Browsing by Author "Sorkness, Ronald L."

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    Determinants of Lung Function Across Childhood in the Severe Asthma Research Program (SARP) 3
    (Elsevier, 2023) Gaffin, Jonathan M.; Petty, Carter R.; Sorkness, Ronald L.; Denlinger, Loren C.; Phillips, Brenda R.; Ly, Ngoc P.; Gaston, Benjamin; Ross, Kristie; Fitzpatrick, Anne; Bacharier, Leonard B.; DeBoer, Mark D.; Teague, W. Gerald; Wenzel, Sally E.; Ramratnam, Sima; Israel, Elliot; Mauger, David T.; Phipatanakul, Wanda; National Heart, Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators; Pediatrics, School of Medicine
    Background: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. Objective: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. Methods: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. Results: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. Conclusions: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.
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    The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: an overview of Network organization, procedures and interventions
    (Elsevier, 2022-02) Georas, Steve N.; Wright, Rosalind J.; Ivanova, Anastasia; Israel, Elliot; LaVange, Lisa M.; Akuthota, Praveen; Carr, Tara F.; Denlinger, Loren C.; Fajt, Merritt L.; Kumar, Rajesh; O’Neal, Wanda K.; Phipatanakul, Wanda; Szefler, Stanley J.; Aronica, Mark A.; Bacharier, Leonard B.; Burbank, Allison J.; Castro, Mario; Alexander, Laura Crotty; Bamdad, Julie; Cardet, Juan Carlos; Comhair, Suzy A. A.; Covar, Ronina A.; DiMango, Emily A.; Erwin, Kim; Erzurum, Serpil C.; Fahy, John V.; Gaffin, Jonathan M.; Gaston, Benjamin; Gerald, Lynn B.; Hoffman, Eric A.; Holguin, Fernando; Jackson, Daniel J.; James, John; Jarjour, Nizar N.; Kenyon, Nicholas J.; Khatri, Sumita; Kirwan, John P.; Kraft, Monica; Krishnan, Jerry A.; Liu, Andrew H.; Liu, Mark C.; Marquis, M. Alison; Martinez, Fernando; Mey, Jacob; Moore, Wendy C.; Moy, James N.; Ortega, Victor E.; Peden, David B.; Pennington, Emily; Peters, Michael C.; Ross, Kristie; Sanchez, Maria; Smith, Lewis J.; Sorkness, Ronald L.; Wechsler, Michael E.; Wenzel, Sally E.; White, Steven R.; Zein, Joe; Zeki, Amir A.; Noel, Patricia; Pediatrics, School of Medicine
    Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here we describe the Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the U.S. The PrecISE Network was designed to conduct phase II/proof of concept clinical trials of precision interventions in the severe asthma population, and is supported by the National Heart Lung and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the Network will evaluate up to six interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for of severe asthma.
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    Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma
    (American Thoracic Society, 2021) Denlinger, Loren C.; Phillips, Brenda R.; Sorkness, Ronald L.; Bleecker, Eugene R.; Castro, Mario; DeBoer, Mark D.; Fitzpatrick, Anne M.; Hastie, Annette T.; Gaffin, Jonathan M.; Moore, Wendy C.; Peters, Michael C.; Peters, Stephen P.; Phipatanakul, Wanda; Cardet, Juan Carlos; Erzurum, Serpil C.; Fahy, John V.; Fajt, Merritt L.; Gaston, Benjamin; Levy, Bruce D.; Meyers, Deborah A.; Ross, Kristie; Teague, W. Gerald; Wenzel, Sally E.; Woodruff, Prescott G.; Zein, Joe; Jarjour, Nizar N.; Mauger, David T.; Israel, Elliot; Pediatrics, School of Medicine
    Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function. Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline. Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant’s post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5–2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline. Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3–1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index. Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.