Airway transcriptome networks identify susceptibility to frequent asthma exacerbations in children.

BACKGROUND: Frequent asthma exacerbators, defined as those experiencing more than 1 hospitalization in a year for an asthma exacerbation, represent an important subgroup of individuals with asthma. However, this group remains poorly defined and understudied in children. OBJECTIVE: Our aim was to determine the molecular mechanisms underlying asthma pathogenesis and exacerbation frequency. METHODS: We performed RNA sequencing of upper airway cells from both frequent and nonfrequent exacerbators enrolled in the Ohio Pediatric Asthma Repository. RESULTS: Through molecular network analysis, we found that nonfrequent exacerbators display an increase in modules enriched for immune system processes, including type 2 inflammation and response to infection. In contrast, frequent exacerbators showed expression of modules enriched for nervous system processes, such as synaptic formation and axonal outgrowth. CONCLUSION: These data suggest that the upper airway of frequent exacerbators undergoes peripheral nervous system remodeling, representing a novel mechanism underlying pediatric asthma exacerbation.

Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor.

BACKGROUND: Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes. METHODS: Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed. RESULTS: ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride. CONCLUSION: ETI is associated with unique changes in innate immune function and clinical outcomes.

Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. INTERPRETATION: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. FUNDING: Vertex Pharmaceuticals.

Weighing in on asthma: Insights on BMI, magnesium, and hospitalizations from the Ohio Pediatric Asthma Repository.

Objective: Little is known about weight status and its effects on clinical course during hospitalization for asthma exacerbation. We sought to evaluate associations between weight status, specifically body mass index (BMI), with inpatient clinical course and clinical history.Methods: We retrospectively analyzed data from 2012 to 2013 on children hospitalized for asthma exacerbation in a state-wide longitudinal cohort, the Ohio Pediatric Asthma Repository. We examined BMI continuously (z scores) and categorically, comparing overweight and obese (Ov/Ob) to non-overweight and non-obese (nOv/nOb) children. We used linear mixed models controlling for site effects to determine if BMI was related to length of stay, as determined by physiologic readiness for discharge (PRD), defined as time to albuterol spaced every 4 h, need for nonstandard care or clinical history.Results: Across six hospitals, 874 children were included in analyses. BMI was positively associated with PRD (p=.008) but this increase was unlikely to be clinically significant. Ov/Ob children were more likely than nOv/nOb to require nonstandard care with repeat magnesium dosing in intensive care after dosing in the emergency department (OR = 3.23, 95%CI 1.39-7.78). Hospitalization in the year prior to enrollment was positively associated with BMI percentile (73.3 vs. 66.0, p=.028). Sleep disordered breathing was also associated with higher BMI percentile (78.2 vs. 65.9; p=.0013).Conclusions: Ov/Ob children had similar PRD to nOv/nOb children and were prone to repeat magnesium dosing. Previous hospitalization for exacerbation was positively associated with increasing BMI percentile. Additional research should investigate differential magnesium use by weight status, quantifying risks and benefits.

Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial.

RATIONALE: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress. OBJECTIVES: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. METHODS: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. MEASUREMENTS AND MAIN RESULTS: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (ß-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. CONCLUSIONS: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Improved quality-of-life of caregivers of children with asthma through guideline-based management.

OBJECTIVE: The quality of life (QOL) of caregivers of children with asthma may be related to children's responses to asthma management. AIM: To evaluate change in QOL over time of caregivers of children with asthma through guideline-based management. DESIGN: This was a 3-year prospective cohort study of children with asthma referred to our pediatric asthma center. Families completed Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), the Asthma Control Test™ (ACT), and reported the number of days/month of albuterol use and wheezing at each clinic visit. RESULTS: We enrolled 143 children, ages 7-17 years (mean = 10.6 ± 2.9), 56.6% male, 70.6% Caucasian. Patients were managed by the same MD (n = 65,45.5%) or APN (n = 78,54.5%) over time. The mean total PACQLQ significantly increased over the 3-year period (F = 67.418, p < .001). Total scores at the first visit were 4.8 ± 1.6, which improved to 6.1 ± 1 at the 3-month follow-up visit. This improvement was sustained at the 1, 2, and 3-year clinic visits. PACQLQ emotional function (F = 60.798, p < .001) and activity limitation (F = 41.517, p < .001) domains significantly improved as well. PACQLQ scores were significantly associated with improved ACT scores (r = .37 to .47, p < .05), fewer days/month of albuterol use (r = -.25 to -.36., p < .05), and wheezing (r = -.28 to -.33, p < .05). There were no significant differences in PACQLQ, or asthma clinical outcome measures between MD and APN providers. CONCLUSION: Use of National Asthma Education and Prevention Program (NAEPP) guidelines significantly improved QOL of caregivers of children with asthma and in asthma-related symptoms. Improvements over time were independent of type of providers.

Environmental exposures and family history of asthma.

BACKGROUND: Asthma pathogenesis is a complex interaction of genetic, ethnic, environmental and social/life style risk factors. AIM: The goal of this study was to identify associations, if any, in children with asthma, between environmental risk factors (exposure to second-hand tobacco smoke (STS), pet ownership, race and a family history of asthma. METHODS: After IRB approval, from June 2011 to December 2014, 823 children with asthma were enrolled in this prospective cross sectional study. At the initial visit, families completed a questionnaire with information on family history of asthma, having a pet at home and exposure to STS by parents at home. Chi square analyses were calculated, with alpha level of significance ≤0.05. RESULTS: History of asthma in parents, siblings or grandparents was reported by 575 (69.8%) patients including father (n = 154, 17.8%) and mother (n = 235, 26.5%). Children with family history of asthma (n = 575) were significantly more likely to have a pet at home and exposure to STS (n = 347, 60.3% and n = 198, 34.4%, respectively) compared to families without a history of asthma (n = 124, 50%, p = 0.006 and n = 44, 17.7%, p < 0.001, respectively). Similarly, asthmatic children with exposure to STS (n = 241) were significantly more likely to have a pet at home and a family history of asthma (n = 153, 63.5% and n = 197, 81.7%, respectively) compared to children with no STS exposure (n = 315, 55.5%, p = 0.034 and n = 371, 65.3%, p < 0.001 respectively). CONCLUSIONS: Significantly more asthmatic children with immediate relatives with a history of asthma have a pet at home and experience STS exposure compared to children without relatives with a history of asthma, suggesting association between life style choices/environmental exposures and family history of asthma.

Improving pediatric asthma care: A partnership between pediatric primary care clinics and a free-standing Children's Hospital.

BACKGROUND: Asthma is a common chronic disease of childhood. Providers' adherence to asthma guidelines is still less than optimal. OBJECTIVES: To determine if an Asthma Education Program aimed at primary care practices can improve asthma care within practices and if the results vary by duration of the program. METHODS: Ten practices were randomly assigned to an Early Asthma Education Intervention (EI) group or a Delayed Asthma Education Intervention (DI) group. The EI group received the intervention for 12 months and was monitored for 6 additional months. The DI group was observed without intervention for 12 months, then received the intervention for 6 months, and was monitored for 6 additional months. The program included training of asthma educators in each practice and then monitoring for improvement in medical record documentation of National Asthma Education and Prevention Program (NAEPP) asthma quality indicators by blinded random review of patient charts. RESULTS: In the EI group, 6-, 12-, and 18-month data revealed significant improvement in documentation of asthma severity, education, action plan, night time symptoms, and symptoms with exercise compared to baseline and compared to DI group at baseline and at the 12-month interval. In the DI group, significant improvement in documentation in all of the above endpoints and also in documentation of NAEPP treatment guidelines was noted at 18 and 24 months. In both groups, documentation levels remained relatively stable at 6 months after the intervention, with no significant differences between groups. While improved, guideline adherence was <80% for half of the indicators. CONCLUSION: In-office training of non-physician asthma providers improves the quality of asthma care.

Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy.

Treatment of liver disease, including hepatic steatosis, in patients with cystic fibrosis (CF) is limited. With the development of ivacaftor, which corrects the gating defect of the CF transmembrane regulator channel, there is a potential new therapy available for this subgroup of the CF patient population. We present an adolescent with CF who had significant improvement in hepatic steatosis with ivacaftor treatment while hypothesizing on a mechanism of why it occurred.

High-risk age window for mortality in children with cystic fibrosis after lung transplantation.

LTx in children with CF remains controversial. The UNOS database was queried from 1987 to 2013 for CF patients <18 yr of age at time of transplant. PCHR model was used to quantify hazard of mortality. 489 recipients were included in the survival analysis. The hazard function of post-transplant mortality was plotted over attained age to identify age window of highest risk, which was 16-20 yr. Unadjusted PCHR model revealed ages immediately after the high-risk window were characterized by lower hazard of mortality (HR = 0.472; 95% CI = 0.302, 0.738; p = 0.001). After adjusting for potential confounders, the decline in mortality hazard immediately after the high-risk window remained statistically significant (HR = 0.394; 95% CI: 0.211, 0.737; p = 0.004). Hazard of mortality in children with CF after LTx was highest between 16 and 20 yr of attained age and declined thereafter.

Screening high-risk children for asthma through a community intervention.

OBJECTIVE: Many children, particularly those from inner city neighborhoods, have undiagnosed asthma. This study was done to evaluate the effectiveness of an asthma screening, referral and follow-up intervention in an inner city community setting in early identification of children at risk for undiagnosed asthma. METHODS: A descriptive longitudinal cohort design was used to assess children at baseline and at a 2-year follow-up. Parents of children in a private day school and a church Sunday school (N = 103) completed a validated Asthma Screening Tool at both time periods. Children with asthma and at risk for asthma were referred to a primary care provider (PCP). RESULTS: At baseline, screening of 103 children, ages 3-17 years (mean=7.7 ± 2.9), were categorized as known asthma diagnosis (n = 22), at-risk for undiagnosed asthma (n = 52) and not at-risk for asthma (n = 29). Sixty-two (60.2%) parents responded to the 2-year follow-up. Referral to PCP was kept by 61.5% from the known asthma group and by 24% of children at-risk for asthma. At 2-year follow-up, among not at-risk group, no one converted to at risk status, but majority of children among known asthma group continued to have uncontrolled asthma symptoms, and very few received daily preventive asthma medications. CONCLUSIONS: The asthma screening, referral and follow-up intervention for inner city children in a community setting was successful in early identification of patients at-risk for asthma. More education for PCPs on guidelines for diagnosis and management of asthma is needed to decrease childhood asthma morbidity.

Changes in Pulmonary Function and Controlled Ventilation-High Resolution CT of Chest After Antibiotic Therapy in Infants and Young Children with Cystic Fibrosis.

BACKGROUND: Infants with cystic fibrosis (CF) develop early progressive lung disease which may be asymptomatic. Infant pulmonary function tests (IPFT) and controlled ventilation-high resolution computed tomography (CV-HRCT) of chest can detect early asymptomatic lung disease. It is not well established that these objective measures can detect changes in lung disease after clinical interventions. OBJECTIVE: The purpose of this study was to evaluate usefulness of IPFT and CV-HRCT to detect changes in lung disease after intravenous (IV) antibiotic therapy in infants with early CF-related lung disease. STUDY DESIGN: IPFTs and CV-HRCT done before and after 2 weeks of IV antibiotics in infants at our institution over the last 12 years were compared. CV-HRCTs were compared using the modified Brody scoring system. RESULTS: The sample included 21 infants, mean age 85.2 ± 47.6 weeks. Mean change in weight was 0.4 ± 0.38 kg (p = 0.001). Significant changes in IPFT included mean % predicted FEV(0.5) (+13.5 %, p = 0.043), mean %FEF(25-75) (+30.2 %, p = 0.008), mean %RV/TLC (-11.2 %, p = 0.008), and mean %FRC/TLC (-4.5 %, p = 0.001). Total Brody scores improved from a median of 10 to 5 (p < 0.001) as did mean scores for airway wall thickening (p = 0.050), air trapping (p < 0.001), and parenchymal opacities (p = 0.003). CONCLUSION: IPFT and CV-HRCT can be used as objective measures of improvement in lung disease for infants with CF treated with antibiotics.

Eucapnic Voluntary Hyperventilation to Detect Exercise-Induced Bronchoconstriction in Cystic Fibrosis.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) has not been well studied in cystic fibrosis (CF), and eucapnic voluntary hyperventilation (EVH) testing has not been used as an objective assessment of EIB in CF to date. METHODS: A prospective cohort pilot study was completed where standard EVH testing was completed by 10 CF patients with forced expiratory volume in 1 s (FEV1) ≥70% of predicted. All patients also completed a cardiopulmonary exercise test (CPET) with pre- and post-CPET spirometry as a comparative method of detecting EIB. RESULTS: No adverse events occurred with EVH testing. A total of 20% (2/10) patients were diagnosed with EIB by means of EVH. Both patients had clinical symptoms consistent with EIB. No patient had a CPET-based exercise challenge consistent with EIB. CONCLUSIONS: EVH testing was safe and effective in the objective assessment for EIB in patients with CF who had well-preserved lung function. It may be a more sensitive method of detecting EIB then exercise challenge.

Pulmonary hypertension in cystic fibrosis with advanced lung disease.

RATIONALE: The impact of pulmonary hypertension (PH) on survival in cystic fibrosis (CF) remains unclear. OBJECTIVES: To determine the influence of PH on survival in the CF population. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013 to identify first-time lung transplant candidates who were tracked from wait list entry date until death or censoring to determine influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure greater than or equal to 25 mm Hg and severe greater than or equal to 35 mm Hg. MEASUREMENTS AND MAIN RESULTS: Of 2,781 CF patients, 2,100 were used for univariate analysis, 764 for Kaplan-Meier survival function, 687 for multivariate Cox models, and 576 and 132 for matching on the propensity of mild PH and severe PH, respectively. Univariate Cox analysis found significant differences in survival for mild PH (hazard ratio [HR], 1.747; 95% confidence interval [CI], 1.387-2.201; P < 0.001) and severe PH (HR, 2.299; 95% CI, 1.639-3.225; P < 0.001). Further assessment by multivariate Cox models identified significant risk for death associated with mild PH (HR, 1.757; 95% CI, 1.367-2.258; P < 0.001) and severe PH (HR, 2.284; 95% CI, 1.596-3.268; P < 0.001). Cox regression stratified on matched pairs of PH cases and control subjects confirmed the risk for death for mild PH (HR, 1.919; 95% CI, 1.290-2.85; P = 0.001) and severe PH (HR, 4.167; 95% CI, 1.709-10.157; P = 0.002). CONCLUSIONS: The manifestation of PH is associated with significantly increased risk for death in CF patients with advanced lung disease.

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.

Demographics, clinical course, and outcomes of children with status asthmaticus treated in a pediatric intensive care unit: 8-year review.

OBJECTIVE: This study was done to understand the demographics, clinical course, and outcomes of children with status asthmaticus treated in a tertiary care pediatric intensive care unit (PICU). METHODS: The medical charts of all patients above 5 years of age admitted to the PICU at Nationwide Children's Hospital, Columbus, OH, USA, with status asthmaticus from 2000 to 2007 were reviewed retrospectively. Data from 222 encounters by 183 children were analyzed. RESULTS: The mean age at admission in years was 11 ± 3.8. The median PICU stay was 1 day (range, 1-12 days) and median hospital stay was 3 days. The ventilated group (n = 17) stayed a median of 2 days longer in the PICU and hospital. Nearly half of the children (n = 91; 50%) did not receive daily controller asthma medications. Adherence to asthma medications was reported in 125 patient charts of whom 43 (34%) were compliant. Exposure to smoking was reported in 167 of whom 70 (42%) were exposed. Among patients receiving metered dose inhaler (MDI), only 39 (18%) were using it with a spacer. Among 105 patient charts asthma severity data were available, of them 21 (20%) were labeled as mild intermittent, 29 (28%) were mild persistent, 26 (25%) were moderate persistent, and 29 (28%) were severe persistent. Compared to children with only one PICU admission during the study period (n = 161), children who had multiple PICU admissions (n = 22) experienced more prior emergency department visits and hospitalizations for asthma symptoms. There were no fatalities. CONCLUSION: Asthmatics with any disease severity are at risk for life-threatening asthma exacerbations requiring PICU stay, especially those who are not adherent with their daily medications.

Dexamethasone reduces IL-17 and Tim-3 expression in BALF of asthmatic mice.

This study investigated the expression of interleukin-17 (IL-17) and T cell immunoglobulin mucin and domain-containing molecule-3 (Tim-3) in bronchoalveolar lavage fluid (BALF) of asthmatic mice and the effect of dexamethasone (DEX) on these factors. Thirty-six mice were randomly divided into three groups: normal group, asthmatic group and DEX group. The mouse model of asthma was established by sensitization with ovalbumin in both the asthmatic and DEX groups. The levels of IL-6, IL-10, IL-17 and TGF-ß were measured in BALF by enzyme-linked immunesorbent assay (ELISA). The mRNA expression level of Tim-3 was detected by reverse transcription polymerase chain reaction (RT-PCR). The ratio of Tim-3+CD4+ cells to total CD4+ cells in BALF was determined by flow cytometry. Differential inflammatory cells in BALF were detected. The correlations among IL-17, IL-6, IL-10, Tim-3 and inflammatory cells were analyzed. The results showed that the levels of IL-17, IL-6 and Tim-3 were substantially increased and the IL-10 level decreased in BALF in the asthmatic mice, which was significantly reversed by DEX treatment. IL-17 expression was positively correlated with IL-6 and Tim-3 expression and the number of inflammatory cells but negatively with IL-10 expression. These results indicate that the increased expression of IL-17 and Tim-3 in BALF may be implicated in the occurrence and development of asthmatic inflammation; the mechanism by which DEX suppresses asthmatic airway inflammation involves down-regulation of IL-17 and Tim-3 levels.

Clinical management of pediatric patients with cystic fibrosis and autism spectrum disorder.

BACKGROUND: Cystic Fibrosis (CF) and autism spectrum disorder (ASD) are life-long conditions with intense treatment burdens for patients and families. Patients with a concurrent diagnosis (CF-ASD) experience unique obstacles to CF care. This study describes the experiences of our multidisciplinary CF team in caring for patients with CF-ASD and provides insight into provider and parental perspectives on clinical management. METHODS: This is a three-part qualitative study involving (1) retrospective chart review of patients with CF-ASD, (2) surveys with multidisciplinary care team members, and (3) semistructured interviews with caregivers of patients with CF-ASD. Challenges in clinical management of this specific cohort were compiled using data from chart review and care team surveys. Strategies to address these concerns were identified and rated by individual families based on relevance and practicality. RESULTS: Within our CF center, 12 patients have an official diagnosis of ASD. Median age of patients with CF-ASD was 8.5 years (range 3-20 years), 67% were male, and 83% were on highly effective modulator therapy. Clinical barriers included sensory processing issues, environmental overstimulation, intolerance to procedures and to disrupted routines. Potentially impactful strategies include patient-specific coping plans, guided behavioral interventions, parental advocacy, and improved communication between the family and multidisciplinary team. CONCLUSION: Children with CF-ASD face extraordinary challenges beyond the experience of neurotypical children with CF. Increased awareness of this complex dual diagnosis will help providers be sensitive to the unique needs of these patients, help build consistent and trustworthy relationships with their families and deliver effective clinical care despite limitations.

Clinical change 2 years from start of elexacaftor-tezacaftor-ivacaftor in severe cystic fibrosis.

RATIONALE: Limited published research is available on the impact of elexacaftor/tezacaftor/ivacaftor (ETI) beyond the initial few months postdrug initiation, especially for those who initiated therapy via individual investigational new drug application. The experiences of patients with cystic fibrosis (CF) experiencing severe lung disease were reviewed for significant improvements in clinical symptoms and quality of life. OBJECTIVES: To examine clinical outcomes 2 years post-ETI in patients with CF and advanced lung disease. METHODS: This single center institutional review board-approved, retrospective chart review assessed clinical markers (percent predicted forced expiratory volume in 1 s, weight, sweat chloride), quality of life and computed tomography scans in patients with advanced lung disease who met criteria for compassionate use/expanded access program due to high risk of death or transplant need within 2 years. RESULTS: Eighteen identified patients (ages 15-49 years) initiated drug between July and September 2019. Clinical markers indicated that therapy was well tolerated, not discontinued by any participant, and lab values did not indicate medical concern or discontinuation. Monitoring results indicated the safety of modulator therapy as there were no adverse clinical occurrences and all patients presented universal stabilization. There were no deaths and no transplants by the end of the study. CONCLUSIONS: This study focused on patients with CF eligible for modulator therapy and were initiated due to advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition, cough, FEV1 , subjective reports of clinical status, level of activity, and a reduction in burden of treatment.