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

The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which-in some cases-leads to gastrointestinal disorders1-4. 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 109 per gram, and these numbers seem to persist throughout life5-7. 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 infections8-10. 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.

Comprehensive Assessment of the Intrinsic Pancreatic Microbiome.

OBJECTIVE: We sought to comprehensively profile tissue and cyst fluid in patients with benign, precancerous, and cancerous conditions of the pancreas to characterize the intrinsic pancreatic microbiome. SUMMARY BACKGROUND DATA: Small studies in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) have suggested that intra-pancreatic microbial dysbiosis may drive malignant transformation. METHODS: Pancreatic samples were collected at the time of resection from 109 patients. Samples included tumor tissue (control, n=20; IPMN, n=20; PDAC, n=19) and pancreatic cyst fluid (IPMN, n=30; SCA, n=10; MCN, n=10). Assessment of bacterial DNA by quantitative PCR and 16S ribosomal RNA gene sequencing was performed. Downstream analyses determined the relative abundances of individual taxa between groups and compared intergroup diversity. Whole-genome sequencing data from 140 patients with PDAC in the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to validate findings. RESULTS: Sequencing of pancreatic tissue yielded few microbial reads regardless of diagnosis, and analysis of pancreatic tissue showed no difference in the abundance and composition of bacterial taxa between normal pancreas, IPMN, or PDAC groups. Low-grade dysplasia (LGD) and high-grade dysplasia (HGD) IPMN were characterized by low bacterial abundances with no difference in tissue composition and a slight increase in Pseudomonas and Sediminibacterium in HGD cyst fluid. Decontamination analysis using the CPTAC database confirmed a low-biomass, low-diversity intrinsic pancreatic microbiome that did not differ by pathology. CONCLUSIONS: Our analysis of the pancreatic microbiome demonstrated very low intrinsic biomass that is relatively conserved across diverse neoplastic conditions and thus unlikely to drive malignant transformation.

Dolosigranulum savutiense sp. nov., isolated from human upper respiratory samples collected in Botswana.

Four strains (MSK211, MSK294T, MSK312, MSK433) of a novel Dolosigranulum species were cultured from nasopharyngeal swabs collected from mother-infant dyads in southern Botswana. These strains grew optimally on tryptic soy agar with 5% sheep blood solid medium and in fastidious bacteria broth. Colonies on tryptic soy agar with 5% sheep blood agar appeared grey or white with a flat, smooth surface and variable alpha haemolysis. Cells were Gram-positive, non-spore-forming, non-motile cocci that lacked catalase or oxidase activity. Major fatty acids were C16 : 0 (palmitic acid), C18 : 1 ω9c (oleic acid), and C18 : 0 (stearic acid). Analyses of 16S rRNA gene sequences identified these strains as belonging to the genus Dolosigranulum (family Carnobacteriaceae), which currently contains only a single validly published species (Dolosigranulum pigrum). Whole-genome sequencing revealed that the genomes of these strains are 1.98-2.07 Mbp in size and have a G+C content of 39.6-39.9 mol%. Comparisons of these genomes to publicly available genomes of D. pigrum yielded average nucleotide identities and in silico DNA-DNA hybridization values of 92.3-92.9% and 49.1-51.4%, respectively. These results indicate that these strains represent a novel species of Dolosigranulum, for which we propose the name Dolosigranulum savutiense sp. nov., with the type strain MSK294T (=DSM 117171T=JCM 36673T).

Host microbiome-pathogen interactions in pediatric infections.

PURPOSE OF REVIEW: In this review, we discuss recent research that has furthered our understanding of microbiome development during childhood, the role of the microbiome in infections during this life stage, and emerging opportunities for microbiome-based therapies for infection prevention or treatment in children. RECENT FINDINGS: The microbiome is highly dynamic during childhood and shaped by a variety of host and environmental factors. In turn, the microbiome influences risk and severity of a broad range of infections during childhood, with recent studies highlighting potential roles in respiratory, gastrointestinal, and systemic infections. The microbiome exerts this influence through both direct interactions with potential pathogens and indirectly through modulation of host immune responses. The elucidation of some of these mechanisms by recent studies and the development of effective microbiome-based therapies for adults with recurrent Clostridioides difficile infection highlight the enormous promise that targeting the microbiome has for reducing the burden of infectious diseases during childhood. SUMMARY: The microbiome has emerged as a key modifier of infection susceptibility and severity among children. Further research is needed to define the roles of microbes other than bacteria and to elucidate the mechanisms underlying microbiome-host and microbiome-pathogen interactions of importance to infectious diseases in children.

Financial burden and recommended multilevel solutions among caregivers of pediatric hematopoietic stem cell transplant recipients.

BACKGROUND: The healthcare costs of patients who receive hematopoietic stem cell transplantation (HSCT) are substantial. At the same time, the increasing use of pediatric HSCT leaves more caregivers of pediatric HSCT recipients at risk for financial burden-an understudied area of research. METHODS: Financial burden experienced by caregivers of recipients who received autologous or allogeneic transplants was assessed using an explanatory mixed-methods design including a one-time survey and semi-structured interviews. Financial burden was assessed through an adapted COmprehensive Score for financial Toxicity (COST) as well as questions about the types of out-of-pocket costs and cost-coping behaviors. Chi-squared or Fisher's exact tests were used to assess differences in costs incurred and coping behaviors by financial toxicity and financial toxicity by demographic factors. Interviews were audio recorded, transcribed, and analyzed using directed content analysis. RESULTS: Of 99 survey participants, 64% experienced high financial toxicity (COST  ≤ $ \le \;$ 22). Caregivers with high financial toxicity were more likely to report costs related to transportation and diet. High financial toxicity was associated with nearly all cost-coping behaviors (e.g., borrowed money). High financial toxicity was also associated with increased use of hospital financial support and transportation assistance. Qualitative analysis resulted in four categories that were integrated with quantitative findings: (1) care-related out-of-pocket costs incurred, (2) cost-coping behaviors, (3) financial support resources used, and (4) multilevel recommendations for reducing financial burden. CONCLUSIONS: Considering the substantial, long-term financial burden among pediatric HSCT patients and their caregivers, this population would benefit from adapted and tailored financial burden interventions.

Evaluation of Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) Vaccines RSV/ΔNS2/Δ1313/I1314L and RSV/276 in RSV-Seronegative Children.

BACKGROUND: This United States-based study compared 2 candidate vaccines: RSV/ΔNS2/Δ1313/I1314L, attenuated by NS2 gene-deletion and temperature-sensitivity mutation in the polymerase gene; and RSV/276, attenuated by M2-2 deletion. METHODS: RSV-seronegative children aged 6-24 months received RSV/ΔNS2/Δ1313/I1314L (106 plaque-forming units [PFU]), RSV/276 (105 PFU), or placebo intranasally. Participants were monitored for vaccine shedding, reactogenicity, and RSV serum antibodies, and followed over the subsequent RSV season. RESULTS: Enrollment occurred September 2017 to October 2019. During 28 days postinoculation, upper respiratory illness and/or fever occurred in 64% of RSV/ΔNS2/Δ1313/I1314L, 84% of RSV/276, and 58% of placebo recipients. Symptoms were generally mild. Cough was more common in RSV/276 recipients than RSV/ΔNS2/Δ1313/I1314L (48% vs 12%; P = .012) or placebo recipients (17%; P = .084). There were no lower respiratory illness or serious adverse events. Eighty-eight and 96% of RSV/ΔNS2/Δ1313/I1314L and RSV/276 recipients were infected with vaccine (shed vaccine and/or had ≥4-fold rises in RSV antibodies). Serum RSV-neutralizing titers and anti-RSV F IgG titers increased ≥4-fold in 60% and 92% of RSV/ΔNS2/Δ1313/I1314L and RSV/276 vaccinees, respectively. Exposure to community RSV during the subsequent winter was associated with strong anamnestic RSV-antibody responses. CONCLUSIONS: Both vaccines had excellent infectivity and were well tolerated. RSV/276 induced an excess of mild cough. Both vaccines were immunogenic and primed for strong anamnestic responses. CLINICAL TRIALS REGISTRATION: NCT03227029 and NCT03422237.

Age-Related Changes in the Nasopharyngeal Microbiome Are Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and Symptoms Among Children, Adolescents, and Young Adults.

BACKGROUND: 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) 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 < .001; R2 = 0.06) and between SARS-CoV-2-infected individuals with and without respiratory symptoms (PERMANOVA, P  = .002; R2 = 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 (OR: .38; 95% CI: .18-.81). Using generalized joint attributed modeling, we identified 9 bacterial taxa associated with SARS-CoV-2 infection and 6 taxa 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.

Understanding the financial and psychological impact of employment disruption among caregivers of pediatric HSCT recipients: a mixed methods analysis.

PURPOSE: Pediatric hematopoietic stem cell transplantation (HSCT) confers a substantial financial burden onto patients' families. In addition to high direct medical costs, HSCTs typically require at least one caregiver to take time away from work or other responsibilities, often leading to reduced household income. Using mixed methods, we sought to understand the impact of pediatric HSCT on caregiver employment and financial need. METHODS: We surveyed caregivers of living pediatric patients who underwent HSCT at one of two southeastern transplant centers between 2012 and 2018 (N = 95). We then interviewed a subset of caregivers (N = 18) to understand whether and how employment disruption contributed to financial distress. RESULTS: Among caregivers surveyed, the majority of household wage earners changed their work schedules to attend medical appointments and missed workdays. This resulted in income loss for 87% of families, with 31% experiencing an income reduction of over 50%. Qualitative interviews pointed to four emergent themes: (1) employment disruption exacerbated existing financial challenges; (2) parental division of labor between caregiving and providing financially led to heightened psychological distress; (3) existing employment leave and protection resources were essential but not sufficient; and (4) the ability to work remotely and having a supportive employer facilitated employment maintenance throughout the HSCT process. CONCLUSION: Expanded employment protections and access to accommodations are needed to limit the impact of HSCT on household income, health insurance, and financial hardship. Additionally, interventions are needed to ensure caregivers are equipped with the information necessary to navigate conversations with employers and prepare for the financial and psychological reality of employment disruption.

Effect of Haemophilus influenzae Type b and 13-Valent Pneumococcal Conjugate Vaccines on Childhood Pneumonia Hospitalizations and Deaths in Botswana.

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 aged 1 to 59 months at 3 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 prevaccine (January 2009 to October 2010) with postvaccine (January 2013 to December 2017) using seasonally adjusted, interrupted time-series analyses. RESULTS: We identified 6943 pneumonia hospitalizations and 201 pneumonia deaths. In the prevaccine period, pneumonia hospitalizations and deaths increased by 24% (rate, 1.24; 95% CI, .94-1.64) and 59% (rate, 1.59; 95% CI, .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 prevaccine period (October 2010) and the beginning of the postvaccine period (January 2013). During the postvaccine period, pneumonia hospitalizations and deaths declined by 6% (rate, .94; 95% CI, .89-.99) and 22% (rate, .78; 95% CI, .67-.92) per year, respectively. CONCLUSIONS: 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 5 years after vaccine introduction, supporting the long-term effectiveness of these vaccines in preventing childhood pneumonia in Botswana.

Severe Acute Respiratory Syndrome Coronavirus 2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.

BACKGROUND: Child with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of SARS-CoV-2-related illnesses that the viruses causes in children. METHODS: We conducted a prospective cohort study of children and adolescents (aged <21 years) 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 polymerase chain reaction assay. RESULTS: Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (P < .0001), less likely to have asthma (P = .005), and more likely to have an infected sibling contact (P = .001) than uninfected children. Children aged 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs 48%; P = .01) or adolescents (29% vs 60%; P < .001). Compared with children aged 6-13 years, adolescents more frequently reported influenza-like (61% vs 39%; P < .001) , and gastrointestinal (27% vs 9%; P = .002), and sensory symptoms (42% vs 9%; P < .0001) and had more prolonged illnesses (median [interquartile range] duration: 7 [4-12] vs 4 [3-8] days; P = 0.01). Despite the age-related variability in symptoms, wWe found no difference 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 clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for coronavirus disease 2019 and in developing screening strategies for schools and childcare settings.

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

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.

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

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.

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

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.

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

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 ß-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.

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

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.

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

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.

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

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.

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

Objective Identify the progression of specific signs of multiorgan dysfunction among infants with fatal sepsis. Study Design 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). Results 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. Conclusion 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.