Rome Foundation Clinical Diagnostic Criteria for Disorders of Gut-Brain Interaction

The Rome criteria, which define disorders of gut-brain interaction (DGBIs), are extensively applied in epidemiologic research, pathophysiologic studies, treatment trials, and clinical practice. The requirement for long periods of symptom presence and high symptom frequencies facilitated the use of the Rome criteria in epidemiology studies and treatment trials but has hampered clinical application when these requirements were not fulfilled. The Rome Foundation proposes a modification of the diagnostic criteria for clinical practice, where a DGBI diagnosis can still be made if (1) the nature of the symptoms corresponds to those in the DGBI Rome IV diagnostic criteria and (2) the symptoms are bothersome (interfering with daily activities or requiring attention, causing worry or interference with quality of life). If this is the case, a lower frequency and a shorter duration (8 weeks or more) than those required for the Rome DGBI diagnostic threshold are allowed, provided that there is clinical confidence that other diagnoses have been sufficiently ruled out based on presentation and additional investigations as needed. Applying these criteria for clinical practice will allow the clinician to make a diagnosis, reduce unnecessary diagnostic studies, and enhance the patient-provider relationship. Further research is needed to validate these recommendations. DGBIs formerly known as functional gastrointestinal disorders, are characterized by clusters of symptoms. Their pathophysiology relates to any combination of altered motility, visceral sensitivity, epithelial barrier, mucosal immune function, microbiota, or gut–central nervous system neural processing. As such, routine investigations identify no underlying structural abnormality that readily explains the symptoms. 1Drossman D. A. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology. 2016; 150: 1262-1279Abstract Full Text Full Text PDF Scopus (1413) Google Scholar The development of symptom-based criteria arose more than 3 decades ago because of the need to identify patients who had gastrointestinal symptoms for which there was no mechanistic explanation for diagnosis in clinical practice and for selection in clinical trials for DGBIs because there was no criterion standard or biomarker. Using irritable bowel syndrome (IBS) as the prime example, in the 1980s, pharmaceutical companies became interested in targeting this disorder for treatment. However, there was no diagnostic standard, and clinically, diagnosis was made by exclusion. A 1988 review of clinical trials for IBS found that entry criteria varied to the degree that patients would enter with and without abdominal pain, or some would have diarrhea and others, constipation. The author concluded that not a single IBS treatment trial reported to date has used an adequate operational definition of IBS. 2Klein K. B. Controlled treatment trials in the irritable bowel syndrome: a critique. Gastroenterology. 1988; 95: 232-241Abstract Full Text PDF PubMed Google Scholar During this period, investigators were doing epidemiologic and factor analytic studies to characterize normal and abnormal bowel habit3Drossman D. A. Sandler R. S. McKee D. C. et al. Bowel patterns among subjects not seeking health care: use of a questionnaire to identify a population with bowel dysfunction. Gastroenterology. 1982; 83: 529-534Abstract Full Text PDF PubMed Scopus (666) Google Scholar, 4Thompson W. G. Heaton K. W. Functional bowel disorders in apparently health people. Gastroenterology. 1980; 79: 283-288Abstract Full Text PDF PubMed Google Scholar, 5Whitehead W. E. Crowell M. D. Bosmajian L. et al. Existence of irritable bowel syndrome supported by factor analysis of symptoms in two community samples. Gastroenterology. 1990; 98: 336-340Abstract Full Text PDF PubMed Google Scholar and performing clinical studies to distinguish patients with IBS from those with other diseases. 6Manning A. P. Thompson W. G. Heaton K. W. et al. Towards positive diagnosis of the irritable bowel. Br Med J. 1978; 2: 653-654Crossref PubMed Scopus (1287) Google Scholar Using these data, a group of experts formed a working team to create diagnostic criteria by consensus using a Delphi approach, 7Milholland A. V. Wheeler S. G. Heieck J. J. Medical assessment by a Delphi group opinion technic. New Engl J Med. 1973; 298: 1272-1275Crossref Scopus (196) Google Scholar, 8Torsoli A. Corazziari E. The WTR’s, the Delphic oracle and the Roman conclaves. Gastroenterol Int. 1991; 4: 44-45Google Scholar and the first consensus-based diagnostic criteria for IBS were published. 9Thompson W. G. Dotevall G. Drossman D. A. et al. Irritable bowel syndrome: guidelines for the diagnosis. Gastroenterol Int. 1989; 2: 92-95Google Scholar Subsequently, additional working teams were formed to develop a classification system for all of the DGBIs based on regional anatomy (esophageal, gastroduodenal, bowel, biliary, and anorectal). 10Drossman D. A. Thompson W. G. Talley N. J. et al. Identification of subgroups of functional bowel disorders. Gastroenterol Int. 1990; 3: 159-172Google Scholar This work resulted in the creation of the Rome Foundation, which in 1994 published the first book characterizing and classifying patients with these disorders (now called Rome I). 11Drossman D. A. Richter J. E. Talley N. J. et al. The functional gastrointestinal disorders: diagnosis, pathophysiology and treatment. Little, Brown and Company, Boston, 1994Google Scholar This process continued with Rome II (2000), Rome III (2006), and Rome IV (2016). Currently, with Rome IV, there are 33 adult and 17 pediatric DGBIs, and validation studies support their use. 12Ford A. C. Bercik P. Morgan D. G. et al. Validation of the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gastroenterology. 2013; 145: 1262-1270Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 13Vanner S. J. Depew W. T. Paterson W. et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol. 1999; 94: 2912-2917Crossref PubMed Scopus (242) Google Scholar, 14Palsson O. S. Taub E. Cook III, E. et al. Validation of Rome criteria for functional gastrointestinal disorders by factor analysis. Am J Gastroenterol. 1996; 91: 2000Google Scholar, 15Whitehead W. E. Palsson O. Thiwan S. M. et al. Development and validation of the Rome III diagnostic questionnaire. in: Drossman D. A. Corazziari E. Delvaux M. Rome III: the functional gastrointestinal disorders. 3rd ed. Degnon Associates, McLean, VA2006: 835-853Google Scholar, 16Palsson O. S. Whitehead W. E. van Tilburg M. A. et al. Rome IV diagnostic questionnaires and tables for investigators and clinicians. Gastroenterology. 2016; 150: 1481-1491Abstract Full Text Full Text PDF Scopus (349) Google Scholar, 17Caplan A. Walker L. Rasquin A. Validation of the pediatric Rome II criteria for functional gastrointestinal disorders using the questionnaire on pediatric gastrointestinal symptoms. J Pediatr Gastroenterol Nutr. 2005; 41: 305-316Crossref PubMed Scopus (131) Google Scholar, 18Clevers E. Whitehead W. E. Palsson O. S. et al. Factor analysis defines distinct upper and lower gastrointestinal symptom groups compatible with Rome IV criteria in a population-based study. Clin Gastroenterol Hepatol. 2018; 16: 1252-1259Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar By using these criteria in clinical research, more scientific data emerged about these patients. This led to better characterization of these disorders and more evidence-based methods for modifying the diagnostic criteria when needed. The US Food and Drug Administration, the European Medicines Agency, the Japanese Pharmaceutical and Medical Devices Agency, and other international regulatory agencies accepted the Rome criteria as the standard method for including patients in clinical trials. Eventually, the criteria were used in almost all clinical studies of DGBIs. Since their acceptance by research and regulatory agencies, the concept of symptom-based criteria has stood the test of time over 3 decades. They remain clinically useful and are promoted in clinical and educational programs and curricula by allowing for a “positive” diagnosis rather than exclusion, the method that preexisted these criteria. As the Rome criteria became more established over time for research, clinicians began to debate their use for clinical practice. 19Corsetti M. Tack J. Are symptom-based diagnostic criteria for irritable bowel syndrome useful in clinical practice? . Digestion. 2004; 70: 207-209Crossref PubMed Scopus (12) Google Scholar, 20Ford A. C. Bercik P. Morgan D. G. et al. The Rome III criteria for the diagnosis of functional dyspepsia in secondary care are not superior to previous definitions. Gastroenterology. 2014; 146: 932-940Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 21Wei Z. Yang Q. Yang Q. et al. Rome III, Rome IV, and potential Asia symptom criteria for functional dyspepsia do not reliably distinguish functional from organic disease. Clin Transl Gastroenterol. 2020; 11e00278Crossref Scopus (8) Google Scholar, 22Van den Houte K. Carbone F. Pannemans J. et al. Prevalence and impact of self-reported irritable bowel symptoms in the general population. United European Gastroenterol J. 2019; 7: 307-315Crossref PubMed Scopus (49) Google Scholar, 23Black C. J. Craig O. Gracie D. J. Ford A. C. Comparison of the Rome IV criteria with the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gut. 2021; 70: 1110-1116Crossref PubMed Scopus (41) Google Scholar One example is related to the change in criteria for IBS from Rome III to Rome IV. The new criteria increased the specificity of the diagnosis at the expense of its sensitivity and identified a patient group with more severe disease, and the prevalence of IBS in the global study dropped by 50%. 24Sperber A. D. Bangdiwala S. I. Drossman D. A. et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation global study. Gastroenterology. 2021; 160: 99-114Abstract Full Text Full Text PDF PubMed Scopus (834) Google Scholar Thus, patients with milder IBS symptoms would not meet the criteria for Rome IV as they did for Rome III. Another major concern was the need for clinicians to make a subthreshold diagnosis for DGBI diagnoses in general when a patient does not meet the full Rome criteria used in research but other clinical evidence supports the diagnosis. An example is if the patient meets the qualitative symptom criteria, but the symptoms have existed for less time than the Rome criteria require. For research purposes, the Rome IV criteria require symptom onset 6 months before the diagnosis and symptoms meeting the Rome IV criteria to have been present during the previous 3 months to exclude the possibility of other diagnoses. This approach increases the reliability of patient selection for epidemiologic studies. It also ensures adequate time to exclude other diagnoses and provide sufficient symptom duration for treatment trials that require symptoms to be present for several months. However, in the clinical setting, patients may be adequately evaluated within a shorter time. This would occur with a patient presenting with chest pain repeatedly over several weeks when the cardiologic and gastroenterological investigations have determined a likely esophageal cause. However, a strict application of the Rome IV diagnostic criteria for functional chest pain requires a symptom history of 6 months. 25Aziz Q. Fass R. Gyawali C. P. et al. Esophageal disorders. Gastroenterology. 2016; 150: 1368-1379Abstract Full Text Full Text PDF Scopus (372) Google Scholar Furthermore, in Asia, prompt endoscopy is a rule for individuals with dyspeptic symptoms. The majority of patients may consult a physician as early as 1 month after the appearance of dyspeptic symptoms. This highlights the need to diagnose at the time of a negative endoscopy result, as demonstrated in Asian publications. However, the more extended time requirement of the Rome criteria has been implicated in the observation that most patients with epigastric symptoms and negative endoscopy results are diagnosed with chronic gastritis. 26Suzuki H. The application of the Rome IV criteria to functional esophagogastroduodenal disorders in Asia. J Neurogastroenterol Motil. 2017; 23: 325-333Crossref PubMed Scopus (35) Google Scholar, 27Chen S. L. Gwee K. A. Lee J. S. et al. Systematic review with meta-analysis: prompt endoscopy as the initial management strategy for uninvestigated dyspepsia in Asia. Aliment Pharmacol Ther. 2015; 41: 239-252Crossref PubMed Scopus (53) Google Scholar Also, the frequency of the symptoms occurring in clinical settings may be less than the stated criteria. For example, with Rome IV, the frequency thresholds were based on a strict application of epidemiologic data (90th percentile). 16Palsson O. S. Whitehead W. E. van Tilburg M. A. et al. Rome IV diagnostic questionnaires and tables for investigators and clinicians. Gastroenterology. 2016; 150: 1481-1491Abstract Full Text Full Text PDF Scopus (349) Google Scholar However, frequencies out of this threshold may still affect the patient’s quality of life or functioning, making it highly desirable for a diagnosis and targeted treatment to be made. Examples include cyclic vomiting syndrome, biliary pain, or abdominal migraine (in children). As the Rome criteria’s impact grew with time, they were also applied in some settings for billing purposes, which restricted reimbursement for services if patients had symptoms not (yet) meeting the duration requirements. 28Farmacotherapeutisch rapport linaclotide (Constella®) bij de indicatie symptomatische behandeling van matig tot ernstig prikkelbaredarmsyndroom met constipatie (PDS-C) bij volwassenen. https: //www. farmacotherapeutischkompas. nl/binaries/content/assets/fk-gegenereerd/2015ₗinaclotideconstella_ₚrikkelbaredarmsyndroomₘetconstipatie. pdfGoogle Scholar The discrepancy between the Rome research criteria and clinical diagnoses became even more prominent with the publication of the Rome IV criteria, where changes in specific parameters compared to Rome III made the diagnosis less prevalent and defined a population with more severe disease. 20Ford A. C. Bercik P. Morgan D. G. et al. The Rome III criteria for the diagnosis of functional dyspepsia in secondary care are not superior to previous definitions. Gastroenterology. 2014; 146: 932-940Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 21Wei Z. Yang Q. Yang Q. et al. Rome III, Rome IV, and potential Asia symptom criteria for functional dyspepsia do not reliably distinguish functional from organic disease. Clin Transl Gastroenterol. 2020; 11e00278Crossref Scopus (8) Google Scholar, 22Van den Houte K. Carbone F. Pannemans J. et al. Prevalence and impact of self-reported irritable bowel symptoms in the general population. United European Gastroenterol J. 2019; 7: 307-315Crossref PubMed Scopus (49) Google Scholar, 23Black C. J. Craig O. Gracie D. J. Ford A. C. Comparison of the Rome IV criteria with the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gut. 2021; 70: 1110-1116Crossref PubMed Scopus (41) Google Scholar, 24Sperber A. D. Bangdiwala S. I. Drossman D. A. et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation global study. Gastroenterology. 2021; 160: 99-114Abstract Full Text Full Text PDF PubMed Scopus (834) Google Scholar, 29Shin A, Chang L. The transition from Rome III to Rome IV irritable bowel syndrome: what we gain and lose. Clin Gastroenterol Hepatol. Published June 29, 2021. https: //doi. org/10. 1016/j. cgh. 2021. 06. 032. Google Scholar In addition, the extent to which doctors are familiar with and apply the Rome diagnostic criteria is not clear. This is particularly important because patients with DGBI are treated at multiple levels of care, including gastroenterologists, family physicians, internists, surgeons, and others. A study conducted by the Rome Foundation Working Team on Multinational, Cross-Cultural Research showed very different degrees of familiarity with and application of the Rome III diagnostic criteria in India, Mexico, Italy, and South Korea. 30Schmulson M. Corazziari E. Ghoshal U. C. et al. A four-country comparison of healthcare systems, implementation of diagnostic criteria, and treatment availability for functional gastrointestinal disorders: a report of the Rome Foundation Working Team on cross-cultural, multinational research. Neurogastroenterol Motil. 2014; 26: 1368-1385Crossref PubMed Scopus (42) Google Scholar It is reasonable to assume that with the development of clinical criteria, their relevance to clinicians will increase, as will the degree of their application in clinical practice. Based on the emerging discrepancy between the Rome criteria and their clinical application, by consensus of the Rome Foundation Board of Directors, we developed a modification for the Rome IV diagnostic criteria in clinical practice. We propose 4 factors to consider when offering recommendations for clinical criteria. •Nature of symptoms. The qualitative clusters of symptoms used in the Rome criteria represent the DGBI diagnostic syndromes. In effect, these symptom clusters are consistent across populations and have been supported and validated by epidemiologic, factor analytic, and clinical cohort studies in many cases. 31Drossman D. A. History of functional gastrointestinal symptoms and disorders and chronicle of the Rome Foundation. in: Drossman D. A. Chang L. Chey W. D. Rome IV functional gastrointestinal disorders—disorders of gut-brain interaction. 4th ed. Rome Foundation, Raleigh, NC2016: 549-577Crossref Google Scholar We recommend that the clinical criteria be based on the Rome IV symptom descriptors and clusters. •Bothersomeness. are bothersome when they with daily require or and are to in quality of It is the of symptoms that patients to health care and for doctors to Also, is a validation in quality of life research, as the of Drossman D. A. et of life in with irritable bowel syndrome: development of a new PubMed Scopus Google Scholar Furthermore, the Rome IV criteria use for some diagnoses functional et disorders. Gastroenterology. 2016; 150: Full Text Full Text PDF PubMed Scopus Google Scholar We that the degree of patients report clinical to identify and the DGBIs. we recommend the of as a clinical criterion for of symptoms. In epidemiologic studies, symptom abnormality is based on frequencies confidence or of standard from the O. S. Whitehead W. E. van Tilburg M. A. et al. Rome IV diagnostic questionnaires and tables for investigators and clinicians. Gastroenterology. 2016; 150: 1481-1491Abstract Full Text Full Text PDF Scopus (349) Google Scholar A symptom frequency abnormality may be a clinical relevance However, some symptoms in clinical practice may be within normal epidemiologic and still be clinically based on or of daily or quality of This when clinicians make to diagnose and not by frequency but by an that patients to the if the symptoms are bothersome to care, require or are sufficient to a diagnosis. this we recommend that the frequency of symptoms not be an criterion for The Rome IV criteria require at 6 months symptom onset and 3 months meeting the diagnostic D. A. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology. 2016; 150: 1262-1279Abstract Full Text Full Text PDF Scopus (1413) Google O. S. Whitehead W. E. van Tilburg M. A. et al. Rome IV diagnostic questionnaires and tables for investigators and clinicians. Gastroenterology. 2016; 150: 1481-1491Abstract Full Text Full Text PDF Scopus (349) Google A. D. Bangdiwala S. I. Drossman D. A. et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation global study. Gastroenterology. 2021; 160: 99-114Abstract Full Text Full Text PDF PubMed Scopus (834) Google D. A. History of functional gastrointestinal symptoms and disorders and chronicle of the Rome Foundation. in: Drossman D. A. Chang L. Chey W. D. Rome IV functional gastrointestinal disorders—disorders of gut-brain interaction. 4th ed. Rome Foundation, Raleigh, NC2016: 549-577Crossref Google Scholar The as an or where the symptoms are likely to or be evaluated sufficiently to exclude other diagnoses. This long their application in epidemiologic studies. However, the duration criteria can be when a clinician has evaluated the symptoms sufficiently and is that other diagnoses are Using these guidelines the for clinicians to rule out other diagnoses will symptom and other patient to additional investigations if needed. If all are in with a DGBI diagnosis, the diagnosis can be made with confidence a lower frequency and We recommend that the be to meet the Rome Foundation clinical symptom criteria. The qualitative features of the Rome IV criteria be the for a of the Rome IV clinical have sufficiently bothersome symptoms to care or affect daily and this the symptoms are severe to affect their quality of For this the clinician would the symptoms as criteria. A frequency lower than the Rome IV threshold is provided that the symptoms are bothersome to with daily or require criteria. The Rome IV requirement of a duration of symptoms is not provide some that other diagnoses have been we that symptoms be present for the previous to the duration requirement are (1) when the clinician to make an diagnosis and is that the other or (2) for diagnoses where the symptoms occur and cyclic vomiting syndrome, abdominal biliary pain, and The use of these criteria that other diagnoses have been sufficiently ruled out based on the clinical presentation and additional investigations when needed. criteria do not the standard Rome IV criteria for clinical trials or epidemiologic or pathophysiologic studies. The Rome Foundation that these criteria for clinical practice and the diagnosis with confidence will patient reduce unnecessary diagnostic studies, and enhance the patient-provider A. A. et diagnostic studies, and for patients with functional gastrointestinal Gastroenterol Hepatol. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar The Foundation also to the relevance of clinical criteria in clinical practice studies and their impact on patient and health and research will need to any thresholds in of the and duration of symptoms can be identified for clinical practice criteria for specific DGBIs. The and of additional investigations that are useful for the of symptoms with a shorter history of onset also will need to be evaluated and may to recommendations for specific DGBIs. The clinical criteria can as a for studies to validate their application in clinical practice. The data from studies will be applied and in the Rome The duration and frequency criteria to be required for epidemiologic research, pathophysiologic studies, and trials in DGBIs. The Board of of the Rome Foundation provided to the study concept and and of the The would to the of the Rome Foundation Board of for their to this E. J. W. and with