Recommencement of atezolizumab with associated pulmonary sarcoid-like reaction.

An 81 year old male with Child-Pugh A cirrhosis and metastatic hepatocellular carcinoma (HCC) treated with 3-weekly atezolizumab and bevacizumab developed a pulmonary sarcoid-like reaction (SLR) after 5 months. Atezolizumab, an immune checkpoint inhibitor, was identified as the likely culprit. He was treated with prednisolone, resulting in improvement, and was successfully rechallenged with both atezolizumab and bevacizumab.

Me, myself, and I: A systematic review of cystic fibrosis and self-concept.

Given extensive pertinent disease factors and evolving medical treatments, this systematic review explores qualitative and quantitative cystic fibrosis (CF) research surrounding self-concept, an overarching perception of self. Research methodologies, self-concept dimensions, prominent self-concept findings and clinical recommendations are identified. Preferred Reporting Items for Systematic Review and Meta-analyses guidelines were applied. PubMed, Scopus, Medline, Psycinfo, CINAHL (ebsco), and CENTRAL Cochrane electronic databases were searched from 2012 to 2022. Methodological quality was assessed using the critical appraisal skills program. Data-based convergent synthesis was applied to analyze and report on qualitative and quantitative studies in parallel. Thirty-seven publications met the inclusion criteria, most of which employed a cross-sectional, single-center design within an adolescent and adult population. Self-efficacy, self-esteem, and self-identity studies were dimensions of self-concept identified, with studies relating to self-efficacy surrounding physical health management most prevalent. All three dimensions were positively associated with improved treatment adherence and psychosocial health. Efficacy tested intervention programs to enhance self-concept are limited; however, an extensive range of clinical recommendations are offered, highlighting the importance of clinician self-concept awareness, quality clinician-patient conversations and online CF peer-support. Self-concept is an important mechanism to optimize patient outcomes. Further CF self-concept research is required, particularly multicenter, longitudinal, and interventional studies. Early childhood, post lung transplant and the older adult CF population in particular, lack research attention. Given the potential impact of rapidly evolving CF transmembrane conductance regulator modulator drugs on many aspects of self, future self-concept research beyond the dimension of self-efficacy may be beneficial.

Quantification of smooth muscle in human airways by polarization-sensitive optical coherence tomography requires correction for perichondrium.

Quantifying airway smooth muscle (ASM) in patients with asthma raises the possibility of improved and personalized disease management. Endobronchial polarization-sensitive optical coherence tomography (PS-OCT) is a promising quantitative imaging approach that is in the early stages of clinical translation. To date, only animal tissues have been used to assess the accuracy of PS-OCT to quantify absolute (rather than relative) ASM in cross sections with directly matched histological cross sections as validation. We report the use of whole fresh human and pig airways to perform a detailed side-by-side qualitative and quantitative validation of PS-OCT against gold-standard histology. We matched and quantified 120 sections from five human and seven pig (small and large) airways and linked PS-OCT signatures of ASM to the tissue structural appearance in histology. Notably, we found that human cartilage perichondrium can share with ASM the properties of birefringence and circumferential alignment of fibers, making it a significant confounder for ASM detection. Measurements not corrected for perichondrium overestimated ASM content several-fold (P < 0.001, paired t test). After careful exclusion of perichondrium, we found a strong positive correlation (r = 0.96, P < 0.00001) of ASM area measured by PS-OCT and histology, supporting the method's application in human subjects. Matching human histology further indicated that PS-OCT allows conclusions on the intralayer composition and in turn potential contractile capacity of ASM bands. Together these results form a reliable basis for future clinical studies.NEW & NOTEWORTHY Polarization-sensitive optical coherence tomography (PS-OCT) may facilitate in vivo measurement of airway smooth muscle (ASM). We present a quantitative validation correlating absolute ASM area from PS-OCT to directly matched histological cross sections using human tissue. A major confounder for ASM quantification was observed and resolved: fibrous perichondrium surrounding hyaline cartilage in human airways presents a PS-OCT signature similar to ASM for birefringence and optic axis orientation. Findings impact the development of automated methods for ASM segmentation.

Telehealth use in Australian cystic fibrosis centers: Clinician experiences.

BACKGROUND: Telehealth has been rapidly adopted by cystic fibrosis (CF) centers and ongoing use in routine CF care is endorsed by CF consumers. However, data describing CF clinician perceptions regarding telehealth are scarce. We aimed to describe clinician experiences and attitudes towards telehealth in CF care among health professionals across Australia. METHODS: CF multidisciplinary health professionals from all CF clinics in Australia were sent an anonymous electronic survey. RESULTS: Eighty-five responses were received representing 15 of 23 (65%) centers. Most clinicians reported using telehealth for routine clinic visits, and a range of other clinical encounters (69.9%). Telehealth was widely perceived as acceptable (91.8%), and clinicians were comfortable/very comfortable (81.2%) integrating telehealth into future CF care. Despite this, 64.1% of respondents considered telehealth clinics to be much worse than face-to-face clinics and 57.5% reported quality of care was somewhat/much worse using telehealth. Home spirometry was available in 73.7% of centers, however, only 26.7% of clinics could provide spirometers for >75% eligible patients. Growth and microbiology assessments were often missed in telehealth clinics and 75.7% reported a technical issue had prevented a telehealth consultation from occurring. CONCLUSIONS: Telehealth for CF in Australia is considered feasible and acceptable by CF clinicians, although use of telehealth varies widely between centers. Concerns exist around the impact of telehealth on health outcomes, especially given core assessments are frequently omitted. Guidelines may help ensure the benefits of telehealth are realized for people with CF without compromising the standard of care.

Measuring energy requirements during pulmonary exacerbations of cystic fibrosis using indirect calorimetry.

OBJECTIVE: The energy demands of individuals with cystic fibrosis (CF) vary depending on pancreatic function, body composition, lung function, and clinical status. In clinical practice, predictive equations are used to determine energy requirements yet do not reliably account for these factors. Research regarding energy requirements during CF pulmonary exacerbation (CFPEx) and clinical stability is conflicting. The aim of this study was to investigate potential within-individual changes in measured resting energy expenditure (mREE) using indirect calorimetry (IC) at the commencement and completion of intravenous antibiotic treatment (IVABx) for CFPEx and during clinical stability. Secondary aims were to investigate potential differences between predicted resting energy expenditure (pREE) using Schofield equation and correlations between clinical factors with mREE. METHODS: Body composition using bioimpedance analysis and mREE were conducted at three time points: commencement of IVABx; completion of IVABx; and clinically stable period thereafter. RESULTS: Twenty-eight adults with CF completed at least one valid IC measurement. No significant within-person changes in mREE and body composition parameters were observed across time points. The mREE was positively correlated with fat-free mass (kg; r = 0.6; P = 0.008). The mREE was significantly higher than pREE at all time points with the mREE/pREE ratio elevated at time point 1:118% ± 19.5%; time point 2: 112% ± 13.2%; and time point 3: 122 ± 14.3%. CONCLUSION: The mREE remained stable during CFPEx and clinical stability. The pREE underestimated mREE and application of injury factor adjustment of 110% to 130% could potentially account for this discrepancy. The potential role of IC and body composition in individualizing CF nutritional assessment and prescription requires further exploration.

Beyond the Lungs-Emerging Challenges in Adult Cystic Fibrosis Care.

Cystic fibrosis (CF) is a multisystem disease. This article provides an up-to-date review of many of the nonrespiratory complications of CF, including mental health issues, nutritional and gastrointestinal problems, fertility issues, diabetes mellitus, bone health and musculoskeletal problems, liver disease, renal problems, and risk of malignancy. It highlights the recent impact of new therapies, including CF transmembrane conductance regulator modulators, on the nonrespiratory complications of CF and provides insights into the potential challenges faced by an aging population of adults with CF and their caregivers, including the potential future risk for cardiovascular disease.

Survival of people with cystic fibrosis in Australia.

Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform the CF community and monitor disease progression. This study aimed to estimate survival among people with CF in Australia and to identify factors associated with survival. This population-based cohort study used prospectively collected data from 23 Australian CF centres participating in the Australian CF Data Registry (ACFDR) from 2005-2020. Period survival analysis was used to calculate median age of survival estimates for each 5-year window from 2005-2009 until 2016-2020. The overall median survival was estimated using the Kaplan-Meier method. Between 2005-2020 the ACFDR followed 4,601 people with CF, noting 516 (11.2%) deaths including 195 following lung transplantation. Out of the total sample, more than half (52.5%) were male and 395 (8.6%) had undergone lung transplantation. Two thirds of people with CF (66.1%) were diagnosed before six weeks of age or by newborn/prenatal screening. The overall median age of survival was estimated as 54.0 years (95% CI: 51.0-57.04). Estimated median survival increased from 48.9 years (95% CI: 44.7-53.5) for people with CF born in 2005-2009, to 56.3 years (95% CI: 51.2-60.4) for those born in 2016-2020. Factors independently associated with reduced survival include receiving a lung transplant, having low FEV1pp and BMI. Median survival estimates are increasing in CF in Australia. This likely reflects multiple factors, including newborn screening, improvement in diagnosis, refinements in CF management and centre-based multidisciplinary care.

Living with cystic fibrosis during the COVID-19 pandemic: a social connectedness perspective.

PURPOSE: This study explores the concept of social connectedness for adults with Cystic Fibrosis (CF), generally and during the onset of the COVID-19 pandemic, to help inform contemporary CF healthcare. Social connectedness is an essential component of belonging and refers to an individual's sense of closeness with the social world. Unique disease factors make exploration of social connectedness pertinent, added to by COVID-19, with the CF population potentially facing increased risk for severe illness. METHODS: Seventeen adults with CF in Western Australia undertook interviews, with findings categorized as overarching themes. RESULTS: In a general sense, participants described social connectedness challenges caused by CF, despite which they reported meaningful connections that benefits their mental and physical health. Within a COVID-19 specific context, participants demonstrated resilience in the face of adversity, highlighted the importance of empathy in relation to the pandemic, and described how social support is both an outcome and enhancer of social connectedness. CONCLUSIONS: This study contributes to limited social connectedness literature within CF and chronic illness in general, highlighting the importance of social connectedness awareness raising, assessments and interventions in CF healthcare inside and outside the COVID-19 pandemic.

Tobramycin safety and efficacy review article.

Pseudomonas aeruginosa is a common respiratory pathogen found in patients with cystic fibrosis (CF), contributing to increased hospitalization, more rapid progression of CF lung disease, and increased risk of death. Guidelines recommend early therapy using tobramycin inhaled solution (TIS) or inhaled powder (TIP). Both TIS and TIP treatment regimens have demonstrated positive clinical outcomes in efficacy and safety, including improvements in FEV1, decreased sputum P. aeruginosa density, decreased rates in antipseudomonal antibiotic use, and reduced rates of hospitalizations due to respiratory events. In a comparison of patient preference for TIS versus TIP, a patient survey cited time savings and convenience as preferences for TIP. However, both TIP and TIS offer advantages that may benefit patients and increase treatment adherence depending on patient circumstances. TIS may be suitable for younger patients at home where parents and caregivers may better control proper administration, older individuals, and those with low FEV1. Dry powder inhalers are suitable when patients have less time to commit to their self-care (eg, patients who work, are remotely located, return home late, or are on vacation), and can reduce the patient treatment burden compared with nebulized delivery. In this expert review, we summarize the available data on tobramycin regarding its molecular characteristics, mechanism of action, and efficacy and safety for the treatment of acute and chronic P. aeruginosa infection.

Preferred health outcome states following treatment for pulmonary exacerbations of cystic fibrosis.

BACKGROUND: Treatment for pulmonary exacerbations of cystic fibrosis (CF) can produce a range of positive and negative outcomes. Understanding which of these outcomes are achievable and desirable to people affected by disease is critical to agreeing to goals of therapy and determining endpoints for trials. The relative importance of outcomes resulting from treatment of these episodes are not reported. We aimed to (i) quantify the relative importance of outcomes resulting from treatment for pulmonary exacerbations and (ii) develop patient and proxy carer-reported weighted outcome measures for use in adults and children, respectively. METHODS: A discrete choice experiment (DCE) survey was conducted. Participants were asked to make a series of hypothetical decisions about treatment for pulmonary exacerbations to assess how they make trade-offs between different attributes of health. Data were analysed using a conditional logistic regression model. The correlation coefficients from these data were rescaled to enable generation of a composite health outcome score between 0 and 100 (worst to best health state). RESULTS: 362 individuals participated (167 people with CF and 195 carers); of these, 206 completed the survey (56.9%). Most participants were female and resided in Australia. Difficult/painful breathing had the greatest impact on the preferred health state amongst people with CF and carers alike. Avoidance of gastrointestinal problems also heavily influenced decision-making. CONCLUSIONS: These data should be considered when making treatment decisions and determining endpoints for trials. Further research is recommended to quantify the preferences of children and to determine whether these align with those of their carer(s).

Novel method to select meaningful outcomes for evaluation in clinical trials.

BACKGROUND: A standardised framework for selecting outcomes for evaluation in trials has been proposed by the Core Outcome Measures in Effectiveness Trials working group. However, this method does not specify how to ensure that the outcomes that are selected are causally related to the disease and the health intervention being studied. Causal network diagrams may help researchers identify outcomes that are both clinically meaningful and likely to be causally dependent on the intervention, and endpoints that are, in turn, causally dependent on those outcomes. We aimed to (1) develop a generalisable method for selecting outcomes and endpoints in trials and (2) apply this method to select outcomes for evaluation in a trial investigating treatment strategies for pulmonary exacerbations of cystic fibrosis (CF). METHODS: We conducted a series of online surveys and workshops among people affected by CF. We used a modified Delphi approach to develop a consensus list of important outcomes. A workshop involving domain experts elicited how these outcomes were causally related to the underlying pathophysiological processes. Meaningful outcomes were prioritised based on the extent to which each outcome captured separate rather than common aspects of the underlying pathophysiological process. RESULTS: The 10 prioritised outcomes were: breathing difficulty/pain, sputum production/clearance, fatigue, appetite, pain (not related to breathing), motivation/demoralisation, fevers/night sweats, treatment burden, inability to meet personal goals and avoidance of gastrointestinal symptoms. CONCLUSIONS: This proposed method for selecting meaningful outcomes for evaluation in clinical trials may improve the value of research as a basis for clinical decisions.

Effect of transfer from a pediatric to adult cystic fibrosis center on clinical status and hospital attendance.

AIM: Transfer from pediatric to adult services could lead to clinical deterioration, few studies have examined this. We sought to examine the clinical impact of a structured individualized transition and transfer process in patients with cystic fibrosis (CF). METHODS: Medical records of all patients with CF in Western Australia who transferred from a pediatric center (Princess Margaret Hospital for Children) to an adult CF center (Sir Charles Gairdner Hospital) between 2008 and 2012 were reviewed. Data were extracted for 2 years before and after transfer. The number of CF outpatient visits, inpatient days, and home intravenous antibiotic therapy (HIVT) days were recorded at yearly intervals before and after transfer. Sputum culture results at transfer were collected. All respiratory function and anthropometric data over the 4 years were extracted. RESULTS: Forty-two patients with CF were transferred between 2008 and 2012. The mean age at transfer was 18.9 years (range 17-22). Compared to 1-year pre-transfer, the frequency of outpatient visits at 1- and 2-year post-transfer increased. After transfer, there was no change in BMI, HIVT days, or inpatient days, and no acceleration in the expected decline in FEV1. CONCLUSION: This study found that transfer from a pediatric to an adult CF center using a structured, individualized transition and transfer process was not associated with accelerated clinical deterioration.

Mepolizumab use in cystic fibrosis-associated allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is common in cystic fibrosis (CF). Treatment is challenging and the relapse rate is high. Standard therapy is oral steroids and antifungals. However, long-term systemic steroid often results in adverse effects and drug interactions between azoles and CFTR modulators are a potential concern. Mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, can benefit patients with severe eosinophilic asthma and there are reports of mepolizumab use in ABPA but not in ABPA complicating CF. We present the case of an adult with CF who had recurrent ABPA and intolerable treatment side effects with steroid, azole, and omalizumab. Mepolizumab was well tolerated and led to significantly improved clinical stability and symptomatic improvement. To our knowledge, this is the first report of successful mepolizumab treatment for ABPA in CF. Mepolizumab may be an important adjunctive treatment for difficult to control ABPA in CF.

Respiratory viral infections in Western Australians with cystic fibrosis.

BACKGROUND: Viral respiratory infections (VRI) in people living with Cystic fibrosis (CF) is less well understood than respiratory bacterial infections, particularly adults with CF and few studies have compared children with adults. This study evaluated the frequency of respiratory viruses in patients with cystic fibrosis (CF) in Western Australia (WA). We determined the VRI in CF and compared them with non-CF patients. Further, we compared CF patients that were hospitalised with those that were not. PATIENTS/METHODS: Nucleic acid from sputum of 157 CF and 348 non-CF patients was analysed for influenzavirus A (Flu A) and B, (Flu B), respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human rhinovirus (RV), and parainfluenza viruses (PIV 1-3) by RT-PCR, during the 2016 winter respiratory season. RESULTS: No significant difference in the frequency of respiratory virus detection between CF and non-CF patients was found. RV was the most frequently detected virus in CF patients, and in hospitalised CF. RSV and hMPV were found less frequently in CF patients and RSV was not found in any hospitalised CF patient. A trend for fewer influenzavirus detections in adult CF patients was observed, however the trend was opposite for paediatric patients. RV and Flu A were the most common viruses detected in hospitalised CF patients. CONCLUSION: There was no significant difference in VRI between CF and non-CF patients. RV and influenza A were most commonly found in hospitalised CF patients, suggesting that infection with these viruses may contribute to hospitalisation for CF respiratory exacerbations.

U-shaped association of vigorous physical activity with risk of metabolic syndrome in men with low lean mass, and no interaction of physical activity and serum 25-hydroxyvitamin D with metabolic syndrome risk.

BACKGROUND: There is uncertainty over how lean mass, physical activity (PA) and 25-hydroxyvitamin D (25-OH-D) status interact on metabolic syndrome (MetS) risk in adults. AIMS: To test the hypothesis that these factors additively influence MetS risk. METHODS: Four thousand eight hundred and fifty-eight adults (54.6% female) mean ± SD age 58.0 ± 5.8 years, body mass index 28.1 ± 4.8 kg/m2 , resident in Busselton, Western Australia. PA assessed by questionnaire (all/total and vigorous), lean mass using dual energy X-ray absorptiometry (% total body mass), serum 25-OH-D via immunoassay, analysed using multivariable logistic regression. RESULTS: In men, lower total PA was associated with MetS (no vs >24 h/week odds ratio (OR) = 3.1; ≤8 vs >24 h/week OR = 1.8, both P < 0.001), as was lower lean mass (low vs high OR = 20.4; medium vs high OR = 7.4, both P < 0.001). Men with low lean mass exhibited a U-shaped relationship of vigorous PA with MetS risk (covariate-adjusted: 0 vs 4-8 h/week OR = 2.1, P = 0.037; >12 vs 4-8 h/week OR = 4.3, P = 0.002; interaction P = 0.039). In women, low PA (0 vs >24 h/week OR = 2.1, P = 0.003) and lean mass (low vs high OR = 13.1; medium vs high OR = 7.2, both P < 0.001) were associated with MetS risk. Low 25-OH-D status was associated with MetS in men (low vs high OR = 4.1; medium vs high OR = 2.3, both P < 0.001) and women (OR = 3.5 and 2.1 respectively, both P < 0.001) with no PA interaction. CONCLUSIONS: Men and women with high lean mass have low risk of MetS regardless of PA. Low lean mass identifies men who may benefit most from increasing PA, with an optimal level associated with lowest risk. 25-OH-D and PA do not interact on MetS risk.

A smartphone application for reporting symptoms in adults with cystic fibrosis improves the detection of exacerbations: Results of a randomised controlled trial.

BACKGROUND: Respiratory exacerbations impair lung function and health-related quality of life in people with CF, with delayed identification of exacerbations often resulting in worse outcomes. We developed a smartphone application (app) for adults with CF to report symptoms to the CF team, and investigated its impact on antibiotic use and other outcomes. METHODS: Participants were randomised to intervention (use of the app weekly or sooner if symptoms had worsened) or control (usual care). The app comprised questions relating to symptoms suggestive of an exacerbation. If worsening symptoms were reported, the participant was contacted by the nurse practitioner. The primary outcome measure was the number of courses and days of intravenous (IV) antibiotics. RESULTS: Sixty participants (29 female, aged [mean ±â€¯SD] 31 ±â€¯9 years, FEV1 60 ±â€¯18% predicted) were recruited, with 29 (48%) allocated to the intervention group. Over the 12-month follow-up, there was no clear effect of the app on the number of courses of IV antibiotics (incidence rate ratio [IRR] 1; 95% confidence interval [CI] 0.6 to 1.7), however number of courses of oral antibiotics increased (IRR 1.5; 95% CI 1.0 to 2.2). The median [IQR] time to detection of exacerbation requiring oral or IV antibiotics was shorter in the intervention group compared with the control group (70 [123] vs. 141 [140] days; p = .02). No between-group differences were observed in other outcomes. CONCLUSION: The use of an app reduced time to detect respiratory exacerbations that required antibiotics, however did not demonstrate a clear effect on the number of courses of IV antibiotics.

The significance of anti-granulocyte-macrophage colony-stimulating factor antibodies in cryptococcal infection: case series and review of antibody testing.

We report two cases of cryptococcosis, associated with anti-granulocyte-macrophage colony-stimulating factor antibodies. We review this recently identified acquired form of autoimmune immune deficiency and discuss the potential applications of granulocyte-macrophage colony-stimulating factor antibody testing by enzyme-linked immunosorbent assay.