Angelika Kindermann

Influence of age on 13C-urea breath test results in children.

BACKGROUND The 13C-urea breath test for diagnosis of Helicobacter pylori infection has not been validated in infants and young children. The influence of age on the test results was studied by conventional validation against invasive methods and by mathematical estimation in a large pediatric population. METHODS The breath test was performed in 1499 children aged 2 months to 18 years. After a fasting period of 4 hours or more, 75 mg 13C-urea was ingested with cold apple juice, breath samples were taken at baseline and at 15 and 30 minutes. The distribution of the natural logarithms of the delta-over baseline (DOB) values were calculated, and the optimal cutoff values between positive and negative test results and gray zones with a risk of misclassification more than 10% were determined for both time points. In a subgroup of 149 children results of the breath test were compared with concordant results of histology and rapid urease test; 53 of them were less than 6 years of age. RESULTS Logarithmic results of 1499 breath tests revealed two normally distributed subgroups with minimal overlap. The calculated optimal cutoff values were 4.7/1000 at 15 minutes and 5.0/1000 at 30 minutes. At 30 minutes, only 2.6% of all results were in the calculated gray zone (2.6-6.5/1000). Age was negatively correlated to DOB values of both negative (r = -0.223) and positive results (r = -0.291; P < 0.001). Breath test-negative and -positive children 6 or less years of age had significantly higher mean DOB values (P < 0.02) and a larger proportion of results within the gray zone than older children. Compared with biopsy-based results, the least discrepancies occurred at a cutoff of 5.0/1000: 0 of 61 infected (sensitivity 100%) and 6 of 88 noninfected children. Because five of the false-positive results were obtained in children less than 6 years of age, specificity and positive predictive values were lower in this age group than in older patients (88.1% vs. 97.8% and 68.8% vs. 98.0%, respectively). CONCLUSIONS Under the applied conditions, the 13C-urea breath test shows an excellent separation between positive and negative results. Because of some overlap and a strong age effect, definition of a gray zone appears more meaningful than a threshold value. Because infants and young children have a high risk for false-positive breath test results, the values for cutoff and gray zones may have to be adapted. Further validation studies against invasive methods are warranted in this age group.

The use of stable isotope techniques for nutritional and metabolic research in paediatrics

Stable isotope methods are increasingly used in paediatrics for clinical diagnosis and research due to marked improvements in analytical technologies and better availability of suitable tracers. The safety of stable isotopes is of major importance for use in children. Large amounts of deuterium well above the doses applied under clinical conditions may induce adverse effects. In contrast, heavier stable isotopes such as 13C, 15N or 18O do not induce adverse effects even at the highest enrichments obtained, and they are safe. Breath tests with measurements of 13CO2 enrichment after oral application of a tracer can reliably evaluate helicobacter pylori infection and gastric emptying kinetics. Combined with an estimation of total CO2 production, 13CO2 breath tests allow estimation of the absorption and oxidation of 13C-labelled substrates, such as medium- and long-chain triglycerides, and demonstrates the beneficial effect of carnitine supplements on fat oxidation in primary carnitine deficiency. The study of metabolic processes may require the sampling of blood for isotopic analyses of metabolites of the applied tracer. Gas chromatography-isotope ratio mass spectrometry can detect tracer in individual components from small plasma samples. The high precision enabled us to utilize the small differences in natural 13C-enrichment between dietary fats to study fatty acid turnover in term infants, in whom the dietary fat source was switched to corn oil with a slightly higher 13C-content. With this approach we demonstrated active conversion of linoleic into arachidonic acid. We also applied biotechnologically produced, U-13C labelled linoleic and alpha-linolenic acids to infants and detected the conversion of these essential fatty acids to their longer chain polyunsaturated derivatives, with an apparent change of conversion activity with age. Moreover, it has become possible to measure tissue protein synthesis from small biopsy samples obtained in situ without surgery, such as forceps biopsies of rectal tumors. These few examples of recent developments demonstrate the great clinical and scientific potential of stable isotope methods in future paediatric applications.

The duration of effect of infliximab maintenance treatment in paediatric Crohn's disease is limited

Aliment Pharmacol Ther 2011; 33: 243–250

Evaluation of two commercial enzyme immunoassays, testing immunoglobulin G (IgG) and IgA responses, for diagnosis of Helicobacter pylori infection in children

ABSTRACT Serological testing to diagnose Helicobacter pyloriinfection in children is still controversial, although commonly used in clinical practice. We compared the immunoglobulin G (IgG) and IgA results of two commercially available enzyme immunoassays (EIAs) (Pyloriset IgG and IgA and Enzygnost II IgG and IgA) for 175 children with abdominal symptoms divided into three age groups (0 to ≤6 years,n = 47; >6 to ≤12 years, n = 77; >12 years, n = 51). A child was considered H. pylori infected if at least two of three tests (histology, rapid urease test, 13C-urea breath test) or culture were positive and noninfected if all results were concordantly negative. Of 175 children, 93 (53%) were H. pylori negative and 82 wereH. pylori positive. With the recommended cutoff values, the overall specificity was excellent for all four EIAs (95.7 to 97.8%) regardless of age. Sensitivity varied markedly between tests and was 92.7, 70.7, 47.5, and 24.4% for Enzygnost II IgG, Pyloriset IgG, Enzygnost II IgA, and Pyloriset IgA, respectively. Sensitivity was low in the youngest age group (25 to 33.3%), except for Enzygnost II IgG (91.6%). Receiver-operating curve analyses revealed that lower cutoff values would improve the accuracy of all of the tests except Enzygnost II IgG. Measurement of specific IgA, in addition to IgG, antibodies hardly improved the sensitivity. The specificity of commercial serological tests is high in children when the cutoff values obtained from adults are used. In contrast, sensitivity is variable, with a strong age dependence in some, but not all, tests. We speculate that young children may have a different immune response to H. pylori, with preferable responses to certain antigens, as well as lower titers than adults. The Pyloriset test may fail to recognize these specific antibodies.

Helicobacter pylori Infection in Pediatrics

This review summarizes the articles published on Helicobacter pylori infection in children between April 2008 and March 2009. Recent evidence highlights the decreasing prevalence trend of H. pylori infection and supports both intrafamilial and extrafamilial transmission. The association with various symptoms is still being debated. Interestingly, H. pylori infection seems inversely associated with allergic diseases. Monoclonal stool antigen tests are widely used and accurate for the diagnosis of H. pylori infection, but less accurate in young children. The new biprobe real‐time PCR assay applied to stools showed a poor sensitivity in children. Using the urea hydrolysis rate next to the delta over baseline values, the 13C‐urea breath test provides excellent results for all age children, even for young children. Treatment of H. pylori infection remains a challenge, considering suboptimal efficacy of current therapy. Among emerging alternatives, sequential treatment appears promising. The adjunction of probiotics to conventional regimens, although eliciting great interest, has shown limited therapeutic benefit.

Reinfection rate in children after successful Helicobacter pylori eradication.

Objectives This study was performed to determine the rate of Helicobacter pylori reinfection after its successful eradication in children living in Germany. Design A total of 102 children (48 boys; 31 German and 71 other nationalities; age 1.8–18 years) with a negative 13C-urea breath test 8 weeks after triple therapy were followed up by a 13C-urea breath test every 6 months. The cohort included 11 children aged < 6 years, 58 children aged ⩾ 6 to < 12 years, and 33 children ⩾ 12 years. Results The mean duration (± standard deviation) of follow-up was 15.5 ± 11.9 months with a maximum of 4.9 years, representing 132 patient years. Only three children (aged 9.7–14.9 years, one German, two Turkish) tested positive at 6, 12, and 18 months, respectively. The calculated reinfection rate was 2.3% per person per year. Conclusion The risk of reinfection with H. pylori is low in children living in Germany. There is no evidence that the reinfection rate depends on the age, sex, or nationality of the child. The low reinfection rate indicates that it is unnecessary to screen or treat asymptomatic family members in order to prevent reinfection.

Discontinuation of tube feeding in young children by hunger provocation.

Objectives: Pathological food refusal (PFR) is not rare in young children with chronic conditions requiring prolonged tube feeding. We investigated whether these children could be weaned from tube feeding with a multidisciplinary hunger provocation program. Patients and Methods: The study included children younger than 2 years with PFR who had been dependent on tube feeding for at least 3 months. They followed a multidisciplinary in-hospital program. During step 1, only 50% of the normal allowance was given by tube. During step 2, oral feeding was offered and completed up to 50% with tube feeding afterwards. During step 3, supplementary tube feeding was given at night. During step 4, only insensible loss (400 mL/m2), was replaced. When the child had started eating, parents took over feeding (step 5). Primary endpoints were eating without tube feeding while gaining weight at 3 and 6 months after discharge. Results: Ten children (age 9–21 months; 7 girls) were exclusively tube fed for 7 to 19 months. Hospital stay lasted 9 to 33 days (mean 17.3 days). All children but 1 remained in clinically stable condition and started to eat within 1 week. Weight loss was 3.7% to 15.6% (mean 9.2%); in 1 child, the program was discontinued because of excessive weight loss. At follow-up after 3 and 6 months, 9 of 10 and 8 of 10 children, respectively, were eating adequately and gaining weight without tube feeding. Two children with recurrent infections resumed partial (25%–50%) tube feeding during follow-up. Conclusions: The multidisciplinary hunger provocation program seems to be a promising method to promote discontinuation of tube feeding in young children.

Use of exclusive enteral nutrition in paediatric Crohn's disease in The Netherlands

BACKGROUND AND AIMS A six-week course of exclusive enteral nutrition (EEN) is recommended as first treatment in active paediatric Crohns disease (CD). We aimed to assess short-term and long-term outcome of EEN, and to identify predictive factors of treatment success. METHODS The medical records of newly diagnosed paediatric CD patients initiating EEN as remission induction therapy between January 2008 and October 2011 were retrospectively studied. Treatment outcome was assessed using a previously described pattern recognition model. RESULTS 77 CD patients (median age 13.9 years, 57% male) initiated a six-week course of EEN, combined with azathioprine maintenance treatment in 92%. Patients received EEN as either hyperosmolar sip feeds or polymeric formula by nasogastric tube. In patients completing a six-week course of EEN (n=58), complete remission was achieved in 71%, partial remission in 26%, and no response in 3%. Complete remission rates were higher in children presenting with isolated ileal/ileocaecal disease and malnutrition. Nineteen patients discontinued EEN before the intended treatment period due to worsening of symptoms (n=9) or adherence issues (n=10). Non-adherence occurred more often in older children, females, children from non-Dutch parents, and patients taking hyperosmolar sip feeds compared with polymeric formula by nasogastric tube. The likelihood of relapsing disease within the first year after EEN treatment was 59%. CONCLUSION A six-week course of EEN is effective in newly diagnosed paediatric CD, with response rates that seem to be influenced by disease location and nutritional status, but not by type of formula. Non-adherence occurs frequently and limits the success of this treatment in everyday clinical practice.

Additional Value of Upper GI Tract Endoscopy in the Diagnostic Assessment of Childhood IBD

Objectives: For the choice of treatment in children with inflammatory bowel disease (IBD), it is important to make a distinction between Crohn disease (CD) and ulcerative colitis (UC). To look for pathognomonic features of CD, upper gastrointestinal tract (UGT) endoscopy has become part of the routine evaluation of children with suspected IBD; however, pathological changes can also be found in the UGT in patients with UC. The aims of the present study were to establish the role of UGT involvement in the diagnostic assessment of suspected IBD in children and to detect histopathological changes in the UGT mucosa, which can distinguish CD from non-CD (UC and non-IBD). Methods: Biopsies (colon, ileum, duodenum, stomach, esophagus) from children suspected of having IBD who underwent endoscopy between 2003 and 2008 were reassessed by a blinded, expert pathologist. The histological findings of the UGT were compared with the diagnosis based on ileocolonic biopsies and the final diagnosis. Results: In 11% of the children with CD, the diagnosis was based solely on the finding of granulomatous inflammation in the UGT. Focal cryptitis of the duodenum and focally enhanced gastritis were found significantly more frequently in children with CD compared with children with UC and non-IBD, with a specificity and positive predictive value of 99% and 93% and 87.1% and 78.6%, respectively. Conclusions: Histology on ileocolonic biopsies alone is insufficient for a correct diagnosis of CD or UC in children. UGT endoscopy should, therefore, be performed in the diagnostic assessment of all children suspected of having IBD.

The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease.

Abstract Objective. Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD. Material and methods. Children aged <18 years receiving IFX maintenance treatment for Crohn’s disease (CD) or ulcerative colitis (UC) at three Dutch hospitals were included. Prior to two consecutive IFX infusions, IFX TLs and ATI levels were measured. Clinical disease activity was determined by Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), for CD and UC, respectively. Biochemical disease activity was assessed by serum C-reactive protein (CRP) and fecal calprotectin (FC). Clinical remission was defined as a PUCAI or PCDAI score of <10. Therapeutic range of IFX was considered 3–7 µg/ml. Results. Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 µg/ml [IQR 2–7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = −0.51; p < 0.01] and FC [rs = −0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 µg/ml [IQR 2–5] and 2.3 µg/ml [IQR 0.3–4.6]; p = 0.2). Conclusions. IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.