Airway Inflammation and Host Responses in the Era of CFTR Modulators.

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

Using Pain Medication Intensity to Stratify Back Pain Among Older Adults.

OBJECTIVE: To examine the prevalence of musculoskeletal back pain among older adults stratified by pain medication intensity to 1) review treatment patterns and 2) consider targeted back pain prevention interventions. METHODS: A random sample of older adults age 64 years and older was utilized to identify new and recurring back pain. Prescription pain medications from drug claims were used to stratify to five unique intensity levels. The characteristics of each level were determined using regression models. RESULTS: About 10% had musculoskeletal back pain. Of these, 54% (N = 20,645) had new back pain and 46% (N = 17,252) had recurring back pain. Overall, about 35% received physical therapy. Pain medication intensity levels included no prescription pain medications, nonsteroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, low-dose opioids, and high-dose opioids (new back pain: 39%, 10%, 6%, 23%, and 23%, respectively; recurring back pain 32%, 9%, 4%, 17%, and 38%, respectively). NSAID and muscle relaxant users were younger, healthier, and received physical therapy. Opioid users were younger, in poorer health, used sleep medications, received physical therapy, and had more falls and higher health care utilization and expenditures. CONCLUSIONS: New and recurring back pain patients can be stratified by pain medication intensity to review treatment patterns and target back pain prevention programs. Those with back pain but taking no prescription pain medications may benefit from back pain prevention programs. More research on guidelines for treatment options for those on high levels of pain medications is warranted.

Coinfection with Pseudomonas aeruginosa and Aspergillus fumigatus in cystic fibrosis.

OBJECTIVES: Cystic fibrosis (CF) lung disease is characterised by mucus stasis, chronic infection and inflammation, causing progressive structural lung disease and eventual respiratory failure. CF airways are inhabited by an ecologically diverse polymicrobial environment with vast potential for interspecies interactions, which may be a contributing factor to disease progression. Pseudomonas aeruginosa and Aspergillus fumigatus are the most common bacterial and fungal species present in CF airways respectively and coinfection results in a worse disease phenotype. METHODS: In this review we examine existing expert knowledge of chronic co-infection with P. aeruginosa and A. fumigatus in CF patients. We summarise the mechanisms of interaction and evaluate the clinical and inflammatory impacts of this co-infection. RESULTS: P. aeruginosa inhibits A. fumigatus through multiple mechanisms: phenazine secretion, iron competition, quorum sensing and through diffusible small molecules. A. fumigatus reciprocates inhibition through gliotoxin release and phenotypic adaptations enabling evasion of P. aeruginosa inhibition. Volatile organic compounds secreted by P. aeruginosa stimulate A. fumigatus growth, while A. fumigatus stimulates P. aeruginosa production of cytotoxic elastase. CONCLUSION: A complex bi-directional relationship exists between P. aeruginosa and A. fumigatus, exhibiting both mutually antagonistic and cooperative facets. Cross-sectional data indicate a worsened disease state in coinfected patients; however, robust longitudinal studies are required to derive causality and to determine whether interspecies interaction contributes to disease progression.

An investigation into biomarkers for the diagnosis of ABPA and aspergillus disease in cystic fibrosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to Aspergillus fumigatus (Af) which occurs in 10% of patients with cystic fibrosis (CF). ABPA is associated with increased morbidity and accelerated lung function decline; however, existing diagnostic criteria are nonspecific and diagnosis remains challenging. As ABPA is driven by Th2 inflammation, the aim of this study was to evaluate exhaled nitric oxide (FE NO ), eosinophilic cationic protein (ECP), peripheral eosinophil count, and bronchodilator response (BDR) in patients with CF. METHODS: A prospective observational cohort study of pediatric CF patients in a tertiary center. Patients had a clinical and serologic ABPA assessment, FENO , serum ECP, peripheral eosinophil count, and assessment of BDR. Patients were stratified into three groups; ABPA, Af sensitized (AFS), and non-ABPA non-Af-sensitized (non-AFS). RESULTS: A total of 62 patients were included in the study: 13% ABPA, 19% AFS, and 68% non-AFS. Mean FENO was higher in the ABPA group at 37.8 ppb compared to AFS 15.1 ppb (P = .05) and non-AFS 13.7 ppb (P = .04). Mean peripheral eosinophil count in ABPA group was also higher at 1000 cells/uL, compared to AFS 221 cells/uL (P = .03) and non-AFS 220 cells/uL (P = .03). Mean BDR in ABPA group was 13% compared to 5.5% in non-AFS (P = .01). Serum ECP was higher in patients with ABPA positive compared to the other groups, although this was not statistically significant. CONCLUSION: In children with cystic fibrosis, FENO and peripheral eosinophil counts are elevated in ABPA compared to those that are just sensitized to Aspergillus and may serve as useful diagnostic tests.

Investigating the clinical use of structured light plethysmography to assess lung function in children with neuromuscular disorders.

BACKGROUND: Children and young people with neuromuscular disorders (NMD), such as Duchenne Muscular Dystrophy (DMD), develop progressive respiratory muscles weakness and pulmonary restriction. Pulmonary function monitoring of the decline in lung function allows for timely intervention with cough assist techniques and nocturnal non-invasive ventilation (NIV). NMD may find the measurement of lung function difficult using current techniques. Structured Light Plethysmography (SLP) has been proposed as a novel, non-contact, self-calibrating, non-invasive method of assessing lung function. The overarching aim of this study was to investigate the use of SLP as a novel method for monitoring respiratory function in children with neuromuscular disease. METHODS: SLP thoraco-abdominal (TA) displacement was correlated with forced vital capacity measurements recorded by spirometry and the repeatability of the measurements with both methods examined. SLP tidal breathing parameters were investigated to assess the range and repeatability of regional right and left side TA displacement and rib cage and abdominal wall displacement. RESULTS: The comparison of the FVC measured with SLP and with spirometry, while having good correlation (R = 0.78) had poor measurement agreement (95% limits of agreement: -1.2 to 1.2L) The mean relative contribution of right and left TA displacement in healthy controls was 50:50 with a narrow range. Repeatability of this measure with SLP was found to be good in healthy controls and moderate in NMD children with/without scoliosis but with a wider range. The majority of the control group displayed a predominant rib cage displacement during tidal breathing and those who displayed predominant abdominal wall displacement showed displacement of both regions close to 50:50 with similar results for the rib cage and abdomen. In comparison, children with NMD have a more variable contribution for all of these parameters. In addition, SLP was able to detect a reduction in abdominal contribution to TA displacement with age in the DMD group and detect paradoxical breathing in children with NMD. Using SLP tracings during tidal breathing we were able to identify three specific patterns of breathing amongst healthy individuals and in children with NMD. CONCLUSIONS: SLP is a novel method for measuring lung function that requires limited patient cooperation and may be especially useful in children with neuromuscular disorders. Measuring the relative contributions of the right and left chest wall and chest versus abdominal movements allows a more detailed assessment.

A Pilot Online Mindfulness Intervention to Decrease Caregiver Burden and Improve Psychological Well-Being.

Interventions to reduce caregiver burden are of great interest as the number of informal family caregivers continues to grow. The purpose of this study was to test the feasibility of an online mindfulness meditation intervention for community-dwelling older adult caregivers and to evaluate its impact on quality of life, caregiver burden, and psychological well-being. A total of 40 caregivers were recruited from 2 community center support groups to participate in an 8-week online mindfulness intervention. Pre and post surveys were administered. Retention rates were high with 55% completing the post surveys and attending at least 5 out of 8 sessions. Matched pairs t test indicated that the intervention reduced caregiver burden, perceived stress, anxiety, and loneliness and improved mental well-being. Online interventions offer flexibility for caregivers regardless of their responsibilities. Future research should expand this opportunity and explore the scalability of online mindfulness interventions.

Nutritional implications of selective eating in a child with autism spectrum disorder.

A 4-year-old boy attending the autism assessment service was identified to have a restricted diet. His food diary documented that he ate a narrow range of foods and consumed excessive quantities of carrot juice (excess 2.5 L daily). Physical examination showed that the boy had a florid orange discolouration of his skin, growth parameters were <91st centile for weight, >50th centile for height and head circumference. Blood investigations showed a raised serum carotene level and vitamin D deficiency. He was referred for urgent specialist input from dietetics and the other disciplines within the autism intervention team.

Bilateral total parenteral nutrition pleural effusions in a 5-week-old male infant.

A 5-week-old male infant was admitted to the paediatric intensive care unit with small bowel obstruction secondary to an inguinal hernia. His postoperative course was complicated by suspected migration of his left internal jugular central venous catheter into branches of the inferior thyroid artery and mediastinum. This resulted in bilateral pleural effusions which were biochemically and visually similar to the total parenteral nutrition he was receiving. After drainage of the pleural effusions he made an uneventful recovery.