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There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD).To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD.CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted.Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay.We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.

Background Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD. Methods A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment. Results Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval [CI], 1.2–1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%–66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%–73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%–44.2%) were properly treated with supplementation therapy. Conclusions In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.

Defective spleen function increases susceptibility to bacterial infections which can be prevented by vaccine prophylaxis. Splenic hypofunction can be found in a number of autoimmune disorders; however, no data are available regarding autoimmune atrophic gastritis (AAG), autoimmune enteropathy (AIE) and autoimmune liver disease (AILD). Peripheral blood samples from patients with AAG (n = 40), AIE (n = 3) and AILD (n = 40) were collected. Patients affected by autoimmune disorders already known to be associated with splenic hypofunction, i.e. coeliac disease (CD) and ulcerative colitis (UC), were included as disease controls, while splenectomised patients and healthy subjects were evaluated as positive and negative controls, respectively. Counting of erythrocytes with membrane abnormalities, i.e. pitted red cells, was used as an indicator of spleen function (normal upper limit 4%). Defective splenic function was observed in 22 of the 40 patients with AAG (55.0%), in two of the three patients with AIE (66.6%) and in 35 of the 40 patients with AILD (87.5%). As expected, in untreated CD, refractory CD and UC there was a high prevalence of hyposplenism (43.7%, 88.2% and 54.4%, respectively). Due to the high prevalence of splenic hypofunction, patients with AAG, AILD and AIE should undergo pitted red cell evaluation and, if hyposplenic, they should be candidate to vaccine prophylaxis against encapsulated bacteria.

Few conflicting data are currently available on the risk of SARS-CoV-2 infection in patients with autoimmune disorders. The studies performed so far are influenced, in most cases, by the treatment with immunosuppressive drugs, making it difficult to ascertain the burden of autoimmunity per se. For this reason, herein we assessed the susceptibility to COVID-19 in immunosuppressive drug-naïve patients with autoimmune diseases, such as autoimmune gastritis (AIG), celiac disease (CD), type 1 diabetes (T1D), and autoimmune thyroid disease (AITD). Telephone interviews were conducted on 400 patients-100 for each group-in May 2021 by looking at the positivity of molecular nasopharyngeal swabs and/or serology for SARS-CoV-2, the need for hospitalization, the outcome, and the vaccination status. Overall, a positive COVID-19 test was reported in 33 patients (8.2%), comparable with that of the Lombardy general population (8.2%). In particular, seven patients with AIG, 9 with CD, 8 with T1D, and 9 with AITD experienced COVID-19. Only three patients required hospitalization, none died, and 235 (58.7%) were vaccinated, 43 with AIG, 47 with CD, 91 with T1D, and 54 with AITD. These results seem to suggest that autoimmunity per se does not increase the susceptibility to COVID-19. Also, COVID-19 seems to be mild in these patients, as indicated by the low hospitalization rates and adverse outcomes, although further studies are needed to better clarify this issue.

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8–14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3–6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count

Introduction: The Multidimensional Prognostic Index (MPI) is a validated tool for assessing mortality risk in hospitalised patients. We aimed to evaluate whether the MPI predicted mortality and the risk of developing diverticular disease (DD) complications in older patients. Methods: This is a multicentre study conducted in January 2016-March 2018. All patients with DD aged 65 years and older were included. Patients were stratified into three groups according to MPI groups (1, low risk; 2, moderate risk; 3, high risk). Risk of developing DD complications and mortality rate were assessed. Bivariate models were fitted. Results: One hundred hospitalised patients with DD (mean age 77.9 ± 10.6 years, 53 female patients) were included. Patients with higher MPI groups were more likely to develop DD complications. In particular, 12 (46.2%), 21 (52.5%), and 28 (82.4%) patients with complicated DD were distributed to the MPI 1, MPI 2, and MPI 3 groups (p = 0.0063), respectively. Two patients died in the MPI 1, 4 in the MPI 2, and 29 in the MPI 3 group, with mortality rates of 4.0 per 100 person-year (95% confidence interval [CI] 1.0–15.9), 5.6 (95% CI 2.1–15.0), and 89.2 (95% CI 62–130), respectively (log-rank test p < 0.001). In bivariate analysis, after adjustment for age >80 years, Charlson Comorbidity Index >4, DD complications, and the presence of thromboembolism, higher MPI group was independently associated with higher mortality. Those in the MPI 3 group experienced a greater risk of 1-year hospital readmission (p < 0.001). Conclusion: MPI predicted mortality in patients with DD and also correlated with the risk of developing DD complications. Studies focussing on possible pathophysiological mechanisms between DD complications and MPI are needed.

BACKGROUND: Pharmacological treatment of iron deficiency anaemia can reduce red blood cell (RBC) transfusions. Intravenous iron provides a more effective and quicker correction of iron deficiency anaemia than oral iron, and third-generation high-dose intravenous iron formulations allow the complete correction of iron deficiency with just one or two drug infusions, thus facilitating iron supplementation therapy and reducing transfusion requirement. MATERIAL AND METHODS: In an observational, retrospective study we compared RBC transfusion requirement during hospitalisation and within 3 months of hospital discharge in 88 patients with iron deficiency anaemia treated with high-dose ferric carboxymaltose and in 85 patients treated with ferric gluconate while hospitalised in the Internal Medicine unit of our Institution. RESULTS: Ferric carboxymaltose reduced the number of RBC units given to each transfused patient during hospitalisation (1.81±0.84 vs 2.39±1.49, p=0.011). At hospital discharge, fewer ferric carboxymaltose patients were prescribed home therapy with iron. No differences between treatment groups were observed in the proportion of patients or the number of RBC units transfused within 3 months of discharge. At one month from discharge, however, only 2 ferric carboxymaltose patients had been transfused compared with 7 ferric gluconate patients (p=0.078). Patients transfused post-discharge were more likely to have an underlying malignancy and/or higher serum creatinine concentrations. DISCUSSION: Treatment with ferric carboxymaltose reduced the number of RBC units per transfused patient. Larger studies are required to define risk factors associated with post-discharge transfusion requirement and to establish if home therapy with iron will reduce subsequent transfusions in patients treated with ferric carboxymaltose.

Glucagon-like peptide GLP-1 and -2 have been shown to regulate immune responses in immune-mediated disorders, including Crohn's disease (CD). Our aim was to investigate post-prandial GLP release and its potential link to chronic inflammation, insulin secretion/sensitivity and body composition changes in CD patients.Fifteen patients with CD, 15 healthy controls (HC) and 15 patients with metabolic syndrome (MS) were recruited. All patients underwent assessment of body composition by means of bio-impedance followed by a meal tolerance test (MTT). Only one CD patient did not tolerate the MTT and was excluded.Basal GLP-1 levels were up-regulated in CD, however, as compared to HC, stimulated GLP-1 secretion was significantly reduced in CD (-31 %, p 0.05) as in MS (-52 %, p 0.003). Similarly, basal GLP-2 levels were comparable to that of HC, while response to MTT in CD was virtually absent (p 0.05). Similar fasting insulin sensitivity, estimated 1CD is characterized by abnormal fasting and post-prandial GLP levels. Circulating GLP influences subclinical inflammation and glucose metabolism in CD patients, but not their body composition parameters.

Introduction Diagnostic delay >12 months is frequent in Crohn’s disease [CD]. Recently, the International Organization for Inflammatory Bowel Disease [IO-IBD] developed a tool to identify early CD and reduce diagnostic delay. Subjects with an index ≥8 are more likely to have suspected CD (odds ratio [OR] 205, p Methods Consecutive adult patients referring to the GP were screened. The GPs administered the Red Flags [RF] questionnaire to the eligible patients. All patients were referred to the nearest participating centre to confirm or exclude the diagnosis of CD. Sensitivity, specificity, and positive and negative predictive values [PPV, NPV] of the RF index [RFI] were calculated. Patients lost to follow-up after the first gastroenterological visit were analysed using a non-responder imputation, assuming they were negative for CD diagnosis. Results From November 2016 to November 2019, 112 patients were included. A total of 66 subjects [59%] completed the study after the first gastroenterological visit. The prevalence of CD was 3.6% in the study population [4/112]. The RF index had 50% sensitivity, 58% specificity, 4% PPV, and 97% NPV. A combined diagnostic strategy with faecal calprotectin [FC] [RFI ≥8 and/or FC >250 ng/g] resulted in significantly improved accuracy: sensitivity 100% [29–100%], specificity 72% [55–85%], PPV = 21% [5–51%], NPV = 100% [88–100%]. Conclusions The RF Index combined with FC is a valid tool to identify patients with high probability of having CD at early stage.

We report the case of a 62-y-old woman with short bowel syndrome (SBS) and chronic renal failure, successfully treated with teduglutide, who underwent comprehensive systematic nutritional assessment including bioelectrical impedance vectorial analysis (BIVA). The patient did not tolerate the attempt of gradual suspension of parenteral nutrition (PN), bumping into the worsening of nutritional status and renal function. She was declared eligible for teduglutide, a glucagonlike peptide 2 analog that stimulates structural and functional intestinal adaptation and increases nutrient and fluid absorption. To date, there is no standardized nutritional management protocol for PN-dependent SBS patients treated with teduglutide. We here report our first 1-y follow-up data. The patient underwent comprehensive systematic nutritional assessment initially every 2 wk, then monthly. It included handgrip strength (HGS), blood tests (particularly serum creatinine, estimated glomerular filtration rate, urea, electrolytes, micronutrients, serum albumin), fluid intake, urine output, quality-of-life (QoL) evaluation, and BIVA, which estimates fat-free mass (FFM) and measures phase angle (PhA) and hydration status. At treatment initiation, the patient was on PN 3 d/wk. After 3 mo, she was weaned off PN. At 1 y, weight and serum albumin were reduced (-7.5 kg and -0.6 g/dL, respectively); FFM, PhA, and HGS slightly decreased; hydration status and renal function were preserved; and QoL subtly improved. No relevant clinical complications or metabolic imbalances occurred. The inclusion of BIVA in the comprehensive systematic nutritional assessment of SBS patients treated with teduglutide could be proposed for appropriate and safe management, particularly in the presence of renal impairment.

SummaryPatients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11–dehydro–thromboxane (TX) B2 (11-dehydro–TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)–α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6–week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (pSupplementary Material to this article is available online at www.thrombosis-online.com.

Background Inflammatory bowel disease (IBD) is associated with neuroendocrine cell hyperplasia. Aims We investigated neuroendocrine cells in J-pouches of patients with ulcerative colitis undergoing restorative proctocolectomy and ileal pouch-anal anastomosis. Methods Sections from pouch biopsies of 17 patients and ileal biopsies of 17 active IBD patients and 16 controls were processed by immunohistochemistry for chromogranin A (CgA) and serotonin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative RT-PCR. TpH-1 and SERT transcripts were detected in pouch biopsies cultured with infliximab or its isotype control, while interleukin (IL)-6 and IL-8 were measured in biopsy supernatants. Results A significant increase in CgA-positive cells and serotonin-positive cells was observed in both pouch and IBD ileum compared to control ileum. Significantly raised transcripts of TpH-1, but not SERT, were found in IBD ileum in comparison to control ileum, with no significant difference between pouch and IBD ileum. Infliximab had no influence on ex vivo pouch expression of TpH-1 and SERT, nor on the production of IL-6 and IL-8. Conclusion We here demonstrated neuroendocrine cell hyperplasia in pouch mucosa. Further studies are needed to clarify the pathophysiological implication of this finding.

Simple Summary Coeliac disease is a common chronic enteropathy that may lead to severe complications, including refractoriness (i.e., nonresponsiveness to a gluten-free diet) and enteropathy-associated T-cell lymphoma. In this study, we found that two serum markers, namely chromogranin A and β2-microglobuline, can predict these complications in patients with coeliac disease. Abstract The persistence or recurrence of symptoms in patients with coeliac disease (CD), despite a gluten-free diet (GFD), must prompt further work-up for excluding refractory CD (RCD). The aim of this study was to assess the accuracy of serum markers in predicting refractoriness in CD patients. This study included 72 patients affected by CD followed-up at our center, namely 49 uncomplicated CD before and after GFD and 23 RCD. Serum levels of chromogranin A (CgA) and β2-microglobuline were measured at baseline and at follow-up (median time of 13 months) in each group of patients. Cut-off points for each marker were estimated to differentiate RCD from uncomplicated CD patients. Serum levels of CgA and β2-microglobuline were significantly higher in patients with RCD compared to uncomplicated CD (p < 0.001), both at baseline and at follow-up, with no significant difference between RCD type 1 and type 2. The estimated cut-off point for CgA was 90.2 ng/mL (sensitivity 83%, specificity 100%), while for β2-microglobuline it was 696 mcg/L (sensitivity 100%, specificity of 100%). To conclude, CgA and β2-microglobuline could be useful serological markers of refractoriness in CD, with the ability to discriminate those patients who should undergo upper gastrointestinal endoscopy for making a definite diagnosis.