OBJECTIVE: To evaluate the association between consolidation on chest radiograph and typical bacterial etiology of childhood community acquired pneumonia (CAP) in the Etiology of Pneumonia in the Community study. STUDY DESIGN: Hospitalized children <18 years of age with CAP enrolled in the Etiology of Pneumonia in the Community study at 3 children's hospitals between January 2010 and June 2012 were included. Testing of blood and respiratory specimens used multiple modalities to identify typical and atypical bacterial, or viral infection. Study radiologists classified chest radiographs (consolidation, other infiltrates [interstitial and/or alveolar], pleural effusion) using modified World Health Organization pneumonia criteria. Infiltrate patterns were compared according to etiology of CAP. RESULTS: Among 2212 children, there were 1302 (59%) with consolidation with or without other infiltrates, 910 (41%) with other infiltrates, and 296 (13%) with pleural effusion. In 1795 children, at least 1 pathogen was detected. Among these patients, consolidation (74%) was the most frequently observed pattern (74% in typical bacterial CAP, 58% in atypical bacterial CAP, and 54% in viral CAP). Positive and negative predictive values of consolidation for typical bacterial CAP were 12% (95% CI 10%-15%) and 96% (95% CI 95%-97%) respectively. In a multivariable model, typical bacterial CAP was associated with pleural effusion (OR 7.3, 95% CI 4.7-11.2) and white blood cell ≥15 000/mL (OR 3.2, 95% CI 2.2-4.9), and absence of wheeze (OR 0.5, 95% CI 0.3-0.8) or viral detection (OR 0.2, 95% CI 0.1-0.4). CONCLUSIONS: Consolidation predicted typical bacterial CAP poorly, but its absence made typical bacterial CAP unlikely. Pleural effusion was the best predictor of typical bacterial infection, but too uncommon to aid etiology prediction.

Ninety-five adults enrolled in the Etiology of Pneumonia in the Community study with negative admission influenza polymerase chain reaction (PCR) tests received influenza vaccination during hospitalization. Acute and convalescent influenza serology was performed. After vaccination, seropositive (>/=1:40) hemagglutination antibody titers (HAI) were achieved in 55% to influenza A(H1N1)pdm09, 58% to influenza A(H3N2), 77% to influenza B (Victoria), and 74% to influenza B (Yamagata) viruses. Sixty-six (69%) patients seroconverted (>/=4-fold HAI rise) to >/=1 strain. Failure to seroconvert was associated with diabetes, bacterial detection, baseline seropositive titers for influenza B (Yamagata), and influenza vaccination in the previous season.

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 Streptococcus pneumoniae (n = 23, 50%), Staphylococcus aureus (n = 6, 13%), and Streptococcus pyogenes (n = 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. S pneumoniae 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.

Background: Plasma gelsolin (pGSN) is an abundant circulating protein that neutralizes actin exposed by damaged cells, modulates inflammatory responses, and enhances alveolar macrophage antimicrobial activity. We investigated whether adults with low pGSN at hospital admission for community-acquired pneumonia (CAP) were at high risk for severe outcomes. Methods: Admission pGSN concentrations were measured by enzyme-linked immunosorbent assay in 455 adults hospitalized with CAP. Patients were grouped into four hierarchical, mutually-exclusive categories based on maximum clinical severity experienced during their hospitalization: (1) general floor care without intensive care (ICU) unit admission, invasive respiratory or vasopressor support (IRVS), or death; (2) ICU care without IRVS or death; (3) IRVS without death; or (4) death. Admission pGSN concentrations were compared across these discrete outcome categories. Additionally, outcomes among patients in the lowest quartile of pGSN concentration were compared with those in the upper three quartiles. Results: Overall, median (interquartile range) pGSN concentration was 38.1 (32.1, 45.7) mug/mL. Patients with more severe outcomes had lower pGSN concentrations (p=0.0001); median values were: 40.3 mug/ml for floor patients; 36.7 mug/ml for ICU patients; 36.5 mug/ml for patients receiving IRVS; and 25.7 mug/ml for patients who died. Compared with patients with higher pGSN concentrations, patients in the lowest quartile (pGSN </=32.1 mug/ml) more often required IRVS (21.2% vs 11.7%, p=0.0114) and died (8.8% vs 0.9%, p<0.0001). Conclusions: Among adults hospitalized with CAP, lower pGSN concentrations were associated with more severe clinical outcomes. Future studies are planned to investigate possible therapeutic benefits of recombinant human pGSN in this population.

Background: Adult community-acquired pneumonia (CAP) guidelines from the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) include indications for urinary antigen tests (UATs) for Streptococcus pneumoniae (SP) and Legionella pneumophila (LP). These recommendations were based on expert opinion and have not been rigorously evaluated. Methods: We used data from a multicenter prospective surveillance study of adults hospitalized with CAP to evaluate the sensitivity and specificity of the IDSA/ATS UAT indications for identifying patients who test positive. SP and LP UATs were completed on all included patients. Separate analyses were completed for SP and LP using two-by-two contingency tables comparing the IDSA/ATS indications (UAT recommended vs not recommended) and UAT results (positive vs negative). Additionally, logistic regression was used to evaluate the association of each individual criterion in the IDSA/ATS indications with positive UAT results. Results: Among 1,941 patients, UATs were positive for SP in 81 (4.2%) and LP in 32 (1.6%). IDSA/ATS indications had 61% (95% CI: 49%-71%) sensitivity and 39% (95% CI: 37%-41%) specificity for SP, and 63% (95% CI: 44%-79%) sensitivity and 35% (95% CI: 33%-37%) specificity for LP. No clinical characteristics were strongly associated with positive SP UATs, while features associated with positive LP UATs were hyponatremia, fever, diarrhea, and recent travel. Conclusions: Recommended indications for SP and LP urinary antigen testing in the IDSA/ATS CAP guidelines have poor sensitivity and specificity for identifying patients with positive tests; future CAP guidelines should consider other strategies for determining which patients should undergo urinary antigen testing.

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.

INTRODUCTION: Adults hospitalized with community-acquired pneumonia are at high risk for short-term mortality. However, it is unclear whether improvements in in-hospital pneumonia care could substantially lower this risk. We extensively reviewed all in-hospital deaths in a large prospective CAP study to assess the cause of each death and assess the extent of potentially preventable mortality. METHODS: We enrolled adults hospitalized with CAP at five tertiary-care hospitals in the United States. Five physician investigators reviewed the medical record and study database for each patient who died to identify the cause of death, the contribution of CAP to death, and any preventable factors potentially contributing to death. RESULTS: Among 2,320 enrolled patients, 52 (2.2%) died during initial hospitalization. Among these 52 patients, 33 (63.4%) were >/=65 years old, and 32 (61.5%) had >/=2 chronic comorbidities. CAP was judged to be the direct cause of death in 27 (51.9%) patients. Ten (19.2%) patients had do-not-resuscitate orders prior to admission. Four patients were identified in whom a lapse in quality of care potentially contributed to death; pre-existing end-of-life limitations were present in two of these patients. Two patients seeking full medical care experienced a lapse in in-hospital quality of pneumonia care that potentially contributed to death. CONCLUSION: In this study of adults with CAP at tertiary-care hospitals with a low mortality rate, most in-hospital deaths did not appear to be preventable with improvements in in-hospital pneumonia care. Pre-existing end-of-life limitations in care, advanced age, and high comorbidity burden were common among those who died.

Background: The burden and epidemiology of Mycoplasma pneumoniae (Mp) among U.S. children (<18 years) hospitalized with community-acquired pneumonia (CAP) are poorly understood. Methods: In the Etiology of Pneumonia in the Community (EPIC) 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: In the EPIC study, 182(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 6/169(4%) isolates. Of 178(98%) Mp-PCR-positive children tested for co-pathogens, 50(28%) had >/=1 co-pathogen detected. Variables significantly associated with higher odds of Mp detection included age {10-17 years [adjusted odds ratio (aOR): 7.9 (95% confidence interval (CI): 4.5-13.6)] and 5-9 years [aOR: 4.8 (CI: 2.9-7.8)] vs. 2-4 years}, outpatient antibiotics </=5 days pre-admission [aOR: 2.3 (CI: 1.5-3.4)], and co-pathogen detection [aOR: 2.1 (CI: 1.3-3.1)]. Clinical characteristics often seen included hilar lymphadenopathy, rales, headache, sore throat, and decreased breath sounds. Conclusions: Usually considered as a mild respiratory infection, M. pneumoniae was the most commonly detected bacteria among children >/=5 years hospitalized with CAP; one-quarter of whom had co-detections. Although associated with clinically non-specific symptoms, there was a need for intensive care support in some cases. M. pneumoniae should be included in the differential diagnosis for school-aged children hospitalized with CAP.

Background: Streptococcus pneumoniae is considered the leading bacterial cause of pneumonia in adults. Yet, it was not commonly detected by traditional culture-based and conventional urinary testing in a recent multicenter etiology study of adults hospitalized with community-acquired pneumonia (CAP). We used novel serotype-specific urinary antigen detection (SSUAD) assays to determine whether pneumococcal cases were missed by traditional testing. Methods: We studied adult patients hospitalized with CAP at 5 hospitals in Chicago and Nashville (2010-2012) and enrolled in the Etiology of Pneumonia in the Community (EPIC) study. Traditional diagnostic testing included blood and sputum cultures and conventional urine antigen detection (ie, BinaxNOW). We applied SSUAD assays that target serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) to stored residual urine specimens. Results: Among 1736 patients with SSUAD and >/=1 traditional pneumococcal test performed, we identified 169 (9.7%) cases of pneumococcal CAP. Traditional tests identified 93 (5.4%) and SSUAD identified 76 (4.4%) additional cases. Among 14 PCV13-serotype cases identified by culture, SSUAD correctly identified the same serotype in all of them. Cases identified by SSUAD vs traditional tests were similar in most demographic and clinical characteristics, although disease severity and procalcitonin concentration were highest among those with positive blood cultures. The proportion of PCV13 serotype cases identified was not significantly different between the first and second July-June study periods (6.4% vs 4.0%). Conclusions: Although restricted to the detection of only 13 serotypes, SSUAD testing substantially increased the detection of pneumococcal pneumonia among adults hospitalized with CAP.

Background: Recognition that co-infections 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 demographics, clinical characteristics, and outcomes between groups with viruses alone, bacteria alone, or co-infections. We also assessed the frequency of selected pairings of co-detected pathogens and their clinical characteristics. Results: 576 (26%) of the children studied had a co-infection. Children with only virus detection were younger and more likely to be black and have co-morbidities such as asthma compared to those with bacteria alone. Children with virus-bacteria co-infections had a higher frequency of leukocytosis, consolidation on chest X-ray, increased length of stay, and more frequent parapneumonic effusions, intensive care unit admission, and need for mechanical ventilation when compared to viruses alone. Virus-virus co-infections 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: Co-infections occurred in 26% of children hospitalized for CAP. Children with bacterial infections, alone or complicated by a virus, have worse outcomes than children infected with a virus alone.

Importance: beta-Lactam monotherapy and beta-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 beta-lactam monotherapy vs beta-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 beta-lactam monotherapy or beta-lactam plus macrolide combination therapy. Data analysis was completed in April 2017. Main Outcomes and Measures: We defined the referent as beta-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 beta-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 beta-lactam monotherapy and 399 (28.1%) received beta-lactam plus macrolide combination therapy. In the unmatched cohort, there was no statistically significant difference in length of hospital stay between children receiving beta-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 beta-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.

Background: Rhinoviruses (RVs) are ubiquitous respiratory pathogens that often cause mild or subclinical infections. Molecular detection of RV 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 RT-PCR. RV species and type were determined by partial genome sequencing. Results: Overall, 57/570 (10%) RV-positive patients were viremic and all were children <10 years old [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 co-detected 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 one out of seven RV-infected children <10 years old hospitalized with CAP were viremic. In contrast with other RV species, RV-C infections were highly associated with viremia and more often the only respiratory pathogen identified, suggesting that RV-C viremia may be an important diagnostic indicator in pediatric pneumonia.

Background: The role of human bocavirus (HBoV) in respiratory illness is uncertain. HBoV genomic DNA is frequently detected in both ill and healthy children. We hypothesized that spliced viral capsid messenger RNA (mRNA) produced during active replication might be a better marker for acute infection. Methods: As part of the Etiology of Pneumonia in the Community (EPIC) study, children aged <18 years who were hospitalized with community-acquired pneumonia (CAP) and children asymptomatic at the time of elective outpatient surgery (controls) were enrolled. Nasopharyngeal/oropharyngeal specimens were tested for HBoV mRNA and genomic DNA by quantitative polymerase chain reaction. Results: HBoV DNA was detected in 10.4% of 1295 patients with CAP and 7.5% of 721 controls (odds ratio [OR], 1.4 [95% confidence interval {CI}, 1.0-2.0]); HBoV mRNA was detected in 2.1% and 0.4%, respectively (OR, 5.1 [95% CI, 1.6-26]). When adjusted for age, enrollment month, and detection of other respiratory viruses, HBoV mRNA detection (adjusted OR, 7.6 [95% CI, 1.5-38.4]) but not DNA (adjusted OR, 1.2 [95% CI, .6-2.4]) was associated with CAP. Among children with no other pathogens detected, HBoV mRNA (OR, 9.6 [95% CI, 1.9-82]) was strongly associated with CAP. Conclusions: Detection of HBoV mRNA but not DNA was associated with CAP, supporting a pathogenic role for HBoV in CAP. HBoV mRNA could be a useful target for diagnostic testing.

BACKGROUND: The clinical significance of pneumonia visualized on computed tomography (CT) in the setting of a normal chest x-ray (CXR) is uncertain. METHODS: In a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia (CAP), we compared the presenting clinical features, pathogens, and outcomes of patients with pneumonia visualized on CT but not on concurrent CXR (CT-only pneumonia) and those with pneumonia visualized on CXR. All patients underwent CXR; the decision to obtain CT imaging was determined by the treating clinicians. CXR and CT images were interpreted by study-dedicated thoracic radiologists blinded to clinical data. RESULTS: The study population included 2,251 adults with CAP; 2,185 (97%) patients had pneumonia visualized on CXR while 66 (3%) had pneumonia visualized on CT but not concurrent CXR. Overall, these patients with CT-only pneumonia had a similar clinical profile to those with pneumonia visualized on CXR, including comorbidities, vital signs, hospital length of stay, prevalence of viral (30% vs 26%) and bacterial pathogens (12% vs 14%), intensive care unit admission (23% vs 21%), mechanical ventilation (6% vs 5%), septic shock (5% vs 4%), and in-hospital mortality (0 vs 2%). CONCLUSIONS: Adults hospitalized with CAP who had radiologic evidence of pneumonia on CT but not concurrent CXR had similar pathogens, disease severity, and outcomes compared with patients who had signs of pneumonia on CXR. These findings support using of the same management principles for patients with CT-only pneumonia as those with pneumonia on CXR.

BACKGROUND: Community-acquired pneumonia (CAP) 2007 guidelines from the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) recommend a respiratory fluoroquinolone or beta-lactam plus macrolide as first-line antibiotics for adults hospitalized with CAP. Few studies have assessed guideline-concordant antibiotic use for patients hospitalized with CAP after the 2007 IDSA/ATS guidelines. We examine antibiotics prescribed and associated factors in adults hospitalized with CAP. METHODS: From January 2010 to June 2012, adults hospitalized with clinical and radiographic CAP were enrolled in a prospective Etiology of Pneumonia in the Community study across 5 US hospitals. Patients were interviewed using a standardized questionnaire, and medical charts were reviewed. Antibiotics prescribed were classified according to defined nonrecommended CAP antibiotics. We assessed factors associated with nonrecommended CAP antibiotics using logistic regression. RESULTS: Among enrollees, 1843 of 1874 (98%) ward and 440 of 446 (99%) ICU patients received ≥1 antibiotic ≤24 hours after admission. Ward patients were prescribed a respiratory fluoroquinolone alone (n = 613; 33%), or beta-lactam plus macrolide (n = 365; 19%), beta-lactam alone (n = 240; 13%), among other antibiotics, including vancomycin (n = 235; 13%) or piperacillin/tazobactam (n = 157; 8%) ≤24 hours after admission. Ward patients with known risk for healthcare-associated pneumonia (HCAP), recent outpatient antibiotic use, and in-hospital antibiotic use <6 hours after admission were significantly more likely to receive nonrecommended CAP antibiotics. CONCLUSIONS: Although more than half of ward patients received antibiotics concordant with IDSA/ATS guidelines, a number received nonrecommended CAP antibiotics, including vancomycin and piperacillin/tazobactam; risk factors for HCAP, recent outpatient antibiotic, and rapid inpatient antibiotic use contributed to this. This hypothesis-generating descriptive epidemiology analysis could help inform antibiotic stewardship efforts, reinforces the need to harmonize guidelines for CAP and HCAP, and highlights the need for improved diagnostics to better equip clinicians.

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.

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 CDC 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, 1.4-3.2) and odds of mechanical ventilation were higher in children with obesity (aOR 2.7, 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, 1.1-2.4), and odds of mechanical ventilation were lowest in adults who were overweight (aOR, 0.5, 0.3-0.9). 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.

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 Streptococcus pneumoniae and Legionella pneumophila and polymerase chain reaction (PCR) on nasopharyngeal and oropharyngeal (NP/OP) swabs for Mycoplasma pneumoniae and Chlamydia pneumoniae. 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%; P < .01) and sputum/ET cultures (50.0% vs 26.8%; P < .01) but not urine antigen (7.0% vs 5.7%; P = .53) or NP/OP PCR (6.7% vs 5.4%; P = .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.

Background: Recent trials suggest procalcitonin-based guidelines can reduce antibiotic use for respiratory infections. However, the accuracy of procalcitonin to discriminate between viral and bacterial pneumonia requires further dissection. Methods: We evaluated the association between serum procalcitonin concentration at hospital admission with pathogens detected in a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia. Systematic pathogen testing included cultures, serology, urine antigen tests, and molecular detection. Accuracy of procalcitonin to discriminate between viral and bacterial pathogens was calculated. Results: Among 1,735 patients, pathogens were identified in 645 (37%), including 169 (10%) with typical bacteria, 67 (4%) with atypical bacteria, and 409 (24%) with viruses only. Median procalcitonin concentration was lower with viral pathogens (0.09 ng/ml; interquartile range [IQR]: <0.05-0.54 ng/ml) than atypical bacteria (0.20 ng/ml; IQR: <0.05-0.87 ng/ml) [p=0.05], and typical bacteria (2.5 ng/ml; IQR: 0.29-12.2 ng/ml) [p<0.01]. Procalcitonin discriminated bacterial pathogens, including typical and atypical bacteria, from viral pathogens with an area under the receiver operating characteristic curve of 0.73 (95% CI: 0.69-0.77). A procalcitonin threshold of 0.1 ng/ml resulted in 80.9% (95% CI: 75.3%-85.7%) sensitivity and 51.6% (95% CI: 46.6%-56.5%) specificity for identification of any bacterial pathogen. Procalcitonin discriminated between typical bacteria and the combined group of viruses and atypical bacteria with an area under the receiver operating characteristic curve of 0.79 (95% CI: 0.75, 0.82). Conclusion: No procalcitonin threshold perfectly discriminated between viral and bacterial pathogens, but higher procalcitonin strongly correlated with increased probability of bacterial pathogens, particularly typical bacteria.

Background: Community-acquired pneumonia (CAP) is a leading cause of pediatric hospitalization. Pathogen identification fails in ~20% of children but is critical for optimal treatment and prevention of hospital-acquired infections. We used two broad-spectrum detection strategies to identify pathogens in test-negative children with CAP and asymptomatic controls. Methods: Nasopharyngeal/oropharyngeal (NP/OP) swabs from 70 children <5 years with CAP of unknown etiology and 90 asymptomatic controls were tested by next-generation sequencing (RNA-seq) and pan viral group (PVG) PCR for 19 viral families. Association of viruses with CAP was assessed by adjusted odds ratios (aOR) and 95% confidence intervals controlling for season and age group. Results: RNA-seq/PVG PCR detected previously missed, putative pathogens in 34% of patients. Putative viral pathogens included human parainfluenza virus 4 (aOR 9.3, p=0.12), human bocavirus (aOR 9.1, p<0.01), Coxsackieviruses (aOR 5.1, p=0.09), rhinovirus A (aOR 3.5, p=0.34), and rhinovirus C (aOR 2.9, p=0.57). RNA-seq was more sensitive for RNA viruses whereas PVG PCR detected more DNA viruses. Conclusion: RNA-seq and PVG PCR identified additional viruses, some known to be pathogenic, in NP/OP specimens from one-third of children hospitalized with CAP without a previously identified etiology. Both broad-range methods could be useful tools in future epidemiologic and diagnostic studies.

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.

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.

New diagnostic platforms often use naso- or oropharyngeal (NP/OP) swabs for pathogen detection for patients hospitalized with community-acquired pneumonia (CAP). We applied multi-pathogen testing to high-quality sputum specimens to determine if more pathogens could be identified relative to NP/OP swabs. Children (<18 years old) and adults hospitalized with CAP were enrolled over 2.5 years through the Etiology of Pneumonia in the Community (EPIC) study. NP/OP specimens with matching high-quality sputum (defined as ≤10 epithelial cells/low power field [lpf] and ≥25 white blood cells/lpf or a q-score definition of 2+) were tested by TaqMan Array Card (TAC), a multi-pathogen real-time polymerase chain reaction (PCR) detection platform. Among 236 patients with matched specimens, a higher proportion of sputum specimens had ≥1 pathogen detected compared with NP/OP specimens in children (93% v. 68%, P<0.0001) and adults (88% v. 61%; P<0.0001); for each pathogen targeted, crossing threshold (Ct) values were earlier in sputum. Both bacterial (361 vs. 294) and viral detections (245 vs. 140) were more common in sputum versus NP/OP specimens, respectively, in both children and adults. When available, high-quality sputum may be useful for testing in hospitalized CAP patients.

Both molecular and serological assays have been used previously to determine the etiology of community-acquired pneumonia (CAP). However, the correlation of these methods and added diagnostic value of serology has not been fully evaluated. Using data from patients enrolled in the Centers for Disease Control and Prevention Etiology of Pneumonia in the Community (EPIC) study, we compared real-time RT-PCR and serology for diagnosis of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza viruses 1-3 (PIV) and adenovirus (AdV) infections. Of 5126 patients enrolled, RT-PCR and serology test results were available for 2023, including 1087 children <18 years of age and 936 adults. For RSV, 287 (14.2%) patients were positive by RT-PCR and 234 (11.6%) were positive by serology; HMPV, 172 (8.5%) tested positive by RT-PCR and 147 (7.3%) by serology; PIVs, 94 (4.6%) tested positive by RT-PCR and 92 (4.6%) by serology; and AdV, 111 (5.5%) positive by RT-PCR and 62 (3.1%) by serology. RT-PCR provided the most 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%). Method concordance estimated by Cohen's kappa (kappa) coefficient ranged from good (RSV, 0.73 kappa) to fair (AdV, 0.27 kappa). Heterotypic seroresponses observed between PIV and persistent low-level AdV shedding may account for 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 non-influenza respiratory viruses to CAP.

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.

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.

BACKGROUND: Prior retrospective studies suggest that statins may benefit patients with community-acquired pneumonia (CAP) due to antiinflammatory and immunomodulatory effects. However, prospective studies of the impact of statins on CAP outcomes are needed. We determined whether statin use was associated with improved outcomes in adults hospitalized with CAP. METHODS: Adults aged ≥18 years hospitalized with CAP were prospectively enrolled at 3 hospitals in Chicago, Illinois, and 2 hospitals in Nashville, Tennessee, from January 2010-June 2012. Adults receiving statins before and throughout hospitalization (statin users) were compared with those who did not receive statins (nonusers). Proportional subdistribution hazards models were used to examine the association between statin use and hospital length of stay (LOS). In-hospital mortality was a secondary outcome. We also compared groups matched on propensity score. RESULTS: Of 2016 adults enrolled, 483 (24%) were statin users; 1533 (76%) were nonusers. Statin users were significantly older, had more comorbidities, had more years of education, and were more likely to have health insurance than nonusers. Multivariable regression demonstrated that statin users and nonusers had similar LOS (adjusted hazard ratio [HR], 0.99; 95% confidence interval [CI], .88-1.12), as did those in the propensity-matched groups (HR, 1.03; 95% CI, .88-1.21). No significant associations were found between statin use and LOS or in-hospital mortality, even when stratified by pneumonia severity. CONCLUSIONS: In a large prospective study of adults hospitalized with CAP, we found no evidence to suggest that statin use before and during hospitalization improved LOS or in-hospital mortality.

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.

Objective. Transcripts from admission chest radiographs could aid in identification of pneumonia cases for public health surveillance. We assessed the reliability of radiographic data abstraction and performance of radiographic key terms to identify pneumonia in patients hospitalized with laboratory-confirmed influenza virus infection. Methods. We used data on patients hospitalized with laboratory-confirmed influenza virus infection from October 2008 through December 2009 from 10 geographically diverse U.S. study sites participating in the Influenza Hospitalization Surveillance Network (FluSurv-NET). Radiographic key terms (i.e., bronchopneumonia, consolidation, infiltrate, airspace density, and pleural effusion) were abstracted from final impressions of chest radiograph reports. We assessed the reliability of radiographic data abstraction by examining the percent agreement and Cohen’s κ statistic between clinicians and surveillance staff members. Using a composite reference standard for presence or absence of pneumonia based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and discharge summary data, we calculated sensitivity, specificity, positive predictive value (PPV), and percent agreement for individual and combined radiographic key terms. Results. For each radiographic key term, the percent agreement between clinicians and surveillance staff members ranged from 89.4% to 98.6% and Cohen’s κ ranged from 0.46 (moderate) to 0.84 (almost perfect). The combination of bronchopneumonia or consolidation or infiltrate or airspace density terms had sensitivity of 66.5%, specificity of 89.2%, PPV of 80.4%, and percent agreement of 80.1%. Adding pleural effusion did not result in significant changes in sensitivity, specificity, PPV, or percent agreement. Conclusion. Radiographic key terms abstracted by surveillance staff members from final impressions of chest radiograph reports had moderate to almost perfect reliability and could be used to identify pneumonia among patients hospitalized with laboratory-confirmed influenza virus infection. This method can inform pneumonia surveillance and aid in public health response.

BACKGROUND: Prevalence of Staphylococcus aureus community-acquired pneumonia (CAP) and its clinical features remain incompletely understood, complicating empirical selection of antibiotics. METHODS: Using a multicenter prospective surveillance study of adults hospitalized with CAP, we calculated the prevalence of methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) among all CAP episodes. We compared the epidemiologic, radiographic and clinical characteristics of S. aureus CAP (per respiratory or blood culture) with those of pneumococcal (per respiratory or blood culture, or urine antigen) and all-cause non-S. aureus CAP using descriptive statistics. RESULTS: Among 2,259 adults hospitalized for CAP, 37 (1.6%) had S. aureus identified, including 15 (0.7%) with MRSA and 22 (1.0%) with MSSA, and 115 (5.1%) had S. pneumoniae Vancomycin or linezolid was administered to 674 (29.8%) patients within the first three days of hospitalization. Chronic hemodialysis use was more common among patients with MRSA (20.0%) than pneumococcal (2.6%) and all-cause non-S. aureus (3.7%) CAP. Otherwise, clinical features at admission were similar, including concurrent influenza infection, hemoptysis, multilobar infiltrates, and pre-hospital antibiotics. Patients with MRSA CAP had more severe clinical outcomes than pneumococcal CAP, including ICU admission (86.7% vs 34.8%) and in-patient mortality (13.3% vs 4.4%). CONCLUSIONS: Despite very low prevalence of S. aureus, and specifically MRSA, nearly one-third of adults hospitalized with CAP received anti-MRSA antibiotics. The clinical presentation of MRSA CAP overlapped substantially with pneumococcal CAP, highlighting the challenge of accurately targeting empirical anti-MRSA antibiotics with currently-available clinical tools and the need for new diagnostic strategies.