Browsing by Author "Sanders, D. B."

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    Antipseudomonal treatment decisions during CF exacerbation management
    (Elsevier, 2022) VanDevanter, D. R.; West, N. E.; Sanders, D. B.; Skalland, M.; Goss, C. H.; Flume, P. A.; Heltshe, S. L.; Pediatrics, School of Medicine
    Background: Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents. Methods: We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted. Results: Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses. Conclusions: We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa.
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    Association of site of treatment with clinical outcomes following intravenous antimicrobial treatment of a pulmonary exacerbation
    (Elsevier, 2022) Sanders, D. B.; Khan, U.; Heltshe, S. L.; Skalland, M.; West, N. E.; VanDevanter, D. R.; Goss, C. H.; Flume, P. A.; Pediatrics, School of Medicine
    Background: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital. Methods: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location. Results: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only. Conclusions: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home.
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    C-reactive protein (CRP) as a biomarker of pulmonary exacerbation presentation and treatment response
    (Elsevier, 2022) VanDevanter, D. R.; Heltshe, S. L.; Skalland, M.; West, N. E.; Sanders, D. B.; Goss, C. H.; Flume, P. A.; Pediatrics, School of Medicine
    BACKGROUND: C-reactive protein (CRP) has been proposed as a biomarker for pulmonary exacerbation (PEx) diagnosis and treatment response. CRP >75mg/L has been associated with increased risk of PEx treatment failure. We have analyzed CRP measures as biomarkers for clinical response during the STOP2 PEx study (NCT02781610). METHODS: CRP measures were collected at antimicrobial treatment start (V1), seven to 10 days later (V2), and two weeks after treatment end (V3). V1 log10CRP concentrations and log10CRP change from V1 to V3 correlations with clinical responses (changes in lung function and symptom score) were assessed by least squares regression. Odds of intravenous (IV) antimicrobial retreatment within 30 days and future PEx hazard associated with V1 and V3 CRP concentrations and V1 CRP >75 mg/L were studied by adjusted logistic regression and proportional hazards modeling, respectively. RESULTS: In all, 951 of 982 STOP2 subjects (92.7%) had CRP measures at V1. V1 log10CRP varied significantly by V1 lung function subgroup, symptom score quartile, and sex, but not by age subgroup. V1 log10CRP correlated moderately with log10CRP change at V3 (r2=0.255) but less so with lung function (r2=0.016) or symptom (r2=0.031) changes at V3. Higher V1 CRP was associated with greater response. CRP changes from V1 to V3 only weakly correlated with lung function (r2=0.061) and symptom (r2=0.066) changes. However, V3 log10CRP was associated with increased odds of retreatment (P=.0081) and future PEx hazard (P=.0114) DISCUSSION: Despite consistent trends, log10CRP change was highly variable with only limited utility as a biomarker of PEx treatment response.
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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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    Preliminary method for profiling volatile organic compounds in breath that correlate with pulmonary function and other clinical traits of subjects diagnosed with cystic fibrosis: a pilot study
    (IOP, 2022-04) Woollam, M.; Siegel, A. P.; Grocki, P.; Saunders, J. L.; Sanders, D. B.; Agarwal, M.; Davis, M. D.; Chemistry and Chemical Biology, School of Science
    Cystic fibrosis (CF) is characterized by chronic respiratory infections which progressively decrease lung function over time. Affected individuals experience episodes of intensified respiratory symptoms called pulmonary exacerbations (PEx), which in turn accelerate pulmonary function decline and decrease survival rate. An overarching challenge is that there is no standard classification for PEx, which results in treatments that are heterogeneous. Improving PEx classification and management is a significant research priority for people with CF. Previous studies have shown volatile organic compounds (VOCs) in exhaled breath can be used as biomarkers because they are products of metabolic pathways dysregulated by different diseases. To provide insights on PEx classification and other CF clinical factors, exhaled breath samples were collected from 18 subjects with CF, with some experiencing PEx and others serving as a baseline. Exhaled breath was collected in Tedlar bags during tidal breathing and cryotransferred to headspace vials for VOC analysis by solid phase microextraction coupled to gas chromatography–mass spectrometry. Statistical significance testing between quantitative and categorical clinical variables displayed percent-predicted forced expiratory volume in one second (FEV1pp) was decreased in subjects experiencing PEx. VOCs correlating with other clinical variables (body mass index, age, use of highly effective modulator treatment (HEMT), and the need for inhaled tobramycin) were also explored. Two volatile aldehydes (octanal and nonanal) were upregulated in patients not taking the HEMT. VOCs correlating to potential confounding variables were removed and then analyzed by regression for significant correlations with FEV1pp measurements. Interestingly, the VOC with the highest correlation with FEV1pp (3,7-dimethyldecane) also gave the lowest p-value when comparing subjects at baseline and during PEx. Other VOCs that were differentially expressed due to PEx that were identified in this study include durene, 2,4,4-trimethyl-1,3-pentanediol 1-isobutyrate and 5-methyltridecane. Receiver operator characteristic curves were developed and showed 3,7-dimethyldecane had higher ability to classify PEx (area under the curve (AUC) = 0.91) relative to FEV1pp values at collection (AUC = 0.83). However, normalized ΔFEV1pp values had the highest capability to distinguish PEx (AUC = 0.93). These results show that VOCs in exhaled breath may be a rich source of biomarkers for various clinical traits of CF, including PEx, that should be explored in larger sample cohorts and validation studies.
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    Study design considerations for the Standardized Treatment of Pulmonary Exacerbations 2 (STOP2): A trial to compare intravenous antibiotic treatment durations in CF
    (Elsevier, 2018-01) Heltshe, Sonya L.; West, Natalie E.; VanDevanter, Donald R.; Sanders, D. B.; Beckett, Valeria V.; Flume, Patrick A.; Goss, Christopher H.; Pediatrics, School of Medicine
    BACKGROUND: Pulmonary exacerbations (PEx) in cystic fibrosis (CF) are common and contribute to morbidity and mortality. Duration of IV antibiotic therapy to treat PEx varies widely in the US, and there are few data to guide treatment decisions. METHODS: We combined a survey of CF stakeholders with retrospective analyses of a recent observational study of CF PEx to design a multicenter, randomized, prospective study comparing the efficacy and safety of different durations of IV antibiotics for PEx to meet the needs of people with CF and their caregivers. RESULTS: IV antibiotic duration was cited as the most important PEx research question by responding CF physicians and top concern among surveyed CF patients/caregivers. During PEx, forced expiratory volume in 1s (FEV1% predicted) and symptom responses at 7-10days of IV antibiotics identified two distinct groups: early robust responders (ERR) who subsequently experienced greater FEV1 improvements compared to non-ERR (NERR). In addition to greater FEV1 and symptom responses, only 14% of ERR patients were treated with IV antibiotics for >15days, compared with 45% of NERR patients. CONCLUSIONS: A divergent trial design that evaluates subjects' interim improvement in FEV1 and symptoms to tailor randomization to IV treatment duration (10 vs. 14days for ERR, 14 vs. 21days for NERR) may alleviate physician and patient concerns about excess or inadequate treatment. Such a study has the potential to provide evidence necessary to standardize IV antibiotic duration in CF PEx care -a first step to conducting PEx research of other treatment features.