Publications by authors named "Matthew S Kelly"

35 Publications

Dysregulated transcriptional responses to SARS-CoV-2 in the periphery.

Nat Commun 2021 02 17;12(1):1079. Epub 2021 Feb 17.

Durham Veterans Affairs Medical Center, Durham, NC, USA.

SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92-0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.
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http://dx.doi.org/10.1038/s41467-021-21289-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889643PMC
February 2021

Microbiology of Bloodstream Infections in Children After Hematopoietic Stem Cell Transplantation: A Single-Center Experience Over Two Decades (1997-2017).

Open Forum Infect Dis 2020 Nov 30;7(11):ofaa465. Epub 2020 Sep 30.

Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA.

Background: Bloodstream infections (BSIs) occur frequently after hematopoietic stem cell transplantation (HSCT). We examined the microbiology of BSI in pediatric HSCT recipients over a 2-decade period at our institution to inform empirical antimicrobial prescribing and infection prevention strategies.

Methods: We conducted a retrospective cohort study of children (<18 years) who underwent HSCT at Duke University between 1997 and 2015. We used recurrent-event gap-time Cox proportional hazards models to determine the hazards of all-cause and cause-specific BSI according to HSCT year. We compared the median time to BSI by causative organism type and evaluated for temporal trends in the prevalence of antibiotic resistance among causative organisms.

Results: A total of 865 BSI occurred in 1311 children, including 412 (48%) Gram-positive bacterial, 196 (23%) Gram-negative bacterial, 56 (6%) fungal, 23 (3%) mycobacterial, and 178 (21%) polymicrobial BSI. The hazard of all BSIs did not change substantially over time during the study period, but the hazard of fungal BSIs declined over time during the study period ( = .04). Most fungal BSIs (82%) occurred in the first 100 days after HSCT, whereas mycobacterial BSIs occurred later after HSCT than BSIs caused by other organisms ( < .0001). The prevalence of vancomycin resistance among BSIs caused by increased during the study period ( = .0007). The risk of 2-year mortality in children was increased with BSI ( = .02), Gram-negative bacterial BSI ( = .02), and fungal BSI ( < .0001).

Conclusions: Despite expanded practices for BSI prevention over the past several decades, the incidence of BSI remains high in pediatric HSCT recipients at our institution. Additional strategies are urgently needed to effectively prevent BSIs in this high-risk population.
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http://dx.doi.org/10.1093/ofid/ofaa465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652097PMC
November 2020

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.

Clin Infect Dis 2020 Nov 3. Epub 2020 Nov 3.

Department of Pediatrics, Division of Infectious Diseases, Duke University School of Medicine, Durham, NC.

Background: Children with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children.

Methods: We conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay.

Results: Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have asthma (p=0.005), and more likely to have an infected sibling contact (p=0.001) than uninfected children. Children ages 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs. 48%; p=0.01) or adolescents (29% vs. 60%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p<0.0001), gastrointestinal (27% vs. 9%; p=0.002), and sensory symptoms (42% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.01]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children.

Conclusions: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.
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http://dx.doi.org/10.1093/cid/ciaa1693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665428PMC
November 2020

Reply to authors.

Clin Infect Dis 2020 Oct 26. Epub 2020 Oct 26.

Botswana-UPenn Partnership, Gaborone, Botswana.

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http://dx.doi.org/10.1093/cid/ciaa1628DOI Listing
October 2020

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.

medRxiv 2020 Sep 1. Epub 2020 Sep 1.

Department of Pediatrics, Division of Infectious Diseases, Duke University School of Medicine, Durham, NC.

Background: Children with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children.

Methods: We conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay.

Results: Of 382 children, 289 (76%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have a history of asthma (p=0.009), and more likely to have an infected sibling contact (p=0.0007) than uninfected children. Children ages 6-13 years were frequently asymptomatic (38%) and had respiratory symptoms less often than younger children (30% vs. 49%; p=0.008) or adolescents (30% vs. 59%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p=0.002), gastrointestinal (26% vs. 9%; p=0.003), and sensory symptoms (43% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.004]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children.

Conclusions: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while a history of asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.
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http://dx.doi.org/10.1101/2020.08.18.20166835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480040PMC
September 2020

Dysregulated transcriptional responses to SARS-CoV-2 in the periphery support novel diagnostic approaches.

medRxiv 2020 Jul 26. Epub 2020 Jul 26.

Center for Applied Genomics and Precision Medicine, Duke University, Durham, NC.

In order to elucidate novel aspects of the host response to SARS-CoV-2 we performed RNA sequencing on peripheral blood samples across 77 timepoints from 46 subjects with COVID-19 and compared them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a conserved transcriptomic response in peripheral blood that is heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, that persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95). The transcriptome in peripheral blood reveals unique aspects of the immune response in COVID-19 and provides for novel biomarker-based approaches to diagnosis.
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http://dx.doi.org/10.1101/2020.07.20.20155507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386527PMC
July 2020

Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 11 17;26(11):2053-2060. Epub 2020 Jul 17.

Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina. Electronic address:

Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes. We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n = 491) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, cefepime, or ceftazidime; n = 723). We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome. Receipt of anaerobic antibiotics was associated with higher hazards of acute gut/liver GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.03 to 1.54) and acute GVHD mortality (HR, 1.63; 95% CI, 1.08 to 2.46), but not chronic GVHD diagnosis (HR, 1.04; 95% CI: .84 to 1.28) or chronic GVHD mortality (HR, .88; 95% CI, .53 to 1.45). Anaerobic antibiotics resulted in decreased gut bacterial diversity, reduced abundances of Bifidobacteriales and Clostridiales, and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome. Acute gut/liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment. Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut/liver GVHD and acute GVHD mortality after allogeneic HSCT. Use of piperacillin-tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug-resistant infections are suspected.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609492PMC
November 2020

Effect of Haemophilus influenzae type b and 13-valent pneumococcal conjugate vaccines on childhood pneumonia hospitalizations and deaths in Botswana.

Clin Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

Division of Pediatric Infectious Diseases, Duke University, Durham, NC.

Background: Globally, pneumonia is the leading cause of death among children. Few data exist regarding the effect of Haemophilus influenzae type b (Hib) vaccine and 13-valent pneumococcal conjugate vaccine (PCV-13) on the burden of childhood pneumonia in African settings.

Methods: We collected data on children 1 to 59 months of age at three hospitals in Botswana. Hib vaccine and PCV-13 were introduced in Botswana in November 2010 and July 2012, respectively. We compared pneumonia hospitalizations and deaths pre-vaccine (January 2009 to October 2010) to post-vaccine (January 2013 to December 2017) using seasonally-adjusted interrupted time-series analyses.

Findings: We identified 6943 pneumonia hospitalizations and 201 pneumonia deaths. In the pre-vaccine period, pneumonia hospitalizations and deaths increased by 24% (rate: 1.24; 95% CI: 0.94, 1.64) and 59% (rate: 1.59; 95% CI: 0.87, 2.90) per year, respectively. Vaccine introduction was associated with a 48% (95% CI: 29%, 62%) decrease in the number of pneumonia hospitalizations and a 50% (95% CI: 1%, 75%) decrease in the number of pneumonia deaths between the end of the pre-vaccine period (October 2010) and the beginning of the post-vaccine period (January 2013). During the post-vaccine period, pneumonia hospitalizations and deaths declined by 6% (rate 0.94; 95% CI: 0.89, 0.99) and 22% (rate: 0.78; 95% CI: 0.67, 0.92) per year, respectively.

Interpretation: Pneumonia hospitalizations and deaths among children declined sharply following introduction of Hib vaccine and PCV-13 in Botswana. This effect was sustained for more than five years after vaccine introduction, supporting the long-term effectiveness of these vaccines in preventing childhood pneumonia in Botswana.
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http://dx.doi.org/10.1093/cid/ciaa919DOI Listing
July 2020

Interpretation of pediatric chest radiographs by non-radiologist clinicians in Botswana using World Health Organization criteria for endpoint pneumonia.

Pediatr Radiol 2020 06 10;50(7):913-922. Epub 2020 Jun 10.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: In low- and middle-income countries, chest radiographs are most frequently interpreted by non-radiologist clinicians.

Objective: We examined the reliability of chest radiograph interpretations performed by non-radiologist clinicians in Botswana and conducted an educational intervention aimed at improving chest radiograph interpretation accuracy among non-radiologist clinicians.

Materials And Methods: We recruited non-radiologist clinicians at a referral hospital in Gaborone, Botswana, to interpret de-identified chest radiographs for children with clinical pneumonia. We compared their interpretations with those of two board-certified pediatric radiologists in the United States. We evaluated associations between level of medical training and the accuracy of chest radiograph findings between groups, using logistic regression and kappa statistics. We then developed an in-person training intervention led by a pediatric radiologist. We asked participants to interpret 20 radiographs before and immediately after the intervention, and we compared their responses to those of the facilitating radiologist. For both objectives, our primary outcome was the identification of primary endpoint pneumonia, defined by the World Health Organization as presence of endpoint consolidation or endpoint effusion.

Results: Twenty-two clinicians interpreted chest radiographs in the primary objective; there were no significant associations between level of training and correct identification of endpoint pneumonia; concordance between respondents and radiologists was moderate (κ=0.43). After the training intervention, participants improved agreement with the facilitating radiologist for endpoint pneumonia from fair to moderate (κ=0.34 to κ=0.49).

Conclusion: Non-radiologist clinicians in Botswana do not consistently identify key chest radiographic findings of pneumonia. A targeted training intervention might improve non-radiologist clinicians' ability to interpret chest radiographs.
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http://dx.doi.org/10.1007/s00247-020-04625-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539136PMC
June 2020

The stepwise assembly of the neonatal virome is modulated by breastfeeding.

Nature 2020 05 15;581(7809):470-474. Epub 2020 Apr 15.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which-in some cases-leads to gastrointestinal disorders. Here we show that the assembly of the viral community in neonates takes place in distinct steps. Fluorescent staining of virus-like particles purified from infant meconium or early stool samples shows few or no particles, but by one month of life particle numbers increase to 10 per gram, and these numbers seem to persist throughout life. We investigated the origin of these viral populations using shotgun metagenomic sequencing of virus-enriched preparations and whole microbial communities, followed by targeted microbiological analyses. Results indicate that, early after birth, pioneer bacteria colonize the infant gut and by one month prophages induced from these bacteria provide the predominant population of virus-like particles. By four months of life, identifiable viruses that replicate in human cells become more prominent. Multiple human viruses were more abundant in stool samples from babies who were exclusively fed on formula milk compared with those fed partially or fully on breast milk, paralleling reports that breast milk can be protective against viral infections. Bacteriophage populations also differed depending on whether or not the infant was breastfed. We show that the colonization of the infant gut is stepwise, first mainly by temperate bacteriophages induced from pioneer bacteria, and later by viruses that replicate in human cells; this second phase is modulated by breastfeeding.
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http://dx.doi.org/10.1038/s41586-020-2192-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263352PMC
May 2020

Long-term stability of microbiome diversity and composition in fecal samples stored in eNAT medium.

Microbiologyopen 2020 07 10;9(7):e1046. Epub 2020 May 10.

Division of Pediatric Infectious Diseases, Duke University, Durham, NC, USA.

Fecal samples collected for microbiome analyses are typically frozen to avoid postcollection changes in microbial composition. eNAT is a guanidine thiocyanate-based medium that stabilizes microbial DNA and allows safe specimen handling and shipping by inactivating microorganisms. We collected fecal samples (n = 50) from children undergoing hematopoietic stem cell transplantation. We divided samples into three aliquots: (a) stored in RNAlater and immediately transferred to -80°C; (b) stored in eNAT medium and immediately transferred to -80°C; and (c) stored in eNAT medium at ambient temperature (~20°C) for 30 days prior to transfer to -80°C. Mean (standard deviation) Shannon diversity and Chao1 indices in sample aliquots were 2.05 (0.62) and 23.8 (16.6), respectively. Comparing samples frozen immediately in RNAlater to samples frozen immediately in eNAT, there were no differences in Shannon diversity (p = .51), Chao1 richness (p = .66), and overall microbiome composition (p = .99). Comparing eNAT samples frozen immediately to samples stored at ambient temperature, we identified no differences in Shannon diversity (p = .65), Chao1 richness (p = .87), and overall microbiome composition (p = .99). Storage of fecal samples in eNAT at ambient temperature for 30 days did not alter microbiome richness, diversity, or composition. eNAT may be a useful medium for fecal microbiome studies, particularly when cold chain storage is unavailable.
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http://dx.doi.org/10.1002/mbo3.1046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349174PMC
July 2020

Lessons From COVID-19 in Children: Key Hypotheses to Guide Preventative and Therapeutic Strategies.

Clin Infect Dis 2020 11;71(8):2006-2013

Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.

The current pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), reveals a peculiar trend of milder disease and lower case fatality in children compared with adults. Consistent epidemiologic evidence of reduced severity of infection in children across different populations and countries suggests there are underlying biological differences between children and adults that mediate differential disease pathogenesis. This presents a unique opportunity to learn about disease-modifying host factors from pediatric populations. Our review summarizes the current knowledge of pediatric clinical disease, role in transmission, risks for severe disease, protective immunity, as well as novel therapies and vaccine trials for children. We then define key hypotheses and areas for future research that can use the pediatric model of disease, transmission, and immunity to develop preventive and therapeutic strategies for people of all age groups.
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http://dx.doi.org/10.1093/cid/ciaa547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239258PMC
November 2020

Microbiology and Risk Factors for Hospital-Associated Bloodstream Infections Among Pediatric Hematopoietic Stem Cell Transplant Recipients.

Open Forum Infect Dis 2020 Apr 16;7(4):ofaa093. Epub 2020 Mar 16.

Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA.

Background: Children undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for hospital-associated bloodstream infections (HA-BSIs). This study aimed to describe the incidence, microbiology, and risk factors for HA-BSI in pediatric HSCT recipients.

Methods: We performed a single-center retrospective cohort study of children and adolescents (<18 years of age) who underwent HSCT over a 20-year period (1997-2016). We determined the incidence and case fatality rate of HA-BSI by causative organism. We used multivariable Poisson regression to identify risk factors for HA-BSI.

Results: Of 1294 patients, the majority (86%) received an allogeneic HSCT, most commonly with umbilical cord blood (63%). During the initial HSCT hospitalization, 334 HA-BSIs occurred among 261 (20%) patients. These were classified as gram-positive bacterial (46%), gram-negative bacterial (24%), fungal (12%), mycobacterial (<1%), or polymicrobial (19%). During the study period, there was a decline in the cumulative incidence of HA-BSI ( = .021) and, specifically, fungal HA-BSIs ( = .002). In multivariable analyses, older age (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], 1.01-1.06), umbilical cord blood donor source (vs bone marrow; IRR, 1.69; 95% CI, 1.19-2.40), and nonmyeloablative conditioning (vs myeloablative; IRR, 1.85; 95% CI, 1.21-2.82) were associated with a higher risk of HA-BSIs. The case fatality rate was higher for fungal HA-BSI than other HA-BSI categories (21% vs 6%;  = .002).

Conclusions: Over the past 2 decades, the incidence of HA-BSIs has declined among pediatric HSCT recipients at our institution. Older age, umbilical cord blood donor source, and nonmyeloablative conditioning regimens are independent risk factors for HA-BSI among children undergoing HSCT.
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http://dx.doi.org/10.1093/ofid/ofaa093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141603PMC
April 2020

Association of Adverse Hearing, Growth, and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight.

JAMA Pediatr 2020 02;174(2):133-140

Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.

Importance: Studies suggest that postnatal cytomegalovirus (CMV) infection can lead to long-term morbidity in infants with very low birth weight (VLBW; <1500 g), including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and neurodevelopmental impairment. However, to date, the association of postnatal CMV with hearing, growth, and length of stay among VLBW infants is unknown.

Objectives: To determine the risk for failed hearing screen, increased postnatal age at discharge, or decreased growth at discharge in VLBW infants with postnatal CMV infection compared with CMV-uninfected infants and to compare the risk for other major outcomes of prematurity, including BPD and NEC, in infants with and without postnatal CMV infection.

Participants: This multicenter retrospective cohort study included VLBW infants from 302 neonatal intensive care units managed by the Pediatrix Medical Group from January 1, 2002, through December 31, 2016. Infants hospitalized on postnatal day 21 with a diagnosis of postnatal CMV and hearing screen results after a postmenstrual age of 34 weeks were included in the study population. Data were analyzed from December 11, 2017, to June 14, 2019.

Main Outcomes And Measures: Infants with and without postnatal CMV infection were matched using propensity scores. Poisson and linear regression were used to examine the association between postnatal CMV and the risk of failed hearing screen, postnatal age at discharge, growth, BPD, and NEC.

Results: A total of 304 infants with postnatal CMV were identified, and 273 of these infants (89.8%; 155 boys [56.8%]) were matched with 273 infants without postnatal CMV (148 boys [54.2%]). Hearing screen failure occurred in 45 of 273 infants (16.5%) with postnatal CMV compared with 25 of 273 infants (9.2%) without postnatal CMV (risk ratio [RR], 1.80; 95% CI, 1.14 to 2.85; P = .01). Postnatal CMV was also associated with an increased postnatal age at discharge of 11.89 days (95% CI, 6.72 to 17.06 days; P < .001) and lower weight-for-age z score (-0.23; 95% CI, -0.39 to -0.07; P = .005). Analysis confirmed an increased risk of BPD (RR, 1.30; 95% CI, 1.17 to 1.44; P < .001), previously reported on infants from this cohort from 1997 to 2012, but not an increased risk of NEC after postnatal day 21 (RR, 2.00; 95% CI, 0.18 to 22.06; P = .57).

Conclusions And Relevance: These data suggest that postnatal CMV infection is associated with lasting sequelae in the hearing and growth status of VLBW infants and with prolonged hospitalization. Prospective studies are needed to determine the full effects of postnatal CMV infection and whether antiviral treatment reduces the associated morbidity.
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http://dx.doi.org/10.1001/jamapediatrics.2019.4532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902194PMC
February 2020

The prevalence and clinical characteristics of pertussis-associated pneumonia among infants in Botswana.

BMC Pediatr 2019 11 16;19(1):444. Epub 2019 Nov 16.

Vaccine Evaluation Center, BC Children's Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.

Background: There are scant data on the prevalence and clinical course of pertussis disease among infants with pneumonia in low- and middle-income countries. While pertussis vaccination coverage is high (≥90%) among infants in Botswana, human immunodeficiency virus (HIV) infection affects nearly one-third of pregnancies. We aimed to evaluate the prevalence and clinical course of pertussis disease in a cohort of HIV-unexposed uninfected (HUU), HIV-exposed uninfected (HEU), and HIV-infected infants with pneumonia in Botswana.

Methods: We recruited children 1-23 months of age with clinical pneumonia at a tertiary care hospital in Gaborone, Botswana between April 2012 and June 2016. We obtained nasopharyngeal swab specimens at enrollment and tested these samples using a previously validated in-house real-time PCR assay that detects a unique sequence of the porin gene of Bordetella pertussis.

Results: B. pertussis was identified in 1/248 (0.4%) HUU, 3/110 (2.7%) HEU, and 0/33 (0.0%) HIV-infected children. All pertussis-associated pneumonia cases occurred in infants 1-5 months of age (prevalence, 1.0% [1/103] in HUU and 4.8% [3/62] in HEU infants). No HEU infants with pertussis-associated pneumonia were taking cotrimoxazole prophylaxis at the time of hospital presentation. One HUU infant with pertussis-associated pneumonia required intensive care unit admission for mechanical ventilation, but there were no deaths.

Conclusions: The prevalence of pertussis was low among infants and young children with pneumonia in Botswana. Although vaccination against pertussis in pregnancy is designed to prevent classical pertussis disease, reduction of pertussis-associated pneumonia might be an important additional benefit.
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http://dx.doi.org/10.1186/s12887-019-1820-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858628PMC
November 2019

Placental Transfer of Respiratory Syncytial Virus Antibody Among HIV-Exposed, Uninfected Infants.

J Pediatric Infect Dis Soc 2020 Jul;9(3):349-356

Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina.

Background: Maternal human immunodeficiency virus (HIV) infection is associated with lower placental transfer of antibodies specific to several childhood pathogens. Our objective for this study was to evaluate the effect of maternal HIV infection on the placental transfer of respiratory syncytial virus (RSV)-neutralizing antibodies.

Methods: We conducted a cross-sectional study of mothers and their newborn infants at a tertiary hospital in Gaborone, Botswana, between March 2015 and December 2015. We measured serum RSV antibody levels by using a microneutralization assay. We used multivariable linear regression to evaluate the effect of maternal HIV infection on maternal RSV antibody levels, placental transfer of RSV antibodies, and newborn RSV antibody levels.

Results: Of 316 mothers, 154 (49%) were infected with HIV. The placental transfer ratios for RSV antibodies to HIV-exposed, uninfected (HEU) and HIV-unexposed, uninfected infants were 1.02 and 1.15, respectively. The geometric mean titer (95% confidence interval) of RSV-neutralizing antibodies was 2657 (2251-3136) among HEU newborns and 2911 (2543-3331) among HIV-unexposed, uninfected newborns. In multivariable analyses, maternal HIV infection was associated with lower placental transfer of RSV antibodies (P = .02) and a lower level of RSV antibodies among newborns (P = .002). Among HEU newborns, higher birth weight (P = .004) and an undetectable maternal antenatal viral load (P = .01) were associated with more effective placental transfer of RSV antibodies.

Conclusions: Maternal human immunodeficiency virus (HIV) infection is associated with lower mother-to-fetus transfer of serum RSV-neutralizing antibodies. HEU infants should be prioritized for preventive interventions for RSV. Maternal viral suppression through combination antiretroviral therapy has the potential to improve immunity to RSV among HIV-exposed infants.
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http://dx.doi.org/10.1093/jpids/piz056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358043PMC
July 2020

Cultivating Research Skills During Clinical Training to Promote Pediatric-Scientist Development.

Pediatrics 2019 08;144(2)

Duke Pediatric Research Scholars Program for Physician-Scientist Development and.

Physician-scientists represent a critical component of the biomedical and health research workforce. However, the proportion of physicians who spend a significant amount of effort on scientific research has declined over the past 40 years. This trend has been particularly noticeable in pediatrics despite recent scientific work revealing that early life influences, exposures, and health status play a significant role in lifelong health and disease. To address this problem, the Duke University Department of Pediatrics developed the Duke Pediatric Research Scholars Program for Physician-Scientist Development (DPRS). The DPRS is focused on research training during pediatric residency and fellowship. We aim to provide sufficient research exposure and support to help scholars develop a research niche and scholarly products as well as identify the career pathways that will enable them to achieve their research goals. Herein, we describe the DPRS's organizational structure, core components, recruitment strategies, and initial results, and we discuss implementation challenges and solutions. Additionally, we detail the program's integration with the department's residency and fellowship training programs (with particular reference to the challenges of integrating research into small- to medium-sized residency programs) and describe the development and integration of related initiatives across Duke University School of Medicine. The program served as the basis for 2 successful National Institutes of Health Stimulating Access to Research in Residency (R38) applications, and we hope it will serve as a model to integrate formalized research training for residents and fellows who wish to pursue research careers in academic medicine.
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http://dx.doi.org/10.1542/peds.2019-0745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855830PMC
August 2019

Gut Colonization Preceding Mucosal Barrier Injury Bloodstream Infection in Pediatric Hematopoietic Stem Cell Transplantation Recipients.

Biol Blood Marrow Transplant 2019 11 18;25(11):2274-2280. Epub 2019 Jul 18.

Division of Pediatric Infectious Diseases, Ann & Robert H. Lurie Children's Hospital, Chicago, Illinois.

The gastrointestinal tract is the predicted reservoir for most bloodstream infections (BSIs) after hematopoietic stem cell transplantation (HSCT). Whole-genome sequencing and comparative genomics have the potential to improve our understanding of the dynamics of gut colonization that precede BSI in HSCT recipients. Within a prospective cohort study of children (age <18 years) undergoing HSCT, 9 subjects met criteria for mucosal barrier injury BSI. We performed whole-genome sequencing of the blood culture isolate and weekly fecal samples preceding the BSI to compare the genetic similarity of BSI isolates to fecal strains. We evaluated temporal associations between antibiotic exposures and the abundances of BSI strains in the gut microbiota and correlated the detection of antibiotic resistance genes with the phenotypic antibiotic resistance of these strains. The median patient age was 2.6 years, and 78% were male. BSIs were caused by Escherichia coli (n = 5), Enterococcus faecium (n = 2), Enterobacter cloacae (n = 1), and Rothia mucilaginosa (n = 1). In the 6 BSI episodes with evaluable comparative genomics, the fecal strains were identical to the blood culture isolate (>99.99% genetic similarity). Gut domination by these strains preceded only 4 of 7 E. coli or E. faecium BSIs by a median of 17 days (range, 6 to 21 days). Increasing abundances of the resulting BSI strains in the gut microbiota were frequently associated with specific antibiotic exposures. E. cloacae and R. mucilaginosa were not highly abundant in fecal samples preceding BSIs caused by these species. The detection of antibiotic resistance genes for β-lactam antibiotics and vancomycin predicted phenotypic resistance in BSI strains. Bacterial strains causing mucosal barrier injury BSI in pediatric HSCT recipients were observed in the gut microbiota before BSI onset, and changes in the abundances of these strains within the gut preceded most BSI episodes. However, frequent sampling of the gut microbiota and sampling of other ecological niches is likely necessary to effectively predict BSI in HSCT recipients.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861666PMC
November 2019

Predictors of Poor Outcomes Among Infants With Respiratory Syncytial Virus-associated Acute Lower Respiratory Infection in Botswana.

Pediatr Infect Dis J 2019 05;38(5):525-527

Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina.

Among children 1-23 months of age with respiratory syncytial virus-associated acute lower respiratory infection in Botswana, young age (<6 months), household use of wood as a cooking fuel, moderate or severe malnutrition and oxygen saturation <90% on room air were independent predictors of clinical nonresponse at 48 hours. Among HIV-uninfected infants less than six months of age, HIV exposure was associated with a higher risk of in-hospital mortality.
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http://dx.doi.org/10.1097/INF.0000000000002168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465100PMC
May 2019

Reduction in Mortality after Umbilical Cord Blood Transplantation in Children Over a 20-Year Period (1995-2014).

Biol Blood Marrow Transplant 2019 04 24;25(4):756-763. Epub 2018 Nov 24.

Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina. Electronic address:

Infections and graft-versus-host disease (GVHD) have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients. We conducted a retrospective cohort study of children (<18years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared 2-year all-cause and cause-specific mortality during 3 time periods based on year of transplantation (1995 to 2001, 2002 to 2007, and 2008 to 2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period. During the 20-year study period 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995 to 2001 to 30% in 2008 to 2014 (P = .0002). White race and nonmalignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which GVHD (18% versus 11%; P = .06) or graft failure (9% versus 3%; P = .01) were contributory than white children. Comparing 2008 to 2014 with 1995 to 2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex (hazard ratio, .09; 95% confidence interval, .01 to .76). With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequentinfectious causes of death in children after UCBT. Advances in clinical practice over the past 20years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453734PMC
April 2019

Pneumococcal Colonization and the Nasopharyngeal Microbiota of Children in Botswana.

Pediatr Infect Dis J 2018 11;37(11):1176-1183

Division of Pediatric Infectious Diseases, Ann and Robert Lurie Children's Hospital, Chicago, IL.

Background: Nasopharyngeal colonization precedes infections caused by Streptococcus pneumoniae. A more detailed understanding of interactions between S. pneumoniae and the nasopharyngeal microbiota of children could inform strategies to prevent pneumococcal infections.

Methods: We collected nasopharyngeal swabs from children 1 to 23 months of age in Botswana between August 2012 and June 2016. We tested samples for S. pneumoniae and common respiratory viruses using polymerase chain reaction. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used random forest models to identify clinical variables and bacterial genera that were associated with pneumococcal colonization.

Results: Mean age of the 170 children included in this study was 8.3 months. Ninety-six (56%) children were colonized with S. pneumoniae. Pneumococcal colonization was associated with older age (P = 0.0001), a lack of electricity in the home (P = 0.02) and household use of wood as a cooking fuel (P = 0.002). Upper respiratory symptoms were more frequent in children with S. pneumoniae colonization (60% vs. 32%; P = 0.001). Adjusting for age, nasopharyngeal microbiota composition differed in colonized and noncolonized children (P = 0.001). S. pneumoniae colonization was associated with a higher relative abundance of Moraxella (P = 0.001) and lower relative abundances of Corynebacterium (P = 0.001) and Staphylococcus (P = 0.03). A decision tree model containing the relative abundances of bacterial genera had 81% sensitivity and 85% specificity for the determination of S. pneumoniae colonization status.

Conclusions: S. pneumoniae colonization is associated with characteristic alterations of the nasopharyngeal microbiota of children. Prospective studies should determine if nasopharyngeal microbial composition alters the risk of pneumococcal colonization and thus could be modified as a novel pneumonia prevention strategy.
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http://dx.doi.org/10.1097/INF.0000000000002174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181769PMC
November 2018

Utility of Autopsy among Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: One Last Chance to Learn?

Biol Blood Marrow Transplant 2018 09 9;24(9):1861-1865. Epub 2018 Jun 9.

Division of Pediatric Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina.

Autopsy may confirm clinical diagnoses or identify conditions that were not suspected prior to a patient's death. Previous studies evaluating the utility of autopsy in hematopoietic stem cell transplant (HSCT) recipients yielded conflicting results. We conducted a retrospective cohort study of children (<18 years of age) undergoing allogeneic HSCT at Duke University who died of any cause between January 1, 1995, and December 31, 2016. We evaluated associations between patient characteristics and autopsy performance using chi-square or Fisher exact tests. We reviewed autopsy reports to determine the concordance between preautopsy causes of death and pathological diagnoses identified on autopsy. We classified unexpected diagnoses on autopsy using criteria developed by Goldman et al. We evaluated for temporal changes in the autopsy consent rate and the frequency of unexpected diagnoses on autopsy using Cochran-Armitage tests. During the 22-year study period, 475 patients died and had data available on autopsy performance, and 130 (27%) of these patients underwent autopsy. The autopsy consent rate declined over time (P < .0001), with autopsies being performed for 40% of deaths in 1995 to 1999 and 17% of deaths in 2009 to 2016. White patients were more likely to undergo autopsy than nonwhite patients (P = .03). There were no associations between autopsy performance and patient age, sex, HSCT indication, or HSCT donor. Unexpected diagnoses were identified in 31 (24%) autopsies. The proportion of autopsies with an unexpected diagnosis did not change during the study period (P = .45). However, infectious diagnoses that would have led to a change in management were more frequently identified on autopsies in 1995 to 2003 than in 2004 to 2016 (20% versus 0%; P = .001). The autopsy consent rate for pediatric HSCT recipients at our institution has declined substantially over the past several decades. The utility of autopsy in this patient population remains high despite a reduction in the identification of unexpected infections.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163060PMC
September 2018

Investigating Mediators of the Poor Pneumonia Outcomes of Human Immunodeficiency Virus-Exposed but Uninfected Children.

J Pediatric Infect Dis Soc 2019 Mar;8(1):13-20

Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina.

Background: Human immunodeficiency virus-exposed but uninfected (HIV-EU) children have a higher mortality rate than the children of HIV-negative mothers (HIV-unexposed). Causal mediators of the poor health outcomes of HIV-EU children remain poorly defined.

Methods: We conducted a hospital-based prospective cohort study of children aged 1 to 23 months with clinically defined pneumonia. The children were recruited at a referral hospital in Gaborone, Botswana, between April 2012 and June 2016. The primary outcome, treatment failure at 48 hours, was assessed by an investigator blinded to the children's HIV-exposure status. We examined associations between HIV exposure and pneumonia outcomes in HIV-uninfected children. We next determined whether the effect of HIV exposure on outcomes was mediated by low-birth-weight status, nonbreastfeeding, malnutrition, in utero exposure to combination antiretroviral therapy, or pneumonia severity.

Results: A total of 352 HIV-uninfected children were included in these analyses, including 245 (70%) HIV-unexposed and 107 (30%) HIV-EU children. Their median age was 7.4 months, and 57% were male. Treatment failure occurred in 111 (32%) children, and 19 (5.4%) children died. HIV-EU children were more likely to fail treatment (risk ratio [RR], 1.57 [95% confidence interval (CI), 1.19-2.07]; P = .002) and had a higher in-hospital mortality rate (RR, 4.50 [95% CI, 1.86-10.85]; P = .001) than HIV-unexposed children. Nonbreastfeeding mediated 47% of the effect of HIV exposure on the risk of in-hospital death.

Conclusions: HIV-EU children have worse pneumonia outcomes than HIV-unexposed children. Nonbreastfeeding mediates nearly half of the effect of HIV exposure on pneumonia mortality. Our findings provide additional evidence for a mortality benefit of breastfeeding by HIV-EU children.
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http://dx.doi.org/10.1093/jpids/pix092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437836PMC
March 2019

Rapid enteric testing to permit targeted antimicrobial therapy, with and without Lactobacillus reuteri probiotics, for paediatric acute diarrhoeal disease in Botswana: A pilot, randomized, factorial, controlled trial.

PLoS One 2017 9;12(10):e0185177. Epub 2017 Oct 9.

Department of Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Introduction: Diarrhoeal disease is the second-leading cause of death in young children. Current guidelines recommend treating children with acute non-bloody diarrhea with oral rehydration solutions and zinc, but not antimicrobials. However, in many resource-limited settings, infections with treatable enteric bacterial and protozoan pathogens are common. Probiotics have shown promise as an adjunct treatment for diarrhoea but have not been studied in sub-Saharan Africa.

Methods: We conducted a pilot, factorial, randomized, placebo-controlled trial of children aged 2-60 months hospitalized in Botswana for acute non-bloody diarrhoea. A rapid test-and-treat intervention, consisting of multiplex PCR testing of rectal swabs taken at enrolment, accompanied by targeted antimicrobial therapy if treatable pathogens were detected, was compared to the reference standard of no stool testing. Additionally, Lactobacillus reuteri DSM 17938 x 60 days was compared to placebo treatment. The main objective of this pilot study was to assess feasibility. The primary clinical outcome was the increase in age-standardized height (HAZ) at 60 days adjusted for baseline HAZ.

Results: Seventy-six patients were enrolled over a seven-month study period. We judged that the recruitment rate, lab processing times, communication protocols, provision of specific antimicrobials, and follow-up rates were acceptable. Compared to the reference arm (no stool testing and placebo treatment), the combination of the rapid test-and-treat strategy plus L. reuteri DSM 17938 was associated with an increase of 0.61 HAZ (95% CI 0.09-1.13) and 93% lower odds of recurrent diarrhoea (OR 0.07, 95%CI 0.01-0.61) at 60 days.

Discussion: We demonstrated that it was feasible to evaluate the study interventions in Botswana. Despite the small sample size, we observed a statistically significant increase in HAZ at 60 days and significantly lower odds of recurrent diarrhoea in children receiving both rapid test-and-treat and L. reuteri. There is sufficient evidence to warrant proceeding with a larger follow-up trial in a similar setting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185177PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633142PMC
October 2017

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

Pediatr Infect Dis J 2017 Sep;36(9):855-859

From the *Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; †Department of Pediatrics, and ‡Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; and §Pediatrix Medical Group, Inc., Sunrise, Florida.

Background: Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking.

Methods: To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to τ (AUCss,0-τ) and steady state maximal drug concentration (Cmaxss). Next, we used multivariable logistic regression to evaluate the association between simulated AUCss,0-τ and Cmaxss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUCss,0-τ and Cmaxss were reported.

Results: We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26-33) and postnatal age of 11 days (6-25). The median (interquartile range) piperacillin dose was 225 mg/kg/d (176-300). No significant associations were found between simulated piperacillin exposure (AUCss,0-τ and Cmaxss) and clinical and laboratory AEs.

Conclusions: We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.
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http://dx.doi.org/10.1097/INF.0000000000001610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555808PMC
September 2017

The Nasopharyngeal Microbiota of Children With Respiratory Infections in Botswana.

Pediatr Infect Dis J 2017 Sep;36(9):e211-e218

From the *Botswana-UPenn Partnership, Gaborone, Botswana; †Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina; ‡Department of Medicine, McMaster University, §Department of Pathology and Molecular Medicine, McMaster University, ¶St. Joseph's Healthcare, and ‖Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; **Global Health Center, and ††Division of Pediatric Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ‡‡Department of Pathology and Laboratory Medicine, BC Children's Hospital, Vancouver, British Columbia, Canada; §§University of Botswana School of Medicine, Gaborone, Botswana; ¶¶Department of Molecular Genetics and Microbiology, Center for the Genomics of Microbial Systems, Duke University Medical Center, Durham, North Carolina; and ‖‖Divisions of Hospital Medicine and Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background: Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the nasopharynx are a reservoir for pneumonia pathogens and remain poorly described in African children.

Methods: Nasopharyngeal swabs were collected from children with pneumonia (N = 204), children with upper respiratory infection symptoms (N = 55) and healthy children (N = 60) in Botswana between April 2012 and April 2014. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used partitioning around medoids to cluster samples into microbiota biotypes. We then used multivariable logistic regression to examine whether microbiota biotypes were associated with pneumonia and upper respiratory infection symptoms.

Results: Mean ages of children with pneumonia, children with upper respiratory infection symptoms and healthy children were 8.2, 11.4 and 8.0 months, respectively. Clustering of nasopharyngeal microbiota identified 5 distinct biotypes: Corynebacterium/Dolosigranulum-dominant (23%), Haemophilus-dominant (11%), Moraxella-dominant (24%), Staphylococcus-dominant (13%) and Streptococcus-dominant (28%). The Haemophilus-dominant [odds ratio (OR): 13.55; 95% confidence interval (CI): 2.10-87.26], the Staphylococcus-dominant (OR: 8.27; 95% CI: 2.13-32.14) and the Streptococcus-dominant (OR: 39.97; 95% CI: 6.63-241.00) biotypes were associated with pneumonia. The Moraxella-dominant (OR: 3.71; 95% CI: 1.09-12.64) and Streptococcus-dominant (OR: 12.26; 95% CI: 1.81-83.06) biotypes were associated with upper respiratory infection symptoms. In children with pneumonia, HIV infection was associated with a lower relative abundance of Dolosigranulum (P = 0.03).

Conclusions: Pneumonia and upper respiratory infection symptoms are associated with distinct nasopharyngeal microbiota biotypes in African children. A lower abundance of the commensal genus Dolosigranulum may contribute to the higher pneumonia risk of HIV-infected children.
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http://dx.doi.org/10.1097/INF.0000000000001607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555803PMC
September 2017

Timing of Multiorgan Dysfunction among Hospitalized Infants with Fatal Fulminant Sepsis.

Am J Perinatol 2017 06 6;34(7):633-639. Epub 2016 Dec 6.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.

 Identify the progression of specific signs of multiorgan dysfunction among infants with fatal sepsis.  Cohort study of 679 infants who died within 3 days of the start of a late-onset sepsis (LOS) episode in neonatal intensive care units from 1997 to 2012. We extracted clinical and laboratory data on the day of death (day 0) and the preceding 5 days (days -5 to -1).  Median (25th percentile-75th percentile) gestational age was 25 (24-28) weeks. Compared with day -1, day 0 was characterized by an increased requirement for mechanical ventilation and higher mean fraction of inspired oxygen. Measures of cardiorespiratory support and the proportion of infants with neutropenia began to rise on day -2.  Hospitalized infants with fatal LOS manifest respiratory, cardiovascular, renal, immune, and hematologic dysfunction. Knowledge of these factors and their timing may be important for the development and testing of novel therapeutics to reduce sepsis mortality.
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http://dx.doi.org/10.1055/s-0036-1597130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604435PMC
June 2017

Postnatal Cytomegalovirus Infection and the Risk for Bronchopulmonary Dysplasia.

JAMA Pediatr 2015 Dec 7;169(12):e153785. Epub 2015 Dec 7.

Division of Pediatric Infectious Diseases, Duke University School of Medicine, Durham, North Carolina.

Importance: Postnatally acquired cytomegalovirus (CMV) is typically benign in term infants but in very low-birth-weight (VLBW) infants can cause pneumonitis and sepsislike illness. Whether postnatal CMV infection results in long-term pulmonary sequelae in these infants is unknown.

Objective: To investigate the association between postnatal CMV infection and bronchopulmonary dysplasia (BPD) and mortality in a large multicenter cohort of VLBW infants.

Design, Setting, And Participants: Conducted between October 2014 and June 2015, this propensity-matched retrospective cohort study involved 101,111 hospitalized VLBW (<1500 g) infants at 348 neonatal intensive care units in the United States from 1997 to 2012. We matched infants with postnatal CMV infection 1:1 to comparison infants using propensity scores, and we used Poisson regression to examine the effect of postnatal CMV on the combined risk for death or BPD at 36 weeks' postmenstrual age. To describe features of postnatal CMV infection, we extracted clinical and laboratory data from 7 days before until 7 days after infants met criteria for postnatal CMV.

Exposures: Postnatal CMV infection was defined as a diagnosis of CMV or detection of CMV from blood, urine, cerebrospinal fluid, or respiratory secretions on or after day of life 21. Infants with a CMV diagnosis or virologic detection of CMV prior to day of life 21 were not considered to have postnatal infection.

Main Outcomes And Measures: The primary outcome was death or BPD at 36 weeks' postmenstrual age.

Results: Of 101,111 infants, 328 (0.3%) had postnatal CMV infection. We matched a comparison infant to 303 CMV-infected infants (92%) for a final cohort of 606 infants. The median gestational age and birth weight of this cohort were 25 weeks and 730 g, respectively. Postnatal CMV infection was associated with an increased risk for death or BPD at 36 weeks' postmenstrual age (risk ratio, 1.21; 95% CI, 1.10-1.32) and BPD (risk ratio, 1.33; 95% CI, 1.19-1.50). Changes in cardiorespiratory status associated with postnatal CMV infection included a new requirement for vasopressor medications (9%; n = 29), intubation for mechanical ventilation (15%; n = 49), a new oxygen requirement (28%; n = 91), and death (1.2%; n = 4).

Conclusions And Relevance: In VLBW infants, postnatal CMV infection was associated with increased risk for BPD. Further studies are needed to determine the role of preventive measures against CMV in this population.
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http://dx.doi.org/10.1001/jamapediatrics.2015.3785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699399PMC
December 2015

Treatment Failures and Excess Mortality Among HIV-Exposed, Uninfected Children With Pneumonia.

J Pediatric Infect Dis Soc 2015 Dec 8;4(4):e117-26. Epub 2014 Oct 8.

Divisions of Global Health Infectious Diseases, The Children's Hospital of Philadelphia, Pennsylvania Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Background: Human immunodeficiency virus (HIV)-exposed, uninfected (HIV-EU) children are at increased risk of infectious illnesses and mortality compared with children of HIV-negative mothers (HIV-unexposed). However, treatment outcomes for lower respiratory tract infections among HIV-EU children remain poorly defined.

Methods: We conducted a hospital-based, prospective cohort study of N = 238 children aged 1-23 months with pneumonia, defined by the World Health Organization. Children were recruited within 6 hours of presentation to a tertiary hospital in Botswana. The primary outcome--treatment failure at 48 hours--was assessed by an investigator blinded to HIV exposure status.

Results: Median age was 6.0 months; 55% were male. One hundred fifty-three (64%) children were HIV-unexposed, 64 (27%) were HIV-EU, and 20 (8%) were HIV-infected; the HIV exposure status of 1 child could not be established. Treatment failure at 48 hours occurred in 79 (33%) children, including in 36 (24%) HIV-unexposed, 30 (47%) HIV-EU, and 12 (60%) HIV-infected children. In multivariable analyses, HIV-EU children were more likely to fail treatment at 48 hours (risk ratio [RR]: 1.83, 95% confidence interval [CI]: 1.27-2.64, P = .001) and had higher in-hospital mortality (RR: 4.31, 95% CI: 1.44-12.87, P = .01) than HIV-unexposed children. Differences in outcomes by HIV exposure status were observed only among children under 6 months of age. HIV-EU children more frequently received treatment with a third-generation cephalosporin, but this did not reduce the risk of treatment failure in this group.

Conclusions: HIV-EU children with pneumonia have higher rates of treatment failure and in-hospital mortality than HIV-unexposed children during the first 6 months of life. Treatment with a third-generation cephalosporins did not improve outcomes among HIV-EU children.
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http://dx.doi.org/10.1093/jpids/piu092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681380PMC
December 2015