Browsing by Author "Kelly, Matthew S"
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Item Open Access Age-related changes in the nasopharyngeal microbiome are associated with SARS-CoV-2 infection and symptoms among children, adolescents, and young adults.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022-03-05) Hurst, Jillian H; McCumber, Alexander W; Aquino, Jhoanna N; Rodriguez, Javier; Heston, Sarah M; Lugo, Debra J; Rotta, Alexandre T; Turner, Nicholas A; Pfeiffer, Trevor S; Gurley, Thaddeus C; Moody, M Anthony; Denny, Thomas N; Rawls, John F; Clark, James S; Woods, Christopher W; Kelly, Matthew SBackground
Children are less susceptible to SARS-CoV-2 infection and typically have milder illness courses than adults, but the factors underlying these age-associated differences are not well understood. The upper respiratory microbiome undergoes substantial shifts during childhood and is increasingly recognized to influence host defense against respiratory pathogens. Thus, we sought to identify upper respiratory microbiome features associated with SARS-CoV-2 infection susceptibility and illness severity.Methods
We collected clinical data and nasopharyngeal swabs from 285 children, adolescents, and young adults (<21 years of age) with documented SARS-CoV-2 exposure. We used 16S ribosomal RNA gene sequencing to characterize the nasopharyngeal microbiome and evaluated for age-adjusted associations between microbiome characteristics and SARS-CoV-2 infection status and respiratory symptoms.Results
Nasopharyngeal microbiome composition varied with age (PERMANOVA, p<0.001, R 2=0.06) and between SARS-CoV-2-infected individuals with and without respiratory symptoms (PERMANOVA, p=0.002, R 2=0.009). SARS-CoV-2-infected participants with Corynebacterium/Dolosigranulum-dominant microbiome profiles were less likely to have respiratory symptoms than infected participants with other nasopharyngeal microbiome profiles (odds ratio: 0.38, 95% confidence interval: 0.18-0.81). Using generalized joint attributed modeling, we identified nine bacterial taxa associated with SARS-CoV-2 infection and six taxa that were differentially abundant among SARS-CoV-2-infected participants with respiratory symptoms; the magnitude of these associations was strongly influenced by age.Conclusions
We identified interactive relationships between age and specific nasopharyngeal microbiome features that are associated with SARS-CoV-2 infection susceptibility and symptoms in children, adolescents, and young adults. Our data suggest that the upper respiratory microbiome may be a mechanism by which age influences SARS-CoV-2 susceptibility and illness severity.Item Open Access Age-related changes in the upper respiratory microbiome are associated with SARS-CoV-2 susceptibility and illness severity.(medRxiv, 2021-03-23) Hurst, Jillian H; McCumber, Alexander W; Aquino, Jhoanna N; Rodriguez, Javier; Heston, Sarah M; Lugo, Debra J; Rotta, Alexandre T; Turner, Nicholas A; Pfeiffer, Trevor S; Gurley, Thaddeus C; Moody, M Anthony; Denny, Thomas N; Rawls, John F; Woods, Christopher W; Kelly, Matthew SChildren are less susceptible to SARS-CoV-2 and typically have milder illness courses than adults. We studied the nasopharyngeal microbiomes of 274 children, adolescents, and young adults with SARS-CoV-2 exposure using 16S rRNA gene sequencing. We find that higher abundances of Corynebacterium species are associated with SARS-CoV-2 infection and SARS-CoV-2-associated respiratory symptoms, while higher abundances of Dolosigranulum pigrum are present in SARS-CoV-2-infected individuals without respiratory symptoms. We also demonstrate that the abundances of these bacteria are strongly, and independently, associated with age, suggesting that the nasopharyngeal microbiome may be a potentially modifiable mechanism by which age influences SARS-CoV-2 susceptibility and severity. SUMMARY: Evaluation of nasopharyngeal microbiome profiles in children, adolescents, and young adults with a SARS-CoV-2-infected close contact identified specific bacterial species that vary in abundance with age and are associated with SARS-CoV-2 susceptibility and the presence of SARS-CoV-2-associated respiratory symptoms.Item Open Access Cultivating Research Skills During Clinical Training to Promote Pediatric-Scientist Development.(Pediatrics, 2019-08) Hurst, Jillian H; Barrett, Katherine J; Kelly, Matthew S; Staples, Betty B; McGann, Kathleen A; Cunningham, Coleen K; Reed, Ann M; Gbadegesin, Rasheed A; Permar, Sallie RPhysician-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.Item Open Access Dysregulated transcriptional responses to SARS-CoV-2 in the periphery support novel diagnostic approaches.(medRxiv, 2020-07-26) McClain, Micah T; Constantine, Florica J; Henao, Ricardo; Liu, Yiling; Tsalik, Ephraim L; Burke, Thomas W; Steinbrink, Julie M; Petzold, Elizabeth; Nicholson, Bradly P; Rolfe, Robert; Kraft, Bryan D; Kelly, Matthew S; Sempowski, Gregory D; Denny, Thomas N; Ginsburg, Geoffrey S; Woods, Christopher WIn 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.Item Open Access Dysregulated transcriptional responses to SARS-CoV-2 in the periphery.(Nature communications, 2021-02-17) McClain, Micah T; Constantine, Florica J; Henao, Ricardo; Liu, Yiling; Tsalik, Ephraim L; Burke, Thomas W; Steinbrink, Julie M; Petzold, Elizabeth; Nicholson, Bradly P; Rolfe, Robert; Kraft, Bryan D; Kelly, Matthew S; Saban, Daniel R; Yu, Chen; Shen, Xiling; Ko, Emily M; Sempowski, Gregory D; Denny, Thomas N; Ginsburg, Geoffrey S; Woods, Christopher WSARS-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.Item Open Access Microbiology and Risk Factors for Hospital-Associated Bloodstream Infections Among Pediatric Hematopoietic Stem Cell Transplant Recipients.(Open forum infectious diseases, 2020-04) Akinboyo, Ibukunoluwa C; Young, Rebecca R; Spees, Lisa P; Heston, Sarah M; Smith, Michael J; Chang, Yeh-Chung; McGill, Lauren E; Martin, Paul L; Jenkins, Kirsten; Lugo, Debra J; Hazen, Kevin C; Seed, Patrick C; Kelly, Matthew SBackground: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 (P = .021) and, specifically, fungal HA-BSIs (P = .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%; P = .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.Item Open Access Reduction in Mortality after Umbilical Cord Blood Transplantation in Children Over a 20-Year Period (1995-2014).(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2019-04) Spees, Lisa P; Martin, Paul L; Kurtzberg, Joanne; Stokhuyzen, Andre; McGill, Lauren; Prasad, Vinod K; Driscoll, Timothy A; Parikh, Suhag H; Page, Kristin M; Vinesett, Richard; Severyn, Christopher; Sung, Anthony D; Proia, Alan D; Jenkins, Kirsten; Arshad, Mehreen; Steinbach, William J; Seed, Patrick C; Kelly, Matthew SInfections 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.Item Open Access SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020-11-03) Hurst, Jillian H; Heston, Sarah M; Chambers, Hailey N; Cunningham, Hannah M; Price, Meghan J; Suarez, Lilianna; Crew, Carter G; Bose, Shree; Aquino, Jhoanna N; Carr, Stuart T; Griffin, S Michelle; Smith, Stephanie H; Jenkins, Kirsten; Pfeiffer, Trevor S; Rodriguez, Javier; DeMarco, C Todd; De Naeyer, Nicole A; Gurley, Thaddeus C; Louzao, Raul; Zhao, Congwen; Cunningham, Coleen K; Steinbach, William J; Denny, Thomas N; Lugo, Debra J; Moody, M Anthony; Permar, Sallie R; Rotta, Alexandre T; Turner, Nicholas A; Walter, Emmanuel B; Woods, Christopher W; Kelly, Matthew SBACKGROUND: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.Item Open Access SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.(medRxiv, 2020-09-01) Hurst, Jillian H; Heston, Sarah M; Chambers, Hailey N; Cunningham, Hannah M; Price, Meghan J; Suarez, Liliana; Crew, Carter G; Bose, Shree; Aquino, Jhoanna N; Carr, Stuart T; Griffin, S Michelle; Smith, Stephanie H; Jenkins, Kirsten; Pfeiffer, Trevor S; Rodriguez, Javier; DeMarco, C Todd; De Naeyer, Nicole A; Gurley, Thaddeus C; Louzao, Raul; Cunningham, Coleen K; Steinbach, William J; Denny, Thomas N; Lugo, Debra J; Moody, M Anthony; Permar, Sallie R; Rotta, Alexandre T; Turner, Nicholas A; Walter, Emmanuel B; Woods, Christopher W; Kelly, Matthew SBACKGROUND: 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.Item Open Access Utility of Autopsy among Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: One Last Chance to Learn?(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018-06-09) Kelly, Matthew S; Spees, Lisa; Vinesett, Richard; Stokhuyzen, Andre; McGill, Lauren; Proia, Alan D; Jenkins, Kirsten; Arshad, Mehreen; Seed, Patrick C; Martin, Paul LAutopsy 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's exact tests. We reviewed autopsy reports to determine the concordance between pre-autopsy 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<0.0001), with autopsies being performed for 40% of deaths in 1995-1999 and 17% of deaths in 2009-2016. White patients were more likely to undergo autopsy than non-white patients (P=0.03). 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=0.45). However, infectious diagnoses that would have led to a change in management were more frequently identified on autopsies in 1995-2003 than in 2004-2016 (20% vs. 0%; P=0.001).The autopsy consent rate for pediatric HSCT recipients at our institution 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.