IX) New Diagnostic Modalities in Digestive Diseases

Symposium (IX)

NEW DIAGNOSTIC MODALITIES IN DIGESTIVE DISEASES

USING TRANSIENT ELASTOGRAPHY & MMP7 FOR EARLY DIAGNOSIS OF LIVER FIBROSIS

Jia-Feng Wu Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

Biliary atresia (BA) is a neonatal, inflammatory, progressive fibro-sclerosing cholangiopathy of infancy, resulting in obstruction of the biliary tract. To date, BA remains the major cause of chronic liver insufficiency, portal hypertension, and liver transplantation in children. Although ongoing cholestasis, which further aggravates liver cirrhosis and portal hypertension, exists in the majority of children with BA, a timely and successful Kasai operation may still delay or even decrease the need for liver transplantation. It is generally accepted that the Kasai operation is more successful in children with BA when performed before 60 days of age. However, early identification and timely Kasai operation in children with BA remain challenging. In Taiwan, we have adopted the “stool color card” concept of Professor Akira Matsui. The universal screening for BA using infant stool color cards leads to earlier detection of BA, more timely Kasai operations, and improved long-term prognoses of children with BA in Taiwan. Other than infant stool color card, the BA screening program with urine sulfated bile acid (USBA) and serum direct bilirubin after birth were also performed in Japan and USA with promising results to detect cholestatic infant in early. After the screening program, the clinicians encounter more and more cholestatic infants than before. Timely identification of BA among large cholestatic infant pool become a new challenge in the universal cholestatic screening era. The diagnostic accuracy of abdominal ultrasound, MRCP, and HIDA scan are not good enough to date. Our serial study demonstrated the beneficial role of transient elastography assessment of LSM and serum MMP-7 in the non-invasive differentiation between BA and non-BA cholestatic infants.

Prompt and early detection of neonatal cholestasis is essential for early workup for the etiology of disease nature. We need the combination various kinds of modalities to assist a correct and prompt diagnosis of BA to ensure early operation. Other than cholestatic liver disease, we also applied the transient elastography in a longterm cohort of chronic HBV infected patients from childhood to adult hood to elucidate the natural course and predictors of liver fibrosis in chronic HBV infected patients. Our serial studies demonstrated the role of transient elastography in the diagnosis and follow-up of both the pediatric viral hepatitis and cholestatic liver diseases.

Symposium (IX)

NEW DIAGNOSTIC MODALITIES IN DIGESTIVE DISEASES

IMPROVEMENT OF DIAGNOSIS METHODS FOR INFECTIOUS DIARRHEA

Shiuh-Bin Fang Division of Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Infectious diarrhea causing considerable morbidity and mortality worldwide and rehydration is the essence of its treatment regardless of pathogenic etiologies. Timely accurate diagnosis for infectious etiologies facilitates epidemiologic analysis and appropriate management, particularly in complicated bacterial infections. Reliable and accurate diagnosis prompts correct use of empirical antibiotics for reducing fatality caused by bacteremia and extra-intestinal complications. Nontyphoidal Salmonella (NTS) remains the leading cause of bacterial enteric infections in children, elderly, and immunocompromised patients and constitutes substantial socioeconomic burden because of increasing antimicrobial resistance (AMR). In 2017, WHO announced Salmonella resistant to fluoroquinolone and third generation cephalosporin as one of the priority pathogens for development and research of new antibiotics. Good diagnostics can provide not only specific micropathogens but also their antimicrobial susceptibility tests in time, especially for bacteria. Diagnostics for detecting virus includes ELISA, multiplex PCR, or viral culture but no AMR. The traditional CLSI bacterial cultures with subsequent antimicrobial susceptibility tests or minimal inhibitory concentrations (MICs) remain the mainstream of diagnosing NTS infection. However, drawbacks of the CLSI methods included false negative results due to partial antibiotic treatment, low detection rates, and time consuming. The currently used CLSI method for detecting bacterial SMR from patients’ samples takes at least 3 days, during which overuse or incorrect use of empirical antibiotics is one of the reasons why bacterial AMR increased dramatically in the past decades. Nowadays we mainly use approaches to reduce antibiotic consumption and AMR, including institutional antimicrobial stewardship programs, infection prevention, rational use of antimicrobials, regulation on over-the-counter availability of antibiotics, improving hand hygiene, and improving infection prevention and control. However, we need more efficient approaches for combating AMR. Our team endeavored in developing improvement and innovation in diagnostics for NTS. In addition to culture-based colony-printing assisted by antibodycoated gold nanoparticles, molecular diagnostics including multiplex PCR for detecting bacteria and their AMR according to the plasmid AMR genes identified by whole genome sequencing (WGS), non-PCR based methods such as biochip, and other new platforms will be introduced. Another challenge is how to rapidly and accurately detect AMR-associated mutations from patients’ samples without relying on expensive and time-consuming WGS or gene sequencing. Promising prospective is to extend diagnostics into prognostics for predicting invasive NTS infections from the aspects of bacterial virulence and host immunity. Taken together, precise diagnostics and prognostics can provide novel tools for efficient evaluation and prediction for better treatment and outcome of patients with infectious diarrhea.

Symposium (IX)

NEW DIAGNOSTIC MODALITIES IN DIGESTIVE DISEASES

GUT ECOSYSTEM, MICROBIOTA, AND DIGESTIVE DISEASES

Alessio Fasano President, European Biomedical Research Institute of Salerno (EBRIS) Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children – Harvard Medical School, Boston, MA, USA

Improved hygiene leading to a reduced exposure to microorganisms have been implicated as one possible cause for the recent ‘epidemic’ of chronic inflammatory diseases (CID) in industrialized countries. That is the essence of the hygiene hypothesis that argues that rising incidence of CID may be, at least in part, the result of lifestyle and environmental changes that have made us too “clean” for our own good. Apart from genetic makeup and exposure to environmental triggers, three more elements have been recently identified being key players in the pathogenesis of CID, including gastrointestinal diseases, including inflammatory bowel diseases (IBD), food allergies, eosinophilic enteropathy (EoE) and celiac disease (CD). A third element is the inappropriate Increase in intestinal permeability, which may be influenced by the composition of the gut microbiota, has been proposed. The immune system responsible of the tolerance-immune response represents the fourth element involved in the pathogenesis of CID. Finally, the composition of gut microbiome and its epigenetic influence on the host genomic expression has been identified as a fifth element in causing CID. The gut microbiome consists of more than 100 trillion microorganisms, most of which are bacteria. It has been just recently recognized that there is a close bidirectional interaction between gut microbiome and our immune system, and this cross talk is highly influential in shaping the host gut immune system function and, ultimately, shifting genetic predisposition to clinical outcome. This observation led to a revisitation of the possible causes of CID epidemics, suggesting a key pathogenic role of microbiome composition. While factors such as modality of deliver, neonatal feeding regimens, use of antibiotics, infections can influence microbiota composition, diet is by far the most important variable affecting gut ecosystem. Therefore, re-shaping gut microbiota is becoming an extremely active area of research for the prevention or treatment of a multitude of CID. In order to achieve this goal, it is necessary to move the microbiota studies from observational to mechanistic, mainly identified diagnostic/ biomarkers tools to stratify patients for possible treatment or, more ambitiously, prevention of these GI CID. The Celiac Disease Genome, Environment, Microbiome, and Metabolome (CD-GEMM) study is a birth cohort prospective observational study designed to achieve this goal. CD-GEMM is the first project to combine a multiomic approach with robust environmental data to identify and validate biomarker predictors of development in at-risk infants. The project provides solid mechanistic evidence of the disease onset and progression in relation to dynamic changes in abnormal gut microbiota causing epigenetic modifications controlling gut barrier and immune functions, based on the in-depth evaluation of 500 infants at risk observed from birth. The project will support novel personalized prediction

(personalize treatment) and disease interception (prevention) approaches that attempt to modulate gut microbiota to re- establish/maintain immune homeostasis. The biomarkers identified in this project will contribute to a better understanding of the pathogenesis of Cd and other GI disorders and the possibility to manipulate the microbiota through pre/pro/symbiotic administration +/- dietary changes for prevention and treatment, a complete paradigm shift in chronic GI diseases pathogenesis and early intervention. The identification of specific CD metabolic phenotypes will also help to define biomarkers that can be used as diagnostic tools and patient stratification models for other conditions in which the interplay between genome, microbiome and metabolic profile has been suspected or proved.