Dejan Micic

Clostridium difficile Ribotype 027: Relationship to Age, Detectability of Toxins A or B in Stool With Rapid Testing, Severe Infection, and Mortality

BACKGROUND Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes. METHODS Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes. RESULTS In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8). CONCLUSIONS Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.

Procalcitonin Levels Associate with Severity of Clostridium difficile Infection

Objective Clostridium difficile infection (CDI) is a major cause of morbidity and biomarkers that predict severity of illness are needed. Procalcitonin (PCT), a serum biomarker with specificity for bacterial infections, has been little studied in CDI. We hypothesized that PCT associated with CDI severity. Design Serum PCT levels were measured for 69 cases of CDI. Chart review was performed to evaluate the presence of severity markers and concurrent acute bacterial infection (CABI). We defined the binary variables clinical score as having fever (T >38°C), acute organ dysfunction (AOD), and/or WBC >15,000 cells/mm3 and expanded score, which included the clinical score plus the following: ICU admission, no response to therapy, colectomy, and/or death. Results In univariate analysis log10 PCT associated with clinical score (OR 3.13, 95% CI 1.69–5.81, P<.001) and expanded score (OR 3.33, 95% CI 1.77–6.23, P<.001). In a multivariable model including the covariates log10 PCT, enzyme immunoassay for toxin A/B, ribotype 027, age, weighted Charlson-Deyo comorbidity index, CABI, and extended care facility residence, log10 PCT associated with clinical score (OR 3.09, 95% CI 1.5–6.35, P = .002) and expanded score (OR 3.06, 95% CI 1.49–6.26, P = .002). PCT >0.2 ng/mL was 81% sensitive/73% specific for a positive clinical score and had a negative predictive value of 90%. Conclusion An elevated PCT level associated with the presence of CDI severity markers and CDI was unlikely to be severe with a serum PCT level below 0.2 ng/mL. The extent to which PCT changes during CDI therapy or predicts recurrent CDI remains to be quantified.

Poor Functional Status as a Risk Factor for Severe Clostridium difficile Infection in Hospitalized Older Adults

To determine the role of impaired functional status as a risk factor for severe Clostridium difficile infection (CDI) in older adults.

Systematic review with meta‐analysis: the efficacy and safety of CT‐P13, a biosimilar of anti‐tumour necrosis factor‐α agent (infliximab), in inflammatory bowel diseases

Biosimilars of anti‐tumour necrosis factor (TNF)‐α agents have now become clinically available for the treatment of inflammatory bowel diseases (IBD).

The Systemic Inflammatory Response to Clostridium difficile Infection

Background The systemic inflammatory response to Clostridium difficile infection (CDI) is incompletely defined, particularly for patients with severe disease. Methods Analysis of 315 blood samples from 78 inpatients with CDI (cases), 100 inpatients with diarrhea without CDI (inpatient controls), and 137 asymptomatic outpatient controls without CDI was performed. Serum or plasma was obtained from subjects at the time of CDI testing or shortly thereafter. Severe cases had intensive care unit admission, colectomy, or death due to CDI within 30 days after diagnosis. Thirty different circulating inflammatory mediators were quantified using an antibody-linked bead array. Principal component analysis (PCA), multivariate analysis of variance (MANOVA), and logistic regression were used for analysis. Results Based on MANOVA, cases had a significantly different inflammatory profile from outpatient controls but not from inpatient controls. In logistic regression, only chemokine (C-C motif) ligand 5 (CCL5) levels were associated with cases vs. inpatient controls. Several mediators were associated with cases vs. outpatient controls, especially hepatocyte growth factor, CCL5, and epithelial growth factor (inversely associated). Eight cases were severe and associated with elevations in IL-8, IL-6, and eotaxin. Conclusions A broad systemic inflammatory response occurs during CDI and severe cases appear to differ from non-severe infections.

Predicting Outcomes to Optimize Disease Management in Inflammatory Bowel Diseases.

Background and Aims: Efforts to slow or prevent the progressive course of inflammatory bowel diseases [IBD] include early and intensive monitoring and treatment of patients at higher risk for complications. It is therefore essential to identify high-risk patients – both at diagnosis and throughout disease course. Methods: As a part of an IBD Ahead initiative, we conducted a comprehensive literature review to identify predictors of long-term IBD prognosis and generate draft expert summary statements. Statements were refined at national meetings of IBD experts in 32 countries and were finalized at an international meeting in November 2014. Results: Patients with Crohn’s disease presenting at a young age or with extensive anatomical involvement, deep ulcerations, ileal/ileocolonic involvement, perianal and/or severe rectal disease or penetrating/stenosing behaviour should be regarded as high risk for complications. Patients with ulcerative colitis presenting at young age, with extensive colitis and frequent flare-ups needing steroids or hospitalization present increased risk for colectomy or future hospitalization. Smoking status, concurrent primary sclerosing cholangitis and concurrent infections may impact the course of disease. Current genetic and serological markers lack accuracy for clinical use. Conclusions: Simple demographic and clinical features can guide the clinician in identifying patients at higher risk for disease complications at diagnosis and throughout disease course. However, many of these risk factors have been identified retrospectively and lack validation. Appropriately powered prospective studies are required to inform algorithms that can truly predict the risk for disease progression in the individual patient.

Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease

Blocking of lymphocyte trafficking to bile ducts is a potential mechanism to alter the disease course of patients with primary sclerosing cholangitis (PSC).

Risk of gastrointestinal cancers in patients with cystic fibrosis: a systematic review and meta-analysis

BACKGROUND The management and life expectancy of patients with cystic fibrosis have improved substantially in the past three decades, which has resulted in an increased number of these patients being diagnosed with malignancies. Our aim was to assess the risk of gastrointestinal cancers in patients with cystic fibrosis. METHODS In this systematic review and meta-analysis, we searched PubMed, MEDLINE, Google Scholar, Scopus, Embase, and Cochrane databases with no language restrictions for studies published from inception of the databases to Aug 1, 2017, assessing the risk of gastrointestinal cancers in patients with cystic fibrosis. We also searched abstracts from scientific meetings and the bibliographies of identified articles for additional references. Studies were included if they reported the standardised incidence ratio (SIR) or incidence ratio per person-years. No exclusion criteria with regard to patient characteristics (age, sex, comorbidities, cystic fibrosis mutation type), study setting (location and time period), or method of reporting cancer diagnoses were applied. The primary outcome was risk of gastrointestinal cancer and site-specific gastrointestinal cancers in patients with cystic fibrosis compared with the general population. Pooled summary estimates were calculated using a random-effects model, and subgroup analyses were done to establish whether risk of gastrointestinal cancer varied according to patient lung transplant status. The study is registered with PROSPERO, number CRD42017075396. FINDINGS Our search identified 95 681 records, of which six cohort studies including 99 925 patients (544 695 person-years) were eligible for the meta-analysis. The overall risk of gastrointestinal cancer was significantly higher in patients with cystic fibrosis than in the general population (pooled SIR 8·13, 95% CI 6·48-10·21; p<0·0001; log SIR 2·10, 95% CI 1·87-2·32; p<0·0001, I2=93·93%). Subgroup analyses showed that the risk of gastrointestinal cancer among patients with cystic fibrosis who had a lung transplant was increased compared with that of patients who did not receive a transplant (pooled SIR 21·13, 95% CI 14·82-30·14; p<0·0001; log SIR 3·05, 95% CI 2·70-3·41; p<0·0001, I2=28·52% vs pooled SIR 4·18, 3·10-5·62; p<0·0001; log SIR 1·43, 1·13-1·73; p<0·0001, I2=22·66%). The risk for the following site-specific cancers was also significantly increased in patients with cystic fibrosis compared with the general population: small bowel cancer (pooled SIR 18·94, 95% CI 9·37-38·27; p<0·0001; log SIR 2·94, 95% CI 2·24-3·64; p<0·0001, I2=38·61%), colon cancer (10·91, 8·42-14·11; p<0·0001; log SIR 2·39, 2·13-2·65; p<0·0001, I2=88·09%), biliary tract cancer (17·87, 8·55-37·36; p<0·0001; log SIR 2·88, 2·15-3·62; p<0·0001, I2=10·16%), and pancreatic cancer (6·18, 1·31-29·27; p=0·022; log SIR 1·82, 0·27-3·38; p<0·0001, I2=62·57%). INTERPRETATION Our study suggests that patients with cystic fibrosis had a significantly increased risk of gastrointestinal cancer compared with the general population, including small bowel, colon, biliary tract, and pancreatic cancers. These findings highlight the need to develop individualised screening strategies for site-specific gastrointestinal cancers in patients with cystic fibrosis. FUNDING None.

In vitro sensitivity assays and clinical response to glucocorticoids in patients with inflammatory bowel disease

BACKGROUND Glucocorticoids (GCs) are steroid hormones used to induce remission in moderate-to-severe inflammatory bowel disease (IBD). A substantial fraction of patients do not respond to GC treatment and require alternate therapies or surgery. At present, non-response can only be assessed empirically by observing continued disease activity. METHODS To identify potential biomarkers of GC response, we retrospectively identified and recruited 18 GC-responsive and 18 GC-nonresponsive IBD patients. This sample included 14 patients with ulcerative colitis (UC) and 22 patients with Crohns disease (CD), all previously treated with steroids. In peripheral blood mononuclear cells from each patient, we performed in vitro assays to measure GC inhibition of three different immune stimulants (phytohemagglutinin [PHA], α-CD3/α-CD28, and lipopolysaccharide [LPS]). RESULTS In both diseases, we found that inhibition of PHA-mediated T cell proliferation was significantly associated with clinical GC response (P=0.04). Inhibition of proliferation due to direct T cell receptor stimulation using α-CD3/α-CD28 was also significantly associated with clinical GC response in UC patients (P=0.009), but not in CD patients (P=0.78). Interestingly, inhibition of LPS-mediated cytokine secretion showed the strongest association with clinical GC response across both diseases (P=0.005). CONCLUSIONS We show that inhibition of LPS stimulation is more strongly associated with clinical GC response in IBD patients than inhibition of PHA and α-CD3/α-CD28-mediated proliferation. These results support an important role of bacterial recognition and innate immunity in the etiology of IBD. This assay could be a powerful predictor of clinical response to GCs.

The benefit of paracentesis on hospitalized adults with cirrhosis and ascites.

The aim of this study is to assess paracentesis utilization and outcomes in hospitalized adults with cirrhosis and ascites.