Clostridium difficile was first described as a cause of diarrhea in 1978 and in the last three decades has reached an epidemic state with increasing incidence and severity in both healthcare and community settings. There also has been a rise in severe outcomes from C. difficile infection (CDI). There have been tremendous advancements in the field of CDI with the identification of newer risk factors, recognition of CDI in populations previously thought not at risk and development of better diagnostic modalities. Several treatment options are available for CDI apart from metronidazole and vancomycin, and include new drugs such as fidaxomicin and other options such as fecal microbiota transplantation. This review discusses the epidemiology, risk factors and outcomes from CDI, and focuses primarily on existing and evolving treatment modalities.
Clostridium difficile infection; risk factors; management; recurrent infection; severe infection
Autoimmune Enteropathy (AIE) is a rare condition characterized by intractable diarrhea, histologic changes on small intestinal biopsy, failed response to dietary manipulation that also may present with extra-intestinal manifestations. In many patients, immunosuppressive therapies are necessary. Although AIE is more common in infants, adult involvement has also been documented. Much of what is known about AIE has been gathered from case reports and small case series; therefore more research in this evolving field is needed. IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome) or APECED (Autoimmune Phenomena, Polyendocrinopathy, Candidiasis, and Ectodermal Dystrophy) are systemic forms of AIE.
Autoimmune Enteropathy (AIE); Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (IPEX); Autoimmune Phenomena Polyendocrinopathy Candidiasis and Ectodermal Dystrophy (APECED); intractable diarrhea
To evaluate the outcomes of corticosteroid-treated microscopic colitis in a population-based cohort, and to compare these outcomes in patients treated with prednisone or budesonide
A historical cohort study of Olmsted County, Minnesota residents diagnosed with collagenous colitis or lymphocytic colitis from 1986 to 2010 was performed using the resources of the Rochester Epidemiology Project.
Of 315 patients, 80 (25.4%) were treated with corticosteroids. The median age was 66.5 years (range: 16 – 95) and 78.7% were female. Forty patients (50%) had lymphocytic colitis and 40 (50%) had collagenous colitis. Six patients were lost to follow-up. The remaining 74 had a median follow-up of 4 years (range: 0.2 – 14); 56 (75.6%) had complete response and 15 (20.3%) had partial response. Fifty patients out of 71 who responded (70.4%) had a recurrence after corticosteroid discontinuation. After 397 person years of follow-up in the 73 patients with long-term data, 47 (64.4%) required maintenance with corticosteroids.
Prednisone was used in 17 patients (21.2%) and budesonide in 63 (78.8%). Patients treated with budesonide had a higher rate of complete response than those treated with prednisone (82.5% vs 52.9%; odds ratio, 4.18; 95% CI, 1.3 – 13.5) and were less likely to recur (hazard ratio, 0.38; 95% CI, 0.18 – 0.85; p=0.02).
Patients with microscopic colitis often respond to corticosteroid therapy, but with a high relapse rate. Budesonide had a higher response rate and a lower risk of recurrence than prednisone.
microscopic colitis; corticosteroid; outcomes; response; recurrence
To examine the rate of Clostridium difficile infection (CDI) and hospital-associated outcomes in a national cohort of hospitalized patients with chronic kidney disease (CKD) and assess the impact of long-term dialysis on outcome in these patients.
Patients and Methods
Data for January 1, 2005, through December 31, 2009 were obtained from the National Hospital Discharge Survey, which includes information on patient demographics, diagnoses, procedures, and discharge types. Data collected and analyzed for this study included age, sex, race, admission type (urgent or emergent combined vs elective), any colectomy diagnosis, length of stay, type of discharge, and mortality. International Classification of Diseases, Ninth Revision, Clinical Modification codes were utilized to identify CKD patients and CDI events. Weighted analysis was performed using JMP version 9.
An estimated 162 million adults were hospitalized during 2005-2009, and 8.03 million (5%) had CKD (median age, 71 years). The CDI rate in CKD patients was 1.49% (0.119 million) compared with 0.70% (1.14 million) in patients without CKD (P<.001). Patients with CKD who were undergoing long-term dialysis were more than 2 times as likely to develop CDI than non-CKD patients and 1.33 times more likely than CKD patients not undergoing dialysis (all P<.001). In a weighted multivariate analysis adjusting for sex and comorbidities, patients with CKD and CDI had longer hospitalization, higher colectomy rate (adjusted odds ratio [aOR], 2.30; 95% confidence interval [CI], 2.14-2.47), dismissal to a health care facility (aOR, 2.22; 95% CI, 2.19-2.25), and increased in-hospital mortality (aOR, 1.55; 95% CI, 1.52-1.59; all P<.001) as compared with CKD patients without CDI. Patients with CKD who were undergoing long-term dialysis did not have worse outcomes as compared with CKD patients who were not undergoing long-term dialysis.
These data suggest that patients with CKD have a higher risk of CDI and increased hospital-associated morbidity and mortality. Future prospective studies are needed to confirm these findings and to identify effective CDI prevention in CKD patients, who appear to have an increased risk of CDI acquisition.
AKI, acute kidney injury; CDI, Clostridium difficile infection; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; NHDS, National Hospital Discharge Survey; OR, odds ratio
Clostridium difficile was first described as a cause of diarrhea in 1978 and is now among the leading 3 hospital-acquired infections in the United States, along with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. In the past 2 decades, there has been an increase in the incidence, severity, and recurrence rates of C difficile infection, all of which are associated with poor outcomes. In addition, several novel risk factors and newer treatment methods are emerging, including fidaxomicin therapy, treatment using monoclonal antibodies, and fecal microbiota transplantation, that have shown promise for the treatment of C difficile infection. This review focuses on the changing epidemiology, risk factors, and newer methods for treatment of C difficile infection.
CDI, Clostridium difficile infection; FDA, Food and Drug Administration; FMT, fecal microbiota transplantation; IDSA/SHEA, Infectious Diseases Society of America/Society for Healthcare Epidemiology of America; IVIG, intravenous immunoglobulin; PCR, polymerase chain reaction; PPI, proton pump inhibitor
Community-acquired Clostridium difficile infection (CA-CDI) is an increasingly appreciated condition. It is being described in populations lacking traditional predisposing factors that have been previously considered at low-risk for this infection. As most studies of CDI are hospital-based, outcomes in these patients are not well known.
To examine outcomes and their predictors in patients with CA-CDI.
A sub-group analysis of a population-based epidemiological study of CDI in Olmsted County, Minnesota from 1991-2005 was performed. Data regarding outcomes, including severity, treatment response, need for hospitalization and recurrence were analyzed.
Of 157 CA-CDI cases, the median age was 50 years and 75.3% were female. Among all CA-CDI cases, 40% required hospitalization, 20% had severe and 4.4% had severe-complicated infection, 20% had treatment failure and 28% had recurrent CDI. Patients who required hospitalization were significantly older (64 vs 44 years, p<0.001), more likely to have severe disease (33.3% vs 11.7%, p=0.001), and had higher mean Charlson comorbidity index scores (2.06 vs 0.84, p=0.001). They had similar treatment failure and recurrence rates as patients who did not require hospitalization.
CA-CDI can be associated with complications and poor outcomes, including hospitalization and severe CDI. As the incidence of CA-CDI increases, clinicians should be aware of risk factors (increasing age, comorbid conditions and disease severity) that predict the need for hospitalization and complications in patients with CA-CDI.
Clostridium difficile infection; community-acquired; outcomes; predictors of hospitalization
To evaluate the association of gastric acid suppression medications, including proton pump inhibitors and histamine type 2 blockers, with outcomes in patients with Clostridium difficile infection (CDI) in a population-based cohort.
Patients and Methods
To understand the association between acid suppression and outcomes in patients with CDI, we conducted a population-based study in Olmsted County, Minnesota, from January 1, 1991, through December 31, 2005. We compared demographic data and outcomes, including severe, severe-complicated, and recurrent CDI and treatment failure, in a cohort of patients with CDI who were treated with acid suppression medications with these outcomes in a cohort with CDI that was not exposed to acid-suppressing agents.
Of 385 patients with CDI, 36.4% were undergoing acid suppression (23.4% with proton pump inhibitors, 13.5% with histamine type 2 blockers, and 0.5% with both). On univariate analysis, patients taking acid suppression medications were significantly older (69 vs 56 years; P<.001) and more likely to have severe (34.2% vs 23.6%; P=.03) or severe-complicated (4.4% vs 2.6% CDI; P=.006) infection than patients not undergoing acid suppression. On multivariable analyses, after adjustment for age and comorbid conditions, acid suppression medication use was not associated with severe or severe-complicated CDI. In addition, no association between acid suppression and treatment failure or CDI recurrence was found.
In this population-based study, after adjustment for age and comorbid conditions, patients with CDI who underwent acid suppression were not more likely to experience severe or severe-complicated CDI, treatment failure, or recurrent infection.
CDI, Clostridium difficile infection; H2, histamine type 2; ICD-9, International Classification of Diseases, Ninth Revision; PPI, proton pump inhibitor; REP, Rochester Epidemiology Project
Screening of high-risk patients for hepatocellular carcinoma (HCC) may result in early diagnosis and improved outcomes. Our aim was to assess gastroenterologists’ knowledge of HCC management guidelines established by the American Association for the Study of Liver Diseases (AASLD) and usual clinical practice.
We surveyed gastroenterologists attending two gastroenterology board review courses regarding their knowledge of HCC screening guidelines and usual practice of screening for HCC. Practices were compared and adherence to the 2005 published HCC guidelines was assessed.
The median age of gastroenterology attending physicians (n = 160) was 41 years, and 75% were men with a median of 11.5 years of practice. A total of 79% of respondents correctly identified the high-risk patients who qualify for HCC screening. Most gastroenterologists correctly identified the screening methods (88.5%) and screening interval (98%). Among those who knew guideline recommendations (i.e., correct identification and certainty of guideline recommendations), 100% reported that they followed the guideline recommendation in their own practices. Regarding the management of abnormal test, 31% of gastroenterologists did not identify that referral for liver transplantation is the recommended management strategy for small HCC in a Child B patient with cirrhosis. The number of years in clinical practice (p = 0.30) and involvement in a malpractice suit (p = 0.34) did not affect the practice patterns.
Most gastroenterologists correctly identified the common high-risk scenarios, methods, and interval of HCC screening as recommended by AASLD. Gastroenterologists who knew the HCC guidelines applied them in their own practice. However, approximately one-quarter do not know the appropriate management of a positive result, thereby likely hampering the overall effectiveness of screening.
Hepatocellular carcinoma; Survey; Outcomes
Clostridium difficile infection (CDI) is a common hospital-acquired infection with increasing incidence, severity, recurrence and associated morbidity and mortality. There is emerging data on the occurrence of CDI in non-hospitalized patients. However, there is a relative lack of community-based CDI studies, as most of the existing studies are hospital-based, potentially influencing the results by referral or hospitalization bias by missing cases of community-acquired CDI.
To better understand the epidemiology of community-acquired Clostridium difficile infection, a population-based study was conducted in Olmsted County, Minnesota using the resources of the Rochester Epidemiology Project. Data regarding severity, treatment response, and outcomes were compared in community-acquired versus hospital-acquired cohorts, and changes in these parameters, as well as in incidence, were assessed over the study period.
Community-acquired Clostridium difficile infection cases accounted for 41% of 385 definite CDI cases. The incidence of both community-acquired and hospital-acquired Clostridium difficile infection increased significantly over the study period. Compared to those with hospital-acquired infection, patients with community-acquired infection were younger (median age 50 years compared to 72 years), more likely to be female (76% versus 60%), had lower comorbidity scores, and were less likely to have severe infection (20% versus 31%) or have been exposed to antibiotics (78% versus 94%). There were no differences in the rates of complicated or recurrent infection in patients with community-acquired compared to hospital-acquired infection.
In this population-based cohort, a significant proportion of cases of Clostridium difficile infection occurred in the community. These patients were younger and had less severe infection than those with hospital-acquired infection. Thus, reports of Clostridium difficile infection in hospitalized patients likely underestimate the burden of disease and overestimate severity.
Clostridium difficile infection; community-acquired; epidemiology
Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28–30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC.
Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer.
Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30–20.10, P=0.02).
Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.
Although the epidemiology of microscopic colitis has been described in Europe, no such data exist from North America. We studied the incidence, prevalence and temporal trends of microscopic colitis in a geographically defined US population.
Design and setting
In this population based cohort study, residents of Olmsted County, Minnesota, with a new diagnosis of microscopic colitis, and all who had colon biopsies for evaluation of diarrhoea, between 1 January 1985 and 31 December 2001 were identified. Biopsies were reviewed for confirmation (cases) and to identify missed cases (diarrhoea biopsies).
Main outcome measures
Incidence rates, age and sex adjusted to the 2000 US white population. Poisson regression assessed the association of calendar period, age and sex with incidence.
We identified 130 incident cases for an overall rate of 8.6 cases per 100 000 person‐years. There was a significant secular trend, with incidence increasing from 1.1 per 100 000 early in the study to 19.6 per 100 000 by the end (p<0.001). Rates increased with age (p<0.001). By subtype, the incidence was 3.1 per 100 000 for collagenous colitis and 5.5 per 100 000 for lymphocytic colitis. Collagenous colitis was associated with female sex (p<0.001) but lymphocytic colitis was not. Prevalence (per 100 000 persons) on 31 December 2001 was 103.0 (39.3 for collagenous colitis and 63.7 for lymphocytic colitis).
The incidence of microscopic colitis has increased significantly over time, and by the end of the study, the incidence and prevalence were significantly higher than reported previously. Microscopic colitis is associated with older age, and collagenous colitis is associated with female sex.
For diagnosis, assessing disease activity, complications and extraintestinal manifestations, and monitoring response to therapy, patients with inflammatory bowel disease undergo many radiological studies employing ionizing radiation. However, the extent of radiation exposure in these patients is unknown.
A population-based inception cohort of 215 patients with inflammatory bowel disease from Olmsted County, Minnesota, diagnosed between 1990 and 2001, was identified. The total effective dose of diagnostic ionizing radiation was estimated for each patient. Linear regression was used to assess the median total effective dose since symptom onset.
The number of patients with Crohn's disease and ulcerative colitis was 103 and 112, with a mean age at diagnosis of 38.6 and 39.4 yr, respectively. Mean follow-up was 8.9 yr for Crohn's disease and 9.0 yr for ulcerative colitis. Median total effective dose for Crohn's disease was 26.6 millisieverts (mSv) (range, 0–279) versus 10.5 mSv (range, 0–251) for ulcerative colitis (P < 0.001). Computed tomography accounted for 51% and 40% of total effective dose, respectively. Patients with Crohn's disease had 2.46 times higher total effective dose than ulcerative colitis patients (P = 0.001), adjusting for duration of disease.
Annualizing our data, the radiation exposure in the inflammatory bowel disease population was equivalent to the average annual background radiation dose from naturally occurring sources in the U.S. (3.0 mSv). However, a subset of patients had substantially higher doses. The development of imaging management guidelines to minimize radiation dose, dose-reduction techniques in computed tomography, and faster, more robust magnetic resonance techniques are warranted.
Autoimmune enteropathy is a rare cause of intractable diarrhea associated with circulating gut autoantibodies and a predisposition to autoimmunity. It is rarely observed in adults with only eleven cases reported to date.
Fifteen adults with autoimmune enteropathy were identified at the Mayo Clinic, Rochester, from May 2001 to June 2006. The demographic, clinical and treatment data were abstracted from their records.
The study population was 87% Caucasian, 47% females, with median age of 55 years (interquartile range: 42 to 67 years). All patients had diarrhea, weight loss and malnutrition. Celiac disease was excluded by lack of response to gluten free diet or absence of the celiac disease susceptibility HLA genotypes. Fourteen patients were tested for gut epithelial cell antibodies and 93% were positive for anti-enterocyte and/or anti-goblet cell antibodies. Predisposition to autoimmune diseases was noted in 80%, as indicated by a variety of circulating autoantibodies. Small intestinal histopathologic findings included subtotal villous atrophy and lymphoplasmacytic infiltration in the lamina propria with relatively few surface intraepithelial lymphocytes. T-cell receptor gene rearrangement studies were negative in all cases. Immunosuppressive therapy was required in 93% cases. Clinical improvement was noted in 60% after 1–8 weeks of steroid therapy.
Autoimmune enteropathy is a heterogeneous disease and should be considered in the differential diagnosis of malabsorption and small bowel villous atrophy. The presence of gut epithelial cell antibodies can help confirm the diagnosis. No single agent is unequivocally effective in inducing remission, and immunosuppressive therapy is required in most cases.
Autoimmune enteropathy; intractable diarrhea; anti-enterocyte antibodies; anti-goblet cell antibodies; malabsorption; refractory sprue; immunosuppressive agent