Cystic Fibrosis: The Dawn of a New Therapeutic Era

Heltshe, Sonya L.; Cogen, Jonathan D; Ramos, Kathleen J.; Goss, Christopher H.

doi:10.1164/rccm.201606-1250pp

Cited by 23 publications

(17 citation statements)

References 58 publications

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“…Cystic fibrosis (CF) is a life-shortening autosomal recessive disorder affecting over 30,000 people in the United States and 70,000 worldwide. 1 It is caused by a genetic defect in the CF transmembrane conductance regulator (CFTR) protein, leading to defective chloride transfer across the cell membrane. 2 The hallmarks of the disease are pulmonary manifestations and digestive issues including exocrine pancreatic insufficiency, which is present in approximately 85% of those with CF.…”

Section: Introductionmentioning

confidence: 99%

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Prevalence and Risk Factors for Iron Deficiency in Adults With Cystic Fibrosis

et al. 2020

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Background: Iron deficiency is common in cystic fibrosis (CF), but previous prevalence studies often reported results confounded by acute exacerbations. This single-center retrospective study aimed to identify the prevalence of iron deficiency in a stable adult CF population, identify the risk factors associated with iron deficiency, and compare common laboratory indicators of iron status. Methods: Medical charts of 105 patients aged 18-67 were reviewed to determine the prevalence of anemia. Of these patients, a subgroup of 67 were included in analyses of iron deficiency, defined as serum ferritin < 12 ng/mL and/or percent transferrin saturation (TSAT) < 16%. Data on sex, age, body mass index, anemia status, vitamin deficiencies, presence of comorbidities, colonization with Pseudomonas aeruginosa, and use of acid blockers and CF transmembrane conductance regulator modulators were collected to evaluate relationship of iron deficiency with these clinical factors. κ agreements between serum iron, ferritin, transferrin, and TSAT were compared. Results: In this stable CF population, the prevalence of iron deficiency was 41.8% (n = 67), and the prevalence of anemia was 33.3% (n = 105). Iron deficiency was associated with presence of anemia (P < .001), vitamin A deficiency (P = .012), and moderate (P = .047) and severe lung disease (P = .045) compared with mild lung disease. Transferrin agreed poorly with other iron status indicators. Conclusion: Iron deficiency is common in CF, although prevalence rates can vary widely depending on the laboratory parameters used. CF centers should consider routine screening for iron deficiency.

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Section: Introductionmentioning

confidence: 99%

“…Cystic fibrosis (CF) is a life‐shortening autosomal recessive disorder affecting over 30,000 people in the United States and 70,000 worldwide 1 . It is caused by a genetic defect in the CF transmembrane conductance regulator (CFTR) protein, leading to defective chloride transfer across the cell membrane 2 .…”

Section: Introductionmentioning

confidence: 99%

Prevalence and Risk Factors for Iron Deficiency in Adults With Cystic Fibrosis

et al. 2020

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“…However, it remains unknown whether similar active dysfunction occurs in neutrophils present in the airway lumen of children with CF, and how this dysfunction may relate to free extracellular NE activity and structural lung damage. This question is particularly important at a time when novel therapies are slowing the appearance of symptoms in patients with CF (34).…”

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confidence: 99%

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

Margaroli

Garratt

Horati

et al. 2019

Am J Respir Crit Care Med

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Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown.Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF.Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects.Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes.Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

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“…Cystic fibrosis (CF) is a heritable, life-shortening disease caused by dysfunction of the CF transmembrane conductance regulator, leading to progressive multisystem organ damage, with lung involvement being the predominant cause of morbidity and mortality. Remarkable strides were made over the past 2 decades in the care of CF patients, driven by advances in basic science, development of robust clinical trial network and multidisciplinary, evidence-based management in care centers, such as those accredited by the CF Foundation in the United States (US) [ 1 , 2 ]. As a result, dramatic improvement was noted in long-term survival of CF patients, with over 50% being 18 year or older, reaching recently a predicted median survival of nearly 42 years [ 3 ], with projected median survival over 50 years, if the recently observed decrease in mortality continues at the same rate [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Critical illness among adults with cystic fibrosis in Texas, 2004–2013: Patterns of ICU utilization, characteristics, and outcomes

Oud

2017

PLoS ONE

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ObjectiveAvailable reports on critically ill adults with cystic fibrosis (CF) suggest improving short-term outcomes. However, there is marked heterogeneity in reported findings, with studies mostly based on single-centered data, limiting generalizability. We sought to examine population-level patterns of demand for critical care resources, and the characteristics, resource utilization, and outcomes of ICU-managed adults with CF.MethodsWe used the Texas Inpatient Public Use Data File to identify ICU admissions with CF aged ≥18 years in Texas between 2004–2013. We examined ICU utilization at population level (using CF Foundation annual reports) and, among ICU admissions, socio-demographic characteristics, burden of comorbidities, organ failure, life-support utilization and hospital disposition. Linear regression and multilevel logistic regression were used to examine temporal trends and predictors of short-term mortality (hospital death and discharge to hospice), respectively.ResultsOf 9,579 hospitalizations of adults with CF, 1,249 (13%) were admitted to ICU. The incidence of ICU admission among adults with CF in Texas increased between 2004–2005 and 2012–2013 from 16.7 to 19.2 per 100 person-years (p = 0.0181), with ICU admissions aged ≥30 years accounting for 80.3% of the change. Among ICU admissions the following changes were noted between 2004–2005 and 2012–2013: any organ failure 30.2% vs. 56.3% (p = 0.0004), mechanical ventilation 11.5% vs. 19.2% (p = 0.0216), and hemodialysis 1.0% vs. 8.1% (p = 0.0007). Short-term mortality for the whole cohort and for those with mechanical ventilation was 11.4% and 41.8%, respectively, with corresponding home discharge among survivors 84% and 62.1%, respectively. Key predictors (adjusted odds ratios [aOR (95% CI)]) of short-term mortality included age ≥45 years (2.051 [1.231–3.415]), female gender (1.907 [1.237–2.941]), and mechanical ventilation (7.982 [5.001–12.739]).ConclusionsAdults with CF had high and rising population-level burden of critical illness. Although ICU admissions were increasingly older and sicker, the majority survived hospitalization, with most discharged home, supporting short-term benefits of critical care in the present cohort.

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Cystic Fibrosis: The Dawn of a New Therapeutic Era

Cited by 23 publications

References 58 publications

Prevalence and Risk Factors for Iron Deficiency in Adults With Cystic Fibrosis

Prevalence and Risk Factors for Iron Deficiency in Adults With Cystic Fibrosis

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

Critical illness among adults with cystic fibrosis in Texas, 2004–2013: Patterns of ICU utilization, characteristics, and outcomes

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