atopy patch test , a mixed immunopathogenesis , both ige- and cell - mediated , has been postulated .
a traditional allergologic screening only based on in vitro and percutaneous tests would not have been sufficient to identify the responsible food allergen .
an increasing number of children , usually with gastrointestinal symptoms , is diagnosed with eosinophilic esophagitis ( ee ) , and a particular subset of these patients complains of airway manifestations . 
 we present the case of a 2-year - old child with chronic dry cough in whom ee was found after a first diagnosis of gastroesophageal reflux disease ( gerd ) due to pathological 24-hour esophageal ph monitoring . 
 traditional allergologic tests were negative , while patch tests were diagnostic for cow 's milk allergy . 
 we discuss the intriguing relationship between gerd and ee and the use of patch test for the allergologic screening of patients .