Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del.

Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were assessed at baseline, one month and three months following ETI therapy, and clinical outcomes were measured, including sweat chloride, lung function, weight, neutrophil count and C-reactive protein (CRP). Cytokine quantifications were measured in serum and following stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and adenosine triphosphate and analysed using LEGEND plex™ Human Inflammation Panel 1 by flow cytometry (n = 19). ASC specks were measured in serum and caspase-1 activity and mRNA levels determined from stimulated PBMCs were determined. Patients remained stable over the study period. ETI therapy resulted in decreased sweat chloride concentrations (p < 0.0001), CRP (p = 0.0112) and neutrophil count (p = 0.0216) and increased percent predicted forced expiratory volume (ppFEV1) (p = 0.0399) from baseline to three months, alongside a trend increase in weight. Three months of ETI significantly decreased IL-18 (p< 0.0011, p < 0.0001), IL-1ß (p<0.0013, p = 0.0476), IL-6 (p = 0.0109, p = 0.0216) and TNF (p = 0.0028, p = 0.0033) levels in CF serum and following PBMCs stimulation respectively. The corresponding mRNA levels were also found to be reduced in stimulated PBMCs, as well as reduced ASC specks and caspase-1 levels, indicative of NLRP3-mediated production of pro-inflammatory cytokines, IL-1ß and IL-18. While ETI therapy is highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to improved long-term clinical outcomes.

Impact of Digital Technologies on Clinical Care for Adults with Cystic Fibrosis.

The coronavirus disease 2019 pandemic accelerated the implementation of digital technologies, which have now become embedded as essential tools for the management of chronic disease, including cystic fibrosis (CF). Despite subsequent easing of restrictions and because of improved clinical stability resulting from the introduction of highly effective modulator therapy, digital technologies including video and telephone consultations and remote monitoring are likely to remain integral to the future delivery of CF health care. In this article, we explore some of the key developments in digital technologies, barriers to their adoption, and how the CF community is likely to embrace lessons learned from the recent pandemic to help modernize and reshape the future of CF care.

Urinary bicarbonate and metabolic alkalosis during exacerbations in cystic fibrosis.

The aetiology of increased serum bicarbonate and metabolic alkalosis in CF is complex and appears to be driven, at least in part, by renal tubular CFTR dysfunction https://bit.ly/3NFPkUu.

Nutritional status and intake in patients with non-cystic fibrosis bronchiectasis (NCFB) - a cross sectional study.

BACKGROUND & AIMS: Bronchiectasis is a heterogeneous, chronic respiratory condition, in which the role of nutrition remains unclear and nutritional guidance is lacking. Few studies have explored the role of nutrition in disease management, and little is known about nutritional requirements during periods of stability or metabolic stress. The aim of this study was to characterise nutritional status and intakes in a cohort of patients and identify potential associations with body composition and functional capacity. METHODS: A prospective observational cohort study was undertaken in an adult population (>17 years). Bronchiectasis was confirmed by high-resolution computerised tomography (HRCT). Anthropometric (weight, height, Body Mass Index (BMI), triceps skinfold thickness (TSF), mid upper-arm circumference (MUAC) and mid arm muscle circumference (MAMC)] lung function and nutritional intakes were measured. Results were analysed as a whole and by disease aetiology [primary ciliary dyskinesia (PCD), Idiopathic cause (IC), bronchiectasis in association with asthma and other] and associations tested. RESULTS: In total, 128 participants (65.5% female) completed the study. Median handgrip strength (HGS) in the total sample was only 66.5% (IQR 60.5-89.8) of reference population norms and was low for those with PCD [58.0% (IQR 43.5-70.0))]. Univariate regression indicated that BMI was a statistically significant predictor of lung function in the whole population with HGS and weight identified as statistically significant predictors of lung function in PCD. The total population and each sub-group failed to meet estimated average requirements for energy but exceeded the Reference nutrient intake (RNI) for protein. Vitamin D was consistently <35% of the RNI. CONCLUSION: BMI lay within normal to overweight ranges within the whole population and sub-groups, but masked important functional, body composition and nutritional deficits. This was particularly so within a younger sub-group with PCD, who had impaired muscle function, when compared to other causal and associative diseases.

Nasal high-flow therapy as an adjunct to exercise in patients with cystic fibrosis: A pilot feasibility trial.

BACKGROUND: Exercise tolerance in people with CF and advanced lung disease is often reduced. While supplemental oxygen can improve oxygenation, it does not affect dyspnoea, fatigue or comfort. Nasal high-flow therapy (NHFT), thanks to its pathophysiological mechanisms, could improve exercise tolerance, saturation and dyspnoea. This study explores the feasibility of conducting a clinical trial of using NHFT in patients with CF during exercise. METHODS: A pilot, open-label, randomized crossover trial was performed, enroling 23 participants with CF and severe lung disease. Participants completed two treadmill walking test (TWT) with and without NHFT at 24-48 h interval. Primary outcome was trial feasibility, and exploratory outcomes were TWT distance (TWTD), SpO2, transcutaneous CO2, dyspnoea and comfort. RESULTS: Recruitment rate was 2.4 subjects/month with 1.3:1 screening-to-randomization ratio. No adverse events caused by NHFT were observed. Tolerability was good and data completion rate was 100%. Twenty subjects (91%) were included in the exploratory study. Mean difference in TWTD on NHFT was 19 m (95% CI [4.8 - 33.1]). SpO2 was similar, but respiratory rate and mean tcCO2 were lower on NHFT (mean difference = -3.9 breaths/min 95% CI [-5.9 - -1.9] and -0.22 kPa 95% CI [-0.4 - 0.04]). NHFT reduced exercise-induced dyspnoea and discomfort. CONCLUSION: Trials using NHFT in patients with CF during exercise are feasible. NHFT appears to improve walking distance, control respiratory rate, CO2, dyspnoea and improve comfort. A larger trial with a longer intervention is feasible and warranted to confirm the impact of NHFT in training programmes for patients with CF.

Noninvasive Ventilation in Cystic Fibrosis: Clinical Indications and Outcomes in a Large UK Adult Cystic Fibrosis Center.

BACKGROUND: Noninvasive ventilation (NIV) is routinely used to treat patients with cystic fibrosis and respiratory failure. However, evidence on its use is limited, with no data on its role in disease progression and outcomes. The aim of this study was to assess the indications of NIV use and to describe the outcomes associated with NIV in adults with cystic fibrosis in a large adult tertiary center. METHODS: A retrospective analysis of data captured prospectively on the unit electronic patient records was performed. All patients with cystic fibrosis who received NIV over a 10-y period were included in the study. A priori, 2 groups were identified based on length of follow-up, with 2 subgroups identified based on duration of NIV treatment. RESULTS: NIV was initiated on 64 occasions. The duration of follow-up was categorized as > 6 months or < 6 months in 31 (48.4%) and 33 (51.6%) occasions, respectively. The most common indications for starting NIV were chronic (48.5%) and acute (32.8%) hypercapnic respiratory failure. Among those with a follow-up > 6 months, subjects who stopped using NIV early showed a steady median (interquartile range) decline in FEV1 (pre-NIV: -0.04 [-0.35 to 0.03] L/y vs post-NIV: -0.07 [-0.35 to 0.01] L/y, P = .51), while among those who continued using it had an improvement in the rate of decline (pre-NIV: -0.25 [-0.52 to -0.02] L/y vs post-NIV: -0.07 [-0.13 to 0.16] L/y, P = .006). No differences in intravenous antibiotic requirement or pulmonary exacerbations were noted with the use of NIV. Pneumothorax and massive hemoptysis occurred independently in 4 cases. CONCLUSIONS: NIV is being used in cystic fibrosis as adjunct therapy for the management of advanced lung disease in a similar fashion to other chronic respiratory conditions. Adherence to NIV treatment can stabilize lung function but does not reduce pulmonary exacerbations or intravenous antibiotic requirement.

Use of nasal high flow oxygen during acute respiratory failure.

Nasal high flow (NHF) has gained popularity among intensivists to manage patients with acute respiratory failure. An important literature has accompanied this evolution. In this review, an international panel of experts assessed potential benefits of NHF in different areas of acute respiratory failure management. Analyses of the physiological effects of NHF indicate flow-dependent improvement in various respiratory function parameters. These beneficial effects allow some patients with severe acute hypoxemic respiratory failure to avoid intubation and improve their outcome. They require close monitoring to not delay intubation. Such a delay may worsen outcome. The ROX index may help clinicians decide when to intubate. In immunocompromised patients, NHF reduces the need for intubation but does not impact mortality. Beneficial physiological effects of NHF have also been reported in patients with chronic respiratory failure, suggesting a possible indication in acute hypercapnic respiratory failure. When intubation is required, NHF can be used to pre-oxygenate patients either alone or in combination with non-invasive ventilation (NIV). Similarly, NHF reduces reintubation alone in low-risk patients and in combination with NIV in high-risk patients. NHF may be used in the emergency department in patients who would not be offered intubation and can be better tolerated than NIV.

Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis.

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1ß, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1ß was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1ß only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1ß and pro-IL-1ß mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Noninvasive Ventilatory Support for Acute Hypercapnic Respiratory Failure.

Noninvasive ventilation is well established as the ventilatory modality of first choice to treat acute or acute-on-chronic hypercapnic respiratory failure in patients with COPD by improving dyspnea and gas exchange, avoiding the need for intubation, and reducing morbidity and mortality rates. Noninvasive ventilation also offers benefit for patients with COPD and with accompanying pneumonia or with hypercapnic respiratory failure in postextubation, postoperative, and do not intubate settings. Noninvasive ventilation, in addition, offers benefit in other forms of acute hypercapnic respiratory failure, including those caused by asthma, cystic fibrosis, and obesity hypoventilation. A newer form of noninvasive ventilatory assistance, high-flow nasal cannula, has emerged in recent years as a technique to not only oxygenate effectively but also to improve ventilatory efficiency and reduce the work of breathing in patients with severe COPD. Results of recent studies indicate that high-flow nasal cannula therapy can benefit some patients with acute hypercapnic respiratory failure, either instead of or in combination with noninvasive ventilation, but more study is needed.

European Respiratory Society International Congress 2018: highlights from Assembly 2 on respiratory intensive care.

The respiratory intensive care Assembly of the European Respiratory Society is proud to present a summary of several important sessions held at the International Congress in Paris in 2018. For the highly esteemed reader who may have missed the Congress, a concise review was written on three topics: the state-of-the-art session on respiratory critical care, hot topics in weaning and the best abstracts in noninvasive ventilation.

High-flow nasal therapy vs standard oxygen during breaks off noninvasive ventilation for acute respiratory failure: A pilot randomized controlled trial.

PURPOSE: To assess the role of high-flow nasal therapy (HFNT) compared to standard oxygen (SO) as complementary therapy to non-invasive ventilation (NIV). METHODS: Multicenter trial including patients (n = 54) anticipated to receive NIV for ≥24 h due to acute or acute-on-chronic respiratory failure. Subjects were randomized (1:1) to SO or HFNT during breaks off NIV. Primary outcome was total time on and off NIV. Secondary outcomes were comfort and dyspnea, respiratory rate (RR), oxygen saturation (SpO2), tolerance and side effects. RESULTS: Total time per patient on NIV (1315 vs 1441 min) and breaks (1362 vs 1196 min), and mean duration of each break (520 vs 370 min) were similar in the HFNT and SO arms (p > .05). Comfort score was higher on HFNT than on SO (8.3 ±â€¯2.7 vs 6.9 ±â€¯2.3, p = .001). Dyspnea, RR and SpO2 were similar in the two arms, but the increase in RR and dyspnea seen with SO during breaks did not occur with HFNT. CONCLUSION: Compared to SO, HFNT did not reduce time on NIV. However, it was more comfortable and the increase in RR and dyspnea seen with SO did not occur with HFNT. Therefore, HFNT could be a suitable alternative to SO during breaks off NIV.

Cytomegalovirus-associated pulmonary exacerbation in patients with cystic fibrosis.

CMV is an unusual cause of pulmonary exacerbation in immunocompetent individuals with CF http://ow.ly/Rdds30hlnjV.

Heated Humidified High-Flow Nasal Oxygen in Adults: Mechanisms of Action and Clinical Implications.

Traditionally, nasal oxygen therapy has been delivered at low flows through nasal cannulae. In recent years, nasal cannulae designed to administer heated and humidified air/oxygen mixtures at high flows (up to 60 L/min) have been gaining popularity. These high-flow nasal cannula (HFNC) systems enhance patient comfort and tolerance compared with traditional high-flow oxygenation systems, such as nasal masks and nonrebreathing systems. By delivering higher flow rates, HFNC systems are less apt than traditional oxygenation systems to permit entrainment of room air during patient inspiration. Combined with the flushing of expired air from the upper airway during expiration, these mechanisms assure more reliable delivery of high Fio2 levels. The flushing of upper airway dead space also improves ventilatory efficiency and reduces the work of breathing. HFNC also generates a positive end-expiratory pressure (PEEP), which may counterbalance auto-PEEP, further reducing ventilator work; improve oxygenation; and provide back pressure to enhance airway patency during expiration, permitting more complete emptying. HFNC has been tried for multiple indications, including secretion retention, hypoxemic respiratory failure, and cardiogenic pulmonary edema, to counterbalance auto-PEEP in patients with COPD and as prophylactic therapy or treatment of respiratory failure postsurgery and postextubation. As of yet, very few high-quality studies have been published evaluating these indications, so recommendations regarding clinical applications of HFNC remain tentative.