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.

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.

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.

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.

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.

When Women with Cystic Fibrosis Become Mothers: Psychosocial Impact and Adjustments.

Advances in the treatment and life expectancy of cystic fibrosis (CF) patients mean that motherhood is now a realistic option for many women with CF. This qualitative study explored the psychosocial impact and adjustments made when women with CF become mothers. Women with CF (n = 11) were recruited via an online forum and participated in semistructured telephone interviews about their experiences of becoming a mother. Transcriptions were analysed using Grounded Theory. Analysis revealed three core categories: (i) "Living with CF": how becoming a mother impacted on health and treatment adherence, requiring a change in support from the CF team, (ii) "Becoming a Mother": balancing issues common to new mothers with their CF, and (iii) "Pooling Personal Resources": coping strategies in managing the dual demands of child and CF care. Participants experienced a variety of complex psychosocial processes. Most participants acknowledged an initial negative impact on CF care; however over time they reported successful adaptation to managing dual commitments and that adherence and motivation to stay well had improved. This study highlights the need for preconceptual psychosocial counselling and postpartum adjustment to CF care.

Bloodstream infections in cystic fibrosis: nine years of experience in both adults and children.

BACKGROUND: We report the aetiology and outcome of bloodstream infections (BSI) occurring at two regional cystic fibrosis (CF) centres (one adult, one paediatric) between 1998 and 2006. METHODS: A retrospective analysis of all positive blood cultures during the study period was performed. RESULTS: During the study period 1691 blood culture sets were taken. Fifty-seven clinically significant episodes of BSI in 48 people with CF (36 adult, 12 paediatric) were identified, along with 28 other episodes considered to be contamination or not clinically significant. The most common BSIs were caused by coagulase-negative staphylococci (13) Candida spp (10), and Stenotrophomonas maltophilia (8). The majority (82%) of significant BSIs were considered to originate from totally-implantable vascular access devices (TIVADs); only 9% were attributed to the lower respiratory tract. The TIVAD was removed in two-thirds of cases of TIVAD-associated BSI. There were three deaths (60% of cases) attributable to BSI originating from the lower respiratory tract but no deaths attributable to TIVAD-associated BSI. CONCLUSION: Most significant BSIs in patients with CF originate from TIVADs. Targeted antimicrobial therapy and appropriate early device removal is associated with good clinical outcome. BSI originating from the lower respiratory tract is associated with poor clinical outcome.

Multicentre trial of weekly risedronate on bone density in adults with cystic fibrosis.

BACKGROUND: The aim of this study was to assess the efficacy, tolerability and safety of risedronate in adults with CF. METHODS: Patients with a lumbar spine (LS), total hip (TH) or femoral neck (FN) bone mineral density (BMD) Z-score of -1 or less were randomised to receive risedronate 35 mg weekly or placebo, and calcium (1g)+vitamin D(3) (800IU). RESULTS: At baseline, BMD Z-scores in the risedronate (n=17) and placebo (n=19) groups were similar. By 24 months, 7/17 risedronate patients vs 0/19 placebo patients stopped the study medication due to bone pain. After 24 months treatment, the mean difference (95% CI) in change in LS, TH and FN BMD between the risedronate vs placebo groups was 4.3% (0.4, 8.2) p=0.03; 4.0% (-0.5, 8.6) p=0.08; and 2.4% (-3.5, 8.2) p=0.41. CONCLUSIONS: After two years treatment there was a significant increase in LS BMD with weekly risedronate compared to placebo.

Sequential bronchoscopy in the management of lobar atelectasis secondary to allergic bronchopulmonary aspergillosis.

Lobar atelectasis is a common complication in patients with cystic fibrosis. Failure to reexpand the lung isassociated with poorer outcomes. We report sequential weekly flexible bronchoscopy, with instillation of recombinant human DNase, in 5 patients with cystic fibrosis who had lobar collapse secondary to allergic bronchopulmonary aspergillosis. The number of procedures ranged from 2 procedures in 3 patients, 3procedures in 1 patient, and 4 procedures in another patient. All the patients achieved full reexpansion radiologically and the procedures were well tolerated. We conclude that sequential bronchoscopy in patients who fail to show reexpansion of the lung is effective and should be considered as part of standard medical management.

Clinical impact of reducing routine susceptibility testing in chronic Pseudomonas aeruginosa infections in cystic fibrosis.

BACKGROUND Susceptibility testing results are not predictive of clinical response to antibiotic therapy in chronic Pseudomonas aeruginosa infections in cystic fibrosis (CF). We assessed the impact of reducing the number of routine susceptibility tests performed on clinical outcome in these cases. METHODS In June 2006, we introduced a protocol whereby susceptibility tests of P. aeruginosa isolates obtained from respiratory samples of people with CF were limited to those taken at the commencement of antibiotic therapy, when there was evidence of clinical failure or routinely if not tested in the previous 3 months. At all other times, isolates were identified and reported as normal but P. aeruginosa isolates were not subjected to susceptibility testing. RESULTS Over a 6 month period, P. aeruginosa was isolated on at least one occasion from 193 patients attending the Adult Cystic Fibrosis Unit. In this period, we reduced the number of routine susceptibility tests by 56% (from a projected 2231 tests on 872 samples to an actual 972 tests on 427 samples). We assessed the response to courses of intravenous antibiotic treatment administered during the 6 month study period in 2006 and for courses administered in the same patients during the same calendar months in 2005. No significant differences in median change of FEV1, FVC, C-reactive protein (CRP), white cell count, weight or duration of intravenous antibiotics were observed. The projected savings of this intervention were 3500 euros in consumables and 170 h (costed at 6500 euros) of laboratory staff time per annum, a total annual saving of 10,000 euros (6500 pounds sterling). CONCLUSIONS For CF units sending regular, routine sputum samples, a reduction in the number of susceptibility tests performed in cases of chronic P. aeruginosa infection can be carried out without impacting on short-term clinical outcomes.

Nutritional status, perceived body image and eating behaviours in adults with cystic fibrosis.

BACKGROUND & AIMS: Achieving and maintaining an ideal nutritional status is the primary aim of the nutritional management of cystic fibrosis (CF). It is unclear how nutritional interventions impact on patients' perceptions and behaviours concerning body image and eating. This work aimed to provide a psychosocial profile and compare CF patients receiving (a) enteral tube feeding, (b) nutritional supplements, (c) no nutritional interventions, and (d) healthy controls. METHODS: A cross-sectional questionnaire design was employed. Age, gender, lung function, and body mass index were recorded. Subjects completed measures of eating attitudes, perceived and desired body shape, body image, self-esteem and quality of life (QoL). RESULTS: A minority of CF patients reported disordered eating. Those receiving nutritional interventions engaged in less dieting behaviour. All CF groups, especially intervention groups, received more pressure from others to eat. For females, control groups desired to be slimmer whereas intervention groups desired to be heavier. Healthy males were content with their body whereas CF males wished to be heavier. Patients receiving enteral tube feeding were less satisfied with their body image, reported lower self-esteem and poorer QoL. CONCLUSION: Body image and eating behaviours are important considerations of nutritional interventions for maintaining QoL.

Associations between clinical variables and quality of life in adults with cystic fibrosis.

BACKGROUND: The disease progression of cystic fibrosis (CF) is marked by an increase in clinical conditions and therapeutic interventions, which have the potential to affect health-related quality of life (HRQoL). This cross-sectional study explored associations between clinical variables and HRQoL. METHODS: HRQoL was measured using the Cystic Fibrosis Quality of Life (CFQoL) questionnaire, which consists of nine domains: physical, social, treatment, chest symptoms, emotional functioning, concerns for the future, relationships, body image, and career concerns. The CFQoL was completed by 223 adults with CF. Clinical and demographic data collected were: age, gender, FEV1% predicted, BMI, Burkholderia cepacia status, lung transplant status, diabetic status, level of nutritional intervention, and presence of an intravenous access device. Multiple regression using forward selection was used to construct models relating these variables to each HRQoL domain. RESULTS: Despite many of the variables being inter-related, some variables were associated with CFQoL domains even in the presence of other important clinical factors. FEV1% predicted was weakly positively associated with all nine domains. Strong evidence emerged that patients who had received a lung transplant reported a higher HRQoL in physical and social functioning, chest symptoms, and treatment issues. Females tended to report a lower quality of life for chest symptoms and career issues, but higher values for body image. Patients with an access device expressed more career concerns. There was no evidence of an association between B. cepacia and any of the nine CFQoL domains. The model for the body image domain explained a high percentage of the variance (R2=30%): negative body image was associated with lower BMI, having an access device, diabetes, and enteral feeding. CONCLUSIONS: While important associations were identified, much of the variance in HRQoL remains unexplained. Other clinical and psychosocial variables merit investigation. A longitudinal study is required to investigate how the disease trajectory and associated treatments affect an individual's quality of life.

Pharmacokinetics and safety of itraconazole in patients with cystic fibrosis.

OBJECTIVE: To assess the pharmacokinetics of itraconazole and hydroxy-itraconazole in patients with cystic fibrosis. METHODS: Patients were divided into those <16 and >/=16 years of age. All received itraconazole oral solution 2.5 mg/kg twice daily for 14 days. Serial blood samples were taken for itraconazole and hydroxy-itraconazole plasma level measurements. Safety was assessed from biochemistry and haematology data and reported adverse events. RESULTS: Seventeen patients entered the study. Steady-state concentrations were achieved after maximally 8 days of dosing. On day 14 average peak plasma concentrations were 404 +/- 268 ng/mL (<16 years, n = 5) and 779 +/- 470 ng/mL (>/=16 years, n = 11 excluding one patient concurrently receiving oral clarithromycin). A high inter-subject variability in itraconazole pharmacokinetics was seen. Intra-subject variability was low. All the younger patients and 50% of the older patients failed to achieve a plasma steady-state trough concentration of >250 ng/mL. Adverse events were reported by 53% of subjects. Most were mild or moderate in intensity and not considered related to treatment. One patient withdrew from the study because of two severe adverse events. Ten significant laboratory abnormalities were reported in seven of 16 patients with paired data. Six of these were clinically relevant. CONCLUSION: 2.5 mg/kg itraconazole oral solution twice daily in patients with cystic fibrosis achieves steady-state concentrations in maximally 8 days. The pharmacokinetics showed marked inter-subject variability. Plasma concentrations of >250 ng/mL were not reached in the paediatric cohort or in 50% of the adult cohort. The dosage regimen was safe and well tolerated.

Serum and sputum concentrations following the oral administration of linezolid in adult patients with cystic fibrosis.

OBJECTIVES: Linezolid is a new oxazolidinone antibiotic with efficacy against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the serum and sputum linezolid concentrations in adults with cystic fibrosis (CF) following oral drug administration. METHODS: Eleven adult patients with CF were recruited. Subjects received 600 mg of linezolid orally every 12 h for a total of six doses. Serum and sputum levels were measured just before and at 2 h after the final dose of linezolid. A further serum level was measured at 4 h. RESULTS: Ten adult patients completed the study. Mean (s.d.) serum linezolid concentrations were 2.3 mg/L (1.5) at 12 h following the fifth dose. At 2 and 4 h following the sixth dose, concentrations were 13.5 (4.3) and 8.1 (3.3). Mean (s.d.) linezolid sputum concentrations were 3.6 (2.1) and 17.4 (7.2) mg/L at 0 and 2 h following drug administration. CONCLUSIONS: The oral administration of linezolid results in good sputum penetration in patients with CF. Mean levels exceed the required MIC for the treatment of MRSA for >80% of the dosing period for serum and the majority of the dosing period for sputum.

Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis.

OBJECTIVES: To define the steady-state pharmacokinetics of colistin methanesulphonate and colistin in patients with cystic fibrosis (CF) following intravenous administration of the former. MATERIALS AND METHODS: The study was conducted in 12 patients with CF following intravenous administration of colistin methanesulphonate (1.63-3.11 mg/kg) every 8 h for at least 2 days. On the day of study, four blood samples were collected from each patient at 60, 120, 240 and 360 min after the end of the infusion. Concentrations of colistin methanesulphonate and colistin in plasma were measured separately by HPLC. RESULTS: At steady-state, colistin methanesulphonate had a mean (+/- S.D.) total body clearance, volume of distribution and half-life of 2.01 +/- 0.46 mL/min per kg, 340 +/- 95 mL/kg and 124 +/- 52 min, respectively. Colistin had a significantly longer mean half-life of 251 +/- 79 min (P<0.001). With the regimen used, colistin methanesulphonate was well tolerated. This is the first report on the pharmacokinetics of colistin methanesulphonate in CF patients determined using concentrations of colistin methanesulphonate and colistin in plasma. CONCLUSIONS: Based on the in vitro pharmacodynamics against Pseudomonas aeruginosa previously published by our group and these pharmacokinetic findings, dose escalating trials may be warranted to maximize efficacy.

Alcaligenes infection in cystic fibrosis.

The aim of this study was to investigate the effect of chronic Alcaligenes species infection of the respiratory tract on the clinical status of patients with cystic fibrosis. We conducted a retrospective case-controlled study. The microbiological records of all patients attending the Leeds Regional Pediatric and Adult Cystic Fibrosis Units from 1992-1999 were examined. Chronic Alcaligenes infection was defined as a positive sputum culture on at least three occasions over a 6-month period. These patients were compared with controls matched for age, gender, respiratory function, and Pseudomonas aeruginosa infection status. Respiratory function tests, anthropometric data, Shwachman-Kulczycki score, Northern chest x-ray score, intravenous and nebulized antibiotic treatment, and corticosteroid treatment were compared from 2 years before to 2 years after Alcaligenes infection. From a clinic population of 557, 13 (2.3%) fulfilled the criteria for chronic infection. The median age at acquisition of infection was 17.2 years (range, 6.5-33.6). There was no significant difference in the changes of percentage predicted values for FEV(1), FVC, FEF(25-75), or Shwachman-Kulczycki and Northern chest x-ray scores, or in weight, height, and body mass index z-scores between Alcaligenes-infected cases and controls. There was also no significant difference in the use of antibiotics (intravenous and nebulized) or corticosteroids (inhaled and oral). We conclude that in our clinic, chronic infection with Alcaligenes species was uncommon. Chronically infected patients showed no excess deterioration in clinical or pulmonary function status from 2 years before to 2 years after primary acquisition.