Pediatr Drugs (2014) 16:391–395 DOI 10.1007/s40272-014-0086-0
ORIGINAL RESEARCH ARTICLE
Oral Viscous Budesonide as a First-Line Approach to Esophageal Stenosis in Epidermolysis Bullosa: an Open-Label Trial in Six Children Andrea Zanini • Sophie Guez • Simona Salera • Giorgio Farris • Anna Morandi Valerio Gentilino • Ernesto Leva • Francesca Manzoni • Maria Angela Pavesi • Susanna Esposito • Francesco Macchini
•
Published online: 20 August 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Esophageal and pharyngeal problems are common in the majority of patients with epidermolysis bullosa (EB). Repeated blister formation and ulceration, coupled with chronic inflammation, result in scarring and development of esophageal strictures. Objective This study aimed to evaluate whether oral viscous budesonide (OVB) was useful for treating esophageal structures in six pediatric patients (aged 8–17 years) with EB who were affected by dysphagia and esophageal strictures. Methods Patients were treated for 4 months with twicedaily oral budesonide nebulizer solution 0.5 mg/2 mL mixed with maltodextrin 5 g and artificial sweeteners. Results One patient developed a severe oral mycotic infection and discontinued treatment. The other five patients completed the treatment regimen and displayed significantly lower stricture indices (SIs) post-treatment (mean SI ± standard deviation 0.736 ± 0.101 pre-treatment versus 0.558 ± 0.162 post-treatment; p = 0.008). Patients experienced a mean SI decrease of 0.178 (range
0.026–0.296), as well as improved dietary habits in the absence of side effects. Conclusion These findings indicated that topical corticosteroids may significantly alleviate strictures in pediatric patients with EB, thereby limiting the need for endoscopic dilation and considerably improving patients’ quality of life.
Key Points Oral viscous budesonide improved esophageal strictures in children with epidermolysis bullosa. Oral viscous budesonide may be recommended for pediatric patients who have epidermolysis bullosa with moderate esophageal problems, in order to eliminate the need for endoscopic dilation. Patient who have epidermolysis bullosa treated with oral viscous budesonide should be monitored for adverse events, since the long-term effects of this treatment are unknown.
A. Zanini G. Farris A. Morandi V. Gentilino E. Leva F. Macchini Pediatric Surgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy S. Guez S. Salera F. Manzoni S. Esposito (&) Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Universita` degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milan, Italy e-mail: [email protected] M. A. Pavesi Pediatric Radiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
1 Introduction Inherited epidermolysis bullosa (EB) encompasses several distinct skin and mucosal diseases, which are separated into four major groups by genetic and clinical characteristics [1]. Dystrophic EB and Kindler disease are two types of inherited EB and are caused by mutations in the collagen type VII alpha 1 (COL7A1) and fermitin family member 1
392
(FERMT1; also known as KIND1) genes, respectively. These mutations reduce synthesis of essential components (i.e., type VII collagen) for anchoring fibrils at the dermal– epidermal junction, resulting in increased skin and mucosae frailty and development of extensive blisters with soft tissue scarring from even minor trauma [1]. Esophageal and pharyngeal problems are common in the majority of these patients. Repeated blister formation and ulceration, coupled with chronic inflammation, result in scarring and development of esophageal strictures [2]. These strictures are primarily located in the proximal esophagus and can become severe enough to impede swallowing. Periodic fluoroscopy-assisted pneumatic balloon dilation is the treatment of choice for strictures in patients with EB, since it involves minimal instrumentation, which reduces the risk of mechanical shearing trauma [3, 4]. A minority of patients (i.e., those with the mildest problems) can limit the need for treatment by adopting dietary modifications—e.g., by eating soft foods [5]. Surgery is recommended only in the case of perforation or total obstruction, since colonic interposition for esophageal replacement or resectioning of a localized esophageal segment are major surgical procedures with considerable morbidity and mortality risks [6]. However, despite being immediately effective in most cases, esophageal dilation has poor long-term outcomes, and the majority of patients with EB require regular pneumatic stretches every few months [7]. Oral administration of some drugs (i.e., phenytoin, verapamil, systemic corticosteroids) has been attempted in order to reduce the frequency of the required dilations, but satisfactory results have been observed only in a minority of patients [8, 9]. Topical administration of corticosteroids has been shown to be effective for treating eosinophilic esophagitis—a chronic condition characterized by severe tissue inflammation, which can lead to esophageal fibrosis and strictures [10]. Thus, oral viscous budesonide (OVB) may be useful for treating esophageal problems in patients with EB. In one study, administration of OVB to two children with EB led to reduced dysphagia and a lower rate of recurrence of esophageal stricture formation [11]. However, despite these favorable results, no other studies have evaluated the efficacy of topical corticosteroids in patients with EB and esophageal strictures. In this study, we administered OVB to six pediatric patients with EB and esophageal strictures.
2 Patients and Methods Patients with EB were followed regularly between January and December 2013 at the Epidemolysis Bullosa Referral Center of the Fondazione IRCCS Ca’ Granda Ospedale
A. Zanini et al.
Maggiore Policlinico (Milan, Italy). Patients who had dysphagia and exhibited signs and symptoms of esophageal strictures were considered potentially eligible for our study. However, patients were excluded if they were receiving drugs (particularly systemic corticosteroids or proton pump inhibitors) or if they underwent surgical procedures, such as endoscopic dilation, within 1 month prior to study enrollment. The parent(s) or legal guardian(s) of eligible patients provided written informed consent, and patients older than 8 years also provided written assent. The study protocol was approved by the Ethics Committee of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and the study was performed in accordance with the standards of Good Clinical Practice for trials of medicinal products in humans. All enrolled patients underwent a contrast esophagram. The presence and severity of esophageal strictures were evaluated by an independent, blinded radiologist. The severity of a stricture was assessed by calculation of its stricture index (SI) [12]; the SI was defined as the ratio between the diameter of the esophagus above the stenosis and the diameter of the stricture. The SI was calculated as A – a/A, where ‘‘A’’ is the diameter of the esophagus above the stenosis, and ‘‘a’’ is the diameter of the stricture. The widest point of the stricture was used to prevent overestimation of the severity of the stenosis due to concomitant peristalsis. The SI was calculated for both the anterior–posterior view and the lateral view, and the highest SI for each patient was used. Children with an SI between 0.3 and 0.9 were treated with topical corticosteroids; those with an SI \0.3 were enrolled only for followup; and those with an SI [0.9 were referred for endoscopic esophageal dilatations. Topical corticosteroid therapy consisted of 4 months of twice-daily oral budesonide nebulizer solution 0.5 mg/ 2 mL mixed with maltodextrin 5 g and artificial sweeteners. Patients were not allowed to eat or drink for 30 min post-ingestion. Anamnestic and clinical data on the patient’s food history were collected by the parents before study enrollment and weekly with clinical visits during study follow-up. Parents were asked about the patient’s duration of meals, frequency of vomiting or regurgitation, and any observed improvements in eating of solid foods. Pharyngeal secretions and feces were collected and cultured before study enrollment, after each month during follow-up, and at the end of treatment, in order to monitor intestinal flora or fungal super-infection. Another contrast esophagram was conducted after 4 months of treatment. Although only six patients were studied, pre- and posttreatment SIs were compared using a two-sided Student’s t test. A p value \0.05 was considered statistically significant.
Oral Viscous Budesonide in Epidermolysis Bullosa
393
Figure 1 shows esophagrams performed in Patient 3 pre- and post-treatment; this patient experienced a significant reduction in the size of her proximal esophageal stricture post-treatment.
3 Results Six pediatric patients (three males and three females; aged 8–17 years) with EB and dysphagia were enrolled in the study and were treated with OVB for 4 months. Five patients had dystrophic EB and one had Kindler disease; the patients had SIs between 0.3 and 0.9 pre-treatment. One patient did not complete the study protocol, because he developed a severe oral mycotic infection due to Candida albicans after 2 weeks of topical corticosteroid therapy. Candidiasis was diagnosed on clinical inspection of the oral region by the clinical team during the visit: the patient was treated with a topical antimycotic preparation and was cured in about 1 week. Five patients completed the study protocol and were included in this evaluation of treatment efficacy. Six strictures (five proximal and one distal) were evaluated; one patient presented with two concomitant stenoses: one at the proximal region and one in the distal region of his esophagus. SIs were significantly lower post-treatment (mean SI ± standard deviation 0.736 ± 0.101 pre-treatment versus 0.558 ± 0.162 post-treatment; p = 0.008; Table 1). Patients experienced a mean SI decrease of 0.178 (range 0.026–0.296), with a mean percentage improvement of 24.2 % (range 3.4–36.1 %). Three patients reported progressively reduced time needed to consume food and increased food intake. Two patients reported no longer vomiting or regurgitating food. All patients reported an increase in the consistency of foods they could eat and were able to include foods such as bread, focaccia, pasta, and meat in their diets; their previous diets had been predominantly based on pureed and semi-solid foods. None of the patients experienced changes in their bowel movements or required endoscopic dilation. The pharyngeal and intestinal microbiota of the patients also did not exhibit any significant variations, and no fungal overgrowths were observed. None of the patients had difficulties with OVB ingestion.
4 Discussion We found that topical corticosteroids may significantly alleviate stricture formation in pediatric patients with EB, thereby limiting the need for endoscopic dilation and considerably improving patients’ quality of life. In this study, we administered OVB to patients with signs and symptoms of esophageal stricture, for whom endoscopic dilation could have been recommended. OVB was administered to those with moderate to severe stenosis, and the five patients who completed 4 months of treatment experienced significant clinical and radiological improvements without needing endoscopic dilation. Thus, OVB appears to delay the need for invasive esophageal treatment in patients with EB, in addition to imparting other significant benefits. Reducing the number of required esophageal dilations limits the damage to the esophageal tissue caused by the procedure, which can also increase the risks of fibrosis and strictures. Furthermore, reducing the number of procedures helps to promote adequate caloric intake in children with EB, which also has beneficial effects, since malnutrition can delay wound healing and can lead to rapid tissue deterioration [11]. Chronic inflammation, which likely results from repeated mechanical trauma from the passage of food, plays an important role in conditioning esophageal lesions in patients with EB, which regularly develop into strictures. Consequently, administration of strong anti-inflammatory drugs, such as topical corticosteroids, can be an effective treatment. Systemic steroids cannot be administered long term, since they cause severe adverse events; however, topical administration of a
Table 1 Variation in the stricture index (SI) and dietary habits before and after 4 months of oral viscous budesonide (OVB) treatment Patient
Gender
Age, years
SI PreOVB
PostOVB
SI difference
Meal duration, min
Vomiting/ regurgitation
PreOVB
PostOVB
Pre-OVB
New solid foods added to diet
Improved food intake
PostOVB
Post-OVB
Post-OVB
1
Male
17
0.772
0.580
0.192
[60
30–60
No
No
Brioches, focaccia
?
2
Male
8
0.640
0.371
0.269
[60
[60
3–4 times daily
No
Meat
???
3
Female
10
0.820
0.524
0.296
30–60
\30
No
No
Pasta, meat
?
4
Male
13
0.580
0.392
0.188
30–60
\30
No
No
Rice, pasta, ham
??
0.822
0.729
0.093
5
Female
16
0.782
0.756
0.026
30–60
30–60
Once weekly
No
Bread
??
? improvement of 25–50 % in food intake, ?? improvement of 50–75 % in food intake, ??? improvement of 75–100 % in food intake
394
A. Zanini et al.
Fig. 1 Esophagrams performed in Patient 3 (a) pre-treatment and (b) post-treatment with oral viscous budesonide (OVB). In each picture, the difference between the diameter of the dilated esophagus above the stenosis (arrow) and the diameter of the stricture (asterisk) is shown. The stricture index (SI) is calculated considering the esophageal diameters at these levels
compound with relatively poor absorption can significantly alleviate this issue. OVB has been widely used to treat eosinophilic esophagitis, with good results [10]. This study confirms that administration of OVB also has potential for treatment of esophageal problems in pediatric patients with EB. We note that not all of the problems related to OVB use were addressed in this study. Additional studies of the lowest effective dosage, the long-term safety and efficacy, and the best delivery vehicle for OVB are needed. Since EB is rare, the randomized controlled trials needed to address these issues are unlikely to be performed. Thus, any physicians who intend to administer OVB in accordance with this study and the study by Dohil et al. [11] should carefully monitor their patient’s health to avoid inducing relevant clinical problems. Children with asthma treated with inhaled budesonide have been shown to have delayed linear growth [13]. Furthermore, some subjects experience drug absorption from the respiratory mucosa, which can have a negative impact. The extent of intestinal absorption of the OVB preparation in the patients with EB in this study is unknown. Despite the lack of any apparent influence of OVB on patient growth in this study, the linear growth of subjects receiving OVB for long periods of time must be evaluated. Moreover, the risk of secondary infections, primarily due to fungi, must also be monitored. In this study, we did not observe any significant changes in oral and intestinal flora; however, one patient who was initially treated with OVB developed a severe oral fungal infection, which led to treatment discontinuation. Mycoses are common in patients receiving topical steroids for bronchial obstructions [14], and the potential issues following oral steroid administration with a viscous preparation require further attention. However, we note that the
incidence of esophageal Candida in patients with eosinophilic esophagitis who were treated with OVB appeared to be relatively low [10]. Finally, the best vehicle for OVB must also be evaluated. A typical preparation of viscous budesonide nebulizer solution is mixed with maltodextrin and artificial sweeteners. Recent studies have suggested use of other components, which are able to confer a slurry-like consistency [15], but it is not clear how long such products can persist on the esophageal mucosa.
5 Conclusion OBV appears to be useful for improving esophageal strictures in children with EB. OBV may be recommended for pediatric patients who have EB with moderate esophageal problems, in order to reduce the need for endoscopic dilation. However, side effects during treatment must be carefully monitored, and data on long-term effects are needed. Acknowledgments This study was supported by a grant from the Italian Ministry of Health (Bando Ricerca Corrente 2014 850/01). The authors declare that they have no conflicts of interest that are directly relevant to the content of this study.
References 1. Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, Marinkovich MP, Martinez AE, McGrath JA, Mellerio JE, Moss C, Murrell DF, Shimizu H, Uitto J, Woodley D, Zambruno G. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014;70:1103–26.
Oral Viscous Budesonide in Epidermolysis Bullosa 2. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. J Am Acad Dermatol. 2009;61:367–84. 3. De Angelis P, Caldaro T, Torroni F, Romeo E, Foschia F, di Abriola GF, Rea F, El Hachem M, Genovese E, D’Alessandro S, Dall’Oglio L. Esophageal stenosis in epidermolysis bullosum: a challenge for the endoscopist. J Pediatr Surg. 2011;46:842–7. 4. Spiliopoulos S, Sabharwal T, Krokidis M, Gkoutzios P, Mellerio J, Dourado R, Adam A. Fluoroscopically guided dilation of esophageal strictures in patients with dystrophic epidermolysis bullosa: long-term results. Am J Roentgenol. 2012;199:208–12. 5. Feuerle GE, Weidauer H, Baldauf G, Schulte-Braucks T, AntonLamprecht I. Management of esophageal stenosis in recessive dystrophic epidermolysis bullosa. Gastroenterology. 1984;87: 1376–80. 6. Demirogullari B, Sonmez K, Turkyilmaz Z, Altuntas¸ B, Karabulut R, Bas¸ aklar AC, Kale N. Colon interposition for esophageal stenosis in a patient with epidermolysis bullosa. J Pediatr Surg. 2001;36:1861–3. 7. Heyman MB, Zwass M, Applebaum M, Rudolph CD, Gordon R, Ring EJ. Chronic recurrent esophageal strictures treated with balloon dilation in children with autosomal recessive epidermolysis bullosa dystrophica. Am J Gastroenterol. 1993;88:953–7. 8. Abahussein AA, Al-Zayir AA, Mostafa WZ, Okoro AN. Recessivedystrophic epidermolysis bullosa treated with phenytoin. Int J Dermatol. 1992;31:730–2.
395 9. Mitchell JD, Eisenberg M. Management of esophageal spasm in epidermolysis bullosa dystrophica using verapamil. J Pediatr Gastroenterol Nutr. 1989;8:133–4. 10. Dohil R, Newbury R, Fox L, Bastian J, Aceves S. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology. 2010;139:418–29. 11. Dohil R, Aceves SS, Dohil MA. Oral viscous budesonide therapy in children with epidermolysis bullosa and proximal esophageal strictures. J Pediatr Gastroenterol Nutr. 2011;52:776–7. 12. Parolini F, Leva E, Morandi A, Macchini F, Gentilino V, Di Cesare A, Torricelli M. Anastomotic strictures and endoscopic dilatations following esophageal atresia repair. Pediatr Surg Intern. 2013;29:601–5. 13. Fuhlbrigge AL, Kelly HW. Inhaled corticosteroids in children: effects on bone mineral density and growth. Lancet Respir Med. 2014;2(6):487–96 (Epub Apr 8). 14. Ellepola ANB, Samaranayake LP. Inhalational and topical steroids, and oral candidosis: a mini review. Oral Dis. 2001;7:211–6. 15. Rubinstein E, Lee JJ, Fried A, Logvinenko T, Ngo P, McDonald D, Hait EJ. Comparison of two delivery vehicles for viscous budesonide to treat eosinophilic esophagitis in children. J Pediatr Gastroenterol Nutr. [Epub 2014 May 11].
ORIGINAL RESEARCH ARTICLE
Oral Viscous Budesonide as a First-Line Approach to Esophageal Stenosis in Epidermolysis Bullosa: an Open-Label Trial in Six Children Andrea Zanini • Sophie Guez • Simona Salera • Giorgio Farris • Anna Morandi Valerio Gentilino • Ernesto Leva • Francesca Manzoni • Maria Angela Pavesi • Susanna Esposito • Francesco Macchini
•
Published online: 20 August 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Esophageal and pharyngeal problems are common in the majority of patients with epidermolysis bullosa (EB). Repeated blister formation and ulceration, coupled with chronic inflammation, result in scarring and development of esophageal strictures. Objective This study aimed to evaluate whether oral viscous budesonide (OVB) was useful for treating esophageal structures in six pediatric patients (aged 8–17 years) with EB who were affected by dysphagia and esophageal strictures. Methods Patients were treated for 4 months with twicedaily oral budesonide nebulizer solution 0.5 mg/2 mL mixed with maltodextrin 5 g and artificial sweeteners. Results One patient developed a severe oral mycotic infection and discontinued treatment. The other five patients completed the treatment regimen and displayed significantly lower stricture indices (SIs) post-treatment (mean SI ± standard deviation 0.736 ± 0.101 pre-treatment versus 0.558 ± 0.162 post-treatment; p = 0.008). Patients experienced a mean SI decrease of 0.178 (range
0.026–0.296), as well as improved dietary habits in the absence of side effects. Conclusion These findings indicated that topical corticosteroids may significantly alleviate strictures in pediatric patients with EB, thereby limiting the need for endoscopic dilation and considerably improving patients’ quality of life.
Key Points Oral viscous budesonide improved esophageal strictures in children with epidermolysis bullosa. Oral viscous budesonide may be recommended for pediatric patients who have epidermolysis bullosa with moderate esophageal problems, in order to eliminate the need for endoscopic dilation. Patient who have epidermolysis bullosa treated with oral viscous budesonide should be monitored for adverse events, since the long-term effects of this treatment are unknown.
A. Zanini G. Farris A. Morandi V. Gentilino E. Leva F. Macchini Pediatric Surgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy S. Guez S. Salera F. Manzoni S. Esposito (&) Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Universita` degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milan, Italy e-mail: [email protected] M. A. Pavesi Pediatric Radiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
1 Introduction Inherited epidermolysis bullosa (EB) encompasses several distinct skin and mucosal diseases, which are separated into four major groups by genetic and clinical characteristics [1]. Dystrophic EB and Kindler disease are two types of inherited EB and are caused by mutations in the collagen type VII alpha 1 (COL7A1) and fermitin family member 1
392
(FERMT1; also known as KIND1) genes, respectively. These mutations reduce synthesis of essential components (i.e., type VII collagen) for anchoring fibrils at the dermal– epidermal junction, resulting in increased skin and mucosae frailty and development of extensive blisters with soft tissue scarring from even minor trauma [1]. Esophageal and pharyngeal problems are common in the majority of these patients. Repeated blister formation and ulceration, coupled with chronic inflammation, result in scarring and development of esophageal strictures [2]. These strictures are primarily located in the proximal esophagus and can become severe enough to impede swallowing. Periodic fluoroscopy-assisted pneumatic balloon dilation is the treatment of choice for strictures in patients with EB, since it involves minimal instrumentation, which reduces the risk of mechanical shearing trauma [3, 4]. A minority of patients (i.e., those with the mildest problems) can limit the need for treatment by adopting dietary modifications—e.g., by eating soft foods [5]. Surgery is recommended only in the case of perforation or total obstruction, since colonic interposition for esophageal replacement or resectioning of a localized esophageal segment are major surgical procedures with considerable morbidity and mortality risks [6]. However, despite being immediately effective in most cases, esophageal dilation has poor long-term outcomes, and the majority of patients with EB require regular pneumatic stretches every few months [7]. Oral administration of some drugs (i.e., phenytoin, verapamil, systemic corticosteroids) has been attempted in order to reduce the frequency of the required dilations, but satisfactory results have been observed only in a minority of patients [8, 9]. Topical administration of corticosteroids has been shown to be effective for treating eosinophilic esophagitis—a chronic condition characterized by severe tissue inflammation, which can lead to esophageal fibrosis and strictures [10]. Thus, oral viscous budesonide (OVB) may be useful for treating esophageal problems in patients with EB. In one study, administration of OVB to two children with EB led to reduced dysphagia and a lower rate of recurrence of esophageal stricture formation [11]. However, despite these favorable results, no other studies have evaluated the efficacy of topical corticosteroids in patients with EB and esophageal strictures. In this study, we administered OVB to six pediatric patients with EB and esophageal strictures.
2 Patients and Methods Patients with EB were followed regularly between January and December 2013 at the Epidemolysis Bullosa Referral Center of the Fondazione IRCCS Ca’ Granda Ospedale
A. Zanini et al.
Maggiore Policlinico (Milan, Italy). Patients who had dysphagia and exhibited signs and symptoms of esophageal strictures were considered potentially eligible for our study. However, patients were excluded if they were receiving drugs (particularly systemic corticosteroids or proton pump inhibitors) or if they underwent surgical procedures, such as endoscopic dilation, within 1 month prior to study enrollment. The parent(s) or legal guardian(s) of eligible patients provided written informed consent, and patients older than 8 years also provided written assent. The study protocol was approved by the Ethics Committee of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and the study was performed in accordance with the standards of Good Clinical Practice for trials of medicinal products in humans. All enrolled patients underwent a contrast esophagram. The presence and severity of esophageal strictures were evaluated by an independent, blinded radiologist. The severity of a stricture was assessed by calculation of its stricture index (SI) [12]; the SI was defined as the ratio between the diameter of the esophagus above the stenosis and the diameter of the stricture. The SI was calculated as A – a/A, where ‘‘A’’ is the diameter of the esophagus above the stenosis, and ‘‘a’’ is the diameter of the stricture. The widest point of the stricture was used to prevent overestimation of the severity of the stenosis due to concomitant peristalsis. The SI was calculated for both the anterior–posterior view and the lateral view, and the highest SI for each patient was used. Children with an SI between 0.3 and 0.9 were treated with topical corticosteroids; those with an SI \0.3 were enrolled only for followup; and those with an SI [0.9 were referred for endoscopic esophageal dilatations. Topical corticosteroid therapy consisted of 4 months of twice-daily oral budesonide nebulizer solution 0.5 mg/ 2 mL mixed with maltodextrin 5 g and artificial sweeteners. Patients were not allowed to eat or drink for 30 min post-ingestion. Anamnestic and clinical data on the patient’s food history were collected by the parents before study enrollment and weekly with clinical visits during study follow-up. Parents were asked about the patient’s duration of meals, frequency of vomiting or regurgitation, and any observed improvements in eating of solid foods. Pharyngeal secretions and feces were collected and cultured before study enrollment, after each month during follow-up, and at the end of treatment, in order to monitor intestinal flora or fungal super-infection. Another contrast esophagram was conducted after 4 months of treatment. Although only six patients were studied, pre- and posttreatment SIs were compared using a two-sided Student’s t test. A p value \0.05 was considered statistically significant.
Oral Viscous Budesonide in Epidermolysis Bullosa
393
Figure 1 shows esophagrams performed in Patient 3 pre- and post-treatment; this patient experienced a significant reduction in the size of her proximal esophageal stricture post-treatment.
3 Results Six pediatric patients (three males and three females; aged 8–17 years) with EB and dysphagia were enrolled in the study and were treated with OVB for 4 months. Five patients had dystrophic EB and one had Kindler disease; the patients had SIs between 0.3 and 0.9 pre-treatment. One patient did not complete the study protocol, because he developed a severe oral mycotic infection due to Candida albicans after 2 weeks of topical corticosteroid therapy. Candidiasis was diagnosed on clinical inspection of the oral region by the clinical team during the visit: the patient was treated with a topical antimycotic preparation and was cured in about 1 week. Five patients completed the study protocol and were included in this evaluation of treatment efficacy. Six strictures (five proximal and one distal) were evaluated; one patient presented with two concomitant stenoses: one at the proximal region and one in the distal region of his esophagus. SIs were significantly lower post-treatment (mean SI ± standard deviation 0.736 ± 0.101 pre-treatment versus 0.558 ± 0.162 post-treatment; p = 0.008; Table 1). Patients experienced a mean SI decrease of 0.178 (range 0.026–0.296), with a mean percentage improvement of 24.2 % (range 3.4–36.1 %). Three patients reported progressively reduced time needed to consume food and increased food intake. Two patients reported no longer vomiting or regurgitating food. All patients reported an increase in the consistency of foods they could eat and were able to include foods such as bread, focaccia, pasta, and meat in their diets; their previous diets had been predominantly based on pureed and semi-solid foods. None of the patients experienced changes in their bowel movements or required endoscopic dilation. The pharyngeal and intestinal microbiota of the patients also did not exhibit any significant variations, and no fungal overgrowths were observed. None of the patients had difficulties with OVB ingestion.
4 Discussion We found that topical corticosteroids may significantly alleviate stricture formation in pediatric patients with EB, thereby limiting the need for endoscopic dilation and considerably improving patients’ quality of life. In this study, we administered OVB to patients with signs and symptoms of esophageal stricture, for whom endoscopic dilation could have been recommended. OVB was administered to those with moderate to severe stenosis, and the five patients who completed 4 months of treatment experienced significant clinical and radiological improvements without needing endoscopic dilation. Thus, OVB appears to delay the need for invasive esophageal treatment in patients with EB, in addition to imparting other significant benefits. Reducing the number of required esophageal dilations limits the damage to the esophageal tissue caused by the procedure, which can also increase the risks of fibrosis and strictures. Furthermore, reducing the number of procedures helps to promote adequate caloric intake in children with EB, which also has beneficial effects, since malnutrition can delay wound healing and can lead to rapid tissue deterioration [11]. Chronic inflammation, which likely results from repeated mechanical trauma from the passage of food, plays an important role in conditioning esophageal lesions in patients with EB, which regularly develop into strictures. Consequently, administration of strong anti-inflammatory drugs, such as topical corticosteroids, can be an effective treatment. Systemic steroids cannot be administered long term, since they cause severe adverse events; however, topical administration of a
Table 1 Variation in the stricture index (SI) and dietary habits before and after 4 months of oral viscous budesonide (OVB) treatment Patient
Gender
Age, years
SI PreOVB
PostOVB
SI difference
Meal duration, min
Vomiting/ regurgitation
PreOVB
PostOVB
Pre-OVB
New solid foods added to diet
Improved food intake
PostOVB
Post-OVB
Post-OVB
1
Male
17
0.772
0.580
0.192
[60
30–60
No
No
Brioches, focaccia
?
2
Male
8
0.640
0.371
0.269
[60
[60
3–4 times daily
No
Meat
???
3
Female
10
0.820
0.524
0.296
30–60
\30
No
No
Pasta, meat
?
4
Male
13
0.580
0.392
0.188
30–60
\30
No
No
Rice, pasta, ham
??
0.822
0.729
0.093
5
Female
16
0.782
0.756
0.026
30–60
30–60
Once weekly
No
Bread
??
? improvement of 25–50 % in food intake, ?? improvement of 50–75 % in food intake, ??? improvement of 75–100 % in food intake
394
A. Zanini et al.
Fig. 1 Esophagrams performed in Patient 3 (a) pre-treatment and (b) post-treatment with oral viscous budesonide (OVB). In each picture, the difference between the diameter of the dilated esophagus above the stenosis (arrow) and the diameter of the stricture (asterisk) is shown. The stricture index (SI) is calculated considering the esophageal diameters at these levels
compound with relatively poor absorption can significantly alleviate this issue. OVB has been widely used to treat eosinophilic esophagitis, with good results [10]. This study confirms that administration of OVB also has potential for treatment of esophageal problems in pediatric patients with EB. We note that not all of the problems related to OVB use were addressed in this study. Additional studies of the lowest effective dosage, the long-term safety and efficacy, and the best delivery vehicle for OVB are needed. Since EB is rare, the randomized controlled trials needed to address these issues are unlikely to be performed. Thus, any physicians who intend to administer OVB in accordance with this study and the study by Dohil et al. [11] should carefully monitor their patient’s health to avoid inducing relevant clinical problems. Children with asthma treated with inhaled budesonide have been shown to have delayed linear growth [13]. Furthermore, some subjects experience drug absorption from the respiratory mucosa, which can have a negative impact. The extent of intestinal absorption of the OVB preparation in the patients with EB in this study is unknown. Despite the lack of any apparent influence of OVB on patient growth in this study, the linear growth of subjects receiving OVB for long periods of time must be evaluated. Moreover, the risk of secondary infections, primarily due to fungi, must also be monitored. In this study, we did not observe any significant changes in oral and intestinal flora; however, one patient who was initially treated with OVB developed a severe oral fungal infection, which led to treatment discontinuation. Mycoses are common in patients receiving topical steroids for bronchial obstructions [14], and the potential issues following oral steroid administration with a viscous preparation require further attention. However, we note that the
incidence of esophageal Candida in patients with eosinophilic esophagitis who were treated with OVB appeared to be relatively low [10]. Finally, the best vehicle for OVB must also be evaluated. A typical preparation of viscous budesonide nebulizer solution is mixed with maltodextrin and artificial sweeteners. Recent studies have suggested use of other components, which are able to confer a slurry-like consistency [15], but it is not clear how long such products can persist on the esophageal mucosa.
5 Conclusion OBV appears to be useful for improving esophageal strictures in children with EB. OBV may be recommended for pediatric patients who have EB with moderate esophageal problems, in order to reduce the need for endoscopic dilation. However, side effects during treatment must be carefully monitored, and data on long-term effects are needed. Acknowledgments This study was supported by a grant from the Italian Ministry of Health (Bando Ricerca Corrente 2014 850/01). The authors declare that they have no conflicts of interest that are directly relevant to the content of this study.
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