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Assessment of Wheezing Frequency and Viral Etiology on Childhood and Adolescent Asthma Risk
Abstracts AB109
354
Viral Induced Disease in Mild Atopic Asthmatics: Dynamics of Pulmonary Function, Speed of Symptom Onset and Implications for Drug Intervention in HRV Inoculated Volunteers
Alex Mann1, Ganesh Balaratnam1, Jane Gunter2, Pawel Rucki2, Chris Poll1, Martin Johnson1, Tony Lockett1; 1hVIVO Services Ltd, 2hVIVO Services Ltd (at time of the study). RATIONALE: The immune response in asthmatics has been shown to be different to non-asthmatics, leading to differences in the response to infection between the populations. This trial was performed to gather evidence about the optimum dose, safety, and pathogenicity of a GMP manufactured HRV-16 strain in asthmatics. METHODS: hVIVO recruited 20 mild atopic asthmatics with low serum neutralizing antibodies. Subjects had full health screens including physical examinations, pulmonary function, and skin prick tests. Subjects were brought to quarantine a day before inoculation and randomized to either a 10TCID50 dose of virus (n513) or placebo (n57). Throughout the controlled quarantine period, regular timed samples were taken and assessments performed for 8 days, before discharge. Asthmatic data were compared to data obtained from healthy subjects given the same dose of virus. RESULTS: Of the 13 asthmatics inoculated with virus, 11 (85%) were infected (confirmed by PCR), 4 of the infected (36%) exacerbated (ACQ score rise by 0.5), and had measurable reductions in PEF. Interestingly the infected asthmatics had a more rapid onset of both upper and lower respiratory symptoms, preceding healthy subjects. CONCLUSIONS: A GMP HRV-16 strain of virus has safely progressed through the 1st two stages of characterization in volunteers. Mild asthmatics exacerbated upon inoculation with a low dose of HRV, had reductions in lung function and a rapid onset of symptoms. Robust assessments and sampling within quarantines can aid in reducing noise and could allow for more precise and dynamic measurement of drug efficacy.
355
Assessment of Wheezing Frequency and Viral Etiology on Childhood and Adolescent Asthma Risk
Halie M. Anderson, MD1, Robert F. Lemanske, Jr, MD, FAAAAI2, Michael D. Evans, MS2, Ronald E. Gangnon, PhD2, James E. Gern, MD, FAAAAI3, Daniel J. Jackson, MD4; 1University of Wisconsin, Madison, WI, 2University of Wisconsin School of Medicine and Public Health, Madison, WI, 3University of Wisconsin-Madison, Madison, WI, 4 Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI. RATIONALE: We have previously reported that early rhinovirus (RV) wheezing illnesses are the most robust predictor of asthma development at age 6 years in high-risk children in the Childhood Origins of ASThma (COAST) birth cohort study. We sought to assess the role of etiology and frequency of wheezing illnesses in asthma risk from ages 6 to 13 years. METHODS: A total of 259 children were followed prospectively to age 6 years, and 217 were followed to age 13 years. A generalized additive logistic regression model (GAM) of asthma was fit for asthma diagnosed at ages 6, 8, 11, 13 years; with smooth terms for number of RV wheezing illnesses, number of non-RV wheezing illnesses, and their interaction. In the absence of significant interaction the main effect p-values are reported. RESULTS: The number of RV wheezing episodes in early childhood was significantly associated with asthma at all ages (6 years: p<0.0001; 8 years: p<0.0001; 11 years: p50.0006; 13 years: p50.002). The number of nonRV wheezing episodes was not significantly associated with asthma (6 years: p50.06; 8 years: p50.09; 11 years: p50.06; 13 years: p50.33). CONCLUSIONS: RV wheezing illnesses remain an important predictor of asthma development in high-risk children and continued research efforts should focus on defining host and viral factors that promote wheezing RV illnesses in early childhood.
356
Cytokine Profiles and Eosinophil Activation in Sensitized and Nonsensitized Cases of VirusInduced Acute Exacerbations of Childhood Wheezing/Asthma.
Masahiko Kato, MD, PhD, FAAAAI1, Kazuo Suzuki, MD1, Yoshiyuki Yamada, MD, PhD2, Kenichi Maruyama, MD, PhD2, Hiroyuki Mochizuki, MD, PhD1; 1Department of Pediatrics, Tokai University School of Medicine, Isehara, Kanagawa, Japan, 2Gunma Children’s Medical Center, Shibukawa, Gunma, Japan. RATIONALE: Viral infections and sensitization to aeroallergens are major factors in the exacerbation of asthma and its development during early childhood. However, the cytokine profiles and eosinophil activation status linked to the association between viral infections and sensitization to aeroallergens are incompletely understood. Here we investigated respiratory viruses, serum eosinophil cationic protein (ECP), and various cytokines/chemokines in acute exacerbation of childhood wheezing/ asthma with or without aeroallergen sensitization. METHODS: We analyzed peripheral eosinophil counts, serum ECP, and 27 cytokines/chemokines in 71 virus-induced acute wheezing/asthma cases with or without aeroallergen sensitization. Wheezing/asthma due to sensitization was defined by a positive reaction to at least one aeroallergen in serum specific IgE antibody tests. Virus detection was performed using antigen detection kits and/or RT-PCR, followed by direct DNA sequencing analysis. Serum cytokines/chemokines were measured using a multi-cytokine detection system. RESULTS: The two major viruses detected, rhinovirus and respiratory syncytial (RS) virus, did not differ significantly between sensitized and nonsensitized cases of acute exacerbations of wheezing/asthma. Peripheral eosinophil counts and serum ECP and IL-5 levels were significantly elevated in sensitized cases compared with nonsensitized cases. Conversely, among the 27 cytokines/chemokines, serum IP-10 values were significantly higher in nonsensitized cases. An inverse correlation between serum IP-10 and IL-5 production was identified in virus-induced acute exacerbations of childhood wheezing/asthma but not in controls. CONCLUSIONS: Cytokine profiles and eosinophil activation status might be different between sensitized and nonsensitized cases of virusinduced acute exacerbations of wheezing/asthma. IP-10 is a biomarker for these virus-induced acute exacerbations, specifically in nonsensitized cases.
SUNDAY
J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 2
354
Viral Induced Disease in Mild Atopic Asthmatics: Dynamics of Pulmonary Function, Speed of Symptom Onset and Implications for Drug Intervention in HRV Inoculated Volunteers
Alex Mann1, Ganesh Balaratnam1, Jane Gunter2, Pawel Rucki2, Chris Poll1, Martin Johnson1, Tony Lockett1; 1hVIVO Services Ltd, 2hVIVO Services Ltd (at time of the study). RATIONALE: The immune response in asthmatics has been shown to be different to non-asthmatics, leading to differences in the response to infection between the populations. This trial was performed to gather evidence about the optimum dose, safety, and pathogenicity of a GMP manufactured HRV-16 strain in asthmatics. METHODS: hVIVO recruited 20 mild atopic asthmatics with low serum neutralizing antibodies. Subjects had full health screens including physical examinations, pulmonary function, and skin prick tests. Subjects were brought to quarantine a day before inoculation and randomized to either a 10TCID50 dose of virus (n513) or placebo (n57). Throughout the controlled quarantine period, regular timed samples were taken and assessments performed for 8 days, before discharge. Asthmatic data were compared to data obtained from healthy subjects given the same dose of virus. RESULTS: Of the 13 asthmatics inoculated with virus, 11 (85%) were infected (confirmed by PCR), 4 of the infected (36%) exacerbated (ACQ score rise by 0.5), and had measurable reductions in PEF. Interestingly the infected asthmatics had a more rapid onset of both upper and lower respiratory symptoms, preceding healthy subjects. CONCLUSIONS: A GMP HRV-16 strain of virus has safely progressed through the 1st two stages of characterization in volunteers. Mild asthmatics exacerbated upon inoculation with a low dose of HRV, had reductions in lung function and a rapid onset of symptoms. Robust assessments and sampling within quarantines can aid in reducing noise and could allow for more precise and dynamic measurement of drug efficacy.
355
Assessment of Wheezing Frequency and Viral Etiology on Childhood and Adolescent Asthma Risk
Halie M. Anderson, MD1, Robert F. Lemanske, Jr, MD, FAAAAI2, Michael D. Evans, MS2, Ronald E. Gangnon, PhD2, James E. Gern, MD, FAAAAI3, Daniel J. Jackson, MD4; 1University of Wisconsin, Madison, WI, 2University of Wisconsin School of Medicine and Public Health, Madison, WI, 3University of Wisconsin-Madison, Madison, WI, 4 Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI. RATIONALE: We have previously reported that early rhinovirus (RV) wheezing illnesses are the most robust predictor of asthma development at age 6 years in high-risk children in the Childhood Origins of ASThma (COAST) birth cohort study. We sought to assess the role of etiology and frequency of wheezing illnesses in asthma risk from ages 6 to 13 years. METHODS: A total of 259 children were followed prospectively to age 6 years, and 217 were followed to age 13 years. A generalized additive logistic regression model (GAM) of asthma was fit for asthma diagnosed at ages 6, 8, 11, 13 years; with smooth terms for number of RV wheezing illnesses, number of non-RV wheezing illnesses, and their interaction. In the absence of significant interaction the main effect p-values are reported. RESULTS: The number of RV wheezing episodes in early childhood was significantly associated with asthma at all ages (6 years: p<0.0001; 8 years: p<0.0001; 11 years: p50.0006; 13 years: p50.002). The number of nonRV wheezing episodes was not significantly associated with asthma (6 years: p50.06; 8 years: p50.09; 11 years: p50.06; 13 years: p50.33). CONCLUSIONS: RV wheezing illnesses remain an important predictor of asthma development in high-risk children and continued research efforts should focus on defining host and viral factors that promote wheezing RV illnesses in early childhood.
356
Cytokine Profiles and Eosinophil Activation in Sensitized and Nonsensitized Cases of VirusInduced Acute Exacerbations of Childhood Wheezing/Asthma.
Masahiko Kato, MD, PhD, FAAAAI1, Kazuo Suzuki, MD1, Yoshiyuki Yamada, MD, PhD2, Kenichi Maruyama, MD, PhD2, Hiroyuki Mochizuki, MD, PhD1; 1Department of Pediatrics, Tokai University School of Medicine, Isehara, Kanagawa, Japan, 2Gunma Children’s Medical Center, Shibukawa, Gunma, Japan. RATIONALE: Viral infections and sensitization to aeroallergens are major factors in the exacerbation of asthma and its development during early childhood. However, the cytokine profiles and eosinophil activation status linked to the association between viral infections and sensitization to aeroallergens are incompletely understood. Here we investigated respiratory viruses, serum eosinophil cationic protein (ECP), and various cytokines/chemokines in acute exacerbation of childhood wheezing/ asthma with or without aeroallergen sensitization. METHODS: We analyzed peripheral eosinophil counts, serum ECP, and 27 cytokines/chemokines in 71 virus-induced acute wheezing/asthma cases with or without aeroallergen sensitization. Wheezing/asthma due to sensitization was defined by a positive reaction to at least one aeroallergen in serum specific IgE antibody tests. Virus detection was performed using antigen detection kits and/or RT-PCR, followed by direct DNA sequencing analysis. Serum cytokines/chemokines were measured using a multi-cytokine detection system. RESULTS: The two major viruses detected, rhinovirus and respiratory syncytial (RS) virus, did not differ significantly between sensitized and nonsensitized cases of acute exacerbations of wheezing/asthma. Peripheral eosinophil counts and serum ECP and IL-5 levels were significantly elevated in sensitized cases compared with nonsensitized cases. Conversely, among the 27 cytokines/chemokines, serum IP-10 values were significantly higher in nonsensitized cases. An inverse correlation between serum IP-10 and IL-5 production was identified in virus-induced acute exacerbations of childhood wheezing/asthma but not in controls. CONCLUSIONS: Cytokine profiles and eosinophil activation status might be different between sensitized and nonsensitized cases of virusinduced acute exacerbations of wheezing/asthma. IP-10 is a biomarker for these virus-induced acute exacerbations, specifically in nonsensitized cases.
SUNDAY
J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 2