Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Herein we analysed the influence of early life factors, including breast milk composition, on the development of the intestinal microbiota of infants born to mothers with and without IBD. METHODS: The MECONIUM [Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome] study is a prospective cohort study consisting of pregnant women with or without IBD and their infants. Longitudinal stool samples were collected from babies and analysed using 16s rRNA sequencing and faecal calprotectin. Breast milk proteomics was profiled using Olink inflammation panel. RESULTS: We analysed gut microbiota of 1034 faecal samples from 294 infants [80 born to mothers with and 214 to mothers without IBD]. Alpha diversity was driven by maternal IBD status and time point. The major influencers of the overall composition of the microbiota were mode of delivery, feeding, and maternal IBD status. Specific taxa were associated with these exposures, and maternal IBD was associated with a reduction in Bifidobacterium. In 312 breast milk samples [91 from mothers with IBD], mothers with IBD displayed lower abundance of proteins involved in immune regulation, such as thymic stromal lymphopoietin, interleukin-12 subunit beta, tumour necrosis factor-beta, and C-C motif chemokine 20, as compared with control mothers [adjusted p = 0.0016, 0.049, 0.049, and 0.049, respectively], with negative correlations with baby´s calprotectin, and microbiome at different time points. CONCLUSION: Maternal IBD diagnosis influences microbiota in their offspring during early life. The proteomic profile of breast milk of women with IBD differs from that of women without IBD, with distinct time-dependent associations with baby's gut microbiome and feacal calprotectin.

Improved Smoking Cessation Rates in a Pharmacist-Led Program Embedded in an Inflammatory Bowel Disease Specialty Medical Home.

BACKGROUND: Cigarette smoking is associated with disease progression, poor outcomes, and increased biologic use in Crohn's Disease (CD). In this prospective study, we describe the structure and results of a pharmacist-driven smoking cessation program in an Inflammatory Bowel Disease (IBD) Specialty Medical Home. METHODS: One pharmacist designed and implemented a collaborative drug therapy management (CDTM) program, which allowed the pharmacist to initiate and modify smoking cessation aids, monitor medication safety and efficacy, and provide behavioral counseling. Crohn's Disease patients who were current smokers and referred to the program were analyzed. Clinical and demographic data, disease activity, and smoking history were collected. The primary outcome was the proportion of patients in the enrolled group and the declined group who quit smoking at least once during the follow-up period. Secondary outcomes include demographic and clinical differences between enrolled and declined patients, and enrolled quitters and non-quitters. RESULTS: Thirty-two patients were referred to the program and 19 participated. Over a median follow-up period of 305 [264-499] days, 42% (8/19) of enrolled patients quit smoking at least once. Fifteen percent (2/13) of declined patients quit smoking. Patients who continued to smoke had more instances of loss of response to a biologic, need to start a new biologic, or escalation of biologic therapy. The CDTM pharmacist was able to provide all necessary clinical services for smokers enrolled in the program. CONCLUSIONS: A pharmacist-led smoking cessation program in a specialty medical home is feasible. It may result in successful quit attempts and may optimize IBD medication use.

Longitudinal Changes in Fecal Calprotectin Levels Among Pregnant Women With and Without Inflammatory Bowel Disease and Their Babies.

BACKGROUND & AIMS: The effect of pregnancy on inflammatory bowel disease (IBD) remains poorly understood. We aimed to monitor intestinal inflammation using fecal calprotectin (FC) in pregnant women and their babies during early life. METHODS: Pregnant women with or without IBD and their infants were prospectively enrolled. FC levels were measured at each trimester of pregnancy and in babies throughout the first 3 years of life. Repeated-measures analysis was applied to investigate changes in FC levels while adjusting for confounders. The FC levels were correlated with the bacterial abundance in both mothers and babies. RESULTS: Six hundred and fourteen fecal samples from 358 mothers (98 with IBD) and 1005 fecal samples from 289 infants (76 born to IBD mothers) were analyzed. Pregnant Patients with IBD maintained higher FC levels through pregnancy compared with controls (P = 7.5 × 10-54). FC gradually increased in controls and declined in Patients with IBD throughout pregnancy (P for interaction = 5.8 × 10-7). Babies born to mothers with IBD presented with significantly higher FC levels than those born to controls up to 3 years of age, after adjusting for sex, delivery mode, feeding behavior, and antibiotics exposure (2 weeks to 3 months of age, P = .015; 12-36 months of age, P = .00003). Subdoligranulum, Roseburia, Fusicatenibacter, and Alistipes negatively correlated, and Streptococcus, Prevotella, Escherichia-Shigella, and Bifidobacterium positively correlated with maternal FC levels at T3. Faecalibacterium, Bifidobacterium, and Alistipes showed negative correlations, and Streptococcus were positively correlated with FC levels within 3 months of birth. CONCLUSIONS: Pregnancy is associated with decreased inflammatory activity in mothers with IBD. Higher FC levels in babies born to mothers with IBD suggest subclinical inflammation in early life, the long-term consequences of which are uncertain.

Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.

BACKGROUND AND AIMS: Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring's microbiome. METHODS: We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines. RESULTS: Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in Gammaproteobacteria and depletion in Bifidobacteria. Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon. CONCLUSION: Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.

High rates of metachronous colon cancer or dysplasia after segmental resection or subtotal colectomy in Crohn's colitis.

BACKGROUND: In ulcerative colitis, total proctocolectomy is the treatment of choice for patients with colonic dysplasia or cancer because of the high risk for metachronous neoplasia. It is unknown whether patients with Crohn's disease and colon cancer or dysplasia have a similar risk. METHODS: We retrospectively reviewed the charts of 75 patients treated at our center from 2001 to 2011 with Crohn's disease and colon cancer who underwent segmental resection or subtotal colectomy (STC). We then identified the presence or absence of subsequent colon cancer or dysplasia in these patients during the follow-up (0-19 years). RESULTS: Of the 64 patients with colon cancer, 25 had at least 1 metachronous cancer (39%). The mean time to a new cancer was 6.8 years. Eighty-five percent of patients (21/25) were undergoing annual screening colonoscopy. Of the 11 patients with dysplasia, 5 (46%) had a new dysplasia. Mean time to a new dysplastic lesion was 5.0 years. Nineteen of the 47 patients (40%) who had a segmental resection for colon cancer developed metachronous cancer and 6/17 patients (35%) with a STC had metachronous cancer. Two of the 4 patients (50%) with STC for dysplasia (50%) had a new dysplasia and 3/7 patients (43%) with segmental resection had a new dysplasia. There was no significant difference (P = 0.61) between recurrence rates in patients with segmental resection versus STC. CONCLUSIONS: The high rate of metachronous colon cancer after surgical resection suggests that total proctocolectomy should be considered. Larger studies are required to determine if the same is true for dysplasia.

Clinical presentation and outcomes of inflammatory bowel disease patients admitted to the intensive care unit.

BACKGROUND: Disease severity, immunosuppression, and malnutrition may impact morbidity and mortality of the critically ill patient with inflammatory bowel disease (IBD). The aim of this study was to identify potential predictive factors for mortality among IBD patients requiring admission to an intensive care unit (ICU). METHODS: All patients with an admitting diagnosis of ulcerative colitis or Crohn's disease presenting to the ICU at the Mount Sinai Medical Center from 2003 to 2008 were retrospectively analyzed. Data regarding IBD-specific features, medications, and surgical outcomes were collected as well as ICU-related morbidity and 30-day mortality. RESULTS: Ninety-five patients were admitted to the ICU out of a total of 6663 IBD-related hospital admissions with an overall 30-day mortality rate of 18.9%. The annual number of ICU admissions of all hospitalized IBD patients increased from 0.1% in 2003 to 2.6% of admissions in 2008. ICU-related variables associated with increased mortality included mechanical ventilation (P=0.0002), vasopressor requirement (P=0.0002), severe sepsis (P=0.0005), acute kidney injury (P=0.001), Acute Physiology and Chronic Health Evaluation II scores (P ≤ 0.0001), hypoalbuminemia (P=0.036), and thromboembolism (P=0.046). On multivariate analysis, elevated Acute Physiology and Chronic Health Evaluation II scores were the only independent predictor of mortality. CONCLUSIONS: Although the overall number of ICU admissions among IBD patients was low, the annual incidence rates of admissions are increasing. This patient subgroup had significant in-hospital morbidity and 30-day mortality. Earlier identification of potential risk factors leading to poorer outcome, particularly within the first 24 hours of ICU admission, may impact the triage and subsequent management of these critically ill patients.

Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis.

BACKGROUND & AIMS: In patients with severe corticosteroid-refractory ulcerative colitis, cyclosporine or infliximab may be added in an effort to induce remission. If the patient then fails either of these drugs, it is unknown whether success can be achieved by using the other agent. The aim of this study was to assess outcomes of using cyclosporine after failure of infliximab, and vice versa. METHODS: We retrospectively reviewed the charts of 19 patients with corticosteroid-refractory ulcerative colitis who received either infliximab after failed cyclosporine or cyclosporine after failed infliximab. Acute salvage therapy was defined as having received the alternate drug within 4 weeks of discontinuing the first agent. RESULTS: Ten patients received infliximab after failing cyclosporine; 9 patients received cyclosporine after failing infliximab. Four patients (40%) in the infliximab-salvage group achieved remission, as did 3 (33%) in the cyclosporine-salvage group. Remission lasted a mean of 10.4 months (range, 4.4-17.03 mo) and 28.5 months (range, 5.0-41.5 mo), respectively. Severe adverse events included one patient who developed sepsis and died after receiving infliximab salvage. One patient who received cyclosporine salvage developed herpetic esophagitis, and another patient who received cyclosporine salvage developed pancreatitis and bacteremia. CONCLUSIONS: In patients with severe corticosteroid-refractory ulcerative colitis who fail treatment with either cyclosporine or infliximab, remission rates using acute salvage therapy by crossing over to the other drug occur in approximately one third of patients and have limited duration. Serious adverse events occurred in 16%, including 1 death, suggesting that the risks of acute salvage therapy may outweigh the benefits.

Pouch-ouch.

PURPOSE OF REVIEW: For patients who require colectomy, the ileal pouch anal anastomosis operation has alleviated the need for permanent ileostomy and has improved associated self-esteem issues. The most common complication of this surgery, however, is pouchitis. This review highlights the most recent research in the pathophysiology, risk factors, diagnosis and management of pouchitis, and pouch surveillance for neoplasia in patients who had ulcerative colitis. RECENT FINDINGS: Markers of inflammation, including fecal lactoferrin and mucosal cytokines, have been reported as useful in differentiating between irritable pouch syndrome and pouchitis. Numerous risk factors for the development of pouchitis have been identified. They include the presence of perinuclear antinuclear cytoplasmic antibodies, steroid use prior to colectomy, dysplasia as the indication for colectomy, the presence of extraintestinal manifestations, and an elevated platelet count. Therapy for acute pouchitis remains a short course of antibiotics. For chronic pouchitis, studies found success with rifaximin, tinidazole, and oral budesonide. Cancer in the residual rectal mucosa, in the ileal mucosa, and in pouch polyps occurs frequently enough to warrant surveillance. SUMMARY: Risk factors for the development of pouchitis should be discussed with patients. Less invasive diagnostic strategies have been proposed and antibiotics are still the mainstay of therapy.

Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease.

BACKGROUND & AIMS: The effect of infliximab infused at scheduled intervals on antibody formation, preinfusion trough serum concentrations of infliximab, and their clinical significance was evaluated in patients with Crohn's disease. METHODS: Antibodies to infliximab and trough serum infliximab were measured in 105 patients with Crohn's disease treated with 5 mg/kg infliximab for induction followed by maintenance episodic re-treatment (n = 23) or scheduled therapy at 6- to 8-week intervals (n = 82). RESULTS: After a median of 14 infusions (range, 2-45), 21% of patients had detectable antibodies, 25% were antibody negative, and 54% were antibody inconclusive. Antibody formation was higher after episodic compared with scheduled treatment (39% vs 16%; P = .036) and was associated with a higher rate of infusion reactions (50% vs 21%; P = .018). Ninety patients continued maintenance scheduled therapy beyond 12 months including 12 converted episodic patients, with a median follow-up of 23 months (range, 16-68 months). The rate of clinical remission was higher for patients with a detectable trough serum infliximab compared with patients in whom serum infliximab was undetectable, including those without antibodies (82% vs 6%; P < .001). A detectable trough serum infliximab was also associated with a lower C-reactive protein (2.0 vs 11.8 mug/L; P < .001) and a higher rate of endoscopic improvement (88% vs 33%; P < .001). Concurrent immunomodulators did not alter outcomes. CONCLUSIONS: For Crohn's disease patients treated with scheduled maintenance infusions of infliximab, the trough serum concentration of infliximab predicts clinical outcome. Factors in addition to antibody formation, likely pharmacokinetic, modulate serum infliximab and thus the response to infliximab therapy.

The interobserver reliability of pretest probability assessment in patients with suspected pulmonary embolism.

INTRODUCTION: Pretest probability assessment and objective testing are combined to appropriately manage patients with suspected pulmonary embolism (PE). However, the interobserver reliability of pretest probability assessment has not been investigated. We sought to determine (for patients with suspected PE) the interobserver reliability of pretest probability assessment (by overall impression (gestalt) versus an explicit clinical model). MATERIALS AND METHODS: A prospective cohort study was conducted at an urban university hospital. For patients referred for ventilation and perfusion (V/Q) scanning for suspected PE, structured assessments (11 history and 4 physical examination parameters) were performed by a referring physician and a designated thrombosis physician. The referring and thrombosis physicians also assigned a pretest probability for PE (low, moderate, or high) by gestalt. An explicit seven-point clinical model for suspected PE was later applied to each structured assessment to determine the pretest probability. Assessments were performed independently and prior to diagnostic test results. Interobserver reliability (two rater unweighted Kappa (kappa) statistic) was determined for each parameter on the structured assessment and the pretest probability assessments (gestalt vs. explicit clinical model). RESULTS: One hundred and ten patients with suspected PE received duplicate assessments. Historical features demonstrated substantial to almost perfect interobserver reliability (kappa=0.60-0.95). For the physical findings, only heart rate had substantial interobserver reliability (kappa=0.60). Pretest probability assessment was not reliable when using physician's gestalt (kappa=0.33), but produced substantial interobserver reliability using the explicit clinical model (kappa=0.62). CONCLUSIONS: Given the inadequate interobserver reliability of pretest probability assessment by overall impression (or gestalt), physicians should use explicit clinical models in the diagnostic management of patients with suspected pulmonary embolism.

Acute HIV seroconversion in a patient receiving pegylated interferon for treatment of hepatitis C.

Hepatitis C is diagnosed frequently in persons with HIV infection. However, the diagnosis of HIV infection during treatment of hepatitis C has not been reported. We present a case of acute HIV seroconversion in a patient who was not responding to interferon therapy for treatment of hepatitis C.