Inhaled mannitol for cystic fibrosis.

Cochrane Database Syst Rev. 2020 May 01;5:CD008649

Authors: Nevitt SJ, Thornton J, Murray CS, Dwyer T

Abstract
BACKGROUND: Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.
OBJECTIVES: To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences. Date of last search: 12 December 2019.
SELECTION CRITERIA: All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.
DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE.
MAIN RESULTS: Six studies (reported in 36 unique publications) were included with a total of 784 participants. Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population. Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies. Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality. For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF. For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations. In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa).
AUTHORS' CONCLUSIONS: There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa. The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.

PMID: 32358807 [PubMed - as supplied by publisher]

The true panel of cystic fibrosis mutations in the Sicilian population.

BMC Med Genet. 2020 May 01;21(1):89

Authors: Chamayou S, Sicali M, Lombardo D, Maglia E, Liprino A, Cardea C, Fichera M, Venti E, Guglielmino A

Abstract
BACKGROUND: The aim was to establish the true risk of having an affected child with Cystic Fibrosis (CF) in the Sicilian infertile population.
METHODS: A longitudinal CFTR screening of 1279 Sicilian infertile patients for all CFTR mutations sequencing the entire gene by Next Generation Sequencing (NGS) was performed from patient's blood.
RESULTS: One patient out of 16 was a carrier of a CFTR mutation. Twenty-four mutations were found. Theoretically one couple out of 256 was at risk of CF transmission.
CONCLUSIONS: The risk of CF transmission is unexpectedly high in Sicily and with a high heterogeneity. Sequencing an entire and long gene such as CFTR makes accessible the true panel of mutations in a specific population and helps better to understand the true risk of having an affected child.

PMID: 32357917 [PubMed - as supplied by publisher]

Staphylococcus aureus Pathogenicity in Cystic Fibrosis Patients-Results from an Observational Prospective Multicenter Study Concerning Virulence Genes, Phylogeny, and Gene Plasticity.

Toxins (Basel). 2020 Apr 26;12(5):

Authors: Lange J, Heidenreich K, Higelin K, Dyck K, Marx V, Reichel C, Wamel WV, Reijer MD, Görlich D, Kahl BC

Abstract
Staphylococcus aureus and cystic fibrosis (CF) are closely interlinked. To date, however, the impact of S. aureus culture in CF airways on lung function and disease progression has only been elucidated to a limited degree. This analysis aims to identify bacterial factors associated to clinical deterioration. Data were collected during an observational prospective multi-center study following 195 patients from 17 centers. The average follow-up time was 80 weeks. S. aureus isolates (n = 3180) were scanned for the presence of 25 virulence genes and agr-types using single and multiplex PCR. The presence of specific virulence genes was not associated to clinical deterioration. For the agr-types 1 and 4, however, a link to the subjects' clinical status became evident. Furthermore, a significant longitudinal decrease in the virulence gene quantity was observed. Analyses of the plasticity of the virulence genes revealed significantly increased plasticity rates in the presence of environmental stress. The results suggest that the phylogenetic background defines S. aureus pathogenicity rather than specific virulence genes. The longitudinal loss of virulence genes most likely reflects the adaptation process directed towards a persistent and colonizing rather than infecting lifestyle.

PMID: 32357453 [PubMed - as supplied by publisher]

Evaluation of Droplet Digital Polymerase Chain Reaction (ddPCR) for the Absolute Quantification of Aspergillus species in the Human Airway.

Int J Mol Sci. 2020 Apr 26;21(9):

Authors: Poh TY, Ali NABM, Chan LLY, Tiew PY, Chotirmall SH

Abstract
BACKGROUND: Prior studies illustrate the presence and clinical importance of detecting Aspergillus species in the airways of patients with chronic respiratory disease. Despite this, a low fungal biomass and the presence of PCR inhibitors limits the usefulness of quantitative PCR (qPCR) for accurate absolute quantification of Aspergillus in specimens from the human airway. Droplet digital PCR (ddPCR) however, presents an alternative methodology allowing higher sensitivity and accuracy of such quantification but remains to be evaluated in head-to-head fashion using specimens from the human airway. Here, we implement a standard duplex TaqMan PCR protocol, and assess if ddPCR is superior in quantifying airway Aspergillus when compared to standard qPCR.
METHODS: The molecular approaches of qPCR and ddPCR were applied to DNA fungal extracts in n = 20 sputum specimens obtained from non-diseased (n = 4), chronic obstructive pulmonary disease (COPD; n = 8) and non-cystic fibrosis bronchiectasis (n = 8) patients where Aspergillus status was known. DNA was extracted and qPCR and ddPCR performed on all specimens with appropriate controls and head-to-head comparisons performed.
RESULTS: Standard qPCR and ddPCR were both able to detect, even at low abundance, Aspergillus species (Aspergillus fumigatus - A. fumigatus and Aspergillus terreus - A. terreus) from specimens known to contain the respective fungi. Importantly, however, ddPCR was superior for the detection of A. terreus particularly when present at very low abundance and demonstrates greater resistance to PCR inhibition compared to qPCR.
CONCLUSION: ddPCR has greater sensitivity for A. terreus detection from respiratory specimens, and is more resistant to PCR inhibition, important attributes considering the importance of A. terreus species in chronic respiratory disease states such as bronchiectasis.

PMID: 32357408 [PubMed - as supplied by publisher]

Repeatability of transient elastography in children.

Pediatr Res. 2020 May 01;:

Authors: Rowland M, McGee A, Broderick A, Drumm B, Connolly L, Daly LE, Drummond J, Fitzpatrick E, Linnane B, McCormick PA, McNally P, Rainford L, Bourke B, Cystic Fibrosis Registry of Ireland, Cystic Fibrosis Liver Disease Research Group

Abstract
BACKGROUND: Poorly performing diagnostic tests can impact patient safety. Clinical investigations must have good precision and diagnostic accuracy before widespread use in clinical practice. Transient elastography (TE) measures liver stiffness, a surrogate marker of liver fibrosis in adults and children. Studies to evaluate its repeatability and reproducibility (precision) in children are limited. Our aim was to determine (i) the normal range of TE measurements and (ii) the repeatability and reproducibility of TE in healthy children.
METHODS: TE was performed in 257 healthy children, of whom 235 (91%, mean age 11.7 years, standard deviation (SD) 2.51, 107 were males (45.5%)) had two valid TE measurements performed, at least 24 h apart, by two operators under similar circumstances. High-quality TE images were obtained for each examination.
RESULTS: The normal range of TE was 2.88-6.52 kPa. The mean difference between paired measurements was 0.044 (SD 0.4). The 95% limits of agreement ranged from -0.8 to +0.76 kPa for repeat measurements. There was a difference of >1 kPa between measurements in 61/235 (25.9%) children. The lack of precision was similar across all age groups.
CONCLUSIONS: This study demonstrates that TE does not have acceptable precision in healthy children, because random measurement variation results in the lack of agreement between paired measurements.
IMPACT: The precision and diagnostic accuracy of a new technology must be determined before it is deployed in children in order to ensure that appropriate clinical decisions are made, and healthcare resources are not wasted.TE is widely used to diagnose liver disease in children without adequate evaluation of the precision (repeatability) of TE either in healthy children or children with liver disease.This study demonstrates that TE does not have adequate precision in children.This study was performed in accordance with methods previously published for children. Refinements to the test protocol, such as duration of fasting or probe size, will have to be evaluated for their impact on precision and accuracy before the test is deployed in research studies or clinical practice.

PMID: 32357363 [PubMed - as supplied by publisher]

A Feasibility Study of Urgent Implementation of Cystic Fibrosis Multidisciplinary Telemedicine Clinic in the Face of COVID-19 Pandemic: Single-Center Experience.

Telemed J E Health. 2020 Apr 30;:

Authors: Compton M, Soper M, Reilly B, Gettle L, List R, Bailey M, Bruschwein H, Somerville L, Albon D

Abstract
Introduction: The coronavirus 2019 (COVID-19) pandemic has become a major world health problem. All U.S. states have advised their cystic fibrosis (CF) populations to socially isolate. Major health care payors such as Medicare and most private insurance companies have agreed to reimburse health care providers for telemedicine and telephone visits. Methods: The CF adult team at the University of Virginia (UVA) transitioned from face-to-face clinics to multidisciplinary telemedicine clinics by using WebEx® (Cisco Systems, San Jose, CA), a Health Insurance Portability and Accountability Act of 1996 (HIPAA) compliant platform. Interventions: Patients were contacted before scheduled visits and triaged into: (1) patients eligible for the multidisciplinary telemedicine clinic, (2) patients to be seen in clinic urgently due to acute needs, and (3) stable patients who can be rescheduled at a later time. Ineligible patients for the telemedicine clinic due to lack of access to technology were followed up via telephone. Results: A total of 63 patients were scheduled to be seen in the UVA clinic over 4 weeks, 10 clinic days. Of these patients, 20 (32%) rescheduled their appointment. In addition, 2 patients (3%) were seen in clinic for acute needs and 38 (60%) were seen by the multidisciplinary team through telemedicine. Conclusions: In the context of the COVID-19 pandemic, implementing a telemedicine clinic process that serves the needs of a multidisciplinary care team is paramount to preserving the CF care model. Through a systematic design and test process, a feasible and sustainable program was created that can be utilized by other multidisciplinary programs to adapt to their context.

PMID: 32357084 [PubMed - as supplied by publisher]

Genetic testing costs and compliance with clinical best practices.

J Genet Couns. 2020 May 01;:

Authors: Montanez K, Berninger T, Willis M, Harding A, Lutgendorf MA

Abstract
We sought to determine the costs of genetic testing and compliance with published guidelines and clinical best practices at our institution. A cost analysis was performed comparing the costs of ordered tests to the cost of the recommended testing. This was an approved quality improvement project at a tertiary teaching hospital in California. We identified charts associated with the genetic testing billing codes for common genetic tests through our contracted laboratory (cystic fibrosis genotyping, Breast cancer susceptibility gene (BRCA 1&2), Methylenetetrahydrofolate reductase (MTHFR), factor V Leiden (FVL), prothrombin gene pathogenic variant, alpha-thalassemia, hemochromatosis, and cell-free fetal DNA). Charts were reviewed retrospectively by a licensed, certified genetic counselor to assess the compliance with published clinical practice guidelines identified on GeneReviews and the American College of Obstetricians and Gynecologists (ACOG). Tests were classified as: appropriate, misordered/not indicated, misordered/false reassurance, and misordered/inadequate. We performed a cost analysis for the recommended test changes. We reviewed 114 charts over a three-month period. Forty-four (38.6%) of the tests were misordered based on published clinical practice guidelines: 24 (21%) were misordered/not indicated, 8 (7%) were misordered/false reassurance, and 12 (10.5%) were misordered/inadequate. Costs of ordered testing ($75,177) were compared to recommended testing after review ($54,265), with a total cost savings of $20,912. In clinical practice, over one-third of genetic tests reviewed were misordered. As these tests are a small fraction of all genetic tests at our institution, future studies should broaden the scope of testing evaluated to understand the magnitude of this problem and potential cost savings. Genetic counselor review and involvement in genetic test ordering can decrease inappropriate healthcare expenditures and improve patient care.

PMID: 32356909 [PubMed - as supplied by publisher]

Influence of pancreatic status, CFTR mutations, Staphylococcus aureus and/or Pseudomonas aeruginosa infection/colonization on lung function in cystic fibrosis during a 2-year follow-up period.

Wien Klin Wochenschr. 2020 Apr 30;:

Authors: Pascoal MA, Marson FAL, Paschoal IA, Levy CE

Abstract
INTRODUCTION: Cystic fibrosis (CF) presents with progressive and chronic deterioration of lung function due to inflammation and colonization/infection of the lungs. This study evaluated spirometry and colonization/infection with Staphylococcus aureus and/or Pseudomonas aeruginosa over a 24-month follow-up period.
METHODS: A total of 52 CF patients were studied with spirometry: forced vital capacity (FVC), forced expiratory volume in one second of FVC (FEV1), FEV1/FVC and forced expiratory flow between 25% and 75% of FVC (FEF25-75%). Colonization/infection was evaluated as predominantly S. aureus, predominantly P. aeruginosa or concomitance of these microorganisms.
RESULTS: In CF, there was a higher prevalence of p.Phe508del/p.Phe508del genotype (16/52; 30.8%) and female gender (33/52; 63.5%). Spirometry (% predicted) markers worsened for the following groups over the 24-month period: (i) male: FVC, FEV1, FEV1/FVC, FEF25-75%; (ii) female: FVC%, FEV1, (iii) predominantly S. aureus: FVC, FEV1, FEV1/FVC, FEF25-75%; (iv) predominantly P aeruginosa: FEV1/FVC; (v) concomitant S. aureus and P. aeruginosa: FVC, FEV1. Age correlated with reduction of FVC(Liter) (Rho = -0.50) and FEV1(Liter) (Rho = -0.46). Pancreatic insufficiency and severe cystic fibrosis transmembrane regultador (CFTR) mutations were associated with deteriorating lung function.
CONCLUSION: In CF, deterioration of lung function as evaluated by spirometry was continuous and varied according to sex, pancreatic insufficiency, and severe CFTR mutations. No differences were observed between groups in terms of predominant type of bacteria, but the reduction of spirometry parameters was significant in the predominantly S. aureus and concomitant infection groups.

PMID: 32356101 [PubMed - as supplied by publisher]

The pig as a model for immunology research.

Cell Tissue Res. 2020 Apr 30;:

Authors: Pabst R

Abstract
The pig is an omnivorous, monogastric species with many advantages to serve as an animal model for human diseases. There are very high similarities to humans in anatomy and functions of the immune system, e g., the presence of tonsils, which are absent in rodents. The porcine immune system resembles man for more than 80% of analyzed parameters in contrast to the mouse with only about 10%. The pig can easily be bred, and there are less emotional problems to use them as experimental animals than dogs or monkeys. Indwelling cannulas in a vein or lymphatic vessel enable repetitive stress-free sampling. Meanwhile, there are many markers available to characterize immune cells. Lymphoid organs, their function, and their role in lymphocyte kinetics (proliferation and migration) are reviewed. For long-term experiments, minipigs (e.g., Göttingen minipig) are available. Pigs can be kept under gnotobiotic (germfree) conditions for some time after birth to study the effects of microbiota. The effects of probiotics can be tested on the gut immune system. The lung has been used for extracorporeal preservation and immune engineering. After genetic modifications are established, the pig is the best animal model for future xenotransplantation to reduce the problem of organ shortage for organ transplantation. Autotransplantation of particles of lymphnodes regenerates in the subcutaneous tissue. This is a model to treat secondary lymphedema patients. There are pigs with cystic fibrosis and severe combined immune deficiency available.

PMID: 32356014 [PubMed - as supplied by publisher]

The role of innate immunity in the long-term outcome of lung transplantation.

Ann Transl Med. 2020 Mar;8(6):412

Authors: Kawashima M, Juvet SC

Abstract
Long-term survival after lung transplantation remains suboptimal due to chronic lung allograft dysfunction (CLAD), a progressive scarring process affecting the graft. Although anti-donor alloimmunity is central to the pathogenesis of CLAD, its underlying mechanisms are not fully elucidated and it is neither preventable nor treatable using currently available immunosuppression. Recent evidence has shown that innate immune stimuli are fundamental to the development of CLAD. Here, we examine long-standing assumptions and new concepts linking innate immune activation to late lung allograft fibrosis.

PMID: 32355856 [PubMed]

Timing it right: the challenge of recipient selection for lung transplantation.

Ann Transl Med. 2020 Mar;8(6):408

Authors: Ainge-Allen HW, Glanville AR

Abstract
Selection criteria for the referral and potential listing of patients for lung transplantation (LTx) have changed considerably over the last three decades but one key maxim prevails, the ultimate focus is to increase longevity and quality of life by careful utilization of a rare and precious resource, the donor organs. In this article, we review how the changes have developed and the outcomes of those changes, highlighting the impact of the lung allocation score (LAS) system. Major diseases, including interstitial lung disease (ILD), chronic obstructive pulmonary disease and pulmonary hypertension are considered in detail as well as the concept of retransplantation where appropriate. Results from bridging to LTx using extracorporeal membrane oxygenation (ECMO) are discussed and other potential contraindications evaluated such as advanced age, frailty and resistant infections. Given the multiplicity of risk factors it is a credit to those working in the field that such excellent and improving results are obtained with an ongoing dedication to achieving best practice.

PMID: 32355852 [PubMed]

Formative evaluation of a dashboard to support coproduction of healthcare services in cystic fibrosis.

J Cyst Fibros. 2020 Apr 27;:

Authors: Van Citters AD, Gifford AH, Brady C, Dunitz JM, Elmhirst M, Flath J, Laguna TA, Moore B, Prickett ML, Riordan M, Savant AP, Gore W, Jian S, Soper M, Marshall BC, Nelson EC, Sabadosa KA

Abstract
BACKGROUND: Healthcare coproduction engages patients and clinicians to design and execute services, yet little is known about tools that facilitate coproduction. Our objective was to understand uptake, experiences, benefits, and limitations of a dashboard to support patient-clinician partnerships within the cystic fibrosis (CF) community.
METHODS: People living with CF (PwCF) and clinicians co-designed a dashboard that displayed patient-reported and clinical data. Eight CF programmes, including 21 clinicians, and 131 PwCF participated in a pilot study of the dashboard. We conducted descriptive statistics and thematic analyses of surveys (82 PwCF; 21 clinicians); semi-structured interviews (13 PwCF; 8 care teams); and passively-collected usage data.
RESULTS: Two-thirds of the 82 PwCF used the dashboard during a visit, and 59% used it outside a visit. Among 48 PwCF using the dashboard outside the clinic, 92% viewed their health information and 46% documented concerns or requests. Most of the 21 clinicians used the dashboard to support visit planning (76%); fewer used it during a visit (48%). The dashboard supported discussions of what matters most (69% PwCF; 68% clinicians). Several themes emerged: access to patient outcomes data allows users to learn more deeply; participation in pre-visit planning matters; coproduction is made possible by inviting new ways to partner; and lack of integration with existing information technology (IT) systems is limiting.
CONCLUSIONS: A dashboard was feasible to implement and use. Future iterations should provide patients access to their data, be simple to use, and integrate with IT systems in use by clinicians and PwCF.

PMID: 32354650 [PubMed - as supplied by publisher]

Extracorporeal membrane oxygenation for grade 3 primary graft dysfunction after lung transplantation: Long-term outcomes.

Clin Transplant. 2019 03;33(3):e13480

Authors: Bellier J, Lhommet P, Bonnette P, Puyo P, Le Guen M, Roux A, Parquin F, Chapelier A, Sage E, Foch Lung Transplantation Group

Abstract
INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is an efficient and innovative therapeutic tool for primary graft dysfunction (PGD). However, its effect on survival and long-term lung function is not well known. This study evaluated those parameters in patients with PGD requiring ECMO.
METHOD: This single-center, retrospective study included patients who underwent LTx at our institute between January 2007 and December 2013. Patients and disease characteristics, survival, and pulmonary function tests were recorded.
RESULTS: A total of 309 patients underwent LTx during the study period and 211 were included. The patients were predominantly male (53.5%), the median age was 39 years, and the primary pathology was suppurative disease (53.1%). ECMO for PGD was mandatory in 24 (11.7%) cases. Mortality at 3 months in the ECMO group was 50% (N = 12). However, long-term survival after PGD did not correlate with ECMO. Forced expiratory volume and vital capacity were significantly reduced in patients with PGD requiring ECMO, especially those with idiopathic pulmonary fibrosis.
CONCLUSION: Veno-arterial ECMO appears to be suitable for management of PGD after LTx. Patients with PGD requiring ECMO show increased initial mortality; however, long-term survival was comparable with that of other patients in the study. Lung function does not appear to be related to PGD requiring ECMO.

PMID: 30657612 [PubMed - indexed for MEDLINE]

Behaviour change techniques to optimise participation in physical activity or exercise in adolescents and young adults with chronic cardiorespiratory conditions: a systematic review.

Intern Med J. 2019 10;49(10):1209-1220

Authors: Sawyer A, Lewthwaite H, Gucciardi DF, Hill K, Jenkins S, Cavalheri V

Abstract
Participation in regular physical activity decreases the risk of developing cardiometabolic disease. However, the proportion of people who participate in the recommended amount of physical activity is low, with common barriers including competing interests and inclement weather. In people with chronic cardiorespiratory conditions, participation in physical activity is reduced further by disease-specific barriers, time burden of treatment and unpleasant symptoms during physical activity. Addressing these barriers during adolescence and early adulthood may promote greater physical activity participation into older age. The aim of this review was to classify interventions aimed at optimising participation in physical activity as 'promising' or 'not promising' in people aged 15-45 years with chronic cardiorespiratory conditions and categorise the behaviour change techniques (BCT) within these interventions. Nine databases and registries were searched (October 2017) for studies that reported objective measures of physical activity before and after an intervention period. Interventions were classified as 'promising' if a between-group difference in physical activity was demonstrated. Michie et al.'s (2013) v1 Taxonomy was used to unpack the BCT within interventions. Across the six included studies (n = 396 participants), 19 (20%) of 93 BCT were described. The interventions of three studies were classified as 'promising'. The most commonly used BCT comprised goal setting, action planning and social support. Five BCT were solely used in 'promising' interventions. Our review demonstrated that only 20% of BCT have been utilised, and those BCT that were used only in 'promising' physical activity interventions in adolescents and adults with chronic cardiorespiratory conditions were isolated.

PMID: 30324769 [PubMed - indexed for MEDLINE]

Esophageal Motility Disorders Associated With Death or Allograft Dysfunction After Lung Transplantation? Results of a Retrospective Monocentric Study.

Clin Transl Gastroenterol. 2020 Mar;11(3):e00137

Authors: Gouynou C, Philit F, Mion F, Tronc F, Sénéchal A, Giai J, Rabain AM, Mornex JF, Roman S

Abstract
OBJECTIVES: Pathological gastroesophageal reflux (GER) is a known risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation. This study aimed at determining whether functional esophageal evaluation might predict BOS occurrence and survival in this setting.
METHODS: Ninety-three patients who underwent esophageal high-resolution manometry and 24-hour pH-impedance monitoring within the first year after lung transplantation were retrospectively included. A univariable analysis was performed to evaluate the parameters associated with GER disease and BOS occurrence. The Cox regression model was used to identify the prognostic factors of death or retransplantation.
RESULTS: Thirteen percent of patients exhibited major esophageal motility disorders and 20% pathological GER. GER occurrence was associated with younger age, cystic fibrosis, and hypotensive esophagogastric junction. Within a median follow-up of 62 months, 10 patients (11%) developed BOS, and no predictive factors were identified. At the end of the follow-up, 10 patients died and 1 underwent retransplantation. The 5-year cumulative survival rate without retransplantation was lower in patients with major esophageal motility disorders compared with that in those without (75% vs 90%, P = 0.01) and in patients who developed BOS compared with that in those without (66% vs 91%; P = 0.005). However, in multivariable analysis, major esophageal motility disorders and BOS were no longer significant predictors of survival without retransplantation.
DISCUSSION: Major esophageal motility disorders and BOS were associated with allograft survival in lung transplantation in the univariable analysis. Although the causes of this association remain to be determined, this observation confirms that esophageal motor dysfunction should be evaluated in the context of lung transplantation.

PMID: 32352712 [PubMed - as supplied by publisher]

Oscillating devices for airway clearance in people with cystic fibrosis.

Cochrane Database Syst Rev. 2020 Apr 30;4:CD006842

Authors: Morrison L, Milroy S

Abstract
BACKGROUND: Chest physiotherapy is widely prescribed to assist the clearance of airway secretions in people with cystic fibrosis. Oscillating devices generate intra- or extra-thoracic oscillations orally or external to the chest wall. Internally they create variable resistances within the airways, generating controlled oscillating positive pressure which mobilises mucus. Extra-thoracic oscillations are generated by forces outside the respiratory system, e.g. high frequency chest wall oscillation. This is an update of a previously published review.
OBJECTIVES: To identify whether oscillatory devices, oral or chest wall, are effective for mucociliary clearance and whether they are equivalent or superior to other forms of airway clearance in the successful management of secretions in people with cystic fibrosis.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. Latest search of the Cystic Fibrosis Trials Register: 29 July 2019. In addition we searched the trials databases ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Latest search of trials databases: 15 August 2019.
SELECTION CRITERIA: Randomised controlled studies and controlled clinical studies of oscillating devices compared with any other form of physiotherapy in people with cystic fibrosis. Single-treatment interventions (therapy technique used only once in the comparison) were excluded.
DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria to publications, assessed the quality of the included studies and assessed the evidence using GRADE.
MAIN RESULTS: The searches identified 82 studies (330 references); 39 studies (total of 1114 participants) met the inclusion criteria. Studies varied in duration from up to one week to one year; 20 of the studies were cross-over in design. The studies also varied in type of intervention and the outcomes measured, data were not published in sufficient detail in most of these studies, so meta-analysis was limited. Few studies were considered to have a low risk of bias in any domain. It is not possible to blind participants and clinicians to physiotherapy interventions, but 13 studies did blind the outcome assessors. The quality of the evidence across all comparisons ranged from low to very low. Forced expiratory volume in one second was the most frequently measured outcome and while many of the studies reported an improvement in those people using a vibrating device compared to before the study, there were few differences when comparing the different devices to each other or to other airway clearance techniques. One study identified an increase in frequency of exacerbations requiring antibiotics whilst using high frequency chest wall oscillation when compared to positive expiratory pressure (low-quality evidence). There were some small but significant changes in secondary outcome variables such as sputum volume or weight, but not wholly in favour of oscillating devices and due to the low- or very low-quality evidence, it is not clear whether these were due to the particular intervention. Participant satisfaction was reported in 13 studies but again with low- or very low-quality evidence and not consistently in favour of an oscillating device, as some participants preferred breathing techniques or techniques used prior to the study interventions. The results for the remaining outcome measures were not examined or reported in sufficient detail to provide any high-level evidence.
AUTHORS' CONCLUSIONS: There was no clear evidence that oscillation was a more or less effective intervention overall than other forms of physiotherapy; furthermore there was no evidence that one device is superior to another. The findings from one study showing an increase in frequency of exacerbations requiring antibiotics whilst using an oscillating device compared to positive expiratory pressure may have significant resource implications. More adequately-powered long-term randomised controlled trials are necessary and outcomes measured should include frequency of exacerbations, individual preference, adherence to therapy and general satisfaction with treatment. Increased adherence to therapy may then lead to improvements in other parameters, such as exercise tolerance and respiratory function. Additional evidence is needed to evaluate whether oscillating devices combined with other forms of airway clearance is efficacious in people with cystic fibrosis.There may also be a requirement to consider the cost implication of devices over other forms of equally advantageous airway clearance techniques. Using the GRADE method to assess the quality of the evidence, we judged this to be low or very low quality, which suggests that further research is very likely to have an impact on confidence in any estimate of effect generated by future interventions.

PMID: 32352564 [PubMed - as supplied by publisher]

Pilot study for cystic fibrosis neonatal screening: the Cuban experience.

Clin Chem Lab Med. 2020 Apr 29;:

Authors: Castells EM, Sánchez A, Frómeta A, Mokdse Y, Ozunas N, Licourt T, Arteaga AL, Silva E, Collazo T, Rodríguez F, Martín O, Espinosa M, Del Río L, Pérez PL, Morejón G, Almira C, Núñez Z, Melchor A, González EC

Abstract
Background In Cuba, no screening program for cystic fibrosis (CF) has been implemented yet. The ultramicro enzyme-linked immunosorbent assay (UMELISA)® TIR NEONATAL has been developed for the measurement of immunoreactive trypsin (IRT) in dried blood spots on filter paper. The analytical performance of the kit was evaluated in the national network of laboratories. Methods Newborn dried blood samples (DBS) were evaluated in 16 laboratories. An IRT/IRT/DNA protocol was followed using a cut-off value of 50 ng/mL. The mean, median and percentiles of the distribution were calculated and a two-sample t-test with unequal variance was used for statistical analysis. Influence of perinatal factors on IRT levels was analyzed. Results From January to June 2018, 6470 newborns were studied, obtaining a mean IRT value of 12.09 ng/mL (ranging 0-358 ng/mL) and a median of 8.99 ng/mL. Fifty-two samples (0.78%) were above the cut-off level and 16 samples (0.24%) were elevated in the re-screening process. One of them was confirmed positive by molecular biology (phe508del/c.3120 + 1G > A), constituting the first newborn screened and diagnosed early in Cuba. Second DBS samples were collected on average at 14 days and processed in the laboratory at 16 days of birth. Significant differences were observed (p < 0.05) when evaluating the influence of gender, birth weight (BW) and gestational age (GA) on the IRT values. Lower IRT concentrations were found in samples processed after 10 days of collection. Conclusions The performance of UMELISA® TIR NEONATAL in the laboratories has been satisfactory; hence CF newborn screening (NBS) was extended throughout the country from January 2019.

PMID: 32352395 [PubMed - as supplied by publisher]

Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis.

mSphere. 2020 Apr 29;5(2):

Authors: Flynn JM, Cameron LC, Wiggen TD, Dunitz JM, Harcombe WR, Hunter RC

Abstract
A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex polymicrobial communities in vitro However, emerging evidence suggests that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on cocolonizing organisms for nutrients (i.e., cross-feeding), multidrug-resistant P. aeruginosa may be indirectly targeted by inhibiting the growth of its metabolic partners. While this has been shown in vitro using synthetic bacterial communities, the efficacy of a "weakest-link" approach to controlling host-associated polymicrobial infections has not yet been demonstrated. To test whether cross-feeding inhibition can be leveraged in clinically relevant contexts, we collected sputa from cystic fibrosis (CF) subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed various antibiotic susceptibilities when grown independently. However, when P. aeruginosa was cultured and treated under cooperative conditions in which it was dependent on anaerobic bacteria for nutrients, the growth of both the pathogen and the anaerobe was constrained despite their intrinsic antibiotic resistance profiles. These data demonstrate that the control of complex polymicrobial infections may be achieved by exploiting obligate or facultative interspecies relationships. Toward this end, in vitro susceptibility testing should evolve to more accurately reflect in vivo growth environments and microbial interactions found within them.IMPORTANCE Antibiotic efficacy achieved in vitro correlates poorly with clinical outcomes after treatment of chronic polymicrobial diseases; if a pathogen demonstrates susceptibility to a given antibiotic in the lab, that compound is often ineffective when administered clinically. Conversely, if a pathogen is resistant in vitro, patient treatment with that same compound can elicit a positive response. This discordance suggests that the in vivo growth environment impacts pathogen antibiotic susceptibility. Indeed, here we demonstrate that interspecies relationships among microbiotas in the sputa of cystic fibrosis patients can be targeted to indirectly inhibit the growth of Pseudomonas aeruginosa The therapeutic implication is that control of chronic lung infections may be achieved by exploiting obligate or facultative relationships among airway bacterial community members. This strategy is particularly relevant for pathogens harboring intrinsic multidrug resistance and is broadly applicable to chronic polymicrobial airway, wound, and intra-abdominal infections.

PMID: 32350096 [PubMed - in process]

Measuring airway clearance outcomes in bronchiectasis: a review.

Eur Respir Rev. 2020 Jun 30;29(156):

Authors: Franks LJ, Walsh JR, Hall K, Morris NR

Abstract
While airway clearance techniques (ACTs) are recommended for individuals with bronchiectasis, many trials have demonstrated inconsistent benefits or failed to reach their primary outcome. This review determined the most common clinical and patient-reported outcome measures used to evaluate the efficacy of ACTs in bronchiectasis. A literature search of five databases using relevant keywords and filtering for studies published in English, up until the end of August 2019, was completed. Studies included randomised controlled trials, using crossover or any other trial design, and abstracts. Studies were included where the control was placebo, no intervention, standard care, usual care or an active comparator. Adults with bronchiectasis not related to cystic fibrosis were included. Extracted data comprised study authors, design, duration, intervention, outcome measures and results. The search identified 27 published studies and one abstract. The most common clinical outcome measures were sputum volume (n=23), lung function (n=17) and pulse oximetry (n=9). The most common patient-reported outcomes were health-related quality of life (measured with St George's Respiratory Questionnaire, n=4), cough-related quality of life (measured with Leicester Cough Questionnaire, n=4) and dyspnoea (measured with Borg/modified Borg scale, n=8). Sputum volume, lung function, dyspnoea and health- and cough-related quality of life appear to be the most common clinical and patient-reported measures of airway clearance treatment efficacy.

PMID: 32350088 [PubMed - in process]

Drugs and Lactation Database (LactMed)

Book. 2006

Authors:

Abstract
No information is available on elexacaftor or tezacaftor during breastfeeding. Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force of respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1]

PMID: 32352700