Publications by authors named "Jonathan A McCullers"

131 Publications

Particulate matter exposure predicts residence in high-risk areas for community acquired pneumonia among hospitalized children.

Exp Biol Med (Maywood) 2021 Sep 29;246(17):1907-1916. Epub 2021 May 29.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA.

Particulate matter exposure is a risk factor for lower respiratory tract infection in children. Here, we investigated the geospatial patterns of community-acquired pneumonia and the impact of PM (particulate matter with an aerodynamic diameter ≤2.5 µm) on geospatial variability of pneumonia in children. We performed a retrospective analysis of prospectively collected population-based surveillance study data of community-acquired pneumonia hospitalizations among children <18 years residing in the Memphis metropolitan area, who were enrolled in the Centers for Disease Control and Prevention sponsored Etiology of Pneumonia in the Community (EPIC) study from January 2010 to June 2012. The outcome measure, residence in high- and low-risk areas for community-acquired pneumonia, was determined by calculating pneumonia incidence rates and performing cluster analysis to identify areas with higher/lower than expected rates of community-acquired pneumonia for the population at risk. High PM was defined as exposure to PM concentrations greater than the mean value (>10.75 μg/m), and low PM is defined as exposure to PM concentrations less than or equal to the mean value (≤10.75 μg/m). We also assessed the effects of age, sex, race/ethnicity, history of wheezing, insurance type, tobacco smoke exposure, bacterial etiology, and viral etiology of infection. Of 810 (96.1%) subjects with radiographic community-acquired pneumonia, who resided in the Memphis metropolitan area and had addresses which were successfully geocoded (Supplementary Figure F2), 220 (27.2%) patients were identified to be from high- ( = 126) or low-risk ( = 94) community-acquired pneumonia areas. Community-acquired pneumonia in Memphis metropolitan area had a non-homogenous geospatial pattern. PM was associated with residence in high-risk areas for community-acquired pneumonia. In addition, children with private insurance and bacterial, as opposed to viral, etiology of infection had a decreased risk of residence in a high-risk area for community-acquired pneumonia. The results from this paper suggest that environmental exposures as well as social risk factors are associated with childhood pneumonia.
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http://dx.doi.org/10.1177/15353702211014456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424632PMC
September 2021

Dynamic Pneumococcal Genetic Adaptations Support Bacterial Growth and Inflammation during Coinfection with Influenza.

Infect Immun 2021 06 16;89(7):e0002321. Epub 2021 Jun 16.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Streptococcus pneumoniae (pneumococcus) is one of the primary bacterial pathogens that complicates influenza virus infections. These bacterial coinfections increase influenza-associated morbidity and mortality through a number of immunological and viral-mediated mechanisms, but the specific bacterial genes that contribute to postinfluenza pathogenicity are not known. Here, we used genome-wide transposon mutagenesis (Tn-Seq) to reveal bacterial genes that confer improved fitness in influenza virus-infected hosts. The majority of the 32 genes identified are involved in bacterial metabolism, including nucleotide biosynthesis, amino acid biosynthesis, protein translation, and membrane transport. We generated mutants with single-gene deletions (SGD) of five of the genes identified, SPD1414, SPD2047 (), SPD0058 (), SPD1098, and SPD0822 (), to investigate their effects on fitness, disease severity, and host immune responses. The growth of the SGD mutants was slightly attenuated and , but each still grew to high titers in the lungs of mock- and influenza virus-infected hosts. Despite high bacterial loads, mortality was significantly reduced or delayed with all SGD mutants. Time-dependent reductions in pulmonary neutrophils, inflammatory macrophages, and select proinflammatory cytokines and chemokines were also observed. Immunohistochemical staining further revealed altered neutrophil distribution with reduced degeneration in the lungs of influenza virus-SGD mutant-coinfected animals. These studies demonstrate a critical role for specific bacterial genes and for bacterial metabolism in driving virulence and modulating immune function during influenza-associated bacterial pneumonia.
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http://dx.doi.org/10.1128/IAI.00023-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208518PMC
June 2021

Effect of Vitamin A Deficiency in Dysregulating Immune Responses to Influenza Virus and Increasing Mortality Rates After Bacterial Coinfections.

J Infect Dis 2021 May;223(10):1806-1816

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

Background: Secondary bacterial coinfections are ranked as a leading cause of hospitalization and morbid conditions associated with influenza. Because vitamin A deficiency (VAD) and insufficiency are frequent in both developed and developing countries, we asked how VAD influences coinfection severity.

Methods: VAD and control mice were infected with influenza virus for evaluation of inflammatory cytokines, cellular immune responses, and viral clearance. Influenza-infected mice were coinfected with Streptococcus pneumoniae to study weight loss and survival.

Results: Naive VAD mouse lungs exhibited dysregulated immune function. Neutrophils were enhanced in frequency and there was a significant reduction in RANTES (regulated on activation of normal T cells expressed and secreted), a chemokine instrumental in T-cell homing and recruitment. After influenza virus infection, VAD mice experienced failures in CD4+ T-cell recruitment and B-cell organization into lymphoid structures in the lung. VAD mice exhibited higher viral titers than controls and slow viral clearance. There were elevated levels of inflammatory cytokines and innate cell subsets in the lungs. However, arginase, a marker of alternatively activated M2 macrophages, was rare. When influenza-infected VAD animals were exposed to bacteria, they experienced a 100% mortality rate.

Conclusion: Data showed that VAD dysregulated the immune response. Consequently, secondary bacterial infections were 100% lethal in influenza-infected VAD mice.
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http://dx.doi.org/10.1093/infdis/jiaa597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161642PMC
May 2021

Parainfluenza Virus Types 1-3 Infections Among Children and Adults Hospitalized with Community-Acquired Pneumonia.

Clin Infect Dis 2020 Jul 18. Epub 2020 Jul 18.

Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN.

Background: Parainfluenza virus (PIV) is a leading cause of lower respiratory tract infections. Although there are several distinct PIV serotypes, few studies have compared the clinical characteristics and severity of infection among the individual PIV serotypes and between PIV and other pathogens in patients with community-acquired pneumonia.

Methods: We conducted active population-based surveillance for radiographically confirmed community-acquired pneumonia hospitalizations among children and adults in eight United States hospitals with systematic collection of clinical data and respiratory, blood, and serological specimens for pathogen detection. We compared clinical features of PIV-associated pneumonia among individual serotypes 1, 2, and 3 and among all PIV infections with other viral, atypical, and bacterial pneumonias. We also compared in-hospital disease severity among groups employing an ordinal scale (mild, moderate, severe) using multivariable proportional odds regression.

Results: PIV was more commonly detected in children (155/2354 [6.6%]) than in adults (66/2297 [2.9%]) (p<0.001). Other pathogens were commonly co-detected among PIV cases (110/221 [50%]). Clinical features of PIV-1, PIV-2, and PIV-3 infections were similar to one another in both children and adults with pneumonia. In multivariable analysis, children with PIV-associated pneumonia exhibited similar severity to children with other non-bacterial pneumonia; whereas children with bacterial pneumonia, exhibited increased severity (OR 8.42 [95% CI 1.88, 37.80]). In adults, PIV-associated pneumonia exhibited similar severity to other pneumonia pathogens.

Conclusions: Clinical features did not distinguish among infection with individual PIV serotypes in patients hospitalized with community acquired pneumonia. However, in children, PIV pneumonia was less severe than bacterial pneumonia.
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http://dx.doi.org/10.1093/cid/ciaa973DOI Listing
July 2020

Clinical Features of Human Metapneumovirus-Associated Community-acquired Pneumonia Hospitalizations.

Clin Infect Dis 2021 01;72(1):108-117

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Background: Human metapneumovirus (HMPV) is a leading cause of respiratory tract infections. Few studies have compared the clinical characteristics and severity of HMPV-associated pneumonia with other pathogens.

Methods: Active, population-based surveillance was previously conducted for radiographically confirmed, community-acquired pneumonia hospitalizations among children and adults in 8 United States hospitals. Clinical data and specimens for pathogen detection were systematically collected. We described clinical features of all HMPV-associated pneumonia and, after excluding codetections with other pathogen types, we compared features of HMPV-associated pneumonia with other viral, atypical, and bacterial pneumonia and modeled the severity (mild, moderate, and severe) and length of stay using multivariable proportional odds regression.

Results: HMPV was detected in 298/2358 (12.6%) children and 88/2320 (3.8%) adults hospitalized with pneumonia and was commonly codetected with other pathogens (125/298 [42%] children and 21/88 [24%] adults). Fever and cough were the most common presenting symptoms of HMPV-associated pneumonia and were also common symptoms of other pathogens. After excluding codetections in children (n = 1778), compared to HMPV (reference), bacterial pneumonia exhibited increased severity (odds ratio [OR], 3.66; 95% confidence interval [CI], 1.43-9.40), respiratory syncytial virus (RSV; OR, 0.76; 95% CI, .59-.99) and atypical (OR, 0.39; 95% CI, .19-.81) infections exhibited decreased severity, and other viral pneumonia exhibited similar severity (OR, 0.88; 95% CI, .55-1.39). In adults (n = 2145), bacterial (OR, 3.74; 95% CI, 1.87-7.47) and RSV pneumonia (OR, 1.82; 95% CI, 1.32-2.50) were more severe than HMPV (reference), but all other pathogens had similar severity.

Conclusions: Clinical features did not reliably distinguish HMPV-associated pneumonia from other pathogens. HMPV-associated pneumonia was less severe than bacterial and adult RSV pneumonia, but was otherwise as or more severe than other common pathogens.
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http://dx.doi.org/10.1093/cid/ciaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823075PMC
January 2021

Prevalence, Risk Factors, and Outcomes of Bacteremic Pneumonia in Children.

Pediatrics 2019 07;144(1)

Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee.

Background: Previous studies examining bacteremia in hospitalized children with pneumonia are limited by incomplete culture data. We sought to determine characteristics of children with bacteremic pneumonia using data from a large prospective study with systematic blood culturing.

Methods: Children <18 years hospitalized with pneumonia and enrolled in the multicenter Etiology of Pneumonia in the Community study between January 2010 and June 2012 were eligible. Bivariate comparisons were used to identify factors associated with bacteremia. Associations between bacteremia and clinical outcomes were assessed by using Cox proportional hazards regression for length of stay and logistic regression for ICU admission and invasive mechanical ventilation or shock.

Results: Blood cultures were obtained in 2143 (91%) of 2358 children; 46 (2.2%) had bacteremia. The most common pathogens were ( = 23, 50%), ( = 6, 13%), and ( = 4, 9%). Characteristics associated with bacteremia included male sex, parapneumonic effusion, lack of chest indrawing or wheezing, and no previous receipt of antibiotics. Children with bacteremia had longer lengths of stay (median: 5.8 vs 2.8 days; adjusted hazard ratio: 0.79 [0.73-0.86]) and increased odds of ICU admission (43% vs 21%; adjusted odds ratio: 5.21 [3.82-6.84]) and invasive mechanical ventilation or shock (30% vs 8%; adjusted odds ratio: 5.28 [2.41-11.57]).

Conclusions: Bacteremia was uncommonly detected in this large multicenter cohort of children hospitalized with community-acquired pneumonia but was associated with severe disease. was detected most often. Blood culture was of low yield in general but may have greater use in those with parapneumonic effusion and ICU admission.
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http://dx.doi.org/10.1542/peds.2018-3090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615516PMC
July 2019

Enhanced IL-1β production is mediated by a TLR2-MYD88-NLRP3 signaling axis during coinfection with influenza A virus and Streptococcus pneumoniae.

PLoS One 2019 22;14(2):e0212236. Epub 2019 Feb 22.

Department of Biology, Missouri State University, Springfield, Missouri, United States of America.

Viral-bacterial coinfections, such as with influenza A virus and Streptococcus pneumoniae (S.p.), are known to cause severe pneumonia. It is well known that the host response has an important role in disease. Interleukin-1β (IL-1β) is an important immune signaling cytokine responsible for inflammation and has been previously shown to contribute to disease severity in numerous infections. Other studies in mice indicate that IL-1β levels are dramatically elevated during IAV-S.p. coinfection. However, the regulation of IL-1β during coinfection is unknown. Here, we report the NLRP3 inflammasome is the major inflammasome regulating IL-1β activation during coinfection. Furthermore, elevated IL-1β mRNA expression is due to enhanced TLR2-MYD88 signaling, which increases the amount of pro-IL-1β substrate for the inflammasome to process. Finally, NLRP3 and high IL-1β levels were associated with increased bacterial load in the brain. Our results show the NLRP3 inflammasome is not protective during IAV-S.p. coinfection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212236PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386446PMC
November 2019

Influenza: annual seasonal severity.

Curr Opin Pediatr 2019 02;31(1):112-118

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

Purpose Of Review: Influenza remains a major cause of morbidity and mortality. The 2017-2018 season was one of the most severe in the past decade. The exact factors determining the severity of a particular influenza season are complex and often poorly understood.

Recent Findings: Factors impacting annual influenza severity include characteristics of the specific virus, influenza vaccination, and antiviral use. Although viral virulence factors are important in this context and our knowledge of these is growing, there is a complex interplay between expression of these factors and their impact on a particular patient population. Vaccination has demonstrated efficacy in preventing disease, but vaccination rates remain sub-optimal and vaccine effectiveness can vary significantly between influenza strains and patient populations. Finally, while antiviral treatment is available and has shown benefits, many patients with influenza do not receive treatment.

Summary: Strides have been made in recent years towards understanding the many factors that contribute to the severity of any particular influenza season. Obvious areas for improvement include improved vaccination rates and antiviral use. Additionally, a more complete understanding of reasons for poor strain and population-specific vaccine effectiveness may help reduce the severity of future influenza seasons.
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http://dx.doi.org/10.1097/MOP.0000000000000712DOI Listing
February 2019

Prevalence of Staphylococcus aureus and Use of Antistaphylococcal Therapy in Children Hospitalized with Pneumonia.

J Hosp Med 2018 12 31;13(12):848-852. Epub 2018 Oct 31.

Division of Hospital Medicine, Monroe Carell Jr. Children's Hospital and the Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Within a cohort of >2,000 children hospitalized with community-acquired pneumonia, staphylococcal pneumonia was rare (1%) but associated with adverse in-hospital outcomes. Despite this low prevalence, use of antistaphylococcal antibiotics was common (24%). Efforts are needed to minimize overuse of antistaphylococcal antibiotics while also ensuring adequate treatment for pathogen-specific diseases.
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http://dx.doi.org/10.12788/jhm.3093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321763PMC
December 2018

Use of Multiple Imputation to Estimate the Proportion of Respiratory Virus Detections Among Patients Hospitalized With Community-Acquired Pneumonia.

Open Forum Infect Dis 2018 Apr 16;5(4):ofy061. Epub 2018 Mar 16.

Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Real-time polymerase chain reaction (PCR) on respiratory specimens and serology on paired blood specimens are used to determine the etiology of respiratory illnesses for research studies. However, convalescent serology is often not collected. We used multiple imputation to assign values for missing serology results to estimate virus-specific prevalence among pediatric and adult community-acquired pneumonia hospitalizations using data from an active population-based surveillance study.

Methods: Presence of adenoviruses, human metapneumovirus, influenza viruses, parainfluenza virus types 1-3, and respiratory syncytial virus was defined by positive PCR on nasopharyngeal/oropharyngeal specimens or a 4-fold rise in paired serology. We performed multiple imputation by developing a multivariable regression model for each virus using data from patients with available serology results. We calculated absolute and relative differences in the proportion of each virus detected comparing the imputed to observed (nonimputed) results.

Results: Among 2222 children and 2259 adults, 98.8% and 99.5% had nasopharyngeal/oropharyngeal specimens and 43.2% and 37.5% had paired serum specimens, respectively. Imputed results increased viral etiology assignments by an absolute difference of 1.6%-4.4% and 0.8%-2.8% in children and adults, respectively; relative differences were 1.1-3.0 times higher.

Conclusions: Multiple imputation can be used when serology results are missing, to refine virus-specific prevalence estimates, and these will likely increase estimates.
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http://dx.doi.org/10.1093/ofid/ofy061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890478PMC
April 2018

Mycoplasma pneumoniae Among Children Hospitalized With Community-acquired Pneumonia.

Clin Infect Dis 2019 01;68(1):5-12

Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: The epidemiology of Mycoplasma pneumoniae (Mp) among US children (<18 years) hospitalized with community-acquired pneumonia (CAP) is poorly understood.

Methods: In the Etiology of Pneumonia in the Community study, we prospectively enrolled 2254 children hospitalized with radiographically confirmed pneumonia from January 2010-June 2012 and tested nasopharyngeal/oropharyngeal swabs for Mp using real-time polymerase chain reaction (PCR). Clinical and epidemiological features of Mp PCR-positive and -negative children were compared using logistic regression. Macrolide susceptibility was assessed by genotyping isolates.

Results: One hundred and eighty two (8%) children were Mp PCR-positive (median age, 7 years); 12% required intensive care and 26% had pleural effusion. No in-hospital deaths occurred. Macrolide resistance was found in 4% (6/169) isolates. Of 178 (98%) Mp PCR-positive children tested for copathogens, 50 (28%) had ≥1 copathogen detected. Variables significantly associated with higher odds of Mp detection included age (10-17 years: adjusted odds ratio [aOR], 10.7 [95% confidence interval {CI}, 5.4-21.1] and 5-9 years: aOR, 6.4 [95% CI, 3.4-12.1] vs 2-4 years), outpatient antibiotics ≤5 days preadmission (aOR, 2.3 [95% CI, 1.5-3.5]), and copathogen detection (aOR, 2.1 [95% CI, 1.3-3.3]). Clinical characteristics were non-specific.

Conclusions: Usually considered as a mild respiratory infection, Mp was the most commonly detected bacteria among children aged ≥5 years hospitalized with CAP, one-quarter of whom had codetections. Although associated with clinically nonspecific symptoms, there was a need for intensive care in some cases. Mycoplasma pneumoniae should be included in the differential diagnosis for school-aged children hospitalized with CAP.
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http://dx.doi.org/10.1093/cid/ciy419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552676PMC
January 2019

Virulent PB1-F2 residues: effects on fitness of H1N1 influenza A virus in mice and changes during evolution of human influenza A viruses.

Sci Rep 2018 05 10;8(1):7474. Epub 2018 May 10.

Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, GA, USA.

Specific residues of influenza A virus (IAV) PB1-F2 proteins may enhance inflammation or cytotoxicity. In a series of studies, we evaluated the function of these virulence-associated residues in the context of different IAV subtypes in mice. Here, we demonstrate that, as with the previously assessed pandemic 1968 (H3N2) IAV, PB1-F2 inflammatory residues increase the virulence of H1N1 IAV, suggesting that this effect might be a universal feature. Combining both inflammatory and cytotoxic residues in PB1-F2 enhanced virulence further, compared to either motif alone. Residues from these virulent motifs have been present in natural isolates from human seasonal IAV of all subtypes, but there has been a trend toward a gradual reduction in the number of virulent residues over time. However, human IAV of swine and avian origin tend to have more virulent residues than do the human-adapted seasonal strains, raising the possibility that donation of PB1 segments from these zoonotic viruses may increase the severity of some seasonal human strains. Our data suggest the value of surveillance of virulent residues in both human and animal IAV to predict the severity of influenza season.
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http://dx.doi.org/10.1038/s41598-018-25707-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945659PMC
May 2018

Etiology and Impact of Coinfections in Children Hospitalized With Community-Acquired Pneumonia.

J Infect Dis 2018 06;218(2):179-188

Department of Pediatrics, University of Tennessee Health Science Center, Memphis.

Background: Recognition that coinfections are common in children with community-acquired pneumonia (CAP) is increasing, but gaps remain in our understanding of their frequency and importance.

Methods: We analyzed data from 2219 children hospitalized with CAP and compared demographic and clinical characteristics and outcomes between groups with viruses alone, bacteria alone, or coinfections. We also assessed the frequency of selected pairings of codetected pathogens and their clinical characteristics.

Results: A total of 576 children (26%) had a coinfection. Children with only virus detected were younger, more likely to be black, and more likely to have comorbidities such as asthma, compared with children infected with typical bacteria alone. Children with virus-bacterium coinfections had a higher frequency of leukocytosis, consolidation on chest radiography, parapneumonic effusions, intensive care unit admission, and need for mechanical ventilation and an increased length of stay, compared with children infected with viruses alone. Virus-virus coinfections were generally comparable to single-virus infections, with the exception of the need for oxygen supplementation, which was higher during the first 24 hours of hospitalization in some virus-virus pairings.

Conclusions: Coinfections occurred in 26% of children hospitalized for CAP. Children with typical bacterial infections, alone or complicated by a viral infection, have worse outcomes than children infected with a virus alone.
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http://dx.doi.org/10.1093/infdis/jix641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108488PMC
June 2018

Effectiveness of β-Lactam Monotherapy vs Macrolide Combination Therapy for Children Hospitalized With Pneumonia.

JAMA Pediatr 2017 12;171(12):1184-1191

Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: β-Lactam monotherapy and β-lactam plus macrolide combination therapy are both common empirical treatment strategies for children hospitalized with pneumonia, but few studies have evaluated the effectiveness of these 2 treatment approaches.

Objective: To compare the effectiveness of β-lactam monotherapy vs β-lactam plus macrolide combination therapy among a cohort of children hospitalized with pneumonia.

Design, Setting, And Participants: We analyzed data from the Etiology of Pneumonia in the Community Study, a multicenter, prospective, population-based study of community-acquired pneumonia hospitalizations conducted from January 1, 2010, to June 30, 2012, in 3 children's hospitals in Nashville, Tennessee; Memphis, Tennessee; and Salt Lake City, Utah. The study included all children (up to 18 years of age) who were hospitalized with radiographically confirmed pneumonia and who received β-lactam monotherapy or β-lactam plus macrolide combination therapy. Data analysis was completed in April 2017.

Main Outcomes And Measures: We defined the referent as β-lactam monotherapy, including exclusive use of an oral or parenteral second- or third-generation cephalosporin, penicillin, ampicillin, ampicillin-sulbactam, amoxicillin, or amoxicillin-clavulanate. Use of a β-lactam plus an oral or parenteral macrolide (azithromycin or clarithromycin) served as the comparison group. We modeled the association between these groups and patients' length of stay using multivariable Cox proportional hazards regression. Covariates included demographic, clinical, and radiographic variables. We further evaluated length of stay in a cohort matched by propensity to receive combination therapy. Logistic regression was used to evaluate secondary outcomes in the unmatched cohort, including intensive care admission, rehospitalizations, and self-reported recovery at follow-up.

Results: Our study included 1418 children (693 girls and 725 boys) with a median age of 27 months (interquartile range, 12-69 months). This cohort was 60.1% of the 2358 children enrolled in the Etiology of Pneumonia in the Community Study with radiographically confirmed pneumonia in the study period; 1019 (71.9%) received β-lactam monotherapy and 399 (28.1%) received β-lactam plus macrolide combination therapy. In the unmatched cohort, there was no statistically significant difference in length of hospital stay between children receiving β-lactam monotherapy and combination therapy (median, 55 vs 59 hours; adjusted hazard ratio, 0.87; 95% CI, 0.74-1.01). The propensity-matched cohort (n = 560, 39.5%) showed similar results. There were also no significant differences between treatment groups for the secondary outcomes.

Conclusions And Relevance: Empirical macrolide combination therapy conferred no benefit over β-lactam monotherapy for children hospitalized with community-acquired pneumonia. The results of this study elicit questions about the routine empirical use of macrolide combination therapy in this population.
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http://dx.doi.org/10.1001/jamapediatrics.2017.3225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583650PMC
December 2017

Rhinovirus Viremia in Patients Hospitalized With Community-Acquired Pneumonia.

J Infect Dis 2017 11;216(9):1104-1111

Centers for Disease Control and Prevention.

Background: Rhinoviruses (RVs) are ubiquitous respiratory pathogens that often cause mild or subclinical infections. Molecular detection of RVs from the upper respiratory tract can be prolonged, complicating etiologic association in persons with severe lower respiratory tract infections. Little is known about RV viremia and its value as a diagnostic indicator in persons hospitalized with community-acquired pneumonia (CAP).

Methods: Sera from RV-positive children and adults hospitalized with CAP were tested for RV by real-time reverse-transcription polymerase chain reaction. Rhinovirus species and type were determined by partial genome sequencing.

Results: Overall, 57 of 570 (10%) RV-positive patients were viremic, and all were children aged <10 years (n = 57/375; 15.2%). Although RV-A was the most common RV species detected from respiratory specimens (48.8%), almost all viremias were RV-C (98.2%). Viremic patients had fewer codetected pathogens and were more likely to have chest retractions, wheezing, and a history of underlying asthma/reactive airway disease than patients without viremia.

Conclusions: More than 1 out of 7 RV-infected children aged <10 years hospitalized with CAP were viremic. In contrast with other RV species, RV-C infections were highly associated with viremia and were usually the only respiratory pathogen identified, suggesting that RV-C viremia may be an important diagnostic indicator in pediatric pneumonia.
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http://dx.doi.org/10.1093/infdis/jix455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724377PMC
November 2017

Low Retinol-Binding Protein and Vitamin D Levels Are Associated with Severe Outcomes in Children Hospitalized with Lower Respiratory Tract Infection and Respiratory Syncytial Virus or Human Metapneumovirus Detection.

J Pediatr 2017 08 31;187:323-327. Epub 2017 May 31.

Department of Pediatrics, UTHSC, Memphis, TN; Le Bonheur Children's Hospital, Memphis, TN.

Retinol binding protein and vitamin D were measured in children aged <5 years hospitalized with lower respiratory tract infection and respiratory syncytial virus and/or human metapneumovirus detections. Low vitamin levels were observed in 50% of the children and were associated with significantly elevated risk of the need for intensive care unit admission and invasive mechanical ventilation.
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http://dx.doi.org/10.1016/j.jpeds.2017.04.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588918PMC
August 2017

Relationship Between Body Mass Index and Outcomes Among Hospitalized Patients With Community-Acquired Pneumonia.

J Infect Dis 2017 06;215(12):1873-1882

Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: The effect of body mass index (BMI) on community-acquired pneumonia (CAP) severity is unclear.

Methods: We investigated the relationship between BMI and CAP outcomes (hospital length of stay [LOS], intensive care unit [ICU] admission, and invasive mechanical ventilation) in hospitalized CAP patients from the Centers for Disease Control and Prevention Etiology of Pneumonia in the Community (EPIC) study, adjusting for age, demographics, underlying conditions, and smoking status (adults only).

Results: Compared with normal-weight children, odds of ICU admission were higher in children who were overweight (adjusted odds ratio [aOR], 1.7; 95% confidence interval [CI], 1.1-2.8) or obese (aOR, 2.1; 95% CI, 1.4-3.2), and odds of mechanical ventilation were higher in children with obesity (aOR, 2.7; 95% CI, 1.3-5.6). When stratified by asthma (presence/absence), these findings remained significant only in children with asthma. Compared with normal-weight adults, odds of LOS >3 days were higher in adults who were underweight (aOR, 1.6; 95% CI, 1.1-2.4), and odds of mechanical ventilation were lowest in adults who were overweight (aOR, 0.5; 95% CI, .3-.9).

Conclusions: Children who were overweight or obese, particularly those with asthma, had higher odds of ICU admission or mechanical ventilation. In contrast, adults who were underweight had longer LOS. These results underscore the complex relationship between BMI and CAP outcomes.
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http://dx.doi.org/10.1093/infdis/jix241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853774PMC
June 2017

Influence of Antibiotics on the Detection of Bacteria by Culture-Based and Culture-Independent Diagnostic Tests in Patients Hospitalized With Community-Acquired Pneumonia.

Open Forum Infect Dis 2017 10;4(1):ofx014. Epub 2017 Feb 10.

Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Specimens collected after antibiotic exposure may reduce culture-based bacterial detections. The impact on culture-independent diagnostic tests is unclear. We assessed the effect of antibiotic exposure on both of these test results among patients hospitalized with community-acquired pneumonia (CAP).

Methods: Culture-based bacterial testing included blood cultures and high-quality sputum or endotracheal tube (ET) aspirates; culture-independent testing included urinary antigen testing (adults) for and and polymerase chain reaction (PCR) on nasopharyngeal and oropharyngeal (NP/OP) swabs for and . The proportion of bacterial detections was compared between specimens collected before and after either any antibiotic exposure (prehospital and/or inpatient) or only prehospital antibiotics and increasing time after initiation of inpatient antibiotics.

Results: Of 4678 CAP patients, 4383 (94%) received antibiotics: 3712 (85%) only inpatient, 642 (15%) both inpatient and prehospital, and 29 (<1%) only prehospital. There were more bacterial detections in specimens collected before antibiotics for blood cultures (5.2% vs 2.6%; < .01) and sputum/ET cultures (50.0% vs 26.8%; < .01) but not urine antigen (7.0% vs 5.7%; = .53) or NP/OP PCR (6.7% vs 5.4%; = .31). For all diagnostic testing, bacterial detections declined with increasing time between inpatient antibiotic administration and specimen collection.

Conclusions: Bacteria were less frequently detected in culture-based tests collected after antibiotics and in culture-independent tests that had longer intervals between antibiotic exposure and specimen collection. Bacterial yield could improve if specimens were collected promptly, preferably before antibiotics, providing data for improved antibiotic selection.
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http://dx.doi.org/10.1093/ofid/ofx014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414111PMC
February 2017

Oseltamivir Use Among Children and Adults Hospitalized With Community-Acquired Pneumonia.

Open Forum Infect Dis 2017 27;4(1):ofw254. Epub 2016 Dec 27.

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Data on oseltamivir treatment among hospitalized community-acquired pneumonia (CAP) patients are limited.

Methods: Patients hospitalized with CAP at 6 hospitals during the 2010-2012 influenza seasons were included. We assessed factors associated with oseltamivir treatment using logistic regression.

Results: Oseltamivir treatment was provided to 89 of 1627 (5%) children (<18 years) and 143 of 1051 (14%) adults. Among those with positive clinician-ordered influenza tests, 39 of 61 (64%) children and 37 of 48 (77%) adults received oseltamivir. Among children, oseltamivir treatment was associated with hospital A (adjusted odds ratio [aOR], 2.76; 95% confidence interval [CI], 1.36-4.88), clinician-ordered testing performed (aOR, 2.44; 95% CI, 1.47-5.19), intensive care unit (ICU) admission (aOR, 2.09; 95% CI, 1.27-3.45), and age ≥2 years (aOR, 1.43; 95% CI, 1.16-1.76). Among adults, oseltamivir treatment was associated with clinician-ordered testing performed (aOR, 8.38; 95% CI, 4.64-15.12), hospitals D and E (aOR, 3.46-5.11; 95% CI, 1.75-11.01), Hispanic ethnicity (aOR, 2.06; 95% CI, 1.18-3.59), and ICU admission (aOR, 2.05; 95% CI, 1.34-3.13).

Conclusions: Among patients hospitalized with CAP during influenza season, oseltamivir treatment was moderate overall and associated with clinician-ordered testing, severe illness, and specific hospitals. Increased clinician education is needed to include influenza in the differential diagnosis for hospitalized CAP patients and to test and treat patients empirically if influenza is suspected.
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http://dx.doi.org/10.1093/ofid/ofw254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413989PMC
December 2016

Eosinophils Promote Antiviral Immunity in Mice Infected with Influenza A Virus.

J Immunol 2017 04 10;198(8):3214-3226. Epub 2017 Mar 10.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103.

Eosinophils are multifunctional cells of the innate immune system linked to allergic inflammation. Asthmatics were more likely to be hospitalized but less likely to suffer severe morbidity and mortality during the 2009 influenza pandemic. These epidemiologic findings were recapitulated in a mouse model of fungal asthma wherein infection during heightened allergic inflammation was protective against influenza A virus (IAV) infection and disease. Our goal was to delineate a mechanism(s) by which allergic asthma may alleviate influenza disease outcome, focused on the hypothesis that pulmonary eosinophilia linked with allergic respiratory disease is able to promote antiviral host defenses against the influenza virus. The transfer of eosinophils from the lungs of allergen-sensitized and challenged mice into influenza virus-infected mice resulted in reduced morbidity and viral burden, improved lung compliance, and increased CD8 T cell numbers in the airways. In vitro assays with primary or bone marrow-derived eosinophils were used to determine eosinophil responses to the virus using the laboratory strain (A/PR/08/1934) or the pandemic strain (A/CA/04/2009) of IAV. Eosinophils were susceptible to IAV infection and responded by activation, piecemeal degranulation, and upregulation of Ag presentation markers. Virus- or viral peptide-exposed eosinophils induced CD8 T cell proliferation, activation, and effector functions. Our data suggest that eosinophils promote host cellular immunity to reduce influenza virus replication in lungs, thereby providing a novel mechanism by which hosts with allergic asthma may be protected from influenza morbidity.
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http://dx.doi.org/10.4049/jimmunol.1600787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384374PMC
April 2017

Procalcitonin Accurately Identifies Hospitalized Children With Low Risk of Bacterial Community-Acquired Pneumonia.

J Pediatric Infect Dis Soc 2018 Feb;7(1):46-53

University of Utah School of Medicine, Salt Lake City.

Background: Lower procalcitonin (PCT) concentrations are associated with reduced risk of bacterial community-acquired pneumonia (CAP) in adults, but data in children are limited.

Methods: We analyzed serum PCT concentrations from children hospitalized with radiographically confirmed CAP enrolled in the Centers for Disease Control and Prevention's Etiology of Pneumonia in the Community (EPIC) Study. Blood and respiratory specimens were tested using multiple pathogen detection methods for typical bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus), atypical bacteria (Mycoplasma pneumoniae and Chlamydophila pneumoniae), and respiratory viruses. Multivariable regression was used to assess associations between PCT concentrations and etiology and severity.

Results: Among 532 children (median age, 2.4 years; interquartile range [IQR], 1.0-6.3), patients with typical bacteria had higher PCT concentrations (±viruses; n = 54; median, 6.10; IQR, 0.84-22.79 ng/mL) than those with atypical bacteria (±viruses; n = 82; median, 0.10; IQR, 0.06-0.39 ng/mL), viral pathogens only (n = 349; median, 0.33; IQR, 0.12-1.35 ng/mL), or no pathogen detected (n = 47; median, 0.44; IQR, 0.10-1.83 ng/mL) (P < .001 for all). No child with PCT <0.1 ng/mL had typical bacteria detected. Procalcitonin <0.25 ng/mL featured a 96% negative predictive value (95% confidence interval [CI], 93-99), 85% sensitivity (95% CI, 76-95), and 45% specificity (95% CI, 40-50) in identifying children without typical bacterial CAP.

Conclusions: Lower PCT concentrations in children hospitalized with CAP were associated with a reduced risk of typical bacterial detection and may help identify children who would not benefit from antibiotic treatment.
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http://dx.doi.org/10.1093/jpids/piw091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251689PMC
February 2018

Glycosylation changes in the globular head of H3N2 influenza hemagglutinin modulate receptor binding without affecting virus virulence.

Sci Rep 2016 10 31;6:36216. Epub 2016 Oct 31.

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

Since the emergence of human H3N2 influenza A viruses in the pandemic of 1968, these viruses have become established as strains of moderate severity. A decline in virulence has been accompanied by glycan accumulation on the hemagglutinin globular head, and hemagglutinin receptor binding has changed from recognition of a broad spectrum of glycan receptors to a narrower spectrum. The relationship between increased glycosylation, binding changes, and reduction in H3N2 virulence is not clear. We evaluated the effect of hemagglutinin glycosylation on receptor binding and virulence of engineered H3N2 viruses. We demonstrate that low-binding virus is as virulent as higher binding counterparts, suggesting that H3N2 infection does not require either recognition of a wide variety of, or high avidity binding to, receptors. Among the few glycans recognized with low-binding virus, there were two structures that were bound by the vast majority of H3N2 viruses isolated between 1968 and 2012. We suggest that these two structures support physiologically relevant binding of H3N2 hemagglutinin and that this physiologically relevant binding has not changed since the 1968 pandemic. Therefore binding changes did not contribute to reduced severity of seasonal H3N2 viruses. This work will help direct the search for factors enhancing influenza virulence.
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http://dx.doi.org/10.1038/srep36216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086918PMC
October 2016

Serology Enhances Molecular Diagnosis of Respiratory Virus Infections Other than Influenza in Children and Adults Hospitalized with Community-Acquired Pneumonia.

J Clin Microbiol 2017 01 28;55(1):79-89. Epub 2016 Dec 28.

Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Both molecular and serological assays have been used previously to determine the etiology of community-acquired pneumonia (CAP). However, the extent to which these methods are correlated and the added diagnostic value of serology for respiratory viruses other than influenza virus have not been fully evaluated. Using data from patients enrolled in the Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) study, we compared real-time reverse transcription-PCR (RT-PCR) and serology for the diagnosis of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus 1 to 3 (PIV1, PIV2, and PIV3), and adenovirus (AdV) infections. Of 5,126 patients enrolled, RT-PCR and serology test results were available for 2,023, including 1,087 children below the age of 18 years and 936 adults. For RSV, 287 (14.2%) patients were positive by RT-PCR and 234 (11.6%) were positive by serology; for HMPV, 172 (8.5%) tested positive by RT-PCR and 147 (7.3%) by serology; for the PIVs, 94 (4.6%) tested positive by RT-PCR and 92 (4.6%) by serology; and for AdV, 111 (5.5%) tested positive by RT-PCR and 62 (3.1%) by serology. RT-PCR provided the highest number of positive detections overall, but serology increased diagnostic yield for RSV (by 11.8%), HMPV (by 25.0%), AdV (by 32.4%), and PIV (by 48.9%). The method concordance estimated by Cohen's kappa coefficient (κ) ranged from good (for RSV; κ = 0.73) to fair (for AdV; κ = 0.27). Heterotypic seroresponses observed between PIVs and persistent low-level AdV shedding may account for the higher method discordance observed with each of these viruses. Serology can be a helpful adjunct to RT-PCR for research-based assessment of the etiologic contribution of respiratory viruses other than influenza virus to CAP.
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http://dx.doi.org/10.1128/JCM.01701-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228265PMC
January 2017

Predicting Severe Pneumonia Outcomes in Children.

Pediatrics 2016 10;138(4)

Departments of Pediatrics.

Background: Substantial morbidity and excessive care variation are seen with pediatric pneumonia. Accurate risk-stratification tools to guide clinical decision-making are needed.

Methods: We developed risk models to predict severe pneumonia outcomes in children (<18 years) by using data from the Etiology of Pneumonia in the Community Study, a prospective study of community-acquired pneumonia hospitalizations conducted in 3 US cities from January 2010 to June 2012. In-hospital outcomes were organized into an ordinal severity scale encompassing severe (mechanical ventilation, shock, or death), moderate (intensive care admission only), and mild (non-intensive care hospitalization) outcomes. Twenty predictors, including patient, laboratory, and radiographic characteristics at presentation, were evaluated in 3 models: a full model included all 20 predictors, a reduced model included 10 predictors based on expert consensus, and an electronic health record (EHR) model included 9 predictors typically available as structured data within comprehensive EHRs. Ordinal regression was used for model development. Predictive accuracy was estimated by using discrimination (concordance index).

Results: Among the 2319 included children, 21% had a moderate or severe outcome (14% moderate, 7% severe). Each of the models accurately identified risk for moderate or severe pneumonia (concordance index across models 0.78-0.81). Age, vital signs, chest indrawing, and radiologic infiltrate pattern were the strongest predictors of severity. The reduced and EHR models retained most of the strongest predictors and performed as well as the full model.

Conclusions: We created 3 risk models that accurately estimate risk for severe pneumonia in children. Their use holds the potential to improve care and outcomes.
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http://dx.doi.org/10.1542/peds.2016-1019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051209PMC
October 2016

Antimicrobial peptides alter early immune response to influenza A virus infection in C57BL/6 mice.

Antiviral Res 2016 09 13;133:208-17. Epub 2016 Aug 13.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Influenza is a disease of the respiratory system caused by single stranded RNA viruses with varying genotypes. Immunopathogenesis to influenza viruses differs based on virus strain, dose, and mouse strain used in laboratory models. Although effective mucosal immune defenses are important in early host defense against influenza, information on the kinetics of these immune defense mechanisms during the course of influenza infection is limited. We investigated changes to antimicrobial peptides and primary innate immune cells at early time points after infection and compared these variables between two prominent H1N1 influenza A virus (IAV) strains, A/CA/04/2009 and A/PR/08/1934 in C57BL/6 mice. Alveolar and parenchymal macrophage ratios were altered after IAV infection and pro-inflammatory cytokine production in macrophages was induced after IAV infection. Genes encoding antimicrobial peptides, β-defensin (Defb4), bactericidal-permeability increasing protein (Bpifa1), and cathelicidin antimicrobial peptide (Camp), were differentially regulated after IAV infection and the kinetics of Defb4 expression differed in response to each virus strain. Beta-defensin reduced infectivity of A/CA/04/2009 virus but not A/PR/08/1934. Beta defensins also changed the innate immune cell profile wherein mice pre-treated with β-defensin had increased alveolar macrophages and CD103(+) dendritic cells, and reduced CD11b(+) dendritic cells and neutrophils. In addition to highlighting that immune responses may vary based on influenza virus strain used, our data suggest an important role for antimicrobial peptides in host defense against influenza virus.
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http://dx.doi.org/10.1016/j.antiviral.2016.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903439PMC
September 2016

Association of sputum microbiota profiles with severity of community-acquired pneumonia in children.

BMC Infect Dis 2016 07 8;16:317. Epub 2016 Jul 8.

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

Background: Competitive interactions among bacteria in the respiratory tract microbiota influence which species can colonize and potentially contribute to pathogenesis of community-acquired pneumonia (CAP). However, understanding of the role of respiratory tract microbiota in the clinical course of pediatric CAP is limited.

Methods: We sought to compare microbiota profiles in induced sputum and nasopharyngeal/oropharyngeal (NP/OP) samples from children and to identify microbiota profiles associated with CAP severity. We used 16S ribosomal RNA sequencing and several measures of microbiota profiles, including principal component analysis (PCA), to describe the respiratory microbiota in 383 children, 6 months to <18 years, hospitalized with CAP. We examined associations between induced sputum and NP/OP microbiota profiles and CAP severity (hospital length of stay and intensive care unit admission) using logistic regression.

Results: Relative abundance of bacterial taxa differed in induced sputum and NP/OP samples. In children 6 months to < 5 years, the sputum PCA factor with high relative abundance of Actinomyces, Veillonella, Rothia, and Lactobacillales was associated with decreased odds of length of stay ≥ 4 days [adjusted odds ratio (aOR) 0.69; 95 % confidence interval (CI) 0.48-0.99]. The sputum factor with high relative abundance of Haemophilus and Pasteurellaceae was associated with increased odds of intensive care unit admission [aOR 1.52; 95 % CI 1.02-2.26]. In children 5 to < 18 years, the sputum factor with high relative abundance of Porphyromonadaceae, Bacteriodales, Lactobacillales, and Prevotella was associated with increased odds of length of stay ≥ 4 days [aOR 1.52; 95 % CI 1.02-2.26]. Taxa in NP/OP samples were not associated with CAP severity.

Conclusion: Certain taxa in the respiratory microbiota, which were detected in induced sputum samples, are associated with the clinical course of CAP.
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http://dx.doi.org/10.1186/s12879-016-1670-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939047PMC
July 2016

The Role of Punctuated Evolution in the Pathogenicity of Influenza Viruses.

Microbiol Spectr 2016 04;4(2)

Department of Pediatrics, The University of Tennessee Health Sciences Center, Memphis, TN 38103.

Influenza is an acute respiratory disease caused by influenza viruses. Evolutionarily, all influenza viruses are zoonoses, arising in the animal reservoir and spilling over into the human population. Several times a century, one of these zoonotic events results in a new influenza virus lineage becoming established in humans and circulating for years or decades as an endemic strain. The worldwide pandemic that occurs shortly after the nascent virus becomes established can have a profound impact on morbidity and mortality. Because influenza viruses continually evolve and the illness they engender can vary considerably based on characteristics of the strain, the weather, other circulating or endemic pathogens, as well as the number of susceptible hosts, the impact of each season on human health is unpredictable. Over time, the general pattern is for pandemic strains to adapt and gradually take on characteristics of seasonal strains with lower virulence and a diminished synergism with bacterial pathogens. Study of this punctuated evolution yields a number of insights into the overall pathogenicity of influenza viruses.
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http://dx.doi.org/10.1128/microbiolspec.EI10-0001-2015DOI Listing
April 2016

Identification of Bacterial and Viral Codetections With Mycoplasma pneumoniae Using the TaqMan Array Card in Patients Hospitalized With Community-Acquired Pneumonia.

Open Forum Infect Dis 2016 Mar 30;3(2):ofw071. Epub 2016 Mar 30.

Division of Bacterial Diseases.

Mycoplasma pneumoniae was detected in a number of patients with community-acquired pneumonia in a recent prospective study. To assess whether other pathogens were also detected in these patients, TaqMan Array Cards were used to test 216 M pneumoniae-positive respiratory specimens for 25 additional viral and bacterial respiratory pathogens. It is interesting to note that 1 or more codetections, predominantly bacterial, were identified in approximately 60% of specimens, with codetections being more common in children.
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http://dx.doi.org/10.1093/ofid/ofw071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867659PMC
March 2016

Immunogenicity and safety of high-dose trivalent inactivated influenza vaccine compared to standard-dose vaccine in children and young adults with cancer or HIV infection.

Vaccine 2016 06 26;34(27):3141-3148. Epub 2016 Apr 26.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address:

Background: Approaches to improve the immune response of immunocompromised patients to influenza vaccination are needed.

Methods: Children and young adults (3-21 years) with cancer or HIV infection were randomized to receive 2 doses of high-dose (HD) trivalent influenza vaccine (TIV) or of standard-dose (SD) TIV. Hemagglutination inhibition (HAI) antibody titers were measured against H1, H3, and B antigens after each dose and 9 months later. Seroconversion was defined as ≥4-fold rise in HAI titer comparing pre- and post-vaccine sera. Seroprotection was defined as a post-vaccine HAI titer ≥1:40. Reactogenicity events (RE) were solicited using a structured questionnaire 7 and 14 days after each dose of vaccine, and adverse events by medical record review for 21 days after each dose of vaccine.

Results: Eighty-five participants were enrolled in the study; 27 with leukemia, 17 with solid tumor (ST), and 41 with HIV. Recipients of HD TIV had significantly greater fold increase in HAI titers to B antigen in leukemia group and to H1 antigen in ST group compared to SD TIV recipients. This increase was not documented in HIV group. There were no differences in seroconversion or seroprotection between HD TIV and SD TIV in all groups. There was no difference in the percentage of solicited RE in recipients of HD TIV (54% after dose 1 and 38% after dose 2) compared to SD TIV (40% after dose 1 and 20% after dose 2, p=0.27 and 0.09 after dose 1 and 2, respectively).

Conclusion: HD TIV was more immunogenic than SD TIV in children and young adults with leukemia or ST, but not with HIV. HD TIV was safe and well-tolerated in children and young adults with leukemia, ST, or HIV.
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http://dx.doi.org/10.1016/j.vaccine.2016.04.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899146PMC
June 2016

Community-Acquired Pneumonia Hospitalization among Children with Neurologic Disorders.

J Pediatr 2016 Jun 23;173:188-195.e4. Epub 2016 Mar 23.

Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA.

Objective: To describe and compare the clinical characteristics, outcomes, and etiology of pneumonia among children hospitalized with community-acquired pneumonia (CAP) with neurologic disorders, non-neurologic underlying conditions, and no underlying conditions.

Study Design: Children <18 years old hospitalized with clinical and radiographic CAP were enrolled at 3 US children's hospitals. Neurologic disorders included cerebral palsy, developmental delay, Down syndrome, epilepsy, non-Down syndrome chromosomal abnormalities, and spinal cord abnormalities. We compared the epidemiology, etiology, and clinical outcomes of CAP in children with neurologic disorders with those with non-neurologic underlying conditions, and those with no underlying conditions using bivariate, age-stratified, and multivariate logistic regression analyses.

Results: From January 2010-June 2012, 2358 children with radiographically confirmed CAP were enrolled; 280 (11.9%) had a neurologic disorder (52.1% of these individuals also had non-neurologic underlying conditions), 934 (39.6%) had non-neurologic underlying conditions only, and 1144 (48.5%) had no underlying conditions. Children with neurologic disorders were older and more likely to require intensive care unit (ICU) admission than children with non-neurologic underlying conditions and children with no underlying conditions; similar proportions were mechanically ventilated. In age-stratified analysis, children with neurologic disorders were less likely to have a pathogen detected than children with non-neurologic underlying conditions. In multivariate analysis, having a neurologic disorder was associated with ICU admission for children ≥2 years of age.

Conclusions: Children with neurologic disorders hospitalized with CAP were less likely to have a pathogen detected and more likely to be admitted to the ICU than children without neurologic disorders.
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http://dx.doi.org/10.1016/j.jpeds.2016.02.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897771PMC
June 2016
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