Browsing by Author "Davis, Miriam"

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    Association of Antibiotics, Airway Microbiome, and Inflammation in Infants with Cystic Fibrosis
    (American Thoracic Society, 2017-10) Pittman, Jessica E.; Wylie, Kristine M.; Akers, Kathryn; Storch, Gregory A.; Hatch, Joseph; Quante, Jane; Frayman, Katherine B.; Clarke, Nadeene; Davis, Miriam; Stick, Stephen M.; Hall, Graham L.; Montgomery, Gregory; Ranganathan, Sarath; Davis, Stephanie D.; Ferkol, Thomas W.; Pediatrics, School of Medicine
    RATIONALE: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation. OBJECTIVES: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF. METHODS: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin 8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid. RESULTS: Thirty-two infants (mean age, 4.7 months) underwent bronchoalveolar lavage and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, although community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily antistaphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated with lower interleukin 8 concentration and absolute neutrophil count. CONCLUSIONS: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.
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    The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials
    (European Respiratory Society, 2018-02-16) Foong, Rachel E.; Harper, Alana J.; Skoric, Billy; King, Louise; Turkovic, Lidija; Davis, Miriam; Clem, Charles C.; Rosenow, Tim; Davis, Stephanie D.; Ranganathan, Sarath; Hall, Graham L.; Ramsey, Kathryn A.; Pediatrics, School of Medicine
    The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3-6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible.
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    Determinants of lung disease progression measured by lung clearance index in children with cystic fibrosis
    (ERS, 2021-07) Stanojevic, Sanja; Davis, Stephanie D.; Perrem, Lucy; Shaw, Michelle; Retsch-Bogart, George; Davis, Miriam; Jensen, Renee; Clem, Charles C.; Isaac, Sarah M.; Guido, Julia; Jara, Sylvia; France, Lisa; McDonald, Nancy; Solomon, Melinda; Sweezey, Neil; Grasemann, Hartmut; Waters, Valerie; Sanders, D. B.; Ratjen, Felix A.; Pediatrics, School of Medicine
    The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis. While LCI worsens during the preschool years in cystic fibrosis, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable. A cohort of children (healthy and cystic fibrosis) previously studied for 12 months as preschoolers were followed during school age (5–10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time. A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 cystic fibrosis subjects were available. The majority of children with cystic fibrosis had elevated LCI at the first preschool and first school age visits (57.8% (37 out of 64)), whereas all but six had normal forced expiratory volume in 1 s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (−0.02 units·year−1 (95% CI −0.14–0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age. Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.
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    Lung Clearance Index to Track Acute Respiratory Events in School-Age Children with Cystic Fibrosis
    (ATS, 2021-04) Perrem, Lucy; Stanojevic, Sanja; Shaw, Michelle; Jensen, Renee; McDonald, Nancy; Isaac, Sarah M.; Davis, Miriam; Clem, Charles; Guido, Julia; Jara, Sylvia; France, Lisa; Soloman, Melinda; Grasemann, Hartmut; Waters, Valerie; Sweezey, Neil; Sanders, Don B.; Davis, Stephanie D.; Ratjen, Felix; Pediatrics, School of Medicine
    Rationale: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF), but its utility to identify and manage these events in school-age children with CF is not well defined. Objectives: To describe changes in LCI with acute respiratory events in school-age children with CF. Methods: In a multisite prospective observational study, the LCI and FEV1 were measured quarterly and during acute respiratory events. Linear regression was used to compare relative changes in LCI and FEV1% predicted at acute respiratory events. Logistic regression was used to compare the odds of a significant worsening in LCI and FEV1% predicted at acute respiratory events. Generalized estimating equation models were used to account for repeated events in the same subject. Measurements and Main Results: A total of 98 children with CF were followed for 2 years. There were 265 acute respiratory events. Relative to a stable baseline measure, LCI (+8.9%; 95% confidence interval, 6.5 to 11.3) and FEV1% predicted (−6.6%; 95% confidence interval, −8.3 to −5.0) worsened with acute respiratory events. A greater proportion of events had a worsening in LCI compared with a decline in FEV1% predicted (41.7% vs. 30.0%; P = 0.012); 53.9% of events were associated with worsening in LCI or FEV1. Neither LCI nor FEV1 recovered to baseline values at the next follow-up visit. Conclusions: In school-age children with CF, the LCI is a sensitive measure to assess lung function worsening with acute respiratory events and incomplete recovery at follow-up. In combination, the LCI and FEV1 capture a higher proportion of events with functional impairment.
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    Multiple-Breath Washout Outcomes Are Sensitive to Inflammation and Infection in Children with Cystic Fibrosis
    (ATS, 2017-09) Ramsey, Kathryn A.; Foong, Rachel E.; Grdosic, Jasmine; Harper, Alana; Skoric, Billy; Clem, Charles; Davis, Miriam; Turkovic, Lidija; Stick, Stephen M.; Davis, Stephanie D.; Ranganathan, Sarath C.; Hall, Graham L.; Pediatrics, School of Medicine
    Rationale: The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. Objectives: We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. Methods: Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3–6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple-breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. Results: Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. Conclusions: These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.
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    Progression of Lung Disease in Preschool Patients with Cystic Fibrosis
    (American Thoracic Society, 2017-05-01) Stanojevic, Sanja; Davis, Stephanie D.; Retsch-Bogart, George t; Webster, Hailey; Davis, Miriam; Johnson, Robin C.; Jensen, Renee; Pizarro, Maria Ester; Kane, Mica; Clem, Charles C.; Schornick, Leah; Subbarao, Padmaja; Ratjen, Felix A.; Pediatrics, School of Medicine
    RATIONALE: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease. OBJECTIVES: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF. METHODS: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age-matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed-effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease. MEASUREMENTS AND MAIN RESULTS: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values. CONCLUSIONS: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF.