Papers by Ioannis Koutroubakis
Journal of Clinical Medicine
Since inflammatory bowel disease (IBD) patients were excluded from vaccine authorization studies,... more Since inflammatory bowel disease (IBD) patients were excluded from vaccine authorization studies, limited knowledge exists regarding perceptions and unfavorable effects of COVID-19 vaccination in this group. We aimed to investigate the real-world use and adverse events (AEs) of COVID-19 vaccines in Greek IBD patients. Fully vaccinated IBD patients followed in Greek centers were invited to participate. All patients filled out an anonymous online survey concerning the vaccination program, which included information regarding demographics, clinical characteristics, treatment, vaccination perceptions and potential AEs. Overall, 1007 IBD patients were included. Vaccine hesitancy was reported by 49%. Total AEs to vaccination were reported by 81% after dose 1 (D1) and 76% after dose 2 (D2), including isolated injection site reactions (36% and 24% respectively). Systemic AEs were more common after D2 (51%, D2 vs. 44%, D1, p < 0.0001). Very few patients reported new onset abdominal sympto...
Gastroenterology, 1998
Although recirculation of lymphocytes through intestinal mucosa is important for specific immune ... more Although recirculation of lymphocytes through intestinal mucosa is important for specific immune defense, homing of lamina proprial lymphocytes (LPLs) has not been clearly understood. The aim of this study was to compare the dynamic process of lymphocyte-endothelium recognition and binding in murine intestinal mucosa between lymphocytes from lamina propria of intestine and spleen under intravital microscope. Methods: BALB/c mice were used in this study. LPLs were separated from non-lymphoid area of small intestine by collagenase treatment and Percoll centrifugation. Ileal Peyer's patches, villus mucosa and spleen were observed under an intravital fluorescence microscope. Lymphocytes collected from lamina propria and spleen were fluorescence labeled and injected into the jugular vein of recipient mice. The cell kinetics of infused lymphocytes were monitored in these organs at 10min-intervals for 60 min. Surface expression of adhesion molecules (ct4-, and 137-integrin, CD 1 la and L-selectin) on lymphocytes was determined by FACScan. Results: By observation of villus mucosa LPLs were accumulated in the microvessels of villus tip and the number was gradually increased time-dependently up to 60 min. These accumulation was significantly inhibited by the treatment of lymphocytes with anti-[37. A small number of lymphocytes were attached to capillaries of crypt base, but there was no adherence of LPLs to submucosal venules of the intestinal mucosa or postcapillary venules of Peyer's patches during the entire course of observation. On the other hands, splenic lymphocytes was shown to adhere selectively to the postcapillary venules of Peyer's patches. In the villus mucosa, some splenic lymphocytes were adhered to microvessels of villus tip and crypt base for the first 10 min, but these lymphocytes were often detached and the number of adherent lymphocytes was decreased at 60 min. LPLs were also found in splenic microvessels, but the number was smaller than those of splenic lymphocytes. By FACscan analysis, decreased expression of L-selectin and increase in 137 expression were observed in LPLs as compared with splenic lymphocytes while CD11a and et4-integrin were not changed. Conclusions: It was demonstrated in vivo for the first time that lymphocytes from lamina proptia adhered selectively to the microvessels of villus tip O f intestine possibly via 137, but not to the postcapillary venules of Peyer's patches in contrast to splenic lymphocytes.
OBJECTIVES: Inflammatory bowel disease (IBD) is a heterogeneous group of chronic inflammatory gas... more OBJECTIVES: Inflammatory bowel disease (IBD) is a heterogeneous group of chronic inflammatory gastrointestinal conditions with variable disease courses often requiring significant healthcare expenditures. We aimed to identify disease trajectory patterns based on longitudinal financial expenditures and to assess the association of classic disease activity parameters with financial charges. METHODS: This was an analysis of a consented, prospective, natural history IBD registry (2009–2013) from a tertiary IBD center of 2,203 patients and their associated medical charges excluding pharmacy expenses. We applied group-based trajectory modeling to longitudinal healthcare financial charges to determine patterns of charges. We assessed the association between charge patterns and disease activity, quality of life, healthcare utilization, and medication requirement. RESULTS: The final model included 1,600 IBD patients with 5-year charges. We identified six distinct trajectories over
In their study, D' Alessio et al. 1 investigated the results of stimulating lymphatic function an... more In their study, D' Alessio et al. 1 investigated the results of stimulating lymphatic function and adaptive immune response via vascular endothelial growth factor (VEGF)-C/VEGFR3 signaling on various parameters including intestinal inflammation, lymphatic drainage, bacterial antigen clearance, and macrophage (MΦs) activation during gut inflammation. The mechanism through which this pathway acts in disease progression was also evaluated. Initial investigation focused on an examination on lymphangiogenesis in human inflammatory bowel disease (IBD), with an immunohistologic characterization of colonic tissues from IBD patients and controls that were stained with antibodies recognizing podoplanin. The total number of lymphatic vessels (LVs) per field in the lamina propria and submucosa of IBD specimens was significantly increased compared with that of the controls. Moreover, the VEGF-C expression was found to be upregulated in the mucosal extracts of IBD patients (mainly those with ulcerative colitis) and increased VEGFR3+ vessel density in inflamed tissue was noticed. An overexpression of VEGFR3 in IBD human intestinal lymphatic endothelial cells (LECs) was also observed using immunofluorescence. The second part of the study was an investigation of the functional role of the VEGF-C/VEGFR3 pathway by systemic inhibition of VEGFR3 or by delivery of the human lymphangiogenic factor VEGF-C in two models of chronic colitis (dextran sodium sulfate and interleukin-10—knockout) using either a blocking Ab or adenoviral transfer. VEGFR3 protein levels were significantly increased in colonic tissue lysates (mainly in the DDS model) during both acute and chronic intestinal inflammation. The systemic administration of Ad-hVEGF-C improved the chronic intestinal inflammation (as was measured by percentage of body weight, endoscopy and disease activity index) in both animal models of colitis. On the other hand, the anti-VEGFR3 antibody (mF431C1) worsened the clinical course of experimental colitis. Increased VEGFR3+ vessel density in inflamed tissues and increased VEGF-C expression protein levels in extracts from the colons of colitic mice compared to controls were also demonstrated. Treatment with the anti-VEGFR3 Ab mF431C1 was found to reduce the number of LVs per area compared with that in the wild-type control group in both animal models of colitis. LV decrease with anti-VEGFR3 Ab was found to inversely correlate with increased disease activity and increased weight loss, suggesting that lymphangiogenesis per se might be important for the resolution of inflammation. Exacerbation of experimental colitis by VEGFR3 blockade with resultant exacerbation of experimental colitis was associated with decreased afferent lymph flow and inflammatory cell migration to draining nodes. The antigen clearance from the inflamed colon was accelerated by systemic delivery of VEGF-C through MΦ mobilization. MΦ depletion was associated with less protection in VEGF-C-treated mice during chronic experimental colitis. MΦ plasticity and activation was found to be regulated both in vivo and in vitro by the VEGF-C/VEGFR3. Finally, the VEGF-C/VEGFR3 pathway was demonstrated to modulate activation of signal transducer and activator of transcription 6 during experimental colitis and in cultured bone marrow − derived MΦs. Commentary Angiogenesis and lymphangiogenesis have been identified as hallmark features of chronic gut inflammation, and expansion of both vascular populations has been hypothesized to play a pathogenic role in IBD. However, the data on the role of lymphangiogenesis in IBD are limited. The complexity of this feature of chronic inflammation is highlighted by the fact that lymphangiogenesis may be either protective or pathogenic. 2 The functions of lymphatics include the control of tissue edema by eliminating the accumulation of interstitial fluid and inflammatory cells as well as the clearance of bacterial antigens and inflammatory chemokines. The obstruction and dysfunction of the LVs are well-known features of IBD. 3,4 Moreover, some experimental data suggest that LVs may be important for the resolution of intestinal inflammation. 5 Research has recently focused
Background There is evidence that fat mass is correlated with bone mineral density (BMD) in infla... more Background There is evidence that fat mass is correlated with bone mineral density (BMD) in inflammatory bowel disease (IBD), but data on the role of adipokines on this association are limited. The aim of this study was to investigate the serum levels of chemerin, visfatin, and vaspin, hormones that act as adipokines, in relation to BMD in patients with ulcerative colitis (UC) and Crohn's disease (CD). Patients and methods Serum from 120 IBD patients (68 CD, 52 UC) and 98 matched healthy controls (HC) was collected. Chemerin, visfatin, and vaspin levels were assessed using an enzyme-linked immunosorbent assay. BMD was determined for the lumbar spine and the proximal femur using dual-energy X-ray absorptiometry. Full-body composition scans were analyzed using enCORE software based on the absorptiometry system. Results Serum chemerin was higher in IBD patients than HC [CD 13.67.1 ± 5.8, UC 13.9 ± 4.3 vs. HC 7.8 ± 2.6 ng/ml, odds ratio (OR): 0.95, 95% confidence interval (CI) 0.93–0.98, P < 0.0001]. Serum visfatin levels in CD patients were significantly higher than those in UC patients (9.3 ± 14.01 vs. 6.5 ± 7.2 ng/ml, OR: 0.86, 95% CI 0.80–0.92, P = 0.039). In multivariate logistic regression analysis, a significant independent association of osteoporosis (T-score ≤ 2.5 SD) with age (OR: 1.04, 95% CI 1.01–1.08, P = 0.02), visfatin (OR: 0.78, 95% CI 0.63–0.97, P = 0.02), and chemerin levels (OR: 0.83, 95% CI 0.70–0.98, P = 0.03), but not with BMI or body composition, was found. Conclusion Serum visfatin and chemerin levels are associated with the development of osteoporosis in IBD. These results suggest a role of visfatin and chemerin in the pathophysiology of osteoporosis in IBD. Eur J Gastroenterol Hepatol 00:000–000
Clinical and Experimental Immunology, 2008
Recent reports have shown that allele 2 of the IL-1 receptor antagonist (IL-1Ra) gene is over-rep... more Recent reports have shown that allele 2 of the IL-1 receptor antagonist (IL-1Ra) gene is over-represented in ulcerative colitis (UC). Healthy individuals carrying allele 2 of this gene have increased production of IL-1Ra protein. Since the final outcome of the biological effects of IL-1β may depend on the relative proportion of these two cytokines, we have studied if a TaqI polymorphism in the IL-1β gene, which is relevant to IL-1β protein production, may be involved in the genetic susceptibility to UC and Crohn's disease (CD), in association with the established IL-1Ra gene polymorphism. Polymorphisms in the closely linked genes for IL-1β and IL-1Ra were typed in 100 unrelated Dutch patients with UC, 79 with CD, and 71 healthy controls. The polymorphic regions in exon 5 of the IL-1β gene and in intron 2 of the IL-1Ra gene, were studied by polymerase chain reaction (PCR)-based methods. The IL-1β allele frequencies in UC and CD patients did not differ from those in healthy controls. In order to study if the IL-1β gene polymorphism might participate synergistically with the IL-1Ra gene polymorphism in susceptibility to UC and CD, individuals were distributed into carriers and non-carriers of allele 2 of the genes encoding IL-1β and IL-1Ra, in each of the patient groups and controls. Results indicated a significant association of this pair of genes, estimated by the odds ratio (OR) after performing Fisher's exact test, in the UC group (P= 0·023, OR = 2·81), as well as in the CD group (P= 0·01, OR = 3·79). Thus, non-carriers of IL-1β allele 2 were more often present in the subgroup of patients carrying the IL-1Ra allele 2. By contrast, no association of these alleles was detected in the group of healthy controls (P= 1·00, OR = 0·92). These results suggest that the IL-1β/IL-1Ra allelic cluster may participate in defining the biological basis of predisposition to chronic inflammatory bowel diseases.
Digestive Diseases and Sciences, 2004
European Journal of Clinical Investigation, 2006
Extraintestinal manifestations [EIMs] are common in inflammatory bowel disease [IBD]. Data on epi... more Extraintestinal manifestations [EIMs] are common in inflammatory bowel disease [IBD]. Data on epidemiology and risk factors of EIMs in IBD patients are limited. The aim of this study was to investigate the prevalence of EIMs in a large cohort of Greek IBD patients and identify risk factors for their development.
Background: Crohn's disease (CD) causes lifelong, progressive bowel damage, which may be quantifi... more Background: Crohn's disease (CD) causes lifelong, progressive bowel damage, which may be quantified using the Le´mann Index (LI). We aimed to analyze patterns of LI and its association with 5-year clinical course, in an independent cohort of CD patients.
Background Inflammatory bowel disease (IBD) has been linked to an increased risk of coronary hear... more Background Inflammatory bowel disease (IBD) has been linked to an increased risk of coronary heart disease and stroke. Dyslipidemia is a well-established risk factor for cardiovascular disease. The aim of this study was to investigate the long-term lipid profiles in a large cohort of IBD patients. Methods Data of patients from an IBD registry who had more than one measurement of total cholesterol and triglyceride levels during the follow-up period were analyzed. The lipid profiles of IBD patients were compared to those of the general population according to National Health and Nutrition Examination Survey (2009-2012). Quartiles of cholesterol or triglyceride levels in relation to surrogate markers of disease severity were analyzed. Results Seven hundred and one IBD patients [54 % Crohn's disease (CD), 46 % ulcerative colitis (UC)] were included. IBD patients had less frequent high total cholesterol and high LDL cholesterol (6 vs. 13 and 5 vs. 10 %) and more frequent low HDL and high triglycerides (24 vs. 17 and 33 vs. 25 %) compared to the general population (all p \ 0.001). Median total cholesterol levels were lower and median triglycerides higher in CD compared to UC (171 vs. 184; 123 vs. 100 mg/dL; both p \ 0.001). In the multiple regression analysis, lipid profile was independently associated with hospitalizations (low cholesterol) and IBD surgeries (low cholesterol and high triglycerides). Conclusions Low total cholesterol and high triglyceride levels are more frequent in IBD patients (in particular CD) compared to healthy controls and are independently associated with more severe disease.
Background: Anemia is a common manifestation of inflammatory bowel disease (IBD), but its prevale... more Background: Anemia is a common manifestation of inflammatory bowel disease (IBD), but its prevalence in the United States is not well defined. Aim of this study was to determine the prevalence and characteristics of anemia in IBD patients who were followed in a US referral center.
Background: Patients with ulcerative colitis (UC) are at increased risk of colorectal neoplasia (... more Background: Patients with ulcerative colitis (UC) are at increased risk of colorectal neoplasia (CRN) presumably because of chronic inflammation. Data on the relationship between long-term serum inflammatory biomarkers and the development of CRN in UC are limited.
Background: Antimicrobial treatment is known to cause short-and long-term changes in the composit... more Background: Antimicrobial treatment is known to cause short-and long-term changes in the composition of normal human microbiota. The relationship between antibiotic use and overall clinical behavior in inflammatory bowel disease (IBD) has not been explored. We aim to prospectively characterize patterns of antibiotic use and clinical IBD activity in a large IBD cohort.
Background: Patient-reported Crohn's disease (CD) symptoms and endoscopic evaluation have histori... more Background: Patient-reported Crohn's disease (CD) symptoms and endoscopic evaluation have historically guided routine care, but the risk of complications in asymptomatic patients with elevated C-reactive protein (CRP) is unknown.
Background: Obesity has been linked with a proinflammatory state and the development of inflammat... more Background: Obesity has been linked with a proinflammatory state and the development of inflammatory diseases. Data on the clinical course and treatment of obese patients with inflammatory bowel disease (IBD) are limited. We used an institutional IBD registry to investigate the impact of obesity on IBD severity and treatment.
Clinical Gastroenterology and Hepatology, 2015
Inflammatory bowel diseases, Jan 30, 2015
Anti-tumor necrosis factor (TNF) agents are an important component of inflammatory bowel disease ... more Anti-tumor necrosis factor (TNF) agents are an important component of inflammatory bowel disease (IBD) treatment, but data on their influence on anemia, a frequent complication of IBD, are limited. The aim of this study was to evaluate the effect of anti-TNF agents on hemoglobin (Hb) levels in a large IBD cohort. Prospectively collected demographic, clinical, laboratory, and treatment data from IBD patients who started anti-TNF treatment at a tertiary referral center during the years 2010 to 2012 were analyzed. Follow-up data including disease activity scores (Harvey-Bradshaw index or ulcerative colitis activity index), quality of life scores (short IBD questionnaire) completed at each visit, and laboratory data were analyzed. Data from the year of anti-TNF initiation (yr 0) to the following year (yr 1) were compared. A total of 430 IBD patients (324 with Crohn's disease, 51.6% females) started anti-TNF treatment. The prevalence of anemia and median Hb levels did not change betw...
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Papers by Ioannis Koutroubakis