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Jennifer C Esbenshade,
Kathryn M Edwards,
Adam J Esbenshade,
Vanessa E Rodriguez,
H Keipp Talbot,
Marlon F Joseph,
Samuel K Nwosu,
James D Chappell, James E Gern,
John V Williams,
Thomas R Talbot
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ABSTRACT: Background. Healthcare-associated transmission of respiratory viruses is a concerning patient safety issue. Design. Surveillance for influenza virus among a cohort of healthcare workers (HCWs) was conducted in a tertiary care children's hospital from November 2009 through April 2010 using biweekly nasal swab specimen collection. If a subject reported respiratory symptoms, an additional specimen was collected. Specimens from ill HCWs and a randomly selected sample from asymptomatic subjects were tested for additional respiratory viruses by multiplex polymerase chain reaction (PCR). Results. A total of 1,404 nasal swab specimens were collected from 170 enrolled subjects. Influenza circulated at very low levels during the surveillance period, and 74.2% of subjects received influenza vaccination. Influenza virus was not detected in any specimen. Multiplex respiratory virus PCR analysis of all 119 specimens from symptomatic subjects and 200 specimens from asymptomatic subjects yielded a total of 42 positive specimens, including 7 (16.7%) in asymptomatic subjects. Viral shedding was associated with report of any symptom (odds ratio [OR], 13.06 [95% confidence interval, 5.45-31.28]; [Formula: see text]) and younger age (OR, 0.96 [95% confidence interval, 0.92-0.99]; [Formula: see text]) when controlled for sex and occupation of physician or nurse. After the surveillance period, 46% of subjects reported working while ill with an influenza-like illness during the previous influenza season. Conclusions. In this cohort, HCWs working while ill was common, as was viral shedding among those with symptoms. Asymptomatic viral shedding was infrequent but did occur. HCWs should refrain from patient care duties while ill, and staffing contingencies should accommodate them.
Infection Control and Hospital Epidemiology 04/2013; 34(4):373-8. · 3.67 Impact Factor
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Minal Calışkan,
Yury A Bochkov,
Eskil Kreiner-Møller,
Klaus Bønnelykke,
Michelle M Stein,
Gaixin Du,
Hans Bisgaard,
Daniel J Jackson, James E Gern,
Robert F Lemanske,
Dan L Nicolae,
Carole Ober
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ABSTRACT: Background Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts. Methods We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs). Results The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific. Conclusions Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).
New England Journal of Medicine 03/2013; · 53.30 Impact Factor
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ABSTRACT: Understanding the underlying mechanisms that cause and exacerbate allergic asthmatic disease is of great clinical interest. Clinical studies have revealed that allergies and viral respiratory illnesses are strongly linked to the inception and exacerbation of asthma, and suggest the possibility that there are interactive inflammatory mechanisms. Recent work has revealed a number of mechanisms of virus and allergen cross-talk that may play a role in the pathophysiology of allergic asthma, including (1) deficiency in virus-induced interferon responses, (2) defective epithelial barrier function, (3) increased release of epithelium-derived cytokines (e.g., thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, IL-33), (4) dysregulation of lymphocytes [e.g., innate lymphoid cells (ILCs), regulatory T cells (Tregs)], and (5) altered activation of purinergic receptors. One or more of these processes may provide targets for new therapeutics to treat allergic asthma and prevent disease exacerbation.
Current Allergy and Asthma Reports 03/2013; · 2.50 Impact Factor
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Emma E Thompson,
Rachel A Myers,
Gaixin Du,
Tessa M Aydelotte,
Christopher J Tisler,
Debra A Stern,
Michael D Evans,
Penelope E Graves,
Daniel J Jackson,
Fernando D Martinez, James E Gern,
Anne L Wright,
Robert F Lemanske,
Carole Ober
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ABSTRACT: BACKGROUND: Maternal asthma and child's sex are among the most significant and reproducible risk factors for the development of asthma. Although the mechanisms for these effects are unknown, they likely involve nonclassical genetic mechanisms. One such mechanism could involve the transfer and persistence of maternal cells to her offspring, a common occurrence known as maternal microchimerism (MMc). MMc has been associated with many autoimmune diseases but has not been investigated for a role in asthma or allergic disease. OBJECTIVE: We hypothesized that some of the observed risks for asthma may be due to different rates of transmission or persistence of maternal cells to children of mothers with asthma compared with children of mothers without asthma, or to sons compared with daughters. We further hypothesized that rates of MMc differ between children with and without asthma. METHODS: We tested these hypotheses in 317 subjects from 3 independent cohorts by using a real-time quantitative PCR assay to detect a noninherited HLA allele in the child. RESULTS: MMc was detected in 20.5% of the subjects (range 16.8%-27.1% in the 3 cohorts). We observed lower rates of asthma among MMc-positive subjects than among MMc-negative subjects (odds ratio, 0.38; 95% CI, 0.19-0.79; P = .029). Neither maternal asthma nor sex of the child was a significant predictor of MMc in the child (P = .81 and .15, respectively). CONCLUSIONS: Our results suggest for the first time that MMc may protect against the development of asthma.
The Journal of allergy and clinical immunology 02/2013; · 9.17 Impact Factor
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Anne Marie Singh,
Paul Dahlberg,
Kristjan Burmeister,
Michael D Evans,
Ronald Gangnon,
Kathy A Roberg,
Christopher Tisler,
Douglas Dasilva,
Tressa Pappas,
Lisa Salazar,
Robert F Lemanske, James E Gern,
Christine M Seroogy
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ABSTRACT: BACKGROUND: T regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use. METHODS: Peripheral blood mononuclear cells from healthy control subjects (N = 93) and asthmatic children of varying disease severity (N = 66) were characterized by multi-parameter flow cytometry. RESULTS: Our findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma. CONCLUSION: We conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency.
Clinical and Molecular Allergy 01/2013; 11(1):1. · 1.39 Impact Factor
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ABSTRACT: BACKGROUND: Magnetic resonance imaging (MRI) with (3)He does not require ionizing radiation and has been shown to detect regional abnormalities in lung ventilation and structure in adults with asthma, but the method has not been extended to children with asthma. Measurements of regional lung ventilation and microstructure in subjects with childhood asthma could advance our understanding of disease mechanisms. OBJECTIVE: We sought to determine whether (3)He MRI in children can identify abnormalities related to the diagnosis of asthma or prior history of respiratory illness. METHODS: Forty-four children aged 9 to 10 years were recruited from a birth cohort at increased risk of asthma and allergic diseases. For each subject, a time-resolved 3-dimensional image series and a 3-dimensional diffusion-weighted image were acquired in separate breathing maneuvers. The numbers and sizes of ventilation defects were scored, and regional maps and statistics of average (3)He diffusion lengths were calculated. RESULTS: Children with mild-to-moderate asthma had lower average root-mean-square diffusion length (X(rms)¯) values (P = .004), increased regional SD of diffusion length values (P = .03), and higher defect scores (P = .03) than those without asthma. Children with histories of wheezing illness with rhinovirus infection before the third birthday had lower X(rms)¯ values (P = .01) and higher defect scores (P = .05). CONCLUSION: MRI with (3)He detected more and larger regions of ventilation defect and a greater degree of restricted gas diffusion in children with asthma compared with those seen in children without asthma. These measures are consistent with regional obstruction and smaller and more regionally variable dimensions of the peripheral airways and alveolar spaces.
The Journal of allergy and clinical immunology 12/2012; · 9.17 Impact Factor
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ABSTRACT: Information about the basic biological properties of human rhinovirus-C (HRV-C) viruses is lacking due to difficulties with culturing these viruses. Our objective was to develop a cell culture system to grow HRV-C. Epithelial cells from human sinuses (HSEC) were differentiated at air-liquid interface (ALI). Differentiated cultures supported 1-2logs growth of HRV-C15 as detected by quantitative RT-PCR. Two distinguishing features of HRVs are acid lability and optimal growth at 33-34°C. We used this system to show that HRV-C15 is neutralized by low pH (4.5). In contrast to most HRV types, replication of HRV-C15 and HRV-C41 was similar at 34 and 37°C. The HSEC ALI provides a useful tool for quantitative studies of HRV-C replication. The ability of HRV-C to grow equally well at 34°C and 37°C may contribute to the propensity for HRV-C to cause lower airway illnesses in infants and children with asthma.
Virology 11/2012; · 3.35 Impact Factor
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James E Gern,
Tressa Pappas,
Cynthia M Visness,
Katy F Jaffee,
Robert F Lemanske,
Alkis Togias,
Gordon R Bloomberg,
William W Cruikshank,
Carin Lamm,
Marina Tuzova,
Robert A Wood,
Wai Ming Lee
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ABSTRACT: Background. The risk of developing childhood asthma has been linked to the severity and etiology of viral respiratory illnesses in early childhood. Since inner-city infants have unique environmental exposures, we hypothesized that patterns of respiratory viral infections would also be distinct. Methods. We compared the viral etiology of respiratory illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285 infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens by multiplex polymerase chain reaction. Results. Overall, inner-city infants had lower rates of viral detection. Considering specific viruses, sick urban infants had lower rates of detectable rhinovirus or respiratory syncytial virus infection and higher rates of adenovirus infection. Every urban site had a higher proportion of adenovirus-positive samples associated with illnesses (10%-21%), compared with Madison (6%). Conclusions. These findings provide evidence that inner-city babies have different patterns of viral respiratory illnesses than babies who grow up in a more suburban location. These findings raise important questions about the etiology of virus-negative illnesses in urban infants and the possibility of long-term consequences of early life infections with adenovirus in this population.
The Journal of Infectious Diseases 09/2012; 206(9):1342-9. · 6.41 Impact Factor
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Kei E Fujimura,
Marcus Rauch,
Elizabeth Matsui,
Shoko Iwai,
Agustin Calatroni,
Henry Lynn,
Herman Mitchell,
Christine C Johnson, James E Gern,
Alkis Togias,
Homer A Boushey,
Suzanne Kennedy,
Susan V Lynch
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ABSTRACT: Standardized studies examining environmental microbial exposure in populations at risk for asthma are necessary to improve our understanding of the role this factor plays in disease development. Here we describe studies aimed at developing guidelines for high-resolution culture-independent microbiome profiling, using a phylogenetic microarray (PhyloChip), of house dust samples in a cohort collected as part of the NIH-funded Inner City Asthma Consortium (ICAC). We demonstrate that though extracted DNA concentrations varied across dust samples, the majority produced sufficient 16S rRNA to be profiled by the array. Comparison of array and 454-pyrosequencing performed in parallel on a subset of samples, illustrated that increasingly deeper sequencing efforts validated greater numbers of array-detected taxa. Community composition agreement across samples exhibited a hierarchy in concordance, with the highest level of agreement in replicate array profiles followed by samples collected from adjacent 1×1m(2) sites in the same room, adjacent sites with different sized sampling quadrants (1×1 and 2×2m(2)), different sites within homes (living and bedroom) to lowest in living room samples collected from different homes. The guidelines for sample collection and processing in this pilot study extend beyond PhyloChip based studies of house-associated microbiota, and bear relevance for other microbiome profiling approaches such as next-generation sequencing.
Journal of microbiological methods 09/2012; 91(2):231-9. · 2.43 Impact Factor
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ABSTRACT: RATIONALE: Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes including asymptomatic infections, common colds, and severe lower respiratory illnesses. OBJECTIVE: To identify factors which influence the severity of HRV illnesses. METHODS: HRV species and types were determined in 1445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate-to-severe illnesses (MSI). Measurements & MAIN RESULTS: Altogether, 670 HRV infections were identified and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of 3 species: 49 A, 9 B and 35 C. HRV-A (OR 8.2 [2.7, 25]) and HRV-C (OR 7.6 [2.6, 23]) were more likely to cause MSI compared to HRV-B. In addition, HRV infections were 5-10-fold more likely to cause MSI in the winter months (p<0.0001) compared to summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (p=0.004) were considered, strain-specific rates of HRV MSI ranged from <1% to over 20%. CONCLUSIONS: Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species, and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months.
American Journal of Respiratory and Critical Care Medicine 08/2012; · 11.08 Impact Factor
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Sandy R Durrani,
Daniel J Montville,
Allison S Pratt,
Sanjukta Sahu,
Mark K DeVries,
Victoria Rajamanickam,
Ronald E Gangnon,
Michelle A Gill, James E Gern,
Robert F Lemanske,
Daniel J Jackson
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ABSTRACT: Children with allergic asthma have more frequent and severe human rhinovirus (HRV)-induced wheezing and asthma exacerbations through unclear mechanisms.
We sought to determine whether increased high-affinity IgE receptor (FcεRI) expression and cross-linking impairs innate immune responses to HRV, particularly in allergic asthmatic children.
PBMCs were obtained from 44 children, and surface expression of FcεRI on plasmacytoid dendritic cells (pDCs), myeloid dendritic cells, monocytes, and basophils was assessed by using flow cytometry. Cells were also incubated with rabbit anti-human IgE to cross-link FcεRI, followed by stimulation with HRV-16, and IFN-α and IFN-λ1 production was measured by Luminex. The relationships among FcεRI expression and cross-linking, HRV-induced IFN-α and IFN-λ1 production, and childhood allergy and asthma were subsequently analyzed.
FcεRIα expression on pDCs was inversely associated with HRV-induced IFN-α and IFN-λ1 production. Cross-linking FcεRI before HRV stimulation further reduced PBMC IFN-α (47% relative reduction; 95% CI, 32% to 62%; P< .0001) and IFN-λ1 (81% relative reduction; 95% CI, 69% to 93%; P< .0001) secretion. Allergic asthmatic children had higher surface expression of FcεRIα on pDCs and myeloid dendritic cells when compared with that seen in nonallergic nonasthmatic children. Furthermore, after FcεRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses than allergic nonasthmatic children (IFN-α, P= .004; IFN-λ1, P= .02) and nonallergic nonasthmatic children (IFN-α, P= .002; IFN-λ1, P= .01).
Allergic asthmatic children have impaired innate immune responses to HRV that correlate with increased FcεRI expression on pDCs and are reduced by FcεRI cross-linking. These effects likely increase susceptibility to HRV-induced wheezing and asthma exacerbations.
The Journal of allergy and clinical immunology 07/2012; 130(2):489-95. · 9.17 Impact Factor
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ABSTRACT: Viral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage caused by infection or allergen inhalation increases ATP levels in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X(7) can enhance airway leukocyte recruitment to the airways, and P2X(7) knockout mice display a reduced asthma-like phenotype.
Based on the P2X(7) knockout mouse, we hypothesized that children with low P2X(7) function would have decreased rates of asthma.
We used a functional assay to determine P2X(7) pore-producing capacity in whole-blood samples in a birth cohort at high risk for asthma development. The P2X(7) assay was validated with known loss-of-function alleles in human subjects. P2X(7) pore status categorization was used to assess asthma and allergy status in the cohort.
Attenuated P2X(7) function was associated with lower asthma rates at ages 6 and 8 years, and the greatest effects were observed in boys. Children with asthma at age 11 years who had low P2X(7) capacity had less severe disease in the previous year. Attenuated P2X(7) function was also associated with sensitization to fewer aeroallergens.
P2X(7) functional capacity is associated with asthma risk or disease severity, and these relationships appear to be age related.
The Journal of allergy and clinical immunology 06/2012; 130(2):496-502. · 9.17 Impact Factor
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The Journal of allergy and clinical immunology 06/2012; 130(4):990-1. · 9.17 Impact Factor
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ABSTRACT: Human rhinovirus (HRV) is a nonenveloped, single stranded RNA virus belonging to the family Picornaviridae. HRV infections can cause both upper and lower respiratory illnesses in children and adults. Lower respiratory illnesses are more likely to occur in specific high risk groups, including infants, and children and adults with asthma. The relationships between rates of infection and the risk of clinical illness and exacerbation are not completely understood. Recent studies employing polymerase chain reaction and other molecular techniques indicate that there are new branches on the HRV family tree, and one characteristic of recently detected viruses is that they cannot be detected by standard tissue culture. Here we review the current literature and discuss new advances in understanding the link between HRV and asthma.
Allergy, asthma & immunology research 05/2012; 4(3):116-21. · 1.91 Impact Factor
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ABSTRACT: Viral respiratory tract infections are the leading cause of acute illness during infancy and are closely linked to chronic inflammatory airway diseases later in life. However, the determinants of susceptibility to acute respiratory tract infections still need to be defined.
We investigated whether the individual variation in antiviral response at birth determines the risk for acute respiratory tract illness in the first year of life.
We studied 82 children who were enrolled in a birth cohort study of inner-city children with at least 1 parent with allergy or asthma. We cultured cord blood monocytes and assessed IFNG and CCL5 mRNA production at 24 hours after inoculation with respiratory syncytial virus. We also monitored the frequency of acute respiratory tract illness at 3-month intervals and analyzed nasal lavage samples for respiratory tract viruses at the time of illness during the first year.
Respiratory tract infection was reported for 88% of subjects, and respiratory tract viruses were recovered in 74% of symptomatic children. We observed a wide range of antiviral responses in cord blood monocytes across the population. Furthermore, a decrease in production of IFNG (but not CCL5) mRNA in response to respiratory syncytial virus infection of monocytes was associated with a significant increase in the frequency of upper respiratory tract infections (r = -0.42, P < .001) and the prevalence of ear and sinus infections, pneumonias, and respiratory-related hospitalizations.
Individual variations in the innate immune response to respiratory tract viruses are detectable even at birth, and these differences predict the susceptibility to acute respiratory tract illness during the first year of life.
The Journal of allergy and clinical immunology 03/2012; 129(5):1267-1273.e1. · 9.17 Impact Factor
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Thorax 03/2012; 67(3):189-90. · 6.84 Impact Factor
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ABSTRACT: The 2009 H1N1 flu appeared to cause more severe cold symptoms during the 2009-2010 flu season.
We evaluated H1N1 infections during peak viral season in children with and without asthma to determine whether the H1N1 infectivity rate and illness severity were greater in subjects with asthma.
One hundred and eighty children, 4-12 years of age, provided eight consecutive weekly nasal mucus samples from September 5 through October 24, 2009, and scored cold and asthma symptoms daily. Viral diagnostics were performed for all nasal samples.
One hundred and sixty-one children (95 with asthma, 66 without asthma) completed at least 6 of the 8 nasal samples. The incidence of H1N1 infection was significantly higher in children with asthma (41%) than in children without asthma (24%; odds ratio, 4; 95% confidence interval, 1.8-9; P < 0.001), but rates of human rhinovirus infection (90% each) and other viral infections (47 vs. 41%) were similar. In children with asthma, there was a nonsignificant trend for increased loss of asthma control during H1N1 infections compared with human rhinovirus infections (38 vs. 21%; odds ratio, 2.6; 95% confidence interval, 0.9-7.2; P = 0.07).
During peak 2009 H1N1 flu season, children with asthma were infected almost twice as often with H1N1 compared with other respiratory viruses. H1N1 infection also caused increased severity of cold symptoms compared with other viral infections. Given the increased susceptibility of children with asthma to infection, these findings reinforce the need for yearly influenza vaccination to prevent infection, and raise new questions about the mechanism for enhanced susceptibility to influenza infection in asthma.
American Journal of Respiratory and Critical Care Medicine 02/2012; 185(12):1275-9. · 11.08 Impact Factor
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ABSTRACT: A newly discovered group of human rhinoviruses (HRVs) has been classified as the HRV-C species based on distinct genomic features. HRV-Cs circulate worldwide, and are important causes of upper and lower respiratory illnesses. Methods to culture and produce these viruses have recently been developed, and should enable identification of unique features of HRV-C replication and biology.
Microbes and Infection 01/2012; 14(6):485-94. · 3.10 Impact Factor
