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2.  Answer to April 2012 Photo Quiz 
doi:10.1128/JCM.06387-11
PMCID: PMC3318553
3.  Photo Quiz: An 11-Year-Old with Abdominal Pain 
doi:10.1128/JCM.06364-11
PMCID: PMC3318565  PMID: 22427604
4.  Nasopharyngeal Lactate Dehydrogenase Concentrations Predict Bronchiolitis Severity in a Prospective Multicenter Emergency Department Study 
We re-examined the finding of an inverse relationship between values of nasopharyngeal lactate dehydrogenase (LDH), a marker of the innate immune response, and bronchiolitis severity. In a prospective, multicenter study of 258 children we found in a mutlivariable model that higher nasopharyngeal LDH values in young children with bronchiolitis were independently associated with a decreased risk of hospitalization.
doi:10.1097/INF.0b013e3182565eae
PMCID: PMC3375381  PMID: 22517336
Severity of illness; biomarker; respiratory syncytial virus; human rhinovirus
5.  John C. Sherris, M.D. 
Journal of Clinical Microbiology  2012;50(11):3416-3417.
doi:10.1128/JCM.02233-12
PMCID: PMC3486217  PMID: 22972815
6.  Relative Impact of Influenza and Respiratory Syncytial Virus in Young Children 
Pediatrics  2009;124(6):e1072-e1080.
OBJECTIVE
We measured the relative impact of influenza and respiratory syncytial virus (RSV) infections in young children in terms of emergency department (ED) visits, clinical care requirements, and overall resource use.
METHODS
Patients who were aged ≤7 years and treated in the ED of a tertiary care pediatric hospital for an acute respiratory infection were enrolled during 2 winter seasons between 2003 and 2005. We quantified health care resource use for children with influenza or RSV infections, and extrapolated results to estimate the national resource use associated with influenza and RSV infections.
RESULTS
Nationally, an estimated 10.2 ED visits per 1000 children were attributable to influenza and 21.5 visits per 1000 to RSV. Children who were aged 0 to 23 months and infected with RSV had the highest rate of ED visits with 64.4 visits per 1000 children. Significantly more children required hospitalization as a result of an RSV infection compared with influenza, with national hospitalization rates of 8.5 and 1.4 per 1000 children, respectively. The total number of workdays missed yearly by caregivers of children who required ED care was 246 965 days for influenza infections and 716 404 days for RSV infections.
CONCLUSION
For young children, RSV is associated with higher rates of ED visits, hospitalization, and caregiver resource use than is influenza. Our results provide data on the large number of children who receive outpatient care for influenza and RSV illnesses and serve to inform analyses of prevention programs and treatments for both influenza and RSV disease.
doi:10.1542/peds.2008-3074
PMCID: PMC3374864  PMID: 19933730
burden of illness; influenza; respiratory syncytial virus; emergency health services
7.  Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes 
Nature Genetics  2011;43(12):1275-1280.
Bacterial pathogens evolve during the infection of their human hosts1-8, but separating adaptive and neutral mutations remains challenging9-11. Here, we identify bacterial genes under adaptive evolution by tracking recurrent patterns of mutations in the same pathogenic strain during the infection of multiple patients. We conducted a retrospective study of a Burkholderia dolosa outbreak among people with cystic fibrosis, sequencing the genomes of 112 isolates collected from 14 individuals over 16 years. We find that 17 bacterial genes acquired non-synonymous mutations in multiple individuals, which indicates parallel adaptive evolution. Mutations in these genes illuminate the genetic basis of important pathogenic phenotypes, including antibiotic resistance and bacterial membrane composition, and implicate oxygen-dependent gene regulation as paramount in lung infections. Several genes have not been previously implicated in pathogenesis, suggesting new therapeutic targets. The identification of parallel molecular evolution suggests key selection forces acting on pathogens within humans and can help predict and prepare for their future evolutionary course.
doi:10.1038/ng.997
PMCID: PMC3245322  PMID: 22081229
8.  Correction: A High-Throughput Screen Identifies a New Natural Product with Broad-Spectrum Antibacterial Activity 
PLoS ONE  2012;7(4):10.1371/annotation/7efd3085-dd48-4210-9b7a-9ddb1acaa608.
doi:10.1371/annotation/7efd3085-dd48-4210-9b7a-9ddb1acaa608
PMCID: PMC3317756
9.  Correction: A High-Throughput Screen Identifies a New Natural Product with Broad-Spectrum Antibacterial Activity 
PLoS ONE  2012;7(4):10.1371/annotation/06010c3b-61a1-4c46-864a-15f64403ec55.
doi:10.1371/annotation/06010c3b-61a1-4c46-864a-15f64403ec55
PMCID: PMC3317757
10.  Current Best Practices for Respiratory Virus Testing 
Journal of Clinical Microbiology  2011;49(9 Suppl):S44-S48.
Diagnostic testing for respiratory viruses has been revolutionized by recent advances that have made rapid and highly accurate tests accessible to clinical laboratories, and it is important that these improved methods be utilized. Accurate detection of respiratory viruses is important in patient care, as it guides both therapy and infection control measures. On a larger scale, the CDC and its collaborating laboratories collect both data and isolates from clinical laboratories for national surveillance, and the use of high-quality tests in clinical laboratories can improve the quality of these data.
doi:10.1128/JCM.00698-11
PMCID: PMC3185851
11.  A High-Throughput Screen Identifies a New Natural Product with Broad-Spectrum Antibacterial Activity 
PLoS ONE  2012;7(2):e31307.
Due to the inexorable invasion of our hospitals and communities by drug-resistant bacteria, there is a pressing need for novel antibacterial agents. Here we report the development of a sensitive and robust but low-tech and inexpensive high-throughput metabolic screen for novel antibiotics. This screen is based on a colorimetric assay of pH that identifies inhibitors of bacterial sugar fermentation. After validation of the method, we screened over 39,000 crude extracts derived from organisms that grow in the diverse ecosystems of Costa Rica and identified 49 with reproducible antibacterial effects. An extract from an endophytic fungus was further characterized, and this led to the discovery of three novel natural products. One of these, which we named mirandamycin, has broad-spectrum antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis. This demonstrates the power of simple high throughput screens for rapid identification of new antibacterial agents from environmental samples.
doi:10.1371/journal.pone.0031307
PMCID: PMC3281070  PMID: 22359585
12.  Shiga Toxin-Producing Escherichia coli in Children: Diagnosis and Clinical Manifestations of O157:H7 and Non-O157:H7 Infection▿ 
Journal of Clinical Microbiology  2011;49(3):955-959.
Shiga toxin-producing Escherichia coli (STEC), a cause of food-borne colitis and hemolytic-uremic syndrome in children, can be serotype O157:H7 (O157) or other serotypes (non-O157). E. coli O157 can be detected by culture with sorbitol-MacConkey agar (SMAC), but non-O157 STEC cannot be detected with this medium. Both O157 and non-O157 STEC can be detected by immunoassay for Shiga toxins 1 and 2. The objectives of this study were first to compare the diagnostic utility of SMAC to that of the Premier EHEC enzyme immunoassay (Meridian Diagnostics) for detection of STEC in children and second to compare the clinical and laboratory characteristics of children with serotype O157:H7 STEC and non-O157:H7 STEC infections. Stool samples submitted for testing for STEC between April 2004 and September 2009 were tested by both SMAC culture and the Premier EHEC assay at Children's Hospital Boston. Samples positive by either test were sent for confirmatory testing and serotyping at the Hinton State Laboratory Institute (HSLI). Chart review was performed on children with confirmed STEC infection. Of 5,110 children tested for STEC, 50 (0.9%) had STEC infection confirmed by culture; 33 were O157:H7 and 17 were non-O157:H7. The Premier EHEC assay and SMAC culture detected 96.0% and 58.0% of culture-confirmed STEC isolates (any serotype), respectively, and 93.9% and 87.9% of STEC O157:H7 isolates, respectively. There were no significant differences in disease severity or laboratory manifestations of STEC infection between children with O157:H7 and those with non-O157 STEC. The Premier EHEC assay was significantly more sensitive than SMAC culture for diagnosis of STEC, and O157:H7 and non-O157:H7 STEC caused infections of similar severity in children.
doi:10.1128/JCM.02119-10
PMCID: PMC3067718  PMID: 21177902
14.  RE-EMERGENCE OF THE TYPE 1 PILUS AMONG STREPTOCOCCUS PNEUMONIAE ISOLATES IN MASSACHUSETTS, USA 
Vaccine  2010;28(30):4842-4846.
Pneumococcal type 1 pilus proteins have been proposed as potential vaccine candidates. Following conjugate pneumococcal vaccination, the prevalence of the pneumococcal type 1 pilus declined dramatically, a decline associated with the elimination of vaccine-type (VT) strains. Here we show that between 2004 and 2007, there has been a significant increase in pilus prevalence, now exceeding rates from the pre-conjugate vaccine era. This increase is primarily due to non-VT strains. These emerging piliated non-VT strains are mostly novel clones, with some exceptions. The rise in pilus type 1 frequency across multiple distinct genetic backgrounds suggests that the pilus may confer an intrinsic advantage.
doi:10.1016/j.vaccine.2010.04.042
PMCID: PMC2897942  PMID: 20434550
S. pneumoniae pilus; PCV7; vaccine- and non-vaccine-types
15.  Higher Prevalence of Pharyngeal than Nasal Staphylococcus aureus Carriage in Pediatric Intensive Care Units▿  
Journal of Clinical Microbiology  2010;48(8):2957-2959.
Sensitive detection of Staphylococcus aureus colonization is important for epidemiologic studies, infection control, and decolonization measures. We examined the sensitivity of nasal and pharyngeal sampling for S. aureus colonization in 331 children admitted to intensive care units. Pharyngeal screening was more sensitive than nasal screening (92.6% versus 63.1%, P < 0.0001).
doi:10.1128/JCM.00547-10
PMCID: PMC2916627  PMID: 20573867
16.  Multicenter Study of Clinical Performance of the 3M Rapid Detection RSV Test▿  
Journal of Clinical Microbiology  2010;48(7):2337-2343.
This multicenter study evaluated the clinical performance of the 3M Rapid Detection RSV test (3MRSV) compared to a composite reference standard of R-Mix culture and direct specimen immunofluorescence for detection of respiratory syncytial virus (RSV). The performance of the BinaxNOW RSV test was also evaluated using this reference standard. In a secondary analysis, discordant results were arbitrated using the Gen-Probe/Prodesse ProFlu+ reverse transcription-PCR (RT-PCR) assay. Subjects were stratified into three groups as follows: group 1 (G1), all ages; G2, subjects <22 years old (FDA-cleared ages for 3MRSV testing); and G3, subjects <5 years old (FDA-cleared ages for BinaxNOW RSV testing). A total of 1,306 specimens (G1, n = 1,306; G2, n = 1,140; G3, n = 953) from subjects of all ages presenting with respiratory symptoms met study criteria for analysis. Sensitivities, specificities, positive predictive values, and negative predictive values of 3MRSV for G1 were 86.5%, 95.8%, 91.4%, and 93.2%, respectively, and those for G2 were 87.3%, 95.6%, 92.4%, and 92.5%, respectively. For those samples analyzed by both 3MRSV and BinaxNOW, the 3MRSV was more sensitive (G1, 86.3%; G2, 87.2%; and G3, 89.9%) than was BinaxNOW (G1, 70.84%; G2, 72.0%; and G3, 72.4%) (P < 0.05). Specificities for RSV detection from nasopharyngeal (NP) aspirates and NP swabs for all groups were comparable for 3MRSV and BinaxNOW, but 3MRSV was less specific than BinaxNOW when nasal washes/aspirates were tested (P < 0.05). The 3MRSV assay performed well for the detection of RSV, and the overall assay performance was superior to that of BinaxNOW. The 3MRSV reader eliminated user misinterpretation and provided test result and quality control documentation.
doi:10.1128/JCM.00130-10
PMCID: PMC2897525  PMID: 20463154
17.  Association of the Pneumococcal Pilus with Certain Capsular Serotypes but Not with Increased Virulence▿  
Journal of Clinical Microbiology  2007;45(6):1684-1689.
The recent discovery of a mobile genetic element encoding a pilus-like structure in Streptococcus pneumoniae and the demonstration of a role for the pilus in virulence in mice have led to the proposal of the use of the pilus as a candidate pneumococcal vaccine. We examined the frequency of occurrence of the pneumococcal pilus, as determined by the presence of the rrgC gene, and analyzed its association with virulence, capsular serotypes, and multilocus sequence types in the American Indian pneumococcal collection and isolates of S. pneumoniae from blood cultures collected at Children's Hospital Boston. Overall, 21.4% of strains in the American Indian collection had the rrgC gene, but there was no difference between isolates obtained from the nasopharynx and those obtained from sterile sites (blood or cerebrospinal fluid). Vaccine-type strains were significantly more likely than non-vaccine-type strains to have this pilus gene (P < 0.001). Among isolates with identical multilocus sequence types, there was a high concordance (95%) between the multilocus sequence type and the presence or the absence of rrgC. Finally, in the era of the pneumococcal conjugate vaccine, the frequency of rrgC in isolates from Children's Hospital Boston has decreased significantly (42.8% before 2000 versus 21.3% after 2000; P = 0.019). Therefore, our data show that the pilus is present in a minority of strains and is associated with certain serotypes and that its frequency has been reduced by the conjugate pneumococcal vaccine.
doi:10.1128/JCM.00265-07
PMCID: PMC1933072  PMID: 17392439
18.  Detection of Multiple Macrolide- and Lincosamide-Resistant Strains of Streptococcus pyogenes from Patients in the Boston Area 
Journal of Clinical Microbiology  2004;42(4):1559-1563.
Macrolide (including erythromycin and azithromycin) and lincosamide (including clindamycin) antibiotics are recommended for treatment of penicillin-allergic patients with Streptococcus pyogenes pharyngitis. Resistance to erythromycin in S. pyogenes can be as high as 48% in specific populations in the United States. Macrolide and lincosamide resistance in S. pyogenes is mediated by several different genes. Expression of the erm(A) or erm(B) genes causes resistance to erythromycin and inducible or constitutive resistance to clindamycin, respectively, whereas expression of the mef(A) gene leads to resistance to erythromycin but not clindamycin. We studied the resistance of S. pyogenes to erythromycin and clindamycin at an urban tertiary-care hospital. Of 196 sequential isolates from throat cultures, 15 (7.7%) were resistant to erythromycin. Three of these were also constitutively resistant to clindamycin and had the erm(B) gene. Five of the erythromycin-resistant isolates were resistant to clindamycin upon induction with erythromycin and had the erm(A) gene. The remaining seven erythromycin-resistant isolates were susceptible to clindamycin even upon induction with erythromycin and had the mef(A) gene. Pulsed-field gel electrophoresis analysis and emm typing demonstrated that the erythromycin-resistant S. pyogenes comprised multiple strains. These results demonstrate that multiple mechanisms of resistance to macrolide and lincosamide antibiotics are present in S. pyogenes strains in the United States.
doi:10.1128/JCM.42.4.1559-1563.2004
PMCID: PMC387580  PMID: 15071004
19.  Resistance of Group B Streptococcus to Selected Antibiotics, Including Erythromycin and Clindamycin 
Journal of Clinical Microbiology  2004;42(3):1263-1264.
Resistance of group B streptococcus (GBS) to antibiotics, particularly erythromycin and clindamycin, was studied. Erythromycin resistance was present in 22% of GBS isolates, and these isolates were constitutively resistant, inducibly resistant, or sensitive to clindamycin. Erythromycin and clindamycin MICs were related to the presence of ermA, ermB, or mefA genes.
doi:10.1128/JCM.42.3.1263-1264.2004
PMCID: PMC356858  PMID: 15004089
21.  B7 Costimulation Is Critical for Antibody Class Switching and CD8+ Cytotoxic T-Lymphocyte Generation in the Host Response to Vesicular Stomatitis Virus 
Journal of Virology  2000;74(1):203-208.
Antibody and cytotoxic T-lymphocyte (CTL) responses have critical roles in eliminating many viral infections. In addition to stimulation of the T-cell receptor, T cells require costimulatory signals to respond optimally. We evaluated the role of B7 costimulatory molecules (B7-1 and B7-2) in the immune response to viral infection using vesicular stomatitis virus (VSV) and mice lacking either B7-1 or B7-2 or both molecules. Mice lacking both B7-1 and B7-2 had essentially no anti-VSV immunoglobulin G1 (IgG1) response, decreased IgG2a responses, and normal IgM responses, while mice lacking either B7-1 or B7-2 had unaltered anti-VSV antibody responses compared to wild-type mice. Depletion of CD4+ cells further reduced the IgG2a response in mice lacking both B7 molecules, suggesting that CD4− cells may supply help for IgG2a in the absence of B7 costimulation. The absence of both B7 molecules profoundly reduced generation of both primary and secondary VSV-specific class I major histocompatibility complex (MHC)-restricted CTL, whereas VSV-specific CTL responses in mice lacking either B7-1 or B7-2 were similar to those of wild-type animals. Class I MHC-restricted CTL in wild-type mice were not dependent on CD4+ cells, suggesting that the failure of CTL in the absence of B7s is due to a lack of B7 costimulation directly to the CD8+ CTL. These data demonstrate that B7-1 and B7-2 have critical, overlapping functions in the antibody and CTL responses to this viral infection.
PMCID: PMC111529  PMID: 10590107
22.  B7-1 or B7-2 Is Required to Produce the Lymphoproliferative Phenotype in Mice Lacking Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4)  
The costimulatory molecules B7-1 and B7-2 regulate T lymphocyte activation by delivering activating signals through CD28 and inhibitory signals through cytotoxic T lymphocyte–associated antigen 4 (CTLA-4). The importance of CTLA-4–mediated inhibition was demonstrated by the uncontrolled T cell activation and lymphoproliferative disease that develops in CTLA-4–deficient (−/−) mice. To examine the role of B7 signaling in the activation of CTLA-4–deficient T cells, we bred CTLA-4−/− mice with mice lacking B7-1, B7-2, or both B7 molecules. The CTLA-4/B7-1−/− and the CTLA-4/B7-2−/− mice develop lymphoproliferation and enhanced T cell activation. Mice lacking CTLA-4, B7-1, and B7-2 have a normal life-span, and do not have lymphocytic infiltrates in any organs, or increased T cell activation. Therefore, the two B7 molecules have overlapping functions, since either B7-1 or B7-2 alone can cause the CTLA-4−/− phenotype. Elimination of both B7-1 and B7-2 from the CTLA-4– deficient mouse abrogates the lymphocyte activation and disease, and does not reveal evidence for additional stimulatory CD28 ligands. The CTLA-4−/− phenotype can be reproduced with anti-CD28 antibody in mice lacking CTLA-4, B7-1, and B7-2, but wild-type mice are unaffected by the same treatment. This suggests that the inhibitory function of CTLA-4 can overcome strong CD28-mediated signaling in vivo.
PMCID: PMC2192978  PMID: 9892625
cytotoxic T lymphocyte–associated antigen 4; B7; knockout mouse; costimulation; T lymphocyte
23.  Targeting Pan-Resistant Bacteria With Antibodies to a Broadly Conserved Surface Polysaccharide Expressed During Infection 
The Journal of Infectious Diseases  2012;205(11):1709-1718.
Background
New therapeutic targets for antibiotic-resistant bacterial pathogens are desperately needed. The bacterial surface polysaccharide poly-β-(1-6)-N-acetyl-glucosamine (PNAG) mediates biofilm formation by some bacterial species, and antibodies to PNAG can confer protective immunity. By analyzing sequenced genomes, we found that potentially multidrug-resistant bacterial species such as Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, and the Burkholderia cepacia complex (BCC) may be able to produce PNAG. Among patients with cystic fibrosis patients, highly antibiotic-resistant bacteria in the BCC have emerged as problematic pathogens, providing an impetus to study the potential of PNAG to be targeted for immunotherapy against pan-resistant bacterial pathogens.
Methods
The presence of PNAG on BCC was assessed using a combination of bacterial genetics, microscopy, and immunochemical approaches. Antibodies to PNAG were tested using opsonophagocytic assays and for protective efficacy against lethal peritonitis in mice.
Results
PNAG is expressed in vitro and in vivo by the BCC, and cystic fibrosis patients infected by the BCC species B. dolosa mounted a PNAG-specific opsonophagocytic antibody response. Antisera to PNAG mediated opsonophagocytic killing of BCC and were protective against lethal BCC peritonitis even during coinfection with methicillin-resistant Staphylococcus aureus.
Conclusions
Our findings raise potential new therapeutic options against PNAG-producing bacteria, including even pan-resistant pathogens.
doi:10.1093/infdis/jis254
PMCID: PMC3415848  PMID: 22448004
24.  Epidemiology and risk factors for Staphylococcus aureus colonization in children in the post-PCV7 era 
Background
The incidence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) has risen dramatically in the U.S., particularly among children. Although Streptococcus pneumoniae colonization has been inversely associated with S. aureus colonization in unvaccinated children, this and other risk factors for S. aureus carriage have not been assessed following widespread use of the heptavalent pneumococcal conjugate vaccine (PCV7). Our objectives were to (1) determine the prevalence of S. aureus and MRSA colonization in young children in the context of widespread use of PCV7; and (2) examine risk factors for S. aureus colonization in the post-PCV7 era, including the absence of vaccine-type S. pneumoniae colonization.
Methods
Swabs of the anterior nares (S. aureus) were obtained from children enrolled in an ongoing study of nasopharyngeal pneumococcal colonization of healthy children in 8 Massachusetts communities. Children 3 months to <7 years of age seen for well child or sick visits in primary care offices from 11/03–4/04 and 10/06–4/07 were enrolled. S. aureus was identified and antibiotic susceptibility testing was performed. Epidemiologic risk factors for S. aureus colonization were collected from parent surveys and chart reviews, along with data on pneumococcal colonization. Multivariate mixed model analyses were performed to identify factors associated with S. aureus colonization.
Results
Among 1,968 children, the mean age (SD) was 2.7 (1.8) years, 32% received an antibiotic in the past 2 months, 2% were colonized with PCV7 strains and 24% were colonized with non-PCV7 strains. The prevalence of S. aureus colonization remained stable between 2003–04 and 2006–07 (14.6% vs. 14.1%), while MRSA colonization remained low (0.2% vs. 0.9%, p = 0.09). Although absence of pneumococcal colonization was not significantly associated with S. aureus colonization, age (6–11 mo vs. ≥5 yrs, OR 0.39 [95% CI 0.24–0.64]; 1–1.99 yrs vs. ≥5 yrs, OR 0.35 [0.23–0.54]; 2–2.99 yrs vs. ≥5 yrs, OR 0.45 [0.28–0.73]; 3–3.99 yrs vs. ≥5 yrs, OR 0.53 [0.33–0.86]) and recent antibiotic use were significant predictors in multivariate models.
Conclusion
In Massachusetts, S. aureus and MRSA colonization remained stable from 2003–04 to 2006–07 among children <7 years despite widespread use of pneumococcal conjugate vaccine. S. aureus nasal colonization varies by age and is inversely correlated with recent antibiotic use.
doi:10.1186/1471-2334-9-110
PMCID: PMC2716346  PMID: 19594890

Results 1-24 (24)