A randomized trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations (PExs) in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 second (ppFEV1) in CF PExs not responding to antibiotic therapy. METHODS: This was a randomized, double-blind, placebo-controlled trial in pwCF treated with intravenous (IV) antibiotics for a PEx. At Day 7, those who had not returned to >90% baseline ppFEV1 were randomized to adjuvant prednisone 1 mg·kg-1 twice daily (max 60 mg/day) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline ppFEV1 at Day 14 of IV antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomized. 50% of subjects in the prednisone group recovered baseline FEV1 on Day 14 compared to 39% of subjects in the placebo group for a difference of 11% (95% CI -11, 34%, p=0.34). The mean (sd) change in ppFEV1 from Day 7 to Day 14 was 6.8% predicted (8.8) in the prednisone group and 4.6% (6.9) in the placebo group (mean difference 2.2% predicted 95% CI -1.5, 5.9%, p=0.24). Time to subsequent exacerbation was not prolonged in prednisone treated subjects (HR 0.83, 95% CI 0.45, 1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in ppFEV1 recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of IV antibiotic therapy for PExs.

Comparing the Hospital Frailty Risk Score and the Clinical Frailty Scale Among Older Adults With Chronic Obstructive Pulmonary Disease Exacerbation.

Importance: Frailty is associated with severe morbidity and mortality among people with chronic obstructive pulmonary disease (COPD). Interventions such as pulmonary rehabilitation can treat and reverse frailty, yet frailty is not routinely measured in pulmonary clinical practice. It is unclear how population-based administrative data tools to screen for frailty compare with standard bedside assessments in this population. Objective: To determine the agreement between the Hospital Frailty Risk Score (HFRS) and the Clinical Frailty Scale (CFS) among hospitalized individuals with COPD and to determine the sensitivity and specificity of the HFRS (vs CFS) to detect frailty. Design, Setting, and Participants: A cross-sectional study was conducted among hospitalized patients with COPD exacerbation. The study was conducted in the respiratory ward of a single tertiary care academic hospital (The Ottawa Hospital, Ottawa, Ontario, Canada). Participants included consenting adult inpatients who were admitted with a diagnosis of acute COPD exacerbation from December 2016 to June 2019 and who used a clinical care pathway for COPD. There were no specific exclusion criteria. Data analysis was performed in March 2022. Exposure: Degree of frailty measured by the CFS. Main Outcomes and Measures: The HFRS was calculated using hospital administrative data. Primary outcomes were the sensitivity and specificity of the HFRS to detect frail and nonfrail individuals according to CFS assessments of frailty, and the secondary outcome was the optimal probability threshold of the HFRS to discriminate frail and nonfrail individuals. Results: Among 99 patients with COPD exacerbation (mean [SD] age, 70.6 [9.5] years; 56 women [57%]), 14 (14%) were not frail, 33 (33%) were vulnerable, 18 (18%) were mildly frail, and 34 (34%) were moderately to severely frail by the CFS. The HFRS (vs CFS) had a sensitivity of 27% and specificity of 93% to detect frail vs nonfrail individuals. The optimal probability threshold for the HFRS was 1.4 points or higher. The corresponding sensitivity to detect frailty was 69%, and the specificity was 57%. Conclusions and Relevance: In this cross-sectional study, using the population-based HFRS to screen for frailty yielded poor detection of frailty among hospitalized patients with COPD compared with the bedside CFS. These findings suggest that use of the HFRS in this population may result in important missed opportunities to identify and provide early intervention for frailty, such as pulmonary rehabilitation.

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension.

BACKGROUND: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Trends in outpatient and inpatient visits for separate ambulatory-care-sensitive conditions during the first year of the COVID-19 pandemic: a province-based study.

Background: The COVID-19 pandemic led to global disruptions in non-urgent health services, affecting health outcomes of individuals with ambulatory-care-sensitive conditions (ACSCs). Methods: We conducted a province-based study using Ontario health administrative data (Canada) to determine trends in outpatient visits and hospitalization rates (per 100,000 people) in the general adult population for seven ACSCs during the first pandemic year (March 2020-March 2021) compared to previous years (2016-2019), and how disruption in outpatient visits related to acute care use. ACSCs considered were chronic obstructive pulmonary disease (COPD), asthma, angina, congestive heart failure (CHF), hypertension, diabetes, and epilepsy. We used time series auto-regressive integrated moving-average models to compare observed versus projected rates. Results: Following an initial reduction (March-May 2020) in all types of visits, primary care outpatient visits (combined in-person and virtual) returned to pre-pandemic levels for asthma, angina, hypertension, and diabetes, remained below pre-pandemic levels for COPD, and rose above pre-pandemic levels for CHF (104.8 vs. 96.4, 95% CI: 89.4-104.0) and epilepsy (29.6 vs. 24.7, 95% CI: 22.1-27.5) by the end of the first pandemic year. Specialty visits returned to pre-pandemic levels for COPD, angina, CHF, hypertension, and diabetes, but remained above pre-pandemic levels for asthma (95.4 vs. 79.5, 95% CI: 70.7-89.5) and epilepsy (53.3 vs. 45.6, 95% CI: 41.2-50.5), by the end of the year. Virtual visit rates increased for all ACSCs. Among ACSCs, reductions in hospitalizations were most pronounced for COPD and asthma. CHF-related hospitalizations also decreased, albeit to a lesser extent. For angina, hypertension, diabetes, and epilepsy, hospitalization rates reduced initially, but returned to pre-pandemic levels by the end of the year. Conclusion: This study demonstrated variation in outpatient visit trends for different ACSCs in the first pandemic year. No outpatient visit trends resulted in increased hospitalizations for any ACSC; however, reductions in rates of asthma, COPD, and CHF hospitalizations persisted.

Development and assessment of an educational intervention to improve the recognition of frailty on an acute care respiratory ward.

BACKGROUND: Frailty is a robust predictor of poor outcomes among patients with chronic obstructive pulmonary disease yet is not measured in routine practice. We determined barriers and facilitators to measuring frailty in a hospital setting, designed and implemented a frailty-focused education intervention, and measured accuracy of frailty screening before and after education. METHODS: We conducted a pilot cross-sectional mixed-methods study on an inpatient respiratory ward over 6 months. We recruited registered nurses (RNs) with experience using the Clinical Frailty Scale (CFS). RNs evaluated 10 clinical vignettes and assigned a frailty score using the CFS. A structured frailty-focused education intervention was delivered to small groups. RNs reassigned frailty scores to vignettes 1 week after education. Outcomes included barriers and facilitators to assessing frailty in hospital, and percent agreement of CFS scores between RNs and a gold standard (determined by geriatricians) before and after education. RESULTS: Among 26 RNs, the median (IQR) duration of experience using the CFS was 1.5 (1-4) months. Barriers to assessing frailty included the lack of clinical directives to measure frailty and large acute workloads. Having collateral history from family members was the strongest perceived facilitator for frailty assessment. The median (IQR) percent agreement with the gold-standard frailty score across all cases was 55.8% (47.2%-60.6%) prior to the educational intervention, and 57.2% (44.1%-70.2%) afterwards. The largest increase in agreement occurred in the 'mildly frail' category, 65.4%-81% agreement. CONCLUSIONS: Barriers to assessing frailty in the hospital setting are external to the measurement tool itself. Accuracy of frailty assessment among acute care RNs was low, and frailty-focused rater training may improve accuracy. Subsequent work should focus on health system approaches to empower health providers to assess frailty, and on testing the effectiveness of frailty-focused education in large real-world settings.

Effects of Bardoxolone Methyl in Alport Syndrome.

BACKGROUND AND OBJECTIVES: Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 m2, to bardoxolone methyl (n=77) or placebo (n=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight. RESULTS: Patients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4; P<0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; P=0.0008] ml/min per 1.73 m2, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; P<0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; P=0.02) ml/min per 1.73 m2 at 52 and 104 weeks, respectively. In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, -1.9 to 4.9] ml/min per 1.73 m2). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure. CONCLUSIONS: In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.

Trends in all-cause mortality and inpatient and outpatient visits for ambulatory care sensitive conditions during the first year of the COVID-19 pandemic: A population-based study.

BACKGROUND: The impact of the COVID-19 pandemic on the management of ambulatory care sensitive conditions (ACSCs) remains unknown. OBJECTIVES: To compare observed and expected (projected based on previous years) trends in all-cause mortality and healthcare use for ACSCs in the first year of the pandemic (March 2020 to March 2021). DESIGN, SETTING AND PARTICIPANTS: We conducted a population-based study using provincial health administrative data on general adul population (Ontario, Canada). OUTCOMES AND MEASURES: Monthly all-cause mortality, and hospitalizations, emergency department (ED) and outpatient visit rates (per 100,000 people at-risk) for seven combined ACSCs (asthma, chronic obstructive pulmonary disease, angina, congestive heart failure, hypertension, diabetes, and epilepsy) during the first year were compared with similar periods in previous years (2016-2019) by fitting monthly time series autoregressive integrated moving-average models. RESULTS: Compared to previous years, all-cause mortality rates increased at the beginning of the pandemic (observed rate in March to May 2020 of 79.98 vs. projected of 71.24 [66.35-76.50]) and then returned to expected in June 2020-except among immigrants and people with mental health conditions where they remained elevated. Hospitalization and ED visit rates for ACSCs remained lower than projected throughout the first year: observed hospitalization rate of 37.29 versus projected of 52.07 (47.84-56.68); observed ED visit rate of 92.55 versus projected of 134.72 (124.89-145.33). ACSC outpatient visit rates decreased initially (observed rate of 4299.57 vs. projected of 5060.23 [4712.64-5433.46]) and then returned to expected in June 2020.

Emerging Nonpulmonary Complications for Adults With Cystic Fibrosis: Adult Cystic Fibrosis Series.

Improved treatments for cystic fibrosis (CF)-related lung disease have resulted in increased longevity, but also increased prevalence and severity of extrapulmonary manifestations of CF, treatment-related complications, age-related conditions, and psychosocial effects of longstanding chronic disease. Likewise, the recognition of mild CF phenotypes has changed the landscape of CF disease. This review outlines our current understanding of the common extrapulmonary complications of CF, as well as the changing landscape and future directions of the extrapulmonary complications experienced by patients with CF.

Dyspnea, focal wheeze, and a slow growing endobronchial tumor.

We describe a case of an otherwise healthy woman who presented with nonspecific respiratory symptoms, but was found to have recurrent focal findings on chest radiograph. Her CT scan showed an endobronchial lesion with distal bronchiectasis which was ultimately diagnosed as a mucoepidermoid carcinoma. In this report we discuss the clinical, radiographic, bronchoscopic and pathologic findings of rarely seen endobronchial mucoepidermoid tumors.

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome.

INTRODUCTION: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. METHODS: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. RESULTS: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study).

OBJECTIVE: Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. METHODS: We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. RESULTS: One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. INTERPRETATION: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

Effects of Bardoxolone Methyl on Hepatic Enzymes in Patients with Type 2 Diabetes Mellitus and Stage 4 CKD.

In a multinational placebo-controlled phase III clinical trial in 2,185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, treatment with the Nrf2 activator bardoxolone methyl increased estimated glomerular filtration rate, a measure of kidney function, but also resulted in increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase. These increases in liver enzyme level(s) were maximal after 4 weeks of treatment and reversible, trending back toward baseline through week 48. Total bilirubin concentrations did not increase, and no cases met Hy's Law criteria, although two subjects had ALT concentrations that exceeded 10 × the upper limit of the population reference range leading to discontinuation of treatment. Animal and cell culture experiments suggested that the increases in ALT and AST induced by bardoxolone methyl may be related to its pharmacological activity. Bardoxolone methyl significantly induced the mRNA expression of ALT and AST isoforms in cultured cells. Expression of ALT and AST isoforms in liver and kidney also positively correlated with Nrf2 status in mice. Overall, these data suggest that the increases in ALT and AST observed clinically were, at least in part, related to the pharmacological induction of aminotransferases via Nrf2 activation, rather than to any intrinsic form of hepatotoxicity.

Sexual and reproductive health in cystic fibrosis.

PURPOSE OF REVIEW: With improving life expectancy and quality of life, sexual and reproductive health (SRH) has become an increasingly important aspect of patient-centered cystic fibrosis care. This review aims to describe advances in cystic fibrosis-related SRH and highlight optimal practices. RECENT FINDINGS: Recent publications suggest that people with cystic fibrosis follow a similar trajectory of sexual development and activity as their noncystic fibrosis peers, although contraception use is lower. Although fertility is reduced in patients with cystic fibrosis, improved survival and assisted reproductive technologies have led to an increasing pursuit and incidence of pregnancy. Cystic fibrosis transmembrane regulator modulators that correct the underlying cystic fibrosis defect might improve fertility and thus far appear safe in pregnancy, though data are limited.Despite medical knowledge of SRH in cystic fibrosis, patients continue to report they lack sufficient education about these aspects of their healthcare, and cystic fibrosis multidisciplinary teams are ill prepared to counsel their patients. SUMMARY: Understanding of the effects of cystic fibrosis on SRH continues to improve, although many questions remain regarding optimal care from the choice of contraception to the safety of cystic fibrosis-specific medications in pregnancy. Further development of cystic fibrosis-informed interdisciplinary specialist networks and a wider framework of practice would both enhance health outcomes and better support patients.

A severe pleural complication associated with granulomatosis with polyangiitis.

We describe the case of a previously healthy male patient who presented to a respiratory clinic with sinusitis, pulmonary cavities, and hemoptysis. Three weeks following a diagnosis of Granulomatosis with Polyangiitis (GPA) and initiation of immunosuppressive treatment, the patient suddenly developed a large pneumothorax that was complicated by empyema. In this report we discuss and highlight the rare pleural complications associated with GPA, and alert clinicians to monitor for these important complications even after disease-modifying treatment is initiated.