History – 2019

Abu-Fraiha Y, Elyashar-Earon H, Shoseyov D, Cohen-Cymberknoh M, Armoni S, Kerem E, Wilschanski M.Increasing Vitamin D Serum Levels Is Associated With Reduced Pulmonary Exacerbations in Patients With Cystic Fibrosis.J Pediatr Gastroenterol Nutr. 2019 Jan;68(1):110-115. [PubMed]

Yasmeen Abu-Frai

Yasmeen Abu-Frai

In 2012, The North American Cystic Fibrosis Foundation (NACFF) published new guidelines for the treatment of vitamin D deficiency in individuals with cystic fibrosis (CF). The objectives of our study were to assess the efficacy of these guidelines, and to test the effect of increasing vitamin D dosage on pulmonary function and exacerbations.Pulmonary function tests and serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured 1 year before increasing vitamin D dosage according to the guidelines and at least 1 year later. In addition, days of hospitalization and pulmonary exacerbations were counted and an average per year (average number of days of hospitalization and average number of pulmonary exacerbations [PEA], respectively) was calculated.

A total of 90 patients from The Cystic Fibrosis Clinic at Hadassah Mount-Scopus Hospital, Jerusalem, Israel. The mean serum concentration of vitamin D increased significantly from 20.97 ng/mL (52.34 nmol/L) at baseline to 25.41 ng/mL (63.42 nmol/L) at the end of follow-up (P < 0.001). The number of PEA decreased significantly from 2.79 ± 3.96 to 2.15 ± 2.91 (P = 0.007). The change in vitamin D levels was correlated with a decrease in PEA (correlation coefficient = -0.318, P = 0.002).

The authors concluded the NACFF guidelines for management of vitamin D deficiency improve vitamin D levels in patients with CF but did not reach the normal values in most patients. The increase in vitamin D serum levels was, however, associated with a decrease in number of pulmonary exacerbations.

A study from the CF Center, Hadassah-University Medcial Center, Jerusalem.

Dr Yasmeen Abu-Fraiha is a young Israeli Arab of Bedouin origincurrently acting as the Executive Director of GENESIS, an NGO she founded that aims to prevent genetic diseases in the Middle East, especially in the Bedouin community, by spearheading premarital genetic testing and matching. She holds a BSc in Medical Science from the Hebrew University of Jerusalem and an MD from the Hebrew University of Jerusalem.

Ahmed B, Cox MJ, Cuthbertson L, James P, Cookson WOC, Davies JC, Moffatt MF, Bush A.   Longitudinal development of the airway microbiota in infants with cystic fibrosis.Sci Rep. 2019 Mar 26;9(1):5143. doi: 10.1038/s41598-019-41597-0 [Pubmed] Free PFMC Article  
The pathogenesis of airway infection in cystic fibrosis (CF) is poorly understood. The authors performed a longitudinal study coupling clinical information with frequent sampling of the microbiota to identify changes in the airway microbiota in infancy that could underpin deterioration and potentially be targeted therapeutically. 

Thirty infants with CF diagnosed on newborn screening (NBS) were followed for up to two years. Two hundred and forty one throat swabs were collected as a surrogate for lower airway microbiota (median 35 days between study visits) in the largest longitudinal study of the CF oropharyngeal microbiota. Streptococcus spp. and Haemophilus spp. were the most common genera (55% and 12.5% of reads respectively) and were inversely related. Only beta (between sample) diversity changed with age (Bray Curtis r2 = 0.15, P = 0.03). Staphylococcus and Pseudomonas were rarely detected. These results suggest that Streptococcus spp. and Haemophilus spp., may play an important role in early CF. Whether they are protective against infection with more typical CF micro-organisms, or pathogenic and thus meriting treatment needs to be determined.

Dr B Ahmed of National Heart and Lung Institute, Imperial College and the Department of Respiratory Paediatrics, Royal Brompton Hospital, London

– The uncertainty regarding the early bacterial content of the CF airways seems to continue

Ahmed MI, Kulkarni H, Shajpal S, Patel D, Patel P, Claydon A, Modha DE, Gaillard EA. Early detection of non-tuberculous mycobacteria in children with cystic fibrosis using induced sputum at annual review.Pediatr Pulmonol. 2019 Mar;54(3):257-263. doi: 10.1002/ppul.24220. Epub 2018 Dec 18.[Pubmed]

        Erol Gaillard

The authors aimed to test the hypothesis that performing sputum induction at routine annual review results in earlier identification of NTM in non-sputum producing children with CF.  They conducted a 5-year prospective observational cohort study involving children with CF aged 5-17 years who had sputum induction with hypertonic saline for microbiological surveillance including NTM at their annual review.

Forty-two children (19 males, mean age 11.4 years ± 3.6, mean FEV1 % predicted 94.7 ± 20.6) participated in the study. Six samples from six children (14% of the cohort) yielded NTM never previously isolated from the patient. We also detected three isolates of Pseudomonas aeruginosa and one isolate each of Burkholderia cepacia complex and Meticillin resistant Staphylococcus aureus (MRSA), all of which were first time isolates.

The author conclude that annual induced sputum for microbiological surveillance is useful for early detection of NTM and other important respiratory pathogens, particularly in non-expectorating children. This may lead to earlier identification and help inform initiation of eradication treatment in children with NTM. Children can also be cohorted earlier, before they potentially infect other children in the clinic.

Dr Erol A Gaillard is Senior Lecturer and lead Paediatric CF Consultant in Leicester

Armirotti A, Tomati V, Matthes E, Veit G, Cholon DM, Phuan PW, Braccia C, Guidone D, Gentzsch M, Lukacs GL, Verkman AS, Galietta LJV, Hanrahan JW, Pedemonte N.   Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity. Sci Rep. 2019 Jul 16;9(1):10310. doi: 10.1038/s41598-019-46639-1.  [Pubmed]

       Andrea Armirotti

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded.                                                                                                                                    Recently thymosin a-1 (Tα-1) was proposed as a single molecule-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, these authors address these potential issues by demonstrating that Tα-1 changes induced by DMSO are fully reversible and that Tα-1 peptides prepared from different stock solutions have equivalent biological activity.                                                                                           

Considering the negative results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Tα-1.    This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin α-1, they do not support its utility as a corrector of F508del-CFTR.

Dr Andrea Armirotti is Researcher Technologist Department of Drug Discovery and Development. Analytical Chemistry and In-vivo Pharmacology Facility, Fondazione Istituto Italiano di Tecnologia, Genova, Italy

– So the initial report that thymosin alpha-1 may be a single molecule-based therapy for CF has not been confirmed by a number of scientists. 

Avedissian SN, Rhodes NJ, Ng TMH, Rao AP, Beringer PM.The Potential for QTc Prolongation with Chronic Azithromycin Therapy in Adult Cystic Fibrosis Patients.   Pharmacotherapy. 2019 May 2. doi: 10.1002/phar.2270. [Epub ahead of print] [Pubmed]
Oral azithromycn (AZM) has been shown to reduce airway inflammation and disrupt biofilm formation. However, chronic AZM therapy may result in QT interval (QTc) prolongation.    The goals of this study were twofold: 1) to characterize the risk of QTc prolongation in adult cystic fibrosis (CF) patients on AZM and other potential QTc prolonging agents, and 2) to describe and capture the number of potential QTc prolonging agents CF patients are prescribed.

A retrospective study was conducted over a 3-year period in an adult CF Center. QTc values were recorded from electrocardiograms. Univariate and multivariate analyses were conducted. Standard QTc prolongation definitions (Males: ≥ 450 msec, Female: ≥ 470 msec) were used.

A total of 89 adult CF patient’s records were reviewed. Sixty-eight patients received chronic AZM therapy. Two male patients had prolonged QTc, but only 1 received chronic AZM therapy. The median QTc interval between patients receiving and not receiving AZM was not significantly different (405 [interquartile range, IQR: 388-425] versus 394 [IQR:384-413] msec, respectively, P=0.14). Also, the QTc interval for patients taking chronic AZM 500mg Monday/Wednesday/Friday or 250mg daily was not significantly different (401 [IQR: 383-419] versus 409 [IQR:394-427] msec, respectively, P=0.48). When stratified by the number of QTc prolonging medications (AZM vs no AZM), there was no significant difference in median QTc values between patients receiving zero to ≥ 5 QTc prolonging medications.

The authors concluded an association between chronic AZM therapy and longer QTc intervals or significant QTc prolongation was not shown in this study.

Sean N Avedissian is in the Department of Pharmacy Practice, Midwestern University, Chicago 

– The early literature up to 2014 has been reviewed by Albert RK, Schuller JL  (AJRCCM 2014; 189(10) PubMed.[Pubmed] ).  Their summary describes the electrophysiological effects of macrolides, reviews literature indicating that the large majority of subjects experiencing cardiac arrhythmias from macrolides have coexisting risk factors and that the incidence of arrhythmias in absence of coexisting risk factors is very low, examines recently published studies describing the relative risk of arrhythmias from macrolides, and concludes that this risk has been overestimated and suggests an approach to patient evaluation that should reduce the relative risk and the incidence of arrhythmias to the point that chronic macrolides can be used safely in the majority of subjects for whom they are recommended. Indeed they are still being recommended and prescribed for people with CF.

Bakhshayeshkaram M, Aghahosseini F, Vaezi F, Kahkooei S, Salehi Y, Hassanzad M, Jamaati HR, Velayati AA.CT-measured pulmonary artery diameter as an independent predictor of pulmonary hypertension in cystic fibrosis.   Pol J Radiol. 2018 Aug 23;83:e401-e406. doi: 10.5114/pjr.2018.79204. eCollection  2018. [Pubmed]
The aim of the present study was to evaluate the diagnostic performance of thoracic vascular parameters on CT to detect pulmonary hypertension (PH).   CF patients who contemporaneously underwent CT and echocardiography were retrospectively enrolled. Baseline characteristics in addition to pulmonary artery diameter (PAD) and pulmonary to aortic (PA/A) ratio were compared between cohorts with and without PH, based on the results of echocardiography separately in paediatric patients (< 18) and adults (≥ 18).

Of a total 119 CF patients, 39 (32.8%) had PH (paediatric: 23/78, 29.5%, adult: 16/41, 39%). In paediatric CF patients, mean age, HCo3, PCo2, and pulmonary artery diameter (PAD) were significantly higher in the PH group compared to the non-PH group. Mean pulmo however, only PAD remained as the independent predictor of PH based on multivariate analysis (overall: 22.86 mm [±3.86] vs. 18.43 mm [±4.72], p = 0.005, paediatric patients: 22.63 mm [±4.4] vs. 17.10 mm [±4.64], p = 0.03). Using a cut off of 19.25 mm, the diagnostic performance of PAD to detect PH was found to be as follows: sensitivity = 82%, specificity = 70%, and accuracy = 73.1%. No significant difference was demonstrated in PAD between PH and non-PH groups in adults with CF (23.19 [±3.60] vs. 21.34 [±3.49], p = 0.7).

In CF patients, PAD revealed an age-dependent performance to detect PH. PAD can be applied to predict pulmonary hypertension in paediatric CF patients and may be recommended to be routinely measured on follow-up chest CT scan in childhood CF.

Beauchamp KA, Johansen Taber KA, Grauman PV Spurka L, Lim-Harashima J, Svenson A, Goldberg JD, Muzzey D.   Sequencing as a first-line methodology for cystic fibrosis carrier screening.  Genet Med. 2019 Apr 30. doi: 10.1038/s41436-019-0525-y. [Epub ahead of print]  [Pubmed]
Medical society guidelines recommend offering genotyping-based cystic fibrosis (CF) carrier screening to pregnant women or women considering pregnancy. The authors assessed the performance of sequencing-based CF screening relative to genotyping, in terms of analytical validity, clinical validity, clinical impact, and clinical utility.

Analytical validity was assessed using orthogonal confirmation and reference samples. Clinical validity was evaluated using the CFTR2 database. Clinical impact was assessed using ~100,000 screened patients. Three screening strategies were compared: genotyping 23 guideline-recommended variants (“CF23”), sequencing all coding bases in CFTR (“NGS”), and sequencing with large copy-number variant (CNV) identification (“NGS + CNV”). Clinical utility was determined via self-reported actions of at-risk couples (ARCs).

They found analytical accuracy of NGS + CNV was 100% for SNVs, indels, and CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant.

The authors’ conclusion was that modern NGS and variant interpretation enable accurate sequencing-based CF screening. Limiting screening to 23 variants does not improve analytical validity, clinical validity, or clinical utility, but does fail to detect approximately 30% (18/58) of ARCs.

DR K A Beauchamp is at Myriad Women’s Health (formerly Counsyl), South San Francisco, CA, USA. and Myriad Genetics, Salt Lake City, UT, USA.

Bellier J, Lhommet P, Bonnette P, Puyo P, Le Guen M, Roux A, Parquin F, Chapelier A, Sage E; Foch Lung Transplantation Group.  Extracorporeal membrane oxygenation for grade 3 primary graft dysfunction after lung transplantation: long-term outcomes.    Clin Transplant. 2019 Jan 18:e13480. doi: 10.1111/ctr.13480. [Epub ahead of print[Pubmed]
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 are not well-known. This study evaluated those parameters in patients with PGD requiring ECMO.    This single-centre, 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.

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.

It is concluded veno-arterial ECMO appears to be suitable for management of primary graft dysfunction after lung transplant. 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.

From Thoracic Surgery Dept., Foch Hospital, Suresnes, France

Bianco B, Horsley A, Brennan A.  Implications of fatherhood in cystic fibrosis.  Paediatr Respir Rev. 2019 Mar 16. pii: S1526-0542(19)30022-3. doi: 10.1016/j.prrv.2019.02.008. [Epub ahead of print] [Pubmed]
Advances in fertility treatment mean that men with CF are increasingly able to become fathers. This is a report of clinical outcomes in 22 men with CF who have become fathers for the first time. Overall mean (SD) FEV1% predicted declined from 60.1(18.0)% to 57.4(20.2)% from baseline to 1 year (p = 0.15). Weight declined from mean (SD) 70.6 kg (10.4) to 68.3 kg (10.2), p = 0.0001. Six men had an FEV1% predicted ≤40% at the time of birth: 50% died or received lung transplantation within the 12-15 month follow up period. Becoming a parent is a major life event, and as with new mothers, fathers with CF may be at risk of significant decline.

From the Manchester Adult CF Centre, Manchester University Hospital NHS Foundation Trust, Manchester M23 9LT, United Kingdom;A

Bisch AL, Wheatley CM, Baker SE, Peitzman ER, Van Iterson EH, Laguna TA, Morgan WJ, Snyder EM. Cystic Fibrosis Transmembrane Conductance Regulator Genotype, Not Circulating Catecholamines, Influences Cardiovascular Function in Patients with Cystic Fibrosis.Clin Med Insights Circ Respir Pulm Med. 2019 Mar 29;13:1179548419835788. doi: 10.1177/1179548419835788. eCollection 2019.[Pubmed] Free PMC Article  
Previous work has shown that a single dose of aβ-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a β-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged β-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation.

A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C2H2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del).

               Dr Eric Snyder

Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m2 vs healthy = 1.84 ± 0.04 m2, P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m2 vs healthy = 39.9 ± 2.5 mL/beat/m2, P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm-5 vs healthy = 1616 ± 74 dynes*s/cm-5, P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV (P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F(2,14) = 7.982, P < .01) and SV index (F(2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions).

The authors concluded individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

From a Thesis by Alexander Louis Bisch in the Department of Kinesiology, University of Minnesota, Minneapolis, MN, USA

The advisor was Dr Eric M Snyder Assistant Professor and Director, Clinical Exercise Physiology Laboratory

Boëlle PY, Debray D, Guillot L, Clement A, Corvol H; French CF Modifier Gene Study Investigators.  Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients.Hepatology. 2019 Apr;69(4):1648-1656. doi: 10.1002/hep.30148. Epub 2018 Dec 28. [Pubmed]

Pierre-Yves Boelle

Cystic fibrosis (CF)-related liver disease (CFLD) is a common symptom in patients with CF. However, its prevalence, risk factors, and evolution are unclear. We analyzed a large database of patients with CF to investigate the incidence of CFLD, its related risk factors, and the use and effect of ursodeoxycholic acid (UDCA) treatment. We retrospectively analyzed 3,328 CF patients with pancreatic insufficiency born after 1985 and recruited into the French CF Modifier Gene Study since 2004. We determined liver status, age at CFLD and severe CFLD onset, sex, CFTR genotype, history of meconium ileus, treatment with UDCA, and respiratory and nutritional status.

The incidence of CFLD increased by approximately 1% every year, reaching 32.2% by age 25. The incidence of severe CFLD increased only after the age of 5, reaching 10% by age 30. Risk factors for CFLD and severe CFLD were male sex, CFTR F508del homozygosity, and history of meconium ileus. Increasingly precocious initiation of UDCA treatment did not change the incidence of severe CFLD. Finally, patients with severe CFLD had worse lung function and nutritional status than other CF patients.

The authors concluded CFLD occurs not only during childhood but also later in the lifetime of patients with CF; male sex, CFTR F508del homozygosity, and history of meconium ileus are independent risk factors for CFLD development; earlier use of UDCA over the last 20 years has not changed the incidence of severe CFLD, leading to questions about the use of this treatment in young children given its possible adverse effects.

– Another large study in CFLD from France with similar findings to those of Toledano et al 2019 using the UK CF Patient Registry data. In contrast to this French study, the UK data identified a positive association with survival and the use of URSO.

Pierre-Yves Boelle is Professor at the Pierre and Marie Curie University Paris

Boyle M, Moore JE, Whitehouse JL, Bilton D, Downey DG. The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice. Med Mycol. 2019 Feb 1;57(2):155-160. doi: 10.1093/mmy/myy014.  [Pubmed]

Damion Downey

Damion Downey

The aim of this survey was to assess the variability in current practice across the UK in diagnosis and management of fungal lung disease in CF patients. A 21 question anonymous online survey was sent to 94 paediatric and adult CF consultants in the UK. The response rate was 60.6% (32 adult physicians, 25 pediatricians) with 55 full and 2 partially completed surveys.

For a first diagnosis of ABPA 20 (35.1%) treat with prednisolone alone, 38 (66.7%) use prednisolone with itraconazole and 2 (3.5%) choose voriconazole. Only 5 (8.8%) treat with prednisolone alone for a 1st relapse, 33 (58%) used prednisolone with itraconazole. To reduce treatment, 21 (36.8%) decrease steroids to zero over time and maintain azole therapy, 18 (31.6%) stop the azole and steroid after a fixed time, and 5 (8.8%) stop the azole after a fixed time and maintain a small steroid dose. Thirty-eight (66.7%) respondents believe Aspergillus colonization of the airway can cause clinical deterioration, and 37 (66.1%) would treat this. Scedosporium apiospermum infection has been diagnosed and treated by 35 (61.4%) of respondents. Results of this survey highlight the variance in clinical practice and the limited evidence available to guide management of fungal infection in CF

Breuer O, Schultz A, Turkovic L, de Klerk N, Keil AD, Brennan S, Harrison J, Robertson C, Robinson PJ, Sly PD, Ranganathan S, Stick SM, Caudri D; AREST CF.The Changing Prevalence of Lower Airway Infections in Young Children with Cystic Fibrosis.Am J Respir Crit Care Med. 2019 Feb 27. doi:10.1164/rccm.201810-1919OC. [Epub ahead of print]     [Pubmed]

Osmed Breuer and daughter

Osmed Breuer and daughter

Historical studies suggest that airway infection in cystic fibrosis (CF) initiates with Staphylococcus aureus and Haemophilus influenzae with later emergence of Pseudomonas aeruginosa. Aspergillus species are regarded as relatively infrequent, late occurring infections.  The authors assessed the prevalence and change in prevalence of early lower airway infections in a modern cohort of children with CF.

All infants diagnosed with CF after newborn screening, participating in the AREST-CF cohort study between 2000-2018, were included. Participants prospectively underwent bronchoalveolar lavage (BAL) at 3-6 months,1 year and annually up to 6 years of age. Lower airway infection prevalence was described. Changes in prevalence patterns were assessed longitudinally using generalized estimating equations controlling for age and repeated visits.

A total of 380 infants underwent 1,759 BALs. The overall prevalence and median age of first acquisition of the most common infections were: S. aureus 11%, 2.5yrs, P. aeruginosa 8%, 2.4yrs, Aspergillus species 11%, 3.2yrs, H. influenzae 9%, 3.1yrs. During the study, a significant decrease in prevalence of P. aeruginosa (p<0.001) and S. aureus (p<0.001) was observed with significant change towards more aggressive treatment. Prevalence of Aspergillus infections did not significantly change (p=0.669).  T

The study demonstrated Aspergillus species and P. aeruginosa are commonly present in the lower airways from infancy. The decrease in prevalence of P. aeruginosa and S. aureus since 2000, coinciding with more aggressive therapeutic approach, has resulted in Aspergillus becoming the most commonly isolated pathogen in young children. Further research is warranted to understand the implication of these findings.

Dr Oded Breuer of the Pediatric Pulmonology Unit Hadassah –Hebrew University Medical Center Jerusalem currently on two year Ausimed Fellowship at the Telethon Kids Institute and Perth Children’s Hospital, Australia.

Calvo-Lerma J, Hulst J Boon M, Colombo C, Masip E, Ruperto M, Fornés-Ferrer V, van der Wiel E, Claes I, Garriga M, Roca M, Crespo-Escobar P, Bulfamante A, Woodcock S, Martínez-Barona S, Andrés A, de Boeck K, Ribes-Koninckx C; MyCyFAPP project.Clinical validation of an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy through a prospective interventional study in paediatric patients with Cystic Fibrosis. PLoS One. 2019 Mar 12;14(3):e0213216. doi: 10.1371/journal.pone.0213216. eCollection  2019.  [PubMed]

Joaquim Calvo-Lerma

Joaquim Calvo-Lerma

A method to adjust Pancreatic Enzyme Replacement Therapy in Cystic Fibrosis is not currently available.   To assess the in vivo efficacy of a method to adjust the dose of enzymatic supplement in CF extrapolated from previous in vitro digestion studies (theoretical optimal dose, TOD). Secondly, to assess how individual patient characteristics influence the expected coefficient of fat absorption (CFA) and thus to identify an individual correction factor to improve TOD.

A prospective interventional study in 43 paediatric patients with CF from 5 European centres. They followed a 24h fixed diet with the theoretical optimal dose for each meal. Faecal collection was carried out between colorimetric markers in order to include all the faeces corresponding to the fixed diet. Beta regression models were applied to assess the associations of individual patient characteristics with the CFA.

Median CFA was 90% (84, 94% 1st, 3rd Q.) with no significant differences among centres. Intestinal transit time was positively associated with CFA (p = 0.007), but no statistical associations were found with and age, gender, phenotype or BMI. Regression model showed no improvement of the in vitro predicted theoretical optimal dose when taking individual patient characteristics into account.

Strict adherence to the theoretical optimal dose of enzymatic supplement for a prescribed meal, led to median CFA levels at the clinical target of 90% with a low variability between patients. The proposed method can be considered as a first approach for an evidence-based method in PERT dosing based on food characteristics. Results have to be confirmed in free dietary settings.

The investigation led by Joaquim Calvo-Lerma Instituto de Investigacion Sanitaria La Fe de Valencia, Spain.

– This is undoubtedly rather involved!  It seems very complex and the problem of lack of adherence to such a regimen would present a real

 Fat absorption in Leeds CF patients

    Fat absorption in Leeds CF patients

possibility. The author’s assumption that “patients with CF have to decided the dose of enzymatic supplement to take every single time they eat”.   In many centres the CF dietitian is regularly involved to help the patient/parents decide on the their enzyme requirements. Published evidence from the few centres where intestinal fat absorption is actually measured suggests that similar CFA are achieved as reported in this publication – for example children at the Leeds Regional CF Centre.

Commonly patients are receiving unnecessarily large doses of enzymes, the dose having been increased in response to abdominal or bowel symptoms without any measure of absorption – even microscopy of the feces for fat – to establish if the symptoms are due to malabsorption.

Calvopina DA, Noble C, Weis A, Hartel GF, Ramm LE, Balouch F, Fernandez-Rojo MA, Coleman MA, Lewindon PJ, Ramm GA.Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis. J Cyst Fibros. 2019 Jul 11. pii: S1569-1993(19)30820-3. doi: 10.1016/j.jcf.2019.06.017. [Epub ahead of print][Pubmed]

Current diagnostic methods for the diagnosis of Cystic fibrosis (CF)-associated liver disease (CFLD) are non-specific and assessment of disease progression is difficult prior to the advent of advanced disease with portal hypertension. This study investigated the potential of(SSWE) to non-invasively detect CFLD and assess hepatic fibrosis severity in children with CF.125 children were enrolled in this study including CFLD (n = 55), CF patients with no evidence of liver disease (CFnoLD = 41) and controls (n = 29). CFLD was diagnosed using clinical, biochemical and imaging best-practice guidelines. Advanced CFLD was established by the presence of portal hypertension and/or macronodular cirrhosis on ultrasound. Liver stiffness measurements (LSM) were acquired using supersonic shear-wave elastography (SSWE) and diagnostic performance for CFLD detection was evaluated alone or combined with aspartate aminotransferase-to-platelet ratio index (APRI).Liver stiffness measurement (LSM) was significantly higher in CFLD (8.1 kPa, IQR = 6.7-11.9) versus CFnoLD (6.2 kPa, IQR = 5.6-7.0; P < 0.0001) and Controls (5.3 kPa, IQR = 4.9-5.8; P < 0.0001). LSM was also increased in CFnoLD versus Controls (P = 0.0192). Receiver Operating Characteristic (ROC) curve analysis demonstrated good diagnostic accuracy for LSM in detecting CFLD using a cut-off = 6.85 kPa with an AUC = 0.79 (Sensitivity = 75%, Specificity = 71%, P < 0.0001). APRI also discriminated CFLD (AUC = 0.74, P = 0.004). Classification and regression tree modelling combining LSM + APRI showed 14.8 times greater odds of accurately predicting CFLD (AUC = 0.84). The diagnostic accuracy of SSWE for discriminating advanced disease was excellent with a cut-off = 9.05 kPa (AUC = 0.95; P < 0.0001).

The authors concluded SSWE-determined LSM shows good diagnostic accuracy in detecting CFLD in children, which was improved when combined with aspartate aminotransferase-to-platelet ratio index (APRI). Supersonic shear-wave elastography alone discriminates advanced CFLD.

From the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute,Herston, Australia; Faculty of Medicine, The University of Queensland, Brisbane,

Casciaro B, d’Angelo , Zhang , Loffredo MR, Conte G, Cappiello F, Quaglia F, Di YP, Ungaro F, Mangoni ML. Poly(lactide- co-glycolide) Nanoparticles for Prolonged Therapeutic Efficacy of Esculentin-1a-Derived Antimicrobial Peptides against Pseudomonas aeruginosa Lung Infection: in Vitro and in Vivo Studies.Biomacromolecules. 2019 Apr 23. doi: 10.1021/acs.biomac.8b01829. [Epub ahead of print].[Pubmed]
Due to their excellent in vitro activity against multi-drug resistant bacteria, antimicrobial peptides (AMPs) hold promise for treatment of Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) sufferers. In this work, poly(lactide- co-glycolide) (PLGA) nanoparticles for lung delivery of AMPs deriving from the frog-skin esculentin-1a, namely, Esc(1-21) and Esc(1-21)-1c (Esc peptides), were successfully developed. Improved peptide transport through artificial CF mucus and simulated bacterial extracellular matrix was achieved in vitro. The formulations were effectively delivered through a liquid jet nebulizer already available to patients. Notably, Esc peptide-loaded nanoparticles displayed an improved efficacy in inhibiting P. aeruginosa growth in vitro and in vivo in the long term. A single intratracheal administration of Esc peptide-loaded nanoparticles in a mouse model of P. aeruginosa lung infection resulted in a 3-log reduction of pulmonary bacterial burden up to 36 h. Overall, results unravel the potential of PLGA nanoparticles as a reliable delivery system of AMPs to lungs.

Laboratory affiliated to Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical Sciences “A. Rossi Fanelli” , Sapienza University of Rome , 

Chaudhary N, Ueno-Shuto K, Ono T, Ohira Y, Watanabe K, Nasu A, Fujikawa H, Nakashima R, Takahashi N, Suico MA, Kai H, Shuto T.Curcumin Down-Regulates Toll-Like Receptor-2 Gene Expression and Function in Human Cystic Fibrosis Bronchial Epithelial Cells.Biol Pharm Bull. 2019 Mar 1;42(3):489-495. doi: 10.1248/bpb.b18-00928. Epub  2019 Jan 10.  [Pubmed]
In CF patients, up-regulation of toll-like receptor-2 (TLR2), a pattern recognition receptor that senses CF-pathogenic bacteria Staphylococcus aureus peptidoglycan (PGN), in airway epithelial cells is observed, and enhanced pro-inflammatory responses towards PGN may result in detrimental effects in CF patients. Here, we showed that curcumin, a well-known anti-inflammatory agent derived from the curry spice turmeric, inhibits TLR2 expression in CF bronchial epithelial cell line, CFBE41o- cells. Strong suppression of TLR2 gene and protein expression was observed at more than 40 µM of curcumin treatment in CFBE41o- cells. Consistent with decreased expression of TLR2, PGN-dependent interleukin-8 (IL-8) gene up-regulation was markedly reduced by 40 µM of curcumin treatment. Strong reductions of TLR2 gene expression and function were also observed in primary human CF bronchial epithelial cells, but not in human non-CF primary cells. Interestingly, curcumin treatment decreased nuclear expression of transcription factor specificity protein 1 (SP1), a factor that is critical for increased basal TLR2 expression in CF cell line and primary cells. Finally, curcumin-dependent SP1 reduction was diminished by anti-oxidant N-acetylcystein (NAC) and proteasomal inhibitor MG-132, suggesting the crucial roles of oxidative and proteasomal degradation pathways.

Taken together, our study shows that curcumin down-regulates TLR2 gene expression and function in CF bronchial epithelial cells possibly by accelerating SP1 degradation via an oxidative process.

From the Dept. of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto, japan

Chouchane I, Stremler-Lebel N, Reix P.    Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles.   Clin Case Rep. 2019 Feb 17;7(4):616-618. doi: 10.1002/ccr3.2053. eCollection 2019 Apr.  [Pubmed]
The authors report the initiation of CFTR modulator lumacaftor/ivacaftor combination (LUM/IVA) in two adolescents with cystic fibrosis who were treated with antifungal azoles (AZO) and tacrolimus (TCS) for liver transplantation. Despite multiple drug-drug interactions, maintaining therapeutic TCS levels was achievable. During the following year, LUM/IVA was well tolerated, providing clinical benefits.

From Service de pédiatrie, Hôpital Mère Enfant Centre Hospitalier Universitaire, Hôpital Dupuytren Limoges France.

Cortes-Santiago N, Leung DH, Castro E, Finegold M, Wu H, Patel KR.Hepatic Steatosis Is Prevalent Following Orthotopic Liver Transplantation in Children With Cystic Fibrosis.J Pediatr Gastroenterol Nutr. 2019 Jan;68(1):96-103. doi: 10.1097/MPG.0000000000002154. [Pubmed]

Nahir Cortes-Santiago

Nahir Cortes-Santiago

A systematic study of allograft liver histology in children undergoing orthotopic liver transplantation (LT) for cystic fibrosis-related liver disease (CFLD). Retrospective clinic-pathologic review of explants and allograft liver biopsies from 13 children and adolescents with CFLD.In this study, the median age at LT for CFLD was 15.7 years. Notably, 10 of 13 (77%) CF explants had >5% steatosis and 8 of 13 (61.5%) demonstrated variable fibrosis. The median age, sex, type of transplant (liver vs liver-lung), pancreatic insufficiency status, body mass index (BMI) percentile, genotype, and prevalence of diabetes were comparable in those with and without explant steatosis. More than half of allograft biopsies showed significant steatosis (17/31, 54.8%) and lobular inflammation (16/31, 51.6%).Hepatocyte ballooning was less frequent (5/31, 16.1%). Overall, 6 patients (46.2%) had allograft steatosis that worsened over time in 2 patients (33%). None had advanced fibrosis (≥stage 3). Patients with allograft steatosis had significantly more biopsies, were more likely to be “liver only” recipients, had a shorter interval since transplant and higher body mass index percentile (although <85). Patients without explant steatosis never demonstrated allograft steatosis, whereas 60% of patients with explant steatosis (n = 6) developed varying degrees of allograft steatosis. The degree of explant steatosis did not predict its severity in allografts (P = 0.3).

The authors concluded this is the first study highlighting the development of allograft steatosis in CF patients. Their findings suggest that allograft steatosis in patients with CF may be related to pre-existing steatosis in native livers, regardless of other risk factors and may have implications on patient management and long-term graft/patient survival.

Dr Nahir Cortes-Santiago is Medical Resident pathology at Baylor College of Medicine

Couroux P, Farias P, Rizvi L, Griffin K, Hudson C, Crowder T, Tarran R, Tullis E.  First clinical trials of novel ENaC targeting therapy, SPX-101, in healthy volunteers and adults with cystic fibrosis.  Pulm Pharmacol Ther. 2019 Jul 11:101819. doi: 10.1016/j.pupt.2019.101819. [Epub ahead of print] [Pubmed]

Elizabeth Tullis

ENaC inhibition has been investigated as a CF treatment; however, small molecule inhibitors of ENaC lack efficacy and/or have shown dose-limiting hyperkalemia. SPX-101 is a novel, investigational small peptide (SPLUNC1 mimetic) that regulates ENaC density with the potential for efficacy without systemic effects.

Two trials are presented: The first was a Phase 1, 2-part, randomized, double-blind, placebo-controlled, ascending-dose study of nebulized SPX-101 in healthy adults. Part 1 evaluated 4 single doses of SPX-101 ranging from 20 to 240 mg. Part 2 evaluated a 14-day regimen of SPX-101 at 4 doses of SPX-101 ranging from 10 to 120 mg BID. Pharmacokinetics, adverse events, spirometry, vital signs, electrocardiograms, pulse oximetry, and clinical laboratory values were assessed. The second trial was a tolerability-confirming, Phase 1b, open-label study conducted in 5 adult subjects with CF. Ascending doses of SPX-101 inhalation solution (10 mg-120 mg BID) were administered for 7 days. Safety was assessed as described above.

All 64 healthy volunteers (32 in each Part) completed the single and multiple dose study. SPX-101 was well tolerated with little/no systemic exposure and with no hyperkalemia. Adverse events were generally mild with reported respiratory events associated with the purported pharmacological activity of SPX-101. Tolerability of SPX-101 was similarly observed in adults with CF; all 5 subjects treated with SPX-101 completed the study.

SPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF.

Dr Peter Couroux is Global Senior Research Director  at Inflamax Research Inc, Mississauga, Ontario, Canada.

Dr Elizabeth Tullis is Director of the Adult Cystic Fibrosis Clinic at St Michael’s Hospital Foundation Toronto. In 2015 she was appointed to the first Cystic Fibrosis Canada Chair in Adult Cystic Fibrosis Research.  Dr. Tullis is a Professor of Medicine at the University of Toronto, the Respirology Division Head at St. Michael’s Hospital, and an Associate Scientist in the Li Ka Shing Knowledge Institute. She is the Cystic Fibrosis Canada Chair in Adult CF Research.

Dankert-Roelse JE., Bouva MJ., Jakobs BS., Janssens HM., de Winter-de Groot KM., Schonbeck Y., Gille JJP., Gulmans VAM., Verschoof-Puite RK., Schielen PCJI., Verkerk PH.Newborn blood spot screening for cystic fibrosis with a four-step screening strategy in the Netherlands J Cyst Fibros 2019; 18: 54 – 63 [Pubmed]

Jeanette Dankert-Roelse

Newborn screening for cystic fibrosis (NBSCF) was introduced in the Dutch NBS program in 2011 with a novel strategy.    Dutch NBSCF consisted of four steps: immuno-reactive trypsin (IRT), Pancreatitis-associated Protein (PAP), DNA analysis by Inno-LiPa (35 mutations), extended gene analysis (EGA) as fourth step and as safety net. Only samples with two CFTR-variants were considered screen-positive, but samples with one disease-causing variant were considered also screen-positive from April 2013. The first 5 years of NBSCF were evaluated during a follow-up ranging from 2 to 6.8 years for sensitivity, specificity, positive predictive value (PPV), ratio of CF/Cystic Fibrosis Screen Positive infants with an Inconclusive Diagnosis (CFSPID) and median age at diagnosis, and were compared to other novel strategies for NBSCF and European Cystic Fibrosis Society (ECFS) Best Practice Standards of Care.
NBSCF achieved a sensitivity of 90% (95% CI 82%-94%), specificity of 99.991% (95% CI 99.989%-99.993%), PPV of 63% (95% CI 55%-69%), CF/CFSPID ratio of 4/1, and median age at diagnosis of 22 days, if samples with two variants as well as samples with one disease-causing variant were considered screen-positive.
The authors concluded the program achieved the goal to minimize the number of false positives and showed a favourable performance but sensitivity and CF/CFSPID ratio did not meet criteria of EFCS Best Standards of Care. Changed cut-off values for PAP and IRT and classification of R117H-7T/9T to non-pathogenic may improve sensitivity to ≥95% and CF/CFSPID ratio to 10/1. PPV is estimated to be around 60%

Dr Jeanette Dankert-Roelse wrote her first paper on neonatal CF screening in early Eighties and made many contributions to the CF literature since then.

From the School for Public Health and Primary Care, Dept Pediatrics, Maastricht University Medical Centre, Debyelaan 25, 6229 HX Maastricht, the Netherlands. Electronic address: jeannettedankert@gmail.com.

David J, Chrastina P, Pešková K, Kožich V, Friedecký D, Adam T, Hlídková E, Vinohradská H, Novotná D, Hedelová M, Al Taji E, Holubová A, Skalická V, Macek M, Gaillyová R, Votava 1.     Epidemiology of rare diseases detected by newborn screening in the Czech Republic.  Cent Eur J Public Health. 2019 Jun;27(2):153-159. doi: 10.21101/cejph.a5441.  [Pubmed]  Presymptomatic detection of patients with rare diseases (RD), defined by a population frequency less than 1 : 2,000, is the task of newborn screening (NBS). In the Czech Republic (CZ), currently eighteen RD are screened: phenylketonuria/hyperphenylalaninemia (PKU/HPA), congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), cystic fibrosis (CF), medium chain acyl-CoA dehydrogenase deficiency (MCADD), long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), very long chain acyl-CoA dehydrogenase deficiency (VLCADD), carnitine palmitoyl transferase I and II deficiency (CPTID, CPTIID), carnitine-acylcarnitine translocase deficiency (CACTD), maple syrup urine disease (MSUD), glutaric aciduria type I (GA I), isovaleryl-CoA dehydrogenase deficiency (IVA), argininemia (ARG), citrullinemia (CIT), biotinidase deficiency (BTD), cystathionine beta-synthase-deficient homocystinuria (CBSD HCU), and methylenetetrahydrofolate reductase deficiency homocystinuria (MTHFRD HCU). The aim was to analyze the prevalence of RD screened by NBS in CZ.

The authors examined the NBS programme in CZ from 1 January 2010 to 31 December 2017, which covered 888,891 neonates. Dried blood spots were primarily analysed using fluorescence immunoassay, tandem mass spectrometry and fluorimetry.   The overall prevalence of RD among the neonate cohort was 1 : 1,043. Individually, 1 : 2,877 for CH, 1 : 5,521 for PKU/HPA, 1 : 6,536 for CF (1 : 5,887 including false negative patients), 1 : 12,520 for CAH, 1 : 22,222 for MCADD, 1 : 80,808 for LCHADD, 1 : 177,778 for GA I, 1 : 177,778 for IVA, 1 : 222,223 for VLCADD, 1 : 296,297 for MSUD, 1 : 8,638 for BTD, and 1 : 181,396 for CBSD HCU.

They observed prevalence of rare diseases, based on NBS, corresponds to that expected, more precisely it was higher for BTD and lower for MSUD, IVA, CBSD HCU, MCADD and VLCADD. Early detection of rare diseases by means of NBS is an effective secondary prevention tool.

From the Department of Children and Adolescents, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic.     Department of Paediatrics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

Davies JC, Drevinek P, Elborn JS, Kerem E, Lee T; European CF Society (ECFS) Strategic Planning Task Force on ‘Speeding up access to new 4 drugs for CF’.  Speeding up access to new drugs for CF: Considerations for clinical trial design and delivery.  J Cyst Fibros. 2019 Jul 11. pii: S1569-1993(19)30815-X. doi: 10.1016/j.jcf.2019.06.011. [Epub ahead of print]. [Pubmed]

Jane Davies

The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group was brought together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organisations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed and efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.

Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J, Jacobs-Sera D, Schooley RT, Hatfull GF, Spencer H.  Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019 May;25(5):730-733. doi: 10.1038/s41591-019-0437-z. Epub 2019 May 8.[Pubmed]

Robert Dedrick

A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-

      Helen Spencer

phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.

Dr Robert Dedrick is Professor and Programme Coordinator, College of Education University of South Florida

Dr Helen Spencer is a Respiratory Paediatrician and has been clinical lead for the Lung Transplantation service at Great Ormond Street since 2007 where this patient was treated.

Dentice R, Elkins MR, Verschuer J, Eberl S, Dwyer G, Bye PTP.   Side lying during nebulisation can significantly improve apical deposition in healthy adults and adults with mild cystic fibrosis lung disease: a randomised crossover trial.  BMC Pulm Med. 2019 Jul 16;19(1):128. doi: 10.1186/s12890-019-0886-7. [Pubmed]

In people with and without Cystic Fibrosis (CF), does side lying during nebulisation change: the proportion of the dose loaded in the nebuliser that is deposited in the lungs; the uniformity of deposition throughout the lungs; or the apical drug density as a percentage of the drug density in the remaining lung? Do these effects differ depending on the degree of lung disease present?

A randomised crossover trial with concealed allocation, intention-to-treat analysis and blinded assessors, involving 39 adults: 13 healthy, 13 with mild CF lung disease (FEV1 > 80%pred), and 13 with more advanced CF lung disease (FEV1 < 80%pred). In random order, 4 mL of nebulised radioaerosol was inhaled in upright sitting and in alternate right and left side lying at 2-min intervals, for 20 min.

Compared to sitting upright, lung deposition and the uniformity of deposition were not significantly altered by side lying in any of the three groups. In sitting, the density of the deposition was significantly less in the apical regions than in the rest of the lung in all participants. Side lying significantly improved apical deposition in healthy adults (MD, 13%; 95% CI, 7 to 19), and in minimal CF lung disease (MD, 4%; 95% CI, 1 to 7) but not in advanced disease (MD, 4%; 95% CI, - 2 to 9).

The authors concluded alternating between right and left side lying during nebulisation significantly improves apical deposition in healthy adults and in adults with mild CF lung disease, without substantial detriment to overall deposition.

Ruth Dentice is physiotherapist at the Royal Prince Alfred Hospital, Sydney, Australia.

DiBattista A, McIntosh N, Lamoureux M, Al-Dirbashi OY2, Chakraborty P, Britz-McKibbin P.   Metabolic Signatures of Cystic Fibrosis Identified in Dried Blood Spots For Newborn Screening Without Carrier Identification.  J Proteome Res. 2019 Mar 1;18(3):841-854. doi: 10.1021/acs.jproteome.8b00351. Epub 2019 Jan 7.    30507207    
The authors report the discovery of a panel of CF-specific metabolites from a single 3.2 mm diameter dried blood spot (DBS) punch when using multisegment injection-capillary electrophoresis-mass spectrometry (MS) as a high-throughput platform for non-targeted metabolite profiling from volume-restricted/biobanked specimens with quality control. This retrospective case-control study design identified 32 metabolites, including a series of N-glycated amino acids, oxidized glutathione disulfide, and nicotinamide that were differentially expressed in normal birth weight CF neonates without meconium ileus ( n = 36) as compared to gestational age/sex-matched screen-negative controls ( n = 44) after a false discovery rate adjustment ( q < 0.05). Also, 16 metabolites from DBS extracts allowed for discrimination of true CF cases from presumptive screen-positive carriers with one identified CFTR mutation and transient neonatal hypertrypsinogenemic neonates ( n = 72), who were later confirmed as unaffected due to a low sweat chloride (<29 mM) test result. Importantly, six CF-specific biomarker candidates satisfying a Bonferroni adjustment ( p < 7.25 × 10-5) from three independent batches of DBS specimens included several amino acids depleted in circulation (Tyr, Ser, Thr, Pro, Gly) likely reflecting protein maldigestion/malabsorption. Additionally, CF neonates had lower ophthalmic acid as an indicator of oxidative stress due to impaired glutathione efflux from exocrine/epithelial tissue and elevation of an unknown trivalent peptide that was directly correlated with IRT (ρ = 0.332, p = 4.55 × 10-4). Structural elucidation of unknown metabolites was performed by high-resolution MS/MS, whereas biomarker validation was realized when comparing a subset of metabolites from matching neonatal DBS specimens independently analyzed by direct infusion-MS/MS at an accredited NBS facility. This work sheds new light into the metabolic phenotype of CF early in life, which is required for better functional understanding of CFTR mutations of unknown clinical consequence and the development of more accurate yet cost-effective strategies for CF screening.

Doyle RM, Rubio M, Dixon G, Hartley J, Klein N, Coll P, Harris KA.  Cross- infection is not the source of new Mycobacterium abscessus infections in a multi-centre cohort of cystic fibrosis patients.  Clin Infect Dis. 2019 Jun 19. pii: ciz526. doi: 10.1093/cid/ciz526. [Epub ahead of print] [Pubmed]

Ronan Doyle

Mycobacterium abscessus is an extensively drug resistant pathogen that causes pulmonary disease particularly in cystic fibrosis (CF) patients. Identifying direct patient-to-patient transmission of M. abscessus is critically important in directing infection control policy for the management of risk in CF patients. A variety of clinical labs have used molecular epidemiology to investigate transmission. However there is still conflicting evidence as to how M. abscessus is acquired and whether cross-transmission occurs. Recently labs have applied whole-genome sequencing (WGS) to investigate this further and in this study we investigate whether WGS can reliably identify cross-transmission in M. abscessus.      These authors retrospectively sequenced the whole genomes of 145 M. abscessus isolates from 62 patients seen at four hospitals in two countries over 16 years.                 They showed that a comparison of a fixed number of core single nucleotide variants (SNVs) alone cannot be used to infer cross-transmission in M. abscessus but does provide enough information to replace multiple existing molecular assays. They detected one episode of possible direct patient-to-patient transmission in a sibling pair. We found that patients acquired unique M. abscessus strains even after spending considerable time on the same wards with other M. abscessus positive patients.They concluded this novel analysis has demonstrated that the majority of patients in this study have not acquired M. abscessus through direct patient-patient transmission or a common reservoir. Tracking transmission using WGS will only realise its full potential with proper environmental screening as well as patient sampling.

Dr Ronan Doyle  is  Assistant Professor in the Department of Clinical Research, the London School of Hygiene and Tropical Medicine.  

Ehre C, Rushton ZL, Wang B, Hothem LN, Morrison CB, Fontana NC, Markovetz MR, Delion MF, Kato T, Villalon D, Thelin WR, Esther CR Jr, Hill DB, Grubb BR, Livraghi-Butrico A, Donaldson SH, Boucher RC. An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases.  Am J Respir Crit Care Med. 2019 Jan 15;199(2):171-180. doi: 10.1164/rccm.201802-0245OC

 Camille Ehre

Mucins, the dominant biopolymer in mucus, organize into complex polymeric networks via the formation of covalent disulfide bonds, which govern the viscoelastic properties of the mucus gel. For decades, inhaled N-acetylcysteine (NAC) has been used as a mucolytic to reduce mucin disulfide bonds with little, if any, therapeutic effects. Improvement of mucolytic therapy requires the identification of NAC deficiencies and the development of compounds that overcome them.

The objectives of this study to elucidate the pharmacological limitations of NAC and test a novel mucin-reducing agent, P3001, in preclinical settings.

The study used biochemical (e.g., Western blotting, mass spectrometry) and biophysical assays (e.g., microrheology/macrorheology, spinnability, mucus velocity measurements) to test compound efficacy and toxicity in in vitro and in vivo models and patient sputa.

Dithiothreitol and P3001 were directly compared with NAC in vitro and both exhibited superior reducing activities. In vivo, P3001 significantly decreased lung mucus burden in βENaC-overexpressing mice, whereas NAC did not (n = 6-24 mice per group). In NAC-treated CF subjects (n = 5), aerosolized NAC was rapidly cleared from the lungs and did not alter sputum biophysical properties. In contrast, P3001 acted faster and at lower concentrations than did NAC, and it was more effective than DNase in CF sputum ex vivo.

The authors consider these results suggest that reducing the viscoelasticity of airway mucus is an achievable therapeutic goal with P3001 class mucolytic agents.

Esther CR Jr, Muhlebach MS, Ehre C, Hill DB, Wolfgang MC, Kesimer M, Ramsey KA, Markovetz MR, Garbarine IC, Forest MG, Seim I, Zorn B, Morrison CB, Delion MF, Thelin WR, Villalon D, Sabater JR, Turkovic L, Ranganathan S, Stick SM, Boucher RC.    Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis.  Sci Transl Med. 2019 Apr 3;11(486). pii: eaav3488. doi: 10.1126/scitranslmed.aav3488.   [Pubmed]

Charles Esther

Although destructive airway disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, the authors performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls.
Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing mucin 5B and mucin 5AC were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography-defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared “permanent” because they did not dissolve in dilute BALF matrix, they could be solubilised by a previously unidentified reducing agent (P2062), but not by N-acetylcysteine or deoxyribonuclease.

The authors suggest these findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.

– An interesting combined contribution to the increasing work to understand early lung changes in CF . 

Charles R Esther Jr of the Division of Paediatric Pulmonology and Marsico Lung Institute, University of N. Carolina

Fink AK, Graff G, Byington CL, Loeffler DR, Rosenfeld M, Saiman L.  Palivizumab and Long-term Outcomes in Cystic Fibrosis.    Pediatrics. 2019 Jun 25. pii: e20183495. doi: 10.1542/peds.2018-3495. [Epub ahead of print] [Pubmed]

                Aliza Fink

The American Academy of Pediatrics does not recommend routine use of palivizumab prophylaxis for infants with cystic fibrosis (CF) but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain.   The authors used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary-related hospitalisations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. We created propensity scores to adjust for potential confounding by indication (ie, sicker infants were more likely to receive palivizumab). For each outcome, we performed regression analyses adjusted by propensity scores.

The sample included 4267 infants; 1588 (37%) received palivizumab. Mean percent forced expiratory volume in 1 second predicted at 7 years old was similar among those who did (98.2; 95% confidence interval: 96.9-99.5) and did not (97.3; 95% confidence interval: 96.1-98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalisation were similar among those who did and did not receive palivizumab.

The authors concluded at the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.

Dr Aliza K Fink is an epidemiologist with the CF Foundation involved with Patient Registry research

Forrest OAChopyk DMGernez YBrown MRConrad CKMoss RBTangpricha VPeng LTirouvanziam R.  Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function. J Cyst Fibros. 2019 Jan;18(1):64-70. doi: 10.1016/j.jcf.2018.05.018. Epub 2018 Jun 21.[Pubmed]
Resistin is an immune-metabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. The authors assessed the relationship of resistin to CF lung disease.

Plasma resistin levels were only marginally higher in CF than in healthy control subjects. By contrast, sputum resistin levels were very high in CF, reaching 50-100 fold higher levels than in plasma. Among CF patients, higher plasma resistin levels were associated with allergic bronchopulmonary aspergillosis, and higher sputum resistin levels were associated with CF-related diabetes. Mechanistically, in vitro release of neutrophil primary granules was concomitant with resistin secretion. Overall, sputum resistin levels were negatively correlated with CF lung function, independently of other variables (age, sex, and genotype).

Our data establish relationships between resistin levels in the plasma and sputum of CF patients that correlate with disease status, and identify resistin as a novel mechanistic link between neutrophilic inflammation and lung disease in CF.

Dr O A Forrest is in the Dept. of Pediatrics, Emory University, Atlanta.

[Resistin, also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1), is a cysteine-rich adipose-derived peptide hormone that in humans is encoded by the RETN gene.  It was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine. It was called “resistin” because of the observed insulin resistance in mice injected with resistin]

Freeman AJ, Sellers ZM, Mazariegos G, Kelly A, Saiman L, Mallory G, Ling SC, Narkewicz MR, Leung DH. A multi-disciplinary approach to pre and post-transplant management of cystic fibrosis associated liver disease.  Liver Transpl. 2019 Jan 29. doi: 10.1002/lt.25421. [Epub ahead of print][Pubmed]
Approximately 5 to 10% of patients with cystic fibrosis (CF) will develop advanced liver disease with portal hypertension, representing the 3rd leading cause of death among patients with CF. CF liver disease (CFLD) represents the most significant risk to patient mortality second only to pulmonary or lung transplant complications in patients with CF. Currently there is no medical therapy to treat or reverse CFLD. Liver transplantation in patients with CFLD with portal hypertension confers a significant survival advantage over those who do not receive LT, although the timing in which to optimize this benefit is unclear. Despite the value and efficacy of LT in selected patients with CFLD, established clinical criteria outlining indications and timing for LT, as well as disease specific transplant considerations are notably absent. The goal of this comprehensive and multi-disciplinary report is to present recommendations on the unique CF-specific pre- and post-LT management issues clinicians should consider and will face.

Alvin Jay Freeman is Pediatric Hepatologist at Children’s Health Care Atlanta

Corresponding author is Daniel H Leung Acting Director, Pediatric Hepatology and Liver Transplant Medicine Texas Chidren’s Hospital and Associate Professor of Pediatrics, Baylor College of Medicine

Fretzayas A, Douros K, Moustaki M, Loukou I. Applications of lung clearance index in monitoring children with cystic fibrosis.  World J Clin Pediatr. 2019 Apr 9;8(2):15-22. doi: 10.5409/wjcp.v8.i2.15. eCollection 2019 Apr 9. [Pubmed]

      Andreas Fretzayas

A sensitive, reproducible and feasible measure of lung function for monitoring the respiratory health is a prerequisite for the optimization of management of the patients with cystic fibrosis (CF). Spirometry has been considered the method of choice, although it is applicable only in children older than 6 years of age, as good cooperation is necessary for its proper performance. However, over the last 15 years, scientific interest in gas dilution techniques and particularly in multiple breath wash out (MBW) method has been revived. The most commonly reported index of MBW is lung clearance index (LCI). The aim of this review is to present the most recent developments in the application of LCI as a monitoring index of respiratory status of CF patients. LCI is a sensitive and reproducible marker of ventilation inhomogeneity. It is more sensitive than spirometry and, unlike spirometry; it can be performed across the whole pediatric age range. Since it is dependent on body size, until at least the age of 6 years, the relative and not the absolute changes are more appropriate for providing clinically meaningful conclusion on ventilation inhomogeneity. Until now, MBW has been mainly used as a research tool. Based on the currently available data LCI cannot safely predict high-resolution computed tomography findings in children with CF, especially in infants. It can be used as an end-point measure for the assessment of beneficial effect of interventions. However, its utility as an outcome measure for the efficacy of therapeutic interventions seems to be dependent on the pathophysiologic mechanisms that underlie each intervention. It seems that more studies, especially longitudinal ones, are required in order to fully clarify the clinical usefulness of LCI, not only in the research setting, but also in every day practice of CF clinic.

Dr Andreas Fretzayas is Professor of Paediatrics, School of Medicine, Athens, Greece

Garg V, Shen J, Li C, Agarwal S, Gebre A, Robertson S, Huang J, Han L, Jiang L, Stephan K, Wang LT, Lekstrom-Himes J.Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.Clin Transl Sci. 2019 Jan 29. doi: 10.1111/cts.12610. [Epub ahead of print]    [Pubmed]
Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4-fold and ivacaftor 15.6-fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P-gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.

– An important paper from Vertex

Garbuzenko OB, Bah N, Kuzmov A, Pogrebnyak N, Pozharov V, Minko T.Inhalation treatment of cystic fibrosis with lumacaftor and ivacaftor co-delivered by nanostructured lipid carriers.  J Control Release. 2019 Jan 21;296:225-231. doi: 10.1016/j.jconrel.2019.01.025. [Epub ahead of print]  [Pubmed]

Olga Garbuzenko

      Olga Garbuzenko

Based on their extensive experience in inhalation delivering of drugs by different nanocarriers, the authors selected nanostructured lipid carriers (NLC) for the delivery both drugs directly to the lungs by inhalation and tested NLC loaded with drugs in vitro (normal and CF human bronchial epithelial cells) and in vivo (homozygote/homozygote bi-transgenic mice with CF). The results show that the designed NLCs demonstrated a high drug loading efficiency and were internalized in the cytoplasm of CF cells. It was found that NLC-loaded drugs were able to restore the expression and function of CFTR protein. As a result, the combination of lumacaftor and ivacaftor delivered by lipid nanoparticles directly into the lungs was highly effective in treating lung manifestations of cystic fibrosis

Dr Olga Garbuzenko is Assistant Research Professor, Ernest Mario School of Pharmacy, Piscataway NJ

Garah J, Rosen I, Shaoul R.Transient Exocrine Pancreatic Insufficiency in Children: An Existing Entity?  J Pediatr Gastroenterol Nutr. 2019 Jan 8. doi: 10.1097/MPG.0000000000002267. [Epub ahead of print]  [Pubmed]
Pancreatic insufficiency in children is usually associated with diseases such as cystic fibrosis, Shwachman-Diamond syndrome, or chronic pancreatitis. Fecal elastase-1 is a reliable laboratory test for the diagnosis of exocrine pancreatic insufficiency (EPI). Transient pancreatic insufficiency has been rarely described and data on this entity are lacking in the medical literature. In this retrospective study we report 17 cases of transient pancreatic insufficiency presented mainly with failure to thrive and/or diarrhoea.

The authors followed 43 children (age range 1 month-18 years) with low fecal elastase-1 between the years 2009 and 2017. We followed growth and laboratory results (particularly, complete blood count, albumin, transaminases, celiac serology, sweat test, and fat-soluble vitamins). Elastase levels <200 mg/g were considered as pancreatic insufficiency.

Twenty-six were excluded due to missing data, a comorbidity or being syndromatic. Enrolled children (17) were all otherwise healthy. The median age at diagnosis was 3 years (range 0.2-15 years), 11 girls and 6 boys. Their main presenting symptoms were failure to thrive and/or diarrhea. Median fecal elastase-1 levels were 71 mg/g (range 18-160). Median time for normalization was 6 months (range 1-48 months). Abdominal sonography, celiac serology, and sweat test were normal for all patients. Most patients were treated with pancreatic enzymes until resolution.

The authors concluded transient EPI without clear aetiology should be in the differential diagnosis of EPI after ruling out known aetiologies. The resolving course pattern may be attributed to an unidentified infectious agent. Further studies to assess the aetiology are mandated.

– Unfortunately I was unable to obtain the full text of this article but one wonders if the transient pancreatic insufficiency was caused by the “failure to thrive and diarrhoea “ rather than it causing the symptoms. Transient pancreatic insufficiency has been described in children with coeliac disease where the pancreatic insufficiency is caused by the malnutrition and reversed when the coeliac disease is treated.

Corresponding author: Dr Ron Shaoul Pediatric Gastroenterology and Nutrition Institute, Ruth Children’s Hospital Haifa, Rambam Medical Center, Israel.

Gardner AI, McClenaghan E, Saint G, McNamara PS, Brodlie M, Thomas MF. Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry. Clin Infect Dis. 2019 Feb 15;68(5):731-737. doi: 10.1093/cid/ciy531. [PubMed]

 Aaron Gardner

   Aaron Gardner

Data from 2010-2015 for individuals aged <16 years (23200 observations from 5333 unique individuals) were obtained. Univariate analysis of unique individuals comparing all key clinical factors and health outcomes to NTM status was performed. The significant factors that were identified were used to generate a multivariate logistic regression model that, following step-wise removal, generated a final parsimonious model.The prevalence of individuals with a NTM-positive respiratory culture increased every year from 2010 (45 [1.3%]) to 2015 (156 [3.8%]). Allergic bronchopulmonary aspergillosis (odds ratio [OR], 2.66; P = 5.0 × 10-8), age (OR, 1.08; P = 3.4 × 10-10), and intermittent Pseudomonas aeruginosa infection (OR, 1.51; P = .004) were significantly associated with NTM infection.

Dr Aaron Gardner id Research Associate at the Institute of Cellular Medicine, Newcastle University medcial School Newcastle upon T

Goetz D, Kopp BT Salvator A, Moore-Clingenpeel M, McCoy K, Leung DH, Kloster M, Ramsey BR, Heltshe SH, Borowitz D.Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study. Pediatr Pulmonol. 2019 Jan 22. doi: 10.1002/ppul.24261. [Epub ahead of print]  [Pubmed]

 Danielle Goetz

Danielle Goetz

To report observations about pulmonary correlates of growth and other clinical features in infants with CF.        The authors analysed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life.

Cough was reported in 84% of infants in the first year. Up to 30% had clinically important cough but only 6.3% had crackles; 16.5% had wheeze. Wisconsin CXR score was above 5 in 23% (normal = 0; maximum score = 100). Pseudomonas was recovered from at least one respiratory culture in 24% of infants and was associated with crackles/wheezes and use of proton pump inhibitors (PPI) (OR = 5.47; 95%CI = 1.36, 21.92; P = 0.02) or PPI plus histamine-2 (H2) blocker (OR = 8.2; 95%CI = 2.41, 27.93; P = 0.001), but not H2 blocker alone. Hospitalization for respiratory indications occurred in 18% of infants and was associated with crackles/wheeze and abnormal CXR but not low weight, Pseudomonas or use of acid blockade.

Conclusions were that cough is common in infants with CF, but few present with crackles/wheeze or CXR changes. Pseudomonas is associated with use of PPI or PPI plus H2 blocker, but not with respiratory hospitalization. These observations cannot prove cause and effect but add to our understanding of pulmonary manifestations of CF in infants

Dr Danielle Goetz is paediatric Pulmonologist in the Dept. of Pediatrics, Jacobs School of Medicine, University of Buffalo

Guimbellot J, Solomon GM, Baines A, Heltshe SL, VanDalfsen J, Joseloff E, Sagel SD, Rowe SM; GOALe(2) Investigators. Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations.  J Cyst Fibros. 2019 Jan;18(1):102-109. doi: 10.1016/j.jcf.2018.04.004. Epub 2018 Apr 21. [Pubmed]

Jennifer Guimbellot

Jennifer Guimbellot

Patients with non-G551D gating mutations were recruited to an open-label study evaluating ivacaftor. Primary outcomes included: lung function, sweat chloride, weight gain, and quality of life scores.   Twenty-one subjects were enrolled and completed 6 months follow-up on ivacaftor; mean age was 25.6 years with 52% <18. Baseline ppFEV1 was 68% and mean sweat chloride 89.6 mEq/L. Participants experienced significant improvements in ppFEV1 (mean absolute increase of 10.9% 95% CI = [2.6,19.3], p = 0.0134), sweat chloride (-48.6 95% CI = [-67.4,-29.9], p < 0.0001), and weight (5.1 kg, 95% CI = [2.8, 7.3], p = 0.0002).

The authors concluded patients with non-G551D gating mutations experienced improved lung function, nutritional status, and quality of life. This study supports ongoing use of ivacaftor for patients with these mutations.

Dr Jennifer Guimbellot is a paediatric pulmonologist at the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; Department of Pediatrics, Division of Pulmonary and Sleep Medicine, UAB, Birmingham, AL, USA

Hardaker KM, Panda H, Hulme K, Wong A, Coward E, Cooper P, Fitzgerald DA, Pandit C, Towns S, Selvadurai H, Robinson PD.Abnormal preschool Lung Clearance Index (LCI) reflects clinical status and predicts lower spirometry later in childhood in cystic fibrosis.J Cyst Fibros   2019 Feb 28. pii: S1569-1993(19)30025-6. doi: 10.1016/j.jcf.2019.02.007. [Epub ahead of print]  [Pubmed]

Kate Hardaker

        Kate Hardaker

Clinical and prognostic value of preschool Multiple Breath Washout (MBW) remains unclear.  Initial MBW results (Exhalyzer® D, EcoMedics AG) in preschool Cystic Fibrosis (CF) subjects (age 2-6 years) at a time of clinical stability were compared to (1) concurrent clinical status measures and (2) later spirometry outcomes. Abnormal Lung Clearance Index (LCI) was defined using published reference data (Upper limit of normal for LCI 8.0).

LCI was abnormal in 56% (28/50), with mean (SD) LCI 8.61(1.85) at age 4.71(1.3) years. Abnormal LCI was associated with higher dornase alfa use, previous positive bacterial cultures and pF508.del homozygous genotype. Later spirometry (n = 44; mean (SD) 2.3(0.5) years after MBW) demonstrated that abnormal initial preschool LCI was a strong predictor of lower later spirometry outcomes.CONCLUSION:

Abnormal preschool LCI was associated with concurrent measures of clinical status and later spirometry deficits, suggesting early prognostic utility of MBW testing in this age range.

Dr. Kate Hardaker is a Respiratory Scientist at the Dept. Respiratory Medicine The Children’s Hospital at Westmead Sydney.

– Further work emphasising the importance of very early intervention in infants with CF.

Hayes D Jr, Kopp BT, Hill CL, Lallier SW, Schwartz CM, Tadesse M, Alsudayri A, Reynolds SD.  Cell Therapy for Cystic Fibrosis Lung Disease: Regenerative Basal Cell Amplification.  Stem Cells Transl Med. 2019 Mar;8(3):225-235. doi: 10.1002/sctm.18-0098. Epub 2018 Dec 1.  [Pubmed] 
The human airway epithelium is regenerated by basal cells. Thus, basal cell therapy has the potential to cure cystic fibrosis (CF) lung disease. We previously reported that the human basal cells repopulated the mouse airway epithelium after transplantation, and we estimated that 60 million cells would be needed to treat a human patient. To further develop cell therapy, we compared the proliferation potential of non-CF and CF tissue-derived bronchial basal cells. Three methods were used: regenerative cell frequency, burst size, and cell division frequency. Second, we used a serial passage strategy to determine if CF basal cells could be amplified to the estimated therapeutic dose. These studies evaluated that tissue-derived bronchial basal cells and the basal cells that were recovered by brushing bronchial airways or the nasal respiratory epithelium. Finally, we used the limiting dilution method to isolate non-CF and CF basal cell clones. The proliferation assays and the air-liquid-interface differentiation method were used to determine if cell amplification altered the proliferation and/or differentiation potential of clonal isolates.

The authors demonstrate that: (a) non-CF and CF basal cell proliferation is similar, (b) CF basal cells can be amplified to a therapeutic cell dose, and (c) amplified non-CF and CF basal cell clones differentiate normally. Despite these encouraging findings, we also find that the cell amplification process depletes the regenerative basal cell pool. Analysis of basal cell clones indicates that serial passage selects for long-lived basal cells and raise the possibility that prospective isolation of these stem-like cells will improve the efficacy of cell replacement therapy.

Héry-Arnaud GBoutin SCuthbertson LElborn SJTunney MM.The lung and gut microbiome: what has to be taken into consideration for cystic fibrosis?  J Cyst Fibros. 2019 Jan;18(1):13-21. doi: 10.1016/j.jcf.2018.11.003. Epub 2018 Nov 25.[Pubmed]
The 15th European Cystic Fibrosis Society (ECFS) Basic Science pre-conference Symposium focused on the topic of the microbiome, asking the question “The lung and gut microbiome: what has to be considered for cystic fibrosis (CF)?” This review gives an overview of the main points raised during the symposium, which dealt with the technical considerations, pathophysiology and clinical implications of the microbiome in CF.

Hoo ZH, Bramley NR, Curley R, Edenborough FP, Walters SJ, Campbell MJ, Wildman MJ.  Intravenous antibiotic use and exacerbation events in an adult cystic fibrosis centre: A prospective observational study.  Respir Med. 2019 Jun 18;154:109-115. doi: 10.1016/j.rmed.2019.06.017. [Epub ahead of print] [Pubmed]

       Martin Wildman

In CF, people with higher FEV1 are less aggressively treated with intravenous (IV) antibiotics, with resultant negative impact on their health outcomes. This could be entirely clinician-driven, but patient choice may also influence IV use. In this prospective observational study, we explored IV recommendations by clinicians and IV acceptance by adults with CF to understand how clinical presentations consistent with exacerbations resulted in IV use.    Clinical presentations consistent with exacerbations, IV recommendation by clinicians and IV acceptance by patients were prospectively identified for every adult with CF in Sheffield throughout 2016, excluding those who had lung transplantation (n = 7) or on ivacaftor (n = 13). Relevant demographic data, e.g. %FEV1, were extracted from medical records. Multi-level mixed-effects logistic regression models were used to compare IV recommendations vs non-recommendations for all clinical encounters, and IV acceptance vs non-acceptance for all IV recommendations.

Among 186 adults (median age 27 years, median FEV1 78.5%), there were 434 exacerbation events and 318 IV use episodes following 1010 clinical encounters. Only 254 (58.5%) of exacerbations were IV treated. A diagnosis of exacerbation, higher number of symptoms and lower %FEV1 were independent predictors for IV recommendation by clinicians. Higher number of symptoms and lower %FEV1 were also independent predictors for IV acceptance by adults with CF.
The authors concluded lower IV use among adults with higher %FEV1 was influenced by both clinicians’ and patients’ decisions. Therefore using IV antibiotics as an exacerbation surrogate could under-estimate exacerbation rates and conceal differential treatment decisions according to varying clinical characteristics.

From the School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK; Sheffield Adult CF Centre, Northern General Hospital, Sheffield, UK. Electronic address:

Dr Martin Wildman is consultant in respiratory medicine and one of the consultants at the Adult CF Centre in Sheffield. He is particularly interested in the various aspects of adherence to treatment ion cystic fibrosis.

Isaiah A, Daher A, Sharma PB, Naqvi K, Mitchell RB.Predictors of sleep hypoxemia in children with cystic fibrosis.Pediatr Pulmonol. 2019 Jan 4. doi: 10.1002/ppul.24233. [Epub ahead of print]  [Pubmed]

Amal Isaiah

Sleep hypoxemia in children with CF is predicted by both apnea hypopnea index (AHI) and percent predicted forced expiratory volume in one second (pFEV1). This is a study to identify the determinants of nocturnal hypoxemia in children with CF using clinical parameters, polysomnography (PSG), and lung function.

A pFEV1 cut-off of 53% indicated a sensitivity of 0.80 and a specificity of 0.87 in predicting sleep hypoxemia.  So pFEV1 is the best predictor of sleep hypoxemia in children with CF and referred for PSG. No demographic or clinical predictors of hypoxemia were identified in this population.

Dr Amal Isaiah is Assistant Professor in the Division of Pediatric Otolaryngology-Head and Neck Surgery, Dallas Texas.

Jones LA, Doucette L, Dellon EP, Esther CR, McKinzie CJ.Use of inhaled imipenem/cilastatin in pediatric patients with cystic fibrosis: A case series. J Cyst Fibros. 2019 May 3. pii: S1569-1993(19)30076-1. doi: 10.1016/j.jcf.2019.04.017. [Epub ahead of print]       31060800 [Pubmed]
M. abscessus complex pulmonary infections are notoriously difficult to treat, and while many antibiotics are approved for children, drug allergies or intolerances can prohibit their use. In this case series, the authors describe two pediatric patients with cystic fibrosis and previous intolerance or lack of response to standard therapies who received inhaled imipenem/cilastatin for the treatment of chronic M. abscessus infection.

Dr Jones is from the Dept of Pharmacy University of North Carolina Medical Center.

Jorth P, Ehsan Z, Rezayat A, Caldwell E, Pope C, Brewington JJ, Goss CH, Benscoter D, Clancy JP, Singh PK.  Direct Lung Sampling Indicates That Established Pathogens Dominate Early Infections in Children with Cystic Fibrosis.  Cell Rep. 2019 Apr 23;27(4):1190-1204.e3. doi: 10.1016/j.celrep.2019.03.086. 31018133 Free full text [Pubmed]

     Peter Jorth

Culture and sequencing have produced divergent hypotheses about cystic fibrosis (CF) lung infections. Culturing suggests that CF lungs are uninfected before colonization by a limited group of CF pathogens. Sequencing suggests diverse communities of mostly oral bacteria inhabit lungs early on and diversity decreases as disease progresses. The authors studied the lung microbiota of CF children using bronchoscopy and sequencing, with measures to reduce contamination. They found no evidence for oral bacterial communities in lung lavages that lacked CF pathogens. Lavage microbial diversity varied widely, but decreases in diversity appeared to be driven by increased CF pathogen abundance, which reduced the signal from contaminants. Streptococcus, Prevotella, and Veillonella DNA was detected in some lavages containing CF pathogens, but DNA from these organisms was vastly exceeded by CF pathogen DNA and was not associated with inflammation. These findings support the hypothesis that established CF pathogens are primarily responsible for CF lung infections

– This is a very detailed complex scientific article with nevertheless a straight forward conclusion that BALs from children with mild disease primarily contain established pathogens; microbiota from BALs lacking pathogens were indistinguishable from controls; rare oral organisms were found in some BALs containing abundant CF pathogens; CF pathogens strongly correlated with inflammation but oral organisms did not.

Dr Peter A Jorth is Assistant Professor, Departments of Pathology and Laboratory Medicine, Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles.

Kalaitzis IS, Rowbotham NJ, Smith SJ, Smyth AR.   Do current clinical trials in cystic fibrosis match the priorities of patients and clinicans? A systematic review.  J Cyst Fibros. 2019 Jun 21. pii: S1569-1993(19)30806-9. doi: 10.1016/j.jcf.2019.06.005. [Epub ahead of print] [Pubmed]

There are many uncertainties regarding Cystic Fibrosis (CF) treatment. Recently, the first James Lind Alliance (JLA) Priority Setting Partnership (PSP) in CF was completed, bringing clinicians, patients and carers together to identify the Top 10 research priorities. Here we investigate how well the current clinical trials landscape reflects these priorities. Trials in CF were identified through searches of research databases (Pubmed, ANZCTR, EU clinical trials register, ClinicalTrials.gov and ISRCTN). Trials meeting inclusion criteria of registered intervention studies in CF published between 01.012016 and 11.09.2017 were matched to the Top 10 priorities. We identified 259 trials, with 193 fulfilling the inclusion criteria. Only 63 (33%) of these matched one or more of the JLA priorities showing that current clinical trials poorly reflect the JLA Top 10. By increasing awareness of the Top 10 priorities, it is hoped that this will fuel future research in areas important to the CF community.

Original article on top ten priorities is summarised below –

Rowbotham NJ, Smith S, Leighton PA, Rayner OC, Gathercole K, Elliott ZC, Nash EF, Daniels T, Duff AJA, Collins S, Chandran S, Peaple U, Hurley MN, Brownlee K, Smyth AR.The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.  Thorax. 2018 Apr;73(4):388-390. doi: 10.1136/thoraxjnl-2017-210473. Epub 2017 Aug 4.28778919  Free full article [Pubmed]

There remain many treatment uncertainties in cystic fibrosis (CF). With limited resources, research should focus on questions which are most important to the CF community. We conducted a James Lind Alliance Priority Setting Partnership in CF. Research questions were elicited and then prioritised in successive surveys. A workshop agreed the final top 10. Online methods avoided cross infection and widened participation. The elicitation survey had 482 respondents (1080 questions) and prioritisation survey 677 respondents. Participants were drawn equally from the patient and clinical communities globally.They have achieved a consensus on 10 research priorities which will be attractive to funders.

Top ten priorities of the James Lind Alliance Priority Setting Partnership in order they were ranked (Rowbotham et al 2018) with the number of trials matching each of the top ten priorities (from Kalaitzis et al 2019). Some trial were matched to more than one priority.

1.  What are effective ways of simplifying the treatment burden  of people with cystic fibrosis (PWCF)?       10                                                                                 2.  How can we relieve gastrointestinal symptoms such as stomach pain, bloating and nausea in PWCF ?        3                                                                                  3.  What is the best treatment for non-tuberculous mycobacterium (NTM) in PWCF?    2                                                                                                                     4.   What therapies are effective in delaying or preventing progression of lung disease in early lig]fe in PWCF?       4                                                                         5.  Is there a way of preventing cystic fibrosis related diabetes in PWCF?     7                                                                                                                                               6.  What effective ways of motivation, support and technologies help PWCF improve and sustain adherence to treatment?       25                                                7.  Can exercise replace chest physiotherapy for PWCF?     2                                                                                                                                                                          8.  What antibiotic combinations and dosing plans should be used for CF exacerbations and should antibiotic combinations be rotated?     6                                    9.  Is there a way of reducing the negative effects of antibiotics e.g. resistance risk and adverse symptoms in PWCF?    3                                                              10. What is the best way of eradicating Pseudomonas aeruginosa in PWCF?    8                                                                                               

With regard to CFTR modulators, the participants believed that research into CFTR modulators would progress whether prioritised or not – hence their absence from the priorities list.

Kerem EOren YSKerem B.  Take it personally: how personal we reach when we are so different from each other?    J Cyst Fibros. 2019 Jan;18(1):6-7. doi: 10.1016/j.jcf.2018.12.009. [Pubmed]

Eitan Kerem

Batsheva Kerem

Discussing the variable response to Kalydeco and Orkambi among patients carrying the same   genotype was shown the authors note that since these drugs are extremely expensive, it could be argued that only patients that show clinical benefit should take them. Therefore, in-vitro cellular models and genetic tools are needed to predict patient-specific clinical outcomes.

The authors discuss three papers in the present issue of JCF (below) that describe cellular systems that can be or are already used to predict response to therapy in vivo. They note that more studies are needed to correlate the response in the different in vitro systems to clinical response, since other genes, most of them unknown yet, can modify the response in vivo. The SLC29A6 gene was suggested to modify response to Kalydeco by modulating the airway response to CFTR directed therapies. The cost of the CFTR modifier therapies, and the possible need to take several in combination in order to achieve full CFTR correction of function, emphasizes the need for various, complementary cellular systems and clinical data that may together enlarge the basis for predicting CFTR drug response in a patient-specific manner.

– Clancy, J.P., Cotton, C.U., Donaldson, S.H., Solomon, G.M., VanDevanter, D.R., Boyle, M.P. et al. CFTR modulator theratyping: Current status, gaps and future directions. J Cyst Fibros. 2019; 18: 22–34. [Pubmed]

– Eckford, P.D.W., McCormack, J., Munsie, L., He, G., Stanojevic, S., Pereira, S.L. et al. The CF Canada-Sick Kids Program in individual CF therapy: A resource for the advancement of personalized medicine in CF. J Cyst Fibros. 2019; 18: 32–40. [Pubmed] 

– Jennings, S., Ng, H.P., and Wang, G. Establishment of a ΔF508-CF promyelocytic cell line for cystic fibrosis research and drug screening. J Cyst Fibros. 2019; 18: 41–50. [Pubmed] 

 King CSBrown AWAryal SAhmad KDonaldson SCritical Care of the Adult Patient With Cystic Fibrosis.2019 Jan;155(1):202-214. doi:10.1016/j.chest.2018.07.025. Epub 2018 Aug 2. [Pubmed]

Christopher King

Adult pulmonary and critical care physicians increasingly will be involved in the care of these patients. Patients with CF are at risk for numerous conditions that require ICU admission, including respiratory failure, massive haemoptysis, pneumothorax, hepatic failure, and bowel obstruction. Multiple aspects of the care of patients with CF benefit from specialized knowledge, including pancreatic enzyme replacement and nutritional support; airway clearance modalities; treatment of multiply resistant, polymicrobial infections, and unique drug metabolism. In extreme cases, patients may benefit from advanced therapies, including extracorporeal support and organ transplant.

Optimal care of patients with CF requires a multidisciplinary care team that includes respiratory therapists, dieticians, social workers, psychologists, pharmacists, and physicians who have expertise in the treatment of this complex, multisystem disorder.

– This is still a very important message. For example an instance many years ago involved admission of a person with CF to an ICU for a respiratory indication. Omission of the pancreatic enzyme therapy led to meconium ileus equivalent intestinal obstruction, subsequent treatment of this complication proved fatal. A CF expert should be part of the ICU team.

Dr Christopher King is pulmonologist in Falls Church Virginia and  Inova Fairfax Hospital

Kirwan LFletcher GHarrington MJeleniewska PZhou SCasserly BGallagher CGGreally PGunaratnam CHerzig MLinnane BMcElvaney NGMcKone EFMcNally PMullane DNí Chróinín MO’Mahony MPlant BJJackson AD. Longitudinal Trends in Real-World Outcomes after Initiation of Ivacaftor. A Cohort Study from the Cystic Fibrosis Registry of Ireland.  Ann Am Thorac Soc. 2019 Feb;16(2):209-216. doi: 10.1513/AnnalsATS.201802-149OC.[Pubmed]

Laura Kirwan

The authors used cystic fibrosis (CF) registry data to assess outcomes after the initiation of ivacaftor, a CF transmembrane conductance regulator (CFTR) potentiator approved for the treatment of CF with a defective gating CFTR mutation.  Longitudinal trends were examined using mixed-effects regression analysis in 80 ivacaftor-treated patients with CF aged 6 to 56 years registered with the CF Registry of Ireland with at least 36 months of before and after commencement data. The effects of ivacaftor treatment on forced expiratory volume in 1 second (FEV1) % predicted, body mass index (BMI), hospitalization for pulmonary exacerbation, and oral and intravenous antibiotic use were assessed.

In the 36 months after ivacaftor initiation, FEV1% predicted improved by 2.26% per annum (95% confidence interval [CI], 0.2 to 4.3) for patients aged younger than 12 years, remained unchanged for 12- to younger than 18-year-olds (95% CI, -1.9 to 2.9), and declined in adults by 1.74% per annum (95% CI, -3.1 to -0.4). BMI in adults increased 0.28 kg/m2 per annum (95% CI, 0.03 to 0.5), and there was no significant change in BMI z-score in children (95% CI, -0.01 to 0.1). In the year after ivacaftor initiation, intravenous antibiotic treatment reduced by 46% (95% CI, -62.5% to -23.3%, oral antibiotic treatment reduced by 49% (95% CI, -61.1% to -32.1%), and there was no significant reduction in hospitalization (95% CI, -59.2% to 9.7%).

In this study of real-world CF registry data, clinical outcomes improved and healthcare resource utilization decreased after commencing ivacaftor.

Dr Laura Kirwan is Research Statistician at the Cystic Fibrosis Registry of Ireland.

Editorial below relating to the above paper of Kirwan et al.

Barry P J, Jones AM, After the Celebrations: Lessons from the New Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy. Ann Am Thorac Soc 2019; 16(2):189-190. [Pubmed]

Peter J Barry

Peter Barry and Andrew Jones of Manchester, in an editorial discuss this paper. They note that the use of national and international registries has become increasingly commonplace. They discuss the potential problems of patient inclusion including the accuracy of registry recorded data. Registry data willl have less strict monitoring than in clinical trials. The headline results of this present study are that the significant benefits ivacaftor therapy seen in clinical trials are replicated in real life practice in patients aged 6 years and over. They discuss the reduced need for intravenous antibiotics on ivacaftor but caution against  considering time on IV antibiotics as synonymous with pulmonary exacerbations and suggest this may be related to a number of different factors including a change in patient and physician thresholds for treatment. The reduced rate of decline appears to be encouraging in children and adolescents  but in adults the initial improvement appears to progress after ivacaftor introduction in contrast to the findings in the initial trails. The possible reasons are discussed including the inevitable progression in lungs already significantly damaged or could the reduced need for antibiotics be related. They consider it essential that such studies are are continued and honed to ensure the maximum benefits of CFTR modulator therapy in the wider context of CF clinical care.

Korten IKieninger EYammine SCangiano GNyilas SAnagnostopoulou PSinger FKuehni CERegamey NFrey UCasaulta CSpycher BDLatzin PSCILDBILD study group. Respiratory rate in infants with cystic fibrosis throughout the first year of life and association with lung clearance index measured shortly after birth.  J Cyst Fibros. 2019 Jan;18(1):118-126. doi: 10.1016/j.jcf.2018.07.002. Epub 2018 Jul 27. [Pubmed]

Phillippe Latzin

Lung impairment in cystic fibrosis (CF) starts in infancy. However, tools to monitor early lung disease are limited. Respiratory rate (RR) as a key vital sign is easy to assess during sleep and is elevated during acute respiratory disease. Thus, elevated RR could indicate early lung impairment and potentially serve as a diagnostic tool in disease monitoring.

In a prospective cohort of infants with CF diagnosed by newborn screening and healthy controls RR was measured and respiratory symptoms reported weekly throughout infancy. Infants performed a lung function measurement within the first weeks of life.

The analyses included 5656 measurements from 153 infants (43 with CF). RR declined from 43.2 (40.5)/min at 6 weeks of age to 28.3 (24.6)/min at 50 weeks in infants with CF (healthy controls). Infants with CF had consistently higher RR than controls (mean difference: 4.15/min; (95% CI 2.86-5.44); p < .001). In both study groups, RR was increased throughout the study period in infants with higher lung clearance indices (LCI) and during episodes of respiratory infections.

The authors concluded infants with CF have a higher RR compared to healthy controls during the first year of life. The association with early LCI measurements, the current gold standard to assess physiology of peripheral airways persisted throughout the study period. This may indicate tracking of lung function by RR. It might thus be an early subtle sign of functional respiratory deficit. Further studies will show if RR can be used as a sensitive and promising marker to monitor early CF lung disease.

Dr Insa Korten Department of Pediatrics, Pediatric Respiratory Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerlan

Prof. Philipp Latzin is the corresponding author.He is Head of Paediatric Pulmonology at University Children’s Hospital Bern.[BILD – Basel-Bern-Infant Lung Development cohort     SCILD – Swiss Cystic Fibrosis Infant Lung development cohort]

– This is a really interesting and valuable study validating good old-fashioned clinical observations of the importance of a raised respiratory rate with the use of sophisticated modern infant respiratory function tests. The authors suggest that respiratory rate could be a simple method lung function tracking in early life – a most important time when early lung damage seems to be relatively common and a time in infancy which is receiving increasing attention.

Kourliouros ATsui SParmar J.Patient outcomes from time of listing for lung transplantation in the UK: are there disease-specific differences?  Thorax. 2019 Jan;74(1):60-68. doi: 10.1136/thoraxjnl-2018-211731. Epub 2018 Oct 3.  [Pubmed]
The demand for lung transplantation vastly exceeds the availability of donor organs. This translates into long waiting times and high waiting list mortality. The authros set out to examine factors influencing patient outcomes from the time of listing for lung transplantation in the UK, examining for differences by patient characteristics, lung disease category and transplant centre.   Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant for adult lung-only registrations between 1January 2004 and 31 March 2014. Pretransplant and post-transplant outcomes were evaluated against lung disease category, blood group and height.

The authors concluded the way donor lungs were allocated in the UK resulted in discrepancies between the risk profile and probability of lung transplantation. A new donor lung allocation scheme was introduced in 2017 to try to address these shortcomings

Wilson LMMorrison LRobinson KA.      Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews.Cochrane Database Syst Rev. 2019 Jan 24;1:CD011231. doi: 10.1002/14651858.CD011231.pub2. [Epub ahead of print]   [Pubmed]
The authors reviewed the latest acceptable information and concluded there is little evidence to support the use of one airway clearance technique over another. People with cystic fibrosis should choose the airway clearance technique that best meets their needs, after considering comfort, convenience, flexibility, practicality, cost, or some other factor. More long-term, high-quality randomised controlled trials comparing airway clearance techniques among people with cystic fibrosis are needed.

Lavergne RA, Morio F, Danner-Boucher I, Horeau-Langlard D, David V, Hagen F, Meis JF, Le Pape P.  One year prospective survey of azole resistance in Aspergillus fumigatus at a French cystic fibrosis reference centre: prevalence and mechanisms of resistance.Author information.  J Antimicrob Chemother. 2019 Apr 30. pii: dkz144. doi: 10.1093/jac/dkz144. [Epub ahead of print].[Pubmed]
Studies on Aspergillus fumigatus azole resistance in cystic fibrosis patients are scarce despite the fact that it is the most frequently isolated fungus from respiratory samples from these individuals.  This study to evaluate resistance prevalence, investigate mechanisms of resistance and explore the relationship between resistant isolates by genotyping.  A prospective 1 year study (from 1 January to 31 December 2015), based on the investigation of up to five colonies per sample from cystic fibrosis patients.

Twenty-three (6.5%) isolates among the 355 tested were resistant to at least one triazole drug, using the EUCAST reference method, leading to a prevalence of 6.8% (6/88 patients). Analysis of resistance mechanisms highlighted TR34/L98H (n = 10), TR46/Y121F/T289A (n = 1), WT cyp51A (n = 11) and F46Y/M172V/N248T/D255E/E427K (n = 1). No genotype was shared between patients.

The authors concluded the study showed a relatively stable resistance prevalence in comparison with the previous study conducted in 2010-11 (8%), although resistance mechanisms varied between the two studies.

From the Parasitology and Medical Mycology Laboratory, Nantes University Hospital, Nantes, France.

Lamoureux CGuilloux CABeauruelle CJolivet-Gougeon AHéry-Arnaud G. Anaerobes in cystic fibrosis patients’ airways.    Crit Rev Microbiol. 2019 Jan 21:1-15. doi: 10.1080/1040841X.2018.1549019. [Epub ahead of print]  [Pubmed]

Li AVigers TPyle LZemanick ENadeau KSagel SDChan CL. Continuous glucose monitoring in youth with cystic fibrosis treated with lumacaftor-ivacaftor. J Cyst Fibros. 2019 Jan;18(1):144-149. doi: 10.1016/j.jcf.2018.07.010. Epub 2018 Aug 10.  [Pubmed]

Christine Chan

The effects of lumacaftor-ivacaftor therapy on glycemia have not been thoroughly investigated. Continuous glucose monitoring (CGM) provides detailed information about glycemic patterns and detects glucose abnormalities earlier than traditional screening tools for diabetes.  CGM measures, HbA1c, and oral glucose tolerance test (OGTT) results were collected and within-subject results compared in F508del homozygous youth with CF before and after initiation of lumacaftor-ivacaftor using the Wilcoxon signed-rank test.

Nine youths with CF (6 males, median age 12.7 years) were enrolled. CGM was performed in all participants before (median 26 weeks) and after lumacaftor-ivacaftor (median 29 weeks). HbA1c and fasting plasma glucose increased (p = .02) after lumacaftor-ivacaftor initiation. No changes in OGTT 1 h or 2 h glucose nor CGM measures were observed overall. When analyzed by sex, males showed lower glycemic variability, as reflected by the mean amplitude of glycemic excursions, on the post-treatment CGM.

The authors concluded glycemic abnormalities persisted in CF patients treated with lumacaftor-ivacaftor, although sex-dependent differences in glycemic response to treatment may exist.

Dr A Li of  University of Colorado School of Medicine, University of Colorado Anschutz medical Campus Aurora

Dr Christine Chan is a paediatric endocrinologist in Aurora Colorado

Lentini L, Melfi R, Cancemi P1, Pibire L, Di Leonardo A.  Caffeine boosts Ataluren’s readthrough activity.Heliyon. 2019 Jun 21;5(6):e01963. doi: 10.1016/j.heliyon.2019.e01963. eCollection 2019 Jun.  [Pubmed]  Free PMC Article

The readthrough of nonsense mutations by small molecules like Ataluren is considered a novel therapeutic approach to overcome the gene defect in several genetic diseases as cystic fibrosis (CF). This pharmacological approach suppresses translation termination at premature termination codons (PTCs readthrough) thus restoring the expression of a functional protein. However, readthrough might be limited by the nonsense-mediated mRNA decay (NMD), a cell process that reduces the amount/level of PTCs containing mRNAs. Here we investigate the combined action of Ataluren and caffeine to enhance the readthrough of PTCs. IB3.1 CF cells with a nonsense mutation were treated with caffeine to attenuate the Nonsense-Mediated mRNA Decay (NMD) activity and thus enhance the stability of the nonsense (ns)-CFTR-mRNA to be targeted by Ataluren. Our results show that NMD attenuation by caffeine enhances mRNA stability and more importantly when combined with Ataluren increase the recovery of the full-length CFTR protein.

Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128, Palermo, Italy

Liu F, Zhang Z, Levit A, Levring J, Touhara KK, Shoichet BK, Chen J.   Structural identification of a hotspot on CFTR for potentiation.   Science. 2019 Jun 21;364(6446):1184-1188. doi: 10.1126/science.aaw7611. [Pubmed]

 Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition.                                                                                                                                                                                The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.

Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, NY 10065, USA

Further potential way to improve the function of the CFTR modulators

Lombardi E, Gambazza S, Pradal U, Braggion C.  Lung clearance index in subjects with cystic fibrosis in Italy. Ital J Pediatr. 2019 May 2;45(1):56. doi: 10.1186/s13052-019-0647-5. [Pubmed]

 Enrico Lombardi

The Lung Clearance Index (LCI) is an index derived from washout recordings, able to detect early peripheral airway damage in subjects with cystic fibrosis (CF) with a greater sensitivity than spirometry.LCI is a marker of overall lung ventilation inhomogeneity; in fact, as pulmonary ventilation worsens, the number of tidal breaths and the expiratory volumes required to clear the lungs of a marker gas are increased, as documented by a greater value.In the field of CF, LCI allows indirect investigation of the small airways (< 2 mm) the site where, from a pathophysiologic point of view, the disease begins due to the defect of the CF transmembrane-conductance regulator (CFTR) protein. Infant pulmonary function changes seem to occur before clinically overt symptoms of lower respiratory illness occur.When performing the test, it is important to refer to the American Thoracic Society and European Respiratory Society consensus statements and apply a strict standardization.In Italy the first tests were carried out in 2014 for research purpose and now approximately 10 centers are collecting data and are experiencing a consistency in repeating exams.Currently in Italian centers children at pre-school age are the main target: in this population it is important to have a sensitive and feasible test, non-invasive, that can be performed at tidal volume without sedation, and requiring minimal cooperation and coordination, and that can be used longitudinally over time. Another target could be the transplanted subjects to detect early signs of lung function decline.The content of this paper captures the experience and discussions among some of the Italian centers where LCI is currently used for research and/or in clinical practice about the method and the need to have a common approach.The aim of this paper is not to describe the methodology of MBW, but to inform the pediatric community about the possible application of LCI in CF

Dr Enrico Lombardi is Head of Paediatric Pulmonology, Paediatric University Hospital, Florence, Italy.

Lommatzsch ST, Taylor-Cousar JL.The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy.   Ther Adv Respir Dis. 2019 Jan-Dec;13:1753466619844424. doi: 10.1177/1753466619844424.   [Pubmed]

     Steve Lommatzsch

Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity. Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition. Traditionally, CF has been symptomatically managed, but over  the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor. To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources.eDr Steven E Lommatzsch is a pulmonologist at National Jewish Health, Denver 

Loureiro CA, Santos JD, Matos AM, Jordan P, Matos P, Farinha CM, Pinto FR.    Network Biology Identifies Novel Regulators of CFTR      Trafficking and Membrane Stability. Front Pharmacol. 2019 Jun 4;10:619. doi: 10.3389/fphar.2019.00619. eCollection 20   [Pubmed]    Free PMC Article  
In cystic fibrosis, the most common disease-causing mutation is F508del, which causes not only intracellular retention and degradation of CFTR, but also defective channel gating and decreased membrane stability of the small amount that reaches the plasma membrane (PM). Thus, pharmacological correction of mutant CFTR requires targeting of multiple cellular defects in order to achieve clinical benefit. Although small-molecule compounds have been identified and commercialized that can correct its folding or gating, an efficient retention of F508del CFTR at the PM has not yet been explored pharmacologically despite being recognised as a crucial factor for improving functional rescue of chloride transport.                                             In ongoing efforts to determine the CFTR interactome at the PM, we used three complementary approaches: targeting proteins binding to tyrosine-phosphorylated CFTR, protein complexes involved in cAMP-mediated CFTR stabilisation at the PM, and proteins selectively interacting at the PM with rescued F508del-CFTR but not wt-CFTR. Using co-immunoprecipitation or peptide-pull down strategies, we identified around 400 candidate proteins through sequencing of complex protein mixtures using the nano-LC Triple TOF MS technique. Key candidate proteins were validated for their robust interaction with CFTR-containing protein complexes and for their ability to modulate the amount of CFTR expressed at the cell surface of bronchial epithelial cells.  Here, the authors describe how they explored the above-mentioned experimental datasets to build a protein interaction network with the aim of identifying novel pharmacological targets to rescue CFTR function in cystic fibrosis (CF) patients. They identified and validated novel candidate proteins that were essential components of the network but not detected in previous proteomic analyses.

  – BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal. Multidisciplinary/Interdisciplinary Research; Life and Health    Sciences; Biomedicine; Exact Sciences & Engineering; Physics; Natural Science & Environment; Bio-based Product Technology or Food Sciences . Scientific Director is Professor Margarida Amaral  

Corresponding author Francisco Pinto,  Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal

Lowery EM, Afshar M, West N, Kovacs EJ, Smith B, Joyce C.   Self-reported alcohol use in the cystic fibrosis community.  J Cyst Fibros. 2019 Jul 11. pii: S1569-1993(19)30805-7. doi: 10.1016/j.jcf.2019.06.004. [Epub ahead of print] [Pubmed]

Erin Lowery

Excessive alcohol use (EAU), a harmful pattern of drinking that includes binge drinking and heavy use, occurs in 25% (binge) and 6% (heavy use) of the US population, respectively. Little is known about alcohol use in individuals with cystic fibrosis (CF). The objective of this investigation is to examine alcohol consumption patterns in individuals with CF using a health survey administered from a social media platform.

Individuals with CF, 18 years of age or older, were recruited for participation through social media and internet-based platforms. 1135 individuals initially participated in the survey and 84% (n = 952) were eligible and completed the survey. Of the respondents, 77% (n = 729) currently consume alcohol, 18% (n = 171) formerly consumed alcohol, and 5% (n = 52) never consumed alcohol. Amongst the people with CF who currently consume alcohol, 54% (N = 391) met criteria for EAU. Thirty percent of current drinkers experienced symptoms of harmful alcohol use. Of those who met criteria for EAU, 7% wore oxygen, 6% had a lung transplant, 10% had liver disease and 32% had diabetes. Those with EAU reported more hospitalizations than those without EAU [244 (62%) vs 182 (54%), p = .034]. Characteristics associated with EAU after multivariable adjustment included younger age, unmarried status, male gender and younger age at initiation of drinking.

The authors concluded EAU is occurring at a much higher proportion in individuals with CF. A substantial percentage of CF individuals with EAU also have medical co-morbidities. Screening, brief intervention, and referral to treatment for EAU in CF clinics is warranted.

Dr Erin Lowery is Pulmonologist at the Department of Medicine, Loyola University Medical Center, Maywood, IL, United States of America; 

McColley SAKonstan MWRamsey BWStuart Elborn JBoyle MPWainwright CEWaltz DVera-Llonch MMarigowda GJiang JGRubin JL. Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1. J Cyst Fibros. 2019 Jan;18(1):94-101. doi: 10.1016/j.jcf.2018.07.011. Epub 2018 Aug 23.   Free full text  [Pubmed]
Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement.  This was a post hoc analyses of pooled phase 3 data (NCT01807923NCT01807949) categorized LUM/IVA-treated patients by percent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change <5% vs ≥5%) and compared PEx rates vs placebo. The LUM (400 mg q12h)/IVA (250 mg q12h)-treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40-0.69; P < .0001], 0.74 [0.55-0.99; P = .04]).

The authors concluded LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.

McCormick JCho DYLampkin BRichman JHathorne HRowe SMWoodworth BA. Ivacaftor improves rhinologic, psychologic, and sleep-related quality of life in G551D cystic fibrosis patients.Int Forum Allergy Rhinol. 2019 Mar;9(3):292-297. doi: 10.1002/alr.22251. Epub 2018 Nov 24 [Pubmed]
The purpose of this study is to evaluate the impact of ivacaftor on chronic rhinosinusitis (CRS) symptoms in this population.The G551D Observational (GOAL) study was a multicenter prospective cohort study enrolling CF patients ≥6 years with at least 1 G551D mutation. Subjects were provided 20-item Sino-Nasal Outcome Test (SNOT-20) questionnaires prior to ivacaftor therapy and at 1, 3, and 6 months afterward. The impact on rhinologic (R), psychological (P), sleep (S), and ear/facial (E) quality of life (QOL) domains was evaluated separately.  Of 153 subjects, 129 (84%) completed all questionnaires.

Ivacaftor improves QOL in the R, P, and S domains in G551D CF patients, although QOL instruments validated for CRS may not translate well to CF CRS patients because symptom burden was surprisingly low.

McNamara JJMcColley SAMarigowda GLiu FTian SOwen CAStiles DLi CWaltz DWang LTSawicki GS. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study.Lancet Respir Med. 2019 Jan 24. pii: S2213-2600(18)30460-0. doi: 10.1016/S2213-2600(18)30460-0. [Epub ahead of print] [Pubmed]

John MacNamara

The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years.

In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132.

The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24.

Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of the disease.

Miah KM, Hyde SC, Gill DR.   Emerging gene therapies for cystic fibrosis.  Expert Rev Respir Med. 2019 Jun 27:1-17. doi: 10.1080/17476348.2019.1634547. [Epub ahead of print]  [Pubmed]

         Deborah Gill and Steve Hyde

Cystic fibrosis (CF) remains a life-threatening genetic disease, with few clinically effective treatment options. Gene therapy and gene editing strategies offer the potential for a one-time CF cure, irrespective of the CFTR mutation class. Areas covered: We review emerging gene therapies and gene delivery strategies for the treatment of CF particularly viral and non-viral approaches with potential to treat CF. Expert opinion: It was initially anticipated that the challenge of developing a gene therapy for CF lung disease would be met relatively easily. Following early proof-of-concept clinical studies, CF gene therapy has entered a new era with innovative vector designs, approaches to subvert the humoral immune system and increase gene delivery and gene correction efficiencies. Developments include integrating adenoviral vectors, rapamycin-loaded nanoparticles, and lung-tropic lentiviral vectors. The characterization of novel cell types in the lung epithelium, including pulmonary ionocytes, may also encourage cell type-specific targeting for CF correction. We anticipate preclinical studies to further validate these strategies, which should pave the way for clinical trials. We also expect gene editing efficiencies to improve to clinically translatable levels, given advancements in viral and non-viral vectors. Overall, gene delivery technologies look more convincing in producing an effective CF gene therapy.

From the Gene Medicine group medical division of clinical laboratory science, Radcliffe Department of Medicine , University of Oxford , Oxford

Stephen Hyde and Deborah Gill are two of the original members of the UK Gene Therapy Consortium formed in 2001 and are co-directors of the Gene Medicine Research Group in Oxford. Stephen Hyde  is now Associate Professor of Molecular Therapy and Deborah Gill is Professor of Gene Medicine at Oxford.    On both their Radcliffe Department of Medicine website entries there is a concise summary of the development in gene therapy in the UK and their respective roles in it.

Modlin SE, Borofka K, Franzini D, Klene-Bowns AC, Nuño VA.  OMT for the Prevention and Management of Chronic Constipation and Distal Intestinal Obstructive Syndrome in Cystic Fibrosis: A Pilot Study. J Am Osteopath Assoc. 2019 Jul 1;119(7):e31-e35. doi: 10.7556/jaoa.2019.084.[Pubmed]

      Sara Modlin

A study to understand the impact of osteopathic manipulative treatment (OMT) on the prevention and management of gastrointestinal symptoms in patients with CF.  This study used OMT for physical manipulation of the viscera, spine, and other somatic components to improve bowel symptoms and prevent DIOS. These effects were achieved by releasing myofascial restrictions found in the abdomen and somatic structures with the intent to optimise the autonomic and lymphatic systems and improve range of motion.Four of 5 participants had a decrease in pain, and 3 participants had a reduced need for laxatives during treatment. Four participants had an overall increase in satisfaction with their bowel movements while being treated with OMT.
The authors concluded their findings support the use of OMT as a method for the management of chronic constipation and DIOS in the CF population. However, because of the small population size, more research with larger populations is needed.

Dr Modlin treats patients at the Family Medicine Institute in Augusta. She has a particular clinical interest in osteopathic manipulative medicine.

Muraglia KAChorghade RSKim BRTang XXShah VSGrillo ASDaniels PNCioffi AGKarp PHZhu LWelsh MJBurke MD.Small-molecule ion channels increase host defences in cystic fibrosisairway epithelia.Nature. 2019 Mar; 567(7748):405-408. doi: 10.1038/s41586-019-1018-5. Epub 2019 Mar 13.[Pubmed]

Martin D Burke, Katrina Muraglia, & Rajeev Choghade

Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3 and Cl secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis. Here the authors report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3 secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in viv

Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.

Dr Katrina A Muraglia is in the Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.  Dr Rajeev Chorghade is a graduate student.  Dr Martin D Burke is leader of the study group and Professor of Chemistry and Associate Dean for Research at the Carle Illinois College of Medicine

Norris AW. Is Cystic Fibrosis-related Diabetes Reversible? New Data on CFTR Potentiation and Insulin Secretion.Am J Respir Crit Care Med. 2019 Feb 1;199(3):261-263. doi: 10.1164/rccm.201808-1501ED.  [Pubmed]
Andrew Norris discusses the question as to whether the new molecular therapies will treat or even prevent cystic fibrosis related diabetes. In a clear detailed review of the effect of the new therapies on the treatment and even prevention CFRD. He discusses the study of Kelly et al (abstracted below) and concludes that Kelly and colleagues’s results provide hope that restoration of CFTR function might treat or even prevent CFRD, although there remains considerable uncertainty. He mentions the severity of pancreatic involvement and even the fact that pancreatic damage occurs in utero.

Kelly ADe Leon DDSheikh SCamburn DKubrak CPeleckis AJStefanovski DHadjiliadis DRickels MRRubenstein RC. Islet Hormone and Incretin Secretion in Cystic Fibrosis after Four Months of Ivacaftor Therapy.
Am J Respir Crit Care Med.
 2019 Feb 1;199(3):342-351. doi: 10.1164/rccm.201806-1018OC.
 
 [Pubmed]

      Andrea Kelly

 Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion.

Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared pre-ivacaftor initiation and 16 weeks post-ivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation.         Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests.

Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on β-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04).

The authors concluded insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.

Dr Andrea Kellyis attending physician in the Division of Endocrinology and Diabetes and Division of Pulmonary Medicine and Cystic Fibrosis Center, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Nichols DP, Durmowicz AG, Field A, Flume PA, VanDevanter DR, Mayer-Hamblett N.    Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities.Ann Am Thorac Soc. 2019 May;16(5):534-539. doi: 10.1513/AnnalsATS.201812-863OT [Pubmed]  Free PMC Article   

     David Nichols

There is no abstract but in summary, the authors note the clinical care of people with CF is rapidly improving. This progress is to be celebrated, but does not negate the need for inhaled antibiotic therapies. Currently available FDA-approved treatment options are meeting the needs of certain important aspects of clinical care, but these drugs have been used now for up to 20 years. Tobramycin solution for inhalation was FDA approved in 1997 (Ramsey BWPM et al N Eng J Med 1999;340:23-30) and later the dry powdered version (Konstan M W et al, J Cyst Fibros 2011; 10:54-61). The other aztreonam was FDA approved in 2010 (Assael Bm et alJ Cyst Fibros 20103;12:130-140;   McCoy KS et alAm J Respir Crit care Med 2008;178:921-928; Retsch-Bogart GZ et al (Chest 2009;135:1223-1232).  The increasing tendency to eliminate the 4 week off period with tobramycin some by using off label intravenous preparations and then alternating tobramycin and aztreonam- this continuous alternating therapy is becoming increasing popular in the US.

New antibiotic options are needed both for those with longstanding infections with P. aeruginosa and for those with other, often less common, but highly resistant, airway pathogens. Years of successful drug development and standardised clinical care guidelines have provided better overall health and led to more common chronic use of one or more inhaled antibiotics. This significantly alters how future trials with new drug candidates can occur. Despite these challenges, feasible, informative developmental pathways exist. Clinical trial leaders and prospective sponsors are encouraged to consider the key points provided here when developing study designs and in discussions with regulatory agencies. It is hoped that this will lead to successful design and completion of trials that will make available new inhaled antibiotics for people with CF.

  – The free PMC article can be strongly recommended

 Dr David P Nichols is at Cystic Fibrosis Therapeutics Development Network Coordinating Center, Department of Pediatrics, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle,Washington

Novel-Catin E Pelletier SReynaud QNove-Josserand RDurupt SDubourg LDurieu IFouque D.Aminoglycoside exposure and renal function before lung transplantation in adult cystic fibrosis patients. Nephrol Dial Transplant. 2019 Jan 1;34(1):118-122. doi: 10.1093/ndt/gfy084.   [Pubmed]
Patients with cystic fibrosis (CF) are at risk of kidney injury even before undergoing lung transplantation, because of prolonged exposure to aminoglycosides (AGs), chronic dehydration and complications of diabetes mellitus. The usual equations estimating the glomerular filtration rate (GFR), such as Cockcroft-Gault and Modification of Diet in Renal Disease, are not adapted to the CF population due to patients’ low body weight and reduced muscle mass. The aim of this study was to precisely measure GFR in adult CF patients and to see whether repeated AG treatment would impair renal function before lung transplantation.

Inulin or iohexol clearances were performed in 25 adult CF patients when they entered the lung transplant waiting list. No patient was treated with AGs at the time of GFR measurement. Body mass index (BMI), history of diabetes mellitus and blood pressure were recorded. Exposure to intravenous (IV) AGs within 5 years prior to the GFR measurement was obtained from the patient’s medical files. Urine samples were collected to check for albuminuria and proteinuria.

The population was predominantly female (67%). The mean age was 32 years, the mean BMI was 19 kg/m2 and 28% had CF-related diabetes. Median exposure to IV AG within 5 years before GFR measurement was 155 days with a mean dosage of 7.7mg/kg/day. The mean measured GFR was 106 mL/min/1.73 m2 and the mean estimated GFR according to the Chronic Kidney Disease Epidemiology Collaboration formula was 124 mL/min/1.73 m2.

This study shows that despite prolonged exposure to high-dose IV aminoglycosides, no decline in GFR was observed in these patients.

– The majority of patients received tobramycin – “A detailed history of antibiotic courses was available for 92% of patients (n = 23). Not surprisingly, tobramycin was the most used AG [88% of cases (n = 22)]. Only one patient was regularly treated with amikacin and none with gentamicin”.

Dr Etienne Novel-Catin is in the Département de Néphrologie, Centre Hospitalier Lyon SUD, Hospices Civils de Lyon, Pierre Bénite, France and has a special interest in aminoglycosides and renal function – “Exposition aux aminoglycosides et fonction rénale pré-transplantation pulmonaire chez des patients adultes atteints de mucoviscidose” 2018.

Paajanen J, Halme M, Palomäki M. Anttila VJ.  Disseminated Scedosporium apiospermum central nervous system infection after lung transplantation: A case report with successful recovery.   Med Mycol Case Rep. 2019 Mar 16;24:37-40. doi: 10.1016/j.mmcr.2019.03.003. eCollection 2019 Jun.  Free PMC Article [Pubmed]

Juuso Paajanen

Scedosporium species are fungal opportunistic pathogens frequently seen in chronic lung diseases such as in cystic fibrosis (CF). They can cause a wide spectrum of diseases mainly in immunodeficient patients. Invasive, disseminated infections with poor prognosis have been described after lung transplantation. We present a CF-patient with disseminated Scedosporium apiospermum infection after lung transplantation. The patient had skin, surgical wound, spinal cord, and brain involvements. She recovered fully after prolonged course of voriconazole treatment.

Dr Juuso Paajanen is at the Department of Pulmonary Medicine, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Finland.

Pascucci C, De Biase RV, Savi D, Quattrucci S, Gnessi L, Lubrano C, Lenzi A.  Impact of CFTR-modulating drugs on GH-IGF-1 axis impairment in adult patients with cystic fibrosis.  Endocrinol Invest. 2019 Apr 20. doi: 10.1007/s40618-019-01051-4. [Epub ahead of print]  [Pubmed]
A new class of drugs in the treatment of cystic fibrosis (CF) includes two agents: lumacaftor, which corrects CFTR channel protein, and ivacaftor, which increases CFTR channel activity. In a previous study the authors recruited 50 stable adults with CF and 16 of them showed growth hormone deficit (GHD): 7 patients severe and 9 patients partial GHD. So they decided to re-evaluate ten patients with the GHRH + arginine test of whom only five were treated with lumacaftor/ivacaftor.      All CF patients in therapy with lumacaftor/ivacaftor showed a marked improvement in GHD. Two patients moved from a severe GHD to a normal response to the GH/IGF-1 axis test, and three patients who had partial GHD moved to normal response.

The authors concluded the pituitary gland may be damaged by CF disease and could benefit fromf the action of correcting drugs.

From  the Section of Medical Pathophysiology, Endocrinology, Department Experimental Medicine, Sapienza University of Rome, italy.

Pedersen MG, Højte C, Olesen HV, Pressler T, Skov M.    Late diagnosis and poor nutrition in cystic fibrosis diagnosed before implementation of newborn screening.  Acta Paediatr. 2019 Jun 19. doi: 10.1111/apa.14908. [Epub ahead of print].. 31218749

         Hanna Oiesen

Denmark has a high standard cystic fibrosis care. However, newborn screening was not implemented until 2016. This article describes the clinical  status of cystic fibrosis patients at time of diagnosis prior to newborn screening.   Patients diagnosed with cystic fibrosis in Denmark in 2010-2014 were reviewed using the Danish Cystic Fibrosis Registry as well as patient files. Parameters collected were age at diagnosis, gender, weight, height, forced expiratory volume at 1 second, cystic fibrosis transmembrane regulator-genotype, lung bacteriology at diagnosis and previous diagnoses.                             A total of 63 patients were diagnosed in the study period. The most typical pre-cystic fibrosis diagnoses were asthma and pneumonia. The median age at diagnosis was 1.4 years for the pancreatic insufficient and 27.3 years for the pancreatic sufficient patients. Of the pancreatic insufficient patients, 21% had moderate to severe malnutrition with BMI below minus 2 SD and 40% had moderate to severe stunting with height below minus 2 SD.               Diagnosis was delayed considerably compared to diagnosis by newborn screening in other countries. Many cystic fibrosis patients diagnosed due to clinical symptoms were moderately to severely underweight or stunted at diagnosis.

Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark and the Department of Pediatrics, Copenhagen University Hospital, Copenhagen, Denmark.

– It difficult to understand the reason for the very late introduction of neonatal CF screening (NBS) for undoubtedly, prior to NBS, a number of infants would not be diagnosed before irreparable damage occurred to the airways and chronic infection became established.

Corresponding author – Dr Hanne Vebert Olesen, Dept of Paediatrics, Aarthus University Hospital, Denmark

Poetter-Lang SStaufer KBaltzer PTamandl DMuin DBastati NHalilbasic EHodge JCTrauner MKazemi-Shirazi LBa-Ssalamah A. The Efficacy of MRI in the diagnostic workup of cystic fibrosis-associated liver disease: A clinical observational cohort study.  Eur Radiol. 2019 Feb;29(2):1048-1058. doi: 10.1007/s00330-018-5650-5. Epub 2018 Jul 27.  30054796 Free PMC article  [Pubmed]

Sarah Poetter-Lang

A study to identify independent imaging features and establish a diagnostic algorithm for diagnosis of cystic fibrosis (CF)-associated liver disease (CFLD) in CF patients compared to controls using gadoxetic acid-enhanced MRI.

A total of 90 adult patients were enrolled: 50 with CF, 40 controls. The CF group was composed of two subgroups: a retrospective test subgroup (n = 33) and a prospective validation subgroup (n = 17). Controls (patients with normal liver enzymes and only benign focal liver lesions) were divided accordingly (27:13). MRI variables, including quantitative and qualitative parameters, were used to distinguish CFLD from controls using clinical symptoms, laboratory tests and Debray criteria. Disease severity was classified according to Child-Pugh and Albumin-Bilirubin (ALBI) scores. Fifteen qualitative single-lesion CF descriptors were defined. Two readers independently evaluated the images. Univariate statistical analysis was performed to obtain significant imaging features that differentiate CF patients from controls. Through multivariate analysis using chi-squared automatic interaction detector (CHAID) methodology the most important descriptors were identified. Diagnostic performance was assessed by receiver-operating characteristic (ROC) analysis.

Three independent imaging descriptors distinguished CFLD from controls: (1) presence of altered gallbladder morphology; (2) peri-portal tracking; and (3) periportal fat deposition. Prospective validation of the classification algorithm demonstrated a sensitivity of 94.1% and specificity of 84.6% for discriminating CFLD from controls. Disease severity was well associated with the imaging features.

The authors concluded a short unenhanced MRI protocol can identify the three cardinal imaging features of CFLD. The hepatobiliary phase of gadoxetic acid-enhanced MRI can define CFLD progression. Using a multivariate classification analysis, we identified three independent imaging features, altered gallbladder morphology (GBAM), periportal tracking (PPT) and periportal fat deposition (PPFD), that could diagnose CFLD with high sensitivity, 94.1 % (95% CI: 71.3-99.9) and moderate specificity, 84.6 % (95% CI: 54.6-98.1). • Based upon the results of this study, gadoxetic acid-enhanced MRI with DWI is able to diagnose early-stage CFLD, as well as its progression.

Dr Sarah Poetter-Lang is in the Department of Biomedical Imaging and Image –guided therapy. Medical University of Vienna, Austria

Poncin WLebecque P.[Lung clearance index in cystic fibrosis]. Rev Mal Respir. 2019 Jan 24. pii: S0761-8425(18)31015-5. doi: 10.1016/j.rmr.2018.03.007. [Epub ahead of print] (French)  [Pubmed]

     William Poncin

  The multiple breath washout (MBW) test is affordable and non-invasive. Lung clearance index (LCI), which is the most used derived parameter, is reproducible and much more sensitive than spirometry in detecting small airways disease. However, MBW is operator dependent.  The recent commercialization of devices assessing LCI launches MBW as a potential tool in routine clinical care, although its use currently remains mostly dedicated to research purposes. However, important differences in LCI between various equipment settings raise a number of theoretical questions. Specific algorithms should be refined and more transparent. Standardization of MBW is still an on going process. Whether other MBW derived indices can prove superior over LCI deserves further study.

The authors conclude that in CF, LCI is now a well-established outcome in research settings to detect early lung function abnormalities and new treatment effects, especially in patients with mild lung disease. In these patients, LCI seems an attractive tool for clinicians too. Yet, further investigation is needed to define clinically significant changes in LCI and to which extent this index can be useful in guiding clinical decisions remains to be studied.

Dr William Poncin is an expert on respiratory physiology at Universite Catholique de Louvain.

Prentice BJ, Ooi CY, Strachan RE, Hameed S, Ebrahimkhani S, Waters SA, Verge CF, Widger J. Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis.  J Cyst Fibros. 2019 Apr 26. pii: S1569-1993(18)30897-X. doi: 10.1016/j.jcf.2019.03.010. [Epub ahead of print]  [Pubmed]

    Bernadette Prentice

Children with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation.  The authors assessed 18 children (5 females) with median age of 3.2 years (range 0∙9-5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level. Peak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG rs = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, β = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015).

The authors concluded children with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.

Dr Bernadette Prentice is a Respiratory Paediatrician in the Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW, Australia.

Roehmel JFKallinich TStaab DSchwarz C.Clinical manifestations and risk factors of arthropathy in cystic fibrosis.  Respir Med. 2019 Feb;147:66-71. doi: 10.1016/j.rmed.2019.01.003. Epub  2019 Jan 17.[Pubmed]

      Jobst Roehmel

     An observational study to assess the clinical manifestations, frequency, and risk factors of CF associated arthropathy. Of 186 patients (Demographics: Mean age 27 years, female gender 104/186 (57%), CFTR F508del homozygous 82/186 (44%) included in the study, 54/186 (29%) had experienced joint symptoms. Joint pain and swelling were the most frequent symptoms. The joints of the hands (JOH) followed by the joints of the feet were most affected. No specific pattern of autoantibodies was discovered. The level of total serum IgG, age, female gender, and pulmonary exacerbations per year were significant risk factors for arthropathy in the study cohort. Pulmonary exacerbations and elevated levels of total serum IgG may reflect chronic inflammation in patients with CF and may lead to a specific arthropathy associated with this condition.

The authors concluded that joint symptoms in CF are a frequent and clinically relevant phenomenon with a distinct clinical pattern. Pulmonary exacerbations and elevated levels of total serum IgG may reflect chronic inflammation in patients with CF and may lead to a specific arthropathy associated with this condition.

From the CF Center / Charité – Universitätsmedizin Berlin, A

– The relationship to inflammation, presumably pulmonary, is supported by our earlier report of clearing of joint symptoms during intravenous antibiotic treatment of respiratory exacerbations in cystic fibrosis (Bowler IM, Littlewood JM. Episodic arthritis in cystic fibrosis. Lancet 1992;340(8813):244)

THE NEXT FOUR PAPERS ARE RELATED

Rosen BHEvans TIAMoll SRGray JSLiang BSun X Zhang YJensen-Cody CWSwatek AMZhou WHe NRotti PGTyler SRKeiser NWAnderson PJBrooks LLi YPope RMRajput MHoffman EAWang KHarris JKParekh KRGibson-Corley KNEngelhardt JF.  Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets.  Am J Respir Crit Care Med. 2018 May 15;197(10):1308-1318. doi: 10.1164/rccm.201708-1616OC.  [Pubmed]

Bradley Rosen

Classical interpretation of cystic fibrosis (CF) lung disease pathogenesis suggests that infection initiates disease progression, leading to an exuberant inflammatory response, excessive mucus, and ultimately bronchiectasis. Although symptomatic antibiotic treatment controls lung infections early in disease, lifelong bacterial residence typically ensues. Processes that control the establishment of persistent bacteria in the CF lung, and the contribution of non-infectious components to disease pathogenesis, are poorly understood.

This study was to evaluate whether continuous antibiotic therapy protects the CF lung from disease using a ferret model that rapidly acquires lethal bacterial lung infections in the absence of antibiotics.

CFTR (cystic fibrosis transmembrane conductance regulator)-knockout ferrets were treated with three antibiotics from birth to several years of age and lung disease was followed by quantitative computed tomography, BAL, and histopathology. Lung disease was compared with CFTR-knockout ferrets treated symptomatically with antibiotics.

The authors maintain these findings demonstrate that lifelong antibiotics can protect the CF ferret lung from infections for several years. Surprisingly, CF animals still developed hallmarks of structural bronchiectasis, neutrophil-mediated inflammation, and mucus accumulation, despite the lack of infection. Quantitative proteomics of BAL from CF and non-CF pairs demonstrated a muco-inflammatory signature in the CF lung dominated by Muc5B and neutrophil chemo-attractants and products.

The authors concluded these findings implicate muco-inflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.

Bradley H Rosen Department of Internal Medicine Carver College of Medicine, Iowa City.

[See précis of Jeffrey Wine’s editorial on these findings summarised below]

Wine JJ. How to live a long and healthy life with cystic fibrosis: Lessons from the CF ferret. J Cyst Fibros.  2019 Jan;18(1):8-9. doi: 10.1016/j.jcf.2018.10.005. Epub 2018 Oct 23.   [Pubmed]

[No abstract so précis below]

          Jeffrey Wine

Jeffrey Wine asks what is the role of infection in driving the rate of decline of lung function? Now, in a remarkable breakthrough, Bradley Rosen, John Engelhardt and their colleagues (Rosen BH et al, 2018) have kept CF ferrets alive and free of lung infections for over 3 years on average, while observing changes in lung structure and biology compared to yoked control animals. Their paper: Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets, presents multiple landmark discoveries that make the case that infection is not necessary for the development of “CF-like” lung disease [below]

Rosen et al. kept 7 CF ferrets alive and free of lung infections for 771–1471 days by careful attention to their GI problems and by daily injections of a cocktail of broad spectrum antibiotics. The CF ferrets had no lung infections as assessed by frequent lung lavages. But, they still developed mucus obstruction, bronchiectasis, and neutrophil dominated inflammatory lung disease.  In sum, at least in the CF ferret it appears that inflammation can precede infection when bacteria are held at bay with multiple antibiotics.

However, Jeffrey Wine notes there is much more to this paper, as indicated by the title of this editorial. The results also provide powerful evidence that prophylactic antibiotics dramatically increase the lifespan of CF ferrets.   In addition to the non-CF control group, Rosen et al. included a group of CF ferrets were given antibiotics symptomatically. The 10 ferrets treated with antibiotics symptomatically survived 105 ± 27 days, in contrast with survival of >1143 ± 77 days for the 7 ferrets treated prophylactically with a daily cocktail of three antibiotics. Thus prophylactic (“continuous”) treatment with a mixture of 3 antibiotics led to a > 10-fold increase in life span! That is exciting news! Nevertheless, it understates the effect of this intervention, because not one of the ferrets being treated with prophylactic antibiotics died from lung disease. Instead, they were sacrificed for 6 different presumptive causes (one was still alive at the time of publication) including heart failure, cholestasis, metastatic lymphoma, metastatic bile duct cancer, enlarged esophagus and accidental death.

Prophylactic antibiotics are controversial (indeed the term ‘continuous’ was used in this report), because it is argued they will lead to antibiotic resistance, but here again this report is groundbreaking—no resistance developed, and none of the ferrets treated had lung infections at time of death. These findings should hasten the adoption of adequate measures to prevent chronic lung infections in humans with CF.    Although no CF ferret treated with prophylactic antibiotics died of lung disease, the mucus plugging, inflammation and bronchiectasis documented in this study are serious concerns, especially given its rapid time course. So, preventing infections is necessary but not sufficient for lung health in CF—it is also essential to mobilize the mucus. This has been a mantra of CF care almost from the beginning. Importantly, these CF ferrets were not exposed to any interventions that might have helped them clear mucus, such as hypertonic saline or vigorous exercise (assuming they were housed in typical conditions

Professor Wine wonders if aggressive, preventative medicine regimens confer advantages to humans with CF? Limited data suggest they do, with improvements at least as dramatic as those seen in ferrets. (He refers to references on early eradication of P. aeruginosa and advantages of specialist CF centres)  Also he describes one patient whose aggressive treatment and progress over many years suggested this was the case.

The author suggests that the remarkable improvement in longevity demonstrated with prophylactic antibiotics should accelerate revisions in standard of care for CF humans to include early and sustained use of multiple, inhaled antibiotics, more aggressive promotion of mucus clearance, and improved protocols for eradication when required. Indeed, while these approaches once appeared to be radical, they can now be envisaged as simply an attempt to replace the natural mechanisms of healthy airways, which stay clean by secreting multiple antimicrobials into free-flowing mucus. Longer and healthier lives can be predicted—especially for those individuals with CF who will not benefit from CFTR modulators.

Jeffrey J Wine is the Benjamin Scott Crocker Professor of Human Biology at Stanford University.

Tsuchiya MKumar PBhattacharyya SChattoraj SSrivastava MPollard HBBiswas R.Differential regulation of inflammation by inflammatory mediators in cystic fibrosis lung epithelial cells.   J Interferon Cytokine Res. 2013 Mar;33(3):121-9. doi: 10.1089/jir.2012.0074. Epub  2013 Jan 4. [Pubmed]?23289731  
Cystic fibrosis (CF) is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause a massively pro-inflammatory phenotype in the CF airway. Discussed in the detailed abstract. The authors interpret these data to suggest that that CF lung epithelial cells respond to PA or bacterial cell products with a novel miR program that may carry with it serious challenges to survival.

– Jeffrey Wine quotes this paper to support the fact that when infection is held at bay with multiple antibiotics prognosis improves which he regards as welcome news for those who have long advanced that view

From School of Medicine, Bethesda, USA

Hoffman LRHajjar AM. Ferreting Out the Role of Infection in Cystic Fibrosis Lung Disease.  Am J Respir Crit Care Med. 2018 May 15;197(10):1243-1244. doi: 10.1164/rccm.201801-0053ED.  [Pubmed]

Lucas Hoffman

 The authors discuss the ongoing controversy of the role of infection in initiating and advancing airway disease in cystic fibrosis. Mentioning the Australian AREST study where there was a strong correlation between bacterial load and subsequent lung function decline, the relationship between symptoms and detectable infection was not perfect. They go on to discuss the findings of Rosen et al 2018 (described here).

Dr. Lucas R Hoffman is a paediatric pulmonologist at Seattle Children’s

Dr Adeline M Hajjar is Affiliate Associate Professor, Comparative Medicine, University of Washington

Roberts AEL, Powell LC, Pritchard MF, Thomas DW, Jenkins RE.  Anti-pseudomonad Activity of Manuka Honey and Antibiotics in a Specialized ex vivo Model Simulating Cystic Fibrosis Lung Infection.  Front Microbiol. 2019 Apr 24;10:869. doi: 10.3389/fmicb.2019.00869. eCollection 2019.[Pubmed]   Free PMC Article  

       Rowena Jenkins

Pseudomonas aeruginosa causes problematic chronic lung infections in those suffering from cystic fibrosis. This is due to its antimicrobial resistance mechanisms and its ability to form robust biofilm communities with increased antimicrobial tolerances. Using novel antimicrobials or repurposing current ones is required in order to overcome these problems. Manuka honey is a natural antimicrobial agent that has been used for many decades in the treatment of chronic surface wounds with great success, particularly those infected with P. aeruginosa. Here we aim to determine whether the antimicrobial activity of manuka honey could potentially be repurposed to inhibit pulmonary P. aeruginosa infections using two ex vivo models. P. aeruginosa isolates (n = 28) from an international panel were tested for their susceptibility to manuka honey and clinically relevant antibiotics (ciprofloxacin, ceftazidime, and tobramycin), alone and in combination, using conventional antimicrobial susceptibility testing (AST). To increase clinical applicability, two ex vivo porcine lung (EVPL) models (using alveolar and bronchiolar tissue) were used to determine the anti-biofilm effects of manuka honey alone and in combination with antibiotics. All P. aeruginosa isolates were susceptible to manuka honey, however, varying incidences of resistance were seen against antibiotics. The combination of sub-inhibitory manuka honey and antibiotics using conventional AST had no effect on activity against the majority of isolates tested. Using the two ex vivo models, 64% (w/v) manuka honey inhibited many of the isolates where abnormally high concentrations of antibiotics could not. Typically, combinations of both manuka honey and antibiotics had increased antimicrobial activity. These results highlight the potential of manuka honey as a future antimicrobial for the treatment of pulmonary P. aeruginosa isolates, clearing potential infection reservoirs within the upper airway.

Dr A E L Roberts, Department of Biomedical Sciences, Cardiff School of Health Sciences, Cardiff Metropolitan University, Cardiff, United Kingdom

Dr Rowena Jenkins is lecturer in Microbiology and Infectious Disease in the College of Medicine at Swansea University (from 2017).

Rosenfeld M, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Chilvers M, Higgins M, Tian S, Cooke J, Davies JC; KLIMB study group.   An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB) J Cyst Fibros. 2019 Apr 30. pii: S1569-1993(19)30061-X. doi: 10.1016/j.jcf.2019.03.009. [Epub ahead of print]  Free full text [Pubmed]
KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, the authors report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI.Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function.

All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters.

The authors concluded Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Dr Rosenfield is from Seattle Children’s Hospital

– With regard to the elevated LFTs the authors note that the lack of a placebo arm made interpretation difficult as to the cause – the ivacaftor itself, ascertainment bias due to increased monitoring or the natural tendency to elevated LFTs in this age group.

Rubin JLO’Callaghan LPelligra CKonstan MWWard AIshak JKChandler CLiou TG. Modeling long-term health outcomes of patients with cystic fibrosis homozygous for F508del-CFTR treated with lumacaftor/ivacaftor.
Ther Adv Respir Dis.
 2019 Jan-Dec;13:1753466618820186. doi: 10.1177/1753466618820186. 
Free PMC Article [Pubmed]

Long-term survival benefits of lumacaftor/ivacaftor (LUM/IVA) cannot yet be quantified. Simulation models can provide predictions about long-term health outcomes. In this study, we aimed to project long-term health outcomes of LUM/IVA plus standard care (SC) in patients with CF homozygous for F508del-CFTR.

This modelling study was an individual patient simulation in US patients aged ⩾6 years with CF, homozygous for F508del-CFTR. The primary outcome was projected survival among (a) a cohort of patients who ever initiated LUM/IVA, accounting for treatment discontinuations, and (b) a cohort of patients who remain on continuous LUM/IVA. Patient characteristics and model parameters were derived from clinical trials: VX14-809-109, VX13-809-011B, TRAFFIC/TRANSPORT, and PROGRESS; published literature; and the US CF Foundation Patient Registry.

Lumacaftor/ivacaftor + SC is expected to increase median survival by 6.1 years versus SC alone, accounting for treatment discontinuations. The incremental median predicted survival versus SC assuming initiation of LUM/IVA at ages 6, 12, 18, and 25 years was 17.7, 12.6, 8.0, and 3.8 years, respectively. Assuming lifetime treatment with LUM/IVA, incremental median survival was predicted to be 7.8 years longer in the LUM/IVA + SC cohort. Initiating LUM/IVA at ages 6, 12, 18, and 25 years and assuming lifetime treatment resulted in incremental median predicted survival of 23.4, 18.2, 11.0, and 4.8 years, respectively.

Lumacaftor/ivacaftor is projected to increase survival for patients with CF. Initiation at an early age and treatment persistence result in further increments in projected survival.

– A paper from staff at Vertex

Ruan JHirai HYang DMa LHou XJiang HWei HRajagopalan CMou HWang GZhang JLi KChen YESun FXu J. Efficient Gene Editing at Major CFTR Mutation Loci.Mol Ther Nucleic Acids. 2019 Feb 16;16:73-81. doi: 10.1016/j.omtn.2019.02.006. [Epub ahead of print]  Free full text [Pubmed]
Nuclease-mediated precise gene editing (PGE) represents a promising therapy for CF, for which an efficient strategy that is free of viral vector, drug selection, and reporter enrichment (VDR free) is desirable. Here the authors compared different transfection methods (lipofectamine versus electroporation) and formats (plasmid DNA versus ribonucleoprotein) in delivering the CRISPR/Cas9 elements along with single-stranded oligodeoxynucleotides (ssODNs) to clinically relevant cells targeting major CFTR mutation loci. They demonstrate that, among different combinations, electroporation of CRISPR/Cas9 and guide RNA (gRNA) ribonucleoprotein (Cas9 RNP) is the most effective one. By using this VDR-free method, 4.8% to 27.2% efficiencies were achieved in creating dF508, G542X, and G551D mutations in a wild-type induced pluripotent stem cell (iPSC) line. When it is applied to a patient-derived iPSC line carrying the dF508 mutation, a greater than 20% precise correction rate was achieved. As expected, genetic correction leads to the restoration of CFTR function in iPSC-derived proximal lung organoids, as well as in a patient-derived adenocarcinoma cell line CFPAC-1.                                                                                                                     The present work demonstrates the feasibility of gene editing-based therapeutics toward monogenic diseases such as CF.

– This is a comprehensive review of the position regarding gene editing and cystic fibrosis. The full free text is recommended.

From the Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, College of Animal Sciences & Technology, Huazhong Agricultural University, Wuhan, China.

Salvatore D, Carnovale V, Iacotucci P, Braggion C, Castellani C, Cimino G, Colangelo C, Francalanci M, Leonetti G, Lucidi V, Manca A, Vitullo P, Ferrara N.    Effectivenesss of ivacaftor in severe cystic fibrosis patients and non-G551D gating mutations.  Pediatr Pulmonol. 2019 Jun 25. doi: 10.1002/ppSul.24424. [Epub ahead of print]  [Pubmed]

        Donatello Salvatore

Ivacaftor is a significant innovation in the treatment of cystic fibrosis (CF) with gating mutations. A substantial percentage of patients with CF have severe lung involvement, but these patients are usually excluded from phase III clinical trials. Thus, the effectiveness of ivacaftor in this population has not been fully determined.   Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use programme (percent predicted [pp] forced expiratory volume in 1 second [FEV1 ] < 40%, or on lung transplant waiting list, or with a fast worsening trend of lung function). Data were collected for 1 year before and 1 year after ivacaftor commencement.

Thirteen patients received ivacaftor for a median of 320 days. Mean (SD) ppFEV1 increased from 35.1% (14.3%) before treatment to 46.6% (18.8%) after 12 months of treatment (absolute increase 11.5%, relative increase 32.8%). Mean distance of the 6-minute walking test improved significantly, from 535.1 m before to 611.6 m after 12 months of treatment (P = .002). The number of pulmonary exacerbations decreased significantly, from 57 during the year before ivacaftor to 28 in the year following ivacaftor (P = .0048). Five of the 13 patients (38.5%) had no exacerbations during the 12 months after starting ivacaftor. Median weight increased significantly, from 52.7 kg to 55.6 kg (P = .0031). Mean (SD) sweat chloride concentration decreased significantly, from 99.5 (22.8) mmol/L to 39.3 (15.8) mmol/L (P < .0001). No safety concerns were registered.

The authors concluded Ivacaftor was safe and effective in patients with CF with severe lung disease and non-G551D gating mutations.

Dr Donatello Salvatore is Director of the Cystic Fibrosis Center, Hospital San Carlo, Potenza, Italy.

Schmid-Mohler GCaress ALSpirig RBenden CYorke J. “Thrust out of normality”-How adults living with cystic fibrosis experience pulmonary exacerbations: A qualitative study. J Clin Nurs. 2019 Jan;28(1-2):190-200. doi: 10.1111/jocn.14646. Epub 2018 Aug 29.[Pubmed]

Gabriela Schmiid-Mohler

A study to explore the experience of pulmonary exacerbation from the perspective of adults with cystic fibrosis.  While management of pulmonary exacerbations is a pillar of cystic fibrosis care, little is known of patients’ perspectives.   The study took place from 2015-2016 in a university hospital. Eighteen patients with cystic fibrosis were included who were ≥18 years of age and had no solid organ transplant.

Patients (11 men and 7 women; median age 29.5 years, range 19-55 years; median FEV1 45%, range FEV1 23%-105%) experienced pulmonary exacerbations as disruptions of their normality, which led to a substantial increase in their emotional distress. Exacerbations represented a period of threat and domination by CF; that is, symptoms and treatment consumed energy, restricted physical activity and daily life roles. “Noting change,” “waiting until antibiotics help,” “returning to normality” and “establishing a new normality” characterised their descriptions of the pulmonary exacerbation trajectory. Emotional distress was the major driver for patients’ self-management, and personal goals and illness beliefs influenced also patients’ self-management decisions.

The experienced degree and source of emotional distress are drivers for self-management decisions in patients with cystic fibrosis who experience a pulmonary exacerbation.  The authors consider their data provide new understanding that will be essential to informing clinical practice, future patient-reported outcomes measures and intervention development.

Gabriela Schmid-Mohler, of the Centre for Clinical Nursing Zurich is an expert in advanced practice nursing and patient education

Shaw LPDoyle RMKavaliunaite ESpencer HBalloux FDixon GHarris KA. Children with cystic fibrosis are infected with multiple subpopulations of Mycobacterium abscessus with different antimicrobial resistance profiles.  Clin Infect Dis. 2019 Jan 26. doi: 10.1093/cid/ciz069. [Epub ahead of print]  [Pubmed]
Children with cystic fibrosis (CF) can develop life-threatening infections of Mycobacterium abscessus. These present a significant clinical challenge, particularly when the strains involved are resistant to antibiotics. Recent evidence of within-patient subclones of M. abscessus in adults with CF suggests the possibility that within-patient diversity may be relevant for the treatment of pediatric CF patients.

The authors performed whole genome sequencing (WGS) on 32 isolates of M. abscessus from multiple body sites for two patients with CF undergoing treatment at Great Ormond Street Hospital, UK, in 2015. They found evidence of extensive diversity within patients over time. Clustering analysis of single nucleotide variants (SNVs) revealed that each patient harboured multiple subpopulations, which were differentially abundant between sputum, lung samples, chest wounds, and pleural fluid. Sputum isolates did not reflect overall within-patient diversity, including failing to detect subclones with mutations previously associated with macrolide resistance (rrl 2058/2059). Some variants were present at intermediate frequencies before lung transplant. The time of transplant coincided with extensive variation, suggesting that this event is particularly disruptive for the microbial community, but transplant did not clear the M. abscessus infection and both patients died as a result of this infection.

So isolates of M. abscessus from sputum do not always reflect the entire diversity present within the patient, which can include subclones with differing antimicrobial resistance profiles. Awareness of this phenotypic variability, with sampling of multiple body sites in conjunction with WGS, may be necessary to ensure the best treatment for this vulnerable patient group.

Singh SB, McLearn-Montz AJ, Milavetz F, Gates LK, Fox C, Murry LT, Sabus A, Porterfield HS, Fischer AJ.Pathogen acquisition in patients with cystic fibrosis receiving ivacaftor or lumacaftor/ivacaftor.Pediatr Pulmonol. 2019 Apr 22. doi: 10.1002/ppul.24341. [Epub ahead of print] [Pubmed]
A single-center cohort of patients with CF was studied during two time periods (2008-2011, Era 1) and (2012-2015, Era 2) based on the January 2012 approval of ivacaftor. Using Kaplan-Meier analysis, we compared the time to any new infection with P. aeruginosa, methicillin-resistant S. aureus (MRSA), or methicillin-sensitive S. aureus (MSSA) that was absent during a 2-year baseline. We stratified the analysis based on whether patients received ivacaftor or lumacaftor/ivacaftor during Era 2. The authors used the log-rank test and considered P < 0.05 statistically significant.

For patients receiving ivacaftor or lumacaftor/ivacaftor in Era 2, there was a statistically significant delay in the time to new bacterial acquisition in Era 2 vs. Era 1 ( P = 0.008). For patients who did not receive CFTR modulators, there was a trend toward slower acquisition of new bacterial infections in Era 2 compared to Era 1, but this was not statistically significant ( P = 0.10).

The authors concluded patients receiving ivacaftor or lumacaftor/ivacaftor for CF had significantly delayed acquisition of P. aeruginosa and S. aureus after these drugs were released. They suggest this method for analysing incident infections may be useful for future studies of CFTR modulators and bacterial acquisition in CF registry cohorts.

Dr S B Singh is from the Sread Family Department of Pediatrics, UNiversity of Iowa Carver College of Medicine, Iowa.

Shawcross A, Murray CS, Pike K, Horsley A.  A novel method for infant multiple breath washout: First report in clinical practice.  Pediatr Pulmonol. 2019 Jun 18. doi: 10.1002/ppul.24384. [Epub ahead of print]   [Pubmed]

Lung clearance index (LCI), measured using multiple breath inert gas washout (MBW) is a potentially useful test in infants with respiratory disease, particularly cystic fibrosis (CF). Clinical use is limited however by the need for specialist staff and equipment. We have previously described a novel method for infant MBW suitable for use outside of specialist laboratories. This study describes its performance in vivo in infants with CF and healthy controls, including a limited comparison with the respiratory mass spectrometer.  Children aged less than 2 years with CF and controls underwent MBW testing on a single occasion. The practical applicability of the system was determined by the number of successful duplicate tests and within-subject repeatability.

Twenty-five children (seven with CF, 18 healthy controls, all sedated with chloral hydrate) attempted MBW. Twenty patients (seven with CF) successfully underwent duplicate testing (80% success rate). Mean within-subject coefficient of variation for functional residual capacity (FRC) was 7.2% and for LCI 5.9%. Comparison of LCI with the mass spectrometer was limited but gave very similar values for LCI and FRC in those patients who underwent technically adequate tests with both methods.

We have described a new MBW method that is feasible and reproducible in sedated infants. Results fall within the expected range, and well within accuracy limits set by international guidelines. This could provide a more accessible alternative to previously described systems for infant MBW, and overcomes many of the technical challenges inherent in conventional MBW

Dr Anna Shawcross is Clinical Research Fellow and Specialist Trainee in Paediatric Respiratory Medicine Manchester  and the Department of Paediatric Respiratory Medicine, Royal Manchester Children’s Hospital, Manchester, UK.

THE ORIGINAL PUBLICATION OF THIS METHOD –

Shawcross A, Murray CS, Goddard N, Gupta R, Watson S, Horsley.  Accurate lung volume measurements in vitro using a novel inert gas washout method suitable for infants.   Pediatr Pulmonol. 2016 May;51(5):491-7. doi: 10.1002/ppul.23348. Epub 2015 Dec 1    [Pubmed]
Multiple breath washout (MBW) in infants presents a number of technical challenges. Conventional MBW is based on simultaneous measurement of flow and gas concentrations. These two signals are aligned and combined to derive expired gas volumes from which lung volumes and measures of ventilation inhomogeneity are calculated. Accuracy of measurement becomes increasingly vulnerable to errors in gas signal alignment at fast respiratory rates. In this paper we describe an alternative method of performing MBW in infants. Expired gas is collected and analyzed to derive functional residual capacity (FRC) and lung clearance index (LCI). This eliminates the need for simultaneous measurement of flow, and integration of flow and gas signals, and significantly reduces deadspace.  A highly accurate lung model incorporating BTPS conditions was used to generate realistic infant breathing parameters: FRC of 100-250 mls with respiratory rate of 20-60 min(-1) . In vitro accuracy of FRC measurement using the novel MBW method was assessed using the model.     Overall mean error (standard deviation) of FRC measurement was -1.0 (3.3)% with 90% of tests falling within ±5%.

FRC measurement using the novel method has superior accuracy in vitro than previously described systems. By uncoupling the measurement of gas volumes from real-time flow and gas measurement, this system offers an alternative method of MBW which is well suited to infants.

Simpson T, Elston C, Macedo P, Perrin F.   Amyloidosis in cystic fibrosis.   Paediatr Respir Rev. 2019 May 7. pii: S1526-0542(19)30042-9. doi: 10.1016/j.prrv.2019.04.007. [Epub ahead of print]. [Pubmed]

      Caroline Elston

As the life expectancy of patients with cystic fibrosis has increased, greater attention has been paid towards the diagnosis and management of the longer term consequences of the condition. A recognised but rare complication of the disease is the development of secondary amyloidosis. Whilst deposition of amyloid protein has been reported in a high proportion of patients with cystic fibrosis at post-mortem [1] and Serum Amyloid A protein has been shown to correlate with disease activity and response to antibiotics [2], the manifestation of clinical disease remains extremely uncommon. The prognosis for patients with amyloid secondary to cystic fibrosis in published reports has been historically bleak [3-6], however there may be novel approaches in the era of biological therapies. The theoretical potential for an increase in the incidence of secondary amyloid amongst the population of cystic fibrosis patients who are experiencing much longer lifespans means that it is worthwhile to consider the condition and its possible treatments in more detail. We report a case and a review of the literature.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Dr Caroline Elston is Director of the Adult Cystic Fibrosis Service, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kin

Singh A, Lodha R, Shastri S, Sethuraman G, Sreedevi KN, Kabra M, Kabra SK. Aquagenic Wrinkling of Skin: A Screening Test for Cystic Fibrosis.  Indian Pediatr. 2019 Feb 15;56(2):109-113.  Free full text [Pubmed]                                                                                              To examine the utility of aquagenic wrinkling as screening test for children with cystic fibrosis.   A total of 64 children with cystic fibrosis, 64 controls and 64 carriers were enrolled in the study. Median (IQR) time to develop aquagenic wrinkling in the three groups was 2 (2.5,3) minutes, 4 (3,5) minutes and 8 (5,11) minutes, respectively. The optimal cut-off was calculated as 3 minutes by Receiver operating characteristic curve with a sensitivity and specificity for identification of children with cystic fibrosis as 81% and 57%, respectively. The area under curve was 76.5%. The 3 minute cut-off for development of aquagenic wrinkling was applied to 54 children referred for sweat test. 20 children had sweat chloride values of ≥60 mEq/l and diagnosed as cystic fibrosis. 15 of these developed aquagenic wrinkling at ≤3 minutes, giving a sensitivity of 75%.

The authors suggest that in places with no facility for sweat test, children with phenotype compatible with cystic fibrosis who develop aquagenic wrinkling in 3 minutes may be diagnosed as probable cystic fibrosis and referred for confirmation by sweat test.

 (Editorial)  Davies G., Aurora P. A Simple Screening Test for Cystic Fibrosis? Indian Pediatrics 2019; 56: 105 – 106 Free full text [Pubmed]  This editorial is a useful historical review of previous work on aquagenic skin wrinkling in CF discussing the obvious limitations as a diagnostic test. However, until sweat tests were generally available and “given that this situation is some way off, wrinkling test represents an extremely simple method of aiding clinical decision making when CF is considered clinically likely, and yet referral for sweat test is complicated by geographical, financial or accessibility constraints. However, for accurate diagnosis and treatment, and to improve population-wide data on the number of patients with CF in any country, the goal must remain for definitive diagnostic testing.” 

Dr Gwyneth Davies is Academic Clinical Lecturer at the Great Ormond Street Institute of Child Health

Somayaji RRussell RCogen JDGoss CHNick SESaavedra MTTaylor-Cousar JLNick JANichols DP.Oral Azithromycin Use and the Recovery of Lung Function from Pulmonary Exacerbations Treated with Intravenous Tobramycin or Colistimethate in Adults with Cystic Fibrosis.  Ann Am Thorac Soc. 2019 Jul; 16(7):853-860. [Pubmed]

     Ranjani Somayagi

The potential of azithromycin to alter the antimicrobial and clinical benefits of inhaled tobramycin in CF patients has been previously reported. The potential interaction between azithromycin and intravenous antibiotics in the treatment of pulmonary exacerbations is unknown. This study aims to determine if chronic azithromycin use as a concomitant therapy associated with change in lung function after receiving IV antibiotic regimens including tobramycin or colistimethate.

A retrospective cohort study evaluating the effect of azithromycin with IV tobramycin or colistimethate in adult CF patients treated for a pulmonary exacerbation. The primary outcome was relative lung function recovery (FEV1) following exacerbation treatment. Generalized estimating equations were applied to account for repeated events with independent correlation structures and robust standard errors, incorporating several confounders.

220 exacerbation events occurred in 121 patients in the tobramycin group (47% using azithromycin), and 207 exacerbation events occurred in 86 patients in the colistimethate group (59% using azithromycin). Azithromycin use was associated with less FEV1% recovery in patients treated with tobramycin (-3% relative FEV1% recovery [95% CI -7, 0.2] and -2.64% absolute FEV1% change [95% CI -4.52, -0.76]). Azithromycin use was associated with greater recovery of FEV1% when treated with colistimethate (+3% relative FEV1% recovery [95% CI -0.1, 7] and 2.00% absolute improvement in FEV1% [95% CI 0.13, 3.87]). The odds of 90% or 100% recovery to baseline FEV1% were lower with azithromycin use in the tobramycin cohort and higher with azithromycin use in the colistimethate cohort but were not statistically significant.

The authors concluded azithromycin use was associated with a more favourable response in patients treated with IV colistimethate but a less favourable response in patients treated with IV tobramycin.

– Not sure of the practical implications of these findings. Perhaps if it had previously been decided not to use azithromycin these results would not enourage one to start?

Dr Ranjani Somayaji is a lecturer at the University of Calgary, Medicine, Alberta. Canada

Sondo E, Falchi F, Caci E, Ferrera L, Giacomini E, Pesce E, Tomati V, Mandrup Bertozzi S, SGoldoni L, Armirotti A, Ravazzolo R, Cavalli A, Pedemonte N.    Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia. Cell Chem Biol. 2018 Jul 19;25(7):891-905.e8. doi: 10.1016/j.chembiol.2018.04.010. Epub 2018 May 10.   [Pubmed]

       Elvira Sondo

Among the known proteins associated with F508del-CFTR processing, the ubiquitin ligase RNF5/RMA1 is particularly interesting. The authors previously demonstrated that genetic suppression of RNF5 in vivo leads to an attenuation of intestinal pathological phenotypes in CF mice, validating the relevance of RNF5 as a drug target for CF. Here, they used a computational approach, based on ligand docking and virtual screening, to discover inh-02, a drug-like small molecule that inhibits RNF5. In in vitro experiments, treatment with inh-02 modulated ATG4B and paxillin, both known RNF5 targets. In immortalized and primary bronchial epithelial cells derived from CF patients homozygous for the F508del mutation, long-term incubation with inh-02 caused significant F508del-CFTR rescue. 

The authors suggest this work validates RNF5 as a drug target for CF, providing evidence to support its “druggability”.

[druggability = “a biological target that is known to or is predicted to bind with high affinity to a drug”]

– In 2018 Elvira Sondo first-authored a paper reporting the discovery of the first pharmacological modulator of the ubiquitin ligase RNF5. Indeed, previous works demonstrated that genetic suppression of RNF5 in vivo leads to an attenuation of intestinal pathological phenotypes in CF mice. Elvira used a computational approach to discover inh-02, a drug-like small molecule that inhibits RNF5 and is able to rescue F508del-CFTR processing defect in primary bronchial epithelial cells from patients with CF. This present work validates RNF5 as a drug target for CF, providing evidence to support its druggability. RNF5 inhibition in patients with CF and chronic lung infection could also have secondary beneficial effects, since RNF5 regulation of autophagy is involved in the innate host defence against bacterial infection.

Dr Elvira Sondo is at U.O.C. Genetica Medica, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, Genova 16147, Italy.

Spoletini GEtherington CShaw NClifton IJDenton MWhitaker PPeckham DG. Use of ceftazidime/avibactam for the treatment of MDR Pseudomonas aeruginosa and Burkholderia cepacia complex infections in cystic fibrosis: a case series. J Antimicrob Chemother. 2019 Jan 11. doi: 10.1093/jac/dky558. [Epub ahead of print]  [Pubmed]

Miles Denton & Daniel Peckham

 The efficacy of antibiotic treatment in pulmonary and systemic infections in cystic fibrosis (CF) is limited by the increased prevalence of MDR strains of Pseudomonas aeruginosa and Burkholderia cepacia complex. Ceftazidime/avibactam is a new combination which, in vitro, appears to have good activity against MDR strains of P. aeruginosa and B. cepacia complex.

A retrospective analysis was performed including adult patients with CF who received at least one course of ceftazidime/avibactam owing to pulmonary exacerbations not responding to conventional antibiotic treatment.  Treatment with ceftazidime/avibactam was associated with reduction in inflammatory markers and improvement in lung function. No episodes of acute kidney injury or elevation in transaminase were observed.

The authors conclude Ceftazidime/avibactam appeared to be well tolerated and improved patients’ outcomes. Further studies are needed to better assess the role of this new combination in CF.

Dr Miles Denton is consultant microbiologist and Professor Daniel Peckham is Director of the Leeds Adult Cystic Fibrosis Centre

Taylor-Cousar JL, Mall MA, Ramsey BW, McKone EF, Tullis E, Marigowda G, McKee CM, Waltz D, Moskowitz SM, Savage J, Xuan F, Rowe SM.Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles.ERJ Open Res. 2019 Jun 17;5(2). pii: 00082-2019. doi: 10.1183/23120541.00082-2019. eCollection 2019 Apr.  [Pubmed]        Free PMC Article

Jennifer Taylor-Cousar

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface. Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508delCFTR alleles. Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508delCFTR alleles.

Corresponding author Dr Steven Rowe, Gregory Flemming James Cystic Fibrosis Research Center, University of Alabama at Birmingham.A very comprehensive review of triple-combination CFTR modulators 

Timmers NKLM, Stellato RK, van der Ent CK, Houwen RHJ, Woestenenk JW.Vitamin D intake, serum 25-hydroxy vitamin D and pulmonary function in paediatric patients with cystic fibrosis: a longitudinal approach.  Br J Nutr. 2019 Jan;121(2):195-201. doi: 10.1017/S0007114518003021. Epub 2018 Nov 16. [Pubmed]  
The authors aimed to assess whether current vitamin D supplement recommendations are optimal for preventing deficiencies and whether higher serum 25(OH)D levels have long-term beneficial effects on pulmonary function. The authors examined the longitudinal relationship between vitamin D intake, serum 25(OH)D and PF in 190 CF children during a 4-year follow-up period. We found a significant relationship between total vitamin D intake and serum 25(OH)D (β = 0·02; 95 % CI 0·01, 0·03; P = 0·000). However, serum 25(OH)D decreased with increasing body weight (β = -0·79; 95 % CI -1·28, -0·29; P = 0·002). Furthermore, we observed a significant relationship between serum 25(OH)D and forced expiratory volume in 1 s (β = 0·056; 95 % CI 0·01, 0·102; P = 0·018) and forced vital capacity (β = 0·045; 95 % CI 0·008, 0·082; P = 0·017).

The authors conclude that in the present large study sample, vitamin D intake is associated with serum 25(OH)D levels, and adequate serum 25(OH)D levels may contribute to the preservation of PF in children with CF. Furthermore, to maintain adequate levels of serum 25(OH)D, vitamin D supplementation should increase with increasing body weight. Adjustments of the international CF nutritional guidelines, in which vitamin D supplementation increases with increasing weight, should be considered.