History – 2019 (Section 3)

 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 meconiuTan SMJm 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 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.

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.

Wakabayashi-Nakao K, Yu Y, Nakakuki M, Hwang TC, Ishiguro H, Sohma Y. Characterization of Δ(G970-T1122)-CFTR, the most frequent CFTR mutant identified in Japanese cystic fibrosis patients.  J Physiol Sci. 2019 Jan;69(1):103-112. doi: 10.1007/s12576-018-0626-4. Epub 2018 Jun 27. [Pubmed]
A massive deletion over three exons 16-17b in the CFTR gene was identified in Japanese CF patients with the highest frequency (about 70% of Japanese CF patients definitely diagnosed). This pathogenic mutation results in a deletion of 153 amino acids from glycine at position 970 (G970) to threonine at 1122 (T1122) in the CFTR protein without a frameshift. We name it Δ(G970-T1122)-CFTR. In the present study, we characterized the Δ(G970-T1122)-CFTR expressed in CHO cells using immunoblots and a super resolution microscopy. Δ(G970-T1122)-CFTR proteins were synthesized and core-glycosylated but not complex-glycosylated. This observation suggests that the Δ(G970-T1122) mutation can be categorized into the class II mutation like ΔF508. However, VX-809 a CFTR corrector that can help maturation of ΔF508, had no effect on Δ(G970-T1122). Interestingly C-terminal FLAG tag seems to partially rescue the trafficking defect of Δ(G970-T1122)-CFTR; however the rescued Δ(G970-T1122)-CFTR proteins do not assume channel function. Japanese, and perhaps people in other Asian nations, carry a class II mutation Δ(G970-T1122) with a higher frequency than previously appreciated. Further study of the Δ(G970-T1122)-CFTR is essential for understanding CF and CFTR-related diseases particularly in Asian countries.

K Wakabayashi-Nakao K was at the Dept. of Pharmaceutical Sciences and Center for Medical Sciences, International University of Health and Welfare Tochigi, Japan and more recently at Epsilon Molecular Engineering Inc.