Publications by authors named "Gabriela Maron"

31 Publications

Successful SCID gene therapy in infant with disseminated BCG.

J Allergy Clin Immunol Pract 2021 Feb 16;9(2):993-995.e1. Epub 2020 Sep 16.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tenn. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870513PMC
February 2021

Experience using intravenous posaconazole in paediatric and young adult oncology patients.

J Antimicrob Chemother 2020 Dec;75(12):3682-3687

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: Posaconazole exhibits broad-spectrum antifungal activity. An IV formulation became available in 2014. Few studies describing the use of this formulation exist in patients under the age of 18 years. This study describes our experience using IV posaconazole in paediatric and young adult cancer patients.

Methods: This single-centre retrospective chart review evaluated patients who received IV posaconazole and had at least one posaconazole plasma concentration obtained after five or more days with a consistent dosage. Relationships between doses required to achieve a plasma concentration of ≥1 µg/mL and patient age, weight and body surface area (BSA) were evaluated. The clinical record was reviewed to identify descriptions of any adverse events.

Results: Twenty-five patients were analysed, with a median age of 10.5 years (range 1.9-22.9 years; 92% were <18 years). All patients were able to achieve a posaconazole plasma concentration ≥1 µg/mL during their treatment course. The daily mg/kg/day dose required to achieve the target concentration decreased significantly with increasing age of the patient (P = 0.018). Assessment of dosage based on BSA suggested a requirement of 225 mg/m2/day across all age groups <18 years. Adverse events documented in the clinical record were consistent with those described with the oral formulations. No CNS toxicities were observed with use of IV posaconazole.

Conclusions: Concentrations ≥1 µg/mL are achievable and a BSA-based dosing approach may allow a consistent empirical dose for patients <18 years of age. Therapeutic drug monitoring is recommended to ensure patients achieve therapeutic concentrations.
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http://dx.doi.org/10.1093/jac/dkaa377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662186PMC
December 2020

The use of imaging to identify immunocompromised children requiring biopsy for invasive fungal rhinosinusitis.

Pediatr Blood Cancer 2020 11 29;67(11):e28676. Epub 2020 Aug 29.

Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee.

Background And Purpose: Children with severe immunocompromise due to cancer therapy or hematopoietic cell transplant are at risk both for potentially lethal invasive fungal rhinosinusitis (IFRS), and for complications associated with gold-standard biopsy diagnosis. We investigated whether early imaging could reliably identify or exclude IFRS in this population, thereby reducing unnecessary biopsy.

Methods: We reviewed clinical/laboratory data and cross-sectional imaging from 31 pediatric patients evaluated for suspicion of IFRS, 19 without (age 11.8 ± 5.4 years) and 12 with proven IFRS (age 11.9 ± 4.6 years). Imaging examinations were graded for mucosal thickening (Lund score), for fungal-specific signs (FSS) of bone destruction, extra-sinus inflammation, and nasal mucosal ulceration. Loss of contrast enhancement (LoCE) was assessed separately where possible. Clinical and imaging findings were compared with parametric or nonparametric tests as appropriate. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) analysis. Positive (+LR) and negative likelihood ratios (-LR) and probabilities were calculated.

Results: Ten of 12 patients with IFRS and one of 19 without IFRS had at least one FSS on early imaging (83% sensitive, 95% specific, +LR = 15.83, -LR = 0.18; P < .001). Absolute neutrophil count (ANC) ≤ 200/mm was 100% sensitive and 58% specific for IFRS (+LR = 2.38, -LR = 0; P = .001). Facial pain was the only discriminating symptom of IFRS (P < .001). In a symptomatic child with ANC ≤ 200/m , the presence of at least one FSS indicated high (79%) probability of IFRS; absence of FSS suggested low (<4%) probability.

Conclusion: In symptomatic, severely immunocompromised children, the presence or absence of fungal-specific imaging findings may effectively rule in or rule out early IFRS, potentially sparing some patients the risks associated with biopsy.
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http://dx.doi.org/10.1002/pbc.28676DOI Listing
November 2020

Effectiveness of Bath Wipes After Hematopoietic Cell Transplantation: A Randomized Trial.

J Pediatr Oncol Nurs 2020 Nov/Dec;37(6):390-397. Epub 2020 Jul 24.

St. Jude Children's Research Hospital, Memphis, TN, USA.

Bacteremia is a leading cause of morbidity and mortality in children undergoing hematopoietic cell transplantation (HCT). Infections of vancomycin-resistant enterococci (VRE) and multidrug resistant (MDR) gram-negative rods (GNRs) are common in this population. Our objective was to assess whether experimental bath wipes containing silver were more effective than standard bath wipes containing soap at reducing skin colonization by VRE and MDR GNRs, and nonmucosal barrier injury bacteremia. Patients undergoing autologous or allogeneic HCT in a tertiary referral center were randomized to receive experimental or standard bath wipes for 60 days post-HCT. Skin swabs were collected at baseline, discharge, and day +60 post-HCT. The rate of VRE colonization was chosen as the marker for efficacy. Experimental bath wipes were well tolerated. Before the study, the rate of colonization with VRE in HCT recipients was 25%. In an interim analysis of 127 children, one (2%) patient in the experimental arm and two (3%) in the standard arm were colonized with VRE. Two (3%) patients had nonmucosal barrier injury bacteremia in the standard arm, with none in the experimental arm. MDR GNRs were not isolated. The trial was halted because the interim analyses indicated equivalent efficacy of the two methods. Skin cleansing with silver-containing or standard bath wipes resulted in very low and equivalent rates of bacteremia and colonization with VRE and MDR GNRs in children post-HCT. Future studies in other high-risk populations are needed to confirm these results.
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http://dx.doi.org/10.1177/1043454220944061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802025PMC
July 2020

Nasal Wash Cytokines during Respiratory Viral Infection in Pediatric Allogeneic Hematopoietic Cell-Transplant Recipients.

Am J Respir Cell Mol Biol 2020 09;63(3):349-361

Department of Immunology.

Allogeneic hematopoietic cell-transplant (alloHCT) recipients are at increased risk of complications from viral respiratory-tract infections (vRTIs). We measured cytokine concentrations in nasal washes (NWs) from pediatric alloHCT recipients to better understand their local response to vRTI. Forty-one immunologic analytes were measured in 70 NWs, collected during and after vRTI, from 15 alloHCT recipients (median age, 11 yr) with 19 episodes of vRTI. These were compared with NW cytokine concentrations from an independent group of otherwise healthy patients. AlloHCT recipients are able to produce a local response to vRTI and produce IFN-α2 and IL-12p40 in significant quantities above an uninfected baseline early in infection. Compared with otherwise healthy comparator-group patients, alloHCT recipients have higher NW concentrations of IL-4 when challenged with vRTI. Further study of these immunologic analytes as well as of type 1 versus type 2 balance in the respiratory mucosa in the context of vRTI during immune reconstitution may be of future research interest in this vulnerable patient population.
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http://dx.doi.org/10.1165/rcmb.2020-0014OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710331PMC
September 2020

Infectious Norovirus Is Chronically Shed by Immunocompromised Pediatric Hosts.

Viruses 2020 06 5;12(6). Epub 2020 Jun 5.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Noroviruses are a leading cause of gastroenteritis worldwide. Although infections in healthy individuals are self-resolving, immunocompromised individuals are at risk for chronic disease and severe complications. Chronic norovirus infections in immunocompromised hosts are often characterized by long-term virus shedding, but it is unclear whether this shed virus remains infectious. We investigated the prevalence, genetic heterogeneity, and temporal aspects of norovirus infections in 1140 patients treated during a 6-year period at a pediatric research hospital. Additionally, we identified 20 patients with chronic infections lasting 37 to >418 days. Using a new human norovirus in vitro assay, we confirmed the continuous shedding of infectious virus for the first time. Shedding lasted longer in male patients and those with diarrheal symptoms. Prolonged shedding of infectious norovirus in immunocompromised hosts can potentially increase the likelihood of transmission, highlighting the importance of isolation precautions to prevent nosocomial infections.
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http://dx.doi.org/10.3390/v12060619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354526PMC
June 2020

Rothia mucilaginosa Infections in Pediatric Cancer Patients.

J Pediatric Infect Dis Soc 2020 May 25. Epub 2020 May 25.

Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

We performed a retrospective study to determine the epidemiology of Rothia mucilaginosa infections among pediatric cancer patients. Over 20 years, 37 cases were identified; 27% developed complications, but there was no infection-related mortality. All cases were successfully treated with vancomycin.
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http://dx.doi.org/10.1093/jpids/piaa047DOI Listing
May 2020

Evolution of vancomycin-resistant during colonization and infection in immunocompromised pediatric patients.

Proc Natl Acad Sci U S A 2020 05 11;117(21):11703-11714. Epub 2020 May 11.

Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;

Patients with hematological malignancies or undergoing hematopoietic stem cell transplantation are vulnerable to colonization and infection with multidrug-resistant organisms, including vancomycin-resistant (VREfm). Over a 10-y period, we collected and sequenced the genomes of 110 VREfm isolates from gastrointestinal and blood cultures of 24 pediatric patients undergoing chemotherapy or hematopoietic stem cell transplantation for hematological malignancy at St. Jude Children's Research Hospital. We used patient-specific reference genomes to identify variants that arose over time in subsequent gastrointestinal and blood isolates from each patient and analyzed these variants for insight into how VREfm adapted during colonization and bloodstream infection within each patient. Variants were enriched in genes involved in carbohydrate metabolism, and phenotypic analysis identified associated differences in carbohydrate utilization among isolates. In particular, a Y585C mutation in the sorbitol operon transcriptional regulator was associated with increased bacterial growth in the presence of sorbitol. We also found differences in biofilm-formation capability between isolates and observed that increased biofilm formation correlated with mutations in the putative capsular polysaccharide () biosynthetic locus, with different mutations arising independently in distinct genetic backgrounds. Isolates with mutations showed improved survival following exposure to lysozyme, suggesting a possible reason for the selection of capsule-lacking bacteria. Finally, we observed mutations conferring increased tolerance of linezolid and daptomycin in patients who were treated with these antibiotics. Overall, this study documents known and previously undescribed ways that VREfm evolve during intestinal colonization and subsequent bloodstream infection in immunocompromised pediatric patients.
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http://dx.doi.org/10.1073/pnas.1917130117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261057PMC
May 2020

Practice patterns and incidence of adenovirus infection in allogeneic hematopoietic cell transplant recipients: Multicenter survey of transplant centers in the United States.

Transpl Infect Dis 2020 Aug 20;22(4):e13283. Epub 2020 Apr 20.

Certara, Montreal, QC, USA.

Background: Adenovirus (AdV) is increasingly recognized as a threat to successful outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Guidelines have been developed to inform AdV screening and treatment practices, but the extent to which they are followed in clinical practice in the United States is still unknown. The incidence of AdV in the United States is also not well documented. The main objectives of the AdVance US study were thus to characterize current AdV screening and treatment practices in the United States and to estimate the incidence of AdV infection in allo-HCT recipients across multiple pediatric and adult transplant centers.

Methods: Fifteen pediatric centers and 6 adult centers completed a practice patterns survey, and 15 pediatric centers and four adult centers completed an incidence survey.

Results: The practice patterns survey results confirm that pediatric transplant centers are more likely than adult centers to routinely screen for AdV, and are also more likely to have a preemptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and preemptive treatment are implemented. Most pediatric centers screen higher-risk patients for AdV weekly, in blood, and have a preemptive AdV treatment approach. The incidence survey results show that from 2015 to 2017, a total of 1230 patients underwent an allo-HCT at the 15 pediatric transplant centers, and 1815 patients underwent an allo-HCT at the 4 adult transplant centers. The incidences of AdV infection, AdV viremia, and AdV viremia ≥ 1000 copies/mL within 6 months after the first allo-HCT were 23%, 16%, and 9%, respectively, for patients at pediatric centers, and 5%, 3%, and 2%, respectively, for patients at adult centers.

Conclusions: These findings provide a more recent estimate of the incidence of AdV infection in the United States, as well as a multicenter view of practice patterns around AdV infection screening and intervention criteria, in pediatric and adult allo-HCT recipients.
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http://dx.doi.org/10.1111/tid.13283DOI Listing
August 2020

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

Am J Transplant 2020 08 10;20(8):2133-2142. Epub 2020 Mar 10.

Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA.

Hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; OR 2.1, 95% CI 1.3-3.4), and exposure to third- (OR 2.4, 95% CI 1.4-4.2) or fourth-generation (OR 2.1, 95% CI 1.2-3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3-0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%), and exposure to PPIs (OR 2.4, 95% CI 1.1-5.4) and third-generation cephalosporin therapy (OR 3.9, 95% CI 1.4-10.5) were identified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.
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http://dx.doi.org/10.1111/ajt.15826DOI Listing
August 2020

Multiple NDM-5-Expressing Isolates From an Immunocompromised Pediatric Host.

Open Forum Infect Dis 2020 Feb 12;7(2):ofaa018. Epub 2020 Jan 12.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: Genes conferring carbapenem resistance have disseminated worldwide among Gram-negative bacteria. Here we present longitudinal changes in clinically obtained isolates from 1 immunocompromised pediatric patient. This report demonstrates potential for antibiotic resistance genes and plasmids to emerge over time in clinical isolates from patients receiving intensive anticancer chemotherapy and broad-spectrum antibiotics.

Methods: Thirty-three isolates obtained over 7 months from 1 patient were included. Clinical data were abstracted from the medical record. For each isolate, studies included phenotypic antibacterial resistance patterns, sequence typing, bacterial isolate sequencing, plasmid identification, and antibiotic resistance gene identification.

Results: Sites of isolation included blood, wound culture, and culture for surveillance purposes from the perianal area. Isolates were of 5 sequence types (STs). All were resistant to multiple classes of antibiotics; 23 (69.6%) were phenotypically resistant to all carbapenems. The blaNDM-5 gene was identified in 22 (67%) isolates, all of ST-167 and ST-940, and appeared to coincide with the presence of the IncFII and IncX3 plasmid.

Conclusions: We present unique microbiologic data from 33 multidrug-resistant isolates obtained over the course of 7 months from an individual patient in the United States. Two sequence types causing invasive infection in the same patient and harboring the blaNDM-5 gene, encoded on the IncX3 plasmid and the IncFII plasmid, were identified. This study highlights the emergence of multidrug-resistant bacteria on antibiotic therapy and the necessity of adequate neutrophil number and function in the clearance of bacteremia.
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http://dx.doi.org/10.1093/ofid/ofaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003983PMC
February 2020

Evaluation of Plasma Microbial Cell-Free DNA Sequencing to Predict Bloodstream Infection in Pediatric Patients With Relapsed or Refractory Cancer.

JAMA Oncol 2020 04;6(4):552-556

Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.

Importance: Bloodstream infection (BSI) is a common, life-threatening complication of treatment for cancer. Predicting BSI before onset of clinical symptoms would enable preemptive therapy, but there is no reliable screening test.

Objective: To estimate sensitivity and specificity of plasma microbial cell-free DNA sequencing (mcfDNA-seq) for predicting BSI in patients at high risk of life-threatening infection.

Design, Setting, And Participants: A prospective pilot cohort study of mcfDNA-seq for predicting BSI in pediatric patients (<25 years of age) with relapsed or refractory cancers at St Jude Children's Research Hospital, a specialist quaternary pediatric hematology-oncology referral center. Remnant clinical blood samples were collected during chemotherapy and hematopoietic cell transplantation. Samples collected during the 7 days before and at onset of BSI episodes, along with negative control samples from study participants, underwent blinded testing using a mcfDNA-seq test in a Clinical Laboratory Improvement Amendments/College of American Pathologists-approved laboratory.

Main Outcomes And Measures: The primary outcomes were sensitivity of mcfDNA-seq for detecting a BSI pathogen during the 3 days before BSI onset and specificity of mcfDNA-seq in the absence of fever or infection in the preceding or subsequent 7 days.

Results: Between August 9, 2017, and June 4, 2018, 47 participants (27 [57%] male; median age [IQR], 10 [5-14] years) were enrolled; 19 BSI episodes occurred in 12 participants, and predictive samples were available for 16 episodes, including 15 bacterial BSI episodes. In the 3 days before the onset of infection, predictive sensitivity of mcfDNA-seq was 75% for all BSIs (12 of 16; 95% CI, 51%-90%) and 80% (12 of 15; 95% CI, 55%-93%) for bacterial BSIs. The specificity of mcfDNA-seq, evaluated on 33 negative control samples from enrolled participants, was 82% (27 of 33; 95% CI, 66%-91%) for any bacterial or fungal organism and 91% (30 of 33; 95% CI, 76%-97%) for any common BSI pathogen, and the concentration of pathogen DNA was lower in control than predictive samples.

Conclusions And Relevance: A clinically relevant pathogen can be identified by mcfDNA-seq days before the onset of BSI in a majority of episodes, potentially enabling preemptive treatment. Clinical application appears feasible pending further study.

Trial Registration: ClinicalTrials.gov identifier: NCT03226158.
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http://dx.doi.org/10.1001/jamaoncol.2019.4120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990667PMC
April 2020

Improved survival rate in T-cell depleted haploidentical hematopoietic cell transplantation over the last 15 years at a single institution.

Bone Marrow Transplant 2020 05 18;55(5):929-938. Epub 2019 Nov 18.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

T-cell depletion of an HLA-haploidentical (haplo) graft is often used to reduce the risk of graft-versus-host disease (GVHD), but the lack of donor T cells in the infused product may lead to graft failure, slow T-cell reconstitution, infections, and relapse. More selective T-cell depletion targeting CD45RA can effectively deplete naive T cells but preserve large numbers of memory T cells leading to robust engraftment of diverse T-cell populations and reduction of viremia in the early posttransplant period. Herein, we report the outcome of 143 pediatric and young adult hematologic malignancy patients receiving a first allogeneic hematopoietic cell transplantation (HCT) on six consecutive ex vivo T-cell depleted haploHCT protocols over the past 15 years at a single institution-including the first 50 patients on an active CD45RA-depleted haploHCT study in which patients also received NK-cells and pharmacological GvHD prophylaxis post transplant. Our data demonstrated an increase in the 3-year overall survival and event-free survival in nonchemorefractory recipients receiving CD45RA-depleted grafts (78.9% and 77.7%, respectively) compared with historic T-cell depleted haploHCT cohorts (46.7% and 42.7%, respectively, p = 0.004, and 0.003). This improvement was primarily due to a reduction in transplant related mortality without significant increase in the rates of GVHD.
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http://dx.doi.org/10.1038/s41409-019-0750-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202974PMC
May 2020

Clinical correlation of influenza and respiratory syncytial virus load measured by digital PCR.

PLoS One 2019 3;14(9):e0220908. Epub 2019 Sep 3.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States of America.

Acute respiratory tract infections are a major cause of respiratory morbidity and mortality in pediatric patients worldwide. However, accurate viral and immunologic markers to predict clinical outcomes of this patient population are still lacking. Droplet digital PCR assays for influenza and respiratory syncytial virus (RSV) were designed and performed in 64 respiratory samples from 23 patients with influenza virus infection and 73 samples from 19 patients with RSV infection. Samples of patients with hematologic malignancies, solid tumors, or sickle cell disease were included. Clinical information from institutional medical records was reviewed to assess disease severity. Samples from patients with fever or respiratory symptoms had a significantly higher viral loads than those from asymptomatic patients. Samples from patients with influenza virus and RSV infection collected at presentation had significantly higher viral loads than those collected from patients after completing a course of oseltamivir or ribavirin, respectively. RSV loads correlated positively with clinical symptoms in patients ≤5 years of age, whereas influenza viral loads were associated with clinical symptoms, irrespective of age. Patients receiving antivirals for influenza and RSV had a significant reduction in viral loads after completing therapy. Digital PCR offers an effective method to monitor the efficacy of antiviral treatment for respiratory tract infections in immunocompromised hosts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720028PMC
March 2020

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

N Engl J Med 2019 06;380(24):2327-2340

From the Departments of Neurology (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), Biochemistry and Biophysics (H.A.S., K.C.Z., J.L.D.), Laboratory Medicine (S.A., G.Y., S.F., D.S., B.B., B.H., S.M., C.Y.C.), and Epidemiology and Biostatistics (J.N.), the Department of Medicine, Division of Infectious Diseases (C.L., C.Y.C.), the Department of Medicine, Division of Hospital Medicine (A.B.), and Weill Institute for Neurosciences (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), University of California, San Francisco (UCSF), UCSF-Abbott Viral Diagnostics and Discovery Center (S.A., G.Y., S.F., D.S., B.B., C.Y.C.), the Chan Zuckerberg Biohub (C.L., J.L.D.), and Zuckerberg San Francisco General Hospital (B.H.), San Francisco, the School of Public Health, University of California, Berkeley, Berkeley (B.D.F.), Children's Hospital Los Angeles (S.N.N., J.B., J.D.B.), the Department of Medicine, Division of Infectious Diseases (J.M., M.C., T.V., P.R.A., J.D.K.), and the Departments of Neurology (P.M.V.) and Pathology and Laboratory Medicine (S.C., R.M.H.), University of California, Los Angeles, Los Angeles, and the Departments of Pathology and Laboratory Medicine (C.D.G., F.M., N.A.O., C.R.P.) and Neurological Surgery (L.L.Z.) and the Department of Internal Medicine, Division of Infectious Diseases (S.H.C., C.R.P.), University of California, Davis, Davis - all in California; the Children's National Medical Center and George Washington University School of Medicine, Washington, DC (R.L.D.); St. Jude Children's Research Hospital, Memphis, TN (R.D., G.M., R.H.); and Children's Hospital Colorado, Aurora (K.M., S.R.D.).

Background: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.

Methods: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.

Results: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.

Conclusions: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).
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http://dx.doi.org/10.1056/NEJMoa1803396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764751PMC
June 2019

Improved yield and accuracy for DNA extraction in microbiome studies with variation in microbial biomass.

Biotechniques 2019 06 24;66(6):285-289. Epub 2019 May 24.

Department of Infectious Disease, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

A major challenge for microbiome studies is maintaining an even and accurate DNA extraction in the presence of samples with a wide range of bacterial content. Here we compare five DNA extraction methods using replicate stool samples that were diluted to create high and low biomass samples. Our results indicate greater variation in microbiome composition between high and low biomass samples than variation between methods. Many of the extraction methods had reduced yield from low biomass samples; however, our adapted plate column-based extraction method was evenly efficient and captured the largest number of high-quality reads. Based on these results, we have identified a DNA extraction method that ensures adequate yield in metagenomic microbiome studies that have samples with a broad range of bacterial content.
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http://dx.doi.org/10.2144/btn-2019-0016DOI Listing
June 2019

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1.

N Engl J Med 2019 04;380(16):1525-1534

From the Departments of Bone Marrow Transplantation and Cellular Therapy (E.M., B.T., W.J., S.G.), Hematology (S.Z., Z.M., J.C., J.D., X.T., B.Y.R., M.J.W., B.P.S.), Therapeutics Production and Quality (T.L., M.M.M.), Immunology (H.A., B.Y.), Pharmaceutical Sciences (S.J.C.), Biostatistics (G.K., C.L.), and Infectious Diseases (G.M.), St. Jude Children's Research Hospital, Memphis, TN; the Allergy and Clinical Immunology Division, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru (J.C.A.B.); the Department of Pediatrics, Allergy-Immunology Division, Children's Hospital Los Angeles, Los Angeles (J.A.C.), and the Department of Pediatrics, Division of Pediatric Allergy-Immunology-Bone Marrow Transplantation, University of California, San Francisco (UCSF) Benioff Children's Hospital, San Francisco (J.R.L.-B., J.M.P., M.J.C.) - both in California; the Department of Pediatrics, Pediatric Allergy and Immunology, University of New Mexico, Albuquerque (E.D.); University of Oklahoma Health Sciences Center, Tulsa (J.T.L.); Departamento de Pediatria da Universidade de Taubaté, Conselho Nacional de Medicina, São Paulo (A.C.M.A.); Copperfield Childcare, Claremont, South Africa (H.W.); and the Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.S.D.R., H.L.M.).

Background: Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.

Methods: We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.

Results: Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.

Conclusions: Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).
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http://dx.doi.org/10.1056/NEJMoa1815408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636624PMC
April 2019

Respiratory Viral Infections in Patients With Cancer or Undergoing Hematopoietic Cell Transplant.

Front Microbiol 2018 12;9:3097. Epub 2018 Dec 12.

Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, United States.

Survival rates for pediatric cancer have steadily improved over time but it remains a significant cause of morbidity and mortality among children. Infections are a major complication of cancer and its treatment. Community acquired respiratory viral infections (CRV) in these patients increase morbidity, mortality and can lead to delay in chemotherapy. These are the result of infections with a heterogeneous group of viruses including RNA viruses, such as respiratory syncytial virus (RSV), influenza virus (IV), parainfluenza virus (PIV), metapneumovirus (HMPV), rhinovirus (RhV), and coronavirus (CoV). These infections maintain a similar seasonal pattern to those of immunocompetent patients. Clinical manifestations vary significantly depending on the type of virus and the type and degree of immunosuppression, ranging from asymptomatic or mild disease to rapidly progressive fatal pneumonia Infections in this population are characterized by a high rate of progression from upper to lower respiratory tract infection and prolonged viral shedding. Use of corticosteroids and immunosuppressive therapy are risk factors for severe disease. The clinical course is often difficult to predict, and clinical signs are unreliable. Accurate prognostic viral and immune markers, which have become part of the standard of care for systemic viral infections, are currently lacking; and management of CRV infections remains controversial. Defining effective prophylactic and therapeutic strategies is challenging, especially considering, the spectrum of immunocompromised patients, the variety of respiratory viruses, and the presence of other opportunistic infections and medical problems. Prevention remains one of the most important strategies against these viruses. Early diagnosis, supportive care and antivirals at an early stage, when available and indicated, have proven beneficial. However, with the exception of neuraminidase inhibitors for influenza infection, there are no accepted treatments. In high-risk patients, pre-emptive treatment with antivirals for upper respiratory tract infection (URTI) to decrease progression to LRTI is a common strategy. In the future, viral load and immune markers may prove beneficial in predicting severe disease, supporting decision making and monitor treatment in this population.
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http://dx.doi.org/10.3389/fmicb.2018.03097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299032PMC
December 2018

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.

Antimicrob Agents Chemother 2018 08 27;62(8). Epub 2018 Jul 27.

Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven pneumonia, and 4 cases (0.5%) of possible pneumonia. The incidence of possible breakthrough pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1128/AAC.00173-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105857PMC
August 2018

Surgical lung biopsy in children after hematopoietic cell transplantation.

J Pediatr Surg 2018 Jun 6;53(6):1129-1133. Epub 2018 Mar 6.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN. Electronic address:

Background/purpose: Pulmonary complications are some of the leading causes of morbidity and mortality in immunocompromised pediatric patients. We sought to assess the value of surgical lung biopsy (SLB) in hematopoietic cell transplantation (HCT) pediatric patients.

Methods: A retrospective review of patients who underwent SLB within one year of HCT between 1999 and 2015 was performed.

Results: Twenty-nine patients (15 females, 14 males) with a median age of 10years (range, 0.6-23) were identified. Median interval between HCT and SLB was 114.8days (range, 16-302). At surgery, 11 (38%) patients were intubated, and 7 (24%) were receiving supplemental oxygen. The most common histological finding was cryptogenic organizing pneumonia in 8 cases (27%), followed by infection in 7 (24%). Perioperative complications (17%) included bronchopleural fistula (n=2), splenic laceration from a trocar injury (n=2), and hemothorax (n=1). Changes in therapy occurred in 25 patients (86%). Twenty-four (83%) patients survived more than 30days post SLB, and the overall survival rate was 41% with a median follow-up of 8.5years (range, 1-13).

Conclusion: SLB appears to be safe and informative in pediatric patients after HCT and led to changes in therapy in most patients. However, long-term survival after this procedure was <50%, reinforcing the fact that pulmonary complications are some of the leading causes of mortality in these patients.

Type Of Study: Retrospective analysis.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.02.069DOI Listing
June 2018

A Multicenter Consortium to Define the Epidemiology and Outcomes of Inpatient Respiratory Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients.

J Pediatric Infect Dis Soc 2018 Dec;7(4):275-282

Departments of Pediatrics and Molecular Genetics and Microbiology, Duke University, Durham, North Carolina.

Background: Respiratory virus infections (RVIs) pose a threat to children undergoing hematopoietic stem cell transplantation (HSCT). In this era of sensitive molecular diagnostics, the incidence and outcome of HSCT recipients who are hospitalized with RVI (H-RVI) are not well described.

Methods: A retrospective observational cohort of pediatric HSCT recipients (between January 2010 and June 2013) was assembled from 9 US pediatric transplant centers. Their medical charts were reviewed for H-RVI events within 1 year after their transplant. An H-RVI diagnosis required respiratory signs or symptoms plus viral detection (human rhinovirus/enterovirus, human metapneumovirus, influenza, parainfluenza, coronaviruses, and/or respiratory syncytial virus). The incidence of H-RVI was calculated, and the association of baseline HSCT factors with subsequent pulmonary complications and death was assessed.

Results: Among 1560 HSCT recipients, 259 (16.6%) acquired at least 1 H-RVI within 1 year after their transplant. The median age of the patients with an H-RVI was lower than that of patients without an H-RVI (4.8 vs 7.1 years; P < .001). Among the patients with a first H-RVI, 48% required some respiratory support, and 14% suffered significant pulmonary sequelae. The all-cause and attributable case-fatality rates within 3 months of H-RVI onset were 11% and 5.4%, respectively. Multivariate logistic regression revealed that H-RVI onset within 60 days of HSCT, steroid use in the 7 days before H-RVI onset, and the need for respiratory support at H-RVI onset were associated with subsequent morbidity or death.

Conclusion: Results of this multicenter cohort study suggest that H-RVIs are relatively common in pediatric HSCT recipients and contribute to significant morbidity and death. These data should help inform interventional studies specific to each viral pathogen.
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http://dx.doi.org/10.1093/jpids/pix051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107490PMC
December 2018

Rotavirus Infection in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients: Clinical Course and Experience Using Nitazoxanide and Enterally Administered Immunoglobulins.

Pediatr Infect Dis J 2018 02;37(2):176-181

From the Department of Infectious Diseases, Department of Pathology, Department of Pharmaceutical Sciences, Department of Bone Marrow Transplantation and Cellular Therapy, and Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Rotaviruses may produce prolonged and severe disease in allogeneic hematopoietic cell transplant (HCT) recipients. Nitazoxanide and enterally administered human immunoglobulins are potential therapeutic options. This retrospective study describes the clinical course of rotavirus infection in pediatric allogeneic HCT recipients and a single-center experience with nitazoxanide and oral immunoglobulins as potential treatment options.

Methods: We identified 36 patients who had positive stool rotavirus antigen assays after allogeneic HCT from May 30, 2012, to July 31, 2015. Clinical, microbiologic and treatment data were collected and analyzed using descriptive statistics.

Results: Forty-nine discrete episodes of rotavirus infection were identified among these 36 patients for a cumulative incidence of 19.7%. For these 49 episodes, the median day to infection after HCT was day 82, and the median duration of diarrhea was 17.5 days (range 4-122). Nitazoxanide and enteral immunoglobulins were prescribed for 41 episodes. The median duration of clinical symptoms after initiation of nitazoxanide was 11 days (range 2-85), 23 days (range 10-107) after enteral immunoglobulins and 26 days (range 6-90) after a combination of nitazoxanide and enteral immunoglobulins (P = 0.1). No adverse effects of either treatment were documented, but efficacy could not be assessed in this patient population.

Conclusions: In pediatric HCT recipients, the clinical illness produced by rotaviruses is prolonged compared with otherwise healthy children. Nitazoxanide appears safe, but its efficacy for this indication requires further study.
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http://dx.doi.org/10.1097/INF.0000000000001740DOI Listing
February 2018

Voriconazole prophylaxis in children with cancer: changing outcomes and epidemiology of fungal infections.

Pediatr Infect Dis J 2013 Dec;32(12):e451-5

From the Departments of *Infectious Diseases, †Pathology, and ‡Oncology, St. Jude Children's Research Hospital; and Departments of §Pediatrics and ¶Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN.

Background: Invasive mould infections are a significant cause of morbidity and mortality in pediatric cancer patients, particularly in those undergoing aggressive myeloablative chemotherapy. Voriconazole has been described as an appropriate and effective prophylactic agent in adults with cancer.

Methods: We compared the etiology, predisposing factors and outcomes of invasive mould infection in patients treated for acute myeloid leukemia before and after implementation of voriconazole prophylaxis in a pediatric cancer center.

Results: We observed no difference in the number of invasive mould infection between groups. However, isolated organisms were markedly different, with a shift from aspergillosis to phaeohyphomycosis after the implementation of voriconazole prophylaxis. Survival at 90 days was improved in patients receiving voriconazole prophylaxis (P = 0.05). We did not identify a significant increase in the incidence of zygomycosis associated with routine use of voriconazole prophylaxis.

Conclusions: Voriconazole prophylaxis was associated with improved survival in pediatric patients with acute myeloid leukemia, although other factors may be involved. Voriconazole prophylaxis was associated with a marked change in the pattern of mould infections, with a significant reduction in aspergillosis.
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http://dx.doi.org/10.1097/INF.0b013e3182a74233DOI Listing
December 2013

Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections.

Support Care Cancer 2012 Oct 26;20(10):2589-94. Epub 2012 Jan 26.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.

Background: Despite recent studies failing to demonstrate the value of routine chest radiography (CXR) in the initial evaluation of the febrile neutropenic patient with cancer, this screening test is advocated by some experts. We evaluated the benefits of CXR for early diagnosis of pulmonary infection at St. Jude Children's Research Hospital (SJCRH) with emphasis on early recognition of mould infections.

Patients And Methods: We reviewed the courses of 200 consecutive febrile neutropenic pediatric patients to determine if routine CXR at initial evaluation was useful in the identification of clinically occult pneumonia. We also reviewed all cases of proven or probable mould infections from the opening of SJCRH in 1962 until 1998 when routine CXR was no longer practiced in our institution to identify cases that were first recognized by routine CXR.

Results: Of 200 febrile neutropenic patients, pulmonary abnormalities consistent with pneumonia were detected by routine CXR in only five patients without pulmonary signs or symptoms. In only one case was a change in management considered. Of the 70 patients with pulmonary mould infection identified from 1962 to 1998, routine CXR was performed in 45 patients at the onset of a febrile, neutropenic episode in which a mould infection was diagnosed. Routine CXR was pivotal in the recognition of the mould infection in only two cases over this 36-year period.

Conclusion: CXR is warranted in the evaluation of the newly febrile neutropenic pediatric oncology patient only when respiratory signs or symptoms are present.
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http://dx.doi.org/10.1007/s00520-011-1366-7DOI Listing
October 2012

Antiretroviral therapy in HIV-infected infants and children.

Pediatr Infect Dis J 2010 Apr;29(4):360-3

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

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http://dx.doi.org/10.1097/INF.0b013e3181d616d8DOI Listing
April 2010

Association between nutritional status and severity of dengue infection in children in El Salvador.

Am J Trop Med Hyg 2010 Feb;82(2):324-9

St. Jude Children's Research Hospital, 262 DannyThomas Place, Memphis, TN 38105-3678, USA.

Clinical observations and some studies suggest that dengue virus infection is more severe among children with better nutritional status. We examined the nutritional status of children in El Salvador and its relationship between this and the severity of dengue infection. Z-scores for weight-for-age, height-for-age, and body mass index (BMI)-for-age of children with dengue fever (66), dengue hemorrhagic fever (62), and healthy controls (74) were compared. There were no differences in weight-for-age or BMI-for-age Z-scores between the three groups. Children with dengue fever had a greater height-for-age than healthy controls but no significant differences in rates of stunting. There was no difference in height between children with dengue fever and dengue hemorrhagic fever. Excess nutrition does not appear to be a risk factor for severe forms of dengue infection in El Salvador, nor does malnutrition appear to be predictive of good outcomes.
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http://dx.doi.org/10.4269/ajtmh.2010.09-0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813176PMC
February 2010

A practical guide to alcohol-based hand hygiene infrastructure in a resource-poor pediatric hospital.

Am J Infect Control 2009 Dec;37(10):851-4

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.

Background: Resource-poor hospitals have many barriers to proper hand hygiene (HH). Alcohol-based HH can compensate for inadequate infrastructure and supplies. We describe the implementation of alcohol-based HH in five high-risk wards of a pediatric hospital in El Salvador.

Methods: In 5 high-risk wards for nosocomial infections, we evaluated the accessibility, supplies, and cleanliness of the hand-washing sinks at 132 time points. We then installed gel dispensers, identified a local gel supplier, and trained nursing staff to maintain the dispensers. We evaluated user acceptance, costs, and the practice and technique of HH before and after installation.

Results: Access and cleanliness were adequate at 18.9% and 11.3% of observation points, and towels and soap were available at 61.3% and 93.18% of points. Placement of 35 gel dispensers increased the ratio of HH stations to beds from 1:6.2 to 1:1.8. Alcohol gel was better tolerated than hand washing among 60 surveyed staff. Installation cost $2558 (US) and the monthly gel supply, $731 (US). HH practice increased from 33.8% to 40.5%; use of correct technique increased from 73.8% to 95.2%.

Conclusion: Alcohol gel can address some of the barriers to effective HH at resource-poor institutions, and its cost may be offset by reduction of nosocomial infection.
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http://dx.doi.org/10.1016/j.ajic.2009.05.009DOI Listing
December 2009

Planning and implementation of an infection control training program for healthcare providers in Latin America.

Infect Control Hosp Epidemiol 2007 Dec 22;28(12):1328-33. Epub 2007 Oct 22.

International Outreach Program, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105-2794, USA.

Objective: The lack of well-trained, dedicated infection control personnel prevents optimal control of nosocomial infections in Latin American pediatric oncology centers. We collaboratively planned and implemented a multinational training course in San Salvador, El Salvador, to address this need.

Methods: The course relied on its organizers' experience in training international healthcare providers, the availability of the International Training Center for Nurses, previous infection control collaboration with the Hospital Nacional de Ninos Benjamin Bloom, and resources available at the University of El Salvador. The 4-week course consisted of lecture sessions combined with practical laboratory and hospital experience.

Results: Two courses, one conducted in 2005 and one in 2006, trained 44 professionals from 15 Latin American countries. Evaluations showed that course content and teacher performance met the trainees' needs and that all trainees acquired the necessary knowledge and skills.

Conclusions: The course met the need for the training of Latin American infection control practitioners. Our experience can serve as a model for other organizations interested in strengthening infection control and prevention at international sites.
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http://dx.doi.org/10.1086/521655DOI Listing
December 2007