Advantages of Proactive Therapeutic Drug Monitoring in a Prospective Cohort of Children With Inflammatory Bowel Disease Treated With Anti-Tumour Necrosis Factor.

ABSTRACT: Few studies have addressed whether proactive therapeutic drug monitoring (TDM) results in improved clinical outcomes in children with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor. The aim of this study was to investigate the impact of using proactive TDM in this patient group.Pilot single-centre observational study to accrue data on patients managed with proactive TDM.More patients in the proactive TDM cohort were managed by escalating the infliximab (IFX) regime (P < 0.001). The need for switching to different biologics was significantly lower in this patient group (P < 0.001).The introduction of proactive TDM resulted in a significant reduction of patients requiring switch of their primary biologic. The results of this study are indicators that proactive TDM offers a better method of managing children with IBD on IFX therapy.

Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Paediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn's and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison. DESIGN: We convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8-10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19. CONCLUSION: Our COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.

Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based Guideline From European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ∼20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. METHODS: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. RESULTS: These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. CONCLUSIONS: These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.

Management of Paediatric Ulcerative Colitis, Part 2: Acute Severe Colitis-An Evidence-based Consensus Guideline From the European Crohn's and Colitis Organization and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND AND AIM: Acute severe colitis (ASC) is one of the few emergencies in pediatric gastroenterology. Tight monitoring and timely medical and surgical interventions may improve outcomes and minimize morbidity and mortality. We aimed to standardize daily treatment of ASC in children through detailed recommendations and practice points which are based on a systematic review of the literature and consensus of experts. METHODS: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Fifteen predefined questions were addressed by working subgroups. An iterative consensus process, including 2 face-to-face meetings, was followed by voting of the national representatives of ECCO and all members of the Paediatric Inflammatory Bowel Disease (IBD) Porto group of ESPGHAN (43 voting experts). RESULTS: A total of 24 recommendations and 43 practice points were endorsed with a consensus rate of at least 91% regarding diagnosis, monitoring, and management of ASC in children. A summary flowchart is presented based on daily scoring of the Paediatric Ulcerative Colitis Activity Index. Several topics have been altered since the previous 2011 guidelines and from those published in adults. DISCUSSION: These guidelines standardize the management of ASC in children in an attempt to optimize outcomes of this intensive clinical scenario.

Real-life Anti-tumor Necrosis Factor Experience in More Than 500 Patients: High Co-immunosuppression Rates But Low Rates of Quantifying Treatment Response.

OBJECTIVE: The aim of this study was to measure the effectiveness, safety, and use of anti-tumor necrosis Factor (TNF) therapy in pediatric inflammatory bowel disease in the United Kingdom (UK). METHODS: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment +/or the Paediatric Crohn Disease Activity Index. RESULTS: A total of 37 centers participated (23/25 specialist pediatric inflammatory bowel disease sites). A total of 524 patients were included: 429 with Crohn disease (CD), 76 with ulcerative colitis (UC), and 19 with IBD unclassified (IBDU). Eighty-seven percent (488/562) of anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (interquartile range 0.63-2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by Physician Global Assessment compared to 41% (88/217) by Paediatric Crohn Disease Activity Index (Kappa (κ) 0.28 = only "fair agreement"; P < 0.001.Where documented, 77% (53/69) of patients with CD responded to induction; and 65% (46/71) entered remission. A total of 2287 infusions and 301.96 years of patient' follow-up (n = 385) are represented; adverse events affected 3% (49/1587) infliximab and 2% (2/98) adalimumab infusions (no deaths or malignancies). Peri-anal abscess drainage was less common after anti-TNF initiation (CD), that is 26% (27/102) before, 7% (3/42) after (P = 0.01); however, pre and post anti-TNF data collection was not over equal time periods. CONCLUSIONS: Anti-TNFs are effective treatments, usually given with thiopurine co-immunosuppression. This study highlights deficiencies in formal documentation of effect and disparity between disease severity scoring tools, which need to be addressed to improve ongoing patient care.

Item Generation and Reduction Toward Developing a Patient-reported Outcome for Pediatric Ulcerative Colitis (TUMMY-UC).

BACKGROUND: The Pediatric Ulcerative Colitis Activity Index (PUCAI) is a noninvasive clinician-based index, which reflects disease severity in pediatric ulcerative colitis (UC) when no endoscopy is performed. Here, we aimed to explore signs and symptoms important to children with UC and their caregivers as the first stage of developing a patient-reported outcome (PRO) measure for pediatric UC (ie, the TUMMY-UC index) to supplement endoscopic assessment. METHODS: Concept elicitation qualitative interviews were performed with children who have UC and their caregivers in 6 centers. Items were rank-ordered by the interviewees according to the frequency of endorsement and importance, graded on a 1 to 5 scale. RESULTS: A total of 46 children (ages 12.5 ±â€Š3.3 years, range 7-18, 48% boys, 83% with pancolitis, 24% with moderate-severe disease) and 33 caregivers were interviewed (ie, 79 interviews). The following items were identified by the children, in decreasing order of weights: abdominal pain (importance × frequency weight 3.9), rectal bleeding (3.6), stool frequency (3.0), stool consistency (3.0), general well-being/fatigue (2.9), urgency (1.9), and nocturnal stools (1.6). Two other items were scored lower: lack of appetite (1.1) and weight loss (0.6). Children 13 to 18 years comprehended adult vocabulary, children 8 to 12 years comprehended simple vocabulary, and younger children had poor understanding in completing the questions. CONCLUSIONS: In this first stage of the TUMMY-UC development, items were generated and ranked by input from patients. These items are now being explored for optimal vocabulary and response options. The TUMMY-UC will supplement the PUCAI in clinical trial outcome assessment.

Does orthodontic treatment harm children's diets?

INTRODUCTION: Despite the many courses of fixed orthodontic treatment being undertaken worldwide, the question of this treatment harming children's diets remains unanswered. METHODS: A hospital-based prospective cohort design was adopted to investigate the effects of treatment on dietary intake and behaviour, body fat (BMI) and fat percentage in 124 patients (41.9% male) aged 11-14 (mean 13.1, SD 0.91) years, consecutively recruited to test and control groups. Both groups completed socio-demographic and food frequency questionnaires, body mass index (BMI) and body fat percentage measures at baseline and follow-up. Test patients completed follow-up pain diaries and dietary questionnaires. RESULTS: Both groups were comparable at baseline, with a dropout rate of 12.1%. The impact on dietary behaviour was significantly higher at 6 weeks compared to 3 months (P<0.002). Pain (biological factor), analgesic consumption or professional dietary advice (behaviour modification) had no influence whilst, a high BMI status at baseline appeared to be the only significant moderator of change in fat percentage (P<0.05) and impacts on dietary behaviour (P<0.049) at follow-up. CONCLUSIONS: The findings show no significant detrimental effect on dietary intake or behaviour, BMI and fat percentage, during the first 3 months, of orthodontic treatment and may impart a beneficial/protective effect.

Contemporary outcomes for ulcerative colitis inpatients admitted to pediatric hospitals in the United Kingdom.

BACKGROUND: Pediatric ulcerative colitis (UC) care is variable with a lack of appropriate guidelines to guide practice until recently. METHODS: UC inpatients <17 years old admitted to 23 U.K. pediatric hospitals had clinical details collected between September 2010 and 2011. Comparative data for 248 patients were available from a previous audit in 2008. RESULTS: One hundred and seventy-six patients (98 males) of median age 13 years (interquartile range, 10-13) were analyzed; 23 were elective surgical admissions, 47 new diagnoses, and 106 needed acute medical care for established UC. Median length of stay was 6 days (interquartile range, 3-10) with no deaths. Eighty-eight of 126 patients (70%) with active disease had standard stool cultures performed (3 [2%] were positive), and 57 (45%) had Clostridium difficile toxin tested (none positive). Twenty-five of 66 (38%) emergency admissions had an abdominal x-ray on admission, and 13 of 66 patients (20%) had a Pediatric Ulcerative Colitis Activity Index score. There were 3 cases of toxic megacolon and 2 thromboses. Eighty-one of 116 patients (71%) responded to steroids. Nineteen patients who did not respond adequately to steroids received rescue therapy (7 infliximab, 11 ciclosporin, and 1 both) with overall response rate of 90%; 7 patients needed surgery acutely, 5 without previous rescue therapy. Compared with the 2008 data, stool culture rates improved significantly (86 of 121 [71%] versus 76 of 147 [52%], P = 0.001) as did heparinization rates (15 of 150 [10%] versus 5 of 215 [2%], P = 0.002) and rescue therapy usage (17 of 33 [52%] versus 10 of 38 [26%], P = 0.03). CONCLUSIONS: There were signs of improving UC care with significantly increased rates of stool culture and rescue therapy. The majority of sites, however, did not use Pediatric Ulcerative Colitis Activity Index scores.

Development of a radial ventricular assist device using numerical predictions and experimental haemolysis.

The objective of this study was to demonstrate the potential of Computational Fluid Dynamics (CFD) simulations in predicting the levels of haemolysis in ventricular assist devices (VADs). Three different prototypes of a radial flow VAD have been examined experimentally and computationally using CFD modelling to assess device haemolysis. Numerical computations of the flow field were computed using a CFD model developed with the use of the commercial software Ansys CFX 13 and a set of custom haemolysis analysis tools. Experimental values for the Normalised Index of Haemolysis (NIH) have been calculated as 0.020 g/100 L, 0.014 g/100 L and 0.0042 g/100 L for the three designs. Numerical analysis predicts an NIH of 0.021 g/100 L, 0.017 g/100 L and 0.0057 g/100 L, respectively. The actual differences between experimental and numerical results vary between 0.0012 and 0.003 g/100 L, with a variation of 5% for Pump 1 and slightly larger percentage differences for the other pumps. The work detailed herein demonstrates how CFD simulation and, more importantly, the numerical prediction of haemolysis may be used as an effective tool in order to help the designers of VADs manage the flow paths within pumps resulting in a less haemolytic device.

The requirements and barriers to successful transition of adolescents with inflammatory bowel disease: differing perceptions from a survey of adult and paediatric gastroenterologists.

BACKGROUND AND AIM: Preliminary data highlight the importance of appropriate transition for successful transfer of adolescents with IBD from paediatric to adult care. The aim of this study was to identify both the perceived needs of adolescent IBD patients and the barriers to successful transition from the perspective of professionals involved in their care. METHODS: A postal questionnaire was distributed to UK adult and paediatric gastroenterologists with an interest in IBD. The questionnaire utilised closed questions as well as ranked items on the importance of the various competencies of adolescents with IBD required for successful transition. RESULTS: Response rate of 62% and 49% for paediatric and adult gastroenterologists respectively was achieved. A structured transition service was perceived as very important by 80% paediatric compared to 47% adult gastroenterologists (p=0.001). A higher proportion of adult than paediatric gastroenterologists identified inadequacies in the preparation of adolescents for transfer (79% and 42%, p=0.001). The main areas of perceived deficiency in preparation identified were patient lack of knowledge about the condition and treatment, lack of self advocacy and co-ordination of care. Lack of resources, clinical time, and a critical mass of patients were the factors ranked highest by both groups as barriers to transition care. Both adult (65%) and paediatric gastroenterologists (62%) highlighted suboptimal training in adolescent medicine for adult gastroenterologists. CONCLUSIONS: This survey highlights differences in the perception of adult and paediatric gastroenterologists in the management of transition care and perceived competencies for adolescents with IBD. Lack of training and inadequate resources are the main barriers identified for development of a successful transition service.

A qualitative study of the early effects of fixed orthodontic treatment on dietary intake and behaviour in adolescent patients.

The aim of this research was to assess the effects of fixed orthodontic treatment on dietary intake and behaviour. The study adopted a qualitative approach by conducting semi-structured one-to-one interviews, with 10 adolescent patients (four males; six females) undergoing fixed orthodontic treatment with a mean age of 13.21 (SD 0.71) years. The interviews were transcribed and analysed, by two independent investigators, using framework principles in which emerging themes and ideas were identified. These emerging themes were characterized and compared between patients until no new themes or ideas were identified. Framework analysis identified the following two main themes arising in adolescent patients undergoing fixed orthodontic treatment: pain experience and dietary change. All patients reported varying degrees of pain during the first few days of treatment, after which it was seen to reduce. All patients reported that their diet had changed in response to pain, inability to bite and chew, and in response to dietary instructions given to them by their orthodontist. Patients felt that their eating habits had become healthier during treatment. The study highlights the need to explore dietary changes in a larger population base.

Prevalence and management of anemia in children, adolescents, and adults with inflammatory bowel disease.

BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) are more likely to have Crohn's disease (CD) than ulcerative colitis (UC) and their disease tends to be more extensive and severe than in adults. We hypothesized that the prevalence of anemia would therefore be greater in children and adolescents than in adults attending IBD outpatient clinics. METHODS: Using the WHO age-adjusted definitions of anemia we assessed the prevalence, severity, type, and response to treatment of anemia in patients attending pediatric, adolescent, and adult IBD clinics at our hospital. RESULTS: The prevalence of anemia was 70% (41/59) in children, 42% (24/54) in adolescents, and 40% (49/124) in adults (P < 0.01). Overall, children (88% [36/41]) and adolescents (83% [20/24]) were more often iron-deficient than adults (55% [27/49]) (P < 0.01). Multivariate logistic regression showed that both active disease (odds ratio [OR], 4.7 95% confidence interval [CI], 2.5, 8.8) and attending the pediatric clinic (OR 3.7; 95% CI, 1.6, 8.4) but not the adolescent clinic predicted iron deficiency anemia. Fewer iron-deficient children (13% [5/36]) than adolescents (30% [6/20]) or adults (48% [13/27]) had been given oral iron (P < 0.05); none had received intravenous iron compared with 30% (6/20) adolescents and 41% (11/27) adults (P < 0.0001). CONCLUSIONS: Anemia is even more common in children than in older IBD patients. Oral iron was given to half of adolescents and adults but, despite similar tolerance and efficacy, only a quarter of children with iron-deficient anemia. Reasons for the apparent underutilization of iron therapy include a perceived lack of benefit and concerns about side effects, including worsening of IBD activity.

Mesh-driven vector field clustering and visualization: an image-based approach.

Vector field visualization techniques have evolved very rapidly over the last two decades, however, visualizing vector fields on complex boundary surfaces from computational flow dynamics (CFD) still remains a challenging task. In part, this is due to the large, unstructured, adaptive resolution characteristics of the meshes used in the modeling and simulation process. Out of the wide variety of existing flow field visualization techniques, vector field clustering algorithms offer the advantage of capturing a detailed picture of important areas of the domain while presenting a simplified view of areas of less importance. This paper presents a novel, robust, automatic vector field clustering algorithm that produces intuitive and insightful images of vector fields on large, unstructured, adaptive resolution boundary meshes from CFD. Our bottom-up, hierarchical approach is the first to combine the properties of the underlying vector field and mesh into a unified error-driven representation. The motivation behind the approach is the fact that CFD engineers may increase the resolution of model meshes according to importance. The algorithm has several advantages. Clusters are generated automatically, no surface parameterization is required, and large meshes are processed efficiently. The most suggestive and important information contained in the meshes and vector fields is preserved while less important areas are simplified in the visualization. Users can interactively control the level of detail by adjusting a range of clustering distance measure parameters. We describe two data structures to accelerate the clustering process. We also introduce novel visualizations of clusters inspired by statistical methods. We apply our method to a series of synthetic and complex, real-world CFD meshes to demonstrate the clustering algorithm results.

Natural history of paediatric inflammatory bowel diseases over a 5-year follow-up: a retrospective review of data from the register of paediatric inflammatory bowel diseases.

OBJECTIVES: The natural history of paediatric inflammatory bowel diseases (IBDs) is poorly understood. We aim to describe the disease course in this cohort and generate prognostic information for patients and clinicians. MATERIALS AND METHODS: Patient records from 6 tertiary paediatric gastroenterology centres were reviewed to generate data concerning original diagnosis, change in diagnosis, family history, surgical interventions, growth, and presence of extragastrointestinal manifestations. RESULTS: Data were collected on 116 children with Crohn disease (CD), 74 with ulcerative colitis (UC), and 20 with indeterminate colitis (IC), followed for a mean period of 3.42, 3.3, and 2.9 years from date of diagnosis, respectively. A male predominance is demonstrated in CD. Revision of diagnosis in patients with IC is mainly to UC, with most children receiving a definitive diagnosis within 2 years of initial presentation. Of the children with UC, 17.6% underwent 1 or more major operations with a median time to surgery of 1.92 years. Of children with CD, 11.6% underwent 1 or more major intraabdominal procedures with a median time to surgery of 1.83 years. We recorded a positive family history in 2.7%, 8.2%, and 10% of cases for CD, UC, and IC, respectively. For both boys and girls with CD, but only for boys with UC, height standard deviation score became more negative over time. CONCLUSIONS: This retrospective study quantifies certain distinctions between IBDs diagnosed in paediatric and adult populations. We document a trend toward male predominance in children with CD. We also note impaired linear growth in children with CD, whereas it appears maintained in girls with UC. We also have recorded a low incidence of IBDs in the families of this cohort and suggest that environmental influences may be of greater importance. We document that major intraabdominal surgery may be required in about 15% of patients with either UC or CD within 2 years of diagnosis, and that the majority of those diagnosed initially with IC will be reclassified as either UC or CD within 2 years.

Genetically modified enterotoxigenic Escherichia coli vaccines induce mucosal immune responses without inflammation.

OBJECTIVE: Enterotoxigenic Escherichia coli (ETEC) is a major cause of acute diarrhoea in children in the developing world, in travellers and in the military. Safe, effective vaccines could reduce morbidity and mortality. As immunity to ETEC is strain specific, the ability to create vaccines in vitro which express multiple antigens would be desirable. It was hypothesised that three genetically attenuated ETEC strains, one with a genetic addition, would be immunogenic and safe, and they were evaluated in the first licensed UK release of genetically modified oral vaccines. METHODS: Phase 1 studies of safety and immunogenicity were carried out at a Teaching Hospital in London. Varying oral doses of any of three oral vaccines, or placebo, were administered to volunteers of both sexes (n = 98). Peripheral blood responses were measured as serum antibodies (IgG or IgA) by ELISA, antibody-secreting cell (ASC) responses by enzyme-linked immunospot (ELISPOT), and antibody in lymphocyte supernatant (ALS) by ELISA. Mucosal antibody secretion was measured by ELISA for specific IgG and IgA in whole gut lavage fluids (WGLFs). RESULTS: Significant mucosal IgA responses were obtained to colonisation factors CFA/I, CS1, CS2 and CS3, both when naturally expressed and when genetically inserted. Dose-response relationships were most clearly evident in the mucosal IgA in WGLF. Vaccines were well tolerated and did not elicit interleukin (IL) 8 or IL6 secretion in WGLF. CONCLUSIONS: Genetically modified ETEC vaccines are safe and induce significant mucosal IgA responses to important colonisation factors. Mucosal IgA responses were clearly seen in WGLF, which is useful for evaluating oral vaccines.

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children.

Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzene-sulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P = 0.023) and increased IGF-I (P = 0.05). In humans, the IL-6 -174 G/C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 -174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growth-retarded than those with the GC or CC genotypes (height SD score, -0.51 vs. -0.10; P = 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg/dl, P = 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P = 0.7). Thus, the IL-6 -174 genotype mediates growth failure in children with Crohn's disease.

IgM: mucosal response in acute diarrhoeal disease of infants.

OBJECTIVE: Investigating the secretory immune response during the acute phase of diarrhoeal disease is hampered by difficulty in collecting suitable control specimens. This is particularly the case in infants, as they are the most severely affected by this disease. In this study we examined the mucosal immunoglobulin response during the acute phase of diarrhoeal disease in infants. MATERIAL AND METHODS: The intestinal outputs of secretory immunoglobulins (IgA, IgM) and non-secretory proteins (IgG, albumin, A1AT, eosinophil cationic protein (ECP)) were measured in 14 African children with acute watery diarrhoea (less than 3 days). These data were compared with those of 38 controls from the same area who had undergone whole-gut lavage (WGL) (inducing non-pathogenic watery diarrhoea) in a previous study of intestinal immunity and inflammation. Intestinal secretion rates were measured by multiplying the concentration of the substances by the rate of administration of WGL fluid (equal to the output) or by the output of diarrhoea. Statistical comparison was made using the Mann-Whitney U-test. RESULTS: IgA output in subjects with diarrhoea was 1.8-fold greater (80.7 versus 45.6 mg/kg/day, p=0.03), whereas IgM output was 10-fold greater (21 versus 2.1 mg/kg/day, p=0.0001). Albumin, A1AT and IgG were all also greater to varying degrees (2.5-6.8-fold). ECP was unchanged. Increases in the non-secretory proteins would suggest increased permeability of the gastrointestinal tract but transudation of serum was insufficient to explain the rise in immunoglobulin output. CONCLUSIONS: The 10-fold increase in IgM secretion compared with a smaller relative increase in IgA suggests that this is the primary mucosal immune response in acute diarrhoeal disease.