Patrick F. van Rheenen

Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis

Objective To evaluate whether including a test for faecal calprotectin, a sensitive marker of intestinal inflammation, in the investigation of suspected inflammatory bowel disease reduces the number of unnecessary endoscopic procedures. Design Meta-analysis of diagnostic accuracy studies. Data sources Studies published in Medline and Embase up to October 2009. Interventions reviewed Measurement of faecal calprotectin level (index test) compared with endoscopy and histopathology of segmental biopsy samples (reference standard). Inclusion criteria Studies that had collected data prospectively in patients with suspected inflammatory bowel disease and allowed for construction of a two by two table. For each study, sensitivity and specificity of faecal calprotectin were analysed as bivariate data to account for a possible negative correlation within studies. Results 13 studies were included: six in adults (n=670), seven in children and teenagers (n=371). Inflammatory bowel disease was confirmed by endoscopy in 32% (n=215) of the adults and 61% (n=226) of the children and teenagers. In the studies of adults, the pooled sensitivity and pooled specificity of calprotectin was 0.93 (95% confidence interval 0.85 to 0.97) and 0.96 (0.79 to 0.99) and in the studies of children and teenagers was 0.92 (0.84 to 0.96) and 0.76 (0.62 to 0.86). The lower specificity in the studies of children and teenagers was significantly different from that in the studies of adults (P=0.048). Screening by measuring faecal calprotectin levels would result in a 67% reduction in the number of adults requiring endoscopy. Three of 33 adults who undergo endoscopy will not have inflammatory bowel disease but may have a different condition for which endoscopy is inevitable. The downside of this screening strategy is delayed diagnosis in 6% of adults because of a false negative test result. In the population of children and teenagers, 65 instead of 100 would undergo endoscopy. Nine of them will not have inflammatory bowel disease, and diagnosis will be delayed in 8% of the affected children. Conclusion Testing for faecal calprotectin is a useful screening tool for identifying patients who are most likely to need endoscopy for suspected inflammatory bowel disease. The discriminative power to safely exclude inflammatory bowel disease was significantly better in studies of adults than in studies of children.

Delayed cord clamping and haemoglobin levels in infancy: a randomised controlled trial in term babies.

Objectives  This study was carried out to assess whether delaying umbilical cord clamping is effective in improving the haematological status of term infants living in a malaria‐endemic area, and whether this is associated with complications in infants and mothers.

A practical approach to timing cord clamping in resource poor settings

There is little agreement among doctors and midwives about the optimal time to clamp the umbilical cord after birth. The most important points of difference relate to maternal and infant safety. Many healthcare workers worldwide tend to clamp the cord and pass the baby off as quickly as possible. Infants in resource poor settings are the main victims of immediate clamping, as this prevents a cost-free means of boosting their small iron stores. Infant anaemia is common in poor communities, especially where malaria is endemic. In sub-Saharan Africa more than 75% of infants are anaemic before 6 months of age.w1-w3 Infant anaemia is associated with increased mortalityw4 w5 and with impaired mental and motor development.w6 Its prevention is of critical importance, and delaying clamping of the umbilical cord could be an effective strategy to reduce anaemia and improve child survival. We propose a practice guideline on cord clamping for resource poor countries for singleton vaginal deliveries, based on published systematic reviews, randomised controlled trials, and biological evidence. Taking account of the safety of mothers and infants, we provide evidence about inclusion and exclusion criteria for delayed cord clamping, optimal timing of clamping, infant position during placental-fetal transfusion, and potential side effects. We present the evidence as a series of structured clinical questions, which identify the population concerned (mothers and infants from resource poor countries), the options being compared (mostly delayed versus immediate cord clamping), and the outcome measures used to measure effectiveness and safety of delayed cord clamping. We also present a practical and simple flow chart for quick reference. ### Is delayed cord clamping associated with improved haematological status in infancy? Four randomised controlled trials, all from developing countries, evaluated haemoglobin concentrations in term infants 2-4 months after birth.2–5 Meta-analysis showed that haemoglobin concentrations were significantly higher after delayed cord clamping (317 infants, weighted mean …

Safely ruling out inflammatory bowel disease in children and teenagers without referral for endoscopy

Background Up to 70% of children and teenagers referred to a paediatric gastroenterology centre with suspected inflammatory bowel disease (IBD) do not have the disease. Objective To evaluate whether faecal calprotectin as an ‘add-on test’ improves the specificity of the clinical case definition for suspected IBD in a general paediatric practice. Design A prospective diagnostic accuracy study. Setting Six outpatient clinics for general paediatrics and one tertiary care hospital in the Netherlands. Patients 117 children and teenagers with a clinical suspicion of IBD. Diagnostic tests Faecal calprotectin was measured (index test) in all patients. Patients with a high index of suspicion on the basis of the paediatricians global assessment, physical examination and blood results were referred for endoscopy (reference standard). Children and teenagers who were not selected for endoscopy initially were followed for half a year for the appearance of possible additional symptoms (delayed type reference standard). Primary outcome The proportion of referred patients with confirmed IBD. Results The mean age of patients was 14 years (range 6–18). A total of 42 (36%) had confirmed IBD. The paediatricians, who were blinded to the faecal calprotectin result, referred 68 children and teenagers for endoscopy. If they had referred only those patients with a positive faecal calprotectin result (>50 μg/g), 54 patients would have undergone endoscopy. Limitation The study relied on clinical follow-up to detect missed IBD. Conclusions A diagnostic strategy in general paediatric practice of using a simple clinical case definition for suspected IBD in combination with a positive faecal calprotectin result increases the specificity to detect IBD and reduces the need for referral to a paediatric gastroenterology centre with a very low risk of missing cases.

Faecal Calprotectin in Suspected Paediatric Inflammatory Bowel Disease

Objectives: The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data. Methods: MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator. Results: According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92–0.99) and a specificity of 0.70 (0.59–0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 &mgr;g/g there would be 17% (95% CI 15–20) false-positive and 2% (1–3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89–0.94). Conclusions: In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients’ risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation.

Role of fecal calprotectin testing to predict relapse in teenagers with inflammatory bowel disease who report full disease control

Background: Teenagers with inflammatory bowel disease undergo regular follow‐up visits to watch for symptoms that may indicate relapse. Current disease activity is frequently estimated with the use of the Pediatric Ulcerative Colitis Activity Index (PUCAI) and the Pediatric Crohns Disease Activity Index (PCDAI). We examined the capacity of fecal calprotectin and C‐reactive protein (CRP) to predict relapse in teenagers who report no symptoms. Second, we examined whether calprotectin and CRP as an “add‐on test” improve the specificity of PUCAI or PCDAI to predict relapse. Methods: We collected data of 62 consecutive teenagers (31 with Crohns disease and 31 with ulcerative colitis) who scored their degree of disease control between 90 and 100% on two successive outpatient clinic visits. Calprotectin, PUCAI or PCDAI, and CRP were measured at baseline. Primary outcome was symptomatic relapse within 3 months of baseline, necessitating the introduction of steroids, exclusive enteral nutrition, or an aminosalicylate dose escalation. Results: Fifteen teenagers (24%) developed symptomatic relapse within 3 months of baseline. Based on the receiver operating characteristic curve, the optimum calprotectin cutpoint to differentiate high from low risk patients was 500 &mgr;g/g. The PUCAI or PCDAI predicted relapse in 42% (11/26) of teenagers with a positive result (score ≥10 points), while a negative PUCAI or PCDAI result reduced the risk of relapse to 11% (4/36). Teenagers with a positive calprotectin test had a 53% (10/19) risk of progressing to symptomatic relapse within 3 months, whereas a negative calprotectin result gave a 12% (5/43) risk of symptomatic relapse. A positive CRP result (cutoff 10 mg/L) gave a 50% (4/8) risk of relapse, whereas a negative CRP result hardly reduced the risk compared with the pretest probability (from 24% to 21% (11/53)). As an add‐on test after PUCAI or PCDAI, the calprotectin test limited the number of false positives and thus increased the specificity to detect gastrointestinal inflammation: 60% (9/15) of teenagers with positive concordant test results progressed to symptomatic relapse. Negative concordance reduced the risk of relapse to 10% (3/32). CRP contributed little as add‐on test after PUCAI or PCDAI: two of five teenagers with positive concordant tests progressed to symptomatic relapse (40%). Conclusions: Unlike CRP, fecal calprotectin as an add‐on test after PUCAI or PCDAI facilitates recognition of preclinical relapse. This could help to identify teenagers who require treatment intensification at the time of minimal disease rather than at the time of clinically overt relapse. Further studies are warranted to determine the impact of fecal calprotectin testing on treatment management and outcome. (Inflamm Bowel Dis 2012;)

Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study

Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear. Objective: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM. Design: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6–59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling. Results: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443–535 mg/kg feces) compared with 698 mg/kg feces (1438–244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112–22 ng/mL) compared with 2036 ng/mL (5800–149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831–131 ng/mL) compared with 3174 ng/mL (5819–357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation. Conclusions: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies. This trial was registered at www.controlled-trials.com as ISRCTN13916953.

Impaired glucose absorption in children with severe malnutrition.

OBJECTIVE To quantify intestinal glucose absorption in children with two types of severe malnutrition, kwashiorkor and marasmus, compared with healthy children. STUDY DESIGN Children with kwashiorkor (n = 6) and marasmus (n = 9) and control subjects (n = 3) received a primed (13 mg/kg), constant infusion (0.15 mg/kg/min) of [6,6H2]glucose for 4.5 hours. Two hours after start of the infusion an oral bolus of glucose 1.75 g/kg labeled with [U-13C]glucose 10 mg/g was given and was followed by periodic blood sampling. Mathematical modeling was applied to determine oral glucose absorption. RESULTS Median total glucose absorption was 5.9 mmol/kg, interquartile range (IQR) 4.5-6.7 mmol/kg and 4.4 (IQR 2.9-5.9) mmol/kg in children with kwashiorkor and marasmus compared with 7.7 (IQR 5.8-9.0) mmol/kg in control subjects; P = .03 compared with marasmus). Children with the lowest glucose absorption were found specifically in the kwashiorkor group and marasmic children with hypoalbuminemia. Severe impairment in absorption correlated with urinary 8-hydroxydeoxyguanosine secretion (r = -0.62, P = .01). CONCLUSIONS Severe malnutrition is associated with an impaired glucose absorption and decreased glucose absorption correlates with oxidative stress in these children.

Human Bocavirus in an Immunocompromised Child Presenting with Severe Diarrhea

ABSTRACT Human bocavirus (HBoV) is frequently detected in young children with respiratory symptoms. However, the prevalence and pathogenicity of HBoV in immunocompromised patients are largely unknown. This report describes a case of life-threatening hypovolemic shock due to diarrhea associated with disseminated HBoV infection in an immunocompromised child.

Clinical Utility of Fecal Calprotectin Monitoring in Asymptomatic Patients with Inflammatory Bowel Disease: A Systematic Review and Practical Guide.

Background: In asymptomatic patients with inflammatory bowel disease (IBD), “monitoring” involves repeated testing aimed at early recognition of disease exacerbation. We aimed to determine the usefulness of repeated fecal calprotectin (FC) measurements to predict IBD relapses by a systematic literature review. Methods: An electronic search was performed in Medline, Embase, and Cochrane from inception to April 2016. Inclusion criteria were prospective studies that followed patients with IBD in remission at baseline and had at least 2 consecutive FC measurements with a test interval of 2 weeks to 6 months. Methodological assessment was based on the second Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Results: A total of 1719 articles were identified; 193 were retrieved for full text review. Six studies met eligibility for inclusion. The time interval between FC tests varied between 1 and 3 months. Asymptomatic patients with IBD who had repeated FC measurements above the studys cutoff level had a 53% to 83% probability of developing disease relapse within the next 2 to 3 months. Patients with repeated normal FC values had a 67% to 94% probability to remain in remission in the next 2 to 3 months. The ideal FC cutoff for monitoring could not be identified because of the limited number studies meeting inclusion criteria and heterogeneity between selected studies. Conclusions: Two consecutively elevated FC values are highly associated with disease relapse, indicating a consideration to proactively optimize IBD therapy plans. More prospective data are necessary to assess whether FC monitoring improves health outcomes.