Marcus R. Pereira

Identification of a Novel Polyomavirus in a Pancreatic Transplant Recipient With Retinal Blindness and Vasculitic Myopathy

BACKGROUND A 33 year-old pancreatic transplant recipient developed weakness, retinal blindness, and necrotic plaques on her face, scalp, and hands. METHODS A muscle biopsy was analyzed by light and electron microscopy and high-throughput nucleic acid sequencing. RESULTS The biopsy revealed microthrombosis and viral particles in swollen endothelial cell nuclei. High-throughput sequencing of nucleic acid revealed a novel polyomavirus. In situ hybridization confirmed the presence of the polyomavirus in endothelial cells at sites of myositis and cutaneous necrosis. CONCLUSIONS New Jersey polyomavirus (NJPyV-2013) is a novel polyomavirus that may have tropism for vascular endothelial cells.

Hepatitis B virus and human immunodeficiency virus drugs in pregnancy: Findings from the Antiretroviral Pregnancy Registry

BACKGROUND & AIMS Fetal safety of antiviral therapies is important given the long-term treatment of women with chronic hepatitis B (CHB) infection who may become pregnant. We analyzed neonatal safety data from the Antiretroviral Pregnancy Registry (APR), the largest safety database in pregnancy for antivirals used for HIV and CHB. METHODS Data were extracted from APR cases prospectively enrolled between 1989 and 2011. Primary outcomes were major birth defects rates with exposure to all antivirals, individual classes, and drugs compared to population-based controls. Relevant to CHB, only lamivudine (LAM) and tenofovir disoproxil fumarate (TDF) had sufficient individual data for review (≥200 cases). RESULTS Of 13,711 cases analyzed, the overall birth defect prevalence (2.8%, 95% CI 2.6-3.1%) was comparable to Centers for Disease Control population-based data (2.72%, 2.68-2.76%, p=0.87) and two prospective antiretroviral exposed newborn cohorts (2.8%, 2.5-3.2%, p=0.90 and 1.5%, 1.1-2.0%, p<0.001). The birth defects prevalence between first and second/third trimesters exposure was similar (3.0% vs. 2.7%). No increased risk of major birth defects with LAM or TDF exposure compared to population-based controls was observed. No specific pattern of major birth defects was observed for individual antivirals or overall. CONCLUSIONS No increased risk of major birth defects including in non-live births was observed for pregnant women exposed to antivirals relevant to CHB treatment overall or to LAM or TDF compared to population-based controls. Continued safety and efficacy reporting on antivirals in pregnancy are essential to inform patients on their risks and benefits during pregnancy.

Risk factors and outcomes of carbapenem-resistantKlebsiella pneumoniaeinfections in liver transplant recipients: Klebsiella PneumoniaeInfections in LT Recipients

Carbapenem‐resistant Klebsiella pneumoniae (CRKP) infection is increasing in incidence and is associated with increased mortality in liver transplantation (LT) recipients. We performed a retrospective cohort study of all patients transplanted between January 2010 and January 2013 to identify the incidence and risk factors for post‐LT CRKP infection and evaluate the impact of this infection on outcomes in a CRKP‐endemic area. We studied 304 recipients, of whom 20 (6.6%) developed CRKP and 36 (11.8%) carbapenem‐susceptible Klebsiella pneumoniae (CSKP) infections in the year following LT. Among the 20 recipients with post‐LT CRKP infection, 8 (40%) were infected in ≥ 2 sites; 13 (65%) had surgical site–intra‐abdominal infections; 12 (60%) had pneumonia; and 3 (15%) had a urinary tract infection. There were 6 patients with a CRKP infection before LT, 5 of whom developed a CRKP infection after LT. Significant risk factors for post‐LT CRKP infection in multivariate analysis included laboratory Model for End‐Stage Liver Disease at LT (odds ratio [OR], 1.07; P = 0.001), hepatocellular carcinoma (OR, 3.19; P = 0.02), Roux‐en‐Y biliary choledochojejunostomy (OR, 3.15; P = 0.04), and bile leak (OR, 5.89; P = 0.001). One‐year estimated patient survival was 55% (95% confidence interval, 31%‐73%), 72% (55%‐84%), and 93% (89%‐96%), for patients with CRKP, CSKP, and no Klebsiella pneumoniae infection, respectively. In multivariate analysis, CRKP (hazard ratio [HR], 6.92; P < 0.001) and CSKP infections (CSKP, HR, 3.84; P < 0.001), as well as bile leak (HR, 2.10; P = 0.03) were the strongest predictors of post‐LT mortality. In an endemic area, post‐LT CRKP infection is common, occurring in 6.6% of recipients, and is strongly associated with post‐LT mortality. Improved strategies for screening and prevention of CRKP infection are urgently needed. Liver Transpl 21:1511‐1519, 2015.

In Vivo and In Vitro Antimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine

ABSTRACT Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies.

Epidemiology and outcomes of carbapenem-resistant Klebsiella pneumoniae bacteriuria in kidney transplant recipients

Little is known about the epidemiology of carbapenem‐resistant Klebsiella pneumoniae (CRKP) bacteriuria following kidney transplantation. We determined the incidence of post‐transplant CRKP bacteriuria in adults who underwent kidney transplant from 2007 to 2010 at 2 New York City centers.

Risk factors associated with Clostridium difficile infection after kidney and pancreas transplantation

Clostridium difficile infection (CDI) is a common cause of nosocomial antibiotic‐associated diarrhea with an increased incidence reported in solid organ transplant recipients. We sought to determine if kidney and/or pancreas transplant recipients possess unique risk factors for CDI.

Effect of ex vivo Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques

BackgroundInfusion of recipient regulatory T (Treg) cells promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic bone marrow transplant (BMT) with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. MethodsCD4+ CD25high Treg cells that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and major histocompatibility complex mismatched BMT with or without Treg cell infusion. Renal transplantation (from the same BMT donor) was performed 4 months post-BMT without immunosuppression to assess for robust donor-specific tolerance. ResultsTransient mixed chimerism, without significant T cell chimerism, was achieved in the animals that received BMT without Treg cells (N = 3). In contrast, 2 of 5 recipients of Treg cell+ BMT that were evaluable displayed chimerism in all lineages, including T cells, for up to 335 days post-BMT. Importantly, in the animal that survived long-term, greater than 90% of donor T cells were CD45RA+ CD31+, suggesting they were new thymic emigrants. In this animal, the delayed (to 4 months) donor kidney graft was accepted more than 294 days without immunosuppression, whereas non–Treg cell BMT recipients rejected delayed donor kidneys within 3 to 4 weeks. Early CMV reactivation and treatment was associated with early failure of chimerism, regardless of Treg cell administration. ConclusionsOur studies provide proof-of-principle that, in the absence of early CMV reactivation (and BM-toxic antiviral therapy), cotransplantation of host Treg cell can promote prolonged and high levels of multilineage allogeneic chimerism and robust tolerance to the donor.

Infectious Complications and Vaccinations in the Posttransplant Population

Infections remain a major cause of mortality and morbidity after both kidney and liver transplantation, and internists increasingly play a major role in diagnosing and treating these infections. Because of immunosuppression, solid organ transplant recipients do not often demonstrate classic signs and symptoms of infection and have a broader variety of common and opportunistic infections, many of which are generally more difficult to diagnose and treat. Although these patients have many risk factors for infection, a major determinant is the time after transplant as it relates to levels of immunosuppression, healing, and hospital or environmental exposures.

Ascites Neutrophil Gelatinase-Associated Lipocalin Identifies Spontaneous Bacterial Peritonitis and Predicts Mortality in Hospitalized Patients with Cirrhosis.

BackgroundNeutrophil gelatinase-associated lipocalin (NGAL) is a marker of both tissue injury and infection. Urine NGAL levels strongly predict acute kidney injury and mortality in patients with cirrhosis, but ascites NGAL is not well characterized. We hypothesized that ascites NGAL level is a marker of spontaneous bacterial peritonitis (SBP) and mortality risk in patients with cirrhosis.MethodsHospitalized patients with cirrhosis and ascites undergoing diagnostic paracentesis were prospectively enrolled and followed until death or discharge. Patients with secondary peritonitis, prior transplantation, or active colitis were excluded. NGAL was measured in the ascites and serum. Ascites NGAL level was evaluated as a marker of SBP (defined as ascites absolute neutrophil count > 250 cells/mm3) and predictor of in-patient mortality.ResultsA total of 146 patients were enrolled, and of these, 29 patients (20%) had SBP. Baseline characteristics were similar between subjects with and without SBP. Median (IQR) ascites NGAL was significantly higher in patients with SBP compared to those without SBP (221.3 [145.9–392.9] vs. 139.2 [73.9–237.2], p < 0.01). Sixteen (11%) patients died in the hospital. In the final multivariable model, ascites NGAL (OR 1.02 per 10 units, p < 0.01) remained predictive of in-hospital mortality, controlling for SBP (OR 9.76, p < 0.01) and MELD (OR 1.11, p = 0.01). In ROC analysis, ascites NGAL had an AUC of 0.79 for inhospital mortality, and the final model including ascites NGAL, MELD, and SBP had an AUC of 0.94.ConclusionsAscites NGAL level may be a biomarker of peritonitis in hospitalized patient with cirrhosis and an independent predictor of short-term in-hospital mortality, even controlling for SBP and MELD.

Clinical Significance of Human Herpesvirus 6 Positivity on the FilmArray Meningitis/Encephalitis Panel

Abstract A review of 15 patients who tested positive for human herpesvirus 6 (HHV-6) on the FilmArray Meningitis/Encephalitis panel revealed that the majority were unlikely to have HHV-6 encephalitis. Criteria to assist interpretation of HHV-6 positive results are presented.