Imaging of Mucosal Inflammation: Current Technological Developments, Clinical Implications, and Future Perspectives

In recent years, various technological developments markedly improved imaging of mucosal inflammation in patients with inflammatory bowel diseases. Although technological developments such as high-definition-, chromo-, and autofluorescence-endoscopy led to a more precise and detailed assessment of mucosal inflammation during wide-field endoscopy, probe-based and stationary confocal laser microscopy enabled in vivo real-time microscopic imaging of mucosal surfaces within the gastrointestinal tract. Through the use of fluorochromes with specificity against a defined molecular target combined with endoscopic techniques that allow ultrastructural resolution, molecular imaging enables in vivo visualization of single molecules or receptors during endoscopy. Molecular imaging has therefore greatly expanded the clinical utility and applications of modern innovative endoscopy, which include the diagnosis, surveillance, and treatment of disease as well as the prediction of the therapeutic response of individual patients. Furthermore, non-invasive imaging techniques such as computed tomography, magnetic resonance imaging, scintigraphy, and ultrasound provide helpful information as supplement to invasive endoscopic procedures. In this review, we provide an overview on the current status of advanced imaging technologies for the clinical non-invasive and endoscopic evaluation of mucosal inflammation. Furthermore, the value of novel methods such as multiphoton microscopy, optoacoustics, and optical coherence tomography and their possible future implementation into clinical diagnosis and evaluation of mucosal inflammation will be discussed.

[1]  Thomas D. Wang,et al.  Targeted endoscopic imaging. , 2009, Gastrointestinal endoscopy clinics of North America.

[2]  Y. Niv Small-bowel mucosal healing assessment by capsule endoscopy as a predictor of long-term clinical remission in patients with Crohn’s disease: a systematic review and meta-analysis , 2017, European journal of gastroenterology & hepatology.

[3]  Markus F Neurath,et al.  Chromoendoscopy and other novel imaging techniques. , 2006, Gastroenterology clinics of North America.

[4]  E. Finlayson,et al.  Changing Paradigms in Detection of Dysplasia and Management of Patients With Inflammatory Bowel Disease: Is Colectomy Still Necessary? , 2017, Gastroenterology.

[5]  M. Neurath,et al.  From bench to bedside: molecular imaging in inflammatory bowel diseases , 2016, Current opinion in gastroenterology.

[6]  S. Cross,et al.  High-magnification chromoscopic colonoscopy in ulcerative colitis: a valid tool for in vivo optical biopsy and assessment of disease extent , 2006, Endoscopy.

[7]  J Mudter,et al.  High definition colonoscopy combined with i-Scan is superior in the detection of colorectal neoplasias compared with standard video colonoscopy: a prospective randomized controlled trial. , 2010, Endoscopy.

[8]  M. Esaki,et al.  Mucosal vascular pattern in ulcerative colitis: observations using narrow band imaging colonoscopy with special reference to histologic inflammation , 2009, International Journal of Colorectal Disease.

[9]  W. Domschke,et al.  Fluorescence Endoscopy Using a Fluorescein-Labeled Monoclonal Antibody Against Carcinoembryonic Antigen in Patients with Colorectal Carcinoma and Adenoma , 2002, Endoscopy.

[10]  Jun Nagata,et al.  Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo. , 2008, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[11]  Confocal laser endomicroscopy , 2014 .

[12]  Anita Mahadevan-Jansen,et al.  Clinical characterization of in vivo inflammatory bowel disease with Raman spectroscopy. , 2017, Biomedical optics express.

[13]  Thomas D. Wang,et al.  Multimodal Video Colonoscope for Targeted Wide-Field Detection of Nonpolypoid Colorectal Neoplasia. , 2016, Gastroenterology.

[14]  B. V. Pedersen,et al.  Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. , 2012, Gastroenterology.

[15]  R. Kiesslich,et al.  Confocal Endomicroscopy Identifies Loss of Local Barrier Function in the Duodenum of Patients with Crohn's Disease and Ulcerative Colitis , 2014, Inflammatory bowel diseases.

[16]  Tri Giang Phan,et al.  The learning curve, interobserver, and intraobserver agreement of endoscopic confocal laser endomicroscopy in the assessment of mucosal barrier defects. , 2016, Gastrointestinal endoscopy.

[17]  Thomas D. Wang,et al.  Molecular imaging in gastrointestinal endoscopy. , 2010, Gastroenterology.

[18]  Alexander Meining,et al.  Intravenous application of fluorescein for confocal laser scanning microscopy: evaluation of contrast dynamics and image quality with increasing injection-to-imaging time. , 2008, Gastrointestinal endoscopy.

[19]  R. Kiesslich,et al.  Virtual Chromoendoscopy for Prediction of Severity and Disease Extent in Patients with Inflammatory Bowel Disease: a Randomized Controlled Study , 2013, Inflammatory bowel diseases.

[20]  D. Kao,et al.  Increased Epithelial Gaps in the Small Intestine Are Predictive of Hospitalization and Surgery in Patients With Inflammatory Bowel Disease , 2012, Clinical and Translational Gastroenterology.

[21]  B E Bouma,et al.  Optical biopsy in human gastrointestinal tissue using optical coherence tomography. , 1997, The American journal of gastroenterology.

[22]  James M. Dahlhamer,et al.  Prevalence of Inflammatory Bowel Disease Among Adults Aged ≥18 Years - United States, 2015. , 2016, MMWR. Morbidity and mortality weekly report.

[23]  Thomas D. Wang,et al.  In vivo targeting of colonic dysplasia on fluorescence endoscopy with near-infrared octapeptide , 2012, Gut.

[24]  Jeroen A. W. Tielbeek,et al.  Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR evidence-based consensus guidelines. , 2013, Journal of Crohn's & colitis.

[25]  M. Shrime,et al.  Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis. , 2014, Gastrointestinal endoscopy.

[26]  Roy M. Soetikno,et al.  Detection of Sessile Serrated Adenomas in the Proximal Colon Using Wide-Field Fluorescence Endoscopy. , 2017, Gastroenterology.

[27]  Thomas D. Wang,et al.  Quantifying human eosinophils using three-dimensional volumetric images collected with multiphoton fluorescence microscopy. , 2012, Gastroenterology.

[28]  M. Neurath,et al.  From the surface to the single cell: Novel endoscopic approaches in inflammatory bowel disease. , 2015, World journal of gastroenterology.

[29]  Roelof J Bennink,et al.  Magnetic resonance imaging in Crohn's disease , 2008 .

[30]  M. Neurath,et al.  Assessment of Crohn's disease activity by confocal laser endomicroscopy , 2012, Journal of Digestive Endoscopy.

[31]  Jürgen Popp,et al.  Raman spectroscopy--a prospective tool in the life sciences. , 2003, Chemphyschem : a European journal of chemical physics and physical chemistry.

[32]  C. Baird,et al.  The pilot study. , 2000, Orthopedic nursing.

[33]  M. Wallace,et al.  Endomicroscopy and Molecular Tools to Evaluate Inflammatory Bowel Disease. , 2016, Gastrointestinal endoscopy clinics of North America.

[34]  Gregory Zuccaro,et al.  Ex vivo histology-correlated optical coherence tomography in the detection of transmural inflammation in Crohn's disease. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[35]  David Armstrong,et al.  Clinical Practice Guidelines for the Use of Video Capsule Endoscopy. , 2017, Gastroenterology.

[36]  T. Levin,et al.  Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. , 2012, Gastroenterology.

[37]  賢二 鈴木 慢性副鼻腔炎に対するrandomized controlled study , 2002 .

[38]  F. Schmidt Meta-Analysis , 2008 .

[39]  Helmut Neumann,et al.  Label-free imaging of inflammatory bowel disease using multiphoton microscopy. , 2013, Gastroenterology.

[40]  S. Gallus,et al.  Role of early ultrasound in detecting inflammatory intestinal disorders and identifying their anatomical location within the bowel , 2003, Alimentary pharmacology & therapeutics.

[41]  K. Abrams,et al.  The risk of colorectal cancer in ulcerative colitis: a meta-analysis , 2001, Gut.

[42]  Michael Vieth,et al.  In vivo molecular imaging of colorectal cancer with confocal endomicroscopy by targeting epidermal growth factor receptor. , 2010, Gastroenterology.

[43]  Hisataka Kobayashi,et al.  Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe , 2012, Gut.

[44]  G. Kaplan,et al.  Targeted Biopsies Identify Larger Proportions of Patients With Colonic Neoplasia Undergoing High-Definition Colonoscopy, Dye Chromoendoscopy, or Electronic Virtual Chromoendoscopy. , 2016, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[45]  M. Neurath,et al.  Mucosal healing in inflammatory bowel diseases: a systematic review , 2012, Gut.

[46]  Thomas D. Wang,et al.  Gastrointestinal imaging in 2015: Emerging trends in endoscopic imaging , 2016, Nature Reviews Gastroenterology &Hepatology.

[47]  A. Amiot,et al.  European evidence based consensus for endoscopy in inflammatory bowel disease. , 2013, Journal of Crohn's & colitis.

[48]  Christopher H Contag,et al.  Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. , 2008, Nature medicine.

[49]  L. Peyrin-Biroulet,et al.  Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. , 2012, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[50]  Jürgen Popp,et al.  Beyond endoscopic assessment in inflammatory bowel disease: real-time histology of disease activity by non-linear multimodal imaging , 2016, Scientific Reports.

[51]  Tristan Barrett,et al.  Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes , 2009, Nature Medicine.

[52]  Markus F Neurath,et al.  Molecular imaging of VEGF in gastrointestinal cancer in vivo using confocal laser endomicroscopy , 2010, Gut.

[53]  H Messmann,et al.  Fluorescence endoscopy for the detection of low and high grade dysplasia in ulcerative colitis using systemic or local 5-aminolaevulinic acid sensitisation , 2003, Gut.

[54]  Noor Mohammed,et al.  Raman spectroscopy of endoscopic colonic biopsies from patients with ulcerative colitis to identify mucosal inflammation and healing , 2016, Biomedical optics express.

[55]  Ina Pavlova,et al.  Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue , 2011, Proceedings of the National Academy of Sciences.

[56]  T. Matsui,et al.  Clinical Practice Guideline for Enteroscopy , 2017, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society.

[57]  B. Sands,et al.  The SCENIC consensus statement on surveillance and management of dysplasia in inflammatory bowel disease: praise and words of caution. , 2015, Gastroenterology.

[58]  Siavash Yazdanfar,et al.  Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met , 2015, Nature Medicine.

[59]  Helmut Neumann,et al.  Beyond white light endoscopy: the role of optical biopsy in inflammatory bowel disease. , 2013, World journal of gastroenterology.

[60]  D. Hommes,et al.  Misclassification of dysplasia in patients with inflammatory bowel disease: Consequences for progression rates to advanced neoplasia , 2011, Inflammatory bowel diseases.

[61]  R. Kiesslich,et al.  In vivo molecular imaging with cetuximab, an anti-EGFR antibody, for prediction of response in xenograft models of human colorectal cancer , 2013, Endoscopy.

[62]  David Lieberman,et al.  Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline , 2013, Endoscopy.

[63]  角田 明良,et al.  結腸癌術後の早期離床・早期経口摂取に関するProspective Randomized Trial , 2002 .

[64]  R. Kiesslich,et al.  Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. , 2007, Gastroenterology.

[65]  Martin Goetz,et al.  Molecular imaging in gastroenterology , 2013, Nature Reviews Gastroenterology &Hepatology.

[66]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[67]  Helmut Neumann,et al.  Prospective evaluation of the learning curve of confocal laser endomicroscopy in patients with IBD. , 2011, Histology and histopathology.

[68]  Helmut Neumann,et al.  Confocal laser endomicroscopy: technical advances and clinical applications. , 2010, Gastroenterology.

[69]  Jordi Rimola,et al.  Magnetic resonance imaging for evaluation of Crohn's disease: Validation of parameters of severity and quantitative index of activity , 2011, Inflammatory bowel diseases.

[70]  S. Cross,et al.  Confocal endomicroscopy in ulcerative colitis: differentiating dysplasia-associated lesional mass and adenoma-like mass. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[71]  Takuya Inoue,et al.  Comparative study of conventional colonoscopy and pan-colonic narrow-band imaging system in the detection of neoplastic colonic polyps: a randomized, controlled trial , 2008, Journal of Gastroenterology.

[72]  Taketo Yamaguchi,et al.  Linked-color imaging improves endoscopic visibility of colorectal nongranular flat lesions. , 2017, Gastrointestinal endoscopy.

[73]  M. Schmitt,et al.  Classification of inflammatory bowel diseases by means of Raman spectroscopic imaging of epithelium cells. , 2012, Journal of biomedical optics.

[74]  Markus F Neurath,et al.  Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. , 2007, Gastroenterology.

[75]  M. Gee,et al.  Imaging in the Evaluation of the Young Patient With Inflammatory Bowel Disease: What the Gastroenterologist Needs to Know , 2014, Journal of pediatric gastroenterology and nutrition.

[76]  U. Mahmood Optical molecular imaging approaches in colorectal cancer. , 2010, Gastroenterology.

[77]  Paul Fockens,et al.  Probe-based confocal laser endomicroscopy. , 2009, Gastroenterology.

[78]  Thomas Rösch,et al.  Narrow-band versus white-light high definition television endoscopic imaging for screening colonoscopy: a prospective randomized trial. , 2009, Gastroenterology.

[79]  Wolfgang Uter,et al.  In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease , 2014, Nature Medicine.

[80]  Maria Pellisé,et al.  Advanced imaging for detection and differentiation of colorectal neoplasia: European Society of Gastrointestinal Endoscopy (ESGE) Guideline , 2014, Endoscopy.

[81]  S. Staibano,et al.  In-vivo characterization of DALM in ulcerative colitis with high-resolution probe-based confocal laser endomicroscopy. , 2011, World journal of gastroenterology.

[82]  P. Rutgeerts,et al.  Predictability of the postoperative course of Crohn's disease. , 1990, Gastroenterology.

[83]  S. Travis,et al.  P213 Influence of clinical history on scoring of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) , 2013 .

[84]  I. Lansdorp-Vogelaar,et al.  Cost effectiveness of surveillance for GI cancers. , 2016, Best practice & research. Clinical gastroenterology.

[85]  Xiu-Li Zuo,et al.  Classification of Inflammation Activity in Ulcerative Colitis by Confocal Laser Endomicroscopy , 2010, The American Journal of Gastroenterology.

[86]  R. Kiesslich,et al.  Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14⁺ macrophages. , 2011, Gastroenterology.

[87]  O. Maeda,et al.  Confocal endomicroscopy in patients with ulcerative colitis , 2008, Journal of gastroenterology and hepatology.

[88]  Jürgen Pohl,et al.  Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial , 2010, Gut.

[89]  K R Abrams,et al.  Meta‐analysis: colorectal and small bowel cancer risk in patients with Crohn's disease , 2006, Alimentary pharmacology & therapeutics.

[90]  M. Gee,et al.  Inflammatory bowel disease imaging: Current practice and future directions. , 2016, World journal of gastroenterology.

[91]  Ralph Weissleder,et al.  Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice. , 2002, Gastroenterology.

[92]  M. Neurath,et al.  Multispectral Optoacoustic Tomography in Crohn's Disease: Noninvasive Imaging of Disease Activity. , 2016, Gastroenterology.

[93]  Anita Mahadevan-Jansen,et al.  Development of Spectral Markers for the Discrimination of Ulcerative Colitis and Crohn's Disease Using Raman Spectroscopy , 2011, Diseases of the colon and rectum.

[94]  Haijun Li,et al.  MEMS-based multiphoton endomicroscope for repetitive imaging of mouse colon. , 2015, Biomedical optics express.

[95]  E. Kowalik SSRI Use in Pregnancy and Congenital Heart Defects: A Meta-Analysis of Population Based Cohort Studies , 2016 .

[96]  S. Vermeire,et al.  IOIBD technical review on endoscopic indices for Crohn's disease clinical trials , 2015, Gut.

[97]  R. Kiesslich,et al.  Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn’s disease: a pilot study , 2014, Endoscopy.

[98]  Pierre Boulanger,et al.  Mind The Gaps: Confocal Endomicroscopy Showed Increased Density of Small Bowel Epithelial Gaps in Inflammatory Bowel Disease , 2011, Journal of clinical gastroenterology.

[99]  R. Kiesslich,et al.  Beyond white light: optical enhancement in conjunction with magnification colonoscopy for the assessment of mucosal healing in ulcerative colitis , 2017, Endoscopy.

[100]  K. Kumamoto,et al.  Blue laser imaging endoscopy system for the early detection and characterization of colorectal lesions: a guide for the endoscopist , 2016, Therapeutic advances in gastroenterology.

[101]  P. Rutgeerts,et al.  Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. , 2004, Gastrointestinal endoscopy.

[102]  A. Sanabria,et al.  Randomized controlled trial. , 2005, World journal of surgery.

[103]  R. Kiesslich,et al.  Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease , 2011, Gut.

[104]  A. Barkun,et al.  Paradigm Shift in the Surveillance and Management of Dysplasia in Inflammatory Bowel Disease (West) , 2016, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society.

[105]  Gregory Zuccaro,et al.  In vivo colonoscopic optical coherence tomography for transmural inflammation in inflammatory bowel disease. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[106]  M. Ooi,et al.  Full-Spectrum Endoscopy Improves Surveillance for Dysplasia in Patients With Inflammatory Bowel Diseases. , 2017, Gastroenterology.

[107]  D. Hommes,et al.  High frequency of early colorectal cancer in inflammatory bowel disease , 2008, Gut.

[108]  Thomas D. Wang,et al.  Molecular endoscopy for targeted imaging in the digestive tract. , 2016, The lancet. Gastroenterology & hepatology.

[109]  Christian Matthäus,et al.  Label-Free Molecular Imaging of Biological Cells and Tissues by Linear and Nonlinear Raman Spectroscopic Approaches. , 2017, Angewandte Chemie.

[110]  Vivek Kaul,et al.  Confocal laser endomicroscopy. , 2009, Gastrointestinal endoscopy.

[111]  P. Lakatos,et al.  The burden of inflammatory bowel disease in Europe. , 2013, Journal of Crohn's & colitis.

[112]  D. Altman,et al.  Translational Gastroenterology , 2011 .

[113]  M. Neurath,et al.  Molecular imaging of mucosal α4β7 integrin expression with the fluorescent anti-adhesion antibody vedolizumab in Crohn's disease. , 2017, Gastrointestinal endoscopy.

[114]  Frcp Dr. Gregory B. Haber MD Role of endoscopy in inflammatory bowel disease , 2005, Digestive Diseases and Sciences.

[115]  S. Aceves Food allergy testing in eosinophilic esophagitis: what the gastroenterologist needs to know. , 2014, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[116]  Wolfgang Uter,et al.  Multispectral Optoacoustic Tomography for Assessment of Crohn's Disease Activity. , 2017, The New England journal of medicine.

[117]  Markus F Neurath,et al.  Molecular imaging: interaction between basic and clinical science. , 2010, Gastroenterology clinics of North America.

[118]  Ralph Weissleder,et al.  Colonic adenocarcinomas: near-infrared microcatheter imaging of smart probes for early detection--study in mice. , 2007, Radiology.

[119]  C. Hawkey,et al.  High definition colonoscopy vs. standard video endoscopy for the detection of colonic polyps: a meta-analysis , 2011, Endoscopy.

[120]  R. Pearson,et al.  Narrow-Band Versus White-Light High Definition Television Endoscopic Imaging for Screening Colonoscopy: A Prospective Randomized Trial , 2009 .

[121]  P. Siersema,et al.  Clinical implications of low grade dysplasia found during inflammatory bowel disease surveillance: a retrospective study comparing chromoendoscopy and white-light endoscopy , 2016, Endoscopy.

[122]  L. Peyrin-Biroulet,et al.  Diffusion-weighted magnetic resonance without bowel preparation for detecting colonic inflammation in inflammatory bowel disease , 2010, Gut.

[123]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[124]  Mihir S. Wagh,et al.  Endoscopic Optical Coherence Tomography (OCT): Advances in Gastrointestinal Imaging , 2014, Gastroenterology research and practice.

[125]  R. Kiesslich,et al.  Confocal laser endomicroscopy for the in vivo detection of intraepithelial neoplasia in Peutz-Jeghers polyps. , 2010, Endoscopy.

[126]  Yingsheng Cheng,et al.  Molecular imaging of inflammatory bowel disease , 2014 .

[127]  R. Kiesslich,et al.  Limited applicability of chromoendoscopy-guided confocal laser endomicroscopy as daily-practice surveillance strategy in Crohn's disease. , 2016, Gastrointestinal endoscopy.

[128]  E. Dekker,et al.  Pilot study of probe-based confocal laser endomicroscopy during colonoscopic surveillance of patients with longstanding ulcerative colitis. , 2011, Endoscopy.

[129]  A. Polglase,et al.  Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. , 2004, Gastroenterology.

[130]  Martin Goetz,et al.  Microscopic imaging in endoscopy: endomicroscopy and endocytoscopy , 2014, Nature Reviews Gastroenterology &Hepatology.