Community-associated Clostridium difficile infection and antibiotics: a meta-analysis.

OBJECTIVES: Antibiotic exposure is the most important risk factor for Clostridium difficile infection (CDI). Most evaluations of antimicrobial risk factors have been conducted in healthcare settings. The objective of this meta-analysis was to evaluate the association between antibiotic exposure and community-associated CDI (CA-CDI) (i.e. symptom onset in the community with no healthcare facility admission within 12 weeks) and to determine the classes of antibiotics posing the greatest risk. METHODS: We searched four electronic databases for subject headings and text words related to CA-CDI and antibiotics. Studies that investigated the risk of CA-CDI associated with antibiotic usage were considered eligible. Data from the identified studies were combined using a random-effects model and ORs were calculated. RESULTS: Of 910 citations identified, eight studies (n = 30 184 patients) met our inclusion criteria. Antibiotic exposure was associated with an increased risk of CA-CDI (OR 6.91, 95% CI 4.17-11.44, I(2) = 95%). The risk was greatest with clindamycin (OR 20.43, 95% CI 8.50-49.09) followed by fluoroquinolones (OR 5.65, 95% CI 4.38-7.28), cephalosporins (OR 4.47, 95% CI 1.60-12.50), penicillins (OR 3.25, 95% CI 1.89-5.57), macrolides (OR 2.55, 95% CI 1.91-3.39) and sulphonamides/trimethoprim (OR 1.84, 95% CI 1.48-2.29). Tetracyclines were not associated with an increased CDI risk (OR 0.91, 95% CI 0.57-1.45). CONCLUSIONS: Antibiotic exposure was an important risk factor for CA-CDI, but the risk was different amongst different antibiotic classes. The risk was greatest with clindamycin followed by fluoroquinolones and cephalosporins, whereas tetracyclines were not associated with an increased risk.

Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis.

BACKGROUND AND AIM: Proton pump inhibitors (PPI) and H(2) -receptor antagonists (H2RA) are frequently prescribed in hospitalized patients with cirrhosis. There are conflicting reports regarding the role of acid-suppressive therapy in predisposing hospitalized patients with cirrhosis to spontaneous bacterial peritonitis (SBP). The aim of this meta-analysis was to evaluate the association between acid-suppressive therapy and the risk of SBP in hospitalized patients with cirrhosis. METHODS: We searched MEDLINE and four other databases for subject headings and text words related to SBP and acid-suppressive therapy. All observational studies that investigated the risk of SBP associated with PPI/H2RA therapy and utilized SBP as an endpoint were considered eligible. Data from the identified studies were combined by means of a random-effects model and odds ratios (ORs) were calculated. RESULTS: Eight studies (n = 3815 patients) met inclusion criteria. The risk of hospitalized cirrhotic patients developing SBP increased when using acid-suppressive therapy. The risk was greater with PPI therapy (n = 3815; OR 3.15, 95% confidence interval 2.09-4.74) as compared to those on H2RA therapy (n = 562; OR 1.71, 95% confidence interval 0.97-3.01). CONCLUSIONS: Pharmacologic acid suppression was associated with a greater risk of SBP in hospitalized patients with cirrhosis. Cirrhotic patients receiving a PPI have approximately three times the risk of developing SBP compared with those not receiving this medication. Prospective studies may help clarify this relationship and shed light on the mechanism(s) by which acid-suppressive therapy increases the risk of SBP in hospitalized patients with cirrhosis.

Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis.

BACKGROUND & AIMS: In the past decade, there has been a growing epidemic of Clostridium difficile infection (CDI). During this time, use of proton pump inhibitors (PPIs) has increased exponentially. We evaluated the association between PPI therapy and the risk of CDI by performing a meta-analysis. METHODS: We searched MEDLINE and 4 other databases for subject headings and text words related to CDI and PPI in articles published from 1990 to 2010. All observational studies that investigated the risk of CDI associated with PPI therapy and used CDI as an end point were considered eligible. Two investigators screened articles independently for inclusion criteria, data extraction, and quality assessment; disagreements were resolved based on consensus with a third investigator. Data were combined by means of a random-effects model and odds ratios were calculated. Subgroup and sensitivity analyses were performed based on study design and antibiotic use. RESULTS: Thirty studies (25 case-control and 5 cohort) reported in 29 articles met the inclusion criteria (n = 202,965). PPI therapy increased the risk for CDI (odds ratio, 2.15, 95% confidence interval, 1.81-2.55), but there was significant heterogeneity in results among studies (P < .00001). This association remained after subgroup and sensitivity analyses, although significant heterogeneity persisted among studies. CONCLUSIONS: PPI therapy is associated with a 2-fold increase in risk for CDI. Because of the observational nature of the analyzed studies, we were not able to study the causes of this association. Further studies are needed to determine the mechanisms by which PPI therapy might increase risk for CDI.

Expression of taste signaling elements in jejunal tissue in subjects with obesity.

Taste-signaling proteins, which are expressed throughout the digestive tract, are involved in regulating metabolism and immunity. This study aimed to determine if these genes are expressed and altered in jejunal tissues from patients with extreme obesity who received bariatric surgery. Reverse transcription polymerase chain reaction revealed that phospholipase C beta 2 and transient receptor potential channel M5 expression was downregulated in the jejunum of patients with a body mass index above 50, whereas gustducin expression remained unchanged. Our data suggest that taste-signaling dysregulation might contribute to obesity.

Diagnostic accuracy of real-time polymerase chain reaction in detection of Clostridium difficile in the stool samples of patients with suspected Clostridium difficile Infection: a meta-analysis.

BACKGROUND: Current detection methods for Clostridium difficile infection (CDI) can be time-consuming and have variable sensitivities. Real-time polymerase chain reaction (PCR) may allow earlier and more accurate diagnosis of CDI than other currently available diagnostic tests. A meta-analysis was performed to determine the diagnostic accuracy of real-time PCR. METHODS: We searched MEDLINE (Pubmed/Ovid) and 4 other online electronic databases (1995-2010) to identify diagnostic accuracy studies that compared PCR with cell culture cytotoxicity neutralization assay (CCCNA) or anaerobic toxigenic culture (TC) of C. difficile. Screening for inclusion, data extraction, and quality assessment were carried out independently by 2 investigators and disagreements resolved. Data were combined by means of a random-effects model, and summary receiver operating characteristic curves and diagnostic odds ratios were calculated. RESULTS: Nineteen studies (7392 samples) met our inclusion criteria. The overall mean sensitivity of PCR was 90% (95% confidence interval [CI]: 88%-91%), specificity 96% (CI: 96%-97%), positive likelihood ratio 26.89 (CI: 20.81-34.74), negative likelihood ratio 0.11 (CI: .08-.15), diagnostic odds ratio 278.23 (CI: 213.56-362.50), and area under the curve 0.98 (CI: .98-.99). Test accuracy depended on the prevalence of C. difficile but not on the reference test used. At C. difficile prevalence of <10%, 10%-20% and >20% the positive predictive value and the negative predictive value were 71%, 79%, 93% and 99%, 98% and 96%, respectively. CONCLUSIONS: Real-time PCR has a high sensitivity and specificity to confirm CDI. Overall diagnostic accuracy is variable and depends on CDI prevalence.

Repeat stool testing to diagnose Clostridium difficile infection using enzyme immunoassay does not increase diagnostic yield.

BACKGROUND & AIMS: Clostridium difficile infection (CDI) is a hospital-acquired infection with increasing incidence and severity. The most frequently used test to diagnose CDI is an enzyme immunoassay (EIA) for toxins A and B in stool samples. It is common to test 2 or more stool samples, based on the assumption that this detects CDI with greater sensitivity than analysis of 1 sample. We investigated whether repeat stool testing significantly improves the diagnostic yield for CDI. METHODS: We performed a retrospective analysis of hospitalized patients who were tested for CDI using EIA. From year 2005 to 2008, 39,402 stool samples from 17,971 patients with 29,373 diarrhea episodes were tested. Transition probabilities were calculated based on results from repeated tests. RESULTS: A total of 2692 diarrheal episodes (9.17%) were diagnosed with CDI. Based on results of 3 consecutive tests, 2675 (99.36%) were diagnosed with CDI. The first stool sample tested produced positive results for 90.7% of cases. When samples were tested consecutively, for the second and third time, an additional 6.6% and 2% patients had positive test results, respectively. If the first test result was negative, the probability of the second test result being positive was 2.7%. If the first 2 test results were negative, the probability of the third test result being positive was 2.3%. CONCLUSIONS: In patients who had multiple stool samples tested for CDI by EIA, almost 91% were accurately diagnosed based on the results of a single stool sample alone. Subsequent testing yielded a positive result in only 8.6% of patients. We therefore recommend that repeat testing not be done on a routine basis because it does not significantly improve diagnostic yield.

Variants at the MHC Region Associate With Susceptibility to Clostridioides difficile Infection: A Genome-Wide Association Study Using Comprehensive Electronic Health Records.

Background: Clostridioides difficile is a major cause of healthcare-associated and community-acquired diarrhea. Host genetic susceptibility to Clostridioides difficile infection has not been studied on a large-scale. Methods: A total of 1,160 Clostridioides difficile infection cases and 15,304 controls were identified by applying the eMERGE Clostridioides difficile infection algorithm to electronic health record data. A genome-wide association study was performed using a linear mixed model, adjusted for significant covariates in the full dataset and the antibiotic subgroup. Colocalization and MetaXcan were performed to identify potential target genes in Clostridioides difficile infection - relevant tissue types. Results: No significant genome-wide association was found in the meta-analyses of the full Clostridioides difficile infection dataset. One genome-wide significant variant, rs114751021, was identified (OR = 2.42; 95%CI = 1.84-3.11; p=4.50 x 10-8) at the major histocompatibility complex region associated with Clostridioides difficile infection in the antibiotic group. Colocalization and MetaXcan identified MICA, C4A/C4B, and NOTCH4 as potential target genes. Down-regulation of MICA, upregulation of C4A and NOTCH4 was associated with a higher risk for Clostridioides difficile infection. Conclusions: Leveraging the EHR and genetic data, genome-wide association, and fine-mapping techniques, this study identified variants and genes associated with Clostridioides difficile infection, provided insights into host immune mechanisms, and described the potential for novel treatment strategies for Clostridioides difficile infection. Future replication and functional validation are needed.

"Bioelectrical impedance analysis in managing sarcopenic obesity in NAFLD".

INTRODUCTION: Sarcopenic obesity and its association with nonalcoholic fatty liver disease (NAFLD) is under-recognized by many healthcare providers in Western medicine due to the lack of awareness and diagnostic guidelines. The result is delayed recognition and treatment, which leads to further health deterioration and increased healthcare costs. Sarcopenic obesity is characterized by the presence of increased fat mass in combination with muscle catabolism related to chronic inflammation and/or inactivity. Previous research has recommended evaluating body composition and physical function performance to adequately diagnose sarcopenic obesity. Body composition analysis can be performed by imaging applications through magnetic resonance imaging, computed tomography, and dual-energy x-ray absorptiometry. Due to the cost of each device and radiation exposure for patients as evidenced in all three modalities, bioelectrical impedance analysis offers a noninvasive approach capable of providing quick and reliable estimates of lean body and fat mass. METHODS AND RESULTS: This review analyzes the current evidence-based literature, indicating a lower skeletal muscle mass and increased visceral adipose tissue correlation to the advancement of fibrosis in fatty liver disease. CONCLUSION: Given the substantial promising research conducted in predominantly Asian populations regarding body tissue distribution and NAFLD, additional prospective research is needed to extend these findings in Western populations.

Obesity as a risk factor for developing functional limitation among older adults: A conditional inference tree analysis.

OBJECTIVE: To examine the risk factors of developing functional decline and make probabilistic predictions by using a tree-based method that allows higher order polynomials and interactions of the risk factors. METHODS: The conditional inference tree analysis, a data mining approach, was used to construct a risk stratification algorithm for developing functional limitation based on BMI and other potential risk factors for disability in 1,951 older adults without functional limitations at baseline (baseline age 73.1 ± 4.2 y). We also analyzed the data with multivariate stepwise logistic regression and compared the two approaches (e.g., cross-validation). Over a mean of 9.2 ± 1.7 years of follow-up, 221 individuals developed functional limitation. RESULTS: Higher BMI, age, and comorbidity were consistently identified as significant risk factors for functional decline using both methods. Based on these factors, individuals were stratified into four risk groups via the conditional inference tree analysis. Compared to the low-risk group, all other groups had a significantly higher risk of developing functional limitation. The odds ratio comparing two extreme categories was 9.09 (95% confidence interval: 4.68, 17.6). CONCLUSIONS: Higher BMI, age, and comorbid disease were consistently identified as significant risk factors for functional decline among older individuals across all approaches and analyses.

Metabolic Health Status and the Obesity Paradox in Older Adults.

The explanation for reduced mortality among older persons with overweight or class I obesity compared to those of desirable weight remains unclear. Our objective was to investigate the joint effects of body mass index (BMI) and metabolic health status on all-cause mortality in a cohort of advanced age. Adults aged 74 ± 4.7 (mean ± SD) years at baseline (n = 4551) were categorized according to BMI (18.5-24.9, 25.0-29.9, 30.0-34.9, and ≥35.0 kg/m(2)) and the presence or absence of a metabolically healthy phenotype (i.e., 0 or 1 risk factors based on a modified Adult Treatment Panel III). Metabolically unhealthy was ≥2 risk factors. There were 2294 deaths over a mean 10.9 years of follow up. Relative to metabolically healthy desirable weight, metabolically healthy overweight or class I obesity was not associated with a greater mortality risk (HR 0.90; 95 CI% 0.73-1.13 and HR 0.58; 95 CI% 0.42-0.80, respectively) (P-interaction <0.001). Results remained consistent in rigorous sensitivity analyses. The "obesity paradox" may be partially explained by the inclusion of metabolically healthy overweight and obese older persons, who do not have elevated mortality risk, in population studies of BMI and mortality.

Nutrient Transporter Expression in the Jejunum in Relation to Body Mass Index in Patients Undergoing Bariatric Surgery.

Nutrient tranters (NT) facilitate nutrient absorption and contribute to the regulation of circulating nutrients. In this cross-sectional study, we determined the associations between the level of obesity; mRNA abundance for NTs; and serum concentrations of amino acids, short-chain fatty acids, and glucose in patients with morbid obesity undergoing a Roux-en-Y gastric bypass. Proximal jejunal samples were obtained at the time of surgery from 42 patients (90% female, age = 42.6 ± 11.9 years, pre-operative body mass index (BMI) = 55.5 ± 11.3 kg/m²) undergoing a Roux-en-Y gastric bypass. RNA was extracted from the jejunal mucosa and quantitative real-time-PCR was performed for the NTs studied. BMI negatively correlated with jejunal mRNA abundance of the amino acid NTs TauT (r = -0.625, p < 0.0001), ASCT2 (r = -0.320, p = 0.039), LAT1 (r = -0.304, p = 0.05). BMI positively correlated with jejunal mRNA abundance of the lactate/short-chain fatty acid NT SMCT1 (r = 0.543, p = 0.0002). Serum concentrations of the short-chain fatty acids, butyric, valeric, and isocaproic acid correlated positively with BMI (n = 30) (r = 0.45, r = 0.44, r = 0.36, p ≤ 0.05; respectively). Lower jejunal mRNA abundance for the amino acid NTs TauT, ASCT2, and LAT1 could protect against further obesity-related elevations in circulating amino acids. The positive correlation between BMI and the jejunal mRNA abundance of the high-affinity short-chain fatty acid/monocarboxylate transporter SMCT1 is intriguing and requires further investigation.

Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis.

OBJECTIVE: An estimated 20-30% of patients with primary Clostridium difficile infection (CDI) develop recurrent CDI (rCDI) within 2 weeks of completion of therapy. While the actual mechanism of recurrence remains unknown, a variety of risk factors have been suggested and studied. The aim of this systematic review and meta-analysis was to evaluate current evidence on the risk factors for rCDI. DESIGN: We searched MEDLINE and 5 other databases for subject headings and text related to rCDI. All studies investigating risk factors of rCDI in a multivariate model were eligible. Information on study design, patient population, and assessed risk factors were collected. Data were combined using a random-effects model and pooled relative risk ratios (RRs) were calculated. RESULTS: A total of 33 studies (n=18,530) met the inclusion criteria. The most frequent independent risk factors associated with rCDI were age≥65 years (risk ratio [RR], 1.63; 95% confidence interval [CI], 1.24-2.14; P=.0005), additional antibiotics during follow-up (RR, 1.76; 95% CI, 1.52-2.05; P<.00001), use of proton-pump inhibitors (PPIs) (RR, 1.58; 95% CI, 1.13-2.21; P=.008), and renal insufficiency (RR, 1.59; 95% CI, 1.14-2.23; P=.007). The risk was also greater in patients previously on fluoroquinolones (RR, 1.42; 95% CI, 1.28-1.57; P<.00001). CONCLUSIONS: Multiple risk factors are associated with the development of rCDI. Identification of modifiable risk factors and judicious use of antibiotics and PPI can play an important role in the prevention of rCDI.

Accuracy of loop-mediated isothermal amplification for the diagnosis of Clostridium difficile infection: a systematic review.

Loop-mediated isothermal DNA amplification (LAMP) is currently used as standalone diagnostic test for C. difficile infection (CDI). We assessed the diagnostic accuracy of LAMP for the diagnosis of CDI. We searched 5 databases to identify studies that compared LAMP with culture cytotoxicity neutralization assay or anaerobic toxigenic culture (TC) of C. difficile. We used the random-effects model to calculate pooled sensitivities, specificities, diagnostic odds ratios, and their 95% confidence intervals (CIs). The search of the databases yielded 16 studies (6979 samples) that met inclusion criteria. When TC was used as the gold standard (6572 samples), bivariate analysis yielded a mean sensitivity of 0.95 (95% CI, 0.93-0.97; I(2)=67.4) and a mean specificity of 0.99 (95% CI, 0.96-1.00; I(2)=97.0). LAMP is a useful diagnostic tool with high sensitivity and specificity for detecting CDI. The results should, however, be interpreted only in the presence of clinical suspicion and symptoms of CDI.

Gastrointestinal symptoms in morbid obesity.

BACKGROUND: Several reports have shown an increased prevalence of gastrointestinal (GI) symptoms in obese subjects in community-based studies. To better understand the role of the GI tract in obesity, and because there are limited clinic-based studies, we documented the prevalence of upper and lower GI symptoms in morbidly obese individuals in a clinic setting. OBJECTIVE: The aim of our study was to compare the prevalence of GI symptoms in morbidly obese individuals in a weight management clinic with non-obese individuals with similar comorbidities as morbidly obese individuals in an Internal Medicine clinic. METHODS: Class II and III obese patients BMI >35 kg/m(2) (N = 114) and 182 non-obese patients (BMI <25 kg/m(2)) completed the GI symptoms survey between August 2011 and April 2012 were included in this study. The survey included 24 items pertaining to upper and lower GI symptoms. The participants rated the frequency of symptoms as absent (never, rarely) or present (occasionally, frequently). The symptoms were clustered into five categories: oral symptoms, dysphagia, gastroesophageal reflux, abdominal pain, and bowel habits. Responses to each symptom cluster were compared between obese group and normal weight groups using logistic regression. RESULTS: Of the 24 items, 18 had a higher frequency in the obese group (p < 0.005 for each). After adjusting for age and gender, the obese patients were more likely to have upper GI symptoms: any oral symptom (OR = 2.3, p = 0.0013), dysphagia (OR 2.9, p = 0.0006), and any gastroesophageal reflux (OR 3.8, p < 0.0001). Similarly, the obese patients were more likely to have lower GI symptoms: any abdominal pain (OR = 1.7, p = 0.042) and altered bowel habits (OR = 2.8, p < 0.0001). CONCLUSION: These observations suggest a statistically significant increase in frequency of both upper and lower GI symptoms in morbidly obese patients when compared to non-obese subjects.

Diarrhea in solid-organ transplant recipients: a review of the evidence.

OBJECTIVE: To provide a comprehensive review of the literature as it relates to diarrhea in solid organ transplant (SOT) recipients. In this article, we review the epidemiology, pathogenesis, clinical manifestations, diagnosis and management of diarrhea in SOT recipients and discuss recent advances and challenges. METHODS: Two investigators conducted independent literature searches using PubMed, Web of Science, and Scopus until January 1st, 2013. All databases were searched using a combination of the terms diarrhea, solid organ transplant, SOT, transplant associated diarrhea, and transplant recipients. Articles that discussed diarrhea in SOT recipients were reviewed and relevant cross-references also read and evaluated for inclusion. Selection bias could be a possible limitation of the approach used in selecting or finding articles for this article. FINDINGS: Post-transplant diarrhea is a common and distressing occurrence in patients, which can have significant deleterious effects on the clinical course and well-being of the organ recipient. A majority of cases are due to infectious and drug-related etiologies. However, various other etiologies including inflammatory bowel disease must be considered in the differential diagnosis. A step-wise, informed approach to post-transplant diarrhea will help the clinician achieve the best diagnostic yield. The use of diagnostic endoscopy should be preceded by exclusion of an infectious or drug-related cause of diarrhea. Empiric management with antidiarrheal agents, probiotics, and lactose-free diets may have a role in managing patients for whom no cause can be determined even after an extensive investigation. CONCLUSIONS: Physicians should be familiar with the common etiologies that result in post-transplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve the diarrhea but also prevent potentially life-threatening consequences including loss of the graft as well. Prospective studies are required to determine the etiology of post-transplant diarrhea in different clinical and geographic settings.

Repeat stool testing for Clostridium difficile using enzyme immunoassay in patients with inflammatory bowel disease increases diagnostic yield.

BACKGROUND: The incidence and severity of Clostridium difficile infection (CDI) in patients with inflammatory bowel disease (IBD) is increasing. CDI is diagnosed by toxin enzyme immunoassay (EIA) or real-time polymerase chain reaction (PCR) performed on stool samples. An earlier study evaluating EIA in IBD patients with CDI suggested that more than one stool sample be tested to increase diagnostic yield. We investigated whether repeat stool testing improves diagnostic accuracy for CDI in hospitalized IBD patients compared to hospitalized patients with CDI and no IBD. METHODS: We performed retrospective data analysis from January 2005-May 2011 on 63,086 hospitalized patients who were tested for CDI using EIA or PCR. Of these, 2579 patients had IBD. Transition probabilities were calculated based on results from repeated tests. RESULTS: Inclusive of all inpatients tested for CDI, 56,583 were tested using toxin EIA and 6503 were tested using PCR. In patients with no IBD, the first stool sample tested was positive in 90% and 94% with EIA and PCR respectively. In IBD patients tested using EIA, 101 were diagnosed with CDI. The first stool sample tested was positive in 81% of patients. Successive second and third stool samples yielded additional 14% and 5% CDI positive IBD patients. CONCLUSIONS: Approximately one in five IBD patients with CDI required repeat testing to yield a positive result with EIA. There are minimal diagnostic gains of repeat testing by EIA or PCR in patients without IBD. We recommend repeat stool testing for CDI when using EIA to increase diagnostic yield in IBD patients.

Uncommon sources and some unsual manifestations of lead poisoning in a tropical developing country.

Lead-containing cooking utensils, sometimes used in South Indian homes, and indigenous medications, widely used in India and increasingly in developed countries, may be responsible for lead intoxication in adults. We report chronic lead poisoning in five adult patients. Not all patients had abdominal colic, while dramatic weight loss, depression and encephalopathy were seen. Once recognized, lead poisoning is treatable and sometimes preventable. Response to chelation therapy with agents such as calcium ethylenediaminetetraacetate (CaEDTA) is impressive, although several courses of therapy may be necessary.