History – 2019 (Section 3 T-V)

Taccetti G, Denton M, Hayes K; ECFS-CTN Microbiology Group, Drevinek P, Sermet-Gaudelus I. Collaborators (10) A critical review of definitions used to describe Pseudomonas aeruginosa microbiological status in patients with cystic fibrosis for application in clinical trials. J Cyst Fibros. 2019 Sep 13. pii: S1569-1993(19)30867-7. doi: 10.1016/j.jcf.2019.08.014. [Epub ahead of print] [Pubmed]

Giovanni Taccetti

Definition of Pseudomonas aeruginosa (Pa) microbiological status is essential for patients’ inclusion in clinical trials. The aim of this study was to agree on the definitions of Pa infection status for initial infection, eradication and chronic infection to be used in clinical trials and to propose additional future study areas. An exhaustive literature search was performed. The clinimetric properties of different definitions of Pa microbiological status were evaluated.
Historical studies have mostly used culture-based definitions, although some have also involved complementary anti-Pa antibodies. Clinimetric analysis showed great variability in the definitions used, leading to differences in reliability, validity, responsiveness to treatment and correlation with outcome measures. Use of serology for initial Pa infection and successful Pa eradication introduced a greater level of complexity as antibody tests are not standardised. Moreover, the chronology of the immune response to Pa antigenic determinants was not completely clear. Chronic Pa infection was characterized by high levels of antibodies and good concordance between culture results and serology.

The authors concluded microbiological monitoring, regular sampling from the airways and standardization of culture methods remain essential requisites for microbiological definitions. Despite limitations, serology should be incorporated in the definitions of initial infection and eradication used in clinical trials to better classify patients at enrolment, mainly in non-expectorating children. This requires standardization of serological testing.

Dr G Taccetti G from the Cystic Fibrosis Centre, Anna Meyer Children’s University Hospital, Viale Pieraccini 24, Firenze 50139, Italy. Electronic address: g.taccetti@meyer.it.

– It is good that the authors recommend antibody testing but they are optimistic if they believe that, in the real world, CF centres will adopt PA antibody levels. These have been available for many decades but used by very few centres. There was always some objection raised to their use – usually lack of standardisation. The Leeds definition of PA infection has been widely used and is likely to continue to be used.

Talbot NP, Flight WG. Anaemia and iron deficiency in relation to fatigue in cystic fibrosis.    J Cyst Fibros. 2019 Jan;18(1):e5. doi: 10.1016/j.jcf.2018.08.002. Epub 2018 Sep 6.[Pubmed]

Nick Talbot

A letter commenting on the paper of Nap-Van Der Vlist, M.,et al.  Prevalence of severe fatigue among adults with cystic fibrosis: A single center study.  (J Cyst Fibros. 2018; 17: 368–374) reporting fatigue as a significant problem and discussing the possibility of iron deficiency as a factor

– The previous work on iron deficiency is discussed briefly and the variable results from iron supplement mentioned. A need for a trial intravenous iron is suggested as apparently this route is more effective in correcting anaemia in some other chronic conditions. Some of the recent work on iron deficiency is noted.  Nap-Van Der Vlist et al reply they did not have data on iron deficiency in their patients but agree such deficiency should be studied and part of the work-up of a fatigued patient with with cystic fibrosis. 

From the Nuffield Dept of Medicine Oxford and Oxford University Hospitals UK

Tangpricha VLukemire JChen YBinongo JNGJudd SEMichalski ESLee MJWalker SZiegler TR1Tirouvanziam RZughaier SMChesdachai SHermes WAChmiel JFGrossmann REGaggar AJoseph PMAlvarez JA.   Vitamin D for the Immune System in Cystic Fibrosis (DISC): a double-blind, multicenter, randomized, placebo-controlled clinical trial. 2019 Mar 1;109(3):544-553. doi: 10.1093/ajcn/nqy291. [Pubmed]

Vin Tangpritcha

The primary objective of this study was to examine the impact of a single high-dose bolus of vitamin D3 followed by maintenance treatment given to adults with CF during an acute pulmonary exacerbation on future recurrence of pulmonary exacerbations.  This was a multicenter, double-blind, placebo-controlled, intent-to-treat clinical trial. Subjects with CF were randomly assigned to oral vitamin D3 given as a single dose of 250,000 International Units (IU) or to placebo within 72 h of hospital admission for an acute pulmonary exacerbation, followed by 50,000 IU of vitamin D3 or an identically matched placebo pill taken orally every other week starting at 3 mo after random assignment. The primary outcome was the composite endpoint of the time to next pulmonary exacerbation or death within 1 y. The secondary outcomes included circulating concentrations of the antimicrobial peptide cathelicidin and recovery of lung function as assessed by the percentage of predicted forced expiratory volume in 1 s (FEV1%).RESULTS: A total of 91 subjects were enrolled in the study. There were no differences between the vitamin D3 and placebo groups in time to next pulmonary exacerbation or death at 1 y. In addition, there were no differences in serial recovery of lung function after pulmonary exacerbation by FEV1% or in serial concentrations of plasma cathelicidin

CONCLUSIONS: Vitamin D3 initially given at the time of pulmonary exacerbation of CF did not alter the time to the next pulmonary exacerbation, 12-mo mortality, serial lung function, or serial plasma cathelicidin concentrations. This trial was registered at clinicaltrials.gov as NCT01426256.

Vin Tangpricha is in the Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA.

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

Teopompi E, Risé P, Pisi R, Buccellati C, Aiello M, Pisi G, Tripodi C, Fainardi V, Clini E, Chetta A, Rovati GE, Sala A. Arachidonic Acid and Docosahexaenoic Acid Metabolites in the Airways of Adults With Cystic Fibrosis: Effect of Docosahexaenoic Acid Supplementation. Front Pharmacol. 2019 Aug 23;10:938. doi: 10.3389/fphar.2019.00938. eCollection 2019. Author information Free PMC article [Pubmed] Cystic fibrosis (CF) is an autosomal recessive disorder, caused by genetic mutations in CF transmembrane conductance regulator protein. Several reports have indicated the presence of specific fatty acid alterations in CF patients, most notably decreased levels of plasmatic and tissue docosahexaenoic acid (DHA), the precursor of specialized pro-resolving mediators. We hypothesized that DHA supplementation could restore the production of DHA-derived products and possibly contribute to a better control of the chronic pulmonary inflammation observed in CF subjects. Sputum samples from 15 CF and 10 chronic obstructive pulmonary disease (COPD) subjects were collected and analyzed by LC/MS/MS, and blood fatty acid were profiled by gas chromatography upon lipid extraction and transmethylation. Interestingly, CF subjects showed increased concentrations of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and 15-hydroxyeicosatetraenoic acid (15-HETE), when compared with COPD patients, whereas the concentrations of DHA metabolites did not differ between the two groups. After DHA supplementation, not only DHA/arachidonic acid (AA) ratio and highly unsaturated fatty acid index were significantly increased in the subjects completing the study (p < 0.05) but also a reduction in LTB4 and 15-HETE was observed, together with a tendency for a decrease in PGE2, and an increase in 17-hydroxy-docosahexaenoic acid (17OH-DHA) levels. At the end of the washout period, LTB4, PGE2, 15-HETE, and 17OH-DHA showed a trend to return to baseline values. In addition, 15-HETE/17OH-DHA ratio in the same sample significantly decreased after DHA supplementation (p < 0.01) when compared with baseline. In conclusion, the authors results show here that in CF patients, an impairment in fatty acid metabolism, characterized by increased AA-derived metabolites and decreased DHA-derived metabolites, could be partially corrected by DHA supplementation. Dr Elisabetta Teopompi is in the Respiratory Disease Unit, Department of Medicine and Surgery, University Hospital, Parma, Italy.Most of the data reported were first incorporated in the PhD thesis work of the first author, E. Teopompi, – Essential fatty acid abnormalities in CF and their correction has been a recurring subject since the studies Kuo et al in the Sixties and of Bob Elliott in New Zealand in the Seventies (see appropriate section Sixties and Seventies). Interest returned with the publications of SD Freedman in 1999 and 2004. This work and other EFA therapy has not been established as beneficial in people with CF nor has the work had a major impact on the understanding of or treatment of CF as was hoped when reported in 1999. For review of some previous work see Topics -> Fatty acids where much of the previous work is reviewed.

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.

Tan SMJ, Coffey MJ, Ooi CY.  Differences in clinical outcomes of paediatric cystic fibrosis patients with and without meconium ileus. J Cyst Fibros. 2019 Oct 28. pii: S1569-1993(19)30892-6. doi: 10.1016/j.jcf.2019.09.008. [Epub ahead of print] [Pubmed]
Meconium ileus (MI) affects up to 20% of newborns with cystic fibrosis (CF). The authors compared clinical outcomes between Australian paediatric CF patients with and without meconium ileus (non-MI).   There were 162 matched pairs (N=324, 52% female) with mean (SD) age of 15.3 (8.2) and 14.9 (7.9) years for MI and non-MI patients respectively (P=0.6).
MI patients aged 5-23 had poorer FEV1% compared to non-MI patients (estimate -0.070 SE [0.02], P=0.003). There were no significant differences in P. aeruginosa isolation rates; however S. aureus isolation rates were lower in MI patients (72%) compared to non-MI (82%) (OR 0.6 [0.3-1.0], P=0.03). Chronic colonisation rates for P. aeruginosa and S. aureus were not significantly different between groups.   MI patients aged 2-20 had significantly lower BMI Z-scores over time (estimate -0.25 SE [0.1], P=0.02). MI patients were more likely to receive oral feed supplements (OR 2.8 [1.4-6.1], P=0.003) and gastrostomy formation (OR 4.4 [1.1-24.6], P=0.02).

The authors concluded CF patients with MI may have worse lung function, growth and nutrition than non-MI patients over time. Meconium ileus may be an early poor prognostic factor for CF.

– There is much previous work supporting the fact that infants with MI seem to have a more severe manifestations of their CF – one being in their growth. Previous work is reviewed clearly in this article. MI seems to “mark the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene” (Dupuis et al 2016)

From the Department of Gastroenterology, Sydney Children’s Hospital, High Street, Randwick NSW 2031, Australia.

Tangpricha VLukemire JChen YBinongo JNGJudd SEMichalski ESLee MJWalker SZiegler TRTirouvanziam RZughaier SMChesdachai SHermes WAChmiel JFGrossmann REGaggar AJoseph PMAlvarez JA.Vitamin D for the Immune System in Cystic Fibrosis (DISC): a double-blind, multicenter, randomized, placebo-controlled clinical trial. Am J Clin Nutr. 2019 Mar 1;109(3):544-553. doi: 10.1093/ajcn/nqy291. [Pubmed] 

Patients with cystic fibrosis (CF) have increased risk of vitamin D deficiency owing to fat malabsorption and other factors. Vitamin D deficiency has been associated with increased risk of pulmonary exacerbations of CF.  The primary objective of this study was to examine the impact of a single high-dose bolus of vitamin D3 followed by maintenance treatment given to adults with CF during an acute pulmonary exacerbation on future recurrence of pulmonary exacerbations.

This was a multicenter, double-blind, placebo-controlled, intent-to-treat clinical trial. Subjects with CF were randomly assigned to oral vitamin D3 given as a single dose of 250,000 International Units (IU) or to placebo within 72 h of hospital admission for an acute pulmonary exacerbation, followed by 50,000 IU of vitamin D3 or an identically matched placebo pill taken orally every other week starting at 3 months after random assignment. The primary outcome was the composite endpoint of the time to next pulmonary exacerbation or death within 1 year. The secondary outcomes included circulating concentrations of the antimicrobial peptide cathelicidin and recovery of lung function as assessed by the percentage of predicted forced expiratory volume in 1 s (FEV1%).

A total of 91 subjects were enrolled in the study. There were no differences between the vitamin D3 and placebo groups in time to next pulmonary exacerbation or death at 1 y. In addition, there were no differences in serial recovery of lung function after pulmonary exacerbation by FEV1% or in serial concentrations of plasma cathelicidin.

The authors concluded that vitamin D3 initially given at the time of pulmonary exacerbation of CF did not alter the time to the next pulmonary exacerbation, 12-mo mortality, serial lung function, or serial plasma cathelicidin concentrations.

Dr Vin Tangpricha is Professor of Medicine Emory University and Distinguished Physician Emory University School of Medicine.

Terlizzi V, Mergni G, Buzzetti R, Centrone C, Zavataro L, Braggion C.   Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy.J Cyst Fibros. 2019 Apr 17. pii: S1569-1993(18)30815-4. doi: 10.1016/j.jcf.2019.04.002. [Epub ahead of print]  [Pubmed]
The implementation of cystic fibrosis (CF) newborn screening (NBS) has led to identification of infants with a positive NBS test but inconclusive diagnosis classified as “CF screen positive, inconclusive diagnosis” (CFSPID). We retrospectively evaluated the prevalence and clinical outcome of CFSPID infants diagnosed by 2 NBS algorithms in the period from 2011 to 2016 in the Tuscany region of Italy.   In 2011-2016, we assessed the diagnostic impact of DNA analysis on the NBS 4-tier algorithm [immunoreactive trypsin (IRT) – meconium lactase – IRT2 – sweat chloride (SC)]. All CFSPID patients repeated SC testing every 6 months, and CFTR gene analysis was performed (detection rate 98%). We reclassified children as: CF diagnosis in presence of at least 2 pathological SC results; healthy carrier or healthy in presence of at least 2 normal SC results for age and either 1 or 0 CF-causing mutations, respectively.

The authors identified 32 CF and 50 CFSPID cases: 20/50 (40%) were diagnosed only by the IRT-DNA-SC algorithm and 16/50 (32%) only by IRT-meconium lactase-IRT2-SC. Both protocols identified the remaining 14 cases (28%). Thirty-seven of 50 (74%) CFSPID patients had a conclusive diagnosis on December 31, 2017:5 (10%) CF, 17 (34%) healthy and 15 (30%) healthy carriers; 13/50 (26%) cases were asymptomatic with persistent intermediate SC and followed as CFSPID (CF:CFSPID ratio 2.85:1).

The authors concluded that in 6 years, the CF:CFSPID ratio modified from 0.64:1 to 2.85:1, and 10% of CFSPID cases progressed to CF. Genetic analysis improved positive predictive value and identified a higher number of CFSPID infants progressing to CF.

Cystic Fibrosis Centre, Department of Paediatric Medicine, Anna Meyer Children’s University Hospital, Florence, Italy. Electronic address: terlizzivito@libero.it.

Dr V Terlizzi is a paediatrician at the Cystic Fibrosis Centre, Meyer Children’s Hospital Florence, Italy

Toledano MBMukherjee SKHowell JWestaby DKhan SA Bilton DSimmonds NJThe emerging burden of liver disease in cystic fibrosis patients: A UK nationwide study.PLoS One. 2019 Apr 4;14(4):e0212779. doi: 10.1371/journal.pone.0212779. eCollection  2019.   Free full text  [Pubmed]

      Mirabelle Toledano

Cystic fibrosis associated liver disease (CFLD) is the third largest cause of mortality in CF. Our aim was to define the burden of

Sujit Mukherjee

CFLD in the UK using national registry data and identify risk factors for progressive disease.  A longitudinal population-based cohort study was conducted. Cases were defined as all patients with CFLD identified from the UK CF Registry, 2008-2013 (n = 3417). Denominator data were derived from the entire UK CF Registry. The burden of CFLD was characterised. Regression analysis was undertaken to identify risk factors for cirrhosis and progression.

Prevalence of CFLD increased from 203.4 to 228.3 per 1000 patients during 2008-2013. Mortality in CF patients with CFLD was more than double those without; cirrhotic patients had higher all-cause mortality (HR 1.54, 95% CI 1.09 to 2.18, p = 0.015). Median recorded age of cirrhosis diagnosis was 19 (range 5-53) years. Male sex, Pseudomonas airway infection and CF related diabetes were independent risk factors for cirrhosis. Ursodeoxycholic acid use was associated with prolonged survival in patients without cirrhosis.

The authors concluded their study highlights an important changing disease burden of CFLD. The prevalence is slowly increasing and, importantly, the disease is not just being diagnosed in childhood. Although the role of ursodeoxycholic acid remains controversial, this study identified a positive association with survival.

 Professor Mireille B Toledano  is an epidemiologist at MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom and holds the Chair in Perinatal and Paedaitric Environmental Epidemiology.

Dr Sujit K Mukherjee is Clinical Research Fellow, Section of Hepatology and Gastroenterology, Imperial College London.

Toprak D, Davis C, Rosenfeld M.  Treating the Airway Consequences of Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction. Semin Respir Crit Care Med. 2019 Oct 28. doi: 10.1055/s-0039-1698462. [Epub ahead of print][Pubmed]

         Demet Toprak

In cystic fibrosis (CF), absent or dysfunctional CF transmembrane conductance regulator (CFTR) on the surface of airway epithelial cells causes abnormal mucociliary clearance, leading to chronic endobronchial infection and inflammation, in turn resulting in life-shortening progressive obstructive lung disease and structural airway damage. Fortunately, CF-specific therapies have been developed that improve lung function and reduce pulmonary exacerbations, contributing significantly to improved survival over the past 4 decades. Therapies not originally developed for CF, such as bronchodilators and corticosteroids, are also widely used by people living with CF. Therapies to be reviewed in this article include mucolytics, airway surface liquid hydrators, anti-inflammatory medications, bronchodilators, inhaled and oral antibiotics, and airway clearance techniques. Determining which therapies to utilize can be challenging, as there is variable evidence for each treatment, differing national guidelines, few head-to-head studies, potential for drug-drug interactions, and synergistic toxicities, as well as issues with burden of care. In this review, the authors summarize the mechanism of action and available evidence, and compare national guidelines for each major medication used to treat the airway consequences of CFTR dysfunction.

  Dr Demet Toprak is an Assistant Professor in the Department of Pediatrics, Division of Pulmonary and Sleep Medicine, Seattle Children’s Hospital, Seattle, Washington.

VanDevanter DR, Gonda I, Dahms J, Cipolla D, Davis AM, Chalmers JD, Froehlich J.  Microbiologic changes observed over 48 weeks of treatment with inhaled liposomal ciprofloxacin in subjects with non-cystic fibrosis bronchiectasis and chronic Pseudomonas aeruginosa lung infection.  Clin Microbiol Infect. 2019 Apr 26. pii: S1198-743X(19)30194-6. doi: 10.1016/j.cmi.2019.04.017. [Epub ahead of print]  [Pubmed]

Donald (“Dutch”) VanDeventer

Non-cystic fibrosis bronchiectasis (NCFBE) with Pseudomonas aeruginosa (Pa) has been associated with increased pulmonary exacerbation (PEx) and mortality risk. European Respiratory Society guidelines conditionally recommend inhaled antimicrobials for persons with NCFBE, Pa, and ≥3 PEx/year. We report microbiologic results of two randomized, 48-week placebo-controlled trials of ARD-3150 (inhaled liposomal ciprofloxacin) in NCFBE subjects with Pa and PEx history [Lancet Respir Med 2019;7:213-26].

Respiratory secretions from 582 subjects receiving up to six 28-day on/off treatment cycles were analyzed for sputum Pa, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Escherichia coli densities, Pa susceptibilities to ciprofloxacin and nine other antimicrobials, and prevalence of other bacterial opportunists. Associations between PEx risk and sputum density, antimicrobial susceptibility, and opportunist prevalence changes were studied.

Sputum Pa density reductions from Baseline after ARD-3150 treatments ranged from 1.77 [95%CI 2.13, 1.40] versus 0.54 [0.89, 0.19] log10CFU/gram for placebo (second period) to 2.07 [2.45, 1.69] versus 0.70 [1.11, 0.29] log10CFU/gram for placebo (fourth period) with only modest correlation between density reduction magnitude and PEx benefit. ARD-3150 (but not placebo) treatment was associated with increased Pa ciprofloxacin minimum inhibitory concentrations (MICs) but not emergence of other bacterial opportunists across the study; ciprofloxacin MIC50 increased from 0.5 to 1 mcg/mL, MIC90 increased from 4 to 16 mcg/mL. Other antimicrobial MICs were mostly unaffected.

The authors concluded microbiologic changes over 48 weeks of ARD-3150 treatment appear modest. Ciprofloxacin (but not other antimicrobial) susceptibility decreases were observed that did not appear to preclude PEx risk reduction benefit.

Dr Donald (“Dutch”) VanDevanter is a research scientist at Case Western Reserve University School of Medicine, Cleveland OH USA.

van Heusden C, Button B, Anderson WH, Ceppe A, Morton LC, O’Neal WK, Dang H, Alexis NE, Donaldson SH, Stephan H, Boucher RC, Lazarowski ER.  Inhibition of ATP hydrolysis restores airway surface liquid production in cystic fibrosis airway epithelia.  Am J Physiol Lung Cell Mol Physiol. 2019 Dec 4. doi: 10.1152/ajplung.00449.2019.[Pubmed]
Airway surface dehydration is a pathological feature of cystic fibrosis (CF) lung disease. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated Cl- channel controlled in part by the adenosine A2B receptor. An alternative, CFTR-independent mechanism of fluid secretion is regulated by ATP, via the P2Y2 receptor (P2Y2R) that activates Ca2+-regulated Cl- channels (CaCC/TMEM16) and inhibits Na+ absorption. However, due to rapid ATP hydrolysis, steady-state ATP levels in CF airway surface liquid (ASL) are inadequate to maintain P2Y2R-mediated fluid secretion. Therefore, inhibiting airway epithelial ecto-ATPases to increase ASL ATP levels constitutes a strategy to restore airway surface hydration in CF. Using [γ32P]ATP as radiotracer, we assessed the effect of a series of ATPase inhibitory compounds on the stability of physiologically occurring ATP concentrations. We identified the polyoxometalate [Co4(H2O)2(PW9O34)2]10- (POM-5) as the most potent and effective ecto-ATPase inhibitor in CF airway epithelial cells. POM-5 caused long-lasting inhibition of ATP hydrolysis in airway epithelia, which was reversible upon removal of the inhibitor. Importantly, POM-5 markedly enhanced steady-state levels of released ATP, promoting increased ASL volume in CF cell surfaces. These results provide proof-of-concept for ecto-ATPase inhibitors as therapeutic agents to restore hydration of CF airway surfaces. As a test of this notion, cell-free sputum supernatants from CF subjects were studied and found to have abnormally elevated ATPase activity, which was markedly inhibited by POM-5.

From the University of North Carolina at Chapel Hill

van Koningsbruggen-Rietschel S, Conrath K, Fischer R, Sutharsan S, Kempa A, Gleiber W, Schwarz C, Hector A, Van Osselaer N, Pano A, Corveleyn S, Bwirire D, Santermans E, Muller K, Bellaire S, Van de Steen O.  GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN).   J Cyst Fibros. 2019 Oct 5. pii: S1569-1993(19)30890-2. doi: 10.1016/j.jcf.2019.09.006. [Epub ahead of print] [Pubmed]

Silke van Koningsbruggen

Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy.    This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics.

Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected.

GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination.

Dr Silke van Koningsbruggen-Rietschel  is at the Cystic Fibrosis Center, Children’s Hospital, University of Cologne, Faculty of Medicine and University Hospital Cologne, Germany. Electronic address: Silke.vanKoningsbruggen@uk-koeln.de.

Van Stormbroek BZampoli MMorrow BM. Nebulized gentamicin in combination with systemic antibiotics for eradicating early Pseudomonas aeruginosa infection in children with cystic fibrosis.  Pediatr Pulmonol. 2019 Jan 18. doi: 10.1002/ppul.24254. [Epub ahead of print]  Full text available [Pubmed]

          Brenda Morrow

Chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) can be prevented with early eradication treatment. In resource-constrained environments, low-cost, off-label nebulized antibiotics, including intravenous gentamicin solution, are often used for eradication therapy. This study aimed to describe the characteristics and clinical course of children with CF and early Pa infection, treated with a Pa eradication protocol combining inhaled gentamicin and systemic antibiotics.

All children (0-18 years) attending a CF clinic in South Africa, with early Pa infections between January 2005 and March 2015, who received nebulized gentamicin-based Pa eradication treatment.  Data were described and compared between those with successful versus unsuccessful eradication, using descriptive and inferential statistics appropriate to normality of distribution.

One hundred and forty-nine children were managed in the CF Clinic over the study period, of whom 44 (29.5%; 28 [63.6%] male) had early Pa infections treated with a gentamicin-based eradication regimen. Thirty-nine (88.6%) patients had successful Pa eradication at 12 months follow-up; of which 28 (71.8%) had Pa reinfection at a median of 37.0 (21.0-101.0) months after initial treatment. Six patients (13%) acquired chronic Pa infection during the median follow-up period of 77 months. Older age was associated with Pa eradication failure and chronic Pa infection. There were no clinically significant adverse events associated with gentamicin inhalational therapy.

The authors concluded nebulized gentamicin solution combined with systemic antibiotics appears to be safe and has comparable efficacy to other strategies in eradicating early Pa infections in children with CF.

Corresponding author is Professor Brenda Morrow in the Department of Child and Adolescent Health, University of Cape Tow

– This is a useful record of experience. It is worth noting that the Heinzl B et al 2002 Austrian study of long term inhaled gentamicin from 1986-1999 (started soon after our 1985 letter to the Lancet regarding colomycin) although effective was stopped in some children due to concerns about rising urinary NAG values reflecting renal toxicity. (Ring E, et al. Urinary N-acetyl-beta-D-glucosaminidase activity in patients with cystic fibrosis on long term gentamicin inhalation. Arch Dis Child 1998; 78:540-543).    Nebulised gentamicin in currently recommended by the British Thoracic Society for non-CF bronchiectasis but a serum creatinine and urea are recommended on commencing and every 12 months.

van Straten MBrody ASErnst CGuillerman RPTiddens HAWMNagle SK. Guidance for computed tomography (CT) imaging of the lungs for patients with cystic fibrosis (CF) in research studies. J Cyst Fibros. 2019 Sep 16. pii: S1569-1993(19)30886-0. doi: 10.1016/j.jcf.2019.09.001. [Epub ahead of print]   [Pubmed]

Marcel van Straten

Numerous issues must be addressed when developing standard operating procedures for clinical research studies involving chest computed tomography of lung disease in patients with cystic fibrosis (CF). Study success depends on the provision of adequate funding and the identification of personnel with the necessary expertise to conduct the study, along with clear guidelines that detail the CT operating procedure at each site, including breathing maneuvers, and image reconstruction. Close coordination of the quality assurance process between sites and the central review organization is required to maintain protocol adherence. The data transfer process must ensure the integrity and security of the data to comply with patient privacy regulations, and study outcome measures are best assessed with a scoring system or other structured method of imaging data analysis. The recommendations provided are designed to serve as a valuable reference guide for planning clinical research studies of patients with CF involving chest CT.

Dr Marcel van Straten is Assistant Professor and Principal Investigator of Physics in CT Technology, Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands

Varrassi G, Pergolizzi JV, Dowling P, Paladini A.  Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review.Adv Ther. 2019 Nov 8. doi: 10.1007/s12325-019-01144-9. [Epub ahead of print]  [Pubmed]

    Giustino Varrassi

Ibuprofen first came to market about 50 years ago and rapidly moved to over-the-counter (OTC) sales. In April 2019, the National Agency for the Safety of Medicines and Health Products (ANSM) of France issued a warning for NSAID uses by patients with infectious diseases based on an analysis of 20 years of real-world safety data on ibuprofen and ketoprofen. Nevertheless, ibuprofen remains a mainstay in the analgesic armamentarium and with numerous randomized clinical trials, head-to-head studies, and decades of clinical experience. The authors offer a review of the safety of ibuprofen and how it may differ from other NSAIDs. Ibuprofen is associated with certain well-known gastrointestinal adverse effects that are related to dose and patient population. Among nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen has a comparatively low risk of cardiovascular adverse effects. It has been associated with renal and hepatic adverse effects, which appear to depend on dose, concomitant medications, and patient population. The association of ibuprofen with infections is more complex in that it confers risk in some situations but benefits in others, the latter in cystic fibrosis. Emerging interest in the literature is providing evidence of the role of ibuprofen as a possible endocrine disrupter as well as its potential antiproliferative effects for cancer cells. Taken altogether, ibuprofen has a favorable safety profile and is an effective analgesic for many acute and chronic pain conditions, although it-like other NSAIDs-is not without risk. After 50 years, evidence is still emerging about ibuprofen and its unique safety profile among NSAIDs. 

Dr Giustino Varassi is President of the World Institute of Pain and specialist in emergency medicine. Widely published on topics relating to pain.

– Ibuprofen has been recommended in cystic fibrosis as an anti-inflammatory (see Topics -> steroids and anti-inflammatories ->NSAID -> ibuprofen) but is not widely used.