Impact of chronic medication de-escalation in patients with cystic fibrosis taking elexacaftor, tezacaftor, ivacaftor: A retrospective review.

BACKGROUND: This single-center, retrospective study evaluated the effects of de-escalating cystic fibrosis (CF) supportive therapies in patients on elexacaftor/tezacaftor/ivacaftor (ETI). For many with CF, the clinical benefit of ETI exceeds that of supportive therapies. Therefore, we anticipated patients would desire to discontinue many of their supportive therapies, leading to the creation of a de-escalation algorithm. If patients were clinically improved and stable on ETI, CF supportive therapies could be de-escalated quarterly in accordance with the algorithm. METHODS: The primary objective was to assess non-inferiority of supportive therapies de-escalation by comparing the absolute change in percent predicted (ppFEV1) from baseline to month 1 versus the absolute change from baseline to month 12 after initiating ETI with patients serving as their own control. A chart review of patients initiated on ETI from September 2019 through December 2020 was conducted. Inclusion criteria included those six years and older with at least one copy of F508del. RESULTS: The study included 174 patients. The mean ppFEV1 at baseline, month 1, and month 12 was 67%, 78%, and 87% respectively. The mean difference in absolute change in ppFEV1 from baseline to month 1 compared to baseline to month 12 after the initiation of ETI was 1.53% (95% CI: -0.49 to 3.55) CONCLUSION: De-escalating supportive therapies for those on ETI was non-inferior to remaining on all supportive therapies. This suggests that medications may be able to be discontinued under the context of a de-escalation algorithm, which may decrease medication burden and cost and increase quality of life.

Sweat metabolomics before and after intravenous antibiotics for pulmonary exacerbation in people with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PWCF) suffer from acute unpredictable reductions in pulmonary function associated with a pulmonary exacerbation (PEx) that may require hospitalization. PEx symptoms vary between PWCF without universal diagnostic criteria for diagnosis and response to treatment. RESEARCH QUESTION: We characterized sweat metabolomes before and after intravenous (IV) antibiotics in PWCF hospitalized for PEx to determine feasibility and define biological alterations by IV antibiotics for PEx. STUDY DESIGN AND METHODS: PWCF with PEx requiring hospitalization for IV antibiotics were recruited from clinic. Sweat samples were collected using the Macroduct® Sweat Collection System at admission prior to initiation of IV antibiotics and after completion prior to discharge. Samples were analyzed for metabolite changes using ultra-high-performance liquid chromatography/tandem accurate mass spectrometry. RESULTS: Twenty-six of 29 hospitalized PWCF completed the entire study. A total of 326 compounds of known identity were detected in sweat samples. Of detected metabolites, 147 were significantly different between pre-initiation and post-completion of IV antibiotics for PEx (average treatment 14 days). Global sweat metabolomes changed from before and after IV antibiotic treatment. We discovered specific metabolite profiles predictive of PEx status as well as enriched biologic pathways associated with PEx. However, metabolomic changes were similar in PWCF who failed to return to baseline pulmonary function and those who did not. INTERPRETATION: Our findings demonstrate the feasibility of non-invasive sweat metabolomic profiling in PWCF and the potential for sweat metabolomics as a prospective diagnostic and research tool to further advance our understanding of PEx in PWCF.

Impact of asthma severity on long-term asthma control.

Background: Asthma is a common childhood disease with significant morbidity. Severe asthma accounts for just 4-6% of patients, but this group is more difficult to treat and is responsible for up to 40% of asthma expenses.Objective: The relationship between asthma severity and control is not well characterized. The main objective of this study was to determine impact of asthma severity on asthma control over time.Methods: This was a three year, prospective observational cohort study at a tertiary care children's hospital. Results were compared over time and between patients with severe and non-severe persistent asthma. Intervention included therapy based on severity and control, accompanied by a NAEPP (EPR-3) guidelines based structured asthma education program.Results: The sample included 471 children referred from primary care offices with the diagnosis of persistent asthma, mean age 6.4 ± 2.4 years. Forty-one children (8.7%) had severe persistent asthma and 430 (91.3%) children had non-severe persistent asthma (mild-moderate persistent). Our sample size decreased over the three-year period and the number of patients completing the third year were 176 (38%) and among them 20 (11.4%) had severe asthma. At the initial visit, children with severe persistent asthma had significantly more acute care needs, more daily symptoms, and lower mean Asthma Control Test™ scores compared to children with non-severe persistent asthma. Differences between groups decreased within six months with significant improvements in most indicators persisting throughout three-year follow up in both groups (p < 0.05).Conclusion: Asthma control improves independent of severity if asthma guidelines are followed.

Mental health history and social barriers impacting caregivers of infants with cystic fibrosis.

OBJECTIVES: Caregivers of infants with cystic fibrosis (CF) carry a heavy treatment burden for their child along with the inherent difficulties of raising an infant. This study investigated the impact of self-reported caregiver mental health diagnoses and social barriers during the 1st year of life on clinical outcomes. METHODS: A retrospective chart review was conducted for infants seen in a large tertiary hospital CF clinic over a 5-year period. Baseline characteristics were collected, and documentation from physician and social work notes were reviewed. Demographics and clinical characteristics were compared by the presence or absence of self-reported mental health diagnoses, social barriers, and "emotional concern." RESULTS: Analyses were conducted on 71 patients. Thirty-five percent of caregivers disclosed mental health diagnoses, 52% identified social barriers to care, and 55% reported feeling upset or fatigued. Having a caregiver with a self-reported mental health diagnosis was associated with tobacco smoke exposure (p < .001) and increased odds of hospitalizations (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.49-6.06), emergency department/urgent care visits (OR, 3.17; 95% CI, 1.32-7.64), and longer lengths of stay (OR, 1.93; 95% CI, 1.69-2.20). Caregivers who expressed emotional concern had infants with significantly lower weight-for-length percentiles (p = .012). DISCUSSION: Caregiver mental health and social barriers to care are important determinants to address as they may impact clinical outcomes in infants with CF. Identifying barriers and struggles early increases the likelihood that clinical teams can intervene and provide support. Further research into mental health and socioeconomic barriers faced by caregivers of infants with CF is crucial.

Correction to: Influence of Cystic Fibrosis­Related Diabetes on Mental Health in Adults: A Single­Center Study.

The original version of this article unfortunately contained a mistake in one of the co-author name Prof. Don Hayes Jr. During production process, "Jr." was missed to add after the author name. The author name is corrected with this correction. The original article has been corrected.

Influence of Cystic Fibrosis-Related Diabetes on Mental Health in Adults: A Single-Center Study.

PURPOSE: People with cystic fibrosis (CF) are predisposed to chronic conditions, such as CF-related diabetes (CFRD). Recent attention has been focused on the addition of screening for anxiety and depression in the CF population. Independently, CFRD and mental health conditions are associated with worse clinical outcomes; however, research assessing the impact of both conditions together is limited. We aimed to characterize the association between CFRD and selected diagnoses of anxiety or depressive disorders on clinical outcomes in adults with CF. METHODS: A single-center, retrospective, cross-sectional study in adult patients with CF was performed. Group comparisons included selected diagnoses of depression, anxiety, and CFRD using two-sample t-tests or rank-sum tests for continuous variables, and Chi-square or Fisher's exact tests for categorical variables. RESULTS: A total of 209 adults were enrolled (mean age of 31.4 ± 11.4 years). Those with a selected diagnoses of depression had a significantly higher proportion of CFRD than those without depression (48% vs. 28%, respectively, p = 0.005), and CFRD was associated with increased odds of depression [OR (CI) = 2.33 (1.28, 4.26), p = 0.006]. We did not see a higher proportion of adults with CFRD and selected diagnoses of anxiety than those without anxiety (41% vs. 31% respectively, p = 0.12), nor an increased odds of anxiety in those with CFRD [OR (CI) = 1.58 (0.88, 2.84), p = 0.12]. CONCLUSION: We show a significant association between CFRD and selected diagnoses of depression in a cohort of adult patients.

Practitioner Due Diligence: Real-World Lumacaftor/Ivacaftor Use.

OBJECTIVE: Previous trials evaluated the efficacy of lumacaftor/ivacaftor in Phe508del homozygotes. These trials are limited by manufacturer sponsorship and were conducted under strict protocol. Additionally, this therapy is costly and does not allow for reduction in daily cystic fibrosis therapies. This study assessed the efficacy of lumacaftor/ivacaftor therapy and its effect on health care utilization in a real-world setting. METHODS: Retrospective chart review comparing the first 12 months of therapy to the 24 months prior was conducted to evaluate the impact of lumacaftor/ivacaftor on pulmonary function following a streamlined process for therapy introduction. The impact on body mass index and healthcare utilization were also evaluated. The following measurements were assessed: percent predicted forced expiratory volume in 1 second, body mass index and z-scores, number of admissions, length of stay, number of emergency department visits. RESULTS: Mean ppFEV1 was improved for the first 12 months on lumacaftor/ivacaftor treatment when compared with the 24 months prior: 78.8 (95% CI: 72.6, 84.9) vs 76.2 (95% CI: 70.1, 82.3) (p = 0.03). Body mass index significantly improved (patients ≥20 years), but improvement in BMI z-score (patients <20 years) was not significant. Number of admissions and LOS were significantly decreased, but ED visits were not. CONCLUSIONS: Lumacaftor/ivacaftor is effective for improving ppFEV1 and BMI and for reducing health care utilization. However, this small reduction does not overcome the financial cost of treatment. Long-term outcomes and use must be studied to determine the overall effect of this therapy on cystic fibrosis interventions and their costs.

Identification of Mycobacterium porcinum in patients with cystic Fibrosis: Pathogen or contaminant?

BACKGROUND: Mycobacterium porcinum is a non-tuberculous mycobacterium (NTM) identified in potable water. The identification and clinical impact of M. porcinum in patients with cystic fibrosis (CF) has not been described. In our institution, M. porcinum was isolated exclusively during hospitalization in a cluster of patients with CF. METHODS: Patients with CF who were hospitalized between September 2016 and September 2018 and could expectorate sputum were included, and samples were processed per institutional guidelines. Post-hospitalization and one-year clinical outcomes on those who isolated M. porcinum in respiratory cultures were reviewed. Whole genome sequencing was performed on M. porcinum isolates obtained from patients and environmental sources to identify source of acquisition. RESULTS: Review of 14 CF patients with 16 M. porcinum isolates revealed rapid time to culture positivity within 0.8 (0.04-8.0) days after admission. M. porcinum was isolated in teenagers and adults irrespective of baseline pulmonary function, body mass index, or CF genotype. Whole genome sequencing suggested all isolates belong to the same M. porcinum strain and confirmed the source of acquisition to the ice machine. Review of patients' clinical course, including three patients who underwent lung transplantation, suggested a pseudo-outbreak with minimal clinical impact. CONCLUSIONS: NTM, including M. porcinum, are ubiquitous in potable water and institutional water reservoirs. Our findings suggest M. porcinum is a transient colonizer rather than a pathogen. Challenges exist in discerning the role of NTM as a contributor of pulmonary morbidity in patients with CF, and adherence to established guidelines regarding NTM related pulmonary disease remains important.

Non-invasive carbon dioxide monitoring in patients with cystic fibrosis during general anesthesia: end-tidal versus transcutaneous techniques.

INTRODUCTION: The gold standard for measuring the partial pressure of carbon dioxide remains arterial blood gas (ABG) analysis. For patients with cystic fibrosis undergoing general anesthesia or polysomnography studies, continuous non-invasive carbon dioxide monitoring may be required. The current study compares end-tidal (ETCO2), transcutaneous (TCCO2), and capillary blood gas carbon dioxide (Cap-CO2) monitoring with the partial pressure of carbon dioxide (PaCO2) from an ABG in patients with cystic fibrosis. METHODS: Intraoperatively, a single CO2 value was simultaneously obtained using ABG (PaCO2), capillary (Cap-CO2), TCCO2, and ETCO2 techniques. Tests for correlation (Pearson's coefficient) and agreement (Bland-Altman analysis) were performed. Data were further stratified into two subgroups based on body mass index (BMI) and percent predicted forced expiratory volume in 1 s (FEV1%). Additionally, the absolute difference in the TCCO2, ETCO2, and Cap-CO2 values versus PaCO2 was calculated. The mean ± SD differences were compared using a paired t test while the number of times the values were ≤ 3 mmHg and ≤ 5 mmHg from the PaCO2 were compared using a Fishers' exact test. RESULTS: The study cohort included 47 patients (22 males, 47%) with a mean age of 13.4 ± 7.8 years, median (IQR) BMI of 18.7 kg/m2 (16.7, 21.4), and mean FEV1% of 87.3 ± 18.3%. Bias (SD) was 4.8 (5.7) mmHg with Cap-CO2 monitoring, 7.3 (9.7) mmHg with TCCO2 monitoring, and 9.7 (7.7) mmHg with ETCO2 monitoring. Although there was no difference between the degree of bias in the population as a whole, when divided based on FEV1% and BMI, there was greater bias with ETCO2 in patients with a lower FEV1% and a higher BMI. The Cap-CO2 vs. PaCO2 difference was 5.2 ± 5.3 mmHg (SD), with 16 (48%) ≤ 3 mmHg and 20 (61%) ≤ 5 mmHg from the ABG value. The TCCO2-PaCO2 difference was 9.1 ± 7.2 mmHg (SD), with 11 (27%) ≤ 3 mmHg and 15 (37%) ≤ 5 mmHg from the ABG value. The ETCO2-PaCO2 mean difference was 11.2 ± 7.9 mmHg (SD), with 5 (12%) ≤ 3 mmHg and 11 (26%) ≤ 5 mmHg from the ABG value. CONCLUSIONS: While Cap-CO2 most accurately reflects PaCO2 as measured on ABG, of the non-invasive continuous monitors, TCCO2 was a more accurate and reliable measure of PaCO2 than ETCO2, especially in patients with worsening pulmonary function (FEV1% ≤ 81%) and/or a higher BMI (≥ 18.7 kg/m2).

Gastroesophageal reflux in cystic fibrosis across the age spectrum.

BACKGROUND: Scientific advances have improved longevity in cystic fibrosis (CF) patients and many of these patients can expect to experience age-related gastrointestinal co-morbidities. We aimed to assess the extent to which age might impact gastroesophageal reflux (GER) in patients with CF. METHODS: Our esophageal pH-multichannel intraluminal impedance monitoring database was searched for tracings belonging to CF patients ≥2 years old without prior fundoplication and not taking anti-reflux medications immediately prior (within 7 days) and during the study. Tracings were retrospectively analyzed; Impedance and pH variables were evaluated with respect to age and pulmonary function. RESULTS: Twenty-eight patients were enrolled; 16 children (3.1-17.7 years) and 12 adults (18.2-48.9 years). Among pH probe parameters, correlation analysis showed DeMeester score (P=0.011) and number of acid reflux events lasting >5 minutes (P=0.047) to be significantly correlated with age. Age was not significantly correlated with any of the impedance parameters. Age was negatively correlated with baseline impedance (BI) in the distal esophagus (r=-0.424, P=0.023) and BI was negatively correlated with several pH parameters, including reflux index (r=-0.553, P=0.002), number of total acid reflux events (r=-0.576, P=0.001), number of acid reflux events lasting >5 minutes (r=-0.534, P=0.003), and DeMeester score (r=-0.510, P=0.006). Pulmonary function (percent predicted forced expiratory volume in one minute; ppFEV1) was negatively correlated with age (r=-0.494, P=0.0007). The interaction of age and ppFEV1 and any of the reflux parameters, however, was not significant (P>0.05); the strongest evidence for an interaction was found for the number of acid reflux events reaching the proximal esophagus, but this interaction still did not reach statistical significance (P=0.070). CONCLUSIONS: In a small cohort, we found evidence that age may be associated with increased acid exposure and that both age and increased acid exposure are associated with reduced BI in the distal esophagus. The negative relationship between pulmonary function and age in our cohort is not related to GER. This pilot study supports the need for esophageal assessment and treatment of GER as standard components of clinical care for an aging CF population.

Timing of Spirometry May Impact Hospital Length of Stay for Cystic Fibrosis Pulmonary Exacerbation.

PURPOSE: The optimal timing of spirometry during hospitalization for acute pulmonary exacerbation (PEx) in patients with cystic fibrosis (CF) is unclear. We retrospectively evaluated whether measuring spirometry earlier during hospitalization was associated with a shorter length of stay (LOS). METHODS: In this retrospective study, we analyzed data from the electronic medical record of CF patients 6 years of age and older admitted to a single center for acute PEx requiring IV antibiotic therapy between 2009 and 2016. After excluding patient encounters with missing data on covariates, random-effects linear regression was used to predict LOS as a function of days to first pulmonary function testing (PFT), which was spirometry for our study. RESULTS: One thousand thirty-five hospitalizations of 242 patients met inclusion criteria, with 801 including complete data on covariates. Mean LOS was 10 ± 7 days, with mean time to first PFT of 4 ± 3 days after admission. In multivariable analysis, each additional day to first PFT was associated with 0.97 days longer LOS (95% CI 0.29, 1.64; p = 0.005). CONCLUSIONS: As CF researchers and clinicians work to improve management of PEx, the timing of spirometry during hospitalization remains an important question. Obtaining objective lung function data earlier during the course of therapy may provide information which can lead to reduced hospital LOS for PEx.

Not All Children with Cystic Fibrosis Have Abnormal Esophageal Neutralization during Chemical Clearance of Acid Reflux.

PURPOSE: Acid neutralization during chemical clearance is significantly prolonged in children with cystic fibrosis, compared to symptomatic children without cystic fibrosis. The absence of available reference values impeded identification of abnormal findings within individual patients with and without cystic fibrosis. The present study aimed to test the hypothesis that significantly more children with cystic fibrosis have acid neutralization durations during chemical clearance that fall outside the physiological range. METHODS: Published reference value for acid neutralization duration during chemical clearance (determined using combined impedance/pH monitoring) was used to assess esophageal acid neutralization efficiency during chemical clearance in 16 children with cystic fibrosis (3 to <18 years) and 16 age-matched children without cystic fibrosis. RESULTS: Duration of acid neutralization during chemical clearance exceeded the upper end of the physiological range in 9 of 16 (56.3%) children with and in 3 of 16 (18.8%) children without cystic fibrosis (p=0.0412). The likelihood ratio for duration indicated that children with cystic fibrosis are 2.1-times more likely to have abnormal acid neutralization during chemical clearance, and children with abnormal acid neutralization during chemical clearance are 1.5-times more likely to have cystic fibrosis. CONCLUSION: Significantly more (but not all) children with cystic fibrosis have abnormally prolonged esophageal clearance of acid. Children with cystic fibrosis are more likely to have abnormal acid neutralization during chemical clearance. Additional studies involving larger sample sizes are needed to address the importance of genotype, esophageal motility, composition and volume of saliva, and gastric acidity on acid neutralization efficiency in cystic fibrosis children.