Clinical manifestations and gastrointestinal pathology in 40 patients with autoimmune enteropathy.

Autoimmune enteropathy (AIE) is a rare condition that may affect pediatric and adult patients, frequently associated with primary immunodeficiencies. We performed a retrospective study on clinical and histological findings from 40 AIE patients. Histological presentation showed a prevalent celiac disease pattern (50%), followed by the mixed pattern (35%), independently of age, chronic active duodenitis (10%), and GVHD-like pattern (5%). Patients with primary immunodeficiencies (24/40) presented mainly with the celiac disease pattern (72.2% versus 22.2%; p < .0001), while patients without primary immunodeficiencies presented with a mixed histological pattern (61.1% versus 13.6%; p < .0001). Our study shows that the prevalent histological presentation is the celiac disease-like pattern, independently of age, and, for the first time, that the histological presentation of AIE differs significantly between patients with and without primary immunodeficiencies. These findings may be helpful for more precise and timely diagnosis and management of this rare disorder.

Clinical and Laboratory Features of 184 Italian Pediatric Patients Affected with Selective IgA Deficiency (SIgAD): a Longitudinal Single-Center Study.

PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.

Efficacy and Safety of Adalimumab in Pediatric Ulcerative Colitis: A Real-life Experience from the SIGENP-IBD Registry.

OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with ulcerative colitis (UC) previously treated with infliximab (IFX). METHODS: Retrospective study including children with UC from a national registry who received ADA therapy. The primary endpoint was the rate of corticosteroid-free remission at week 52. Secondary outcomes were the rate of sustained clinical remission, primary nonresponse, and loss of response at weeks 12, 30, and 52 and rate of mucosal healing and side effects at week 52. RESULTS: Thirty-two children received ADA (median age 10 ±â€Š4 years). Median disease duration before ADA therapy was 27 months. All patients received previous IFX (43% intolerant, 50% nonresponders [37.5% primary, 42.5% secondary nonresponders], 6.7% positive anti-IFX antibodies). Fifty-two weeks after ADA initiation, 13 patients (41%) were in corticosteroid-free remission. Mucosal healing occurred in 9 patients (28%) at 52 weeks. The cumulative probability of a clinical relapse-free course was 69%, 59%, and 53% at 12, 30, and 52 weeks, respectively. Ten patients (31%) had a primary failure and 5 (15%) a loss of response to ADA. No significant differences in efficacy were reported between not-responders and intolerant to IFX (P = 1.0). Overall, 19 patient (59%) maintained ADA during 52-week follow-up. Seven patients (22%) experienced an adverse event, no serious side effects were observed and none resulted in ADA discontinuation. CONCLUSIONS: Based on our data, ADA seems to be effective in children with UC, allowing to recover a significant percentage of patients intolerant or not-responding to IFX. The safety profile was good.

Gastrointestinal Pathologic Abnormalities in Pediatric- and Adult-Onset Common Variable Immunodeficiency.

BACKGROUND: Common variable immunodeficiency is the most common form of primary symptomatic immunodeficiency. Gastrointestinal manifestations, such as gastritis, diarrhea, gastrointestinal infections, and malabsorption, may complicate the clinical history in almost 50 % of patients. AIM: To evaluate gastrointestinal histopathological findings in pediatric- and in adult-onset common variable immunodeficiency patients. METHODS: Twenty-two patients with common variable immunodeficiency (13 children, nine adults) were retrospectively studied from a clinical and histopathological point of view. RESULTS: Increased T lymphocyte infiltrate and the absence of plasma cells in duodenal lamina propria and submucosa were the most frequent findings, independently from onset age, whereas follicular lymphoid hyperplasia and polymorphonuclear infiltrate, as well as parasitic and viral infections, were only present in the adult group. Common variable immunodeficiency patients with minor gastrointestinal symptoms also presented pathological findings, mainly the absence of plasma cells, T cell infiltrate, and infections, independently of age. CONCLUSIONS: Gastrointestinal pathological abnormalities are common in both pediatric- and adult-onset common variable immunodeficiency patients. Histological alterations may vary depending upon the age of onset, possibly due to duration of disease. Minor gastrointestinal symptoms are also associated with pathological findings; therefore, these should be searched in all symptomatic patients.

Dilated intercellular spaces in eosinophilic esophagitis.

OBJECTIVES: Dilated intercellular spaces (DIS) in the esophageal epithelium can be induced by acid and reduced by proton pump inhibitors (PPI), and are thus considered a marker of gastroesophageal reflux disease (GERD). Over the years, however, DIS have also been reported in esophagitis unrelated to GERD. Because DIS have never been formally measured in eosinophilic esophagitis (EoE), we aimed at detecting and measuring DIS in EoE before and after nutritional or pharmacological therapy. METHODS: In 22 children with EoE, DIS were measured by morphometry and transmission electron microscopy (TEM), before and after treatment with topical steroids (n = 16) and/or exclusion diet (n = 13). A total of 30 children undergoing upper gastrointestinal endoscopy with biopsy for nonesophageal disorders acted as controls. RESULTS: In controls, the mean (± standard deviation [SD]) number of esophageal eosinophils was 0.91 (± 0.47) and the mean DIS values were 0.62 (± 0.08) µm at morphometry and 0.33 (± 0.24) µm at TEM. In patients with EoE, the mean (± SD) number of esophageal eosinophils decreased from 31.8 (± 6.96) to 6.64 (± 5.01) (P < 0.0001), and the mean DIS values decreased from 2.26 (± 0.21) to 1.23 (± 0.20) µm at morphometry (P < 0.0001), and from 2.24 (± 0.28) to 0.98 (± 0.19) µm at TEM (P < 0.0001), respectively, before and after treatment. CONCLUSIONS: DIS are a prominent morphological feature of EoE, in which they can be significantly reduced by an appropriate non-PPI therapy.

Histopathological findings in the oral mucosa of celiac patients.

BACKGROUND: Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible subjects. Although the small intestinal mucosa is the main site of the gut's involvement in CD, other mucosal surfaces belonging to the gastrointestinal tract and the gut-associated lymphoid tissue are known to be affected. AIM: Assuming that the oral mucosa could reflect the histopathological inflammatory alterations of the intestine in CD patients, this study wishes to assess the pattern of T-cell subsets in the oral mucosa of young adults with CD. METHODS: A group of 37 patients (age range 20-38 years; female: male ratio 28:9) with CD were enrolled. Out of 37 patients, 19 patients (group A) followed a gluten free diet (GFD) -2 patients from less than one year; 6 patients between 1 and 5 years; 11 patients more than 5 years- while 18 patients (group B) were still untreated. Fifteen healthy volunteers (age range 18-35 years, female: Male ratio 11:4) served as controls for the CD patients. Ethical approval for the research was granted by the Ethics Committee. Biopsy specimens were taken from normal looking oral mucosa. The immunohistochemical investigation was performed with monoclonal antibodies to CD3, CD4, CD8, and gamma/delta-chains T cell receptor (TCR). RESULTS: The T-lymphocytic inflammatory infiltrate was significantly (p < 0.0001) increased in group B (both compared with group A and with the control group). CONCLUSION: This study confirms the oral cavity to be a site of involvement of CD and its possible diagnostic potentiality in this disease.

The correct methodological approach to the diagnosis of celiac disease: the point of view of the pathologist.

The diagnosis of celiac disease relies on the assessment of serological data and the presence of histological alterations in the duodenal mucosa. The duodenal biopsy is pivotal in adults, and in some circumstances in children, to confirm the clinical suspicion of celiac disease. The correct interpretation of duodenal biopsies is influenced by numerous variables. The aim of this overview is to describe the correct methodological approach including the procedures of biopsy sampling, orientation, processing, staining and histopathological classification in order to avoid or minimize the errors and the variability in duodenal biopsy interpretation. Multiple biopsies taken from different sites of the duodenum during endoscopy maximize the diagnostic yield of duodenal histological sampling. Proper orientation of the biopsy samples is of the utmost importance to assess histological features of pathological duodenal mucosa and to avoid artifacts that may lead even an experienced pathologist to a wrong histological interpretation with subsequent misdiagnosis of celiac disease. An immunohistochemical stain for CD3 can be invaluable to aid the pathologist in obtaining a more accurate intra-epithelial T lymphocytes count. A simplified histological classification facilitates the clinician's work and improves the communication between pathologist and clinician. An integrated clinical and pathological approach is required for a correct diagnosis of celiac disease since a relatively large number of conditions may cause duodenal damage with a histological appearance similar to that of celiac disease.

Is 99mTc-HMPAO granulocyte scan an alternative to endoscopy in pediatric chronic inflammatory bowel disease (IBD)?

Although endoscopy with biopsy is the gold standard for the diagnosis of inflammatory bowel disease (IBD), this procedure is invasive and its repetition is stressful, especially in children. The purpose of this study was to evaluate prospectively the role of (99m)Tc-HMPAO-labeled granulocyte scintigraphy in the diagnosis and follow-up of pediatric IBD and its possible use as an alternative to colonoscopy to determine the disease extent and severity beyond its ability to differentiate ulcerative colitis from Crohn's disease. During a 10-year period, 52 children, aging between 2 and 17 years (median, 11.09 years), were subjected to (99m)Tc-HMPAO granulocyte scan 7-28 days from conventional diagnostic tests, and the results were compared with endoscopic and bioptic results. Disease severity was graded by the focal uptake intensity versus iliac bone uptake (Scan Activity Index) and compared with Endoscopy Mayo Score. In 15 out of 16 patients, IBD diagnosis was obtained with a full correspondence of location and severity of lesions, respectively, in 14 out of 16 and 13 out of 16, while in 31 out of 36 patients, IBD was correctly excluded (sensitivity of 93.7%, specificity of 86.1%, and negative predictive value of 96.4%). During the follow-up, all relapses (24) and remissions (13) were correctly recognized (sensibility and specificity of 100%). In conclusion, (99m)Tc-HMPAO granulocyte scan is an accurate minimally invasive technique with very good accuracy, able to diagnose and to grade the intensity and extent of the disease; it is also a useful tool in the follow-up of pediatric IBD where it could reliably replace the invasive endoscopic assessment in most cases.

How patchy is patchy villous atrophy?: distribution pattern of histological lesions in the duodenum of children with celiac disease.

OBJECTIVES: In celiac disease (CD) the degree of histological damage in the duodenum may vary, but there is some controversy about the coexistence of villous atrophy and normal mucosa in different biopsy sites, i.e., patchy villous atrophy. We prospectively evaluated the degree, frequency, and distribution of histological lesions among different duodenal sites as well as within each duodenal biopsy. METHODS: Over the last 4 years, in each patient with suspected CD (positive anti-transglutaminase antibodies), four to five endoscopic biopsies were taken from the duodeno-jejunal flexure/distal duodenum (D3), intermediate duodenum (D2), proximal duodenum (D1), and duodenal bulb (B). Biopsies were subjected to hematoxylin/eosin staining and immunostaining with anti-CD3 monoclonal antibodies for intraepithelial lymphocyte (IEL) count. Duodenal lesions were classified according to Marsh-Oberhuber, and CD was diagnosed according to the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition criteria. RESULTS: Six hundred and eighty-six children did have CD. A degree of villous atrophy was found in 660/686 patients (96.2%), total villous atrophy was present in 550/686 (80.1%), and 320/686 (46.6%) had different lesions at different sites, but none of these patients had entirely normal biopsies. In all, 116 of 686 (16.9%) had variable lesions within the same biopsy, with grade 2+3A being the most frequent association (43%), followed by 2+3A+3B (27%) and 2+3A+3B+3C (22%). All these 116 patients also had histologically normal areas within the same biopsy, but anti-CD3 immunostaining showed that IELs were always increased in such areas. In all the cases, the severity of duodenal lesions significantly increased in an aborad manner (chi(2)=52.38 with alpha=0.01 and d.f.=12; P<0.0001). No correlation was found between type and distribution of histologic lesions and clinical presentation of CD. CONCLUSIONS: In newly diagnosed CD, some variability of histological lesions can be found, even within the same duodenal biopsy, in which areas of apparently normal mucosa with increased IEL number often exist. We also confirm our previous findings that duodenal lesions may vary among different biopsies; lesion severity has a proximal-to-distal gradient, but no patient has entirely normal duodenal biopsies. The awareness of such histological variability may help establish a correct diagnosis of CD.

Celiac disease seropositivity in Saharawi children: a follow-up and family study.

BACKGROUND: Celiac disease (CD) is a common disease in the Saharawi population of Arab-Berber origin. Saharawi patients with CD and their families were invited to participate in a follow-up study aimed at checking the CD serology status in patients being treated with the gluten-free diet (GFD) and investigating the prevalence of CD in first-degree relatives. PATIENTS AND METHODS: We investigated 975 subjects (62.8% females and 37.2% males, age range 0.7 to 75.4 years, median age 13.4 years) belonging to 212 families, by determining the serum immunoglobulin A anti-transglutaminase and anti-endomysial antibody levels. Thirty-two first-degree relatives were already receiving GFD when tested. RESULTS: Overall, 42.2% of the 244 treated subjects with CD showed a borderline/positive anti-transglutaminase determination, and 36.6% were also anti-endomysial positive. The serologic family screening detected 33 previously undiagnosed CD cases. The 65 affected first-degree relatives were sibling (42), mother (12), son/daughter (7), and father (4). The overall prevalence of CD among first-degree relatives was 65 of 763 (8.5%, 95% confidence interval 6.5-10.5). Based on our previous estimate of CD prevalence in the pediatric Saharawi population (5.6%), the sibling relative risk was 1.5. CONCLUSIONS: The risk of CD in the Saharawis is only modestly increased in first-degree relatives compared with the general population, probably because of the higher frequency of CD predisposing genes in the general population. Saharawi patients with CD receiving GFD showed poor adherence to the treatment, which could contribute to residual CD-related morbidity and mortality.

Implications of gluten exposure period, CD clinical forms, and HLA typing in the association between celiac disease and dental enamel defects in children. A case-control study.

BACKGROUND: The association between coeliac disease (CD) and dental enamel defects (DED) is well known. AIM: The aim of this study was to investigate the prevalence of DED in children with CD and to specifically find the association of DED and gluten exposure period, CD clinical forms, HLA class II haplotype. DESIGN: This study was designed as a matched case-control study: 250 children were enrolled (125 coeliac children - 79 female and 46 male, 7.2 +/- 2.8 years and 125 healthy children). Data about age at CD diagnosis, CD clinical form, and HLA haplotype were recorded. RESULTS: Dental enamel defects were detected in 58 coeliac subjects (46.4%) against seven (5.6%) controls (P < 0.005). We found an association between DED and gluten exposure period, as among CD subjects the mean age at CD diagnosis was significantly (P = 0.0004) higher in the group with DED (3.41 +/- 1.27) than without DED (1.26 +/- 0.7). DED resulted more frequent (100%) in atypical and silent CD forms than in the typical one (30.93%). The presence of HLA DR 52-53 and DQ7antigens significantly increased the risk of DED (P = 0.0017) in coeliac children. CONCLUSIONS: Our results confirmed a possible correlation between HLA antigens and DED.

Food hypersensitivity as a cause of rectal bleeding in adults.

BACKGROUND & AIMS: Rectal bleeding and lymphonodular hyperplasia (LNH) in children can be caused by food hypersensitivity (FH). Our aim was to verify whether similar clinical and endoscopy presentations in adults can be due to FH. METHODS: Consecutive adult patients with rectal bleeding were enrolled. All underwent routine assays, colonoscopy, and histology study. RESULTS: Ten of 64 (15%) patients showed LNH as the unique sign at colonoscopy. An oligoantigenic diet resolved the rectal bleeding in 9 patients, and the reintroduction of several foods caused symptom reappearance. Double-blind placebo-controlled challenges with cow's milk and wheat protein confirmed the FH; symptoms reappeared 1-96 hours after the challenge. None of the patients were positive for IgE-mediated assays. In patients with LNH and FH, histology of the ileum and colon mucosa showed a higher number of lymphoid follicles and intraepithelial and lamina propria eosinophils compared with the other patients with rectal bleeding. CONCLUSIONS: Recurrent rectal bleeding can be caused by FH in adult patients. Endoscopic evidence of LNH characterizes these cases.

Efficacy of adalimumab as second-line therapy in a pediatric cohort of Crohn's disease patients who failed infliximab therapy: the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition experience.

BACKGROUND: Adalimumab (Ada) treatment is an available option for pediatric Crohn's disease (CD) and the published experience as rescue therapy is limited. OBJECTIVES: We investigated Ada efficacy in a retrospective, pediatric CD cohort who had failed previous infliximab treatment, with a minimum follow-up of 6 months. METHODS: In this multicenter study, data on demographics, clinical activity, growth, laboratory values (CRP) and adverse events were collected from CD patients during follow-up. Clinical remission (CR) and response were defined with Pediatric CD Activity Index (PCDAI) score ≤10 and a decrease in PCDAI score of ≥12.5 from baseline, respectively. RESULTS: A total of 44 patients were consecutively recruited (mean age 14.8 years): 34 of 44 (77%) had active disease (mean PCDAI score 24.5) at the time of Ada administration, with a mean disease duration of 3.4 (range 0.3-11.2) years. At 6, 12, and 18 months, out of the total of the enrolled population, CR rates were 55%, 78%, and 52%, respectively, with a significant decrease in PCDAI scores (P<0.01) and mean CRP values (mean CRP 5.7 and 2.4 mL/dL, respectively; P<0.01) at the end of follow-up. Steroid-free remission rates, considered as the total number of patients in CR who were not using steroids at the end of this study, were 93%, 95%, and 96% in 44 patients at 6, 12, and 18 months, respectively. No significant differences in growth parameters were detected. In univariate analysis of variables related to Ada efficacy, we found that only a disease duration >2 years was negatively correlated with final PCDAI score (P<0.01). Two serious adverse events were recorded: 1 meningitis and 1 medulloblastoma. CONCLUSION: Our data confirm Ada efficacy in pediatric patients as second-line biological therapy after infliximab failure. Longer-term prospective data are warranted to define general effectiveness and safety in pediatric CD patients.

Dietary protein-induced proctocolitis in childhood.

Cow's milk protein-induced proctocolitis presents with overt rectal bleeding in otherwise healthy infants and is characterized by an eosinophilic infiltrate of the left colonic mucosa. Although it is the most common cause of proctocolitis in infancy, dietary protein-induced proctocolitis had hardly ever been reported in childhood so far. We hereby report 16 otherwise healthy children aged 2-14 yr, who presented over a 6-yr period with persistent or recurrent rectal bleeding related to a mild form of left-sided colitis characterized by a prominent eosinophilic infiltration, focal lymphoid follicle hyperplasia, and a prompt clinical and histological response to a cow's milk-free diet. No patient had a history of food-induced proctocolitis during infancy, and most patients did not show an IgE-mediated response to cow's milk protein. Half of the patients did have other gastrointestinal symptoms, but no systemic symptoms were present and other causes of colitis were excluded by appropriate investigation. Tolerance to cow's milk protein developed in half of the patients within a year. Dietary protein-induced proctocolitis is a relatively common cause of overt rectal bleeding in childhood, and its features are remarkably similar to those of dietary protein-induced proctocolitis of infancy.

Colonic lymphoid nodular hyperplasia in children: relationship to food hypersensitivity.

BACKGROUND & AIMS: The clinical significance of lymphoid nodular hyperplasia (LNH) of the lower gastrointestinal tract is unclear. The aim of this study was to define the frequency and clinical significance of LNH in pediatric patients undergoing colonoscopy. METHODS: Two hundred forty-five children (101 male, 144 female; median age, 8.5 years) for whom colonoscopy had been indicated were evaluated during a 3-year period. Apart from ileocolonoscopy with biopsy, all patients underwent routine biochemistry, serum total and specific IgE, and/or skin prick tests for food allergens. Patients with LNH underwent elimination diet and subsequent food challenges. RESULTS: LNH was observed in 73 of 245 (30%) consecutive colonoscopies. LNH was the only abnormal finding in 52 of the 73 cases (71%). In 43 of these 52 patients a diagnosis of cow's milk or multiple food hypersensitivity was made. Food allergy was significantly more common than in patients without LNH (83% vs 31%; P < .0001). The patients with LNH and food hypersensitivity presented hematochezia (P < .0001), elevated serum anti-beta-lactoglobulin IgG (P < .0001), anemia (P < .005), and failure to thrive (P < .03) more frequently than those without LNH. In the LNH patients histologic examination showed a higher number of lymphoid follicles throughout the colon and the terminal ileum and an increased number of lamina propria and intraepithelial eosinophils. CONCLUSIONS: The presence of LNH in the colon and/or terminal ileum is a frequent finding in symptomatic children undergoing colonoscopy. Unless associated with other specific endoscopic or histologic lesions, LNH is related to a condition of delayed-type food hypersensitivity.

Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.

INTRODUCTION: Eosinophilic esophagitis (EoE) is one of the most prevalent esophageal diseases and the leading cause of dysphagia and food impaction in children and young adults. This underlines the importance of optimizing diagnosys and treatment of the condition, especially after the increasing amount of knowledge on EoE recently published. Therefore, the UEG, EAACI ESPGHAN, and EUREOS deemed it necessary to update the current guidelines regarding conceptual and epidemiological aspects, diagnosis, and treatment of EoE. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted up to August 2015 and periodically updated. The working group consisted of gastroenterologists, allergists, pediatricians, otolaryngologists, pathologists, and epidemiologists. Systematic evidence-based reviews were performed based upon relevant clinical questions with respect to patient-important outcomes. RESULTS: The guidelines include updated concept of EoE, evaluated information on disease epidemiology, risk factors, associated conditions, and natural history of EoE in children and adults. Diagnostic conditions and criteria, the yield of diagnostic and disease monitoring procedures, and evidence-based statements and recommendation on the utility of the several treatment options for patients EoE are provided. Recommendations on how to choose and implement treatment and long-term management are provided based on expert opinion and best clinical practice. CONCLUSION: Evidence-based recommendations for EoE diagnosis, treatment modalities, and patients' follow up are proposed in the guideline.

Pulmonary aspiration shown by scintigraphy in gastroesophageal reflux-related respiratory disease.

OBJECTIVES: Gastroesophageal reflux (GER) may underlie respiratory manifestations via vagally mediated airway hyperresponsiveness or microaspiration, and intraesophageal pH monitoring is generally used to identify GER in patients with such manifestations. We aimed to establish the frequency of retrograde pulmonary aspiration in patients with unexplained respiratory manifestations. METHODS: Fifty-one patients with refractory respiratory symptoms (cough, n = 18; pneumonia, n = 14; apnea, n = 8; asthma, n = 7; and laryngitis, n = 4) were prospectively evaluated. They underwent 24-h intraesophageal pH monitoring and gastroesophageal 99Tc scintigraphy with lung scan 18 to 20 h after the test meal. RESULTS: Thirteen of 51 patients (25.5%) had abnormal intraesophageal pH study results (mean reflux index, 11.3%; range, 6.5 to 50%); and in 25 of 51 patients (49%), overnight scintigraphy showed pulmonary aspiration. Nineteen of these 25 patients had entirely normal pH study results, whereas 6 of 13 patients with abnormal pH study results had aspiration. Pulmonary aspiration was demonstrated in all patients with apnea and 61.5% of patients with recurrent pneumonia. Nine of 25 patients (36%) with aspiration had histologic evidence of esophagitis, whereas histologic esophagitis was present in 5 of 13 patients (38.4%) with pathologic GER as shown by intraesophageal pH monitoring. CONCLUSIONS: Pulmonary aspiration as demonstrated by overnight scintigraphy is common in children with unexplained and refractory respiratory manifestations, suggesting that GER could be the underlying cause of these manifestations. Since only a few children with chronic or recurrent respiratory symptoms have a pathologic gastroesophageal acid reflux, a normal intraesophageal pH study result does not rule out GER in these children.

Dilated intercellular spaces: a major morphological feature of esophagitis.

OBJECTIVES: Dilated intercellular spaces (DIS) in the esophageal epithelium have been identified by electron microscopy as marker of acid reflux damage in experimental animals and adults with gastroesophageal reflux disease (GERD). We aimed to identify and quantify DIS by light microscopy in pediatric GERD and esophagitis. METHODS: We prospectively took esophageal biopsies in 70 consecutive pediatric patients, 48 of whom had GERD symptoms. On hematoxylin and eosin-stained sections esophagitis was scored histologically, and DIS were graded as 0 (absent), + (small and focal), ++ (moderate) or +++ (large and diffuse). A computerized image analysis identified total, cellular and nuclear areas and DIS were quantified as percentage of total minus cellular area. RESULTS: Forty of 48 GERD patients had histological esophagitis (33 G1, 4 G2, 3 G3, 1 of which with Barrett esophagus), and all 40 had DIS (33 +, 4 ++, 3 +++) with 100% interobserver agreement; 15 of 29 (55%) had abnormal pH study (reflux index, 5.7%-36%). In 30 patients the esophagus was histologically normal. DIS values were 2.21% +/- 2.60% (range, 0.11%-12%) in patients with esophagitis and 0.44% +/- 0.13% (0.2%-0.7%) in patients with normal histology (P < 0.00001), with 0.71% bearing 70% sensitivity and 100% specificity for GERD versus controls. Five other children with esophagitis unrelated to GERD (eosinophilic, Candida, food allergy) also had DIS + to +++, and median DIS area was 5% (1.3%-12%). CONCLUSIONS: DIS can be detected and evaluated by light microscopy, and the image analysis used provides an objective quantification of DIS and supports the light microscopy evaluation. DIS are a morphological feature of GERD and esophagitis in infancy and childhood.

Tricks of the trade: How to avoid histological pitfalls in celiac disease.

Currently, the diagnosis of celiac disease (CD) is based upon the combination of raised serum anti-tissue transglutaminase or anti-endomysial antibodies and the presence of histological alterations of variable degree in the duodenal mucosa. Interpretation of duodenal biopsies is subjected to a number of variables, and the lack of standardization may cause diagnostic controversy or even misdiagnosis. The aim of this overview is to solicit a standardization of the procedures of biopsy taking, orientation, processing, staining and interpretation in order to avoid or minimize misinterpretation of duodenal biopsies. Based on a literature review and extensive personal experience, the appropriate methodology of duodenal biopsy taking, orientation, fixation, processing, staining and interpretation was thoroughly reviewed, and the most common and relevant errors and artifacts were identified. To maximize the diagnostic yield of duodenal biopsy in CD, multiple specimens are best taken from different sites of the duodenum during endoscopy, and careful visual inspection of the duodenal mucosa may help identify abnormalities related to villous atrophy. Biopsy handling and orientation are of utmost importance to avoid artifacts that may impair the pathologist's ability to detect pathology and normality. Immunostaining with anti-CD3 monoclonal antibody should be carried out, and a simplified histological classification may help distinguish atrophic from non-atrophic stages of CD enteropathy. Meticulous attention to biopsy orientation, handling and processing - together with the knowledge of the most common histological artifacts - is necessary to avoid a wrong histological interpretation which, in turn, may lead to misdiagnosis in CD.