- Open Access
Increased risk of chronic fatigue syndrome in patients with inflammatory bowel disease: a population-based retrospective cohort study
© The Author(s) 2019
- Received: 19 October 2018
- Accepted: 14 February 2019
- Published: 22 February 2019
Similarities in the symptoms of chronic fatigue syndrome (CFS) and inflammatory bowel disease (IBD) have been observed as follows: severe disease activity in IBD correlates with severe fatigue, major psychiatric signs, the common use of medication, and bacterial translocation. One of several hypotheses for explaining the mechanisms underlying CFS suggests a similarity to the impaired intestinal mucosa of IBD. “This study investigated the risk of incident CFS among patients with IBD”.
We conducted a population-based retrospective cohort study by using Taiwan’s National Health Insurance Research Database to evaluate the subsequent risk of CFS in patients with IBD, according to demographic characteristics and comorbidities. The exposure cohort comprised 2163 patients with new diagnoses of IBD. Each patient was randomly selected and frequency matching according to gender and age with four participants from the general population who had no history of CFS at the index date (control cohort). Cox proportional hazards regression analysis was conducted to estimate the relationship between IBD and the subsequent risk of CFS.
The exposure cohort had a significantly higher overall risk of subsequent CFS than that of the control group [adjusted hazard ratio (Christophi in Inflamm Bowel Dis 18(12):2342–2356, 2012) = 2.25, 95%, confidence interval (Aaron and Buchwald in Ann Intern Med 134(9 Pt 2):868–881, 2001; Farraye et al. in Am J Gastroenterol 112:241, 2017) 1.70–2.99]. Further analysis indicated a significantly higher risk of CFS in patients who were male (HR = 3.23, 95% CI 2.12–4.91), were older than 35 years, and had IBD but without comorbidity status, e.g. Cancers, diabetes, obesity, depression, anxiety, sleep disorder, renal disease (HR = 2.50, 95% CI 1.63–3.84) after adjustment.
The findings from this population-based retrospective cohort study suggest that IBD, especially Crohn’s disease, is associated with an increased risk of subsequent CFS.
- Chronic fatigue syndrome (CFS)
- Myalgic encephalomyelitis (ME)
- Inflammatory bowel disease
- Oxidative and nitrosative stress (O&NS) pathways
- Microbiota-gut-brain interactions
- Bacterial translocation
- Immunoinflammatory pathways
Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis, is not only fatigue. This is a cluster of clinical symptoms which is defined as the presence of unexplainable fatigue lasting more than 6 months and accompanied by four or more of the following symptoms: substantial impairment in short-term memory, tender lymph nodes, sore throat, muscle pain, multiple joint pain without swelling or redness, headache, unrefreshing sleep, and postexertional malaise lasting more than 24 h . A recent study indicated that several infectious agents, such as varicella zoster virus, are linked to CFS . Most importantly, CFS majorly affects productivity. Half of the patients with CFS had discontinued their employment because of fatigue-related symptoms, and the total productivity costs owing to such discontinuation each year represented to the UK economy of approximately £102.2 million . Parents of children with CFS also experienced loss of monthly income (mean = £247) and increased monthly expenditure (mean = £206). Thus, identifying the potential CFS population is crucial for early intervention.
Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic disorders characterized by the chronic inflammation of the gastrointestinal tract. Fatigue can be observed in patients with IBD, and severe disease activity  and psychosocial factors  have been associated with severe fatigue, even when the disease is in remission . Major psychiatric signs of CFS, such as cognitive impairment  and insecure attachment, have been observed in patients with IBD . Interestingly, bacterial translocation is one among the several proposed hypotheses explaining mechanisms underlying CFS  and it is also observed in patients with IBD . There has been others working on the correlation between IBD and CFS, and find them coexisting [11–14]. These results raise the speculation of a possible common pathophysiology between IBD and CFS.
Although prolonged fatigue is well known in IBD, there were just some research about CFS comorbid with IBD , and no research focusing on the development of myalgic encephalomyelitis or CFS currently. Therefore, we conducted a population-based retrospective cohort study by using the National Health Insurance Research Database (NHIRD) to evaluate the subsequent risk of CFS in patients with IBD.
The Taiwan National Health Insurance program provides affordable health care to all residents of Taiwan and covered over 99% of the 23 million Taiwan residents since March 1, 1995 (Database NHIR. Taiwan, http://nhird.nhri.org.tw/en/index.html).
Large computerized databases derived from this system by the National Health Insurance Administration, Taiwan and maintained by the National Health Research Institutes, Taiwan, are provided to scientists in Taiwan for research purposes. The National Health Research Institutes (NHRI) has collected health claims data in a de-identified format and established the NHIRD. We used the Longitudinal Health Insurance Database (LHID), which contained the historical claims data from 1996 to 2011 of one million patients randomly sampled from the entire insured population. Disease history is recorded using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.
The primary study outcome was the diagnosis of incident CFS. Both groups were followed from the index date until the diagnosis of CFS, withdrawal from the NHI program, or December 31, 2011.
The proportionate distributions of demographic data and comorbidities in the IBD and non-IBD groups were compared and analyzed using the Chi-square test for categorical variables, and the differences were analyzed using the Student t test for continuous variables. The Kaplan–Meier method was used to estimate the cumulative rate of CFS, and the log-rank test was used to examine differences between the survival curves. Cox proportional hazards models were used to assess the independent effects of IBD after adjustment for sex, age, and comorbidities in the model. In addition, we compared the hazard ratio (HR) of CFS between the IBD and non-IBD groups after stratification by sex, age groups, and comorbidity status. We used the SAS software (Version 9.4 for Windows; SAS Institute Inc, Cary, NC) to perform all data analyses, and P < 0.05 was considered statistically significant.
The Ethics Review Board of China Medical University Hospital (CMUH-104-REC2-115) and the Institutional Review Board of MacKay Memories Hospital (16MMHIS074) have approved the study.
Demographic factors and comorbidity of study participants according to inflammatory bowel disease status
N = 8652
N = 2163
Incidence density rates and hazard ratios of chronic fatigue syndrome according to inflammatory bowel disease status stratified by sex, age, and comorbidity
Compared to the non-IBD group
HR (95% CI)
The age-specific analysis revealed that the incidence density rates of CFS increased with age in both groups. In addition, the IBD group had a higher risk of CFS than did the non-IBD group, except for those in the age group of 20 to 34 years. Regardless of the patients’ comorbidity status, the risk of CFS was higher in the IBD group than in the non-IBD group (adjusted HR, 2.50; CI 1.36–3.84 for those without comorbidities; adjusted HR, 2.11; CI 1.46–3.05 for those with comorbidities, respectively).
Incidence density rates and hazard ratios of chronic fatigue syndrome in different subgroups
HRa (95% CI)
A thorough review of relevant research showed that the current study is the first nationwide population-based study to investigate the risk of CFS in patients with IBD. We observed that the risk of CFS was significantly higher in patients with IBD than in the general population. In addition, we identified male sex, advanced age, absence of comorbidities, and CD as the predictors of increased CFS risk. The average age of the sample of newly diagnosed IBD patients was 47.5 years, which is higher than epidemiological studies suggesting peak onset is in the 20s and 30s. This average age may reflect geographic differences . CFS has a multifactorial etiology and several models have been proposed to explain mechanisms underlying CFS, including immunoinflammatory pathways , oxidative and nitrosative stress (O&NS) pathways , and bacterial translocation .
We observed that the risk of CFS was higher in patients with CD than in patients without IBD; however, the risk was not higher in patients with UC. Although it may be caused by the underpowered of the data of UC (26.3% power), there are some possible implications from a clinical point of view. The extent of the intestinal barrier integrity may have a crucial role. Firstly, the extent of the inflammation of UC is restricted in colorectal region, and it invades mainly within the mucosa, whereas CD invades different areas of the digestive tract with transmural involvement. On the other hand, a curative operation can be conducted in UC patients, while there is no known cure for Crohn’s disease. To be speculative, the impairment of the intestinal barrier and bacterial translocation may be more severe in CD, and the immune responses exhibited in UC may be less because of the relatively complete integrity of the gut barrier.
It is noteworthy that certain probiotics, such as Lactobacillus acidophilus, Bifidobacterium bifidum and Lactobacillus bulgaricus, and a specific formula diet showed protective effects on the intestinal barrier and decreased rate of bacterial translocation among patients with biliary disease . Future studies can aim to access the response of these therapies in IBD patient with CFS.
The strength of the study obviously is the large number of patients included in both groups (cases and controls). The NHI database of Taiwan provides complete and valid information regarding the demographic characteristics of patients in both the case and control groups. Since we have considered variables, such as sex, age, comorbilities and medical treatment and adjust them individually as well.
Our study has some limitations. First, because of the availability of limited information related to claims data in the NHIRD, we could not further evaluate the effect of biochemical laboratory data and disease severity of patients with IBD. However, this can be investigated by conducting a hospital-based study in which the biochemical laboratory data can be obtained, following which the patients can be stratified into groups according to the severity of their clinical diagnoses. In addition, prescription details are not included in this study. Fatigue has been reported as a side effect to certain medications used in IBD, but we believe that the impact on the incidence rate of CFS is minimal, because the diagnosis of CFS requires not only the long lasting complaints of fatigue but should be “unexplainable” in nature . Theoretically, the diagnoses of IBD and CFS were reliable because this study only included hospitalized patients whose diagnoses were strictly audited for the purpose of reimbursement. Reasonably, specialists should address the issue of adverse events from the use of biologic agents and steroid during the diagnosis. Moreover, the high prevalence of fatigue in IBD is not related to the tapering of steroid .
Furthermore, genetic and territorial discrepancies among the different populations should be investigated by conducting additional multinational further studies.
Based on our findings, it’s essential to pay attention not only to the medications applied on the patients with IBD and susceptible CFS, but also to variability in the type and cost of care delivered to patients. Thus, several gastroenterology societies are developing measures to assess quality of care, which should be integrated to quality measures of care in practice .
This study is the first nationwide population-based study to investigate the risk of CFS in patients with IBD. The incidence of CFS, especially CD, was significantly higher in the IBD group than in the non-IBD group. The pilot study finding is essential to provide insights for identifying high-risk patients likely to suffer from CFS and to open a new avenue of research on the intrinsic defects in IBD patients that precipitates CFS. Future studies may aim to access the response of these therapies in IBD patient with CFS. Therefore, immunotherapy to alleviate the state of illness in IBD patients and consequently to improve the patients’ quality of life warrants research (Additional files 1, 2).
S-YT had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: S-YT, C-FL. Acquisition, analysis, or interpretation of data: S-YT, C-FL, H-JC. Drafting of the manuscript: All authors. Critical revision of the manuscript for important: S-YT. Intellectual content: S-YT; Statistical analysis: H-JC. Obtained funding: S-YT, T-YY, H-JC. Administrative, technical, or material supports: S-YT, H-JC. Study supervision: S-YT, T-YY. Submission: S-YT. Obtained funding: S-YT, T-YY, H-JC, W-SW, W-CY. All authors read and approved the final manuscript.
We would like to extend acknowledgements to the valuable advices for revision from Cheng-Li Lin, and Fang-Ju Sun, and Taiwan Ministry of Health and Welfare Clinical Trial Center; China Medical University Hospital; Academia Sinica Stroke Biosignature Project; MOST Clinical Trial Consortium for Stroke; Tseng-Lien Lin Foundation, Taichung, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; The Department of Medical Research at Mackay Memorial Hospital for the help with funding support.
The authors declare that they have no competing interests.
Consent for publication
The authors agree the publication of this paper.
The data underlying this study is from the National Health Insurance Research database (NHIRD). Interested researchers can obtain the data through formal application to the Ministry of Health and Welfare, Taiwan.
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW108-TDU-B-212-133004); China Medical University Hospital; Academia Sinica Stroke Biosignature Project (BM10701010021); MOST Clinical Trial Consortium for Stroke (MOST 107-2321-B-039 -004-); Tseng-Lien Lin Foundation, Taichung, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; The Department of Medical Research at Mackay Memorial Hospital (MMH-105-87; MMH-106-81; MMH-107-71; MMH-107-102; MMH-107-135).
The Institutional Review Board of China Medical University (CMUH-104-REC2-115) and the Institutional Review Board of MacKay Memories Hospital (16MMHIS074) approved this study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Fukuda K, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Tsai SY, et al. Increased risk of chronic fatigue syndrome following herpes zoster: a population-based study. Eur J Clin Microbiol Infect Dis. 2014;33(9):1653–9.PubMedView ArticleGoogle Scholar
- Collin SM, et al. The impact of CFS/ME on employment and productivity in the UK: a cross-sectional study based on the CFS/ME national outcomes database. BMC Health Serv Res. 2011;11:217.PubMedPubMed CentralView ArticleGoogle Scholar
- Pellino G, et al. Fatigue in inflammatory bowel diseases: relationship with age and disease activity. Int J Surg. 2014;12(Suppl 2):S60–3.PubMedView ArticleGoogle Scholar
- Artom M, et al. The contribution of clinical and psychosocial factors to fatigue in 182 patients with inflammatory bowel disease: a cross-sectional study. Aliment Pharmacol Ther. 2017;45(3):403–16.PubMedView ArticleGoogle Scholar
- Graff LA, et al. Changes in fatigue over 2 years are associated with activity of inflammatory bowel disease and psychological factors. Clin Gastroenterol Hepatol. 2013;11(9):1140–6.PubMedView ArticleGoogle Scholar
- Dancey CP, et al. Words fail me: the verbal IQ deficit in inflammatory bowel disease and irritable bowel syndrome. Inflamm Bowel Dis. 2009;15(6):852–7.PubMedView ArticleGoogle Scholar
- Agostini A, et al. Adult attachment and early parental experiences in patients with Crohn’s disease. Psychosomatics. 2010;51(3):208–15.PubMedGoogle Scholar
- Maes M, et al. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 2012;136(3):909–17.PubMedView ArticleGoogle Scholar
- Gutierrez A, et al. Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn’s disease. Gut. 2014;63(2):272–80.PubMedView ArticleGoogle Scholar
- Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med. 2001;134(9 Pt 2):868–81.PubMedView ArticleGoogle Scholar
- Korszun A, et al. The relationship between temporomandibular disorders and stress-associated syndromes. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol. 1998;86(4):416–20.View ArticleGoogle Scholar
- Gomborone JE, et al. Prevalence of irritable bowel syndrome in chronic fatigue. J R Coll Physicians Lond. 1996;30(6):512–3.PubMedPubMed CentralGoogle Scholar
- Morriss RK, et al. The role of depression in pain, psychophysiological syndromes and medically unexplained symptoms associated with chronic fatigue syndrome. J Affect Disord. 1999;55(2–3):143–8.PubMedView ArticleGoogle Scholar
- Dansie EJ, et al. Conditions comorbid with chronic fatigue in a population-based sample. Psychosomatics. 2012;53(1):44–50.PubMedView ArticleGoogle Scholar
- Tsai S-Y, et al. Increased risk of chronic fatigue syndrome following burn injuries. J Transl Med. 2018;16(1):342.PubMedPubMed CentralView ArticleGoogle Scholar
- Tsai SY, et al. Increased risk of varicella zoster virus infection in inflammatory bowel disease in an Asian population: a nationwide population-based cohort study. Int J Clin Pract. 2015;69(2):228–34.PubMedView ArticleGoogle Scholar
- Du Preez S, et al. A systematic review of enteric dysbiosis in chronic fatigue syndrome/myalgic encephalomyelitis. Syst Rev. 2018;7(1):241.PubMedPubMed CentralView ArticleGoogle Scholar
- Wei S-C, et al. A nationwide population-based study of the inflammatory bowel diseases between 1998 and 2008 in Taiwan. BMC Gastroenterol. 2013;13:166.PubMedPubMed CentralView ArticleGoogle Scholar
- Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010;8:35.PubMedPubMed CentralView ArticleGoogle Scholar
- Maes M, Mihaylova I, De Ruyter M. Lower serum zinc in chronic fatigue syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2006;90(2–3):141–7.PubMedView ArticleGoogle Scholar
- Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.PubMedPubMed CentralView ArticleGoogle Scholar
- McGuckin MA, et al. Intestinal barrier dysfunction in inflammatory bowel diseases. Inflamm Bowel Dis. 2009;15(1):100–13.PubMedView ArticleGoogle Scholar
- Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. 2007;99(1–3):237–40.PubMedView ArticleGoogle Scholar
- Ogura Y, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411(6837):603–6.View ArticleGoogle Scholar
- Maes M, Mihaylova I, Bosmans E. Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol Lett. 2007;28(4):456–62.PubMedGoogle Scholar
- Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6(4):193–201.PubMedView ArticleGoogle Scholar
- Christophi GP, et al. Immune markers and differential signaling networks in ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 2012;18(12):2342–56.PubMedPubMed CentralView ArticleGoogle Scholar
- Qin L, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55(5):453–62.PubMedPubMed CentralView ArticleGoogle Scholar
- Giloteaux L, et al. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016;4(1):30.PubMedPubMed CentralView ArticleGoogle Scholar
- Wallis A, et al. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. J Transl Med. 2018;16(1):24.PubMedPubMed CentralView ArticleGoogle Scholar
- Newberry F, et al. Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome? Clin Sci. 2018;132(5):523–42.PubMedPubMed CentralView ArticleGoogle Scholar
- Sarac F, et al. Effect of probiotic supplementation on bacterial translocation in common bile duct obstruction. Pediatr Surg Int. 2015;31(2):155–61.PubMedView ArticleGoogle Scholar
- Minderhoud IM, et al. High prevalence of fatigue in quiescent inflammatory bowel disease is not related to adrenocortical insufficiency. Am J Gastroenterol. 2003;98(5):1088–93.PubMedView ArticleGoogle Scholar
- Farraye FA, et al. ACG clinical guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol. 2017;112:241.PubMedView ArticleGoogle Scholar