Cystic Fibrosis Group Research Articles

Adaptive Immune Response to <i>Mycobacterium abscessus</i> Complex and Cross-Reactivity of BCG Vaccination

Background: Mycobacterium abscessus complex (MABSC) is a major pathogenic group among nontuberculous mycobacteria (NTM). Here we characterized the adaptive immune response to MABSC and its cross reactivity with Mycobacterium bovis (Bacille Calmette-Guerin, BCG) using cystic fibrosis (CF) lung infection as a model. Methods: This was a cross-sectional study enrolling CF patients with and without history of NTM infection (CF/NTM+ and CF/NTM-), non-CF controls vaccinated and not vaccinated with BCG (C/BCG+ and C/BCG-). The anti-MABSC response was assessed in terms of lymphocyte activity and cytokine production after challenge with MABSC, and measurement of specific IgG. Results: The CF/NTM+ and C/BCG+ groups had cellular and cytokine responses with similar intensity, characterized by a Th1-dominated phenotype – high CD4 T-cell proliferation, increased IFN-γ and TNF-α production. The B-cell response and its associated cytokines CD40L and IL-4 were less pronounced, although IgG levels were higher in the CF/NTM+ group than in controls. Proliferating lymphocytes, increased IFN-γ and TNF-α production were also observed in part of the individuals of the CF/NTM- and C/BCG- groups, indicating environmental exposure, undetected or past infection. IL-2 increased only in the CF groups and may be specifically linked to the anti-MABSC response. Altogether, BCG-vaccinated individuals (CF and non-CF) had higher lymphocyte proliferation intensity than the non-vaccinated ones. Conclusion: The anti-MABSC response follows a pattern seen in other mycobacterial infections. BCG vaccination provides a cross-reactive response against MABSC and can have potential to mitigate the pathology of NTM infections. The potential of cytokine measurement for diagnosing MABSC infection is under investigation. Funding Information: RMM was granted a fellowship by the Sao Paulo Research Foundation (FAPESP, grant reference #2019/14134-5) and the study received funds from the Cystisk Fibrose Foreningen (Danish Cystic Fibrosis Association). Declaration of Interests: The authors have no conflicts of interests to declare. Ethics Approval Statement: The study was approved by the Regional Scientific Ethical Committees, Denmark (VEK, RH-19022288) and was in accordance with the Declaration of Helsinki and guidelines from the Danish Data Protection Agency. All participants signed a written informed consent, confirming their voluntary participations.

Reliability of impulse oscillometry parameters in healthy children and in children with cystic fibrosis.

Impulse oscillometry system (IOS) is an instrument developed to evaluate the mechanical lung properties. It has been reported that to analyse the exam in a proper way it is necessary to carry out more than one measure. However, studies addressing the standardisation are still scarce. The objective was to determine within trial reliability of three measures in IOS parameters in healthy children and children with cystic fibrosis (CF). Weight, height, body mass index, forced spirometric and the oscillometric parameters (resistance, respiratory impedance, respiratory reactance and resonance frequency) data were collected, in a way that all participants performed three IOS measures. To evaluate, the reproducibility was used the intraclass correlation coefficient [two-way mixed model, absolute agreement definition, ICC]. The response stability was appraised using the standard error of measurements (SEM) in three repetitions of the IOS in the healthy children group (HCG) and in the cystic fibrosis group (CFG). About 95 subjects participated, in each group with a mean age of 10.89±2.21years old in the HCG and 9.73±2.43years old in the CFG, having been 41 and 43 boys and 54 and 52 girls, in the respectively group. In both groups, all IOS parameters evaluated in the three measures presented an ICC of 0.9, which is a high reproducibility. The IOS parameters are reproducible for healthy children and CF children in three measures. However, according to the population studied, the performance of only one measure is sufficient to assess respiratory mechanics, whereas the SEM were low, except for Fres, in both groups.

Assessment of Distinct Electrophysiological Parameters in Rectal Biopsies for the Choice of the Best Diagnosis/Prognosis Biomarkers for Cystic Fibrosis.

Most cases of Cystic Fibrosis (CF) are diagnosed early in life. However, people with atypical CF forms pose diagnosis dilemmas, requiring laboratory support for diagnosis confirmation/exclusion. Ex vivo analysis of fresh rectal biopsies by Ussing chamber has been the best discriminant biomarker for CF diagnosis/prognosis so far. Here we aimed to evaluate different electrophysiological parameters from Ussing chamber analysis of rectal biopsies from people with CF (PwCF) to establish the one with highest correlations with clinical features as the best CF diagnosis/prognosis biomarker. We analyzed measurements of CFTR-mediated Cl– secretion in rectal biopsies from 143 individuals (∼592 biopsies), the largest cohort so far analyzed by this approach. New parameters were analyzed and compared with the previous biomarker, i.e., the IBMX (I)/Forskolin (F)/Carbachol (C)-stimulated short-circuit current (I’sc–I/F/C). Correlations with clinical features showed that the best parameter corresponded to voltage measurements of the I/F + (I/F/CCH) response (VI/F+I/F/C), with higher correlations vs. I’sc–I/F/C for: sweat chloride (59 vs. 52%), fecal elastase (69 vs. 55%) and lung function, measured by FEV1 (27 vs. 20%). Altogether data show that VI/F+I/F/C is the most sensitive, reproducible, and robust predictive biomarker for CF diagnosis/prognosis effectively discriminating classical, atypical CF and non-CF groups.

Respiratory muscle training for cystic fibrosis.

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. To determine the effectiveness of respiratory muscle training on clinical outcomes in people with cystic fibrosis. 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 October2020. Randomised controlled studies comparing respiratory muscle training with a control group in people with cystic fibrosis. 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. Authors identified 20studies, of which 10studies with 238participants 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. 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.

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

BackgroundThis is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations. MethodsSafety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level. ResultsClass IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del. ConclusionsIcenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations.ClinicalTrials.gov: NCT02190604

Gene therapy for sickle cell disease.

Sickle cell diseaseencompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormalallelethat could allow abnormal haemoglobin polymerisation leading to a symptomatic disorder. Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. This is an update of a previously published Cochrane Review. The objectives of this review are: - to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease; - to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings. We also searched online trial registries, Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 21 September 2020. All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. No trials of gene therapy for sickle cell disease were found. No trials of gene therapy for sickle cell disease were reported. No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

Transitioning from paediatric to adult services with cystic fibrosis or bronchiectasis: What is the impact on engagement and health outcomes?

To determine whether the transfer of young people with cystic fibrosis (CF) or bronchiectasis from paediatric to adult services is associated with changes in service engagement and/or health outcomes. Young people aged ≥15 years of age with CF or bronchiectasis who transferred from the Auckland-based paediatric service (Starship Children's Hospital) to one of three Auckland-based District Health Boards between 2005 and 2012 were identified and included if they had 3 years care both pre-transfer and post-transfer care. Transfer preparation, service engagement (clinics scheduled, clinics attended) and health outcomes (lung function, hospitalisations) were collected per annum. Fifty-seven young people transferred in this period with 46 meeting inclusion criteria (CF n = 20, bronchiectasis n = 26). The CF group had better transfer documentation, were transferred at an older age (11 months older P < 0.0001 95%CI: 6.7 months, 14.7 months), were 20 times more likely to attend clinics (P < 0.0001, 95%CI: 7.8, 66.1) and had 3-4 more clinics scheduled pre-transfer (P < 0.0001, 95%CI: 3.4, 4.9) and post-transfer (P < 0.0001, 95%CI: 2.4, 3.8) despite having less severe respiratory disease as measured by FEV1 for each year (P < 0.01, 95%CI: 0.34, 1.22). The transfer of young people with CF to adult services did not affect health engagement or outcomes, in contrast to those with bronchiectasis. Use of a formalised transfer process, more clinic appointments offered and greater resources for CF may be responsible for this difference. Comprehensive transition with purposeful, planned movement and developmentally appropriate care is a key goal.

Should the dosage of propofol be higher and independent of immunosuppressive therapy in adult cystic fibrosis patients undergoing sedation during flexible video bronchoscopy?

Flexible video bronchoscopy (FVB) performed under sedation is a useful procedure in adults with cystic fibrosis (CF). Propofol dosage for CF is poorly described, although it is of high importance for professionals. The study aimed to assess whether propofol dosage should be higher in adults CF undergoing sedation during FVB. 50 adult CF and non-CF patients undergoing sedation during FVB were included. Clinical features of studied patients were assessed. In CF group spirometry, liver enzymes, inflammatory biomarkers, albumin, protein concentration, WBC were estimated. Propofol and fentanyl dosage was calculated. Multiple regression model was performed. CF patients were characterized by a lower mean value of body weight and lower mean requirement of total propofol (135 mg in CF vs. 145 mg in non-CF). Calculated propofol dose per kg of body weight was significantly higher in CF (2.43 mg/kg vs. 2.04 mg/kg) and did not depend on the bronchopulmonary disease stage. Propofol dose per kg of body weight was predicted by CF status (CF vs. non-CF), sex, and age. Adult CF patients not receiving immunosuppressive therapy require higher propofol dose per kg of body weight compared to non-CF, independently on bronchopulmonary disease stage showing a narrow therapeutic window for propofol in CF group.

Drug treatments for managing cystic fibrosis-related diabetes.

Drug treatments for managing cystic fibrosis-related diabetes.

S0367 Cystic Fibrosis Patients Are More Likely to Develop Barrett’s Esophagus and Esophageal Carcinoma

INTRODUCTION: Gastroesophageal reflux disease (GERD) is highly prevalent in cystic fibrosis (CF) patients and manifests at early age of life. Barrett’s esophagus (BE) is a metaplastic transformation of the esophageal lining that predisposes to esophageal cancer (EC). Using a large multi-center database, we sought to describe the epidemiology and risk of BE and EC in CF patients. METHODS: We queried a multi-institutional database (Explorys Inc, Cleveland, OH, USA), an aggregate of electronic health record data from 26 US healthcare systems. A cohort of patients with a Systematized Nomenclature of Medicine-Clinical Terms of “cystic fibrosis” 2016-2020 was identified. Subsequently, another cohort of those who developed BE and EC after at least 30 days of CF diagnosis was identified. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS version 25, IBM Corp). For all analyses, a 2-sided P value of < 0.05 was considered statistically significant. RESULTS: Of the 39,328,760 individuals in the database, 14,390 had CF (0.04%). Baseline characteristics of study and control (no CF) groups are shown in Table 1. The prevalence of patients with new diagnosis of BE and EC after at least 30 days of CF was 1.29% and 0.07% respectively. Compared to the general population, patients with CF had higher risk of BE diagnosis [OR: 1.95; 95% CI: 1.66-2.29, P < 0.0001] as well as EC [OR: 2.99; 95% CI: 1.93-4.65, P < 0.0001]. Among CF patients, predictors of having BE were male gender, and Caucasian race, history of GERD, hiatal hernia, smoking, alcohol abuse, obesity, and metabolic syndrome (Table 2). CONCLUSION: In this large database, we found that CF patients have a two-fold increased risk of BE and three-fold increased risk of EC. Further prospective studies are required to validate these findings as it has important clinical implications for screening and surveillance in CF patients.Table 1.: Baseline Characteristics of Patients with Cystic Fibrosis and Control Group. GERD; gastroesophageal reflux disease, PPI; proton pump inhibitors; H2-blockers; histamine receptor blocker, BE; Barrett's esophagusTable 2.: Overall Risk and Predictors of Developing Barrett’s Esophagus Among Cystic Fibrosis. GERD; gastroesophageal reflux disease

S0112 Evaluating the Outcomes of Endoscopic Retrograde Cholangiopancreatography in Patients With Cystic Fibrosis

INTRODUCTION: There is a known association of biliary stones with cystic fibrosis (CF). The CFTR expression in the gallbladder is described as one of the highest of all human tissues. Consequently, CFTR activity is imperative in the biliary tree and its absence can lead to significant biliary disease due to decreased secretion of biliary bicarbonate and disturbance of normal bile acid circulation. ERCP has an important role in the diagnosis and management of CF patients. However, there is very limited data evaluating the outcomes and the adverse events (AEs) post ERCP in these patients. Therefore, we conducted this study to evaluate ERCP-related AEs in CF patients using a large national cohort. METHODS: A retrospective cohort study was performed using the National Inpatient Sample (NIS) database 2011–2014. We identified all adult patients (≥18 year old) who underwent ERCP using ICD-9 codes. Primary outcomes comprised ERCP-related AEs including post ERCP pancreatitis (PEP), bleeding and perforation. Secondary outcomes included all-cause mortality (ACM) and length of hospital stay (LOS). Primary and secondary outcomes were compared between the study and control group using multivariate logistic regression analysis. RESULTS: We identified a total of 108,182 patients underwent ERCP, of which 73 (0.07%) had CF. CF patients were younger (31.75 ± 14.5 vs 58.48 ± 20.14), less females (49.7% vs 59.7%) and less likely to be African American (4.3% vs 9.1%) compared to the control group, (P < 0.05 for all. In addition, CF patients had less alcohol (1.4% vs 4.3%, P > 0.05) compared to the control group. Using multivariate logistic regression and after adjusting for potential cofounding factors including age, race, gender and Elixhauser comorbidities, patients with CF had no statistically significant difference in PEP (OR 0.99, 95% CI: 0.31–3.23) or bleeding (OR 3.22, 95% CI: 0.44–23.63). In addition, the control group had 0.04% (n = 48) total cases of post ERCP perforation reported and 1% (n = 1093) of ACM while none were reported in CF patients. Further, the adjusted LOS was slightly longer in the CF group compared to the control group (8.33 ± 6.37 vs 5.49 ± 5.04 day, P < 0.05). CONCLUSION: CF patients undergoing ERCP might have slightly increase in the LOS, however they have comparable outcomes and similar risk of AEs comparing to other patients who don’t carry this diagnosis.

Prophylactic anti-staphylococcal antibiotics for cystic fibrosis.

Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis. Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage. Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa. This is an update of a previously published review. To assess continuous oral antibiotic prophylaxis to prevent the acquisition of Staphylococcus aureus versus no prophylaxis in people with cystic fibrosis, we tested the following hypotheses to investigate whether prophylaxis: 1. improves clinical status, lung function and survival; 2. leads to fewer isolates of Staphylococcus aureus; 3. causes adverse effects (e.g. diarrhoea, skin rash, candidiasis); 4. leads to fewer isolates of other common pathogens from respiratory secretions; 5. leads to the emergence of antibiotic resistance and colonisation of the respiratory tract with Pseudomonas aeruginosa. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Companies manufacturing anti-staphylococcal antibiotics were contacted. Most recent search of the Group's Register: 27 February 2020. Online trials registries were also searched. Most recent search of online trials registries: 15 September 2020. Randomised trials of continuous oral prophylactic antibiotics (given for at least one year) compared to intermittent antibiotics given 'as required', in people with cystic fibrosis of any disease severity. The authors assessed studies for eligibility and methodological quality and extracted data. The quality of the evidence was assessed using the GRADE criteria. The review's primary outcomes of interest were lung function by spirometry (forced expiratory volume in one second (FEV1)) and the number of people with one or more isolates of Staphylococcus aureus (sensitive strains). We included four studies, with a total of 401 randomised participants aged zero to seven years on enrolment; one study is ongoing. The two older included studies generally had a higher risk of bias across all domains, but in particular due to a lack of blinding and incomplete outcome data, than the two more recent studies. We only regarded the most recent study as being generally free of bias, although even here we were not certain of the effect of the per protocol analysis on the study results. Evidence quality was judged to be low for all outcomes assessed after being downgraded based on GRADE assessments. Downgrading decisions were due to limitations in study design (all outcomes), for imprecision and for inconsistency . Prophylactic anti-staphylococcal antibiotics probably make little or no difference to lung function measured as FEV1 % predicted after six years (mean difference (MD) -2.30, 95% confidence interval (CI) -13.59 to 8.99, one study, n = 119, low-quality evidence); but may reduce the number of children having one or more isolates of Staphylococcus aureus at two years (odds ratio (OR) 0.21, 95% CI 0.13 to 0.35, three studies, n = 315, low-quality evidence). At the same time point, there may be little or no effect on nutrition as reported using weight z score (MD 0.06, 95% CI -0.33 to 0.45, two studies, n = 140, low-quality evidence), additional courses of antibiotics (OR 0.18, 95% CI 0.01 to 3.60, one study, n = 119, low-quality evidence) or adverse effects (low-quality evidence). There was no difference in the number of isolates of Pseudomonas aeruginosa between groups at two years (OR 0.74, 95% CI 0.45 to 1.23, three studies, n = 312, low-quality evidence), though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis. Anti-staphylococcal antibiotic prophylaxis may lead to fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.

Phytomedicines (medicines derived from plants) for sickle cell disease.

Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an updated version of a previously published Cochrane Review. To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International StandardRandomised Controlled Trial NumberRegister (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 17 March 2020; ISRCTN: 19 April 2020; AMED: 18 May 2020; ClinicalTrials.gov: 24 April 2020; and the WHO ICTRP: 27 July 2017. Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. Both authors independently assessed trial quality and extracted data. Three trials (212 participants) of three phytomedicines: Niprisan® (also known as Nicosan®), Ciklavit® and a powdered extract of Pfaffia paniculata were included. The Phase IIB (pivotal) trial suggests that Niprisan® may be effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not appear to affect the risk of severe complications or the level of anaemia (low-quality evidence). The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence). We are uncertain of the effect of Pfaffia paniculata on the laboratory parameters and symptoms of SCD (very low-quality of evidence). No adverse effects were reported with Niprisan® and Pfaffia paniculata (low- to very low-quality evidence). While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in managing people with SCD and the results of its multicentre trials are awaited. Currently, no conclusions can be made regarding the efficacy of Ciklavit® and the powdered root extract of Pfaffia paniculata in managing SCD. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of the three trials, phytomedicines may have a potential beneficial effect in reducing painful crises in SCD. This needs to be further validated in future trials. More trials with improved study design and data collection are required on the safety and efficacy of phytomedicines used in managing SCD.

Do pulmonary and extrapulmonary features differ among cystic fibrosis, primary ciliary dyskinesia, and healthy children?

Primary ciliary dyskinesia (PCD) is generally likened to cystic fibrosis (CF) due to similarities in impaired mucociliary clearance and some other symptoms. The aim of our study was to investigate pulmonary and extrapulmonary characteristics of children with CF and PCD since no studies have addressed respiratory muscle strength in children with PCD and to compare the results to those obtained from healthy age-matched controls. Pulmonary and extrapulmonary characteristics were assessed by 6-min walk test, spirometry, maximum inspiratory and expiratorypressure measurements, and knee extensor strength test in the children with CF, PCD, and healthy controls. Children with PCD and CF had similar PFT results, except forced expiratory flow between 25% and 75% of vital capacity (FEF25-75 ) which was lower in PCD (p = .04). Maximum inspiratory pressure (MIP) value was lower in the children with CF compared with the healthy controls (p = .016), MEP value of the children with PCD was worse than those with CF and healthy controls (p = .013 andp = .013), respectively. 6-min walk test (6MWT) distance of the children with CF was lower than their healthy counterparts (p = .003). Knee extensor muscle strength differed among the children with PCD, CF, and healthy control groups, but post hoc test failed to show statistical significance (p = .010). Children with CF and PCD had some impairments in pulmonary functions, respiratory muscle strength, functional capacity, and peripheral muscle strength compared with healthy children. However, the unique characteristics of each disease should be considered during physiotherapy assessment and treatment. The clinicians may especially focus on the respiratory and peripheral muscle strength of the children with PCD.

Vitamin E supplementation in people with cystic fibrosis.

People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency, including vitamin E. Vitamin E deficiency can cause a host of conditions such as haemolytic anaemia, cerebellar ataxia and cognitive difficulties. Vitamin E supplementation is widely recommended for people with cystic fibrosis and aims to ameliorate this deficiency. This is an updated version of the review. To determine the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders in people with cystic fibrosis. We searched the Cochrane Group's Cystic Fibrosis Trials Register and also searched international online trial registries for any ongoing clinical trials that were not identified during our register search. Date of last search of the Register: 11 August 2020. Date of last search of international online trial registries: 20 July 2020. Randomised controlled trials and quasi-randomised controlled trials comparing any preparation of vitamin E supplementation to placebo or no supplement, regardless of dosage or duration. Two authors extracted outcome data from each study (published information) and assessed the risk of bias of each included study. They assessed the quality of the evidence using GRADE. Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and two did not specify participants' age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo. There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. None of the studies in either comparison report the review's primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Water-soluble vitamin E Water-soluble vitamin E may improve serum vitamin E levels compared with control at six months, one study (45 participants), mean difference (MD) 19.74 umol/L (95% confidence interval (CI) 13.48 to 26.00) (low-quality evidence). Similar results were also seen at one month, two studies (32 participants), MD 17.66 umol/L (95% CI 10.59 to 24.74) and at three months, one study (45 participants), MD 11.61 umol/L (95% CI 4.77 to 18.45). Only one study (45 participants) reported weight (secondary outcome of growth and nutritional status) at one and six months, but showed no difference between treatment and control at either time point. Fat-soluble vitamin E Two studies (36 participants) reported higher levels of serum vitamin E at one month with fat-soluble vitamin E compared with control, MD 13.59 umol/L (95% CI 9.52 to 17.66); however, at three months one study (36 participants) showed no difference between treatment and control. No studies in this comparison reported on growth or nutritional status. Vitamin E supplementation may lead to an improvement in vitamin E levels in people with cystic fibrosis, although evidence we assessed was low quality. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy. In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.

Physical activity in children and adolescents with cystic fibrosis: A systematic review and meta-analysis.

Exercise and physical activity (PA) are essential components of the care of cystic fibrosis (CF) patients. Lower PA levels have been associated with worse pulmonary function, aerobic fitness, glycemic control, and bone mineral density. Most people with CF do not engage in the recommended amounts of PA. To determine the level of PA in children and adolescents with CF. A systematic review with meta-analysis was conducted without language restrictions in five databases. Were included studies that analyzed PA measured by objective and subjective instruments in children and adolescents with CF. Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of evidence. The risk of bias of the included studies was assessed with the National Heart, Lung, and Blood Institute's risk-of-bias tool. Of the 1535 reports returned by the initial search, 20 articles reporting on 785 patients were included in the data synthesis. The forest plot showed that the CF group had a similar moderate-to-vigorous PA (MVPA) (mean difference, -7.79; 95% CI -15.65 to 0.08 min/d; P = .05) and sedentary time (mean difference, -50.81; 95%CI, -109.96 to 8.35 min/d; P = .09) to the control group. Children and adolescents with CF have a similar MVPA and sedentary time compared to controls. There are many options, subjective and objective, for assessing PA in this population. Optimal tool selection should guarantee more valid results.

Vulnerable Child Syndrome and Newborn Screening Carrier Results for Cystic Fibrosis or Sickle Cell

To measure parental perceptions of child vulnerability, as a precursor to developing a population-scale mechanism to mitigate harm after newborn screening. Participants were parents of infants aged 2-5months. Parental perceptions of child vulnerability were assessed with an adapted version of the Vulnerable Baby Scale. The scale was included in the script for a largerstudy of telephone follow-up for 2 newborn blood screening samples (carrier status for cystic fibrosis or sicklecell hemoglobinopathy). A comparison sample was added using a paper survey with well-baby visits to an urban/suburban clinic. Sample sizes consisted of 288 parents in the cystic fibrosis group, 426 in the sickle cell hemoglobinopathy group, and 79 in the clinic comparison group. Parental perceptions of child vulnerability were higher in the sickle cellgroup than cystic fibrosis group (P<.0001), and both were higher than the clinic comparison group (P<.0001). Parental perceptions of child vulnerability were inversely correlated with parental age (P<.002) and lower health literacy (P<.015, sickle cell hemoglobinopathy group only). Increased parental perceptions of child vulnerability seem to be a bona fide complication of incidental newborn blood screening findings, and healthcare professionals should be alert to the possibility. From a public health perspective, we recommend routine follow-up after incidental findings to mitigate psychosocial harm.

Tissue oxygenation in peripheral muscles and functional capacity in cystic fibrosis: a cross-sectional study.

What is the central question of this study? How do peripheral muscle tissue oxygenation and physical conditioning levels of children and adolescents with cystic fibrosis compare to demographically matched controls? What is the main finding and its importance? Children and adolescents with cystic fibrosis consumed more oxygen, more quickly and exhibited slower recovery, demonstrating that there may have been deficiencies in oxygen supply related to both oxygen uptake and oxygen transport. Cystic fibrosis affects skeletal muscle performance and functional capacity. However, it is currently unclear how peripheral muscle behaviour is affected, especially in children and adolescents. To examine this, we compared tissue oxygenation of children and adolescents with cystic fibrosis against healthy volunteers. We also evaluated the functional capacity of participants via the modified shuttle test (MST) and assessed for associations between performance and near-infrared spectroscopy. A total of 124 participants enrolled. Participants were divided into either the cystic fibrosis group (CFG) or the healthy group (HG). Statistical comparisons between groups were evaluated with the Mann-Whitney U test and associations with functional capacity were evaluated using Spearman's correlation coefficient. CFG volunteers scored lower on the MST compared to the HG. They walked shorter distances (P=0.001) with less efficiency because they performed the tests with a less efficient walking economy (P=0.001) and a greater deoxyhaemoglobin concentration (P=0.001). Further, they experienced reduced tissue oxygen saturation (P=0.037) faster than the HG. As a result, they presented lower respiratory (P=0.001) and lower heart (P=0.001) rate values at the end of the MST, with a longer post-test heart rate recovery time (P=0.005). There was a significant association between deoxygenation time and functional capacity. The CFG consumed more oxygen, more quickly, with a slower recovery, reflecting impairments in the dynamics of muscle oxygen extraction. The results suggest differences in functional capacity and haemodynamic recovery in children and adolescents with cystic fibrosis.

Pancreatic enzyme replacement therapy for people with cystic fibrosis.

Most people with cystic fibrosis (CF) (80% to 90%) need pancreatic enzyme replacement therapy (PERT) to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of PERT is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. This is an updated version of a published review. To evaluate the efficacy and safety of PERT in children and adults with CF and to compare the efficacy and safety of different formulations of PERT and their appropriateness in different age groups. Also, to compare the effects of PERT in CF according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 07 November 2019. We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 26 December 2019. Randomised and quasi-randomised controlled trials in people of any age, with CF and receiving PERT, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other PERT preparations. Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias and quality of the evidence (GRADE) of the trials included in the review. 14 trials were included in the review (641 children and adults with CF), two of these were parallel trials and 12 were cross-over trials. Interventions included different enteric and non-enteric-coated preparations of varying formulations in comparison to each other. The number of participants in each trial varied between 14 and 129. 13 trials were for a duration of four weeks and one trial lasted seven weeks. The majority of the trials had an unclear risk of bias from the randomisation process as the details of this were not given; they also had a high risk of attrition bias and reporting bias. The quality of the evidence ranged from moderate to very low. We mostly could not combine data from the trials as they compared different formulations and the findings from individual trials provided insufficient evidence to determine the size and precision of the effects of different formulations. There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over trials is likely to underestimate the level of inconsistency between the results of the trials due to over-inflation of CIs from the individual trials.There is no evidence on the long-term effectiveness and risks associated with PERT. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed trial that can answer these questions.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review. To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries. Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 19 March 2020. Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. No randomized controlled trials matching the selection criteria were eligible for inclusion. No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.