Nonbiopsy Approach for Celiac Disease Is Accurate When Using Exact Duodenal Histomorphometry: Prospective Study in 2 Countries.

GOALS: To test the accuracy of serology-based criteria for diagnosing celiac disease utilizing quantitative histomorphometry. BACKGROUND: The revised European pediatric guidelines allow noninvasive celiac disease diagnosis for a subgroup of children. However, in some of the studies on this issue, the positive predictive value (PPV) of serology has remained suboptimal, possibly because of challenges of histopathology as the reference standard. STUDY: Prospectively enrolled children with transglutaminase 2 antibodies (TGA) above the upper limit of normal (ULN) underwent blood sampling and duodenal biopsy in Finland and Romania. Those with TGA ≥10× ULN, positive endomysium antibodies (EmA), and disease-associated genetics were considered to fulfill triple criteria for celiac disease. Initial histopathologic analysis was conducted using grouped classification, whereupon centralized morphometry was performed. RESULTS: Altogether 88 (54%) children were triple positive. In local evaluation, 99% of triple-positive children and 73% of children with TGA <10× ULN had celiac disease. These figures increased to 100% and 85% after more precise morphometric analysis. Triple-positive children had more anemia and higher median EmA and liver enzyme values than those with TGA<10× ULN; the groups were comparable in other clinical features and laboratory parameters. CONCLUSIONS: When applied as recommended, the nonbiopsy strategy had already yielded excellent PPV regardless of the site of diagnosis or clinical presentation in the local analysis. PPV further increased to 100% with standardized duodenal morphometry.

Severity of Villous Atrophy at Diagnosis in Childhood Does Not Predict Long-term Outcomes in Celiac Disease.

OBJECTIVES: Current pediatric guidelines allow noninvasive diagnosis of celiac disease in selected children. We investigated in a large cohort study whether the severity of villous atrophy at diagnosis is associated with clinical characteristics or long-term health outcomes, thus having a prognostic significance. METHODS: Comprehensive medical data on 906 children with celiac disease were analyzed. Long-term health outcomes of 503 adult patients diagnosed in childhood were moreover assessed with a specific study questionnaire and validated Gastrointestinal Symptom Rating Scale (GSRS) and Psychological General Well-Being (PGWB) questionnaires. Patients were classified into 3 groups according to the severity of villous atrophy at diagnosis, and all variables were compared. RESULTS: Altogether 34% of the patients had partial, 40% subtotal, and 26% total villous atrophy. Children with milder lesions were diagnosed more recently (median year 2007 vs 2006 vs 2001, respectively, P < 0.001), more often by screening (30% vs 25% vs 17%, P < 0.001) and they suffered less often from anemia (16% vs 21% vs 32%, P < 0.001) and growth disturbances (22% vs 36% vs 54%, P < 0.001) and had lower transglutaminase-2 antibody levels (median 64 U/L vs 120 U/L vs 120 U/L, P < 0.001). There was no difference in other disease features.Altogether 212 adults diagnosed in childhood completed the questionnaires. Severity of villous atrophy at childhood diagnosis did not predict presence of complications or comorbidities, persistent symptoms, and self-perceived health, quality of life or adherence to a gluten-free diet in adulthood. CONCLUSION: Presence of advanced villous atrophy at diagnosis is associated with more severe clinical characteristics but not with poorer long-term health and treatment outcomes.

Clinical characteristics and long-term health in celiac disease patients diagnosed in early childhood: Large cohort study.

BACKGROUND: Early detection of celiac disease could theoretically prevent most of the disease-associated complications, but long-term effects of this approach are unclear. AIMS: To investigate features at diagnosis and adulthood health in celiac disease patients diagnosed in early childhood in 1965-2014. METHODS: Medical data on 978 pediatric patients were collected and study questionnaires sent to 559 adult patients who were diagnosed in childhood. Results were compared between patients diagnosed in early (≤3.0 years) and later (3.1-17.9 years) childhood. RESULTS: Early diagnosed patients (n=131) had more often total villous atrophy (37% vs 25%, p=0.001), gastrointestinal presentation (61% vs 47%, p<0.001), growth disturbances (70% vs 32%, p=0.001) and severe symptoms (30% vs 9%, p<0.001) and were less often screen-detected (10% vs 27%, p<0.001) at diagnosis than those diagnosed later (n=847). Among 239 adult responders, early diagnosed patients (n=36) had fewer comorbidities (33% vs 53%, p=0.034) but considered their health less often good/excellent (69% vs 84%, p=0.029). The groups were comparable in current age, dietary adherence, symptoms and health-related quality of life. CONCLUSION: Despite more severe initial presentation, the long-term health in early diagnosed patients was mostly comparable or even better to those diagnosed later in childhood. Poorer self-perceived health suggests a need for support during the transition to adulthood care.

Prevalence and diagnostic outcomes of children with duodenal lesions and negative celiac serology.

BACKGROUND: Celiac disease diagnostics begin by measuring autoantibodies, which may fail to identify seronegative patients. Duodenal lesion in the absence of antibodies is scarcely studied, especially in children. AIMS: To investigate the prevalence and diagnostic outcomes of children with seronegative duodenal lesion in two countries with different disease profiles. METHODS: Medical data, including the results of histology and transglutaminase (tTGab) and endomysium (EmA) antibody measurements were collected from 1172 Finnish and 264 Romanian children with systematic duodenal sampling. Database of 509 Finnish children with celiac disease was examined to identify earlier seronegative patients. RESULTS: Celiac disease was diagnosed in 307 Finnish and 83 Romanian children in the endoscopy cohorts. No seronegative patients were found among 899 celiac disease patients, although some were only tTGab or EmA positive. Non-celiac duodenal lesion was detected in eight Finnish and 32 Romanian children, their most common diagnoses being inflammatory bowel disease and infections, respectively. Six children with morphological lesion received no diagnosis. None of them developed celiac disease during a follow-up of 3-11 years. CONCLUSION: Pediatric seronegative celiac disease is exceptional in the era of modern autoantibodies. Other reasons for duodenal lesion should therefore be sought, bearing in mind possible differences across countries.

Secular trends in poisonings leading to hospital admission among Finnish children and adolescents between 1971 and 2005.

OBJECTIVE: To investigate the secular trends in childhood poisonings leading to hospitalization in Finland. STUDY DESIGN: All children and adolescents age 0 to 19 years hospitalized in Finland with the primary diagnosis of poisoning between 1971 and 2005 were identified using the International Classification of Diseases. RESULTS: During the study period, there were 41 862 hospitalizations with 96 427 hospital bed days for poisoning in 38 582 children and adolescents. The incidence of hospitalization declined from 91.3 admissions per 100 000 person-years in boys and 105.2 per person-years in girls in 1971 to 64.8 in boys and 83.5 in girls in 2005. In the 0- to 4-year age group, admissions declined by 51%. Hospitalizations for alcohol poisoning increased 1.7-fold (95% confidence interval = 1.4 to 2.2) in boys and 2.4-fold (95% confidence interval = 1.8 to 3.3) in girls. Alcohol poisoning was the primary diagnosis in 53% of those in the 10- to 14-year age group. CONCLUSIONS: Poisoning remains an important cause of morbidity in Finnish children and adolescents despite the decreased overall incidence of poisonings leading to hospitalization between 1971 and 2005. The increasing trend of hospital admissions for alcohol poisoning, especially in 10- to 14-year-olds, is noteworthy. Effective primary prevention programs and adult supervision should be targeted at reducing alcohol consumption and alcohol-related poisonings in youth.

Long-term health and treatment outcomes in adult coeliac disease patients diagnosed by screening in childhood.

BACKGROUND: The diagnostic yield of coeliac disease could be improved by screening in at-risk groups, but long-term benefits of this approach are obscure. OBJECTIVE: To investigate health, quality of life and dietary adherence in adult coeliac patients diagnosed in childhood by screening. METHODS: After thorough evaluation of medical history, follow-up questionnaires were sent to 559 adults with a childhood coeliac disease diagnosis. The results were compared between screen-detected and clinically-detected patients, and also between originally asymptomatic and symptomatic screen-detected patients. RESULTS: In total, 236 (42%) patients completed the questionnaires a median of 18.5 years after childhood diagnosis. Screen-detected patients (n = 48) had coeliac disease in the family and type 1 diabetes more often, and were less often smokers and members of coeliac societies compared to clinically-detected patients, whereas the groups did not differ in current self-experienced health or health concerns, quality of life or dietary adherence. Screen-detected, originally asymptomatic patients had more anxiety than those presenting with symptoms, whereas the subgroups were comparable in other current characteristics. CONCLUSION: Comparable long-term outcomes between screen-detected and clinically-detected patients support risk-group screening for coeliac disease. However, asymptomatic patients may require special attention.

Paediatric poisonings treated in one Finnish main university hospital between 2002 and 2006.

AIM: Acute poisonings are a major cause of morbidity among children. This study aims to describe the incidence and nature of emergency visits for acute paediatric poisoning among Finnish children. METHODS: All patients younger than 16 years admitted to the Tampere University Hospital's emergency department with a diagnosis of poisoning during 2002-2006 were identified from the Hospital Information System using the International Classification of Diseases (ICD-10). RESULTS: Altogether 369 emergency visits were diagnosed with poisoning, the overall incidence being 8.1 per 10 000 person-years (95% CI 7.3-9.0). A majority of patients were adolescents aged 10-15 years (48%) and children under 5 years (45%). Boys represented 55% of the cases. Nonpharmaceutical agents were suspected to be the cause in 60.4% and pharmaceuticals in 30.6% of the intoxications. Multiple agents were involved in 8.4% of the cases. Ethanol was the agent in 30.9% of the poisonings. Most patients (78.9%) were hospitalized (median length of stay 1 day). Overall mortality was 0.3%. CONCLUSION: Acute paediatric poisonings represent a relatively frequent problem in Finland, and remain a life-threatening problem. The high proportion of alcohol poisonings highlights the necessity to develop more effective primary prevention programs.

Rectal bleeding in infancy: clinical, allergological, and microbiological examination.

OBJECTIVE: Rectal bleeding is an alarming symptom and requires additional investigation. In infants it has been explained mainly by hypersensitivity. In addition to dietary antigens, intraluminal microbial agents challenge the immature gut mucosa. Although controlled in the mature gut, these antigens may induce inflammation in the developing gastrointestinal tract. The objectives of this study were to evaluate prospectively the clinical course of rectal bleeding and evaluate the impact of cow's milk allergy and aberrant gut microbiota on the condition. Because withdrawal of cow's milk antigens from the infants' diet is used as a first treatment without evidence of its efficacy, we also aimed to asses the effect of a cow's milk-elimination diet on the duration of rectal bleeding. METHODS: The study involved 40 consecutive infants (mean age: 2.7 months) with visible rectal bleeding during a 2-year period at the Tampere University Hospital Department of Pediatrics. Most of the infants (68%) were fully breastfed. At enrollment the infants were randomly allocated to receive a cow's milk-elimination diet (n = 19) or continue their previous diet (n = 21) for 1 month. Findings of colonoscopy, fecal bacterial culture, fluorescence in situ hybridization of selected gut genera, specific detection of fecal enteroviruses, rotaviruses, and adenoviruses, fecal electron microscopy for viruses, and mucosal electron microscopy for viruses were assessed. During each visit the severity of atopic eczema, if any, was assessed according to the SCORAD method. In evaluating the extent of sensitization, serum total immunoglobulin E (IgE) and specific IgE and skin-prick tests for cow's milk, egg, and wheat were studied. Cow's milk allergy was diagnosed by elimination and provocation testing. Five patients were hospitalized; all others were treated on an outpatient basis. The follow-up visits were scheduled 1 month later and at the age of 1 year. Sixty-four healthy reference infants were selected as controls according to the following criteria: age and timing of fecal sampling being identical to within 1 month. RESULTS: Altogether, 32 (80%) infants manifested bloody stools during follow-up (mean [range]: 2.1 [1-15] per day). The mean number of days with rectal bleeding on follow-up was 6. Typically, bloody stools occurred irregularly, for which reason the mean time to the last occurrence of rectal bleeding was 24 (range: 1-85) days from admission. Atopic eczema at presentation or during follow-up was diagnosed in 38% of the infants. Increased specific IgE concentrations or a positive skin-prick test were uncommon. The growth of the infants was normal on admission and during follow-up. Colonoscopy revealed typically focal mucosal erythema and aphthous ulcerations. The mucosa appeared normal in less than half of the patients. No anorectal fissures or colonic polyps were found. Light microscopy revealed that the overall architecture of the mucosa was well maintained. Acute inflammation or postinflammatory state and focal infiltration of eosinophils in the lamina propria were the most common abnormalities. A cow's milk-elimination diet did not affect the duration of rectal bleeding. Cow's milk allergy was diagnosed in 7 (18%) patients. Virus-particle aggregates were found in the microvillus layer of the colon epithelium in 8 cases. The surface epithelium of the virus-positive colon biopsy specimens regularly showed degenerative changes in the microvillus layer and epithelial cells. Electron microscopy study of the colon biopsies disclosed virus particles (30 nm in diameter) on the surface of epithelial cells. Virus particles or RNA were present in feces in only a minority of the patients. All fecal cultures were negative for Salmonella, Shigella, and Yersinia. Campylobacter jejuni was found in the feces of 1 patient, and fecal cultures were positive for Clostridium difficile in 4 patients, Staphylococcus aureus in 8 patients, and yeast in 2 patients. Fluorescence in situ hybridization revealed that at the time of admission the total numbers of bacteria and the numbers of bifidobacteria and lactobacilli in feces were lower in the patients compared with controls. The fecal concentrations of microbes characterized in this study (Bacteroides, bifidobacteria, Clostridium, lactobacilli, and enterococci) did not differ significantly between the time of admission and the second visit in the patients or controls. At the age of 1 year, 7 patients still suffered from cow's milk allergy, 5 of whom also suffered from multiple food allergies. Atopic eczema and histopathologically confirmed inflammation of the colonic mucosa at presentation were associated with persistence of cow's milk allergy at the age of 1 year. No patients exhibited gastrointestinal complaints or visible blood in stools. CONCLUSIONS: Rectal bleeding in infants is generally a benign and self-limiting disorder. Bloody stools occurred irregularly for only a few days during the following months. As in a previous report, most infants were exclusively breastfed. In the majority of the patients the cause of the condition remains unknown. An association with viruses can be seen in some patients. The microbes that commonly lead to bloody diarrhea in older children and adults, Salmonella, Shigella, and Yersinia, were absent in the present material. The low bifidobacterial numbers in fecal samples may indicate a significant aberrance that may provide a target for probiotic intervention to normalize gut microbiota. The gut microbiota overall seemed stable, because the numbers of major groups of microbiota tested did not change significantly between the time of admission and after 1 month. Cow's milk allergy among these patients is more uncommon than previously believed. Cow's milk challenge is thus essential in infants who become symptom-free during a cow's milk-free diet to reduce the number of false-positive cow's milk-allergy diagnoses.

Characterization of breast milk received by infants with gross blood in stools.

OBJECTIVE: The aim of this study was to ascertain factors that might be protective of the appearance of gross blood in the stools of breast-fed infants. METHODS: Logistic regression models were formed to search for variables possibly explaining the condition. In addition to the analyzed breast milk factors, mother's allergic disease was introduced into the models to control for its possible confounding effect. The breast milk samples, collected from mothers of infants with gross blood in stools (n = 23) and from mothers of healthy age-matched infants (n = 71), were analyzed for concentrations of transforming growth factor-beta2, tumor necrosis factor-alpha, interleukin (IL)-4, IL-10, prostaglandin (PG)E2, cysteinyl leukotrienes (Cys-LTs) and fatty acid composition. RESULTS AND CONCLUSIONS: Increase in the concentrations of PGE2 and Cys-LTs in the breast milk together with mother's allergic disease reduced the likelihood of gross blood in stools in the breast-fed infant. The results suggest that no single factor, but a combination of immunomodulatory factors may protect the child from gross blood in the stools of breast-fed infants. Allergic disease was not a risk factor as mother's allergic disease appeared to counterbalance the gross blood in stools. Due to the preliminary nature of the study, the results need to be verified in a larger setting. The challenge for the future lies in identifying of such active compounds for dietary modification to enforce particularly the properties of the breast milk which are immunoprotective for the infant and to reduce the likelihood of intestinal disorders in at risk infants.

Weaning to hypoallergenic formula improves gut barrier function in breast-fed infants with atopic eczema.

OBJECTIVES: Infants may be sensitized to dietary antigens even during exclusive breast-feeding. Because food antigen traces in breast milk may have harmful effects on gut barrier function in infants with atopy, the authors sought to evaluate whether or not it is beneficial to shift such infants from breast milk to a hypoallergenic formula. METHODS: Fifty-six infants (mean age, 5.0 months) manifesting atopic eczema during exclusive breast-feeding were studied at weaning to a tolerated hypoallergenic formula. The urinary recovery ratios of orally administered lactulose and mannitol, fecal alpha-1 antitrypsin and urinary methylhistamine, and eosinophil protein X concentrations were assessed during breast-feeding and after weaning. RESULTS: The median (interquartile range, IQR) concentration of fecal alpha-1 antitrypsin was 2.3 mg/g (range, 1.2-3.3 mg/g) during breast-feeding and 0 (0.0-1.9 mg/g) after weaning to a tolerated hypoallergenic formula, z = -4.23, P < 0.0001. The urinary recovery ratio of lactulose and mannitol decreased from 0.029 (range, 0.021-0.042) to 0.023 (range, 0.016-0.031), respectively, z = -3.45, P = 0.0006. Concomitantly, the atopic eczema improved, and the concentration of urinary eosinophil protein X decreased significantly. CONCLUSIONS: In breast-fed infants with atopy, gut barrier function is improved after cessation of breast-feeding and starting of hypoallergenic formula feeding.

Microbiota composition of the intestinal mucosa: association with fecal microbiota?

The fecal and mucosal microbiota of infants with rectal bleeding and the fecal microbiota of healthy age-matched controls were investigated by fluorescent in situ hybridization. Bifidobacteria were the main genus in both the feces and mucosa. The other genera tested, Bacteroides, Clostridium, Escherichia coli and lactobacilli/enterococci, represented only minor constituents. No differences in fecal microbiota were observed between patients and controls. In the patients, however, four times greater numbers of bifidobacteria were observed in the feces when compared to the mucosa. Notwithstanding this difference, a strong positive correlation prevailed for bifidobacteria in feces and mucosal samples. The genera assessed accounted for 16% of total bacterial counts on mucosal samples and for 47% of total bacterial counts in feces. This indicates that the unidentified part of the microbiota, especially on the mucosa, deserves more attention.

Breast milk fatty acids, eicosanoids, and cytokines in mothers with and without allergic disease.

Allergic disease (AD), including atopic eczema, asthma, allergic rhinitis, and food allergy, is characterized by an imbalance between cytokines produced by distinct T-helper cell subtypes. Whether this imbalance can be transferred from mother to breast milk remains to be established. The objective was to investigate the concentrations and interactions of nutritional and inflammatory factors in breast milk. Breast milk samples were collected from mothers with AD (n = 43) and without AD (n = 51). The concentrations of transforming growth factor (TGF)-beta2, tumor necrosis factor-alpha, IL-4, IL-10, prostaglandin E2, and cysteinyl leukotrienes were measured by immunoassays and fatty acid composition by gas chromatography. Mothers with AD had a lower concentration of TGF-beta2 in breast milk [median (interquartile range), 420 (278-701) ng/L] compared with those without AD [539 (378-1108) ng/L; p = 0.003], whereas other cytokines, prostaglandin E2, and cysteinyl leukotriene concentrations or fatty acid composition were not significantly different between the groups. The breast milk inflammatory factors and fatty acid composition were shown to be related. A positive association was observed between TGF-beta2 and the proportion of polyunsaturated fatty acids (p = 0.038) and a negative association between TGF-beta2 and the proportion of saturated fatty acids (p = 0.029) in breast milk. The reduced TGF-beta2 concentration in the breast milk of mothers with AD may interfere with the development of the mucosal immune system of the breast-fed infant. The observed associations between nutritional and inflammatory factors in breast milk suggest that it may be possible to influence the immunologic properties of breast milk by dietary intervention of the mother.