Browsing by Author "Chmiel, James"

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    Drug Development for Cystic Fibrosis
    (Wiley, 2021-02) Sanders, Don; Chmiel, James; Pediatrics, School of Medicine
    The first regulatory approval for a drug developed specifically for cystic fibrosis (CF) occurred in 1993, and since then, several other drugs have been approved. Median predicted survival in people with CF in the United States has increased from approximately 30 years to 44.4 years over that same period. Highly effective modulators of the cystic fibrosis transmembrane conductance regulator became available to approximately 90% of people with CF ages 12 years and older in the United States in 2019 and in Europe in 2020. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies advance, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in outcome measures has become more difficult as the health status of people with CF improves. Innovative approaches are required to continue to advance drug development in CF. This review provides a general overview of drug development from the preclinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF.
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    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 Medicine
    Asthma 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.
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    Social Determinants of Health and Clinical Outcomes in Children With Cystic Fibrosis
    (2024-05-20) de Laosa, Mary; Ayub, Jinan; Bilinski, Sarah; Fultz, Megan; Petit, Rebecca; Chmiel, James; Sanders, Don
    Rationale: Among children with cystic fibrosis (CF), clinical outcomes vary among genetically similar patients, in part due to the contributions of social determinants of health (SDOH). Changes to patient assistance programs and Medicaid re-enrollment requirements may further impact people affected by SDOH. This project aimed to identify socially vulnerable patients and evaluate the impacts of SDOH on clinical outcomes. Methods: From January to July 2023, SDOH questionnaires were distributed to families of children with CF at Riley Hospital for Children. Patients were categorized by SDOH vulnerability and associations with clinical outcomes were analyzed using the Chi-squared test of independence. Results: 193 screeners were analyzed: the mean age was 9.2 years; 53% were males, 2.6% identified as non-White race, 3.6% reported Hispanic ethnicity, 51.6% were enrolled in Medicaid, and 70.5% were taking either ivacaftor or elexacaftor-tezacaftor-ivacaftor (ETI), consistent with the overall CF Center population. Overall, 100 (51.8%) screened positive for at least one SDOH (SDOH+): 60 screened positive for 1, 25 for 2, and 13 for 3+ SDOH. Of the SDOH+ patients, 64% were affected by the medical needs of another family member, 30% by food insecurity, 28% by difficulties affording utilities or rent, 22% by transportation needs, 11% by housing, and 9% by medication costs. In addition, 16 (8.3%) reported being negatively affected by changes to patient assistance programs and 7 (3.6%) by difficulties with Medicaid re-enrollment; 12 (75%) and 3 (43%) of whom were SDOH+, respectively. Of those who were SDOH+, 62% received immediate social work intervention.Mean (SD) FEV1 among SDOH+ patients was 5.8 (5.2)% predicted lower than their 2022 mean, vs 3.5 (5.0)% lower for SDOH- patients, p=0.001. A higher proportion of SDOH+ patients were 35% predicted below their 2022 mean FEV1 (24% vs 13% for SDOH-, p=0.037) and to have been hospitalized for a pulmonary exacerbation in the prior 12 months (21% vs 10% for SDOH-, p=0.030). There were no differences in mean BMI percentile, CFRD, or P. aeruginosa. Conclusions: Half of our CF Center population that completed a questionnaire screened positive for at least one SDOH. Some of these were not previously known by the CF Center team and this information provided opportunities to support families. SDOH+ patients have benefited from support from the multidisciplinary team, which may have mitigated negative impacts on clinical outcomes of insurance/payment assistance program changes. We will continue to routinely track SDOH, and changes to patient assistance programs and Medicaid.
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    The Effects of Social Determinants of Health on Clinical Outcomes in Pediatric Cystic Fibrosis Patients
    (2023-07-27) Ayub, Jinan; de Laosa, Mary; Bilinski, Sarah; Chmiel, James; Sanders, Don B.
    BACKGROUND AND OBJECTIVE Advances in the treatment of cystic fibrosis (CF) with cystic fibrosis transmembrane regulator modulators have improved morbidity and mortality, however, clinical outcomes vary among genetically similar patients due to contributions of social determinants of health (SDOH). Pancreatic insufficiency, CF-related diabetes (CFRD), Pseudomonas infections, and lower BMI increase risk of severe lung disease, measured by forced expiratory volume in 1 second (FEV1). This project aims to identify socially vulnerable patients and evaluate the impact of SDOH on clinical outcomes. METHODS From January to July 2023, SDOH screeners were distributed to families of children with CF at Riley Hospital for Children, documenting transportation, housing, food insecurity, insurance, and medication costs. Clinical outcomes for each patient including FEV1% predicted, BMI/WFL percentile, CFRD, hospitalizations, respiratory infections with Pseudomonas aeruginosa, and pancreatic insufficiency within the past 12 months were recorded. Patients were categorized by SDOH vulnerability, and associations with poor clinical outcomes were analyzed using the Chi-squared test of independence. RESULTS A total of 193 screeners were analyzed: males represented 52.6% of the cohort, 2.60% identified as non-white race, and 3.65% reported Hispanic ethnicity. Overall, 51.8% screened positive for at least one SDOH (SDOH+) and 48.1% screened negative (SDOH-). The average FEV1% predicted decline among SDOH+ patients was 5.79% and 3.51% among SDOH- patients. SDOH+ patients were more likely to have at least a 5% decline in FEV1% predicted (p=0.037) and to be hospitalized due to exacerbations of CF lung disease at least once in the past 12 months (p=0.030). Although low BMI percentile, Pseudomonas infection, and CFRD were not significantly associated with SDOH, socially vulnerable patients demonstrated higher rates of these clinical outcomes. CONCLUSION AND IMPLICATIONS SDOH impact CF clinical outcomes. Screeners are effective in identifying socially vulnerable patients and serve as the first step in addressing unmet social needs.