History – 2019

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.

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.

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.

Walicka-Serzysko KPostek MMilczewska J, Sands D. Change in lung clearance index with microbiological status in children with cystic fibrosis.Pediatr Pulmonol. 2019 Mar 5. doi: 10.1002/ppul.24278. [Epub ahead of print]   [Pubmed]

Katarzyna Walicka- Serzysko

The impact of infections caused by bacteria, especially Gram-negative, on the progression of lung disease in cystic fibrosis is well established. Decline in pulmonary function commence already at early age. In this group of patients, the lung clearance index seems to be a better marker than FEV1 allowing non-invasive monitoring of changes in small airways.

The aim of this study was to investigate the association between the microbiological status and LCI derived from multiple breath washout (MBW) technique as well as FEV1 and FVC in children suffering from cystic fibrosis. Over the 1-year recruitment period, 136 CF patients aged 5-18 with: Staphylococcus aureus (n-27), Pseudomonas aeruginosa (first time (n-27), intermittent (n-9), and chronic (34) infection), Aspergillus fumigatus (n-6) and without pathogenic flora (n-33) were included in the study. Patients had performed a spirometry and MBW test during the visit at outpatient clinic.

The study showed that the lung clearance index in patients infected with Aspergillus fumigatus was significantly higher (P < 0.05) than in those with normal throat flora. There were also statistically significant differences in the lung clearance index obtained in subjects with chronic Pseudomonas aeruginosa infection and those with first Pseudomonas aeruginosa infection (P < 0.05). Furthermore, significant statistical differences (P < 0.05) were observed between the groups of patients with chronic Pseudomonas aeruginosa infection FEV1 > 70% and FEV1 < 70%. In conclusion, LCI was associated with microbiological status of CF patients. Chronic lung infections, especially Aspergillus fumigatus and Pseudomonas aeruginosa, were associated with increased LCI. Early eradication of pathological flora positively affects the maintenance of lower LCI.

Katarzyna Walicka-Serzysk is from Cystic Fibrosis Department Institute of Mother and Child Warsaw and Cystic Fibrosis Centre, Pediatric Hospital, Dziekandw Lesny, Poland

Walker S, Flume P, McNamara J, Solomon M, Chilvers M, Chmiel J, Harris RS, Haseltine E, Stiles D, Li C, Ahluwalia N, Zhou H, Owen CA, Sawicki G; VX15-661-113 Investigator Group.   A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. J Cyst Fibros. 2019 Jun 25. pii: S1569-1993(19)30813-6. doi: 10.1016/j.jcf.2019.06.009. Free full text [Epub ahead of print]  [Pubmed
Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations.

Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score.

After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks.

Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.Tezacaftor/ivacaftor treatment improved SwCl levels and CFQ-R respiratory domain child version scores, and lung function and normal growth were maintained over 24 weeks. These results support tezacaftor/ivacaftor as an alternative treatment option to CFTR modulators previously approved in children aged 6 through 11 years with CF and F/F and F/RF genotypes in the United States. These results also support tezacaftor/ivacaftor as a new treatment option for children aged 6 through 11 years with CF and F/RF genotypes in regions that currently lack a CFTR modulator for the treatment of this population.

Dr Seth Walker  (figure) is a pulmonologist affiliated with University Hospitals of Cleveland, Cleveland Medical Center, Rainbow Babies and Children’s Hospital, Cleveland.USA

Warrier R, Skoric B, Vidmar S, Carzino R, Ranganathan S.The role of geographical location and climate on recurrent Pseudomonas infection in young children with Cystic Fibrosis.  J Cyst Fibros. 2019 Apr 24. pii: S1569-1993(19)30072-4. doi: 10.1016/j.jcf.2019.04.013. [Epub ahead of print]  [Pubmed]
A study to determine the association between residence and climate with risk of Pseudomonas aeruginosa (Pa) and other respiratory outcomes.  Regular bronchoalveolar lavage and upper airway cultures were performed in young children with CF to identify Pa infection. Children were classified for residence as regional or metropolitan. Bronchiectasis was detected on periodic chest computed tomography scans. Multilocus sequence typing determined Pa genotype. Lung function was assessed using Multiple Breath Washout.

Of infants diagnosed with CF between 2006 and 2017, 129 were included in the study. There was weak evidence of a 15% increase in the rate of Pa episodes with increasing average annual maximum temperature, while the rate of Pa acquision decreased with average annual 3 pm humidity. The rate of Pa episodes was 2.1 times higher in regional participants (95%CI (1.4, 3.1); p = .001) and risk of second episode was more than five times greater (HR 5.7; 95%CI 1.9, 17); p = .002). No difference between regions in lung clearance index and presence of bronchiectasis was detected.

The authors concluded regional residence (as opposed to metropolitan) is associated with risk of acquiring recurrent infection with Pseudomonas aeruginosa in young children with CF.

Dr Ranjani Warrier is a PhD student at the Department of Respiratory Medicine, Royal Children’s Hospital, Victoria, Australia. 

Prof. Sarath Ranganathan is Director of Respiratory Medicine, Royal Children’s Hospital Melbourne

Welsner M, Straßburg S, Taube C, Sutharsan S.   Use of ivacaftor in late diagnosed cystic fibrosis monozygotic twins heterozygous for F508del and R117H-7T – a case report.  BMC Pulm Med. 2019 Apr 11;19(1):76. doi: 10.1186/s12890-019-0840-8.[Pubmed]   Free PMC Article
CFTR modulator therapy with ivacaftor is a treatment option for Cystic Fibrosis (CF) patients with at least one copy of a R117H-7T mutation in the CFTR gene. Desirable effects of this therapy are improvement of lung function, decrease in exacerbation rate, normalization or reduction of sweat chloride and weight gain. Monogenetic CF-twins carry identical genetic information, so therapy response and side effects are expected to be nearly identical under this specific therapy.

In monozygotic twins, at the age of 55, two pathogenic variants in the CFTR gene (F508del and R117H-7T) were detected. Both patients presented with a borderline sweat test (30-59 mmol/L) and despite the same genetic information and similar life circumstances the disease proceeds completely different. While one patient has severe pulmonary involvement with chronic P. aeruginosa infection, her twin sister is almost unimpaired. Liver or pancreatic involvement was not seen in either patient. Due to the presence of one copy of a R117H-7T mutation, CFTR modulator therapy with ivacaftor was initiated in both. Response and side effects were significantly different. In the less affected patient, we observed an improvement in lung function and a normalization of sweat chloride. In the severely affected patient, no functional response to treatment was seen, but stabilization of the disease state with a decrease in exacerbation and hospitalization rate and weight gain as well as a normalization of sweat chloride. There was an increase in liver enzymes in the less affected patient, which normalized after halving the dose of ivacaftor, while the therapeutic effect was maintained.

Despite nearly identical genetic information, as in monogenetic twins, therapy response and onset of side effects of CFTR modulating therapy are very different. In patients with late diagnosis and severe pulmonary involvement, ivacaftor does not seem to improve lung function, whereas in patients with late diagnosis and low disease severity a relevant therapy response was obtained. In addition to lung function, additional clinical parameters such as reduction of exacerbation and hospitalization rate and weight gain should be used to assess therapy response, especially in severely affected patients.

From the Department of Pulmonary Medicine, University Hospital Essen – Ruhrlandklinik, Adult Cystic Fibrosis Center, University of Duisburg-Essen, Tueschener Weg 40, 45329, Essen, Germany. matthias.welsner@rlk.uk-essen.de.                                                                                                   Department of Pulmonary Medicine, University Hospital Essen – Ruhrlandklinik, Adult Cystic Fibrosis Center, University of Duisburg-Essen, Tueschener Weg 40, 45329, Essen, Germany.

Witters P, Libbrecht L, Roskams T, et al. Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension. J Cyst Fibros 2017;16:e11–e13. Free Full text (with figures)  [Pubmed]

       Peter Witters

In the present work, we studied 8 patients with CFLD and PHT and 5 CFLD explant livers. In our patient cohort, both haemodynamic (HVPG) measurements and histological findings were identical to those in non-cirrhotic portal hypertension (NCPH). Hence, in at least a subset of CFLD patients, CFLD-related PHT is not due to the paradigmal “biliary” cirrhosis but corresponds to vascular damage as in NCPH. Although PHT clearly precedes the development of cirrhosis and end-stage liver failure in our patients, which percentage of PHT patients will go on to develop cirrhosis remains to be determined.

Prof. Dr Peter Witters. Dept Paediatric Gastroenterology and Hepatology, University Hospitals,  Belgium

Wood MEStockwell REJohnson GRRamsay KASherrard LJKidd TJCheney JBallard ELO’Rourke P Jabbour NWainwright CEKnibbs LDSly PDMorawska LBell SC.      Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei.Thorax. 2019 Jan;74(1):87-90. doi: 10.1136/thoraxjnl-2018-211567. Epub 2018 Apr 7.  [Pubmed]
The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis(CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non-Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens we measured.

Wu H, Vu M, Dhingra S, Ackah R, Goss JA, Rana A, Quintanilla N, Patel K, Leung DH.  Obliterative Portal Venopathy Without Cirrhosis Is Prevalent in Pediatric Cystic Fibrosis Liver Disease With Portal Hypertension.  Clin Gastroenterol Hepatol. 2019 Sep;17(10):2134-2136. doi: 10.1016/j.cgh.2018.10.046. Epub 2018 Nov 4.[Pubmed]
Cystic fibrosis liver disease (CFLD) has long been postulated to be secondary to dysfunctional cystic fibrosis transmembrane conductance regulator in the apical biliary epithelium, leading to bile stasis and eventually cirrhosis with portal hypertension. However, pathologic changes in the cystic fibrosis (CF) liver are distinct from the pancreas and lungs in that fibrocystic changes are absent. Furthermore, the lack of clinically evident biliary obstruction and liver dysfunction suggest there may be alternative mechanisms that contribute to CFLD. Two recent studies (both reviewed below) in young adults described obliterative portal venopathy (OPV) and non-cirrhotic portal hypertension (NCPH) as the predominant pathophysiology in young adults (median, 22 y) with CFLD. It is unknown if OPV develops early in childhood.

The present authors report the clinical features and liver pathology in 17 explants from children and adolescents with CF.  Diffuse nodularity of the capsular surfaces was seen in 76.5%, but only in 56.3% of cut surfaces of explants. No explants showed bile duct cystic dilatation or luminal inspissated material.  The classic CF-associated eosinophilic granular material was seen within hepatocyte lobules of 6 explants (35.3%), all in association with neutrophilic lobulitis, but none was found within an interlobular bile duct. There was no cholate stasis or copper deposition in periportal hepatocytes. 

The absence of focal biliary cirrhosis (FBC) in the majority of cases, reviewed in great detail, raises important questions about FBC as the primary driver of liver disease progression in CFLD. Their consistent observations of portal vascular compromise or paucity in a younger cohort may have important implications for both clinical management and in elucidating the complex and likely multifactorial aetiology of CF liver disease. 

Dr Has Wu is in the Department of Pathology, Baylor College of Medicine, Houston, Texas. 

Yan JKevat AMartinez ETeese NJohnson KRanganathan SHarrison JMassie JDaley A.     Investigating transmission of Mycobacterium abscessusamongst children in an Australian cystic fibrosis centre.  J Cyst Fibros. 2019 Mar 7. pii: S1569-1993(18)30918-4. doi: 10.1016/j.jcf.2019.02.011. [Epub ahead of print] [Pubmed]

Mycobacterium abscessus is an emerging pathogen in cystic fibrosis (CF) lung disease. Hospital transmission of M. abscessus has been described. This paper details the investigation into possible cross-transmission of M. abscessus locally at our paediatric hospital CF centre, and the subsequent infection control response. Whole genome sequencing (WGS) of M. abscessus respiratory isolates with epidemiological linkage analysis using hospital electronic medical records.

6.7% (22/328) of CF patients had M. abscessus isolated from respiratory specimens. WGS revealed a cluster of three patients with genomically related isolates that differed by <7 single nucleotide polymorphisms (SNPs), suggesting a shared recent ancestor and probable cross-transmission. Epidemiological investigation revealed multiple potential crossovers between patients with genomically similar M. abscessus isolates.

The authors concluded cross-infection of NTM occurs in CF hospital patients and advise that hospital infection control practices should be upgraded to reflect this. Consensus is needed between centres.

From the Department of Microbiology, Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia; Department of Infection Prevention and Control, Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia.

Zhao J, Huang W, Zhang S, Xu J, Xue W, He B, Zhang Y.   Efficacy of Glutathione for Patients With Cystic Fibrosis: A Meta-analysis of Randomized-Controlled Studies.    Am J Rhinol Allergy. 2019 Sep 24:1945892419878315. doi: 10.1177/1945892419878315. [Epub ahead of print][Pubmed]The impact of glutathione on pulmonary function remains elusive for patients with cystic fibrosis. The aim of this systematic review and meta-analysis is to explore the influence of glutathione versus placebo on pulmonary function of cystic fibrosis.

The authors searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2019, and randomized-controlled trials (RCTs) regarding the effect of glutathione on pulmonary function of cystic fibrosis are included in this meta-analysis.

Four RCTs are included. Compared with control group in patients with cystic fibrosis, glutathione treatment shows positive impact on forced expiratory volume 1 second (FEV1) (mean difference [MD] = 0.19; 95% confidence interval (CI), 0.10–0.28; P < .0001) and body mass index (MD = 0.27; 95% CI, 0.02–0.51; P = .03), but has no obvious influence on 6-minute walk test (standard MD = 0.28; 95% CI, −0.08 to 0.64; P = .13), number of exacerbations (MD = −0.10; 95% CI, −0.34 to 0.15; P = .43), abdominal pain or distal intestinal obstruction (risk ratios [RR] = 0.78; 95% CI, 0.32–1.90; P = .58), or hemoptysis (RR = 1.87; 95% CI, 0.43–8.26; P = .41).

The authors concluded glutathione treatment provides some benefits to improve pulmonary function of patients with cystic fibrosis, as evidenced by the increase in FEV1.

– Abstract not clear regarding benefits but I have described the long saga of glutathione in CF  in Topics. However, their is a great deal written about glutathione and cystic fibrosis although it is still not a regular recommended component of treatment. Readers are advised to consult Medline where glutathione in cystic fibrosis retrieves no less than 349 references

Jinqiu Zhao is from the Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Bin He is from the Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.