Browsing by Subject "asthma"
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Item Ceramide in apoptosis and oxidative stress in allergic inflammation and asthma(Elsevier, 2021) James, Briana N.; Oyeniran, Clement; Sturgill, Jamie L.; Newton, Jason; Martin, Rebecca; Bieberich, Erhard; Weigel, Cynthia; Maczis, Melissa A.; Palladino, Elisa N. D.; Lownik, Joseph C.; Trudeau, John B.; Cook-Mills, Joan M.; Wenzel, Sally; Milstein, Sheldon; Spiegel, Sarah; Pediatrics, School of MedicineBackground Nothing is known about the mechanisms by which increased ceramide levels in the lung contribute to allergic responses and asthma severity. Objective We sought to investigate the functional role of ceramide in mouse models of allergic airway disease that recapitulate the cardinal clinical features of human allergic asthma. Methods Allergic airway disease was induced in mice by repeated intranasal administration of house dust mite or the fungal allergen Alternaria alternata. Processes that can be regulated by ceramide and are important for severity of allergic asthma were correlated with ceramide levels measured by mass spectrometry. Results Both allergens induced massive pulmonary apoptosis and also significantly increased reactive oxygen species in the lung. Prevention of increases in lung ceramide levels mitigated allergen-induced apoptosis, reactive oxygen species, and neutrophil infiltration. In contrast, dietary supplementation of the antioxidant α-tocopherol decreased reactive oxygen species but had no significant effects on elevation of ceramide level or apoptosis, indicating that the increases in lung ceramide levels in allergen-challenged mice are not mediated by oxidative stress. Moreover, specific ceramide species were altered in bronchoalveolar lavage fluid from patients with severe asthma compared with in bronchoalveolar lavage fluid from individuals without asthma. Conclusion Our data suggest that elevation of ceramide level after allergen challenge contributes to the apoptosis, reactive oxygen species generation, and neutrophilic infiltrate that characterize the severe asthmatic phenotype. Ceramide might be the trigger of formation of Creola bodies found in the sputum of patients with severe asthma and could be a biomarker to optimize diagnosis and to monitor and improve clinical outcomes in this disease.Item Childhood Respiratory Viral Infections and the Microbiome(Elsevier, 2023-10) Kloepfer, Kirsten M.; Kennedy, Joshua L.; Pediatrics, School of MedicineThe human microbiome associated with the respiratory tract is diverse, heterogeneous, and dynamic. The diversity and complexity of the microbiome and the interactions between microorganisms, host cells, and the host immune system are complex and multifactorial. Furthermore, the lymphatics provide a direct highway, the gut-lung axis, for the gut microbiome to affect outcomes related to respiratory disease and the host immune response. Viral infections in the airways can also alter the presence or absence of bacterial species, which might increase the risks for allergies and asthma. Viruses infect the airway epithelium and interact with the host to promote inflammatory responses that can trigger a wheezing illness. This immune response may alter the host's immune response to microbes and allergens, leading to T2 inflammation. However, exposure to specific bacteria may also tailor the host's response long before the virus has infected the airway. The frequency of viral infections, age at infection, sampling season, geographic location, population differences, and preexisting composition of the microbiota have all been linked to changes in microbiota diversity and stability. This review aims to evaluate the current reported evidence for microbiome interactions and the influences that viral infection may have on respiratory and gut microbiota, affecting respiratory outcomes in children.Item Community-acquired rhinovirus infection is associated with changes in the airway microbiome(Elsevier, 2017) Kloepfer, Kirsten M.; Sarsani, Vishal K.; Poroyko, Valeriy; Lee, Wai Ming; Pappas, Tressa E.; Kang, Theresa; Grindle, Kristine A.; Bochkov, Yury A.; Janga, Sarath Chandra; Lemanske, Robert F., Jr.; Gern, James E.; Department of Pediatrics, IU School of MedicineItem Detection of Pathogenic Bacteria During Rhinovirus Infection is Associated with Increased Respiratory Symptoms and Exacerbations of Asthma(Elsevier, 2014-05) Kloepfer, Kirsten M.; Lee, Wai Ming; Pappas, Tressa E.; Kang, Teresa; Vrtis, Rose F.; Evans, Michael D.; Gangnon, Ronald E.; Bochkov, Yury A.; Jackson, Daniel J.; Lemanske, Robert F.; Gern, James E.; Department of Pediatrics, IU School of MedicineBackground Detection of either viral or bacterial pathogens is associated with wheezing in children, however the influence of both bacteria and virus on illness symptoms has not been described. Objective We evaluated bacterial detection during peak RV season in children with and without asthma to determine if an association exists between bacterial infection and the severity of RV illnesses. Methods 308 children (166 with asthma, 142 without asthma) ages 4–12 years provided five consecutive weekly nasal samples during September, and scored cold and asthma symptoms daily. Viral diagnostics and quantitative PCR for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were performed on all nasal samples. Results Detection rates were 53%, 17% and 11% for H. influenzae, S. pneumoniae and M. catarrhalis, respectively, with detection of RV increasing the risk of detecting bacteria within the same sample (OR 2.0, 95% CI 1.4–2.7, p<0.0001) or the following week (OR 1.6 (1.1–2.4), p=0.02). In the absence of RV, S. pneumoniae was associated with increased cold symptoms (mean 2.7 (95% CI 2.0–3.5) vs. 1.8 (1.5–2.2), p=0.006) and moderate asthma exacerbations (18% (12%–27%) vs. 9.2% (6.7%–12%), p=0.006). In the presence of RV, S. pneumoniae was associated with increased moderate asthma exacerbations (22% (16%–29%) vs. 15% (11%–20%), p=0.01). Furthermore, M. catarrhalis detected alongside RV increased the likelihood of experiencing cold and/or asthma symptoms compared to isolated detection of RV (OR 2.0 (1.0–4.1), p=0.04). Regardless of RV status, H. influenzae was not associated with respiratory symptoms. Conclusion RV infection enhances detection of specific bacterial pathogens in children with and without asthma. Furthermore, these findings suggest that M. catarrhalis and S. pneumoniae contribute to the severity of respiratory illnesses, including exacerbations of asthma.Item Evaluation of a web-based asthma self-management system: a randomised controlled pilot trial(BioMed Central, 2015-02) Wiecha, John M.; Adams, William G.; Rybin, Denis; Rizzodepaoli, Maria; Keller, Jeremy; Clay, Jayanti M.; Department of Obstetrics and Gynecology, IU School of MedicineBackground Asthma is the most common chronic condition of childhood and disproportionately affects inner-city minority children. Low rates of asthma preventer medication adherence is a major contributor to poor asthma control in these patients. Web-based methods have potential to improve patient knowledge and medication adherence by providing interactive patient education, monitoring of symptoms and medication use, and by facilitation of communication and teamwork among patients and health care providers. Few studies have evaluated web-based asthma support environments using all of these potentially beneficial interventions. The multidimensional website created for this study, BostonBreathes, was designed to intervene on multiple levels, and was evaluated in a pilot trial. Methods An interactive, engaging website for children with asthma was developed to promote adherence to asthma medications, provide a platform for teamwork between caregivers and patients, and to provide primary care providers with up-to-date symptom information and data on medication use. Fifty-eight (58) children primarily from inner city Boston with persistent-level asthma were randomised to either usual care or use of BostonBreathes. Subjects completed asthma education activities, and reported their symptoms and medication use. Primary care providers used a separate interface to monitor their patients’ website use, their reported symptoms and medication use, and were able to communicate online via a discussion board with their patients and with an asthma specialist. Results After 6-months, reported wheezing improved significantly in both intervention and control groups, and there were significant improvements in the intervention group only in night-time awakening and parental loss of sleep, but there were no significant differences between intervention and control groups in these measures. Emergency room or acute visits to a physician for asthma did not significantly change in either group. Among the subgroup of subjects with low controller medication adherence at baseline, adherence improved significantly only in the intervention group. Knowledge of the purpose of controller medicine increased significantly in the intervention group, a statistically significant improvement over the control group. Conclusions This pilot study suggests that a multidimensional web-based educational, monitoring, and communication platform may have positive influences on pediatric patients’ asthma-related knowledge and use of asthma preventer medications.Item High levels of soluble herpes virus entry mediator in sera of patients with allergic and autoimmune diseases(Springer Nature, 2003-12-01) Jun, Hyo Won; La, Su Jin; Kim, Ji Young; Heo, Suk Kyeung; Kim, Ju Yang; Wang, Sa; Kim, Kack Kyun; Lee, Ki Man; Cho, Hong Rae; Lee, Hyeon Woo; Kwon, Byungsuk; Kim, Byung Sam; Kwon, Byoung Se; Microbiology and Immunology, School of MedicineHerpes virus entry mediator (HVEM) is a newly discovered member of the tumor necrosis factor receptor (TNFR) superfamily that has a role in herpes simplex virus entry, in T cell activation and in tumor immunity. We generated mAb against HVEM and detected soluble HVEM (SHVEM) in the sera of patients with various autoimmune diseases. HVEM was constitutively expressed on CD4+ and CD8+ T cells, CD19+ B cells, CD14+ monocytes, neutrophils and dendritic cells. In three-way MLR, mAb 122 and 139 were agonists and mAb 108 had blocking activity. An ELISA was developed to detect sHVEM in patient sera. sHVEM levels were elevated in sera of patients with allergic asthma, atopic dermatitis and rheumatoid arthritis. The mAbs discussed here may be useful for studies of the role of HVEM in immune responses. Detection of soluble HVEM might have diagnostic and prognostic value in certain immunological disorders.Item Institutional Variability in Respiratory Support Use for Pediatric Critical Asthma: A Multicenter Retrospective Study(American Thoracic Society, 2024) Rogerson, Colin M.; White, Benjamin R.; Smith, Michele; Hogan, Alexander H.; Abu-Sultaneh, Samer; Carroll, Christopher L.; Shein, Steven L.; Pediatrics, School of MedicineRationale: Over 20,000 children are hospitalized in the United States for asthma every year. Although initial treatment guidelines are well established, there is a lack of high-quality evidence regarding the optimal respiratory support devices for these patients. Objectives: The objective of this study was to evaluate institutional and temporal variability in the use of respiratory support modalities for pediatric critical asthma. Methods: We conducted a retrospective cohort study using data from the Virtual Pediatrics Systems database. Our study population included children older than 2 years old admitted to a VPS contributing pediatric intensive care unit from January 2012 to December 2021 with a primary diagnosis of asthma or status asthmaticus. We evaluated the percentage of encounters using a high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), noninvasive bilevel positive pressure ventilation (NIV), and invasive mechanical ventilation (IMV) for all institutions, then divided institutions into quintiles based on the volume of patients. We created logistic regression models to determine the influence of institutional volume and year of admission on respiratory support modality use. We also conducted time-series analyses using Kendall’s tau. Results: Our population included 77,115 patient encounters from 163 separate institutions. Institutional use of respiratory modalities had significant variation in HFNC (28.3%, interquartile range [IQR], 11.0–49.0%; P < 0.01), CPAP (1.4%; IQR, 0.3–4.3%; P < 0.01), NIV (8.6%; IQR, 3.5–16.1%; P < 0.01), and IMV (5.1%; IQR, 3.1–8.2%; P < 0.01). Increased institutional patient volume was associated with significantly increased use of NIV (odds ratio [OR], 1.33; 1.29–1.36; P < 0.01) and CPAP (OR, 1.20; 1.15–1.25; P < 0.01), and significantly decreased use of HFNC (OR, 0.80; 0.79–0.81; P < 0.01) and IMV (OR, 0.82; 0.79–0.86; P < 0.01). Time was also associated with a significant increase in the use of HFNC (11.0–52.3%; P < 0.01), CPAP (1.6–5.4%; P < 0.01), and NIV (3.7–21.2%; P < 0.01), whereas there was no significant change in IMV use (6.1–4.0%; P = 0.11). Conclusions: Higher-volume centers are using noninvasive positive pressure ventilation more frequently for pediatric critical asthma and lower frequencies of HFNC and IMV. Treatment with HFNC, CPAP, and NIV for this population is increasing in the last decade.Item Neonatal hyperoxia promotes asthma-like features through IL-33–dependent ILC2 responses(Elsevier, 2017) Cheon, In Su; Son, Young Min; Jiang, Li; Goplen, Nicholas P.; Kaplan, Mark H.; Limper, Andrew H.; Kita, Hirohito; Paczesny, Sophie; Prakash, Y. S.; Tepper, Robert; Ahlfeld, Shawn K.; Sun, Jie; Pediatrics, School of MedicineBackground Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. Objective We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. Methods Mice were exposed to neonatal hyperoxia followed by a period of room air recovery. A group of mice was also intranasally exposed to house dust mite antigen. Assessments were performed at various time points for evaluation of airway hyperresponsiveness, eosinophilia, mucus production, inflammatory gene expression, and TH and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and levels of IL-33 and type 2 cytokines were measured. Results Neonatal hyperoxia induced asthma-like features including airway hyperresponsiveness, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic TH responses to house dust mite exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13 but not IL-4 in preterm infants. Conclusions These data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity.Item Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation(Elsevier, 2021-01) Phipatanakul, Wanda; Mauger, David T.; Guilbert, Theresa W.; Bacharier, Leonard B.; Durrani, Sandy; Jackson, Daniel J.; Martinez, Fernando D.; Fitzpatrick, Anne M.; Cunningham, Amparito; Kunselman, Susan; Wheatley, Lisa M.; Bauer, Cindy; Davis, Carla M.; Geng, Bob; Kloepfer, Kirsten M.; Lapin, Craig; Liu, Andrew H.; Pongracic, Jacqueline A.; Teach, Stephen J.; Chmiel, James; Gaffin, Jonathan M.; Greenhawt, Matthew; Gupta, Meera R.; Lai, Peggy S.; Lemanske, Robert F.; Morgan, Wayne J.; Sheehan, William J.; Stokes, Jeffrey; Thorne, Peter S.; Oettgen, Hans C.; Israel, Elliot; Pediatrics, School of MedicineAsthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma – viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2–3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.Item Serum MicroRNA-21 as a Biomarker for Allergic Inflammatory Disease in Children(Bentham, 2016) Sawant, Deepali V.; Yao, Weiguo; Wright, Zachary; Sawyers, Cindy; Tepper, Robert S.; Gupta, Sandeep K.; Kaplan, Mark H.; Dent, Alexander L.; Department of Microbiology & Immunology, IU School of MedicineMicroRNAs (miRs) have emerged as useful biomarkers for different disease states, including allergic inflammatory diseases such as asthma and eosinophilic esophagitis (EoE). Serum miRs are a possible non-invasive method for diagnosis of such diseases. We focused on microRNA-21 (miR-21) levels in serum, in order to assess the feasibility of using this gene as a non-invasive biomarker for these diseases in the clinic, as well as to better understand the expression pattern of miR-21 in allergic inflammation. We used quantitative PCR (QPCR) to assay miR-21 and other control miRs in esophageal biopsies from EoE patients and serum samples from EoE and asthma patients. Serum levels of miR-21 were significantly elevated in patients with asthma, whereas serum miR-21 levels were not associated with the presence of allergen-specific IgE (i.e. atopy). Esophageal biopsies showed a large elevation of miR-21 in EoE and an increase in miR-21 in EoE serum. Control U6 miR did not vary between asthma and control patients, however EoE serum had significantly decreased U6 microRNA compared to controls. The decreased U6 in EoE sera did not completely account for the relative increase in miR-21 in the sera of EoE patients. We report for the first time that miR-21 is elevated in the sera of both asthma and EoE patients. We find no relation between serum miR-21 levels and atopy. Our results thus suggest miR-21 is a novel biomarker for human allergic inflammatory diseases.