IU Indianapolis ScholarWorks :: Browsing by Author "Farrell, Philip M."

Browsing by Author "Farrell, Philip M."

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Association of Lung Function, Chest Radiographs and Clinical Features in Infants with Cystic Fibrosis
(European Respiratory Society, 2013) Rosenfeld, Margaret; Farrell, Philip M.; Kloster, Margaret; Swanson, Jonathan O.; Vu, Thuy; Brumback, Lyndia; Acton, James D.; Castile, Robert G.; Colin, Andrew A.; Conrad, Carol K.; Hart, Meeghan A.; Kerby, Gwendolyn S.; Hiatt, Peter W.; Mogayzel, Peter J.; Johnson, Robin C.; Davis, Stephanie D.; Pediatrics, School of Medicine
The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease.
Defining and identifying early-onset lung disease in cystic fibrosis with cumulative clinical characteristics
(Wiley, 2022) Huang, Leslie; Lai, HuiChuan J.; Antos, Nicholas; Rock, Michael J.; Asfour, Fadi; Howenstine, Michelle; Gaffin, Jonathan M.; Farrell, Philip M.; Pediatrics, School of Medicine
Background: Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early-onset lung disease is needed. Objective: To develop a CF early-onset lung disease (CFELD) scoring system by utilizing prospectively collected longitudinal data on manifestations in the first 3 years of life. Design: We studied 145 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and followed to 36 months of age. Cough severity, pulmonary exacerbations (PEx), respiratory cultures, and hospitalizations were collected at each CF center visit (every 1-2 months in infancy and quarterly thereafter). These data were used to construct the CFELD system and to classify lung disease into five categories: asymptomatic, minimal, mild, moderate, and severe. Results: The most frequent manifestation of CF early lung disease was MD-reported PEx episodes, PEx hospitalizations, and positive Pseudomonas aeruginosa cultures. Parent-reported cough severity was correlated with the number of respiratory hospitalizations (r = 0.48, p < 0.0001). The distribution of CFELD categories was 10% asymptomatic, 17% minimal, 29% mild, 33% moderate, and 12% severe. The moderate and severe categories occurred threefold higher in pancreatic insufficient (PI, 49%) versus sufficient subjects (16%), p < 0.0001. In addition to PI, gastrointestinal and nutrition-related hospitalizations, plasma cytokines interleukin (IL)-6 and IL-10, duration of CFTR modulator therapy, and type of health insurance were significant predictors of CFELD scores. Conclusion: The CFELD scoring system is novel, allows systematic evaluation of lung disease prognosis early, and may aid in therapeutic decision-making particularly in the initiation of CFTR modulator therapy.
Diagnosis of Cystic Fibrosis in Screened Populations
(Elsevier, 2017-02) Farrell, Philip M.; White, Terry B.; Howenstine, Michelle S.; Munck, Anne; Parad, Richard B.; Rosenfeld, Margaret; Sommerburg, Olaf; Accurso, Frank J.; Davies, Jane C.; Rock, Michael J.; Sanders, Don B.; Wilschanski, Michael; Sermet-Gaudelus, Isabelle; Blau, Hannah; Gartner, Silvia; McColley, Susanna A.; Pediatrics, School of Medicine
Objective Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. Study design To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. Results After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. Conclusions It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.
Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation
(Elsevier, 2017-02) Farrell, Philip M.; White, Terry B.; Ren, Clement L.; Hempstead, Sarah E.; Accurso, Frank; Derichs, Nico; Howenstine, Michelle; McColley, Susanna A.; Rock, Michael; Rosenfeld, Margaret; Sermet-Gaudelus, Isabelle; Southern, Kevin W.; Marshall, Bruce C.; Sosnay, Patrick R.; Department of Pediatrics, School of Medicine
Objective Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. Study design To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. Results After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. Conclusions It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.
Early life growth patterns persist for 12 years and impact pulmonary outcomes in cystic fibrosis
(Elsevier, 2018-07) Sanders, Don B.; Zhang, Zhumin; Farrell, Philip M.; Lai, HuiChuan J.; Pediatrics, School of Medicine
BACKGROUND: In children with cystic fibrosis (CF), recovery from growth faltering within 2 years of diagnosis (Responders) is associated with better growth and less lung disease at age 6 years. This study examined whether these benefits are sustained through 12 years of age. METHODS: Longitudinal growth from 76 children with CF enrolled in the Wisconsin CF Neonatal Screening Project was examined and categorized into 5 groups: R12, R6, and R2, representing Responders who maintained growth improvement to age 12, 6, and 2 years, respectively, and I6 and N6, representing Non-responders whose growth did and did not improve during ages 2-6 years, respectively. Lung disease was evaluated by % predicted forced expiratory volume in one second (FEV1) and chest radiograph (CXR) scores. RESULTS: Sixty-two percent were Responders. Within this group, 47% were R12, 28% were R6, and 25% were R2. Among Non-responders, 76% were N6. CF children with meconium ileus (MI) had worse lung function and CXR scores compared to other CF children. Among 53 children with pancreatic insufficiency without MI, R12 had significantly better FEV1 (97-99% predicted) and CXR scores during ages 6-12 years than N6 (89-93% predicted). Both R6 and R2 experienced a decline in FEV1 by ages 10-12 years. CONCLUSIONS: Early growth recovery in CF is critical, as malnutrition during infancy tends to persist and catch-up growth after age 2 years is difficult. The longer adequate growth was maintained after early growth recovery, the better the pulmonary outcomes at age 12 years.
Impact of acid blocker therapy on growth, gut microbiome, and lung disease in young children with cystic fibrosis
(Wiley, 2024) Liu, Cathy; Bach, Taiya R.; Farrell, Philip M.; Pavelec, Derek; Antos, Nicholas J.; Rock, Michael J.; Asfour, Fadi; Howenstine, Michelle; Gaffin, Jonathan M.; Lai, HuiChuan J.; Pediatrics, School of Medicine
Objective: Acid blocker therapy (ABT) has become common in cystic fibrosis (CF), despite insufficient evidence for benefits and studies showing potentially negative effects. We examined associations between ABT usage and growth, gut microbiome (GM), and early-onset lung disease in young children with CF. Methods: One hundred and forty-five infants with CF born during 2012-2017, diagnosed through newborn screening by age 3 months and followed to 36 months of age at six CF centers were evaluated. Longitudinal data on growth, pancreatic functional status, pulmonary symptoms, and acid blocker medications were prospectively collected. Early-onset lung disease severity was evaluated by a clinical scoring system. GM composition was assessed by 16S rRNA methodology. Results: ABT use before age 3 years was frequent, with 81 (56%) of patients on H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI), and higher among pancreatic insufficient (60%) versus pancreatic sufficient (26%) children. H2RA was commonly prescribed in infancy before transitioning to PPI. Growth improvements were not significantly greater, while GM α-diversity at 3 years of age was significantly lower and early-onset lung disease more severe, in persistent ABT users compared to nonusers of ABT. Conclusion: In our cohort of young children with CF, early and persistent ABT use was not associated with significant growth benefits and instead showed associations with reduced GM diversity and negative effects on early-onset lung disease. Consequentially, there is a critical need for systematic evaluation and comprehensive risk-benefit analysis of ABT to ensure proper guidelines for children with CF.
Outcomes of infants born during the first 9 years of CF newborn screening in the United States: successes and the need for improvement
(TechRxiv, 2021-02-18) Martiniano, Stacey L.; Elbert, Alexander A.; Farrell, Philip M.; Ren, Clement L.; Sontag, Marci K.; Wu, Runyu; McColley, Susanna A.; Medicine, School of Medicine
Introduction: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis generating study was designed to form the basis of additional research and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS. Methods: We included participants in the CF Foundation Patient Registry born 2010-2018 with age at first CF event (first sweat test, clinic visit or hospitalization) by age 365 days. We assessed age of center-reported diagnosis, age at first CF event, demographics and outcomes for three consecutive 3-year cohorts born in 2010-2012, 2013-2015, and 2016-2018. Results: In 6354 infants, median age at diagnosis was earlier than median age at first CF event, which decreased from 1st cohort to 3rd cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was > 0 but height-for-age (HFA) z-score was < 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection rates decreased over time. About 1/3 of infants were hospitalized in the first year of life across cohorts. Conclusion: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts but improving nutritional deficits and reducing infant hospitalizations remain targets for improvement.
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.
The Frequency and Potential Implications of HFE Genetic Variants in Children With Cystic Fibrosis
(Wiley, 2025) Huang, Leslie; Lai, HuiChuan J.; Furuya, Katryn N.; Antos, Nicholas J.; Asfour, Fadi; Boyne, Kathleen L.; Howenstine, Michelle; Rock, Michael J.; Sawicki, Gregory S.; Gaffin, Jonathan M.; Worthey, Elizabeth A.; Farrell, Philip M.; Pediatrics, School of Medicine
Background: Genetic modifiers have been identified that increase the risks of lung disease and other complications, such as diabetes in people with cystic fibrosis (CF). Variants in the hemochromatosis gene (HFE) were reported in a study of adults to be associated with worse lung disease. Objectives: To ascertain the frequency of HFE variants, particularly C282Y (c.845G > A) and H63D (c.187C > G) and to determine if they are associated with variations in the onset and early severity of CF lung disease as well as abnormalities in iron status. Design: We studied with whole genome sequencing and clinical outcome measures in a cohort of 104 children with CF at 5-6 years old who were previously found to show an association between aggregated genetic modifiers and an earlier onset and a more severe lung disease phenotype. Results: In our cohort, 23% have H63D and 11% have C282Y. Lung function at age 6 years and Pseudomonas aeruginosa infections did not differ by HFE variants, but having C282Y was associated with more pulmonary exacerbations in the first 6 years of life. Three patients have H63D/C282Y genotype, and all showed phenotypic expression of hemochromatosis with abnormal iron indices. Conclusion: Our study revealed that the presence of HFE variant C282Y in people with CF may lead to more severe lung disease manifestations beginning in early childhood. There is a risk of hemochromatosis in CF patients with two HFE variants, and thus they should be followed for evidence of iron overload.

Browsing by Author "Farrell, Philip M."

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