Background Living with undiagnosed symptomatic coeliac disease is connected with deteriorated health, and persons with coeliac disease often wait a long time for their diagnosis. A mass screening would lower the delay, but its cost-effectiveness is still unclear. Our aim was to determine the cost-effectiveness of a coeliac disease mass screening at 12 years of age, taking a life course perspective on future benefits and drawbacks. Methods The cost-effectiveness was derived as cost per quality-adjusted life-year (QALY) using a Markov model. As a basis for our assumptions, we mainly used information from the Exploring the Iceberg of Celiacs in Sweden (ETICS) study, a school-based screening conducted in 2005/2006 and 2009/2010, where 13,279 12-year-old children participated and 240 were diagnosed with coeliac disease, and a study involving members of the Swedish Coeliac Association with 1031 adult participants. Results The cost for coeliac disease screening was 40,105 Euro per gained QALY. Sensitivity analyses support screening based on high compliance to a gluten-free diet, rapid progression from symptom-free coeliac disease to coeliac disease with symptoms, long delay from celiac disease with symptoms to diagnosis, and a low QALY score for undiagnosed coeliac disease cases. Conclusions A coeliac disease mass screening is cost-effective based on the commonly used threshold of 50,000 Euro per gained QALY. However, this is based on many assumptions, especially regarding the natural history of coeliac disease and the effects on long-term health for individuals with coeliac disease still eating gluten.

LINKED CONTENTThis article is linked to Størdal et al papers. To view these articles, visit https://doi.org/10.1111/apt.16361 and https://doi.org/10.1111/apt.16389

In 1970, the European Society for Paediatric Gastroenterology, Hepatolgy and Nutrition (ESPGHAN) published guidelines for diagnosing coeliac disease based on the morphological changes in the small intestinal mucosa. Very recently, revised criteria were published.1 Here, we present a short review of the history of coeliac diagnosis and a summary of the current diagnostic guidelines, including the extended use of non-biopsy diagnosis in specific cases. Seventy years have now passed since the Dutch paediatrician Willem Karel Dicke (1905-1962) made the ground-breaking discovery that gluten is the offensive agent in coeliac disease (CD). During World War II, there was a great shortage of food, particularly bread. He noticed that children with CD improved and saw a connection between low dietary wheat intake and low coeliac rate. He reported his research findings, first in his doctoral thesis in Dutch in 1950, and three years later in two seminal papers in English. At that time, diagnosis of CD was based on standard malabsorption tests such as determination of faecal fat and the xylose absorption test. A second decisive step forward in the diagnosis of CD was the small intestinal suction biopsy technique developed by the British adult gastroenterologist Margot Shiner (1923-1998). In the 1950s, she was working under the illustrious hepatologist Dame Sheila Sherlock (1918-2001) in London and began to perform gastric biopsies in adult patients with liver disease. As quoted from A Phillips,2 ‘it is thought that Sheila Sherlock prompted Margot Shiner to push on into the duodenum’. So she did, and in 1963 Shiner published a report on the procedure in children.2 Since then, the introduction of endoscopic biopsy under deep sedation has refined the technique for obtaining small intestinal mucosal material in a fast, safe, and, for the child, more comfortable way. The histopathologic classification of coeliac enteropathy had no standardised way of reporting until the 1990s when M Marsh published the ‘Marsh criteria’, further specified by G Oberhuber, the ‘Marsh-Oberhuber criteria’. These comprised increased number of intraepithelial lymphocytes, crypt hyperplasia and various degrees of villous atrophy. As time went by, it became evident that the mucosal lesion can be patchy and sometimes confined to the most proximal part of duodenum only, so-called bulbar CD. Thus, multiple biopsies performed endoscopically are now recommended. Beginning in the 1970s, the use of safe serologic markers indicating CD was successively introduced. First out were anti-reticulin and anti-gliadin antibody tests, soon followed by the more sensitive and specific analyses of antibodies against endomysium (EMA) and against the enzyme tissue transglutaminase (tTGA). Both tests are routinely performed on IgA antibodies, therefore, the patient´s IgA status should be evaluated as part of the serologic workup. Biopsy of the small intestine made it possible to be more precise when diagnosing CD based on the morphology of the small bowel enteropathy in the biopsy. Thus, in 1970, ESPGHAN published a three-biopsy scheme for diagnosis: Biopsy 1. showing a subtotal/total villous atrophy when the child was on a diet containing gluten; Biopsy 2. showing mucosal recovery while on a gluten-free diet; Biopsy 3. showing mucosal relapse following a period of gluten challenge. This diagnostic procedure gained wide acceptance and was implemented into routine paediatric care. The added diagnostic value of serological tests was acknowledged by ESPGHAN in their revised criteria formulated in 1990. Accordingly, in a child with suspected CD, a biopsy showing typical coeliac enteropathy at presentation, followed by serologic normalisation and clinical remission on a gluten-free diet, was considered sufficient for the definite diagnosis. The movement to a non-biopsy based diagnosis was first recommended by ESPGHAN in their revised guidelines published in 2012. Thus, in children with clinical symptoms indicating CD, a tTGA antibody test showing titres more than ten times the upper normal limit, plus raised EMA titres and positive HLA DQ2/DQ8 genotype test was accepted as a definite CD diagnosis. These criteria reduced the need for biopsy in up to 50% of children investigated for suspected CD. In non-symptomatic children, however, a biopsy was still mandatory. The so-called ProCeDE study showed that children could be accurately diagnosed with CD without biopsy analysis.3 Of note, the recommendation on omitting biopsy is a ‘conditional recommendation’ that should be discussed with the family which should be informed about the option of biopsy for diagnosis. Very recently, ESPGHAN published a further revision of the diagnostic guidelines.1 The recommendation for HLA typing has now been removed and there is no requirement for biopsy in non-symptomatic children with high coeliac serology marker titres. Thus, a diabetic child with high TGA titres but without gastrointestinal symptoms can be diagnosed as CD without biopsy. In contrast to the situation in Europe, North American paediatric gastroenterologists still rely on 15-year-old guidelines for the diagnosis of CD, which means that small intestinal biopsy is still required in every case with suspected symptoms despite access to modern well established serologic testing, a practice now questioned.4 The extended use of non-biopsy diagnosis will reduce the need for endoscopic biopsy and release resources for increasing efforts to find children with hitherto undiagnosed CD. This may pave the way for mass screening projects with the potential of finding many cases of undiagnosed CD in the paediatric population. This is exemplified by a large Swedish screening study including 12-year-old schoolchildren, where a CD incidence of 3% was established.5 Of the children shown to have CD, only one third had a diagnosis of CD prior to screening. In view of the increased risk for complications in untreated or inadequately treated CD, general screening for CD should be considered if shown to be health economically cost-effective. The authors thank Dr Peter Cox for revising the English language. The authors have no conflicts of interest to declare.

OBJECTIVE:We previously performed a population-based mass screening of coeliac disease in children aged 12 years in two birth cohorts resulting in 296 seropositive children, of whom 242 were diagnosed with coeliac disease after duodenal biopsies. In this follow-up study, we wanted to identify new cases in the screening population that tested negative-either converting from potential coeliac disease (seropositive but normal duodenal mucosa) or converting from seronegative at screening to diagnosed coeliac disease. METHODS:All seropositive children were invited to a follow-up appointment 5 years after the screening with renewed serological testing and recommended endoscopic investigation if seropositive. Seronegative children in the screening study (n=12 353) were linked to the National Swedish Childhood Coeliac Disease Register to find cases diagnosed in healthcare during the same period. RESULTS:In total, 230 (77%) came to the follow-up appointment, including 34 of 39 with potential coeliac disease. Of these, 11 (32%) had converted to coeliac disease. One new case was found in the National Swedish Childhood Coeliac Disease Register who received the diagnosis through routine screening in children with type 1 diabetes. CONCLUSIONS:There is a high risk of conversion to coeliac disease among those with potential disease. However, a negative screening test was associated with a very low risk for a clinical diagnosis within a follow-up period of 5 years.

To the Editor,Van Kruiningen has recently suggested that the obstruction of the lymphatic vasculature is the fundamental mechanism in the pathogenesis of Crohn´s disease (CD).[1, 2] Accordingly, CD was described as "segmental elephantiasis of the intestine, and sometimes other body parts."This was supported by impressive images of obstructed lymphatic drainage in patients with CD. [1] Van Kruiningen thus dismissed other putative pathogenic factors, such as dysbiosis of the intestinal microbiota and aberrant mucosal immune responses, as being of secondary importance compared to the lymphatic obstruction.We believe, however, that the pathogenesis of CD is considerably OBM Hepatology and Gastroenterology

Seventy years ago, the Swedish pediatrician Rolf Kostmann (1909-1982) was the first to report on a previous unknown lethal hereditary neutropenia in infants, Kostmann's disease. This essay presents the man behind the syndrome rather than focusing on the disease itself.

Background: Dysbiosis, that is, disturbed gut microbial balance, is well documented in Crohn's disease (CD). We aimed at studying CD-linked dysbiosis in children by analyzing fecal microbe-associated characteristics, previously not reported in children. Methods: This observational study included 28 children with active CD and healthy controls. We assessed the following three indicators of gut microbiota metabolism in the feces: the presence of tryptic activity, the conversion of cholesterol to coprostanol, and the conversion of bilirubin to urobilinogen. Results: The fecal tryptic activity was significantly higher in children with active CD compared to the control group (P < 0.01). The fecal coprostanol of the CD children was close to zero and differed significantly from the controls (P < 0.001). Furthermore, the children with CD had very low fecal urobilinogen, differing significantly from the control group (P < 0.001). Conclusions: The significant differences in levels of fecal bacterial metabolites in patients with active CD compared to healthy controls reflect major perturbation of gut microbial functions and have not previously been reported in children. This fits well with the prevailing concept of a dysbiotic gut microbiota in CD and may have important clinical implications by bringing the dysbiosis back into balance.

In 2012, revised criteria for diagnosing childhood coeliac disease were published by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and incorporated into the revised Swedish guidelines the same year. These made it possible, in certain cases, to diagnose coeliac disease without taking small bowel biopsies. This survey assessed the extent to which the new guidelines were implemented by Swedish paediatric clinics two years after their introduction. In October 2014, we distributed a paper questionnaire including five questions on diagnostic routines to the 40 paediatric clinics in university or regional hospitals in Sweden that perform small bowel biopsies. All 36 (90%) clinics that responded used anti-tissue transglutaminase antibodies as the initial diagnostic test and some also used serological markers. Most clinics (81%) used endoscopy and took multiple duodenal biopsies, whereas only a few (19%) occasionally employed a suction capsule. Almost all clinics (86%) omitted taking small bowel biopsies in symptomatic children with repeatedly high coeliac serology and positive genotyping, thereby avoiding the need for invasive endoscopy under anaesthesia. The 2012 Swedish Paediatric Coeliac Disease Diagnostic Guidelines had been widely accepted and implemented in routine health care two years after their introduction.

Aim In 2012, revised criteria for diagnosing childhood coeliac disease were published by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and incorporated into the revised Swedish guidelines the same year. These made it possible, in certain cases, to diagnose coeliac disease without taking small bowel biopsies. This survey assessed the extent to which the new guidelines were implemented by Swedish paediatric clinics two years after their introduction. Methods In October 2014, we distributed a paper questionnaire including five questions on diagnostic routines to the 40 paediatric clinics in university or regional hospitals in Sweden that perform small bowel biopsies. Results All 36 (90%) clinics that responded used anti-tissue transglutaminase antibodies as the initial diagnostic test and some also used serological markers. Most clinics (81%) used endoscopy and took multiple duodenal biopsies, whereas only a few (19%) occasionally employed a suction capsule. Almost all clinics (86%) omitted taking small bowel biopsies in symptomatic children with repeatedly high coeliac serology and positive genotyping, thereby avoiding the need for invasive endoscopy under anaesthesia. Conclusion The 2012 Swedish Paediatric Coeliac Disease Diagnostic Guidelines had been widely accepted and implemented in routine health care two years after their introduction.

Crohn's disease (CD) is a chronic mucosal inflammation that affects the intestinal barrier function, for example, by altering the intestinal permeability. This pilot clinical study investigated the impact of oral human immunoglobulin (OHIG) treatment on permeability characteristics in children with active luminal Crohn's disease. The study was performed at the Department of Paediatrics, Norrköping Hospital, Sweden. Intestinal permeability was studied in three boys aged 13, 15 and 18 years with active CD, before and after a six-week treatment programme with OHIG, using different-sized polyethylene glycols as the test molecules. Three age- and sex-matched children with active CD treated with exclusive enteral nutrition (EEN) were also studied. OHIG and EEN resulted in virtually similar reductions in the signs and symptoms of mucosal inflammation. However, OHIG, unlike EEN, appeared to normalise mucosal transfer leading to a normalisation of the maximum permeation of the small PEG molecules, as well as less restrictions of the larger PEG molecules. Our study found that OHIG appeared to normalise the mucosal barrier. This suggests that it could offer a new additional and versatile treatment for paediatric CD patients, with a minimal risk of adverse effects.

In the medical literature, diseases and syndromes are sometimes named after the first person to publish a report on, or describe, a condition. This is, of course, a great honour, both for the physician and his or her country and only a handful of Swedish medical researchers have achieved this. Swedish paediatrician Rolf Kostmann (Fig. 1) joined this elite group following his report on what he called infantile hereditary agranulocytosis (agranulocytosis infantilis hereditaria), which was first published 1950 in Swedish (1), and his dissertation in 1956 (2), He was the first to describe severe chronic neutropenia as an inherited disease. This article is protected by copyright. All rights reserved.

Aim: Crohn's disease (CD) is a chronic mucosal inflammation that affects the intestinal barrier function, for example, by altering the intestinal permeability. This pilot clinical study investigated the impact of oral human immunoglobulin (OHIG) treatment on permeability characteristics in children with active luminal Crohn's disease.Methods: The study was performed at the Department of Paediatrics, Norrkoping Hospital, Sweden. Intestinal permeability was studied in three boys aged 13, 15 and 18 years with active CD, before and after a six-week treatment programme with OHIG, using different-sized polyethylene glycols as the test molecules. Three age-and sex-matched children with active CD treated with exclusive enteral nutrition (EEN) were also studied.Results: OHIG and EEN resulted in virtually similar reductions in the signs and symptoms of mucosal inflammation. However, OHIG, unlike EEN, appeared to normalise mucosal transfer leading to a normalisation of the maximum permeation of the small PEG molecules, as well as less restrictions of the larger PEG molecules.Conclusion: Our study found that OHIG appeared to normalise the mucosal barrier. This suggests that it could offer a new additional and versatile treatment for paediatric CD patients, with a minimal risk of adverse effects.

Acta PaediatricaVolume 107, Issue 2 p. 219-222 Paediatric Essay John Walker-Smith: the father of European paediatric gastroenterology Lars Stenhammar, Corresponding Author Lars Stenhammar larsstenhammar@yahoo.com Department of Paediatrics, Linköping University, Norrköping Hospital, Norrköping, SwedenSearch for more papers by this authorLotta Högberg, Lotta Högberg Department of Paediatrics, Linköping University, Norrköping Hospital, Norrköping, SwedenSearch for more papers by this authorLars Browaldh, Lars Browaldh Department of Paediatrics, Sachsska Children′s Hospital, Stockholm, SwedenSearch for more papers by this authorMats Eriksson, Mats Eriksson Department of Paediatrics, Uddevalla Hospital, Uddevalla, SwedenSearch for more papers by this authorBo Tjellström, Bo Tjellström Department of Paediatrics, Linköping University, Norrköping Hospital, Norrköping, Sweden Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, SwedenSearch for more papers by this author Lars Stenhammar, Corresponding Author Lars Stenhammar larsstenhammar@yahoo.com Department of Paediatrics, Linköping University, Norrköping Hospital, Norrköping, SwedenSearch for more papers by this authorLotta Högberg, Lotta Högberg Department of Paediatrics, Linköping University, Norrköping Hospital, Norrköping, SwedenSearch for more papers by this authorLars Browaldh, Lars Browaldh Department of Paediatrics, Sachsska Children′s Hospital, Stockholm, SwedenSearch for more papers by this authorMats Eriksson, Mats Eriksson Department of Paediatrics, Uddevalla Hospital, Uddevalla, SwedenSearch for more papers by this authorBo Tjellström, Bo Tjellström Department of Paediatrics, Linköping University, Norrköping Hospital, Norrköping, Sweden Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, SwedenSearch for more papers by this author First published: 08 December 2017 https://doi.org/10.1111/apa.14156Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume107, Issue2February 2018Pages 219-222 RelatedInformation

Background The features of paediatric coeliac disease have changed in recent decades. We hypothesised that the age at diagnosis might continue to increase, whereas the severity of symptoms should decrease. Methods In the present study, filed data on 1030 paediatric patients diagnosed with coeliac disease between 1973 and 2013 were analysed. The information available covered 99.8% of small bowel biopsies and included information on sex, age and clinical symptoms. Results The age at diagnosis increased significantly, from a mean of 2.2 years during the first 10 years to 8.2 years in recent years. The proportion of children with severe symptoms declined from 92.8% to 78%, as did the proportion of biopsies characterised by severe pathology. In recent years, the monosymptomatic form of coeliac disease has been more common, and the number of patients detected at screening has increased. The frequency of patients with gastrointestinal symptoms, extra-intestinal symptoms, and failure to thrive and/or short stature at presentation decreased. Conclusions The mean age of newly diagnosed patients has increased over the last 15 years. Currently, coeliac disease shows a less severe picture in terms of symptoms and intestinal pathology. Younger children suffer primarily from gastrointestinal symptoms and growth failure, and adolescents from extra-intestinal manifestations.