Hospitalized burden and outcomes of coccidioidomycosis: A nationwide analysis, 2005-2012.

The incidence of coccidioidomycosis (CM) infection has increased over the last 20 years. We investigated recent trends of CM-associated hospitalization in the United States. patients with CM-associated hospitalization were identified from the Nationwide Inpatient Sample, 2005-2012. The outcomes of interest were the trend of annual hospitalization, in-hospital mortality, and independent risk factors for mortality. A total of 30,870 hospitalizations with CM (29,584 of adults; 1,286 of children) were identified. Over the 8-year study period, the number of hospitalizations for CM fluctuated but increased overall with successively higher peaks in 2009 and 2011. The annual median length of stay (LOS) shortened from 6 to 7 days in 2005-2010 to 4 days in 2011 and 5 days in 2012. The inflation-adjusted hospital charges were highest in 2006 then trended down by 21% in 2012. The in-hospital mortality declined from the highest level in 2005 (5.2%) to a low in 2010 (1.1%), then increased modestly in 2011 (1.9%) and 2012 (1.5%). Hospitalizations were identified in 46 states, with nearly half in Arizona (49.1%), followed by California (36.8%), Texas (3.3%), and Nevada (1.6%). Logistic regression analysis in adults revealed that in-hospital mortality was associated with age groups 61-70 years and >70 years (OR = 3.3 and 3.5, respectively. Ref: 18-30 years) and Charlson Index ≥1 (OR = 2.0-8.3). In children, males had lower risk for mortality than females (OR = 0.2). This study shows that CM-associated hospitalizations occur widely throughout the United States with an increasing admission trend; however, patient outcomes have improved and the cost of hospitalization has decreased.

Increasing Volume but Decreasing Mortality of Hospitalized Hepatitis C Patients in the United States, 2005 to 2011.

BACKGROUND: Patients with hepatitis C virus infection often require hospitalization for progressive liver disease and complications, incurring high cost and risk of death. GOALS: The aim of our study was to investigate recent trends in the economic burden and outcomes of patients hospitalized for hepatitis C in the United States. STUDY: Patients with hepatitis C-associated hospitalization were identified from the Nationwide Inpatient Sample 2005 to 2011. We analyzed the in-hospital mortality, hospital service utilization, demographic, and clinical features of patients. A prognostic model to predict in-hospital survival and death with independent risk factors for mortality was developed. RESULTS: A total of 607,279 cases of hepatitis C-associated hospitalization were identified. Over 7 years, the annual hospitalized volume increased by 28.8%. In-hospital mortality declined from 8.2% to 6.4%. Median length of stay (4 d) was unchanged but the inflation-adjusted hospital charges increased by 33.3%. Acute respiratory failure was the greatest independent risk factor for mortality [odds ratio (OR)=7.3; 95% confidence interval (CI), 7.0-7.5], followed by septicemia (OR=4.1; 95% CI, 4.0-4.3), renal failure (OR=3.4; 95% CI, 3.3-3.5), and acute liver failure (OR=2.9; 95% CI, 2.7-3.0). On the basis of the major risk factors for mortality, a risk-adjusted model was developed that could predict the in-hospital outcome of hepatitis C patients with an accurate rate of 89.2%. CONCLUSIONS: Despite decreasing in-hospital mortality, both hospital volume and charges related to hepatitis C increased from 2005 to 2011. Use of a risk-adjusted model could help predict mortality and improve outcomes of hepatitis C inpatients.

A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.

Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

Efalizumab, a human monoclonal anti-CD11a antibody, in the treatment of moderate to severe Crohn's Disease: an open-label pilot study.

BACKGROUND AND AIMS: Efalizumab is a monoclonal antibody targeting CD11a, an adhesion molecule involved in the activation and trafficking of T-lymphocytes. This agent has proven efficacy in the treatment of psoriasis. We performed an open-label study to evaluate the efficacy and safety of efalizumab in Crohn's disease (CD). METHODS: Fifteen subjects with moderate to severe CD (Crohn's Disease Activity Index [CDAI] score 220-450) and who were refractory or intolerant to standard therapy, received a weekly 1 mg/kg subcutaneous injection of efalizumab for 8 weeks. The primary endpoint was clinical response (decrease in the CDAI score of at least 70 points) at week 8. Secondary endpoints included change in mean CDAI scores, the proportion of subjects who achieved clinical remission (CDAI score ≤ 150), change in the Inflammatory Bowel Disease Questionnaire (IBDQ) scores, and report of adverse events. RESULTS: At 8 weeks, ten (67%) subjects had clinical response and six (40%) were in remission. The mean baseline and week 8 CDAI scores were 300 and 167 respectively (P < 0.001). Mean IBDQ scores at baseline and week 8 were 124 and 168 respectively (P < 0.001). One subject with Crohn's colitis had pre- and post-treatment colonoscopy that demonstrated mucosal healing. No serious adverse events occurred. CONCLUSIONS: Efalizumab induced a clinical response in the majority of subjects with moderate to severe CD in this small, open-label pilot study. There were no serious adverse events reported during this short-term trial.

Patients with late-adult-onset ulcerative colitis have better outcomes than those with early onset disease.

BACKGROUND & AIMS: The influence of age on the presentation, clinical course, and therapeutic response of patients with adult-onset ulcerative colitis (UC) is understudied. Given potential age-related differences in risk factors and immune function, we sought to determine if disease behavior or clinical outcomes differed between patients diagnosed with UC in later versus earlier stages of adulthood. METHODS: We performed a retrospective cohort study of 295 patients with UC seen at a tertiary care center from 2001 to 2008. Adult subjects newly diagnosed with UC between the ages of 18 and 30 years were defined as early onset, those newly diagnosed at age 50 or older were defined as late onset. The 2 groups were analyzed for differences in medication use and clinical end points, including disease extent, severity at the time of diagnosis, and steroid-free clinical remission at 1 year after disease onset. RESULTS: Disease extent and symptom severity were similar between groups at the time of diagnosis. One year after diagnosis, more patients in the late-onset group achieved steroid-free clinical remission (64% vs 49%; P = .01). Among those who required systemic steroid therapy, more late-onset patients achieved steroid-free remission by 1 year (50% vs 32%; P = .01). Former smoking status was a more common risk factor in the late-onset cohort (P < .001), whereas more early onset patients had a positive family history (P = .008). CONCLUSIONS: Patients with early and late-adult-onset UC have similar initial clinical presentations, but differ in disease risk factors. Late-onset patients have better responses to therapy 1 year after diagnosis.

Risk of arterial thrombotic events in inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) have an increased risk of venous thrombotic events. The risk of arterial thrombotic events in IBD, however, has been less well characterized. We explored whether Crohn's disease (CD) and ulcerative colitis (UC) are associated with a higher risk for thrombotic events involving the mesenteric, cardiac, or cerebral arteries. METHODS: Using the Thomson Reuters MarketScan Research claims database, we conducted a retrospective cohort study of IBD patients observed for the occurrence of pre-defined thrombotic events. For comparison, four non-IBD controls were age-, sex-, and index date-matched to each IBD case. The outcomes of interest were acute mesenteric ischemia, transient ischemic attack, cerebrovascular occlusion, atherosclerosis, peripheral vascular disease, and myocardial infarction. We performed a multivariate analysis adjusting for potential confounders for thrombotic events, including hypertension, diabetes, hyperlipidemia, and, in women, the use of contraceptives. We calculated the adjusted hazard ratios (HRs) for each event by comparing IBD patients with controls and used the log-rank test to determine statistical significance. RESULTS: The study included 17,487 IBD patients and 69,948 controls. Overall, IBD patients had a markedly increased risk of acute mesenteric ischemia (HR=11.2, P<0.001). IBD patients as a whole did not have an increased risk of other arterial thrombotic events, including myocardial infarction and transient ischemic attack, when compared with controls. However, women with IBD who were over the age of 40 years had a higher risk of myocardial infarction (HR=1.6, P=0.003). In addition, women with IBD below the age of 40 years who showed a significantly higher risk for stroke (HR=2.1, P=0.04). For all events, the risks in CD and UC were similar. CONCLUSIONS: Patients with IBD have a markedly increased risk of acute mesenteric ischemia. Subgroup analysis reveals that women over the age of 40 years with IBD are at increased risk of myocardial infarction, whereas those below the age of 40 years exhibit a two-fold higher risk for stroke. In contrast, men with IBD did not share these same risks for arterial thrombotic events.

Risk factors for surgical recurrence after ileocolic resection of Crohn's disease.

PURPOSE: We evaluated the effect of potential clinical factors on surgical recurrence of ileal Crohn's disease after initial ileocolic resection. METHODS: One hundred seventy-six patients with ileal Crohn's disease who underwent an ileocolic resection with anastomosis were identified from our database. The outcome of interest was time from first to second ileocolic resection. Survival analysis was used to assess the significance of the Montreal phenotype classification, smoking habit, a family history of inflammatory bowel disease and other clinical variables. RESULTS: In our final Cox model, a family history of inflammatory bowel disease (hazard ratio 2.24, 95 percent confidence interval 1.16-4.30, P = 0.016), smoking at time of initial ileocolic resection (hazard ratio 2.08, 95 percent confidence interval 1.11-3.91, P = 0.023) was associated with an increased risk of a second ileocolic resection while postoperative prescription of immunomodulators (hazard ratio 0.40, 95 percent confidence interval 0.18-0.88, P = 0.022) was associated with a decreased risk of a second ileocolic resection. CONCLUSIONS: Both a family history of inflammatory bowel disease and smoking at the time of the initial ileocolic resection are associated with an increased risk of a second ileocolic resection. Postoperative prescription of immunomodulators is associated with a reduced risk of surgical recurrence. This study supports the concept that both genetic and environmental factors influence the risk of surgical recurrence of ileal Crohn's disease.

Incidence of Clostridium difficile infection in inflammatory bowel disease.

BACKGROUND & AIMS: Clostridium difficile-associated disease (CDAD) rates have been increasing. We sought to determine whether CDAD incidence has increased specifically in hospitalized patients with IBD. We also explored possible differences in the risk for and time to presentation of CDAD between IBD and non-IBD patients. METHODS: We analyzed hospital admissions from 1998-2004 for demographics, length of stay, C difficile infections, and time from admission to a positive C difficile test. We calculated CDAD incidence for non-IBD, all IBD, CD, and UC admissions and used logistic regression to estimate the risk for CDAD. RESULTS: CDAD incidence increased in each group and was higher in all IBD than non-IBD groups. During the observation period, CDAD rates approximately doubled in CD (9.5 to 22.3/1000 admissions) and tripled in UC (18.4 to 57.6/1000). Length of stay was similar among the groups. For all years combined, the adjusted odds ratios for CDAD in all IBD, CD, and UC admissions were 2.9 (95% confidence interval, 2.1-4.1), 2.1 (1.3-3.4), and 4.0 (2.4-6.6), respectively. The median times from admission to a positive C difficile test result for non-IBD, CD, and UC were 4.0, 0.8, and 0.5 days, respectively. CONCLUSIONS: CDAD incidence in IBD has increased and is higher than in the non-IBD population. IBD and UC patients in particular have a higher risk for CDAD. C difficile infections in IBD are confirmed predominantly within 48 hours of admission, suggesting most were acquired before hospitalization.

Clostridium difficile infection in inflammatory bowel disease: challenges in diagnosis and treatment.

The problem of Clostridium difficile infection (CDI) has reached epidemic proportions, particularly in industrialized nations. The pathophysiology, disease course and the potential complications are well appreciated in the general hospitalized patient. However, when CDI occurs in the setting of inflammatory bowel disease (IBD), a number of distinct differences in the diagnosis and clinical management of the infection in this population should be appreciated by gastroenterologists, hospitalists and other care providers. This review highlights the unique aspects of CDI when it occurs in IBD patients with an emphasis on the challenge of distinguishing persistent infection from exacerbation of underlying chronic colitis. An understanding of how CDI may differ in presentation and how management should be altered can prevent serious and life-threatening complications.

Combination of corticosteroids and 5-aminosalicylates or corticosteroids alone for patients with moderate-severe active ulcerative colitis: A global survey of physicians' practice.

AIM: To examine treatment decisions of gastroenterologists regarding the choice of prescribing 5-aminosalycilates (5ASA) with corticosteroids (CS) versus corticosteroids alone for patients with active ulcerative colitis (UC). METHODS: A cross-sectional questionnaire exploring physicians' attitude toward 5ASA + CS combination therapy vs CS alone was developed and validated. The questionnaire was distributed to gastroenterology experts in twelve countries in five continents. Respondents' agreement with stated treatment choices were assessed by standardized Likert scale. Background professional characteristics of respondents were analyzed for correlation with responses. RESULTS: Six hundred and sixty-four questionnaires were distributed and 349 received (52.6% response rate). Of 340 eligible respondents, 221 (65%) would continue 5ASA in a patient hospitalized for intravenous CS treatment due to a moderate-severe UC flare, while 108 (32%) would stop the 5ASA (P < 0.001), and 11 (3%) are undecided. Similarly, 62% would continue 5ASA in an out-patient starting oral CS. However, only 140/340 (41%) would proactively start 5ASA in a hospitalized patient not receiving 5ASA before admission. Most (94%) physicians consider the safety profile of 5ASA as very good. Only 52% consider them inexpensive, 35% perceive them to be expensive and 12% are undecided. On multi-variable analysis, less years of practice and perception of a plausible additive mechanistic effect of 5ASA + CS were positively associated with the decision to continue 5ASA with CS. CONCLUSION: Despite the absence of data supporting its benefit, most gastroenterologists endorse combination of 5ASA + CS for patients with active moderate-to-severe UC. Randomized controlled trials are needed to assess if 5ASA confer any benefit for these patients.

Reactive hemophagocytic syndrome complicating the treatment of inflammatory bowel disease.

BACKGROUND AND AIMS: Reactive hemophagocytic syndrome (RHS) is a rare disease in which inappropriately activated macrophages consume bone marrow-derived cells. Most cases are associated with infection in the setting of immunodeficiency. The widespread use of immunosuppressive therapy in the treatment of inflammatory bowel disease (IBD) places patients with Crohn's disease and ulcerative colitis at risk of this complication. No concerted effort has been made to alert gastroenterologists of this condition, and treatment recommendations are lacking. The aims of this study were to describe the clinical and laboratory features of RHS associated with IBD and to review diagnostic criteria, treatment options, and pathogenesis. MATERIALS AND METHODS: Clinical and laboratory data were pooled from the clinical practice of the investigators and from published cases. Descriptive statistics were performed. RESULTS AND CONCLUSIONS: Seven cases of RHS complicating the treatment of IBD were identified. All patients were on immunosuppressive therapy, with nearly half taking >1 agent. All patients presented with fever, leukopenia, anemia, and hyperferritinemia. Infection by a member of the herpesvirus family or an intracellular pathogen precipitated RHS in 6 of 7 patients. The mortality rate was 29%. The diagnosis of RHS should be considered in patients with IBD taking immunosuppressive therapy who present with fever and cytopenia. Evaluation should begin with a serum ferritin. In patients with a serum ferritin > or =10,000 ng/mL, a bone marrow biopsy should be performed to confirm hemophagocytosis. If the initial evaluation is negative, then clinical suspicion should be maintained until the episode resolves.

Portal vein thrombosis.

Portal vein thrombosis (PVT) is a rare event in the general medical setting that commonly complicates cirrhosis with portal hypertension, and can also occur with liver tumors. The diagnosis is often incidental when a thrombus is found in the portal vein on imaging tests. However, PVT may also present with clinical symptoms and can progress to life-threatening complications of ischemic hepatitis, liver failure, and/or small intestinal infarction. This article reviews the pathophysiology of this disorder, with a major focus on PVT in patients with cirrhosis, and presents detailed guidelines on optimal diagnostic and therapeutic strategies.

Outcomes of Clostridium difficile infection in hospitalized leukemia patients: a nationwide analysis.

BACKGROUND The incidence of Clostridium difficile infection (CDI) has increased among hospitalized patients and is a common complication of leukemia. We investigated the risks for and outcomes of CDI in hospitalized leukemia patients. METHODS Adults with a primary diagnosis of leukemia were extracted from the United States Nationwide Inpatient Sample database, 2005-2011. The primary outcomes of interest were CDI incidence, CDI-associated mortality, length of stay (LOS), and charges. In a secondary analysis, we sought to identify independent risk factors for CDI in leukemia patients. Logistic regression was used to derive odds ratios (ORs) adjusted for potential confounders. RESULTS A total of 1,243,107 leukemia hospitalizations were identified. Overall CDI incidence was 3.4% and increased from 3.0% to 3.5% during the 7-year study period. Leukemia patients had 2.6-fold higher risk for CDI than non-leukemia patients, adjusted for LOS. CDI was associated with a 20% increase in mortality of leukemia patients, as well as 2.6 times prolonged LOS and higher hospital charges. Multivariate analysis revealed that age >65 years (OR, 1.13), male gender (OR, 1.14), prolonged LOS, admission to teaching hospital (OR, 1.16), complications of sepsis (OR, 1.83), neutropenia (OR, 1.35), renal failure (OR, 1.18), and bone marrow or stem cell transplantation (OR, 1.27) were significantly associated with CDI occurrence. CONCLUSIONS Hospitalized leukemia patients have greater than twice the risk of CDI than non-leukemia patients. The incidence of CDI in this population increased 16.7% from 2005 to 2011. Development of CDI in leukemia patients was associated with increased mortality, longer LOS, and higher hospital charges.

Gut-enriched Krüppel-like factor regulates colonic cell growth through APC/beta-catenin pathway.

Studies on colorectal carcinogenesis have suggested a critical role of the adenomatous polyposis coli (APC) gene in the development of colorectal cancer. Gut-enriched Krüppel-like factor (GKLF) is a zinc-finger transcription protein with high expression in the colonic epithelium. Our previous studies have shown that GKLF transcript was significantly decreased in colon cancer tissue and suggested that it might play a role in the tumorigenesis of the colon. The signaling pathway of GKLF-regulated cell growth is currently unknown. We sought to determine if the functions of GKLF are mediated through the APC/beta-catenin pathway. In a colon cancer cell line (HT29-APC), containing a zinc-inducible APC gene, GKLF mRNA levels were significantly increased when wild-type APC protein was induced. No effect on GKLF mRNA concentration was observed in a control cell line (HT29-beta-gal), containing an analogous inducible lacZ gene. GKLF promoter activity was induced by co-transfection with wild-type APC DNA, suggesting that APC might be involved in transcriptional activation of the GKLF gene. In HT-29 cells, overexpression of GKLF resulted in decreases in beta-catenin protein and mRNA levels and down-regulation of GKLF expression led to increase in beta-catenin concentration. Overexpression of GKLF in HT-29 cells inhibited DNA synthesis and this effect was attenuated by co-transfection with wild-type beta-catenin, suggesting an essential role of beta-catenin in GKLF signaling. Furthermore, co-transfection of GKLF in colon cancer SW 480 cells abrogated the transcriptional activity of a beta-catenin-T-cell factor (Tcf) reporter construct in a dose-dependent manner. These findings indicate that the growth-suppressive effect of GKLF may be mediated through the APC/beta-catenin pathway. We speculate that when APC is mutated, GKLF gene expression is down-regulated, resulting in increases in beta-catenin level and transactivation of growth-promoted genes.

Clinical experience of natalizumab in Crohn's disease patients in a restricted distribution program.

BACKGROUND: Natalizumab (NAT) is a humanized monoclonal antibody against a4-integrin initially approved for the treatment of multiple sclerosis, and then withdrawn from the market in 2005 due to the risk of progressive multifocal leukoencephalopathy. NAT was approved for the treatment of Crohn's disease in the United States in 2008 under a restricted distribution program. There has been limited data on NAT since then. The purpose of this study was to review the experience with NAT in Crohn's disease patients at a tertiary inflammatory bowel disease center. METHODS: A retrospective chart review was performed on all patients who received NAT for treatment of refractory Crohn's disease from January 2008 to August 2010 at Washington University Medical Center in St. Louis. RESULTS: A total of 20 patients were identified and included in our study. Four patients did not complete induction therapy. Seven patients had a clinical response, with 5 patients continuing treatment up to 2012. Four patients had a partial response, 3 had adverse events, and 2 experienced loss of response. Two patients were pregnant while on NAT, and neither had significant adverse pregnancy outcomes. One patient dependent on total parenteral nutrition developed recurrent line sepsis while on NAT. Of the 5 patients on long-term maintenance therapy, 4 have a positive anti-JC virus antibody. No patients developed progressive multifocal leukoencephalopathy or other neurological complications. CONCLUSION: NAT remains a valuable alternative treatment option for patients with refractory Crohn's disease under a restricted distribution program.

Practice of gastroenterologists in treating flaring inflammatory bowel disease patients with clostridium difficile: antibiotics alone or combined antibiotics/immunomodulators?

BACKGROUND: The optimal management of Clostridium difficile infection (CDI) in flaring inflammatory bowel disease (IBD) patients has not been defined. Limited data suggest that coadministration of immunomodulators (IM) with antibiotics (AB) results in a worse outcome. We investigated the prevalent practice among North American gastroenterologists in this scenario. METHODS: A structured questionnaire presented the clinical cases of two hospitalized patients with ulcerative colitis and concomitant CDI, either with or without prior IM treatment. The questionnaire was distributed to a sample of gastroenterologists at medical centers across North America. Respondents were requested to denote their therapeutic choices for these patients. RESULTS: The survey included 169 gastroenterologists, 122 from the US and 47 from Canada, with an average of 12 ± 10 years of experience in gastroenterology. Forty-two (25%) of the respondents were IBD experts. Seventy-seven (46%) respondents elected to add an IM in combination with AB, whereas 82/169 (54%) treated the flare with AB alone (P = NS). The rate of administering combined AB+IM was similar for the IBD experts and the non-IBD experts. Only 11% of respondents withdrew maintenance azathioprine upon the diagnosis of CDI. More IBD experts stopped azathioprine treatment compared to the non-IBD experts (12/42 versus 6/127, P < 0.001). Overall, 65% of surveyed gastroenterologists stated they believe these patients are afflicted by two simultaneous but separate disease processes. CONCLUSIONS: There is significant disagreement among gastroenterologists on whether combination AB+IM or AB alone should be given to IBD patients with CDI-associated flares. Controlled trials are needed to investigate the optimal management approach to this clinical dilemma.