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Eosinophilic esophagitis (EoE) represents a chronic, immuneantigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor–responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE.

Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in =1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor–responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid–based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field.

Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field. Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance. The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

Assessment of fecal calprotectin, a surrogate marker of mucosal inflammation, is a promising means to monitor therapeutic response in pediatric inflammatory bowel disease, especially if the result is readily available. We tested the performance of a novel calprotectin rapid test, Quantum Blue, versus the conventional enzyme-linked immunosorbent assay in 134 stool samples from 56 pediatric patients with Crohn disease. The intraclass correlation coefficient analysis reflected good agreement (intraclass correlation coefficient 0.97 95 confidence interval 0.95–0.98) but agreement was better in lower values, where dilutions were not required. Using a cutoff of 100gg for normal values, the percentage agreement between the 2 tests was 87. The optimal cutoff values to guide clinical decisions in the therapy of inflammatory bowel disease have yet to be determined.

Assessment of fecal calprotectin, a surrogate marker of mucosal inflammation, is a promising means to monitor therapeutic response in pediatric inflammatory bowel disease, especially if the result is readily available. We tested the performance of a novel calprotectin rapid test, Quantum Blue, versus the conventional enzyme-linked immunosorbent assay in 134 stool samples from 56 pediatric patients with Crohn disease. The intraclass correlation coefficient analysis reflected good agreement (intraclass correlation coefficient 0.97 [95% confidence interval 0.95–0.98]) but agreement was better in lower values, where dilutions were not required. Using a cutoff of 100 µg/g for normal values, the percentage agreement between the 2 tests was 87%. The optimal cutoff values to guide clinical decisions in the therapy of inflammatory bowel disease have yet to be determined.

This guideline provides recommendations for the diagnosis and management of suspected cow's-milk protein allergy (CMPA) in Europe. It presents a practical approach with a diagnostic algorithm and is based on recently published evidence-based guidelines on CMPA.

This guideline provides recommendations for the diagnosis and management of suspected cow's-milk protein allergy (CMPA) in Europe. It presents a practical approach with a diagnostic algorithm and is based on recently published evidence-based guidelines on CMPA. If CMPA is suspected by history and examination, then strict allergen avoidance is initiated. In certain circumstances (eg, a clear history of immediate symptoms, a life-threatening reaction with a positive test for CMP–specific IgE), the diagnosis can be made without a milk challenge. In all other circumstances, a controlled oral food challenge (open or blind) under medical supervision is required to confirm or exclude the diagnosis of CMPA. In breast-fed infants, the mother should start a strict CMP-free diet. Non–breast-fed infants with confirmed CMPA should receive an extensively hydrolyzed protein-based formula with proven efficacy in appropriate clinical trials; amino acids–based formulae are reserved for certain situations. Soy protein formula, if tolerated, is an option beyond 6 months of age. Nutritional counseling and regular monitoring of growth are mandatory in all age groups requiring CMP exclusion. Patients should be reevaluated every 6 to 12 months to assess whether they have developed tolerance to CMP. This is achieved in >75% by 3 years of age and >90% by 6 years of age. Inappropriate or overly long dietary eliminations should be avoided. Such restrictions may impair the quality of life of both child and family, induce improper growth, and incur unnecessary health care costs.

A revision of criteria for diagnosing coeliac disease (CD) is being conducted by The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In parallel, we have performed a survey aimed to evaluate present practices for CD among paediatric gastroenterologists and to learn their views on the need for modification of present criteria for CD diagnosis.

Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

A revision of criteria for diagnosing coeliac disease (CD) is being conducted by The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In parallel, we have performed a survey aimed to evaluate present practices for CD among paediatric gastroenterologists and to learn their views on the need for modification of present criteria for CD diagnosis. Questionnaires were distributed to experienced paediatric gastroenterologists (ESPGHAN members) via the Internet. Overall, 95 valid questionnaires were available for analysis, pertaining to 28 different countries, with the majority of responders treating patients with CD for >15 years. Only about 12% of the responders comply with present criteria, noncompliance being related mainly to the challenge policy. Approximately 90% request a revision and modification of the present criteria. Forty-four percent want to omit the small bowel biopsy in symptomatic children with positive anti-tissue transglutaminase immunoglobulin (Ig) A or endomysial IgA antibodies, especially if they are DQ2/DQ8 positive. For silent cases detected by screening with convincingly positive anti-tissue transglutaminase IgA or EMA IgA, about 30% consider that no small bowel biopsy should be required in selected cases. Adding human leukocyte antigen typing in the diagnostic workup was asked for by 42% of the responders. As for gluten challenge, a new policy is advocated restricting its obligation to cases whenever the diagnosis is doubtful or unclear. Based on these opinions, revision of the ESPGHAN criteria for diagnosing CD is urgently needed.

Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved.

The increasing number of pediatric patients infected with multiresistant Helicobacter pyloristrains calls for evaluation of treatment regimens. Second-line antibiotics such as tetracycline or quinolones are not licensed for children. Because in vivo resistance to metronidazole may be overcome in vivo by a high dose and prolonged intake, we evaluated the eradication rate and side effects of a high-dose triple therapy in pediatric patients with culture-proven double resistance. In this open multicentre trial, 62 children (<18 years, body weight >15 kg) infected with an H pyloristrain resistant to metronidazole and clarithromycin were treated according to body weight classes with amoxicillin (~75 mg/kg/day), metronidazole (~25 mg/kg/day) and esomeprazole (~1.5 mg/kg/day) for 2 weeks. Adherence and adverse events were assessed by a 2-week diary and telephone interviews at days 7 and 14 of treatment. Primary outcome was a negative 13C-urea breath test after 6 weeks. Of 62 patients, 5 were lost to follow-up, 12 were nonadherent, and 45 treated per protocol. Eradication rates were 66% (41/62) [confidence interval 54–78] (intention to treat) and 73% (33/45) [confidence interval 60–86] (per protocol). Success of treatment was not related to dose per kilogram body weight. Mild to moderate adverse events were reported by 21 patients, including nausea (10.8%), diarrhoea (8.9%), vomiting (7.1%), abdominal pain (5.4%), and headache (3.6%), and led to discontinuation in 1 child. High-dose amoxicillin, metronidazole, and esomeprazole for 2 weeks is a good treatment option in children infected with a double resistant H pyloristrain.

The increasing number of pediatric patients infected with multiresistant Helicobacter pyloristrains calls for evaluation of treatment regimens. Second-line antibiotics such as tetracycline or quinolones are not licensed for children. Because in vivo resistance to metronidazole may be overcome in vivo by a high dose and prolonged intake, we evaluated the eradication rate and side effects of a high-dose triple therapy in pediatric patients with culture-proven double resistance.

ABSTRACTBackground: A 15 year old girl with Prader-Willi Syndrome (PWS) died of gastric rupture. Systematic literature research revealed seven case reports of PWS patients with acute gastric dilatation, two had a lethal course. The objective of this study was to determine if delayed gastric emptying in PWS patients might contribute to gastric dilatation.Methods: Gastric emptying was measured in eight patients with PWS by nucleotid scintigraphy after a standardized test meal.Results: Median age was 17.8 years (range 10.1-19.5). Median BMI of the male patients was 29.5 (range 18.4-34.8), of the female patients 28 (range 20.0-44.8). Half time of gastric emptying was delayed in five of the eight patients (median 78.5 minutes, range 59-134).Conclusion: Scintigraphic measurement of gastric emptying in eight PWS patients revealed delay in comparison to normal values. This might be a risk factor for gastric dilatation and rupture in patients with PWS.

ABSTRACTA modified version of a rapid office based one-step monoclonal immunoassay for detection of Helicobacter pyloriantigen in stool samples from children was evaluated against biopsy specimen-based methods and compared to a monoclonal enzyme immunoassay using the same antigen. Blinded stool samples from 185 children (0.3 to 18.2 years) were investigated at the time of upper endoscopy prior to anti-H. pyloritherapy; 62 children were H. pyloriinfected and 123 noninfected according to predefined reference standards. Samples obtained 6 to 8 weeks after anti-H. pyloritherapy were available from 58 children (3.8 to 17.7 years) and were compared to results of the [13C]urea breath test (14/58 were positive). The rapid stool tests were performed by two independent readers. Of 243 rapid tests performed, 1 (0.4%) was invalid for technical reasons. Equivocal results (very weak line) were reported 16 times by reader 1 and 27 times by reader 2. When equivocal results were considered positive, the two observers agreed on 76 positive and 160 negative results and disagreed on 7 samples (2.9%). The sensitivity was 90.8% for reader 1 and 85.5% for reader 2, and the specificity was 91.0% and 93.4%, respectively. The monoclonal enzyme immunoassay revealed a sensitivity and specificity of 94.7% and 97.6%, respectively. The modified chromatographic immunoassay is a good alternative in settings or situations when the monoclonal enzyme immunoassay or the [13C]urea breath test are not available or feasible. In order to improve sensitivity, very weak lines should be considered positive test results.

ABSTRACTExperimental data from human adults or animal models indicate that the Helicobacter pylori-specific immune response is dominated by inflammatory T cells of the Th1 type. To investigate whether a Th1 immune response is established in early H. pyloriinfection, gastric biopsy samples from 70 children were subjected to immunohistochemical analysis. To this end, T cells, B cells, monocytes, neutrophils, and chemokine receptor 5 (CCR5)-expressing (CCR5+) cells, which are associated with Th1 immune responses, were quantified. Children were classified according to H. pyloristatus and clinical, laboratory, and macroscopic (during endoscopy) findings, without knowledge of histological findings. Group 1 included 31 H. pylori-infected children, group 2 contained 24 children with other conditions possibly affecting the stomach, and group 3 contained 15 children without verifiable pathological findings in the stomach. Lymphoid follicles were present in 90% of biopsy samples from group 1 and 48% of those from group 2 but absent in group 3 biopsy samples. Intraepithelial T cells and CCR5+cells were regularly detected in all groups without significant differences. B cells, monocytes, and neutrophils were not found. In contrast, the numbers of lamina propria T cells (P< 0.003) and CCR5+cells (P< 0.001) were increased significantly in H. pylori-infected children. B cells (in 13 of 66 children) were detected in children with active (n= 11) or previously cleared (n= 2) H. pyloriinfections but were absent in healthy children. The numbers of monocytes (in 10 of 67 children) did not differ among the groups. Calculations indicated that the majority of gastric T cells express CCR5; this finding is in contrast to the low percentage of CCR5+T cells in the peripheral circulation. Thus, an increase in the numbers of CCR5+cells in H. pylori-infected stomach mucosa suggests that this molecule may play an important role in gastric immune responses.

In this paper, a Working Group on Gastro-Oesophageal Reflux discusses recommendations for the first line diagnostic and therapeutic approach of gastro-oesophageal reflux disease in infants and children. All members of the Working Group agreed that infants with uncomplicated gastro-oesophageal reflux can be safely treated before performing (expensive and often unnecessary) complementary investigations. However, the latter are mandatory if symptoms persist despite appropriate treatment. Oesophageal pH monitoring of long duration (18–24 h) is recommended as the investigation technique of choice in infants and children with atypical presentations of gastro-oesophageal reflux. Upper gastro-intestinal endoscopy in a specialised centre is the technique of choice in infants and children presenting with symptoms suggestive of peptic oesophagitis. Prokinetics, still a relatively new drug family, have already obtained a definitive place in the treatment of gastro-oesophageal reflux disease in infants and children, especially if “non-drug” treatment (positional therapy, dietary recommendations, etc.) was unsuccessful. It was the aim of the Working Group to help the paediatrician with this consensus statement and guide-lines to establish a standardised management of gastro-oesophageal reflux disease in infants and children.

A newly developed isotope selective nondispersive infrared (NDIR) spectrometer for the measurement of 13CO2 and 12CO2 concentrations in breath samples was applied as a low cost and very simple to operate alternative to isotope ratio mass spectrometry (IRMS). We used this device for several biomedical applications ([13C]urea breath test, [13C]leucine metabolism, [13C]methacetin catabolism of rats) and found that the results agree very well with IRMS.

Screening for coeliac disease (CD) with serum antigliadin antibodies (AGA) was performed in 1032 diabetic children and adolescents. In 8 children CD had been diagnosed before study entry. Of the remaining 1024 children, 33 had an elevated AGA titre in the first serum sample. On follow-up an elevated AGA titre was confirmed in only 17 of 31 patients. Nine of the repeatedly positive patients underwent jejunal biopsy, and CD was diagnosed in two asymptomatic patients; both were positive for IgG- and IgA-AGA. Among 10 AGA-positive patients in whom biopsies could not be performed, only 1 showed IgA-AGA and thus carried a high risk for CD. From our results we estimate a prevalence of CD in Swiss and German diabetic children between 1.1% and 1.3%. Falsepositive AGA titres occurred significantly more often in patients with diabetes duration of less than 1 year. AGA testing teached a specificity of 99% if performed at least 1 year after the onset of diabetes. Children suffering from both diabetes and CD showed a diabetes manifestation at a significantly younger age than non-coeliac patients, whereas CD tended to be diagnosed at a remarkably late age.

Optimal regimen for insulin therapy should lead to normal longitudinal growth and weight gain in children with diabetes mellitus. However, reports published so far indicate that this goal of paediatric diabetology is currently not achieved in a considerable number of patients. In a cross-sectional sample of 89 children with insulin dependent diabetes mellitus (IDDM) for more than 3 years, we found the relation of height to weight to be significantly different compared to 102 healthy school children of similar age. Using bivariate analysis, body shape in these children with diabetes was shifted towards small and obese (P<0.05) compared to control children. We subsequently initiated a longitudinal study and followed children from the onset of diabetes for the following 3 years, recording height, weight and bone age as well as glycosylated haemoglobin and daily insulin requirement. At diagnosis, height SDS was identical in children with IDDM (+0.04±0.10) compared to control children (−0.07±0.10; M±SE), while weight SDS was −0.26±0.10 in children with diabetes (controls: +0.01±0.1). Bone age was identically retarded in newly diagnosed IDDM children (−0.73±0.12 SDS) and in our control group of children from the same regional background (−0.50±0.12; n.s.). In this group of children with diabetes mellitus followed prospectively, height to weight relationship differed from controls after 2 and after 3 years of the disease (P<0.05). At 2 years, body size in children with diabetes was shifted towards taller and heavier compared to controls, while at 3 years, the relation of height to weight was even more abnormal with increased obesity but a reduction of standardized height. This is the same relation encountered in the cross-sectional sample of children with a duration of diabetes beyond 3 years. These data demonstrate that even modern insulin therapy does not guarantee normal development of height and weight in children with IDDM.

Pharmacologic agents effective in the treatment of Crohn's disease confined to the small intestine are limited. The therapeutic efficacy of oral mesalazine in small bowel inflammation, although theoretically promising, remains unproven. In an open-labeled initial trial, timed-release 5-aminosalicylic acid (5-ASA), administered al a daily dosage of 30.6 ± 9.0 mg/kg (mean ± SEM) to children with active Crohn's disease involving the small intestine, was associated with improvement on the Harvey index in six of 12 patients treated for 8.1 ± 3.9 weeks. In a subsequent prospective, double-blind study 14 children, ages 9.3 to 16.1 years, with active Crohn's disease limited radiologically in the small intestine were randomized to receive either timed-release 5-ASA [50 mg/kg/day (maximum 3 g/day)] or placebo for 8 weeks. Following a 4-week washout period, patients crossed over to receive the other study drug for a further 8 weeks. Six children completed the entire 20-week trial. The van Hees index improved among patients receiving 5-ASA for 8 weeks (Δ = - 18 ± 6.4) but deteriorated among patients given placebo (Δ = 14 ± 4.1) (p < 0.05). Mean Crohn's Disease Activity Index (CDAI) decreased marginally after 8 weeks of 5-ASA treatment (Δ = - 48 ± 38.2) but not with placebo (Δ = - 3.0 ± 7.9) (p = 0.31). Of the eight noncompleters, more patients dropped out of the study because of lack of therapeutic response to placebo (n = 5) than to 5-ASA (n = 2). No serious adverse clinical effects were observed during either trial, but one adolescent girl reported mild hair loss that was promptly reversed after the drug was discontinued. These results indicate that timed-release 5-ASA may be beneficial in the medical therapy of children with active small bowel Crohn's disease.

Pharmacologic agents effective in the treatment of Crohn's disease confined to the small intestine are limited. The therapeutic efficacy of oral mesalazine in small bowel inflammation, although theoretically promising, remains unproven. In an open-labeled initial trial, timed-release 5-aminosalicylic acid (5-ASA), administered al a daily dosage of 30.6 ± 9.0 mg/kg (mean ± SEM) to children with active Crohn's disease involving the small intestine, was associated with improvement on the Harvey index in six of 12 patients treated for 8.1 ± 3.9 weeks. In a subsequent prospective, double-blind study 14 children, ages 9.3 to 16.1 years, with active Crohn's disease limited radiologically in the small intestine were randomized to receive either timed-release 5-ASA [50 mg/kg/day (maximum 3 g/day)] or placebo for 8 weeks. Following a 4-week washout period, patients crossed over to receive the other study drug for a further 8 weeks. Six children completed the entire 20-week trial. The van Hees index improved among patients receiving 5-ASA for 8 weeks (? = - 18 ± 6.4) but deteriorated among patients given placebo (? = + 14 ± 4.1) (p < 0.05). Mean Crohn's Disease Activity Index (CDAI) decreased marginally after 8 weeks of 5-ASA treatment (? = - 48 ± 38.2) but not with placebo (? = - 3.0 ± 7.9) (p = 0.31). Of the eight noncompleters, more patients dropped out of the study because of lack of therapeutic response to placebo (n = 5) than to 5-ASA (n = 2). No serious adverse clinical effects were observed during either trial, but one adolescent girl reported mild hair loss that was promptly reversed after the drug was discontinued. These results indicate that timed-release 5-ASA may be beneficial in the medical therapy of children with active small bowel Crohn's disease.

Background and aims: Atopic eczema generates a high economic burden, eg. 1.2-3.5 billion [euro ] per annum in Germany. The GINI trial, a prospective, randomized, double-blind intervention study in Germany that recruited a cohort of 2,252 infants with parental and/or sibling-related heredity for atopy between 1995 and 1998 showed that children fed with certain hydrolysate formulas at least the first four months of life have a reduction of the relative risk for atopic dermatitis by 26-45% compared to a cow's milk formula. The objective of this study was to assess the cost-effectiveness of feeding hydrolysate formulas in the prevention of atopic eczema.Methods: Cost-effectiveness was assessed with a decision tree model programmed with the software TreeAge. Children were followed over a 6 year period. Costs and effects were analyzed using the perspective of the German statutory health insurance (SHI) and a societal perspective.Results: In the base case scenario both the partial whey hydrolysate and the extensively hydrolysed casein formula-feeding are cost-effective in preventing infantile atopic eczema from a societal perspective. In the sixth year both formulas generated cost-savings. From the SHI perspective, the extensively hydrolysed casein formula was cost-effective and the partial whey hydrolysate cost-saving after six years. The third formula, an extensively hydrolysed whey formula, was dominated in both analyses.Conclusion: Our results show that for the prevention of atopic eczema two formulas can be cost-effective or even cost-saving depending on the scenario.Economic studies indicate that atopic dermatitis generates a high economic burden.