Gut transit time, using radiological contrast imaging, to predict early signs of necrotizing enterocolitis.

BACKGROUND: Immature gut motility in preterm neonates may be a risk factor for necrotizing enterocolitis (NEC). Using preterm pigs as a model for infants, we hypothesized that intestinal dysmotility precedes NEC development. METHODS: Eighty-five preterm pigs were fed increasing amounts of milk diets to induce NEC lesions, as detected at autopsy on day 5. Gut transit time was determined on day 4 by x-ray imaging after oral intake of contrast solution. RESULTS: No clinical or radiological signs of NEC were detected on day 4, but macroscopic NEC lesions were recorded in 59% of pigs (n = 50) on day 5. Relative to pigs without NEC (noNEC, n = 35), pigs with small intestinal lesions (siNEC, n = 18) showed delayed stomach emptying time (StEmpty) and time for contrast to reach cecum (ToCecum) already on day 4. Pigs with lesions only in colon (coNEC, n = 20) showed more diarrhea, shorter ToCecum time, but longer small intestinal emptying time (SiEmpty). ToCecum time predicted siNEC and coNEC lesions with a receiver-operator characteristic area under the curve of 78-81%. CONCLUSIONS: Region-dependent changes in gut transit time is associated with early NEC development in preterm pigs. How gut dysmotility is related to NEC in preterm infants requires further investigations. IMPACT: Using preterm pigs as a model for preterm infants, we show that gut transit time, using serial x-ray contrast imaging, was changed in individuals with NEC-like lesions before they showed the typical radiological signs of NEC. Thus prolonged transit time across the entire gut was recorded when NEC lesions appeared in the small intestine but not when lesions were detected only in the colon. Until now, recordings of food transit have mainly investigated changes in the upper gut. Using serial x-rays, this study describes food transit across the entire gut and documents a region-dependent effect of NEC lesions on gut transit changes in preterm individuals. The findings provide proof of concept for use of x-ray contrast imaging as a tool to monitor gut transit in preterm pigs as models for infants. Delayed passage across the entire gut may be an early sign of small intestinal NEC, at least in pigs. More studies are needed to confirm relations in infants. In the future, it might be possible to use x-ray contrast imaging in preterm infants to better understand gut motility in relation to early NEC progression and need for medical NEC treatment.

Staging of necrotising enterocolitis by Bell's criteria is supported by a statistical pattern analysis of clinical and radiological variables.

AIM: Necrotising enterocolitis (NEC) is often staged according to Bell's 1978 system, but today's NEC cases are more immature than the ones that were used to develop Bell's stages. Our aim was to explore the clinical and radiographic findings of contemporary cases of NEC and spontaneous intestinal perforation. METHODS: We coded the clinical records of all cases of NEC stages I-III and spontaneous intestinal perforation born in 2006-2015 at the tertiary department of neonatology at Rigshospitalet, Denmark, for 16 clinical and radiographic symptoms and signs at disease onset and at climax. These variables were explored using principal component analysis, which can detect patterns in large datasets. RESULTS: We reviewed 640 clinical records and included 158 cases of NEC or spontaneous intestinal perforation. When we entered the clinical and radiographic signs at disease climax, the cases were roughly grouped according to Bell's stages, except for a small group of NEC III cases, who were grouped with the cases of spontaneous intestinal perforation. CONCLUSION: An analysis of the pattern of clinical and radiographic findings in a 2006-2015 population of NEC cases supported Bell's 1978 staging system. However, the separation between NEC and spontaneous intestinal perforation still poses a difficult task.

Biopsy-verified bronchiolitis obliterans and other noninfectious lung pathologies after allogeneic hematopoietic stem cell transplantation.

Bronchiolitis obliterans (BO) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Lung biopsy is the gold standard for diagnosis. This study describes the course of BO and assesses the congruity between biopsy-verified BO and a modified version of the National Institutes of Health's consensus criteria for BO syndrome (BOS) based exclusively on noninvasive measures. We included 44 patients transplanted between 2000 and 2010 who underwent lung biopsy for suspected BO. Of those, 23 were diagnosed with BO and 21 presented other noninfectious pulmonary pathologies, such as cryptogenic organizing pneumonia, diffuse alveolar damage, interstitial pneumonia, and nonspecific interstitial fibrosis. Compared with patients with other noninfectious pulmonary pathologies, BO patients had significantly lower values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and maximal mid-expiratory flow throughout follow-up, but there was no difference in the change in pulmonary function from the time of lung biopsy. The BO diagnosis was not associated with poorer overall survival. Fifty-two percent of patients with biopsy-verified BO and 24% of patients with other noninfectious pulmonary pathology fulfilled the BOS criteria. Pathological BO diagnosis was not superior to BOS criteria in predicting decrease in pulmonary function beyond the time of biopsy. A lung biopsy may provide a characterization of pathological patterns that can extend our knowledge on the pathophysiology of HSCT-related lung diseases.

Radiographic Imaging to Evaluate Food Passage Rate in Preterm Piglets as a Model for Preterm Infants.

Objectives and study: Gut motility in infants mature with increasing post-menstrual age and is affected by numerous hormonal, immunological and nutritional factors. However, it remains unclear how age and diet influence gut motility and its relation to feeding intolerance and gastric residuals in preterm neonates. Using preterm piglets as a model for infants, we investigated if contrast passage rate, as determined by X-ray contrast imaging, is affected by gestational age at birth, advancing postnatal age and different milk diets. Methods: Contrast passage rate was evaluated using serial abdominal X-ray imaging on postnatal day 4 and 18 in preterm and near-term piglets fed infant formula, colostrum or intact bovine milk, with or without added fortifier (total n = 140). Results: Preterm piglets had a faster small intestinal passage rate of contrast solution at day 4 of life than near-term piglets (SIEmpty, hazard ratio (HR): 0.52, 95%CI [0.15, 0.88], p < 0.01). Formula fed piglets at day 4 had a faster passage rate of contrast to caecum (ToCecum, HR: 0.61, 95%CI [0.25,0.96], p = 0.03), and through the colon region (CaecumToRectum, p < 0.05, day 4) than colostrum fed preterm piglets. The time for contrast to leave the stomach, and passage through the colon in day 4 preterm piglets were slower than in older piglets at day 18 (both, p < 0.05). Adding a nutrient fortifier increased body growth, gastric residuals, intestinal length and weight, but did not affect any of the observed passage rates of the contrast solution. Conclusion: Serial X-ray contrast imaging is a feasible method to assess food passage rate in preterm piglets. Contrast passage rate through different gut segments is affected by gestational age at birth, postnatal age, and milk diet. The preterm piglet could be a good model to investigate clinical and dietary factors that support maturation of gut motility and thereby feeding tolerance and gut health in preterm infants.

Early puberty in internationally adopted girls: hormonal and clinical markers of puberty in 276 girls examined biannually over two years.

BACKGROUND AND AIMS: Retrospective studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Hypothetically, this could be due to selection bias. The aim of this study was to determine age at reaching pubertal milestones in healthy internationally adopted girls in a prospective, clinical study. METHODS: A longitudinal cohort study including 276 randomly recruited internationally adopted girls. At baseline, age ranged from 4 to 13 years. Participants were followed with biannual examinations over a period of 2 years. Examinations included height, weight, Tanner staging, blood sampling and bone age assessment. Age distribution at entering pubertal stages B2-B5 (breast development), PH1-PH5 (pubic hair development) and menarche was estimated by probit analysis. Data were compared to a reference population of Danish-born girls, studied cross-sectionally. RESULTS: Mean age at B2+ was 9.5 years (95% prediction interval 7.1-12.0 years) and mean age at menarche was 12.1 (10.2-14.0) years in adopted girls, which was significantly lower compared to the reference group (p < 0.0003). 16% of adopted girls entered stage B2 before 8 years of age. The puberty-related rise in LH, FSH and estradiol was detected at earlier ages in adopted girls compared to the reference group. CONCLUSION: Internationally adopted girls have a significantly higher risk of precocious pubertal maturation compared to Danish-born girls.

Early pituitary-gonadal activation before clinical signs of puberty in 5- to 8-year-old adopted girls: a study of 99 foreign adopted girls and 93 controls.

CONTEXT: Recent studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Clinical studies including a contemporary control group are lacking. OBJECTIVE: The objective was to study clinical, biochemical, and ultrasonographic markers of pituitary-gonadal activation in prepubertal adopted girls and a control group in the same age categories. SETTING: The study took place at University Hospital, Copenhagen, Denmark. DESIGN AND PARTICIPANTS: The study included randomly selected internationally adopted girls [(n = 99; mean age, 6.9 (5.1-8.5) yr] and controls of Danish origin [n = 93; mean age, 6.8 (5.2-8.5) yr] who were studied cross-sectionally. METHODS: Height, weight, and pubertal stage were assessed with serum levels of reproductive hormones. Size and morphology of internal genitals were evaluated by ultrasonography. Bone age was evaluated by x-ray of the left hand. RESULTS: Serum values of FSH were significantly higher in prepubertal adopted girls compared with controls [median, 1.4 (95% confidence interval, 0.4-3.6) vs. 1.0 (0.4-2.4) IU/liter; P <0.001]. Serum estradiol was above detection limit (>18 pmol/liter) in 46.5% of prepubertal adopted girls and 20.7% of controls (P = 0.001). In prepubertal adopted girls, the proportion of measurable samples increased significantly with age [odds ratio, 2.5 (95% confidence interval, 1.3-5.0; P = 0.009]. In controls, the odds ratio was 1.0 (0.6-1.7) (P = 0.9). Serum SHBG levels were significantly lower in prepubertal adopted girls compared with controls [99.0 (50.4-153.0) vs. 115.0 (53.1-202.1); P < 0.001]. CONCLUSION: Five- to 8-yr-old adopted girls showed signs of increased pituitary as well as gonadal activity despite prepubertal phenotype in the majority of girls. Our findings suggest that early onset of puberty in adopted girls is centrally driven.

Chronic infection with Achromobacter xylosoxidans in cystic fibrosis patients; a retrospective case control study.

BACKGROUND: In cystic fibrosis (CF), chronic infection of the airways with Achromobacter xylosoxidans have become more frequent. The pathogenic role of this is yet unclear. METHODS: A retrospective case-control study of all patients chronically infected with A. xylosoxidans for at least 3 years. 15 patients (6 males) with chronic A. xylosoxidans infection were matched by age, FEV(1) and body mass index z-score to 15 controls (7 males) at the time of establishment of chronic infection. Clinical parameters of the groups were compared from the time of establishment of chronic infection until spring 2006, giving a follow-up time of 3-11 years. Chest X-rays taken 3 years prior to establishment of chronic infection and after 3 years of chronic infection were compared using a modified Brasfield score. Finally, strains from individual patients were analysed using PFGE to investigate possible cross-infection. RESULTS: The median slope of decline of FEV(1) in the case group changed from +3.1% to -0.5% predicted/year (p<0.002). In the control group, median slope of decline in FEV(1) changed from +1.5% to -0.4% predicted/year (n.s.). Median slope of decline in FVC in the case group changed from +3.5% to -0.5% predicted/year (p<0.002). In the control group, median slope of decline in FVC changed from +1.7% to +0.4% predicted/year (n.s.). No significant difference in the slopes of decline of FEV(1) or FVC was found between the case group and the control group at either time. Change in BMI z-score was calculated for each group before and during chronic infection. No difference was found between the groups at any time or within a group. Specific antibodies against A. xylosoxidans were measured in patients with chronic infection. Patients with rapidly increasing antibody levels showed significantly faster deterioration in FEV(1) (p<0.05) and FVC (p<0.02). Chest X-ray scores increased in 6 of 10 chronically infected patients and in 3 of 10 controls (n.s.). Eight patients harboured a common A. xylosoxidans strain, indicating either cross-infection or a common source. CONCLUSION: A. xylosoxidans may lead to a decline in lung function in a subgroup of chronically infected CF patients characterised by a rapid increase in specific precipitating antibodies. Cross-infection may possibly occur.

Probiotics to prevent necrotising enterocolitis in very preterm infants.

INTRODUCTION: Meta-analyses of randomised trials have shown that probiotics reduce the risk of necrotising enterocolitis (NEC) in preterm infants. However, the generalisability of these results, particularly for the most preterm infants, remains unresolved. Hence, we wanted to evaluate the benefit of implementing prophylactic use of probiotics as standard care in infants younger than 30 weeks of gestation. METHODS: Two three-year periods were compared. The first period was prior to a policy change. In this period no probiotics were used. The second period featured routine administration of probiotics (bifidobacillus and lactobacillus) once daily by nasogastric tube from the third day of life. The main outcome: NEC grades 2 and 3 were assessed in a blinded fashion from a clinical abstract and available X-rays. RESULTS: A total of 381 infants treated before the change of policy were compared with 333 infants treated after the policy change had been introduced. There was no statistically significant change in NEC (odds ratio (OR) = 0.75, p = 0.34, 95% confidence interval (CI): 0.43-1.30). The OR for death was 0.92 (p = 0.55, 95% CI: 0.62-1.40). Unexpectedly, symptoms of NEC appeared earlier in the latter period (median six versus 14 days, p = 0.004). No side effects and no blood cultures with lactobacillus or bifidobacterium were observed. CONCLUSIONS: This historically controlled study did not indicate that probiotics had a significant effect on NEC. We continue our practice, but larger cohort studies or meta-analyses of such studies are needed to confirm previous beneficial findings in randomised trials. FUNDING: none. TRIAL REGISTRATION: Clinicaltrials.gov NCT01670916.