Browsing by Subject "FEV1"

Now showing 1 - 6 of 6
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    5-HTP inhibits eosinophilia via intracellular endothelial 5-HTRs; SNPs in 5-HTRs associate with asthmatic lung function
    (Frontiers Media, 2024-05-23) Walker, Matthew T.; Bloodworth, Jeffrey C.; Kountz, Timothy S.; McCarty, Samantha L.; Green, Jeremy E.; Ferrie, Ryan P.; Campbell, Jackson A.; Averill, Samantha H.; Beckman, Kenneth B.; Grammer, Leslie C.; Eng, Celeste; Avila, Pedro C.; Farber, Harold J.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose R.; Serebrisky, Denise; Thyne, Shannon M.; Seibold, Max A.; Burchard, Esteban G.; Kumar, Rajesh; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    Background: Previous research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers. Objective: It is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans. Methods: Serotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts. Results: Pharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics. Conclusions: Serotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.
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    Poor recovery from a pulmonary exacerbation does not lead to accelerated FEV1 decline
    (Elsevier, 2017-07-29) Sanders, Don B.; Li, Zhanhai; Zhao, Qianqian; Farrell, Philip; Pediatrics, School of Medicine
    BACKGROUND: Patients with CF treated for pulmonary exacerbations (PEx) may experience faster subsequent declines in FEV1. Additionally, incomplete recovery to baseline FEV1 occurs frequently following PEx treatment. Whether accelerated declines in FEV1 are preceded by poor PEx recovery has not been studied. METHODS: Using 2004 to 2011 CF Foundation Patient Registry data, we randomly selected one PEx among patients ≥6years of age with no organ transplantations, ≥12months of data before and after the PEx, and ≥1 FEV1 recorded within the 6months before and 3months after the PEx. We defined poor PEx recovery as the best FEV1 in the 3months after the PEx <90% of the best FEV1 in the 6months before the PEx. We calculated mean (95% CI) hazard ratios (HR) of having >5% predicted/year FEV1 decline and poor PEx recovery using multi-state Markov models. RESULTS: From 13,954 PEx, FEV1 declines of >5% predicted/year were more likely to precede poor spirometric recovery, HR 1.17 (1.08, 1.26), in Markov models adjusted for age and sex. Non-Responders were less likely to have a subsequent fast FEV1 decline, HR 0.41 (0.37, 0.46), than patients who recovered to >90% of baseline FEV1 following PEx treatment. CONCLUSIONS: Accelerated declines in FEV1 are more likely to precede a PEx with poor recovery than to occur in the following year. Preventing or halting declines in FEV1 may also have the benefit of preventing PEx episodes.
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    Poor recovery from cystic fibrosis pulmonary exacerbations is associated with poor long-term outcomes
    (Wiley, 2017-10) Sanders, Don B.; Zhao, Qianqian; Li, Zhanhai; Farrell, Philip M.; Pediatrics, School of Medicine
    RATIONALE: People with CF treated with IV antibiotics for a pulmonary exacerbation (PEx) frequently fail to recover to baseline FEV1 . The long-term impact of these events has not been studied. OBJECTIVES: To determine if a patient's spirometric recovery after a PEx is associated with time to next PEx within 1 year, the spirometric recovery after the next PEx, and/or the number of PEx episodes in the next 3 years. METHODS: We used data from the CF Foundation Patient Registry from 2004 to 2011. We randomly selected one PEx per patient that met inclusion/exclusion criteria. Patients were defined as Non-Responders if their best FEV1 (in liters) recorded in the 3 months after the PEx was <90% of the best FEV1 (in liters) in the 6 months before the PEx. We compared Responders and Non-Responders using multivariable regression models. RESULTS: We randomly chose 13 954 PEx episodes that met inclusion/exclusion criteria. A total of 2 762 (19.8%) patients were classified as Non-Responders. Non-Responders had a shorter median time to the next PEx, 235 (95%CI 218, 252) days, versus >365 days for Responders. Thirty-four percent of Non-Responders at the initial PEx were also Non-Reponders at the next PEx, versus 20% of Responders at the initial PEx. Non-Responders had more PEx episodes over the next 3 years, 4.99 (95%CI 4.84, 5.13), than Responders, 3.46 (95%CI 3.41, 3.51). CONCLUSIONS: Poor recovery after a PEx is associated with a shorter time to the next PEx, increased risk of poor recovery at a second PEx, and more frequent subsequent PEx treatments.
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    Quantitative chest computerized tomography and FEV1 equally identify pulmonary exacerbation risk in children with cystic fibrosis
    (Wiley, 2018-10) Sanders, Don B.; Li, Zhanhai; Parker-McGill, Katelyn; Farrell, Philip; Brody, Alan S.; Pediatrics, School of Medicine
    Background: Chest computerized tomography (CT) scores are associated with the frequency of future pulmonary exacerbations in people with cystic fibrosis (CF). However, cut-off values to identify children with mild lung disease with different risks for frequent future pulmonary exacerbations have not been identified. Methods: Chest CT scans were assessed using the Brody score for participants of the Pulmozyme Early Intervention Trial (PEIT) and Wisconsin Randomized Clinical Trial of CF Newborn Screening (WI RCT). We determined the area under the receiver operating characteristic (ROC) curve for Brody scores and forced expiratory volume in 1 s (FEV1) to compare with the frequency of pulmonary exacerbations up to 10 years later. Results: There were 60 participants in the PEIT with mean (SD) age 10.6 (1.7) years at the time of the CT and 81 participants in the WI RCT with mean age 11.5 (3.0) years. The Brody score cut-off that best identified children at-risk for ≥0.3 annual pulmonary exacerbations was 3.6 in the PEIT and 2.1 in the WI RCT. There were no statistical differences between ROC curves for the Brody CT score and FEV1 % predicted in either study (P ≥ 0.4). Conclusions: CT score cut-off values that identify children with CF with mild lung disease at different risks for frequent pulmonary exacerbations over an extended follow up period are similar in separate cohorts. Brody scores and FEV1 % predicted have similar abilities to identify these children, suggesting that FEV1 % predicted alone may be adequate for predicting future frequency of pulmonary exacerbations.
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    Quantitative chest computerized tomography and FEV1 equally identify pulmonary exacerbation risk in children with cystic fibrosis
    (Wiley, 2018-10) Sanders, Don B.; Li, Zhanhai; Parker-McGill, Katelyn; Farrell, Philip; Brody, Alan S.; Pediatrics, School of Medicine
    Background Chest computerized tomography (CT) scores are associated with the frequency of future pulmonary exacerbations in people with cystic fibrosis (CF). However, cut‐off values to identify children with mild lung disease with different risks for frequent future pulmonary exacerbations have not been identified. Methods Chest CT scans were assessed using the Brody score for participants of the Pulmozyme Early Intervention Trial (PEIT) and Wisconsin Randomized Clinical Trial of CF Newborn Screening (WI RCT). We determined the area under the receiver operating characteristic (ROC) curve for Brody scores and forced expiratory volume in 1 s (FEV1) to compare with the frequency of pulmonary exacerbations up to 10 years later. Results There were 60 participants in the PEIT with mean (SD) age 10.6 (1.7) years at the time of the CT and 81 participants in the WI RCT with mean age 11.5 (3.0) years. The Brody score cut‐off that best identified children at‐risk for ≥0.3 annual pulmonary exacerbations was 3.6 in the PEIT and 2.1 in the WI RCT. There were no statistical differences between ROC curves for the Brody CT score and FEV1 % predicted in either study (P ≥ 0.4). Conclusions CT score cut‐off values that identify children with CF with mild lung disease at different risks for frequent pulmonary exacerbations over an extended follow up period are similar in separate cohorts. Brody scores and FEV1 % predicted have similar abilities to identify these children, suggesting that FEV1 % predicted alone may be adequate for predicting future frequency of pulmonary exacerbations.
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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.