Wellness in the modulator era: An observational study of the impact of CFTR modulator therapy on the well-being of people with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) have experienced substantial improvements in health following use of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies. However, less is known about how modulator therapies impact well-being. METHODS: We used a cross-sectional observational study to identify relationships between CFTR modulator therapies, health-related quality of life (HRQoL), and well-being. Adult PwCF and caregivers of children with CF completed the Wellness in the Modulator Era (Well-ME) survey between June 22 and July 31, 2022. HRQoL was measured with PROMIS Global 10/Global 7 + 2 Parent Proxy. We used a mixed methods analysis to compare experiences and concerns of PwCF who currently (n = 665), no longer (n = 51), or never (n = 184) took modulator therapy. RESULTS: Adult PwCF taking a modulator (n = 416) reported better PROMIS global physical health than those who no longer (n = 37) or never took a modulator (n = 94) and better PROMIS global mental health than those who never took a modulator. Caregiver-reported HRQoL was similar across children with CF who currently, no longer, or never took a modulator. PwCF taking a modulator reported larger improvements in physical health, quality of life, social well-being, and treatment burden than those who no longer or never took a modulator. Nearly one-quarter (23 %) of PwCF taking modulator therapy reported worsening of mental well-being. CONCLUSIONS: This study expands our knowledge of well-being among PwCF in the CFTR modulator era as reported by patients and parents. Findings lay the groundwork for establishing future research priorities, policy efforts, and communications in areas that improve well-being for PwCF.

Recombinant Alpha-1 Antitrypsin-Fc Fusion Protein INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency: A Phase 1 Study.

Background: Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT. Methods: In this phase 1 dose-escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX-101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX-101. Results: INBRX-101 was well tolerated. Most treatment-emergent adverse events were grade ≤2. In part 2 (n=18; each dose, n=6), dose-related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21 µM target for up to 4 weeks after the final dose in the 120-mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX-101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady-state serum fAAT ≥21µM at 120 mg/kg Q3W (average concentration ≈43µM; trough concentration ≈28µM) and Q4W (≈34µM; ≈21µM). Conclusion: The favorable safety profile and ability to maintain serum fAAT levels >21µM with extended-interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX-101.

A survey assessing the impact of COVID-19 and elexacaftor/tezacaftor/ifavacaftor on both physical and mental health in adults with cystic fibrosis.

In this letter to the editor, we report 82 persons with CF (PwCF) self-reported changes in mental and physical health and potential attribution with either the COVID-19 pandemic and the initiation elexacaftor/tezacaftor/ivacaftor (ETI). Emerging evidence has shown an association with ETI and mental health adverse events. The close proximity of ETI FDA approval and prescribing in PwCF and the COVID-19 pandemic present a challenge in determining the cause of mental health decline. We report 33 (40%) of respondents felt that COVID-19 contributed to a worsening of either their anxiety, depression, or both and 7 (9%) of respondents felt that ETI contributed to a worsening in their anxiety, depression, or both. Eighteen (23%) of respondents felt that ETI had contributed to improvement their mental health. This letter highlights multiple factors that could be impacting mental health beyond ETI. As the COVID-19 pandemic is moving toward an endemic phase, future studies may have more success in deciphering ETI effects on mental health.

Opportunity for pharmacogenomic testing in patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) are exposed to many drugs in their lifetime and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines that are available to guide dosing. Contemporary CF treatments are targeted to specific mutations in the CF transmembrane conductance regulator (CFTR) gene, and thus, require patients to have genetic testing before initiation of modulator therapy. However, aside from CFTR genetic testing, pharmacogenomic testing is not standard of care for CF patients. AIM: The aim of this study is to determine the number of non-CFTR modulator medications with CPIC guidelines that are prescribed to patients with CF. MATERIALS & METHODS: We identified all patients with a diagnosis of CF and queried our hospital electronic medical records (EMR) for all orders, including inpatient and prescriptions, for all drugs or drug classes that have CPIC actionable guidelines for drug-gene pairs that can be used to guide therapy. RESULTS: We identified 576 patients with a diagnosis of CF that were treated at our institution during this 16-year period between June 2005 and May 2021. Of these patients, 504 patients (87.5%) received at least one drug that could have been dosed according to CPIC guidelines if pharmacogenomic results would have been available. CONCLUSIONS: Patients with CF have high utilization of drugs with CPIC guidelines, therefore preemptive pharmacogenomic testing should be considered in CF patients at the time of CFTR genetic testing.

Social complexity negatively influences lung function in cystic fibrosis after transfer to adult care.

BACKGROUND: Several nongenetic factors, such as socioeconomic status, environmental exposures, and adherence have been described to have an impact on outcomes in cystic fibrosis (CF). OBJECTIVE: To determine the effect of social complexity on the % predicted forced expiratory volume (ppFEV1 ) before and after transfer to adult care among adolescents with CF. METHODS: Retrospective, single center, cohort study included all patients with CF who were transitioned into adult care between 2005 and 2015 at Indiana University. Social complexity (Bob's level of social support, [BLSS]) was collected at transfer. Linear mixed regression models assessed the relationship between ppFEV1 decline over time and BLSS with other covariates. RESULTS: The median age of the patients (N = 133) at the time of transfer was 20 years (interquartile range: 19-23). Overall, there was a decline in lung function over time in our population (ppFEV1 at 24 months pretransfer 77 ± 20%, ppFEV1 at 24 months, posttransfer 66 ± 24%; P < .001). The relationship between BLSS and ppFEV1 became more negative over time, even after adjusting for other covariates. CONCLUSION: Social complexity is strongly associated with lung function decline after transfer to adult care.

Impact of social complexity on outcomes in cystic fibrosis after transfer to adult care.

OBJECTIVE: This study evaluates the roles of medical and social complexity in health care use outcomes in cystic fibrosis (CF) after transfer from pediatric to adult care. METHODS: Retrospective cohort design included patients with CF who were transitioned into adult care at Indiana University from 2005 to 2015. Predictor variables included demographic and comorbidity data, age at transition, treatment complexity score (TCS), and an objective scoring measure of their social complexity (Bob's Level of Social Support, BLSS). Outcome variables included outpatient visit rates and hospitalization rates. Pearson's correlations and linear regression were used to analyze the data. RESULTS: The median age of the patients (N = 133) at the time of transition was 20 (IQR 19-23) years. The mean FEV1 % predicted at transition was 69 ± 24%. TCS correlated with outpatient visit rates (r = 0.3, P = 0.003), as well as hospitalization rates (r = 0.4, P < 0.001); while the BLSS only correlated with hospitalization rates (r = 0.7, P < 0.001). After adjusting for covariates, the strongest predictors of post-transfer hospitalizations are BLSS (P < 0.0001) and pre-transfer hospitalization rate (P < 0.0001). CONCLUSION: Greater treatment complexity is associated with greater healthcare utilization overall, while greater social complexity is associated with increased hospitalizations (but not outpatient visits). Screening young adults for social complexity may identify high-risk subpopulations and allow for patient centered interventions to support them and prevent avoidable health care use.

Effects of sleep apnea on nocturnal free fatty acids in subjects with heart failure.

STUDY OBJECTIVES: Sleep apnea is common in patients with congestive heart failure, and may contribute to the progression of underlying heart disease. Cardiovascular and metabolic complications of sleep apnea have been attributed to intermittent hypoxia. Elevated free fatty acids (FFA) are also associated with the progression of metabolic, vascular, and cardiac dysfunction. The objective of this study was to determine the effect of intermittent hypoxia on FFA levels during sleep in patients with heart failure. DESIGN AND INTERVENTIONS: During sleep, frequent blood samples were examined for FFA in patients with stable heart failure (ejection fraction < 40%). In patients with severe sleep apnea (apnea-hypopnea index = 65.5 ± 9.1 events/h; average low SpO2 = 88.9%), FFA levels were compared to controls with milder sleep apnea (apnea-hypopnea index = 15.4 ± 3.7 events/h; average low SpO2 = 93.6%). In patients with severe sleep apnea, supplemental oxygen at 2-4 liters/min was administered on a subsequent night to eliminate hypoxemia. MEASUREMENTS AND RESULTS: Prior to sleep onset, controls and patients with severe apnea exhibited a similar FFA level. After sleep onset, patients with severe sleep apnea exhibited a marked and rapid increase in FFA relative to control subjects. This increase persisted throughout NREM and REM sleep exceeding serum FFA levels in control subjects by 0.134 mmol/L (P = 0.0038). Supplemental oxygen normalized the FFA profile without affecting sleep architecture or respiratory arousal frequency. CONCLUSION: In patients with heart failure, severe sleep apnea causes surges in nocturnal FFA that may contribute to the accelerated progression of underlying heart disease. Supplemental oxygen prevents the FFA elevation.

Exercise testing in severe emphysema: association with quality of life and lung function.

Six-minute walk testing (6MWT) and cardiopulmonary exercise testing (CPX) are used to evaluate impairment in emphysema. However, the extent of impairment in these tests as well as the correlation of these tests with each other and lung function in advanced emphysema is not well characterized. During screening for the National Emphysema Treatment Trial, maximum ergometer CPX and 6MWT were performed in 1,218 individuals with severe COPD with an average FEV(1) of 26.9 +/- 7.1 % predicted. Predicted values for 6MWT and CPX were calculated from reference equations. Correlation coefficients and multivariable regression models were used to determine the association between lung function, quality of life (QOL) scores, and exercise measures. The two forms of exercise testing were correlated with each other (r = 0.57, p < 0.0001). However, the impairment of performance on CPX was greater than on the 6MWT (27.6 +/- 16.8 vs. 67.9 +/- 18.9 % predicted). Both exercise tests had similar correlation with measures of QOL, but maximum exercise capacity was better correlated with lung function measures than 6-minute walk distance. After adjustment, 6MWD had a slightly greater association with total SGRQ score than maximal exercise (effect size 0.37 +/- 0.04 vs. 0.25 +/- 0.03 %predicted/unit). Despite advanced emphysema, patients are able to maintain 6MWD to a greater degree than maximum exercise capacity. Moreover, the 6MWT may be a better test of functional capacity given its greater association with QOL measures whereas CPX is a better test of physiologic impairment.

Field tests of exercise in COPD: the six-minute walk test and the shuttle walk test.

Exercise testing is useful to assess the degree of disability, prognosis for survival, presence of exercise-induced hypoxemia, and response to treatment in individuals with chronic obstructive pulmonary disease. Simple walking tests have been developed and are increasingly used in assessment of chronic obstructive pulmonary disease patients for clinical and research purposes. This article reviews how these tests are performed and to what degree they are reliable, and how these tests are used in assessment of individuals with chronic obstructive pulmonary disease.

Minimal clinically important differences in the six-minute walk test and the incremental shuttle walking test.

Simple walking tests are widely used for the assessment of functional status in patients with cardiorespiratory disorders. These tests require far less instrumentation than formal cardiopulmonary exercise tests, but they do require standardization of procedures to achieve reproducible results. The most widely used tests for patients with COPD are the 6-minute walking test (6MWT) and the incremental shuttle walking test (SWT). The 6MWT has been characterized in COPD patients with respect to reproducibility and responsivity to change in health status. The 6MWT results are correlated with pulmonary function, health-related quality of life, maximum exercise capacity, and mortality. The minimal clinically important difference (MCID) for the 6MWT is conservatively estimated to be 54-80 meters using both distributional and discriminative methods. For an individual patient, the 6MWT would need to change by about 86 meters to be statistically confident that there has been a change. The SWT has been less extensively validated than the 6MWT, but has similar reproducibility in COPD (CV = approximately 20%). The SWT results improve with pulmonary rehabilitation and bronchodilation, and are highly correlated with maximum oxygen consumption. There are no studies that address the issue of MCID for the SWT. In addition to the MCID, the design and interpretation of COPD clinical trials should take into account the severity of initial impairment, the asymmetry between positive and negative changes, the proportion of patients who show substantial improvement, and the costs and risks of the treatment.

Lung volume reduction surgery.

Lung volume reduction surgery (LVRS) has been widely studied and has been available for the treatment of advanced emphysema for 10 years. This paper reviews some of the historical attempts at surgical treatment of emphysema, the physiology of LVRS, and the modern data on patient selection, risks, and benefits. Data from the National Emphysema Treatment Trial are presented in the context of the large body of case series and smaller randomized trials that have preceded that study. Future technologies of bronchoscopic lung volume reduction are also discussed.

Health-related quality of life of persons with sarcoidosis.

STUDY OBJECTIVES: To describe the health-related quality of life (HRQL) and mental health of persons with sarcoidosis, as well as to assess physician-patient agreement about the presence of sarcoidosis symptoms. DESIGN AND SETTING: Cross-sectional study at three university medical center outpatient pulmonary clinics. PATIENTS: One hundred eleven outpatients with sarcoidosis seen between March and July 2002. MEASUREMENTS: The HRQL of sarcoidosis patients was measured using generic and respiratory disease-specific forms (ie, Medical Outcomes Study 36-item short form survey [SF-36] and the St. George respiratory questionnaire [SGRQ], respectively). Depression was assessed using the Center for Epidemiologic Studies depression scale, and stress was assessed with the perceived stress scale four-item questionnaire. The kappa-statistic was calculated to compare physician-patient agreement in assessing sarcoidosis-related symptoms. RESULTS: Patients had moderate-to-severe reductions across all measured domains in perceived HRQL. Those patients who were prescribed oral corticosteroids had lower scores on both the SF-36 and the SGRQ than did those patients who were not. These differences were statistically significant and clinically important. The prevalence of depression was 66%, and that of significant stress was 55%. Spirometry values (FEV(1), 82% predicted; FVC, 86% predicted) were associated neither with HRQL nor with patients' perceived sarcoidosis symptoms, although they were correlated (r = 0.43; p < 0.0001) with physicians' perceptions that patients were symptomatic. Physicians and patients had only fair agreement (kappa-statistic range, 0.24 to 0.36 [by center]) in assessing perceived sarcoidosis symptoms. CONCLUSIONS: Outpatients with sarcoidosis had global reductions in measured HRQL and mental health indexes, although patients receiving therapy with oral corticosteroids had significantly worse HRQL. Experienced physicians based their assessments of patients' sarcoidosis symptoms on measures that were not related to issues of importance to patients. HRQL measurement may provide a unique insight into the impact that sarcoidosis may have on a patient's life that is not captured in traditional physiologic measures.

The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life.

The Sarcoidosis Health Questionnaire (SHQ) is a health-related quality-of-life (HRQL) instrument we designed in a two-part study to allow patients to describe their satisfaction with life as it is affected by sarcoidosis. In the Development Study, we created the SHQ from a 151-item pool generated from interviews with 107 patients, a search of the relevant literature, and discussion with sarcoidosis experts. Using clinical impact methodology and the questionnaire responses of a separate group of 149 patients, we reduced the total number of items to 29. The final SHQ has three domains: Daily Functioning, Physical Functioning, and Emotional Functioning. In the Validation Study, performed with a different group of 111 patients, we found that the SHQ had good internal consistency reliability, as well as evidence of content, criterion, and construct validity based on its comparison with other measures of HRQL (Medical Outcomes Study 36-Item short form and the St. George's Respiratory Questionnaire) and of mental health (the Center for Epidemiologic Study-Depression Scale), as well as with clinical variables including spirometry. The SHQ alone was sensitive to differences in HRQL based on the number of involved organ systems. In conclusion, we have developed a self-completed HRQL questionnaire for U.S. patients with sarcoidosis.