Paediatric eosinophilic oesophagitis: Towards early diagnosis and best treatment

Digestive and Liver Disease 38 (2006) 245–251

Alimentary Tract

Paediatric eosinophilic oesophagitis: Towards early diagnosis and best treatment P. De Angelis a,∗ , J.E. Markowitz c , F. Torroni a , T. Caldaro a , A. Pane a , G. Morino b , R. Sforza Wietrzykowska b , G. Federici di Abriola a , A. Ponticelli a , L. Dall’Oglio a a

Digestive Surgery and Endoscopic Unit, Pediatric Hospital ‘Bambino Gesu’, Piazza S. Onofrio, 4, IRCCS, 00189 Rome, Italy b Dietology, Pediatric Hospital ‘Bambino Ges` u’, IRCCS, Rome, Italy c Children’s Hospital of Philadelphia, USA Received 6 April 2005; accepted 29 August 2005 Available online 29 September 2005

Abstract Eosinophilic oesophagitis is an emerging disease, well known also in paediatric age, probably caused by both IgE and non-IgE mediated food allergies, diagnosed by upper endoscopy with biopsy. The most severe complication is oesophageal stenosis. The identification of the offending allergens is often difficult; therapy is focused to eliminate the supposed antigenic stimulus, to control the acute symptoms and to induce long-term remission. Aim. We report the clinical outcome and the typical endoscopic findings of children and adolescents affected by eosinophilic oesophagitis, referring a proposal of diagnostic and treatment protocol. Patients and methods. Twelve patients, affected by eosinophilic oesophagitis with a histological diagnosis, underwent radiographic upper gastro-intestinal series, 24 h pH-probe and standardised allergic testing; they were treated with steroids (oral prednisone and swallowed aerosolised fluticasone) and elimination diet. Dilations were performed when eosinophilic oesophagitis was not yet diagnosed, or in patients resistant to conventional treatment. Results. Two patients were lost to follow up (mean follow up: 1 year 11 months); seven patients have no symptoms and normal histology, five of them on restricted diet (without cow’s milk protein) and two patients on elemental diet (amino acid formula). In two patients (no allergens identified), mild dysphagia and eosinophilic infiltration persist; one patients underwent Nissen fundoplication for Barrett’s oesophagus: he has no symptoms and normal oesophagus, on restricted diet (without cow’s milk/eggs protein and wheat). Conclusion. The recognition of typical endoscopic picture with careful biopsies extended to the whole oesophagus, even in emergency, could more quickly lead to the correct diagnosis and avoid severe complications of eosinophilic oesophagitis in children, as stricture and failure to growth. Elimination diet is the key of resolution when the allergens are identified. A great challenge remains the relation between gastro-oesophageal reflux disease and eosinophilic oesophagitis, which should however be explained. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Eosinophilic oesophagitis; Oesophageal stenosis; Treatment

1. Introduction Eosinophilic oesophagitis (EoE) is an inflammatory chronic disease, often mistaken for reflux oesophagitis [1]. EoE is characterised by periods of remission and relapses. ∗

Corresponding author. Tel.: +39 06 685 92 841; fax: +39 06 685 92 543. E-mail addresses: [email protected], [email protected] (P. De Angelis).

The clinical features are heterogeneous, varying from mild and non-specific symptoms such as regurgitation, vomiting and epigastric pain, to food impaction, dysphagia, anorexia and failure to thrive; these signs are sometimes related to a real oesophageal stenosis or to rigidity of the oesophageal wall caused by eosinophilic infiltration, which has been shown by endoscopic ultrasonography (EUS)[2]. The severity of endoscopic and clinical expression of EoE is likely determined by duration of the disease. The correct

1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2005.08.004

246

P. De Angelis et al. / Digestive and Liver Disease 38 (2006) 245–251

diagnosis is always based on demonstrating dense infiltration by eosinophils in oesophageal mucosa (typically more than 15–20 eosinophils per microscopic high-power field, HPF) regardless of location (mid or distal oesophagus). Evaluation with pH-probe monitoring does not demonstrate significant gastro-oesophageal reflux disease (GERD), and patients are unresponsive or partially responsive to antiacid therapy, either medical or surgical [1]. It is now accepted that findings are almost universally related to food hypersensitivity, but as with eosinophilic gastro-enteritis, there may be an immune dysregulatory component [3]. A major difficulty in treatment is the identification of the offending allergens, because a mixed or a type IV allergic reaction are often involved [1,3]. Ideally, therapy is limited to elimination of allergens which induce the inflammatory reaction, but this approach is often difficult. The evaluation of a patient with EoE must include a search for food and environmental allergies, through a comprehensive history and physical, and IgEbased blood and/or skin prick tests. Commonly, skin patch testing is useful in those with non-IgE mediated sensitivities and is often a necessary component of the allergy evaluation; formal food challenge often confirms the diagnosis [4]. Therapy is focused to eliminate the presumed allergens with dietary restriction, which should treat the acute symptoms and induce long-term remission [5–7]. However, adherence to a restricted diet in children and in adolescents may be difficult to manage, leading to poor compliance and consequent persistence of disease. The aim of our study is to report the outcome of a series of paediatric patients, referring our treatment protocol, which expresses a dynamic process towards the research of the best therapy.

They underwent upper endoscopy (Olympus GIF160 and XP160) with multiple biopsies (proximal, mid and distal oesophagus, corpus-antrum of stomach and duodenum) and EUS with radial miniprobe of 20 MHz (UM-BS 20–26R; balloon sheath Olympus MAJ-643-R), for a clinical suspicion of an oesophago-gastric disease. After diagnosis of EoE, the patients underwent radiographic upper gastro-intestinal series, 24-h pH-probe and standardised allergic testing (IgE level, radio-allergosorbent—RAST—testing for IgE antibodies, skin prick and patch tests). The therapy of the acute phase consisted of Savary Gillard dilations (dilator diameter: 5–7–9–11–12.8 mm) in patients not diagnosed yet or in patients with severe stenosis resistant to medical treatment; oral corticosteroids in patients with severe disease (prednisone 1.5 mg/kg twice daily full dosage for 2 weeks and then withdrawn by 10 mg/week); and diet begun together with prednisone (diet restriction without the identified food allergens or trial challenge without the most involved allergens, as cow’s milk proteins, eggs and wheat; elemental diet with amino acid-based formula in patients not responsive to diet restriction or in the youngest patients, maximum for 2 months, with further progressive food reintroduction). Maintenance therapy was composed of swallowed aerosolised fluticasone (two puffs/twice daily on a 220 ␮g/ puff inhaler for 3 months in patients more than 15 kg) and diet restriction, according to food allergy identified. Upper endoscopy with multiple biopsies were repeated after therapy of acute phase, 2 or 3 months later, in case of symptoms relapse, and during progressive food reintroduction.

3. Results 2. Patients and methods In a retrospective and prospective study, we observed 12 patients affected by EoE according to histological criteria.

The characteristics of patients and patients’ outcome are summarised in Table 1 and in Fig. 1. We observed 12 patients (8 male), who presented dysphagia for solids, accompanied by food impaction and slow

Fig. 1. Patients’ outcome.

P. De Angelis et al. / Digestive and Liver Disease 38 (2006) 245–251

247

Table 1 Patients’ characteristics Number of patients

12 (8 male)

Personal history

Allergic disease: 10 patients (83%) Long gap oesophageal atresia: 1 patient GERD: 4 patients

Family history of allergic disease Peripheral eosinophilia Age at symptoms beginning (mean age, range)

8 patients (67%) 8 patients (67%) 5 years 6 months (6 months–17 years)

Symptoms at presentationa

Dysphagia, food impaction, slow growth: 6 patients Epigastric pain, vomiting: 4 patients Heartburn, chest pain: 2 patients

Age at diagnosis (mean age, range)

11 years 5 months (7 months–18 years 10 months)

Upper endoscopy before diagnosis (No.: 8 patients)

Oesophageal stricture and rigidity: 5 patients Distal non-specific oesophagitis: 3 patients

Response to PPI

Partially responsive: 3 patients

Upper endoscopy at diagnosis (No.: 12 patients)

White specks and granularity: 4 patients Vertical linear furrow: 6 patients (5 patients of them: rigidity) Concentric rings: 2 patients

Eosinophilic infiltration in biopsy specimens proximal–mid–distal oesophagus Eosinophilic infiltration stomach/duodenum Latency between pre-diagnostic/diagnostic endoscopy 24-h pH-metry High IgE level Positive RAST food and airborne allergens Skin patch test food allergens Follow up a

16–80 eosinophils/HPF (median: 43 cells) Mild mucosal eosinophilia (10 cells) in gastric and duodenal tissue in 1 patient 3 months (1 month–13 months) Brief reflux episodes, normal index 8 patients 8 patients 5 patients (3 of them also RAST food positive) 10 patients (mean time 1 year 11 months)

Some patients had more than one presenting symptom.

growth (6 patients), epigastric abdominal pain and vomiting (4 patients), heartburn and chest pain (2 patients). In four patients past signs of GERD occurred in the first 2 years. One patient had a history of long gap oesophageal atresia, status post repair. Ten patients (83%) presented with personal history of atopy (wheezing, asthma, atopic dermatitis, allergic rhinitis and conjunctivitis). Family history (first-degree relatives) of allergic disease (food allergies, asthma, allergic rhinitis and conjunctivitis, EoE) were found in eight patients (67%). Two patients are cousins. Mean age at beginning of symptoms: 5 years 6 months (range: 6 months–17 years). Upper endoscopy performed in eight patients before diagnosis revealed: oesophageal stricture (less than 9 mm of diameter) in five patients (one focal stricture at proximal, three at mid oesophagus and one diffuse narrowing of the oesophageal lumen; three of whom required endoscopic disimpaction of a food bolus, two of them for real stenosis, the third for rigidity and small calibre, Fig. 2). Three patients presented with non-specific oesophagitis, partially responsive to proton pump inhibitors (PPI). Mean age at diagnosis: 11 years 5 months (range: 7 months–18 years 10 months). Latency between symptomonset and diagnosis: 4 months–13 years (mean: 4 years).

Interval between the pre-diagnostic and diagnostic endoscopy was 3 months (1 month–13 months). Upper endoscopy at diagnosis showed granularity and white specks without erosions in four patients, concentric rings (trachealisation) in two patients, vertical linear furrows

Fig. 2. Endoscopy for a food bolus in the distal oesophagus: linear furrows in oesophageal wall (arrow), as precocious sign of EoE.

248

P. De Angelis et al. / Digestive and Liver Disease 38 (2006) 245–251

Fig. 3. Endoscopy (distal oesophagus): granularity and white specks (arrow).

Fig. 5. Endoscopy (middle oesophagus): multiple concentric rings with normal mucosa (trachealisation).

in six patients, with rigid oesophagus and small calibre in five of them (Figs. 3–5). Biopsy specimens from both proximal, mid and distal oesophagus revealed 16–80 eosinophils/HPF (median concentration: 43 cells) within the squamous epithelium of oesophagus; mucosal eosinophilia was absent in gastric and duodenal tissue of 11 patients, it was mild in one patient. In eight patients (67%) peripheral eosinophilia occurred. In all the patients, 24 h pH-probe monitoring of the distal oesophagus detected brief reflux episodes with normal reflux index. Oesophageal stationary manometry performed only in the first two patients demonstrated completely normal motility. Barium oesophagogram performed at diagnosis was normal in three patients; it showed mild GER in three patients,

hiatal hernia in one patient and oesophageal small calibre and rigidity in five patients, with cervical stricture in one patient, mid stricture in two patients and diffuse narrowing in one patient. EUS with miniprobe detected circumferential, asymmetric thickening of mucosa/submucosa in 10 patients, extending to the muscularis in two patients (Fig. 6). IgE level, RAST and skin prick test for food or airborne allergens were positive in eight patients. Skin patch tests were positive for wheat, cow’s milk protein, eggs in five patients (three of whom also had positive prick test). Two patients were treated by Savary dilation: the first of them before histological diagnosis of EoE, the second one because resistant to medical treatment (mean dilations 3; range: 1–6), with an initial success and further recurrence of stenosis. Two patients, who refused either diet or prednisone, were lost to follow up after endoscopic food disimpaction and simultaneous histological diagnosis of EoE.

Fig. 4. Endoscopy (middle oesophagus): vertical linear furrows (arrow).

Fig. 6. EUS with miniprobe (20 MHz): circumferential and asymmetric thickening of mucosa/submucosa (arrow).

P. De Angelis et al. / Digestive and Liver Disease 38 (2006) 245–251

The mean time of follow up is of 1 year 11 months (range: 7 months–4 years 2 months). Eight patients underwent diet restriction (cow’s milk and eggs proteins, wheat), five patients for documented food hypersensitivity and three as a trial challenge. Two patients, 7 months old and 10 years old, respectively, had amino acid-based formula, the last one after failure of elimination diet. As acute therapy, eight patients were successfully treated with oral prednisone; two patients who immediately responded to diet restriction (one cow’s milk protein, one amino acid-based formula) did not undergo either oral or aerosolised steroids. Initial symptom relief was complete, and endoscopic and histological findings improved significantly in 10 patients. In the same patients, EUS showed normalisation. As maintenance therapy all the patients—except the youngest one (amino acid-based formula) and the other patient who immediately responded to diet—used swallowed aerosolised fluticasone into mouth for 3 months; eight patients are following the elimination diet (cow’s milk and eggs proteins, wheat, amino acid-based formula). This is the outcome of the patients: seven patients remained non-symptomatic, with a documented histological remission, during the follow up; five of them are continuing the elimination diet (cow’s milk proteins) and two the elemental diet (amino acid-based formula); the last two patients are beginning the gradual food reintroduction (this aspect is not analysed in this paper). In two patients (no food allergies identified, on free diet) mild dysphagia persisted and a clinical–histological relapse occurred after 11 months and 2 years, respectively, from diagnosis: they were successfully treated with a second steroid challenge. One patient underwent laparoscopic fundoplication: he presented also with a hiatal hernia with associated GERD dependent on PPI and Barrett’s oesophagus; he is free of symptoms and endoscopic–histological signs of EoE, still following elimination diet (cow’s milk and wheat proteins).

4. Discussion The oesophagus is not only a passive conduit for food, but an active participant in immune responses [8]. EoE is certainly an immune mediated condition, probably caused by an immunological dysregulation, still not completely clarified. The demonstration of clinical, endoscopic and histological response, eliminating some food allergens, allows to explain in the most cases the pathogenesis of the disease. Family and personal history of atopy in patients affected by EoE supports an allergic hypothesis. As in other series, we have seen a male predominance in our population. To date, there remains no clear explanation for this finding, although it is clear from other immune related diseases that sex may confer differential risk; murine models of stress injury show differential activation of neutrophils [9],

249

and even healthy individuals have immune differences that relate to age, race and gender [10]. Before every therapy for EoE, GERD must be always accurately excluded to avoid ineffective antireflux treatment, such as long-standing PPI or fundoplication: oesophageal biopsies performed in the whole oesophagus with accurate evaluation of eosinophilic cell infiltration are mandatory for diagnosis and should be performed in all patients undergoing upper endoscopy regardless of visual findings. The right link between GERD and EoE has not been fully explained, as our patient affected by EoE and Barrett’s oesophagus demonstrated. Long latency between the first observation of symptoms and diagnosis in our early patients is not surprising, as this disease is only now becoming well recognised. In fact endoscopic findings reported before diagnosis did not underline the typical picture and biopsies were not always performed and were often taken only in distal oesophagus. Besides, lag in diagnosis despite previous endoscopies and biopsies, could be explained by non-specified histological report and noncounted eosinophils by the pathologists. Furthermore, we have observed that endoscopic findings should suggest the suspicion of EoE, even at endoscopy performed in emergency for an impacted foreign body. We can at least emphasise the great importance of always obtaining biopsies during endoscopy and consequent histology with the exact degree of eosinophilic infiltration in the biopsy specimens to reach a timely diagnosis. Regarding therapy, oesophageal dilation, which produce mucosal tears and also in our patients transient improvement of dysphagia, should be reserved only to severe strictures unresponsive to steroid or dietary elimination; we could add that after the first two patients treated with Savary dilators, we never needed dilations, because prednisone combined to diet resolved also the most severe oesophageal strictures. Dietary restriction of the appropriate foods is the ideal way to prevent recurrent inflammation and relapse [5]. However, when the causative foods are not readily identified by allergy testing (both patch and prick), complete dietary restriction with an elemental formula is indicated; this may be a difficult proposition in the paediatric or adolescent patient. Corticosteroids are useful to heal the lesions and to resolve the acute symptoms, and may lead to better long-term compliance with elimination diet [3,6]. It is not clear what the true benefit of the maintenance therapy with fluticasone is at this time; recent data suggests symptomatic improvement instead of complete healing, and a high risk of relapse when treatment is discontinued. Further, there seems to be a significant risk of oesophageal candidiasis [7,11]. In our patients, the use of fluticasone as a maintenance therapy did not give any complications; probably, it could represent an alternative treatment in those patients without evidence of food allergy, with a severe and documented airborne allergy [12]. Other treatment (i.e. antileukotriens) could be attempted, especially when presumable antigens are unknown, but

250

P. De Angelis et al. / Digestive and Liver Disease 38 (2006) 245–251

Fig. 7. Proposal of diagnostic and therapeutic protocol.

definitive evidence of their effectiveness is still lacking. Further investigations regarding aetiology may lead to better knowledge and to possible utilisation of cytokines implied in EoE, such as interleukin 5 and eotaxin [12]. The antigen that initiates the inflammatory cascade is unique to the individual patients; moreover food allergens, airborne allergens and urban environments could be involved, even if in some patients the standardised allergic testing can be negative and it is very difficult to clear the supposed cause of EoE. Endoscopy with histology remains the only way to monitor for disease response at this time, even if it represent an invasive procedure that should be often repeated in every patients, during the follow up. In the meantime, we propose a protocol to early diagnosis of EoE and to treat better our patients; this synthesis represents the way run in our endoscopic centre, throughout the clinical experience in the early paediatric patients. The issues of the different treatment, always examined by the clinical and histological checks, allowed to improve our approach to disease, reaching to a simple diagnostic and therapeutic tool,

that could be applied in the commonest paediatric conditions (Fig. 7). This new inflammatory disease of XXI century is certainly an interesting challenge, the complexity of which is only now becoming well recognised: a disease with immunological, gastro-enterologic and psychological implications, that calls for investigators from several disciplines to collaborate. Early diagnosis with consequent treatment are desirable to improve quality of life and to prevent severe complications such as stricture and failure to thrive. Conflict of interest statement None declared. List of abbreviations EoE, eosinophilic oesophagitis; EUS, endoscopic ultrasonography; GERD, gastro-oesophageal reflux disease; PPI, proton pump inhibitors.

P. De Angelis et al. / Digestive and Liver Disease 38 (2006) 245–251

Acknowledgements We thank Marisa Bettini and Stella Fiorenza, Nurse of Digestive Surgical and Endoscopic Unit of ‘Ospedale Pediatrico Bambino Ges`u’ (Rome), for their priceless help.

References [1] Liacouras CA. Eosinophilic esophagitis in children and adults. J Pediatr Gastroenterol Nutr 2003;37(Suppl. 1):S23–8. [2] Fox VL, Nurko S, Teitelbaum JE, Badizadegan K, Furuta GT. Highresolution EUS in children with eosinophilic “allergic” esophagitis. Gastrointest Endosc 2003;57:30–6. [3] Markowitz JE, Liacouras CA. Eosinophilic esophagitis. Gastroenterol Clin N Am 2003;32:949–66. [4] Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 2002;109:363–8. [5] Markowitz JE, Spergel JM, Ruchelli E, Liacouras CA. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol 2003;98:777–82.

251

[6] Liacouras CA, Wenner WJ, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998;26: 380–5. [7] Faubion Jr WA, Perrault J, Burgart LJ, Zein NN, Clawson M, Freese DK, et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 1998;27:90–3. [8] Fox VL, Nurko S, Furuta GT. Eosinophilic esophagitis: it’s not just kid’s stuff. Gastrointest Endosc 2002;56:260–9. [9] Adams JM, Adams CA, Xu DZ, Fekete Z, Lu Q, Livingston DH, et al. Sexual dimorphism in the activation of neutrophils by shock mesenteric lymph. Surg Infect 2003;4:37–44. [10] Bartlett JA, Schleifer SJ, Demetrikopoulos MK, Delaney BR, Shiflett SC, Keller SE, et al. Immune function in healthy adolescents. Clin Diagn Lab Immunol 1998;5:105–13. [11] Teitelbaum JE, Fox VL, Twarog FJ, Nurko S, Antonioli D, Gleich G, et al. Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate. Gastroenterology 2002;122:1216–25. [12] Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. Gastroenterology 2003;125:1419–27.

Commentary

Ten years of eosinophilic oesophagitis: Small steps or giant leaps? J.E. Markowitz∗ , C.A. Liacouras Division of Gastroenterology and Nutrition, Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA Available online 7 February 2006

What can be accomplished in 10 years? In May 1961, U.S. President John F. Kennedy addressed the U.S. Congress and issued a challenge: land a man on the moon and deliver him safely back to Earth. By July 1969 the feat was accomplished. Over the past 10 years, eosinophilic oesophagitis (EOE) has grown from an obscure and rarely reported disorder to one of the most important gastrointestinal diseases to affect children. It would have been difficult to predict when Kelly et al. [1] published their case series on the resolution of refractory oesophagitis and reflux symptoms with elemental diet that an explosion of publications would ensue. Nevertheless, the number of publications relating to this disorder seems to be increasing on an exponential basis. For example, using the MEDLINE database, a person searching with the keywords ‘eosinophilic esophagitis’ in the years 1995–1996 would have found three publications. Of the more than 100

∗ Corresponding author. Tel.: +1 215 590 9146; fax: +1 215 590 3606. E-mail address: [email protected] (J.E. Markowitz)

publications that now exist with these keywords, 41 have been published within the last year. Why the dramatic increase in interest in this disease? This is likely a disease that is dramatically increasing in incidence. According to a letter published in the New England Journal of Medicine, a group in Cincinnati are experiencing an explosion in cases [2]. From 1991 to 2003, they were able to identify 315 cases of EOE. However, 97% of these cases were diagnosed since 2000. They calculated an incidence of one new case per 10,000 people aged 19 or less. In our centre, we have experienced a doubling of incident cases in the last 4 years. Several factors likely contribute to this finding. First, because of increased awareness EOE is now more easily recognised by both clinical gastroenterologists and pathologists. In the past, many patients presenting with GERD symptoms either did not undergo endoscopy or if endoscopy was performed were not biopsied. This practice has changed, and now more patients with refractory GERD are undergoing endoscopy and are biopsied—even when the mucosa appears normal. Previously, when biopsies were obtained, pathologists may have