Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent.

Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.

Risk Factors, Methods, and Timing of Suicide Attempts Among US Army Soldiers.

IMPORTANCE: Suicide attempts in the US Army have risen in the past decade. Understanding the association between suicide attempts and deployment, as well as method and timing of suicide attempts, can assist in developing interventions. OBJECTIVE: To examine suicide attempt risk factors, methods, and timing among soldiers currently deployed, previously deployed, and never deployed at the time this study was conducted. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal, retrospective cohort study of Regular Army-enlisted soldiers on active duty from 2004 through 2009 used individual-level person-month records to examine risk factors (sociodemographic, service related, and mental health), method, and time of suicide attempt by deployment status (never, currently, and previously deployed). Administrative data for the month before each of 9650 incident suicide attempts and an equal-probability sample of 153 528 control person-months for other soldiers were analyzed using a discrete-time survival framework. MAIN OUTCOMES AND MEASURES: Suicide attempts and career, mental health, and demographic predictors were obtained from administrative and medical records. RESULTS: Of the 9650 enlisted soldiers who attempted suicide, 86.3% were male, 68.4% were younger than 30 years, 59.8% were non-Hispanic white, 76.5% were high school educated, and 54.7% were currently married. The 40.4% of enlisted soldiers who had never been deployed (n = 12 421 294 person-months) accounted for 61.1% of enlisted soldiers who attempted suicide (n = 5894 cases). Risk among those never deployed was highest in the second month of service (103 per 100 000 person-months). Risk among soldiers on their first deployment was highest in the sixth month of deployment (25 per 100 000 person-months). For those previously deployed, risk was highest at 5 months after return (40 per 100 000 person-months). Currently and previously deployed soldiers were more likely to attempt suicide with a firearm than those never deployed (currently deployed: OR, 4.0; 95% CI, 2.9-5.6; previously deployed: OR, 2.7; 95% CI, 1.8-3.9). Across deployment status, suicide attempts were more likely among soldiers who were women (currently deployed: OR, 3.4; 95% CI, 3.0-4.0; previously deployed: OR, 1.5; 95% CI, 1.4-1.7; and never deployed: OR, 2.4; 95% CI, 2.3-2.6), in their first 2 years of service (currently deployed: OR, 1.9; 95% CI, 1.5-2.3; previously deployed: OR, 2.2; 95% CI, 1.9-2.7; and never deployed: OR, 3.1; 95% CI, 2.7-3.6), and had a recently received a mental health diagnosis in the previous month (currently deployed: OR, 29.8; 95% CI, 25.0-35.5; previously deployed: OR, 22.2; 95% CI, 20.1-24.4; and never deployed: OR, 15.0; 95% CI, 14.2-16.0). Among soldiers with 1 previous deployment, odds of a suicide attempt were higher for those who screened positive for depression or posttraumatic stress disorder after return from deployment and particularly at follow-up screening, about 4 to 6 months after deployment (depression: OR, 1.4; 95% CI, 1.1-1.9; posttraumatic stress disorder: OR, 2.4; 95% CI, 2.1-2.8). CONCLUSIONS AND RELEVANCE: Identifying the timing and risk factors for suicide attempt in soldiers requires consideration of environmental context, individual characteristics, and mental health. These factors can inform prevention efforts.

Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure.

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis.

Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin's therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-ß) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4 + CD25hiCD127lo and CD4 + FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC + IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC + IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.

Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic.

BACKGROUND: Primary sclerosing cholangitis is a rare chronic cholestatic condition of unknown etiology, frequently associated with inflammatory bowel disease and characterized by diffuse fibrosing and inflammatory destruction of the intra- and/or extrahepatic biliary duct system. PATIENTS AND METHODS: The study involved 14 children with primary sclerosing cholangitis confirmed by either liver biopsy, endoscopic retrograde cholangiopancreatography, and/or magnetic resonance cholangiogram. In each of the 14 cases, liver histology showed characteristic features consistent with primary sclerosing cholangitis. Eleven children had intrahepatic biliary beading and strictures (6 by endoscopic retrograde cholangiopancreatography; 5 by magnetic resonance cholangiogram). Biochemical tests of liver function including alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase and the erythrocyte sedimentation rate were elevated for a mean 17 +/- 22 months before vancomycin treatment was initiated. All of the patients were shown to have inflammatory bowel disease histologically; 13 of those patients had clinical evidence of colitis. Oral vancomycin was given to all 14 patients. RESULTS: All 14 patients showed improvement in their alanine aminotransferase (P = 0.007), gamma-glutamyl transpeptidase (P = 0.005), erythrocyte sedimentation rate (P = 0.008), and clinical symptoms with oral vancomycin treatment. There was less improvement noted in the patients with cirrhosis when compared with the patients without cirrhosis. CONCLUSIONS: Before this study, there has not been an effective long-term treatment for sclerosing cholangitis to prevent the usual progression of this disease to cirrhosis. This study showed that oral vancomycin could be an effective long-term treatment of sclerosing cholangitis in children, especially those without cirrhosis.

Outcomes of transplantation in children with primary hepatic malignancy.

HBL and HCC are the most common hepatic malignancies in children. The role of OLT in children with HCC is still a matter of debate. The aim of this study was to review our experience of OLT for HCC. Medical records of patients (<18 yr) who underwent OLT for HCC were reviewed and compared to children who underwent OLT for HBL and for indications other than malignancy. There were 25 patients: HCC (10 cases) and HBL (15 cases). The actuarial patient survival for HCC at one and five yr was 100% and 83.3%, for the HBL group the survival was 86.7% at both one and five yr, and for indications (n=377) other than malignancy the patient survival for pediatric OLT at our center was 87.7% and 84.7% at one and five yr, respectively. The actuarial recurrence free survival at five yr was 83.3% for HCC and 66.8% for HBL. In conclusion, OLT is a good therapeutic modality for children with HCC and HBL.

Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients is associated with a high mortality (up to 60%) and the younger age groups, who are predominantly EBV-naïve, are at highest risk for development of this disease. The aim of this study is to assess, in this high-risk group, patient outcome and graft loss to rejection when complete withdrawal of immunosuppressive agents (IMS) is instituted as the mainstay of treatment in addition to the use of standard therapy. A retrospective analysis of 335 pediatric patients whose liver transplants were performed by our team between September 1988 and September 2002, was carried out through review of computer records, database and patient charts. Fifty patients developed either EBV or PTLD; 80% were < or =2 yr of age. Of these 50 patients, 19 had a positive tissue diagnosis for PTLD and 31 were diagnosed with EBV infection, 14 of whom had positive tissue for EBV. Fifty-eight percent of patients who developed PTLD and 51.6% of patients with EBV received antibody for induction or treatment of rejection prior to onset of disease. Forty-six patients (92%) received post-transplant antiviral prophylaxis with ganciclovir or acyclovir. Antiviral treatment included ganciclovir in 76%, acyclovir in 20% and Cytogam (in addition to one of the former agents) in 44%. In those with PTLD, treatment included chemotherapy (n = 1), Rituximab (n = 2), and ocular radiation (n = 1). IMS was stopped in all patients with PTLD and in 19 with EBV infection and was held as long as there was no allograft rejection. Eight patients have remained off IMS for a mean of 1535.5 +/- 623 days. Of the 21 patients who were restarted on IMS for acute rejection, 18 responded to steroids and/or reinstitution of low-dose calcineurin inhibitors. The mean time to rejection while off IMS in this group was 107.43 +/- 140 days (range: 7-476). Two patients were re-transplanted for chronic rejection; one had chronic rejection that existed prior to discontinuing IMS. The mortality rate in our series was 31.6% in those with PTLD and 6% in those with EBV disease. The cause of death was related to PTLD or sepsis in all cases; no deaths were due to graft loss from acute or chronic rejection. PTLD is associated with high mortality in the pediatric population. Based on this report, we advocate aggressive management of PTLD that is composed of early cessation of IMS, the use of antiviral therapy, and chemotherapy when indicated. Episodes of rejection that occur after stopping IMS can be successfully treated with standard therapy without graft loss to acute rejection.

Cause-specific mortality among Kelly Air Force Base civilian employees, 1981-2001.

In response to concerns about occupational and environmental exposures, and a perceived cluster of amyotrophic lateral sclerosis (ALS) in the community, the mortality experience among 31,811 civilian employees who worked for at least 1 year between 1981 and 2000 at Kelly Air Force Base, Texas was ascertained. A total of 3264 deaths occurred through October 31, 2001. Overall, significant deficits in mortality were observed for all causes of death and all cancers combined. An excess of breast cancer [standardized mortality ratio (SMR) = 216; 95% confidence interval (CI) = 128-341] among blue-collar women was identified, and remained elevated after adjusting for race and ethnicity [rate ratio (RR) = 2.83; 95% CI = 1.50-5.34]. Mortality from motor neuron disease, which includes ALS deaths, was not increased overall (SMR = 0.98; 95% CI = 0.52-1.68), and was lower among blue-collar employees and higher among white-collar employees than expected, based on small numbers. Overall, mortality patterns indicated a healthy worker population and no large increased mortality associated with employment at Kelly Air Force Base.

Identification of Epstein-Barr virus-specific CD8+ T lymphocytes in the circulation of pediatric transplant recipients.

BACKGROUND: Pediatric transplant recipients are at increased risk for Epstein Barr virus (EBV)-related B cell lymphomas. In healthy individuals, the expansion of EBV-infected B cells is controlled by CD8+ cytotoxic T cells. However, immunosuppressive therapy may compromise antiviral immunity. We identified and determined the frequency of EBV-specific T cells in the peripheral blood of pediatric transplant recipients. METHODS: HLA-B*0801 and HLA-A*0201 tetramers folded with immunodominant EBV peptides were used to detect EBV-specific CD8+ T cells by flow cytometry in peripheral blood mononuclear cells from 24 pediatric liver and kidney transplant recipients. The expression of CD38 and CD45RO on EBV-specific, tetramer-binding cells was also examined in a subset of patients by immunofluorescent staining and flow cytometry. RESULTS: Tetramer-binding CD8+ T cells were identified in 21 of 24 transplant recipients. EBV-specific CD8+ T cells were detected as early as 4 weeks after transplant in EBV seronegative patients receiving an organ from an EBV seropositive donor. The frequencies (expressed as a percentage of the CD8+ T cells) of the tetramer-binding cells were HLA-B8-RAKFKQLL (BZLF1 lytic antigen peptide) tetramer, range=0.96 to 3.94%; HLA-B8-FLRGRAYGL (EBNA3A latent antigen peptide) tetramer, range=0.03 to 0.59%; and HLA-A2-GLCTLVAML (BMLF1 lytic antigen peptide) tetramer, range=0.06 to 0.76%. The majority of tetramer reactive cells displayed an activated/memory phenotype. CONCLUSIONS: Pediatric transplant recipients receiving immunosuppression can generate EBV-specific CD8+ T cells. Phenotypic and functional analysis of tetramer cells may prove useful in defining and monitoring EBV infection in the posttransplant patient.