An Overlooked Cause in The Differential Diagnosis of Fever of Unknown Origin: Inflammatory Bowel Disease

A Genomewide Analysis Provides Evidence for Novel Linkages in Inflammatory Bowel Disease in a Large European Cohort

Background The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions with a polygenic and multifactorial pathogenesis. Intensified treatment early in the disease course of IBD results in better outcomes. This is, however, challenged by the diagnostic delay faced in IBD, and especially in CD. Therefore, markers supporting early and differential diagnosis are needed. In this study, we aimed to discriminate IBD patients from non-IBD controls, and CD from UC patients, using serum protein profiles combined with an IBD polygenic risk score. Methods Patients naïve for immunosuppressives and biologicals, and without previous IBD-related surgery were prospectively included within 3 months after diagnosis, across three Belgian IBD referral centres (PANTHER study). We collected serum from 127 patients (88 CD, 39 UC) and 66 age- and gender-matched non-IBD controls. Relative serum levels of 576 unique proteins were quantified (OLINK). Proteins were ranked according to (1) adjusted (adj.) p values obtained from differential expression analysis; (2) importance scores from machine-learning feature-selection algorithms (univariate feature selection, logistic regression with L2 penalty and Random Forest). For all individuals, a weighted IBD polygenic risk score (PRS) was calculated (PRSice 2.0) for the 242 known IBD risk loci. Receiver operating characteristics (ROC) and area under the curve (AUC) analysis were performed to measure the performance of top-ranked proteins and the IBD PRS (R package ROCR). Results Following statistical analysis, 243 serum proteins were found to be differentially expressed (adj. p < 0.05) between IBD patients and controls. Three top-ranked markers were also identified as top 10 ranked proteins by all feature-selection algorithms, and resulted in a significant AUC of 93% (95% CI: 89–97%) to distinguish IBD from controls. While adding the IBD PRS did not further contribute (AUC 93% [95% CI: 89–97%]), the top-ranked protein on its own had a strong discriminative power with an AUC of 87% (95% CI: 82–92%). When comparing UC and CD, we found 15 differentially expressed proteins. Two proteins ranked within the top 10 across all feature-selection algorithms. This two-marker panel could discriminate UC from CD with an accuracy of 88% (95% CI: 82–96%). Adding the IBD PRS did not further improve the prediction model (AUC=88% [95% CI: 81–96%]). Conclusion Machine learning approaches validated top differentially expressed serum proteins with diagnostic potential in IBD. We identified a three-marker panel classifying IBD patients and non-IBD controls, and a two-marker panel discriminating UC from CD.

Diarrhea is a common problem in the setting of solid-organ transplantation, especially orthotopic liver transplant (OLT). De novo or preexisting inflammatory bowel disease (IBD) is one of the differential diagnoses. The aims of our study were to evaluate the frequency of de novo IBD in patients with OLT and to assess the impact of de novo IBD and preexisting IBD on the outcome of OLT. This case-control study included all eligible patients who had OLT from January 2001 to December 2009. The study group included all patients who had a biopsy-proven diagnosis of IBD after their OLT (the de novo IBD group). The control groups included patients with existing IBD before OLT and those without IBD before and after OLT. The groups were matched based on their underlying diagnoses of end-stage liver disease. Univariate and multivariate analyses were performed. A total of 66 subjects were included in the study. The mean age was 45.4 ± 13.4 years, with 44 (66.7%) being male. Fifteen patients (23%) had de novo IBD, 21 (32%) had existing IBD before OLT, and 30 (45%) had no underlying IBD before or after OLT. There were no significant differences between the 2 IBD groups in any of the IBD characteristics, including IBD medications. Subjects without IBD were more likely to receive mycophenolate mofetil within 1 week of OLT than those in the de novo or preexisting IBD (70% versus 23% P = 0.018). Episodes of graft rejection were more commonly observed in subjects with preexisting IBD (52%) than de novo IBD (27%) or no IBD (20%) (P = 0.045). The rate of retransplantation was highest in the de novo IBD group followed by the preexisting IBD group and non-IBD group (20% versus 14% versus 0%; P = 0.029). Combined together, patients with IBD in the setting of OLT were more likely to be retransplanted than those without IBD (16.7% versus 0%, P = 0.045). In multivariate analysis, we found that patients with IBD were 6.7 (95% confidence interval, 1.9-23.9) times more likely to have an adverse outcome after liver transplant (P = 0.004), after adjusting for primary sclerosing cholangitis. De novo IBD can occur in patients after OLT. De novo IBD and preexisting IBD were found to be associated with a higher risk for graft failure, suggesting that early diagnosis and closer monitoring of the patients at risk are critical.

The gastrointestinal pathologies have increased over the last years. The clinical pictures of inflammatory and irritable bowel disease might overlap, leading to expensive and invasive tests. Our study aims to investigate fecal calprotectin as an effective tool for differential diagnosis of gastrointestinal disorders. Two hundred fifty-six patients with the diagnosis of the gastrointestinal disorder and subjected to colonoscopy were collected for the statistical analysis of fecal calprotectin. The differential diagnosis of intestinal inflammation or non-inflammation was performed according to the Receiver Operating Characteristic (ROC) curve that outlines the Area Under Curve (AUC), Sensitivity (Se), Specificity (Sp). Fecal calprotectin was significantly elevated in patients with inflammatory bowel disease compared with patients with irritable bowel syndrome. Especially, the mean values of fecal calprotectin were 522 g/g (IQR=215-975) and 21 g/g (IQR=14-34.5) in patients with and without inflammation, respectively (P<0.0001). AUC value of fecal calprotectin was 0.958 (Se=88.9%, Sp=91.1%, with a cut-off value of 50 g/g) for differentiating between inflammatory bowel disease and irritable bowel syndrome. Fecal calprotectin seems to be a non-invasive and inexpensive biomarker useful for the purpose of a differential diagnosis between inflammatory bowel disease and irritable bowel syndrome.

Does inflammatory bowel disease develop in infants?

BackgroundClostridioides difficile infection (CDI) frequently occurs concurrently in patients with inflammatory bowel disease (IBD), and differential diagnosis from IBD flares is critical. However, clinical management of C. difficile in IBD patients with polymerase chain reaction toxin-positive (tPCR+)/enzyme immunoassay toxin-negative (tEIA−) results has not yet been investigated.AimsWe aimed to assess the clinical significance of C. difficile tPCR+/tEIA− in patients with IBD and the impact of antibiotic treatment on IBD outcomes.MethodsThis single-center, retrospective cohort study included patients with IBD with CDI test results between January 01, 2018, and August 01, 2022. First, the clinical outcomes of IBD, such as medication escalation, hospitalization, and surgery, were compared between patients with IBD with tPCR−/tEIA− and those with tPCR+/tEIA− using Cox regression and propensity score matching. Next, the clinical outcomes of IBD were assessed based on whether antibiotic treatment for CDI was administered to both groups.ResultsAmong 412 patients with IBD with PCR test, 71 (17.2%) showed tPCR+/tEIA− results. The tPCR+/tEIA− group showed no statistically significant difference in IBD outcomes compared to the tPCR−/tEIA− group. The antibiotic-treated tPCR+/tEIA− group showed a higher risk of drug escalation and admission than the tPCR−/tEIA− group, while the antibiotic-untreated tPCR+/tEIA− group did not. After drug escalation during the follow-up, the treated tPCR+/tEIA− group showed IBD outcomes similar to those of the tPCR−/tEIA− group.ConclusionsIn patients with IBD with indeterminate CDI, the need for antibiotics should be thoroughly assessed and proper management of underlying IBD such as drug escalation may lead to favorable outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10620-025-09045-4.

Background: Shiga-toxin Escherichia coli productor (STEC) provokes frequently an important intestinal damage that may be considered in differential diagnosis with the onset of Inflammatory Bowel Disease (IBD). The aim of this workis to review in the current literature about Hemolytic Uremic Syndrome (HUS) and IBD symptoms at the onset, comparing the clinical presentation and symptoms, as the timing of diagnosis and of the correct treatment of both these conditions is a fundamental prognostic factor. A focus is made about the association between typical or atypical HUS and IBD and a possible renal involvement in patient with IBD (IgA-nephropathy). Methods: A systematic review of scientific articles was performed consulting the databases PubMed, Medline, Google Scholar, and consulting most recent textbooks of Pediatric Nephrology. Results: In STEC-associated HUS, that accounts for 90% of cases of HUS in children, the microangiopathic manifestations are usually preceded by gastrointestinal symptoms. Initial presentation may be considered in differential diagnosis with IBD onset. The transverse and ascending colon are the segments most commonly affected, but any area from the esophagus to the perianal area can be involved. The more serious manifestations include severe hemorrhagic colitis, bowel necrosis and perforation, rectal prolapse, peritonitis and intussusception. Severe gastrointestinal involvement may result in life-threatening complications as toxic megacolon and transmural necrosis of the colon with perforation, as in Ulcerative Colitis (UC). Transmural necrosis of the colon may lead to subsequent colonic stricture, as in Crohn Disease (CD). Perianal lesions and strictures are described. In some studies, intestinal biopsies were performed to exclude IBD. Elevation of pancreatic enzymes is common. Liver damage and cholecystitis are other described complications. There is no specific form of therapy for STEC HUS, but appropriate fluid and electrolyte management (better hyperhydration when possible), avoiding antidiarrheal drugs, and possibly avoiding antibiotic therapy, are recommended as the best practice. In atypical HUS (aHUS) gastrointestinal manifestation are rare, but recently a study evidenced that gastrointestinal complications are common in aHUS in presence of factor-H autoantibodies. Some report of patients with IBD and contemporary atypical-HUS were found, both for CD and UC. The authors conclude that deregulation of the alternative complement pathway may manifest in other organs besides the kidney. Finally, searching for STEC-infection, or broadly for Escherichia coli (E. coli) infection, and IBD onset, some reviews suggest a possible role of adherent invasive E. coli (AIEC) on the pathogenesis of IBD. Conclusions: The current literature shows that gastrointestinal complications of HUS are quite exclusive of STEC-associated HUS, whereas aHUS have usually mild or absent intestinal involvement. Severe presentation as toxic megacolon, perforation, ulcerative colitis, peritonitis is similar to IBD at the onset. Moreover, some types of E. coli (AIEC) have been considered a risk factor for IBD. Recent literature on aHUS shows that intestinal complications are more common than described before, particularly for patients with anti-H factor antibodies. Moreover, we found some report of patient with both aHUS and IBD, who benefit from anti-C5 antibodies injection (Eculizumab). (www.actabiomedica.it)

Emotional state should not be used to differentiate IBD from IBS – Authors' reply

BACKGROUND A group of Inflammatory Bowel Disease (IBD) specialists have been utilizing a weekly live video conference “IBD Live” to discuss multidisciplinary management of challenging cases. Since 2009 the conference has featured robust interactive case discussions among 150-200 gastroenterologists and colorectal surgeons from multiple academic institutions. Although the majority of cases presented are IBD, there have been a number of cases where IBD was not the ultimate diagnosis. Hence, we sought to characterize these “IBD mimics” to provide a structure for differential diagnosis. METHODS All 106 hours of case conferences recorded and archived between May 2018 and June 2021 were reviewed. A total of 183 of the 215 cases discussed had an IBD diagnosis including 124 Crohn’s disease (CD), 54 ulcerative colitis (UC) and 5 IBD unclassified. RESULTS Many of the remaining 32 (14.9%) cases (Table 1) were referred to a specialist with a prior diagnosis of IBD. There were 10 cases of colonic inflammation initially diagnosed as UC. Etiologies included drug-induced colitis secondary to checkpoint inhibitors for cancers, ocrelizumab for multiple sclerosis, and nintedanib for pulmonary fibrosis. There were cases of ischemic colitis, idiopathic myointimal hyperplasia of mesenteric veins, segmental colitis associated with diverticulosis, and diversion colitis. There were 8 cases of systemic diseases, diagnosed as Common Variable Immunodeficiency, sarcoidosis and vasculitis, including cases of Henoch–Schönlein purpura and CTLA4 haploinsufficiency with autoimmune infiltrates. There were 5 cases of ileal disorders, ultimately diagnosed as lymphoma, tuberculosis, Meckel’s diverticulum, and appendiceal carcinoid all previously thought to be CD. There were small bowel mucosal disorders including collagenous sprue and autoimmune enteropathy, and 2 polyposis cases secondary to Cronkhite-Canada and juvenile polyposis syndromes. There were also cases thought to be penetrating complications of CD, including a case of abdominal actinomyces infection. Finally, there were 3 cases where no consensus diagnosis was made, with broad differential diagnoses including cryptogenic multifocal ulcerous stenosis enteritis. CONCLUSIONS IBD mimics were found in 15% of cases presented at a global IBD webinar in a 3-year period. Clinicians should have a high level of suspicion and actively pursue alternative etiologies when patients do not respond as anticipated to IBD therapy and/or when the disease characteristics are not completely consistent with IBD. These non-IBD diagnoses will lead to a significant change in medical, surgical and pharmacological treatment approaches, which will impact total cost, unplanned care and quality. Our IBD Live conference has positively impacted the care of our patients, and magnified the importance of considering a broad differential for IBD "mimics."

Objective To investigate the clinical significance of serum anti-Saccharomyces cerevisias antibody （ASCA）,anti-outer membrane porin C （anti-OmpC）,antibody to Pseudomonas fluorescens-associated sequence I2 （anti-I2 ）and antibody to bacterial flagellin （anti-CBirl ）in the diagnosis and treatment of inflammatory bowel disease （IBD）.Methods From 2011 to 2013,87 patients with IBD were enrolled and divided into Crohn′s disease （CD）group （66 cases）and ulcerative colitis （UC）group （21 cases）.A total of 62 age and gender matched healthy individuals were enrolled as the control group. Fasting blood samples （2 mL）of the subjects were collected.The expression of ASCA,anti-OmpC,anti-I2 and anti-Cbirl antibodies was detected with enzyme-linked immunosorbent assay （ELISA）kits.The diagnosis value of each antibody in IBD and the differential diagnostic value of in UC and CD were compared by receiver operating characteristic （ROC）curve.Results The area under the curve （AUC）of ASCA between IBD and the healthy control group,between CD group and UC group was 0.580 and 0.512, respectively;the accuracy in diagnosis was low.The AUC of anti-CBirl between IBD and the healthy control group was 0.617.There was no differential diagnosis significance of the other antibodies.The positive rate of ASCA in IBD group was 62.1 % （54/87）,which was significantly higher than that in the control group （38.7%,24/62）.The positive rates of anti-OmpC and anti-I2 in IBD group was significantly lower than those in the control group and the differences were statistically significant （both P 〈0.05）.No difference was observed in positive rates of serum antibodies among the others groups （all P 〉0.05）.The specificity,sensitivity,positive predictive value （PPV）and negative predictive value （NPV）of ASCA in differential diagnosis of CD and UC was 52.4%,66.7%,81 .48% and 33.33%,respectively.The specificity and sensitivity of anti-OmpC,anti-I2 and anti-CBirl in differential diagnosis of CD and UC was 81 .0% to 100.0% and 9.1 % to 37.9%,respectively.The specificity,sensitivity,PPV and NPV of double-positive ASCA and anti-I2 in the diagnosis of CD was 57.1 %,86.4%,82.6% and 50.0%, respectively.The positive rate of ASCA and anti-I2 in CD group was significantly higher than that in UC group （84.8%（56/66）vs 57.1 % （12/21 ）;χ2 =5 .633,P =0.018 ）.Conclusions Positive ASCA has some significance in the diagnosis of patients with IBD in our country.The detection of anti-I2 can help to diagnose ASCA negative CD.Because of low sensitivity and positive rate,anti-OmpC and anti-CBirl have limited value in the diagnosis of IBD and the differential diagnosis of UC and CD in our country. Key words: Inflammatory bowel diseases; Diagnosis, differential; Antibodies, fungal; Antibodies, bacterial; Anti-Saccharomyces cerevisiae antibodies~ Bacterial outer membrane pore protein C; Pseudomonas fluorescens associated sequence I2

Background In a previous qualitative study, interviews were conducted with people with inflammatory bowel disease (IBD) using NHS services and healthcare professionals (HCPs1). Themes arising from the findings of this research included “Human matters” and “Accessibility matters”. Participants described generally accepting eHealth solutions, but some concerns were expressed about accessibility and challenges to effective eHealth. This study aimed to gain a broader understanding of the themes identified. Methods A 32-item online questionnaire was developed with items relating to demographic characteristics, level of agreement with statements based on the themes identified in the previous study, experiences of using eHealth, and opinions on the future use of eHealth in IBD care. People with IBD and their HCPS were invited to participate via professional networks, patient groups, and charities. The online survey was available between June and October 2024. Descriptive statistics were used to summarise the data. Results Two hundred and thirty respondents completed the survey; 103 (45%) reported being healthcare professionals (HCPs), and 127 (55%) participants had IBD. HCP respondents reported to be medical doctors (n=17, 17%), nurses (n=73, 71%), dietitians (n=5, 5%), surgeons (n=2, 2%), pharmacists (n=4, 4%), an Advanced Clinical Practitioner (n=1, 1%), and psychologist (n=1, 1%). Participants with IBD reported a diagnosis of Ulcerative Colitis (n=52, 41%), Crohn’s Disease (n=57, 45%) or IBD of unknown origin (n=18, 14%). Only 5 (4%) participants with IBD and 5 (5%) HCPs reported not using eHealth to support condition management. Most HCPs (n=97, 86%) and participants with IBD (n=116, 91%) reported valuing in-person care, with 94 (91%) HCPs emphasising its relevance for eHealth effectiveness. 45 (32%) HCPs and 33 (36%) participants with IBD reported technology in the NHS supports IBD care effectively. However, some participants (n=75, 37%) responded "yes" or "not sure" when asked if there were negative impacts of eHealth on IBD management. Conclusion Preliminary results of this study indicate that people with IBD and HCPs value eHealth and face-to-face contact. Some participants expressed that the use of eHealth could negatively impact their experience during healthcare delivery. Further data analysis, including free text responses in the survey, aims to explore further participants’ views on e-health to manage IBD.

P-049: Reproducibility of serologic antibody activity at diagnosis and after treatment in pediatric ulcerative colitis and Crohn’s disease

Background/Objectives: Endometriosis and inflammatory bowel disease (IBD) share some epidemiological, clinical and pathogenetic features. A differential diagnosis between pelvic endometriosis and IBD may be challenging, even for expert clinicians. In the present review, we aimed to summarize the currently available data regarding the relationship between endometriosis and IBD and their possible association. Methods: The PubMed and Scopus database were considered, by searching the following terms: "Crohn's Disease", "Ulcerative Colitis", "Endometriosis", "Adenomyosis", and "Inflammatory Bowel Disease", individually or combined. Full-text papers published in English with no date restriction were considered. Results: Few studies have researched the possible association between endometriosis and IBD. Both conditions are characterized by chronic recurrent symptoms, which may be shared (abdominal pain, fatigue, infertility, menstrual irregularities, diarrhea, constipation). Deep infiltrating endometriosis (DIE) can cause bowel symptoms. In a large Danish study, a 50% increased risk of IBD was observed in women with endometriosis. A missed diagnosis of endometriosis and an increased risk of endometriosis has been reported in IBD. Current evidence does not support an association between endometriosis and IBD characteristics. However, IBD may be associated with DIE, characterized by pelvic symptoms (dyschezia, dyspareunia). Preliminary observations suggest an increased IBD risk in patients with endometriosis treated with hormonal therapy. Conclusions: Current findings suggest that a careful search is needed for concomitant endometriosis in subgroups of patients with IBD showing compatible symptoms and vice versa. A multidisciplinary approach including dedicated gastroenterologists and gynecologists is required for a proper search for IBD and endometriosis in subgroups of patients. This approach may avoid diagnostic delays or overtreatments for these conditions.

Neither Hide Nor Hair: The Difficulty of Identifying Useful Disease Biomarkers

Dermatologic Manifestations of Systemic Diseases in Childhood