Role of Tris-CaEDTA as an adjuvant with nebulised tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa lung infections: A randomised controlled trial.

J Cyst Fibros. 2020 Dec 16;:

Authors: Puvvadi R, Mikkelsen H, McCahon L, Grogan S, Ditcham W, Reid DW, Lamont I, Stick SM, Clements B

Abstract
BACKGROUND: We tested if disrupting iron utilisation by P. aeruginosa by adding the Tris-buffered chelating agent CaEDTA to nebulised tobramycin would enhance bacterial clearance and improve lung function in CF patients.
METHODS: In this double-blind, randomised controlled trial, 26 episodes (25 patients) with P. aeruginosa infection admitted to two CF centres for treatment of an acute pulmonary exacerbation were randomly assigned to receive either 75 mg CaEDTA in Tris-buffered saline or placebo (Tris-buffered saline) nebulised in combination with 250 mg tobramycin twice daily for six weeks followed with four week safety follow-up. Primary endpoints were safety, tolerability, and bacterial density of P. aeruginosa. A secondary endpoint was lung function.
RESULTS: The study drug was well tolerated with adverse events comparable in both groups. The mean (SD) reduction in sputum P. aeruginosa count (log10 CFU/g) in the CaEDTA vs placebo group was 2·05 (2·57) vs 0·82 (2·71) at two weeks relative to admission (p = 0·39). The mean improvement in ppFEV1 was 16 vs 5 (p = 0·16); 11 vs 2 (p = 0·28); and 6 vs 2 percentage points (p = 0·47) at two, six, and ten weeks in CaEDTA and placebo groups, respectively.
CONCLUSIONS: In this pilot study in CF patients, an increase in the reduction of sputum density of P. aeruginosa and an increase in ppFEV1 was observed in the group of patients who received Tris-CaEDTA added to inhaled tobramycin compared to the group who received inhaled tobramycin alone, although these differences were not statistically significant. The treatment was also shown to be safe.

PMID: 33341406 [PubMed - as supplied by publisher]

Hallmarks of Health.

Cell. 2020 Dec 15;:

Authors: López-Otín C, Kroemer G

Abstract
Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology. The biological causes or hallmarks of health include features of spatial compartmentalization (integrity of barriers and containment of local perturbations), maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration). Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system coupled to the loss of numerous stigmata of health.

PMID: 33340459 [PubMed - as supplied by publisher]

Usefulness of autofluorescence bronchoscopy in early diagnosis of airway complications after lung transplantation.

Sci Rep. 2020 Dec 18;10(1):22316

Authors: Mendogni P, Carrinola R, Gherzi L, Tosi D, Palleschi A, Righi I, Damarco F, Morlacchi LC, Bonitta G, Vaira V, Nosotti M, Rosso L

Abstract
Despite the promising results achieved so far in long-term survival after lung transplantation (LuTx), airway complications (ACs) still arise in the post-operative period. Early diagnosis and prompt treatment of ACs play a critical role in preventing their onset. Specifically, large bronchi ischemia has been recognized as a triggering factor for ACs. Autofluorescence bronchoscopy, which was first introduced for early cancer diagnosis, displays ischemic mucosae as red spots, while normal vascularized mucosae appear in green. The aim of this study is to investigate whether a significant correlation exists between ACs and the red/green (RG) ratio detected on scheduled autofluorescence bronchoscopy up to 1 year after LuTx. This prospective, observational, single-center cohort study initially considered patients who underwent LuTx between July 2014 and February 2016. All patients underwent concomitant white-light and autofluorescence bronchoscopy at baseline (immediately after LuTx), on POD7, POD14, POD21, POD28, POD45, 3 months, 6 months, and 1 year after LuTx. An autofluorescence image of the first bronchial carina distal to the anastomosis was captured and analyzed using histograms for red and green pixels; the R/G ratio was then recorded. Potential ACs were classified according according to the presence of a white-light following the MDS (macroscopic aspect, diameter and suture) criteria. The authors assessed the association between the R/G ratio and the ACs occurrence using a generalized estimating equations model. Thirty-one patients met the inclusion criteria and were therefore selected. Out of a total of 53 bronchial anastomoses, 8 developed complications (late bronchial stenosis), with an average onset time of 201 days after LuTx. ACs showed a similar baseline covariate value when compared to anastomoses that involved no complication. Generalized estimating equations regression indicated a clear association over time between the R/G ratio and the rise of complications (p = 0.023). The authors observed a significant correlation between post-anastomotic stenosis and the delayed decrease of the R/G ratio. Preliminary outcomes suggest that autofluorescence bronchoscopy may be an effective and manageable diagnostic tool, proving complementary to other instruments for early diagnosis of ACs after LuTx. Further research is needed to confirm and detail preliminary findings.

PMID: 33339959 [PubMed - as supplied by publisher]

A phase 3, randomized, double-blind, parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation.

J Cyst Fibros. 2020 Dec 15;:

Authors: McKone EF, DiMango EA, Sutharsan S, Barto TL, Campbell D, Ahluwalia N, Higgins M, Owen CA, Tullis E

Abstract
BACKGROUND: Tezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes.
METHODS: Enrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1). Key secondary endpoints were relative change in ppFEV1 and absolute change in CF Questionnaire-Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8.
RESULTS: Sixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV1 or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF.
CONCLUSIONS: This Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111).

PMID: 33339768 [PubMed - as supplied by publisher]

Human Papilloma Virus Vaccination Among Female Patients Attending French Paediatric Cystic Fibrosis Centres.

J Pediatr Adolesc Gynecol. 2020 Dec 15;:

Authors: Rousset-Jablonski C, Haesebaert J, Denis A, Reix P, Llerena C, Perceval M, Touzet S, Durieu I

Abstract
STUDY OBJECTIVE: To describe HPV vaccination practice among adolescent girls with cystic fibrosis (CF) and to identify reasons for non-vaccination.
DESIGN: Cross-sectional multicentric study.
SETTING: and Participants: Girls aged 9 to 17, attending 7 French paediatric CF centres and their accompanying adult.
INTERVENTIONS: The administration of a self-report questionnaire.
MAIN OUTCOME MEASURES: The proportion of girls having received or receiving HPV vaccination, compliance with the vaccination schedule, factors associated with vaccination, and reasons for vaccination and for non-vaccination.
RESULTS: A total of 113 girls and 104 accompanying adults participated. The mean age was 13.6 (SD 2.5) (range 9-17). A total of 34 (30.9%) patients declared having received HPV vaccination. Among the 34 girls aged 15 or older, 15 (44.1%) were vaccinated. Most patients (58.8%) started vaccination between 11 and 14 years of age (mean age 13.9). Most vaccine prescriptions (67.6%) were made by a CF centre health care provider. Factors associated with vaccination were older age (OR=1.27 (95% CI=1.01-1.6), p=0.037 for each year older), previous vaccination by the accompanying parent of one of their children for hepatitis B (OR=8.01 (95% CI=0.96-67.02), p=0.055), and parental influence on decision-making (OR=2.77 (95% CI=0.97-7.95), p=0.058). Health-care providers' positive advice and fear of HPV-related disease were the main reasons given to justify vaccination decisions. Insufficient knowledge, and concerns about potential side effects were the main barriers.
CONCLUSION: HPV vaccination remains insufficient among girls with CF. CF health-care providers may play a crucial role in HPV vaccination acceptance, and their sensitization to cervical cancer prevention is mandatory.

PMID: 33338628 [PubMed - as supplied by publisher]

Impact of biofilm formation and azoles' susceptibility in Scedosporium/Lomentospora species using an in vitro model that mimics the cystic fibrosis patients' airway environment.

J Cyst Fibros. 2020 Dec 14;:

Authors: Mello TP, Lackner M, Branquinha MH, Santos ALS

Abstract
BACKGROUND: Scedosporium species are the second most isolated filamentous fungi from cystic fibrosis (CF) patients; however, little is known about their virulence aspects in a CF environment. In this context, the current study aimed to evaluate the (i) antifungal susceptibility profiles, (ii) ability to form biofilm and (iii) impact of biofilm formation on the susceptibility to azoles in 21 clinical isolates of Scedosporium recovered from CF patients.
METHODS: Scedosporium apiospermum (n=6), S. aurantiacum (n=6), S. minutisporum (n=3) and Lomentospora prolificans (n=6) were firstly used to compare the antifungal susceptibility profile using a standard culture broth (RPMI-1640) and a mucin (M)-containing synthetic CF sputum medium (SCFM). The ability to form biofilms was investigated in polystyrene microtiter plates containing Sabouraud-dextrose (a classical medium), SCFM and SCFM+M. Mature biofilms were tested for their susceptibility to azoles by microdilution assay.
RESULTS: Our results showed that the minimum inhibitory concentrations (MICs) for planktonic conidia ranged from 0.25 to >16.0 mg/L for voriconazole and 1.0 to >16.0 mg/L for posaconazole. Overall, the MICs for azoles increased from 2- to 8-folds when the susceptibility tests were performed using SCFM+M compared to RPMI-1640. All fungi formed robust biofilms on polystyrene surface at 72 h, with a significant increase in the MICs (ranging from 128- to 1024-times) against both azoles compared to the planktonic cells.
CONCLUSION: These findings confirm the challenge of antifungal treatment of CF patients infected with Scedosporium/Lomentospora and also demonstrated a strong biofilm formation, with extensive increase in antifungal resistance, triggered underconditions mimicking the CF patient airway.

PMID: 33334714 [PubMed - as supplied by publisher]

Systemic steroids have a role in treating esophageal strictures in pediatric eosinophilic esophagitis.

Dig Liver Dis. 2020 Dec 15;:

Authors: Hoofien A, Rea F, Espinheira MDC, Amil Dias J, Romano C, Oliva S, Auth MK, Zangen T, Kalach N, Domínguez-Ortega G, De Angelis P, Zevit N, ESPGHAN EGID Working Group

Abstract
BACKGROUND: The role of systemic steroids in the treatment of esophageal strictures in children with Eosinophilic Esophagitis (EoE) is poorly defined.
AIMS: To describe a cohort of children with EoE-associated esophageal strictures responding to systemic steroids.
METHODS: Retrospective review of medical records of children with EoE and moderate (<9 mm) to severe (<6 mm) strictures, who responded clinically and endoscopically to systemic steroids.
RESULTS: Twenty children (median age 10.6 ± 4.2 years; 17 males) from nine centers in six countries were included in the analysis; 16 had moderate and four, severe strictures; 18 had dysphagia or bolus impaction; median diagnostic delay was 8 months (IQR 3.5-35). Eighteen patients received oral systemic steroids (mean dose 1.4 mg/kg/day) for a median of 4 weeks, while two initially received IV steroids. All patients showed clinical improvement and 15/20 became asymptomatic. Stricture resolution at endoscopy was found in 19/20, while histological resolution of EoE (<15 eos/hpf) in 13/20. Only minor side effects were reported: hyperphagia (10/20); weight gain (5/20); hyperactivity (2/20) and acne (1/20). Esophageal dilation was required in 3/20 patients during a median follow-up of 48.5 months (IQR 26.7-73.2).
CONCLUSION: Children with EoE and esophageal strictures, may benefit from the use of a short course of systemic steroids, avoiding mechanical dilation.

PMID: 33334703 [PubMed - as supplied by publisher]

Addressing Reduced Laboratory-Based Pulmonary Function Testing During a Pandemic.

Chest. 2020 12;158(6):2502-2510

Authors: Kouri A, Gupta S, Yadollahi A, Ryan CM, Gershon AS, To T, Tarlo SM, Goldstein RS, Chapman KR, Chow CW

Abstract
To reduce the spread of the severe acute respiratory syndrome coronavirus 2, many pulmonary function testing (PFT) laboratories have been closed or have significantly reduced their testing capacity. Because these mitigation strategies may be necessary for the next 6 to 18 months to prevent recurrent peaks in disease prevalence, fewer objective measurements of lung function will alter the diagnosis and care of patients with chronic respiratory diseases. PFT, which includes spirometry, lung volume, and diffusion capacity measurement, is essential to the diagnosis and management of patients with asthma, COPD, and other chronic lung conditions. Both traditional and innovative alternatives to conventional testing must now be explored. These may include peak expiratory flow devices, electronic portable spirometers, portable exhaled nitric oxide measurement, airwave oscillometry devices, and novel digital health tools such as smartphone microphone spirometers and mobile health technologies along with integration of machine learning approaches. The adoption of some novel approaches may not merely replace but could improve existing management strategies and alter common diagnostic paradigms. With these options comes important technical, privacy, ethical, financial, and medicolegal barriers that must be addressed. However, the coronavirus disease 19 pandemic also presents a unique opportunity to augment conventional testing by including innovative and emerging approaches to measuring lung function remotely in patients with respiratory disease. The benefits of such an approach have the potential to enhance respiratory care and empower patient self-management well beyond the current global pandemic.

PMID: 32652095 [PubMed - indexed for MEDLINE]

The challenge of medication acquisition in cystic fibrosis; cracking the nut with pharmacy technicians.

Pediatr Pulmonol. 2020 Dec 17;:

Authors: Kuhn RJ

PMID: 33333626 [PubMed - as supplied by publisher]

Office-Based Sinus Surgery for Cystic Fibrosis Chronic Rhinosinusitis.

ORL J Otorhinolaryngol Relat Spec. 2020 Dec 17;:1-4

Authors: Spielman DB, Gudis DA

Abstract
OBJECTIVE: Chronic rhinosinusitis (CRS) is nearly ubiquitous in the cystic fibrosis (CF) population, and many patients require multiple endoscopic sinus surgeries throughout their lifetime. Recent studies have demonstrated the profound pulmonary and systemic health benefits of comprehensive CRS treatment. Both endotracheal intubation with mechanical ventilation and inpatient hospital care represent significant risks for CF patients. The goal of this study is to evaluate the safety and feasibility of performing revision endoscopic sinus surgery for CF patients in the outpatient office setting using only local anesthesia to decrease the need for mechanical ventilation and inpatient hospitalization.
METHODS: This is a prospective cohort study conducted at a tertiary care academic medical center with a CF Foundation-accredited care center. Patients with CF and refractory CRS despite prior surgery and medical therapy were eligible for inclusion. Comprehensive revision ESS was performed in the office using only local anesthesia.
RESULTS: Five patients were enrolled and underwent revision endoscopic sinus surgery without complication. The average preoperative Sinonasal-Outcome Test-22 score was 52.0 ± 12.1 and the average preoperative Lund-Mackay score was 15.2 ± 3.8. No patients requested aborting the procedure early due to pain, discomfort, or any other reason. No subjects required prolonged observation or postoperative hospital admission.
CONCLUSION: This prospective pilot study is the first to demonstrate the safety and feasibility of performing comprehensive revision endoscopic sinus surgery for CF patients in the outpatient office setting using only local anesthesia.

PMID: 33333509 [PubMed - as supplied by publisher]

Sensitization to A.fumigatus in subjects with non-cystic fibrosis bronchiectasis.

Mycoses. 2020 Dec 17;:

Authors: Sehgal IS, Dhooria S, Prasad KT, Muthu V, Aggarwal AN, Rawat A, Pal A, Bal A, Garg M, Chakrabarti A, Agarwal R

Abstract
BACKGROUND: Patients with chronic lung diseases, including cystic fibrosis (CF), are frequently sensitized to Aspergillus fumigatus. Whether patients with non-CF bronchiectasis develop sensitization to A.fumigatus remains unknown.
OBJECTIVE: To evaluate the prevalence of sensitization and chronic infection with A.fumigatus in subjects with bronchiectasis. We also performed a multivariate logistic regression analysis to identify factors predicting sensitization and chronic A.fumigatus infection.
METHODS: Subjects with bronchiectasis were investigated with serum A.fumigatus-specific IgE and IgG, and sputum cultures for bacteria, fungus, and mycobacteria. We defined A.fumigatus sensitization and chronic A.fumigatus infection as serum A.fumigatus-specific IgE and IgG >0.35 kUA/L and >27 mgA/L, respectively. We excluded subjects with bronchiectasis secondary to allergic bronchopulmonary aspergillosis.
RESULTS: We included 258 subjects (TB [n=155], idiopathic [n=66] and other causes [n=37]) with bronchiectasis. The prevalence of Aspergillus sensitization, chronic Aspergillus infection, and both sensitization and chronic infection was 29.5% (76/258), 76% (196/258), and 26% (68/258), respectively. In a multivariate logistic regression analysis, TB-related bronchiectasis was an independent risk factor for Aspergillus sensitization. Chronic Aspergillus infection was predicted by the duration of symptoms and specific etiologies (tuberculosis and idiopathic) of bronchiectasis. The growth of Aspergillus species was also frequent in the TB group compared to other causes (32% vs. 2%; p<0.001).
CONCLUSIONS: We found a significant occurrence of Aspergillus sensitization and chronic infection in non-CF bronchiectasis, especially in TB-bronchiectasis. In addition to Aspergillus sensitization, investigations for chronic Aspergillus infection should be routinely performed in non-CF bronchiectasis, both at diagnosis and during followup.

PMID: 33332671 [PubMed - as supplied by publisher]

Glucose tolerance stages in Cystic Fibrosis are idenfied by a unique pattern of defects of Beta-cell function.

J Clin Endocrinol Metab. 2020 Dec 17;:

Authors: Piona C, Volpi S, Zusi C, Mozzillo E, Tosco A, Franzese A, Raia V, Boselli ML, Trombetta M, Cipolli M, Bonadonna RC, Maffeis C

Abstract
AIM: To assess the order of severity of the defects of three direct determinants of glucose regulation, i.e., beta-cell function, insulin clearance and insulin sensitivity, in patients with CF categorized according their glucose tolerance status, including early elevation of mid-OGTT glucose values (>140 and < 200 mg/dL), named AGT140.
METHODS: Two hundred and thirty-two CF patients aged 10-25 underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modelling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between five glucose tolerance stages [NGT, AGT140, Indeterminate glucose Tolerance (INDET), impaired glucose tolerance (IGT), Cystic fibrosis related diabetes (CFRD)] and glucometabolic variables was assessed with general linear model.
RESULTS: Beta-cell function and insulin sensitivity progressively worsened across glucose tolerance stages (p<0.001) with AGT140 patients significantly differing from NGT (all p<0.01). AGT140 and INDET showed a degree of beta-cell dysfunction similar to IGT and CFRD, respectively (all p<0.01). Insulin clearance was not significantly associated with glucose tolerance stages (p=0.162). Each class of glucose tolerance was uniquely identified by a specific combination of defects of the direct determinants of glucose regulation.
CONCLUSIONS: In CF patients each of the five glucose tolerance stages shows a unique pattern of defects of the direct determinants of glucose regulation, with AGT140 patients significantly differing from NGT and being similar to IGT. These findings suggest to recognize AGT 140 as a distinct glucose tolerance class and to reconsider the grade of glucometabolic deterioration across glucose tolerance stages in CF.

PMID: 33331877 [PubMed - as supplied by publisher]

Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring AMR bacterial pneumonia.

Elife. 2020 Dec 17;9:

Authors: Gregorova M, Morse D, Brignoli T, Steventon J, Hamilton F, Albur M, Arnold D, Thomas M, Halliday A, Baum H, Rice C, Avison MB, Davidson AD, Santopaolo M, Oliver E, Goenka A, Finn A, Wooldridge L, Amulic B, Boyton RJ, Altmann DM, Butler DK, McMurray C, Stockton J, Nicholls S, Cooper C, Loman N, Cox MJ, Rivino L, Massey RC

Abstract
Here we describe the case of a COVID-19 patient who developed recurring ventilator-associated pneumonia caused by Pseudomonas aeruginosa that acquired increasing levels of antimicrobial resistance (AMR) in response to treatment. Metagenomic analysis revealed the AMR genotype, while immunological analysis revealed massive and escalating levels of T-cell activation. These were both SARS-CoV-2 and P. aeruginosa specific, and bystander activated, which may have contributed to this patient's persistent symptoms and radiological changes.

PMID: 33331820 [PubMed - as supplied by publisher]

Respiratory muscle training for cystic fibrosis.

Cochrane Database Syst Rev. 2020 Dec 17;12:CD006112

Authors: Stanford G, Ryan H, Solis-Moya A

Abstract
BACKGROUND: Cystic fibrosis is the most common autosomal recessive disease in white populations, and causes respiratory dysfunction in the majority of individuals. Numerous types of respiratory muscle training to improve respiratory function and health-related quality of life in people with cystic fibrosis have been reported in the literature. Hence a systematic review of the literature is needed to establish the effectiveness of respiratory muscle training (either inspiratory or expiratory muscle training) on clinical outcomes in cystic fibrosis. This is an update of a previously published review.
OBJECTIVES: To determine the effectiveness of respiratory muscle training on clinical outcomes in people with cystic fibrosis.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials register comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of most recent search: 11 June 2020. A hand search of the Journal of Cystic Fibrosis and Pediatric Pulmonology was performed, along with an electronic search of online trial databases. Date of most recent search: 05 October 2020.
SELECTION CRITERIA: Randomised controlled studies comparing respiratory muscle training with a control group in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS: Review authors independently selected articles for inclusion, evaluated the methodological quality of the studies, and extracted data. Additional information was sought from trial authors where necessary. The quality of the evidence was assessed using the GRADE system.
MAIN RESULTS: Authors identified 20 studies, of which 10 studies with 238 participants met the review's inclusion criteria. There was wide variation in the methodological and written quality of the included studies. Four of the 10 included studies were published as abstracts only and lacked concise details, thus limiting the information available. Eight studies were parallel studies and two of a cross-over design. Respiratory muscle training interventions varied dramatically, with frequency, intensity and duration ranging from thrice weekly to twice daily, 20% to 80% of maximal effort, and 10 to 30 minutes, respectively. Participant numbers ranged from 11 to 39 participants in the included studies; five studies were in adults only, one in children only and four in a combination of children and adults. No differences between treatment and control were reported in the primary outcome of pulmonary function (forced expiratory volume in one second and forced vital capacity) or postural stability (very low-quality evidence). Although no change was reported in exercise capacity as assessed by the maximum rate of oxygen use and distance completed in a six minute walk test, a 10% improvement in exercise duration was found when working at 60% of maximal effort in one study (n = 20) (very low-quality evidence). In a further study (n = 18), when working at 80% of maximal effort, health-related quality of life improved in the mastery and emotion domains (very low-quality evidence). With regards to the review's secondary outcomes, one study (n = 11) found a change in intramural pressure, functional residual capacity and maximal inspiratory pressure following training (very low-quality evidence). Another study (n=36) reported improvements in maximal inspiratory pressure following training (P < 0.001) (very low-quality evidence). A further study (n = 22) reported that respiratory muscle endurance was longer in the training group (P < 0.01). No studies reported significant differences on any other secondary outcomes. Meta-analyses could not be performed due to a lack of consistency and insufficient detail in reported outcome measures.
AUTHORS' CONCLUSIONS: There is insufficient evidence to suggest whether this intervention is beneficial or not. Healthcare practitioners should consider the use of respiratory muscle training on a case-by-case basis. Further research of reputable methodological quality is needed to determine the effectiveness of respiratory muscle training in people with cystic fibrosis. Researchers should consider the following clinical outcomes in future studies; respiratory muscle function, pulmonary function, exercise capacity, hospital admissions, and health-related quality of life. Sensory-perceptual changes, such as respiratory effort sensation (e.g. rating of perceived breathlessness) and peripheral effort sensation (e.g. rating of perceived exertion) may also help to elucidate mechanisms underpinning the effectiveness of respiratory muscle training.

PMID: 33331663 [PubMed - in process]

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

Cochrane Database Syst Rev. 2020 Dec 17;12:CD010966

Authors: Southern KW, Murphy J, Sinha IP, Nevitt SJ

Abstract
BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.
OBJECTIVES: To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del).
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020.
SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data.
MAIN RESULTS: We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV1) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV1 (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV1 (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence).
AUTHORS' CONCLUSIONS: There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.

PMID: 33331662 [PubMed - in process]

[Rare diseases on the agenda for innovation in health: progress and challenges with cystic fibrosis].

Cad Saude Publica. 2020;36(12):e00115720

Authors: Amaral MB, Rego S

Abstract
The article proposes to discuss the many complexities involved in the incorporation of new health technologies for rare diseases, with a central focus on the case of cystic fibrosis. Cystic fibrosis was chosen because it is a autosomal recessive genetic disorder, considered the most common of the rare diseases. The disease has also benefited greatly from investments in research in the field of molecular biology, mainly in the United States, but also among European research groups, which resulted in the registration and marketing of four new drugs. These new drugs act for the first time on the basic defect in cystic fibrosis. From a perspective that views rare diseases as a field of research woven among many others, the article aims to problematize cystic fibrosis from a more person-centered approach, the duality of witnessing from afar the molecularization of life, the emergence of last-generation drugs that interrupt, at the molecular level, the cascade of errors and thus the symptoms and evolution of the disease. The article aims to bring various elements to the debate that traverse the complex local reality of Brazilian cystic fibrosis patients in a global context of technological innovation and with a break in the treatment paradigm. Based on the field of rare diseases, including the presentation of cystic fibrosis in the age of precision medicine, alongside discussions on biopolitics in a context of health innovation and high-cost drugs, the article aims to shed light on the current challenges and possibilities.

PMID: 33331552 [PubMed - in process]

Microbiome data enhances predictive models of lung function in people with cystic fibrosis.

J Infect Dis. 2020 Dec 17;:

Authors: Zhao CY, Hao Y, Wang Y, Varga JJ, Stecenko AA, Goldberg JB, Brown SP

Abstract
BACKGROUND: Microbiome sequencing has brought increasing attention to the polymicrobial context of chronic infections. However, clinical microbiology continues to focus on canonical human pathogens, which may overlook informative, but non-pathogenic, biomarkers. We address this disconnect in lung infections in people with cystic fibrosis (CF).
METHODS: We collected health information (lung function, age, BMI) and sputum samples from a cohort of 77 children and adults with CF. Samples were collected during a period of clinical stability and 16S rDNA sequenced for airway microbiome compositions. We use Elastic Net regularization to train linear models predicting lung function and extract the most informative features.
RESULTS: Models trained on whole microbiome quantitation outperform models trained on pathogen quantitation alone, with or without the inclusion of patient metadata. Our most accurate models retain key pathogens as negative predictors (Pseudomonas, Achromobacter) along with established correlates of CF disease state (age, BMI, CF related diabetes). In addition, our models select non-pathogen taxa (Fusobacterium, Rothia) as positive predictors of lung health.
CONCLUSIONS: These results support a reconsideration of clinical microbiology pipelines to ensure the provision of informative data to guide clinical practice.

PMID: 33330902 [PubMed - as supplied by publisher]

Hospitalization, Asthma Phenotypes, and Readmission Rates in Pre-school Asthma.

Front Pediatr. 2020;8:562843

Authors: Donath H, Kluge S, Sideri G, Trischler J, Jerkic SP, Schulze J, Zielen S, Blumchen K

Abstract
Objective: Children with pre-school asthma suffer disproportionally more often from severe asthma exacerbations with emergency visits and hospital admissions compared to school children. Despite this high disease burden, there are only a few reports looking at this particular severe asthma cohort. Similarly, there is little real-life research on the distribution of asthma phenotypes and personalized treatment at discharge in this age group. Patients and Methods: Retrospective analysis of the electronic charts of all children aged 1-5 years with asthma hospitalizations (ICD J45) at the Frankfurt University between 2008 and 2017. An acute severe asthma exacerbation was defined as dyspnea, oxygen demand, and/or systemic steroid therapy. Age, gender, duration of hospitalization, asthma phenotype, treatment, and readmission rate were analyzed. Results: Of 572 patients, 205 met the definition of acute severe asthma. The phenotypic characterization showed 56.1% had allergic asthma, 15.2% eosinophilic asthma and 28.7% non-allergic asthma. Of these patients, 71.7% were discharged with inhaled corticosteroids (ICS) or ICS + long-acting-beta-agonists (LABA), 15.1% with leukotriene antagonists (LTRA) and 7.3% salbutamol on demand. The rate of emergency presentations (emergency department and readmission) within 12 months after discharge was high (n = 42; 20.5%). No phenotype tailored treatment was detectable. Neither the number of eosinophils (>300/μl) nor the treatment at discharge had an effect on emergency visits and readmission rate. Conclusion: Despite protective therapy with ICS, ICS + LABA, or LTRA, the readmission rate was high. Thus, current care and treatment strategies should be reevaluated continuously, in order to better control asthma in pre-school children and prevent hospitalization.

PMID: 33330266 [PubMed]

Can we Train the Immune System of Patients With Cystic Fibrosis?

Arch Bronconeumol. 2020 Nov 09;:

Authors: Tur-Torres J, Traversi L, Martínez-Gallo M, Assante G, Romero Mesones CE, Clofent Alarcon D, Chang-Macchiu P, Alvarez A, Polverino E

PMID: 33328136 [PubMed - as supplied by publisher]

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