History – 2020 (Section 2)
First author M to Z
Meeker SM, Mears KS, Sangwan N, Brittnacher MJ, Weiss EJ, Treuting PM, Tolley N, Pope CE, Hager KR, Vo AT, Paik J, Frevert CW, Hayden HS, Hoffman LR, Miller SI, Hajjar AM. CFTR dysregulation drives active selection of the gut microbiome.
PLoS Pathog. 2020 Jan 21;16(1):e1008251. doi: 10.1371/journal.ppat.1008251. eCollection 2020 Jan.Free full text [Pubmed]
Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear. To test the relationships between CFTR dysfunction, microbes, and intestinal health, the authors established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses.
The authors consider their findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome.
Dr Stacy M Meeker is in the Department of Comparative Medicine, University of Washington, Seattle, WA, United States of America.
Mithal A, Capilla A, Heinze D, Berical A, Villacorta-Martin C, Vedaie M, Jacob A, Abo K, Szymaniak A, Peasley M, Stuffer A, Mahoney J, Kotton DN, Hawkins F, Mostoslavsky G. Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells.Nat Commun. 2020 Jan 10;11(1):215. doi: 10.1038/s41467-019-13916-6. [Pubmed]
Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, we report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, we follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or colonic epithelium. We employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modeling and therapeutic screening applications.
Dr A Mithal is at the Center for Regenerative Medicine of Boston University and Boston Medical Center, 670 Albany Street, Boston, MA, 02118, USA.
Munck A, Bourmaud A, Bellon G, Picq P, Farrell PM; DPAM Study Group. Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening.
Pediatr Pulmonol. 2020 Jan 9. doi: 10.1002/ppul.24634. [Epub ahead of print] [Pubmed]
To characterize the phenotypic expression of children with conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labelling if applicable and better define these children’s prognosis.
A multicentre cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)-diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment.
Results – Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow-up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P < .0001, respectively), Wisconsin and Brasfield chest radiograph scores, pulmonary function tests, and improved nutritional status. Among the inconclusive CF diagnosis cohort, 28 cases (44%) converted to CF diagnosis based on genotype (44%), SC (28%) or both (28%); yet, comparing those with or without final CF diagnosis, we found no differences, possibly related to their young age and mild degree of lung disease. In the total cohort, we found significant associations between Brody scores and IRT, SC values, genotype, Wisconsin and Brasfield score and spirometry.
The authors concluded the matched CRMS/CFSPID and CF cohorts showed differences in outcomes. By a mean age of 7.6 years, a high proportion of the CRMS/CFSPID cohort converted to CF. Our results highlight that monitoring at CF clinics until at least 6 years is needed as well as further studies.
Dr Anne Munck is at the Service des maladies digestives et respiratoires de l’enfant, CRCM, Hôpital Robert Debré, Paris, France.
-The final practical message of this useful paper is important – these infants should be followed up by experts in CF for a long time.
Misgault B, Chatron E, Reynaud Q, Touzet S, Abely M, Melly L, Dominique S, Troussier F, Ronsin-Pradel O, Gerardin M, Mankikian J, Cosson L, Chiron R, Bounyar L, Porzio M, Durieu I, Weiss L, Kessler R, Kessler L. Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cyst Fibros. 2020 Mar 19. pii: S1569-1993(20)30073-4. doi: 10.1016/j.jcf.2020.03.002. [Epub ahead of print] [Pubmed
To investigate the effects of 1-year lumacaftor-ivacaftor treatment on abnormalities in glucose tolerance (AGT) in Phe508del homozygous cystic fibrosis (CF) patients. Untreated CF patients with glucose intolerance or newly diagnosed diabetes were included in a prospective, observational study. After 1-year lumacaftor-ivacaftor treatment, AGT were evaluated by using oral glucose tolerance test.
Forty patients participated. 78% of patients had glucose intolerance and 22% diabetes at baseline. After one-year treatment, 50% of patients had normal glucose tolerance, 40% glucose intolerance, and 10% diabetes (p <0.001). The two-hour OGTT glycemia decreased from 171 (153-197) to 139 (117-162) mg/dL (p <0.001). 57.5% (n = 23) of patients improved their glucose tolerance with a significant decrease in both 1-hour (p<0.01) and 2-hour (p<0.001) OGTT glycemia.
The authors concluded improvements in AGT were observed following 1-year lumacaftor-ivacaftor treatment. Larger studies are needed to comprehensively assess CF transmembrane conductance regulator (CFTR) modulators.
Dr B Misgault is at the Service d’endocrinologie, diabète et nutrition, Hôpitaux Universitaires de Strasbourg, place de l’hôpital, Strasbourg 67091, France
Mithal A, Capilla A, Heinze D, Berical A, Villacorta-Martin C, Vedaie M, Jacob A, Abo K, Szymaniak A, Peasley M, Stuffer A, Mahoney J, Kotton DN, Hawkins F, Mostoslavsky G. Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells. Nat Commun. 2020 Jan 10;11(1):215. doi: 10.1038/s41467-019-13916-6. [Pubmed] Free PMC Article
Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, the authors report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, they follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or colonic epithelium. They employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modelling and therapeutic screening applications.
Dr Aditya Mithal is at the Center for Regenerative Medicine of Boston University and Boston Medical Center.
Dr Gustavo Mostoslavsky is Associate Professor of Medicine and Microbiology Boston University School of Medicine.
Mingione A, Dei Cas M, Bonezzi F, Caretti A, Piccoli M, Anastasia L, Ghidoni R, Paroni R, Signorelli P.Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis. Cell Physiol Biochem. 2020 Jan 31;54(1):110-125. doi: 10.33594/000000208. Free full text [Pubmed]
Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we describe the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells.
Cystic Fibrosis bronchial epithelia accumulate lipids, exacerbating inflammation. Myriocin administration: i) activates the transcriptions of genes involved in enhancing autophagy-mediated stress clearance; ii) reduces the content of several lipid species and, at the same time, iii) enhances mitochondrial lipid oxidation. Silencing the expression of Sptlc1 reproduces Myriocin induced autophagy and transcriptional activities, demonstrating that the inhibition of sphingolipid synthesis drives a transcriptional program aimed at addressing cell metabolism towards lipid oxidation and at exploiting autophagy mediated clearance of stress. They speculate that regulating sphingolipid de novo synthesis can relieve from chronic inflammation, improving energy supply and anti-oxidant responses, indicating an innovative therapeutic strategy for CF.
From the Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, Italy.
Nabi Z, Talukdar R, Venkata R, Aslam M, Shava U, Reddy DN. Genetic Evaluation of Children with Idiopathic Recurrent Acute Pancreatitis. Dig Dis Sci. 2020 Jan 3. doi: 10.1007/s10620-019-06026-2. [Epub ahead of print] [Pubmed]
Several genetic risk factors have been identified in adults with idiopathic acute recurrent pancreatitis (IARP). However, the literature regarding the genetics of IARP is sparse in children. In this study, we aimed to analyse the genetic risk factors in children with IARP.
All children (< 18 years) with ARP from January 2015 to May 2018 were prospectively enrolled in the study. Children with a known cause of ARP like obstructive, toxic/metabolic, and autoimmune were excluded from the final analysis. Children with IARP underwent genetic testing for mutations/polymorphisms in genes known to predispose to pancreatitis including cationic trypsinogen protease serine 1 (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsin C (CTRC), claudin-2 (CLDN2) and cathepsin B (CTSB).
Results: A total of 239 children (116 boys, 10.3 ± 3.7 years) were enrolled during the study period. Of these, 204 (85.35%) children were identified as IARP. The mean age of symptom onset and the number of pancreatitis episodes were 8.3 ± 3.7 years and 3.3 ± 1.8, respectively. A family history of pancreatitis was noted in 4.6% children. Mutations/polymorphisms in at least 1 gene were identified in 89.5% (129/144) children including SPINK1 in 41.9%, PRSS1 (rs10273639) in 58.2%, CTRC in 25.6%, CTSB in 54.9%, CLDN2 in 72.9%, and CFTR in 2.3%. There was no significant incidence of genetic mutations/polymorphisms in IARP with or without pancreas divisum (95.7 vs 88.4%; p = 0.467).
The authors concluded genetic alterations are present in the majority of the children with IARP. The incidence of genetic mutations is similar in children with or without pancreas divisum
Dr Zaheer Nabi is at the Asian Institute of Gastroenterology, Hyderabad, India
-Interesting that only 2.3% of the mutations were of CFTR
Nash EF, Middleton PG, Taylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators – an international survey. J Cyst Fibros. 2020 Mar 6. pii: S1569-1993(20)30067-9. doi: 10.1016/j.jcf.2020.02.018. [Epub ahead of print] [Pubmed]
A survey was sent to lead clinicians of adult CF centres in Europe, the United Kingdom (UK), United States of America (USA), Australia and Israel requesting anonymised data on pregnancy outcomes in women using CFTR modulators before and during pregnancy and lactation. The survey identified 64 pregnancies in 61 women taking IVA (n = 31), LUM/IVA (n = 26) or TEZ/IVA (n = 7), resulting in 60 live births. In 44 pregnancies, CFTR modulators were either continued throughout pregnancy or temporarily stopped and then restarted. Two maternal complications were deemed related to CFTR modulator therapy; cessation of modulator therapy resulted in clinical decline in 9 women prompting resumption of therapy during pregnancy. No modulator-related complications were reported in infants exposed in utero and/or during breastfeeding.
CFTR modulators were reported to be generally well tolerated in pregnancy and breastfeeding, with only 2 maternal complications that were deemed related to CFTR modulator therapy. Women stopping CFTR modulators in pregnancy may experience a decline in clinical status and in the cases identified in this survey, restarting therapy led to a clinical improvement. Current experience remains limited and longer-term prospective follow-up is required to exclude delayed adverse effects.
Dr Edward Nash is a Pulmonologist West Midlands Adult Cystic Fibrosis Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham
New Drug Hailed as Major Breakthrough in Cystic Fibrosis. Am J Med Genet A. 2020 Jan;182(1):8-9. doi: 10.1002/ajmg.a.61420.[Pubmed] My summary as their is no abstract: No authors are listed for this neat account of the progress in the development of CFTR modulator therapy from the FDA approval of ivacaftor (VX-771) in January 2012 for patients with one copy of the G551D mutation, to Orkambi, the combination of lumacaftor (VX-809) and ivacaftor, for those with 2 copies of the F508del mutation in 2015, to another drug combination of tezacaftor (VX-661) and ivacaftor (Symdeko) in 2018 for those people with at least one F508del mutation.
In 2019 the combination drug Trikafta, combining elexacaftor (VX-445), ivacaftor (Kalydeco) and tezacaftor (VX-661), was approved for patients aged 12 years and over with at least one F508del – a group comprising some 90% of the CF population. Approval was based on two phase III clinical trials (Middleton et al, 2019; Heijerman et al, 2019). Sadly these drugs are very expensive and funding is and will remain a major problem.
Nichols DP, Moss RB. Early Aspergillosis in Cystic Fibrosis and Air Trapping: Guilt by Association? Am J Respir Crit Care Med. 2020 Jan 6. doi: 10.1164/rccm.201912-2309ED. [Epub ahead of print] [Pubmed]
These authors discuss recent work on the significance of Aspergillus in young children and in particular the study of Breuer et. (Am J Respir Crit Care Med [online ahead of print] 20 November 2019) that provides substantial further evidence for relatively high prevalence and potential pathogenicity of early lower airways Aspergillus infection without allergic sensitization. They find the longitudinal patterns of association and a clear dose-response between Aspergillus positive cultures and CT abnormalities are compelling. They are encouraged by reports indicating that effective CFTR modulator drugs significantly reduce Aspergillus positivity in respiratory cultures, and the years ahead may allow us to test the impact of early introduction of these therapies in young children with CF. Despite anticipated advances in care, they consider it is important to continue to wrestle with how best to detect, diagnose, and treat lower airway infections in young children with this disease. An increased appreciation for the role of non-allergic fungal infections appears to be an important part of that discussio
-Wise advice from two experts. Once infection in the airways causes damage the course is relentlesly downwards – the speed of which is dependent on the intensity of treatment.
Dr Dave P Nichols is at Seattle Children’s Hospital, 7274, Pediatrics, Seattle, Washington, United States.
Dr Richard Moss is at the Department of Pedaitrics, Stanford University School of Medicine, Palo Alto, California.
Ogbolu C, Arregui-Fresneda I, Daniels T, Holt RIG. Some young adults with cystic fibrosis-related diabetes may safely stop insulin without any adverse clinical sequelae. Diabet Med. 2020 Mar 1. doi: 10.1111/dme.14288. [Epub ahead of print] [Pubmed]
University Hospital Southampton NHS Foundation Trust hosts the Wessex regional CFRD service. In 2018, there were 45 men and 31 women aged 18–25 years attending the service. Of these, 34 had CRFD, 12 had impaired glucose tolerance and 30 had normal glucose tolerance. Of the 34 with CFRD, 29 were treated with insulin at transition from the paediatric to adult services. The organization of care across our region means that children are seen by paediatric teams at different hospitals prior to transition to adult services in Southampton. We were therefore unable to determine why insulin was initiated as we did not have access to the paediatric records. The remaining five people with CFRD were managing their diabetes with lifestyle modification alone.
Fourteen (53%) of the 26 people treated with insulin at the point of transition stopped taking insulin at a mean ± SD age of 20.6 ± 2.4 years. The mean dose of insulin and the mean HbA1c at insulin cessation were 5.8 ± 1.3 units/day and 38 ± 6 mmol/mol (5.7 ± 0.7%), respectively. There were 1-year post-insulin cessation assessments available for all 14 people; 12 were followed for 2 years and eight had 3-year post-insulin cessation data. There were no differences in sex, gene mutation, baseline BMI or lung function between those who stopped insulin compared with those who continued, but those who stopped insulin were older when CFRD was diagnosed (Table 1). After the insulin was stopped, there was no deterioration in HbA1c (P=0.923) or decrease in body weight (P=0.588; Figs 1a,b). No one needed to re-start insulin. Figure 1c shows a small expected decline in lung function with time, but the rate of decline was unaffected by the decision to stop insulin (P=0.135).
In conclusion, although further work is needed to ascertain who can stop insulin safely in early adulthood, the authors suggest that stopping insulin in selected people with CFRD may be one way to simplify their treatment burden.
From the Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and the Wessex Adult Cystic Fibrosis Service, Southampton, UK.
Richard Holt is Professor in Diabetes and Endocrinology within Medicine at the University of Southampton.
Olivereau L, Nave V, Garcia S, Perceval M, Rabilloud M, Durieu I, Reynaud Q. Adherence to lumacaftor-ivacaftor therapy in patients with cystic fibrosis in France.
J Cyst Fibros. 2020 Jan 2. pii: S1569-1993(19)30901-4. doi: 10.1016/j.jcf.2019.09.018. [Epub ahead of print] [Pubmed]
This retrospective study used pharmacy refills data to calculate proportion of days covered (PDC). Adherence was defined as a PDC ≥80%. A logistic regression analysis was conducted to examine factors associated with medication adherence.
Ninety-six patients were included in the final cohort for analysis. The mean PDC was 96% ± 14 at 6 months, and 91% ± 17 at 12 months. The proportion of adherent patients was 89% and 83% at 6 and 12 months respectively. Age and ppFEV1 were found to affect medication adherence.
Considering the medico-economic impact of CFTR modulator therapy, high adherence rates to lumacaftor-ivacaftor found in this study are encouraging.
Dr L Olivereau is at the Pharmacie Centrale, Hospices Civils de Lyon, F-69230 Saint Genis Laval, France.
Oudraad MCJ, Kuo W, Rosenow T, Andrinopoulou ER, Stick SM, Tiddens HAWM Assessment of early lung disease in young children with CF: A comparison between pressure-controlled and free-breathing chest computed tomography. Pediatr Pulmonol. 2020 Mar 2. doi: 10.1002/ppul.24702. [Epub ahead of print] [Pubmed]
Chest computed tomography (CT) in children with cystic fibrosis (CF) is sensitive in detecting early airways disease. The pressure-controlled CT-protocol combines a total lung capacity scan (TLC PC-CT) with a near functional residual capacity scan (FRC PC-CT) under general anaesthesia, while another CT-protocol is acquired during free breathing (FB-CT) near functional residual capacity. The aim of this study was to evaluate the sensitivity in detecting airways disease of both protocols in two cohorts.
Routine PC-CTs (Princess Margaret Children’s Hospital) and FB-CTs (Erasmus MC-Sophia Children’s Hospital) were retrospectively collected from CF children aged 2 to 6 years. Total airways disease (%disease), bronchiectasis (%Bx), and low attenuation regions (%LAR) were scored on CTs using the Perth-Rotterdam annotated grid morphometric analysis-CF method. The Wilcoxon signed-rank test was used for differences between TLC and FRC PC-CTs and the Wilcoxon rank-sum test for differences between FRC PC-CTs and FB-CTs.
RESULTS: Fifty patients with PC-CTs (21 male, aged 2.5-5.5 years) and 42 patients with FB-CTs (26 male, aged 2.3-6.8 years) were included. %Disease was higher on TLC PC-CTs compared with FRC PC-CTs (median 4.51 vs 2.49; P < .001). %Disease and %Bx were not significantly different between TLC PC-CTs and FB-CTs (median 4.51% vs 3.75%; P = .143 and 0.52% vs 0.57%; P = .849). %Disease, %Bx, and %LAR were not significantly different between FRC PC-CTs and FB-CTs (median 2.49% vs 3.75%; P = .055, 0.54% vs 0.57%; P = .797, and 2.49% vs 1.53%; P = .448).
The authors consider their data suggest that FRC PC-CTs are less sensitive than TLC PC-CTs and that FB-CTs have similar sensitivity to PC-CTs in detecting lung disease. FB-CTs seem to be a viable alternative for PC-CTs to track CF lung disease in young patients with CF.
Dr Merel C J Oudraad was Student researcher of the Lung Analysis research group Erasmus MC and now Clinical Fellow Emergency Department Royal Infirmary Edinburgh.
Palmer DJ, Turner DL, Ng P. A Single “All-in-One” Helper-Dependent Adenovirus to Deliver Donor DNA and CRISPR/Cas9 for Efficient Homology-Directed Repair. Mol Ther Methods Clin Dev. 2020 Feb 4;17:441-447. doi: 10.1016/j.omtm.2020.01.014. eCollection 2020 Jun 12 Free PMC Article [Pubmed]
In this study, we developed a single helper-dependent adenovirus (HDAd) to deliver all of the components (donor DNA, CRISPR-associated protein 9 [Cas9], and guide RNA [gRNA]) needed to achieve high-efficiency gene targeting and homology-directed repair in transduced cells. We show that these “all-in-one” HDAds are up to 117-fold more efficient at gene targeting than donor HDAds that do not express CRISPR/Cas9 in human induced pluripotent stem cells (iPSCs). The vast majority (>90%) of targeted recombinants had only one allele targeted, and this was accompanied by high-frequency indel formation in the non-targeted allele at the site of Cas9 cleavage. These indels varied in size and nature, and included large deletions of ∼8 kb. The remaining minority of recombinants had both alleles targeted (so-called bi-allelic targeting). These all-in-one HDAds represent an important platform for accomplishing and expanding the utility of homology-directed repair, especially for difficult-to-transfect cells and for in vivo applications.
Donna J Palmer is in the Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.
Papale M, Parisi GF, Spicuzza L, Licari A, Bongiovanni A, Mulè E, Rotolo N, Manti S, Leonardi S. Lung clearance index evaluation in detecting nocturnal hypoxemia in cystic fibrosis patients: Toward a new diagnostic tool. Respir Med. 2020 Apr;164:105906. doi: 10.1016/j.rmed.2020.105906. Epub 2020 Feb 19. [Pubmed]
Nocturnal hypoxemia adversely affects outcomes in patients with cystic fibrosis (CF). Although an early detection of this abnormality may be desirable, still its predictability remains uncertain. The Lung Clearance Index (LCI) is a measure of lung ventilation distribution obtained from a multiple-breath washout technique (MBW), recently implemented in patients with CF. This study aimed to establish whether the LCI predicts nocturnal hypoxemia in patients with stable CF, with mild to moderate disease, and normal diurnal gas exchange.
31 stable patients (15 males, mean age 17.4 ± 5.2 years) with mild to moderate CF, normoxic when awake, were enrolled. In all patients we performed nocturnal cardio-respiratory polygraphy, lung function measurement, and MBW test to derive LCI values.
LCI was abnormal in most of the patients and inversely correlated with mean nocturnal SpO2 (r = -0.880 p < 0.01). A receiver operating characteristic (ROC) analysis, performed to assess whether LCI predicted nocturnal hypoxemia, revealed a high predictive accuracy of LCI for nocturnal desaturation (AUC = 0.96; Youden index = 0.79). Forced expiratory volume in 1 s (FEV1) was predictive only in patients with more severe airway obstruction, with a moderate degree of accuracy (AUC 0.71).
The authors concluded the LCI showed a high effectiveness in predicting nocturnal hypoxemia in stable patients with CF, particularly when compared with a traditional parameter of lung function such as FEV1.
From the Respiratory Unit, AOU Policlinico-Vittorio Emanuele, Department of Clinical and Experimental Medicine, University of Catania, Via Santa Sofia 78, I-95123, Catania, Italy.
Patel D, Popple S, Claydon A, Modha DE, Gaillard EA. Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease Med Mycol. 2020 Jan 1;58(1):11-21. doi: 10.1093/mmy/myz0 [Pubmed]
A prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3-17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy.
Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.
Dr Erol Gaillard, Senior Lecturer in Child Heath and Honorary Consultant in Paediatric Respiratory Medicine. Department of Respiratory Sciences, NIHR Biomedical Research Centre (Respiratory theme) and Institute for Lung Health, University of Leicester, Leicester, United Kingdom and the Department of Paediatric Respiratory Medicine, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom.
Pedemonte N, Bertozzi F, Caci E, Sorana F, Di Fruscia P, Tomati V, Ferrera L, Rodríguez-Gimeno A, Berti F2, Pesce E, Sondo E, Gianotti A, Scudieri P, Bandiera T, Galietta LJV. Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel. Sci Adv. 2020 Feb 21;6(8):eaay9669. doi: 10.1126/sciadv.aay9669. eCollection 2020 Feb. [Pubmed] Free PMC Article
F508del, the most frequent mutation causing cystic fibrosis (CF), results in mistrafficking and premature degradation of the CFTR chloride channel. Small molecules named correctors may rescue F508del-CFTR and therefore represent promising drugs to target the basic defect in CF. The authors screened a carefully designed chemical library to find F508del-CFTR correctors. The initial active compound resulting from the primary screening underwent extensive chemical optimization.
The final compound, ARN23765, showed an extremely high potency in bronchial epithelial cells from F508del homozygous patients, with an EC50 of 38 picomolar, which is more than 5000-fold lower compared to presently available corrector drugs. ARN23765 also showed high efficacy, synergy with other types of correctors, and compatibility with chronic VX-770 potentiator. Besides being a promising drug, particularly suited for drug combinations, ARN23765 represents a high-affinity probe for CFTR structure-function studies.
Corresponding authors are Tiziano Bandiera of D3 PharmaChemistry, Fondazione Istituto Italiano di Tecnologia, Genova, Italy and Luis J V Gallietta of Telethon Institute of Genetics and Medicine (TIGEM) Possuoli and University of Naples.
Pierre-Régis Burgel , Anne Munck , Isabelle Durieu , Raphaël Chiron , Laurent Mely , Anne Prevotat et al, French Cystic Fibrosis Reference Network Study Group. Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients With Cystic Fibrosis. Am J Respir Crit Care Med. 2020 Jan 15;201(2):188-197. doi: 10.1164/rccm.201906-1227OC. [Pubmed]
To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life post approval setting. The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society’s recommendations.
Main findings – Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or non-respiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.
The authors concluded Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.
Dr Pierre-Régis Burgel is at the Faculty of Medicine, Paris Descartes CPSC.
Prentice BJ, Ooi CY, Verge CF, Hameed S, Widger J. Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis. J Cyst Fibros. 2020 Feb 25. pii: S1569-1993(20)30057-6. doi: 10.1016/j.jcf.2020.02.009. [Epub ahead of print] [Pubmed]
It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test.
Young children with CF have glucose abnormalities detected by CGM that fluctuate over time.
Dr Bernadette Prentice is a respiratory paediatrician in the Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, NSW, Australia.
Rang C, Keating D, Wilson J, Kotsimbos T. Re-Imagining Cystic Fibrosis Care: Next Generation Thinking. Eur Respir J. 2020 Mar 5. pii: 1902443. doi: 10.1183/13993003.02443-2019. [Epub ahead of print][Pubmed]
Cystic fibrosis is a common multi-system genetically inherited condition, predominately found in individuals of Caucasian decent. Since the identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, and the subsequent improvement in understanding of CF pathophysiology, significant increases in life-expectancy have followed. Initially this was related to improvements in the management and systems of care for treating the various affected organ systems. These cornerstone treatments are still essential for CF patients born today. However, over the last decade, the major advance has been in therapies that target the resultant genetic defect – the dysfunctional CFTR protein. Small molecule agents that target this dysfunctional protein via a variety of mechanisms have led to lung function improvements, reductions in pulmonary exacerbation rates and increases in weight and quality of life indices. As more patients receive these agents earlier and earlier in life, it is likely that general CF care will increasingly pivot around these specific therapies, although it is also likely that effects other than those identified in the initial trials will be discovered and need to be managed. Despite great excitement for modulator therapies, they are unlikely to be suitable or available for all: whether this is due to a lack of availability for specific CFTR mutations, drug-reactions or the health economic set-up in certain countries. Nevertheless, the CF community must be applauded for its ongoing focus on research and development for this life-limiting disease. With time, personalised individualised therapy would ideally be the mainstay of CF care.
– This is a clear summary of the future changing nature of CF care. As with many other such articles there is no mention of prevention.
Dr Tom Kotsimbos is Associate Professor and Head of Respiratory Medicine Laboratory, AIRMed Department, Central Clinical School, Monash University.
Reynaud Q, Rousset Jablonski C, Poupon-Bourdy S, Denis A, Rabilloud M, Lemonnier L, Nove-Josserand R, Durupt S, Touzet S, Durieu I; Participating Centers of the French Cystic Fibrosis Registry. Pregnancy outcome in women with cystic fibrosis and poor pulmonary function. J Cyst Fibros. 2020 Jan;19(1):80-83. doi: 10.1016/j.jcf.2019.06.003. Epub 2019 Jul 1.[Pubmed]
A study to investigate how poor pre-gestational pulmonary function influenced pregnancy outcome and clinical status evolution in women with cystic fibrosis. Pregnancies in women without lung transplantation with a first delivery reported to the French cystic fibrosis registry between 2000 and 2012 were identified. Pregnancy outcomes and clinical trends (body mass index – BMI, and pulmonary function) over a 4-year follow-up in women with poor pre-gestational pulmonary function, defined as forced expiratory volume (FEV1) ≤ 50%, were compared to those in women with FEV1 ˃ 50%.
A total of 149 women had a first delivery and 36 (24.2%) of these had pre-gestational FEV1 ≤ 50%. There was no significant difference in age or frequency of assisted conception between the 2 groups. The rate of caesarean section was significantly higher in women with FEV1 ≤ 50% (43.7% vs. 21.1%, p = .01). The frequency of preterm birth did not differ significantly between the two groups, but median infant birthweight was significantly lower in women with FEV1 ≤ 50% (2705 g; range: 650-3700 vs. 3044 g; range: 1590-3860, p = .003). Despite significantly lower FEV1 and BMI the year before pregnancy for women with poor pulmonary function, the decline in these parameters during the study period did not differ significantly between the two groups.
Poor pre-gestational pulmonary function in women with cystic fibrosis was associated with a higher rate of caesarean section and a clinically significant impact on fetal growth, but was not associated with more important pulmonary and nutritional decline over the study period.
Dr Quitterie Reynaud is a Sub-Investigator at the Centre de référence Adulte de la Mucoviscidose, Service de médecine interne, Hospices Civils de Lyon and the Universite de Lyon
Schwensen HF, Moser C, Perch M, Pressler T, Høiby N. Pseudomonas aeruginosa antibody response in cystic fibrosis decreases rapidly following lung transplantation. J Cyst Fibros. 2020 Feb 7. pii: S1569-1993(20)30044-8. doi: 10.1016/j.jcf.2020.01.012. [Epub ahead of print] [Pubmed]
Specific Pseudomonas aeruginosa (PA) precipitating immunoglobulin G antibodies in serum are correlated with PA biofilm infection and are used as diagnostic and prognostic markers in cystic fibrosis (CF). The aim of this study was to examine the change of PA antibody response in CF patients after bilateral sequential lung transplantation (LTx).
PA antibodies and airway bacteriology were retrospectively evaluated in 20 chronically infected CF patients, who underwent LTx between 2001 and 2016 at Rigshospitalet, Copenhagen. Yearly precipitin counts from one year before LTx and up to five years after LTx were compared. Monthly airway cultures were examined in the five-year period after LTx. In addition, crossed immunoelectrophoresis (CIE) were analysed for each patient for antigenic similarities from time of infection, pre-LTx and post-LTx.
Results: All patients experienced a significant drop in PA antibodies from one year pre-LTx to one year post-LTx (p < 0.0001). The PA antibody level did not differ between those, who became re-infected immediately after LTx, and those, who did not. No patients regained the high pre-LTx precipitin levels in the following five years. The antigenic specificities of the sera post-LTx were in each patient similar to the antigenic specificities at the beginning of infection indicating a decades long memory of their immune response like an “immunological fingerprint”.
The authors concluded that after LTx a significant and continuous reduction in PA antibodies was observed. The reduction was independent of immediate reinfection after LTx. A novel three-factor explanatory model is presented.
From the Department of Clinical Microbiology, Rigshospitalet (Copenhagen University Hospital), Denmark.
Professor Niels Hoiby. the late Dr Christian Koch and their colleagues in Copenhagen have been one of the major influences, well ahead of their time, in recognising the significance of P. aeruginosa infection (1973 Hoiby N, Axelsen NH. Identification and quantitation of precipitins against Pseudomonas aeruginosa in patients with cystic fibrosis by means of crossed immunoelectrophoresis with intermediate gel. Acta Path Microbiol Scand 1973; 81:298-308. [PubMed]) and introducing more aggressive treatment both for chronic infection (1983 Szaff M, Hoiby N, Flensborg EW. Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection. Acta Paediatr Scand 1983; 72; 651-657.[PubMed]) and early infection (1991 Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa infection in cystic fibrosis by early treatment. Lancet 1991; 338:725-726.[ PubMed]. All these papers are abstracted in the appropriate year section of this history.
Niels Hoiby and his colleagues in Copenhagen have been one of the major influences, well ahead of their time, in recognising the significance of P. aeruginosa infection and introducing more aggressive treatment both for chronic and early infection. No one has made a more significant contribution to the treatment of CF than Niels and his colleagues at the Rigshospitalet in Copenhagen. Certainly they were a major influence on us at the Leeds Regional CF Centre in the Eighties. It was great privilege to be invited to speak at Niels’s celebration of 25 years as Professor at the University in Copenhagen.
Shaw M, Oppelaar MC, Jensen R, Stanojevic S, Davis SD, Retsch-Bogart G, Ratjen FA. The utility of moment ratios and abbreviated endpoints of the multiple breath washout test in preschool children with cystic fibrosis. Pediatr Pulmonol. 2020 Jan 3. doi: 10.1002/ppul.24618. [Epub ahead of print] [Pubmed]
The multiple breath washout (MBW) test may be most useful in tracking disease progression over time to inform treatment decisions. In the clinical setting, alternative outcomes, which can be obtained quickly and easily, may facilitate interpretation of clinically relevant changes in lung function.
In this secondary analysis of data from 78 cystic fibrosis (CF) and 72 healthy control (HC) subjects between the ages of 2.6 and 5.9 years, MBW was performed at enrolment, 1, 3, 6, 9, and 12 months, as well as during symptomatic visits using the Exhalyzer D (EcoMedics AG, Duernten, Switzerland). The lung clearance index, LCI2.5, was compared to moment ratios (M1/M0 and M2 /M0 ) at the standard cutoff (1/40th of starting tracer gas concentration) as well as LCI5 and moment ratios at 1/20th of the starting concentration (M1 /M0 at LCI5 , and M2 /M0 at LCI5 ).
All outcomes were able to distinguish between health and disease. LCI5 reduced testing time by 40% and increased feasibility by more than 10%. The limits of biological reproducibility in healthy children were similar between LCI2.5 (15%), LCI5 (12%), M1 /M0 at LCI2.5 (14%), and M1 /M0 at LCI5 (12%), but markedly larger for M2 /M0 at LCI2.5 (30%) and M2/M0 at LCI5 (25%). Each outcome deteriorated significantly with worsening pulmonary symptoms, the magnitude of deterioration was greatest for M2 /M0 .
The authors concluded that in preschool children with CF, LCI5 was more feasible to obtain and track disease progression. The second moment ratio was most sensitive to pulmonary symptoms, but had the greatest variability both within and between subjects.
Dr M Shaw is at the Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
-LCI seems to be established as an effective non-invasive generally applicable way of monitoring respiratory function in pre-school children – filling a long present need.
Shteinberg M, Taylor-Cousar JL. Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease. Eur Respir Rev. 2020 Mar 20;29(155). pii: 190112. doi: 10.1183/16000617.0112-2019. Print 2020 Mar 31. Free full text [Pubmed]
Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug-drug interactions, are discussed.
Dr Michal Shteinberg is heading the bronchiectasis and adult CF service in the Pulmonology institute and CF Center, Carmel medical Center, Haifa, Israel and a Clinical Assistant Professor in the Faculty of medicine at the Technion, Israel Institute of Technology.
Professor Stuart Elborn comments on this article as follows –
Elborn JS. Modulator treatment for people with cystic fibrosis: moving in the right direction. Eur Respir Rev. 2020 Mar 20;29(155). pii: 200051. doi: 10.1183/16000617.0051-2020. Print 2020 Mar 31. Free full text [Pubmed]
Stuart Elborn in this issue of the European Respiratory Review, describes Shteinberg and Taylor-Cousar’s article as providing a very useful review of the current state of play in Europe for CFTR modulators
There is a benefit from these therapies even in individuals with severely reduced FEV1 who are excluded from the trials in follow-up clinical studies, and people with CF benefit from a significant reduction in pulmonary exacerbations. The adverse events and drug/drug interactions are comprehensively covered in the article by Shteinberg and Taylor-Cousar. Drug/drug interactions are also important in this group of drugs as they interact with a number of hepatic enzymes important in drug metabolism. These are particularly relevant for antibacterial and antifungal agents, which are often used in people with CF.
Elborn suggests the delivery of healthcare services for people with CF is likely to evolve over the next decade with a wide implementation of highly effective modulator treatment. It is important for respiratory clinical teams and the wider group of specialists in the multidisciplinary team to understand how these drugs are used, the side-effects and potential for drug interactions. The article by Shteinberg and Taylor-Cousar provides a very useful summary of the current position.
Full texts of both these above articles are available and are excellent.
Siegel MJ, Freeman AJ, Ye W, Palermo JJ, Molleston JP, Paranjape SM, Stoll J, Leung D, Masand P, Karmazyn B, Harned R, Ling SC, Navarro OM, Karnsakul W, Alazraki A, Schwarzenberg SJ, Seidel FG, Towbin A, Alonso EM, Nicholas JL, Murray KF, Otto RK, Sherker AH, Magee JC, Narkewicz MR; CFLD Network. Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study. J Pediatr. 2020 Feb 11. pii: S0022-3476(19)31712-3. doi: 10.1016/j.jpeds.2019.12.033. [Epub ahead of print] [Pubmed]
To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease. Planned 4-year interim analysis of a 9-year multi-center, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease.
The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern).
The authors’ main conclusion was that research liver research ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.
Dr Marilyn J Siegel is Professor of Radiology and Pediatric Radiology at the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO.
Singh H, Coffey MJ, Ooi CY. Cystic Fibrosis-related Liver Disease is Associated With Increased Disease Burden and Endocrine Comorbidities. J Pediatr Gastroenterol Nutr. 2020 Mar 5. doi: 10.1097/MPG.0000000000002694. [Epub ahead of print] [Pubmed]
Cystic fibrosis-related liver disease (CFLD) is the leading non-pulmonary cause of mortality in cystic fibrosis (CF). The authors evaluated and compared the burden of disease and non-respiratory comorbidities of those with severe CFLD and those without (no CFLD). A retrospective nationwide (Australia) longitudinal review (from 1998 to 2016) of severe CFLD patients compared with no CFLD controls (matched 1 : 1 for age, genotype, pancreatic insufficiency, and center).
One hundred sixty-six patients with severe CFLD and 166 with no CFLD were identified. Forced expiratory volume in 1 second percentage of predicted (FEV1%) was significantly lower in CFLD than no CFLD across all ages. Median (IQR) hospitalizations per patient per year were higher in CFLD than noCFLD for: respiratory indications; gastrointestinal indications); and other indications. In the CFLD cohort, there was increased use of nasogastric and gastrostomy nutritional supplementation Additionally, the CFLD cohort had a higher frequency of bone diseases, osteopenia and osteoporosis, as well as CF-related diabetes.
The authors demonstrated patients with severe CFLD have greater disease burden, with significantly higher number of hospitalizations (both respiratory and non-respiratory indications), nutritional interventions, and are at higher risk of CF-related bone disease and diabetes.
Dr H Singh is in the Department of Gastroenterology, Sydney Children’s Hospital, Randwick.
The present situation regarding the new CFTR modulators is neatly summarised by Prof. Ros Smyth in this BMJ article. As some readers may not have access to the full text, I have summarised some of the key points and added the key references –
Mutations that result in CFTR being expressed on the cell surface but incorrectly regulated, such as G551D, were the most straightforward targets. Ivacaftor, a potentiator, increases the time that the CFTR chloride channel remains open. In a phase III randomised placebo controlled trial, ivacaftor improved forced expiratory volume in one second (FEV1) by 11% as well as respiratory symptoms and weight gain without substantial adverse effects (Ramsey et al 2011). The trial recruited 161 patients and was completed in 19 months despite the small pool of just 2000 people worldwide with the G551D mutation. Ivacaftor was licensed in Europe in 2012.
Ivacaftor is effective for only 4-5% of patients with cystic fibrosis. Many more patients have the F508del mutation, which causes misfolding of CFTR protein so that it remains trapped in the cell’s endoplasmic reticulum. Any CFTR that does reach the cell surface is unable to activate normally. Although potentiators can enhance activation at the cell surface, dealing with the trapped protein requires agents that correct the misfolding (correctors).
In 2015, a trial of Orkambi, a drug combining the corrector lumacaftor with the potentiator ivacaftor, showed improvements in weight gain and respiratory exacerbations among patients who were homozygous for F508del, but the modest 3% increase in FEV1 relative to placebo was associated with transient dyspnoea and abnormal liver function (Wainwright et al, 2015)
Subsequent trials of a different corrector, tezacaftor, combined with ivacaftor showed similar improvements in FEV1 to Orkambi but with fewer side effects (Taylor-Cousar et al, 2017; Rowe SM et al, 2017)
In 2018, tezacaftor-ivacaftor (Symkevi) was licensed in the US and Europe for patients with F508del (either homozygous or F508del plus an allele with another mutation associated with residual CFTR function), representing around 50% of patients worldwide (Davies JC et al, 2018; Keating D et al, 2018).
Although 90% of people with cystic fibrosis have at least one copy of the F508del mutation, around 30% also have other minimal function mutations that are unresponsive to current CFTR modulators. This led to the development of next generation correctors and trials of “triple therapy” combining two correctors and a potentiator.
In 2019, phase III trials of elexacaftor-ivacaftor-tezacaftor in patients with F508del reported greater than 10% improvements in FEV1 compared with placebo and substantial reductions in respiratory exacerbations (Heijerman et al, 2019; Middleton et al, 2019).
– Ramsey BW, Davies J, McElvaney NG, et al., VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-72. doi:10.1056/NEJMoa1105185 [Pubmed] –Wainwright CE, Elborn JS, Ramsey BW, et al., TRAFFIC Study Group, TRANSPORT Study Group. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med2015;373:2231.doi:10.1056/NEJMoa1409547 [Pubmed]
– Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med2017;377:2013-23. doi:10.1056/NEJMoa1709846 [Pubmed]
– Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med2017;377:2024-35. doi:10.1056/NEJMoa1709847 [Pubmed]
– Davies JC, Moskowitz SM, Brown C, et al., VX16-659-101 Study Group. VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med2018; 379:1599-611. doi:10.1056/NEJMoa1807119 pmid [Pubmed
– Keating D, Marigowda G, Burr L, et al., VX16-445-001 Study Group. VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med2018; 379:1612-20. doi:10.1056/NEJMoa1807120 pmidL [Pubmed]
– Heijerman HGM, McKone EF, Downey DG, et al., VX17-445-103 Trial Group. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet2019; 394:1940-8. doi:10.1016/S0140-6736(19)32597-8 [Pubmed]
– Middleton PG, Mall MA, Dřevínek P, et al., VX17-445-102 Study Group. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381:1809-19. doi:10.1056/NEJMoa1908639 [Pubmed]
Stockwell RE, Wood ME, Ballard E, Moore V, Wainwright CE, Bell SC. Current infection control practices used in Australian and New Zealand cystic fibrosis centers. BMC Pulm Med. 2020 Jan 17;20(1):16. doi: 10.1186/s12890-020-1052-y. [Pubmed]
The 2013 update of the Infection Prevention and Control (IP&C) Guideline outlined recommendations to prevent the spread of CF respiratory pathogens. The authors aimed to investigate the current infection control practices used in Australian and New Zealand (NZ) CF centers.
Two online surveys were distributed to Australian and NZ CF centers regarding the uptake of selected IP&C recommendations. One survey was distributed to all the Medical Directors and Lead CF Nurses and the second survey was distributed to all the Lead CF Physiotherapists.
The response rate was 60% (60/100) for medical/nursing and 58% (14/24) for physiotherapy. Over 90% (55/60) of CF centers followed CF-specific infection control guidelines and consistent infection control practices were seen in most CF centers; 76% (41/54) had implemented segregation strategies for ambulatory care and no CF centers housed people with CF in shared inpatient accommodation. However, the application of contact precautions (wearing gloves and apron/gown) by healthcare professionals when reviewing a CF person was variable between CF center respondents but was most often used when seeing CF persons with MRSA infection in both ambulatory care and hospital admission (20/50, 40% and 42/45, 93% of CF centers, respectively). Mask wearing by people with CF was implemented into 61% (36/59) of centers. Hospital rooms were cleaned daily in 79% (37/47) of CF centers and the ambulatory care consult rooms were always cleaned between consults (49/49, 100%) and at the end of the clinic session (51/51, 100%); however the staff member tasked with cleaning changed with 37% (18/49) of CF centers responding that CF multidisciplinary team (MDT) members cleaned between patients whereas at the end of the clinic session, only 12% (6/51) of the CF MDT cleaned the consult room.
Overall, Australian and NZ CF centers have adopted many recommendations from the IP&C. Although, the application of contact precautions was inconsistent and had overall a low level of adoption in CF centers. In ~ 25% of centers, mixed waiting areas occurred in the ambulatory care. Given the variability of responses, additional work is required to achieve greater consistency between centers.
-These results are really surprising in view of the experience of serious cross infection with P. aeruginosa even with some fstalities, reported from this region
Dr Rebecca E Stockwell is with the Lung Bacteria Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
Tang Y, Yan Z, Engelhardt JF. Viral Vectors, Animal Models, and Cellular Targets for Gene Therapy of Cystic Fibrosis Lung Disease. Hum Gene Ther. 2020 Mar 5. doi: 10.1089/hum.2020.013. [Epub ahead of print] [Pubmed]
After more than two decades since clinical trials tested the first use of recombinant adeno-associated virus (rAAV) to treat cystic fibrosis (CF) lung disease, gene therapy for this disorder has undergone a tremendous resurgence. Fueling this enthusiasm has been an enhanced understanding of rAAV transduction biology and cellular processes that limit transduction of airway epithelia, the development of new rAAV serotypes and other vector systems with high level tropism for airway epithelial cells, an improved understanding of CF lung pathogenesis and the cellular targets for gene therapy, and the development of new animal models that reproduce the human CF disease phenotype. These advances have created a preclinical path for both assessing the efficacy of gene therapies in the CF lung and interrogating the target cell types in the lung required for complementation of the CF disease state. Lessons learned from early gene therapy attempts with rAAV in the CF lung have guided thinking for the testing of next generation vector systems. Although unknown questions still remain regarding the cellular targets in the lung that are required or sufficient to complement CF lung disease, the field is now well positioned to tackle these challenges. This review will highlight the role next-generation CF animal models are playing in the preclinical development of gene therapies for CF lung disease and the knowledge gaps in disease pathophysiology these models are attempting to fill.
Dr Yinghua (Edward) Tang is at the University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, United States.
Taylor-Cousar JL, Evans TA, Cutting GR, Sharma N. Potentially lethal cystic fibrosis gene variant in the orangutan. Am J Primatol. 2020 Jan 22:e23097. doi: 10.1002/ajp.23097. [Epub ahead of print [Pubmed]
A syndrome of chronic upper and lower airway disease leading to increased morbidity and mortality occurs primarily in captive orangutans. Similarities in symptoms to the inherited human respiratory disease, cystic fibrosis, led the authors to hypothesize that orangutan respiratory disease is a result of variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. They identified the nonsense variant, c.484A>T (p.Lys162X), in heterozygosity in an unaffected orangutan. Analysis of the pedigree of this orangutan confirmed that both his sire and deceased fetus also harboured the c.484A>T allele. An expression minigene harbouring c.484A>T produced no full-length CFTR protein in HEK293 cells. Finally, the c.484A>T CFTR messenger RNA abundance was severely reduced in primary nasal epithelial cells of the orangutan indicating that c.484A>T (p.Lys162X) is potentially lethal. Genetic screening of the captive orangutan population could be used to prevent transmission of this potentially lethal variant, and thus aid in the conservation of this critically endangered species
Taylor SL, Leong LEX, Ivey KL, Wesselingh S, Grimwood K, Wainwright CE, Rogers GB; Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group. Total bacterial load, inflammation, and structural lung disease in paediatric cystic fibrosis. J Cyst Fibros. 2020 Mar 18. pii: S1569-1993(20)30079-5. doi: 10.1016/j.jcf.2020.03.008. [Epub ahead of print] [Pubmed]
Cystic fibrosis (CF) is characterised by reduced airway clearance, microbial accumulation, inflammation, and lung function decline. Certain bacterial species may contribute disproportionately to worsening lung disease. However, the relative importance of these microorganisms compared to the absolute abundance of all bacteria is uncertain. The authors aimed to identify the characteristics of lower airway microbiology that best reflect CF airway inflammation and disease in children.
Analysis was performed on bronchoalveolar lavage (BAL) fluid from 78 participants of the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial, aged 4.5-5.5 years. Universal bacterial quantitative PCR (qPCR), species-specific qPCR, and 16S rRNA gene sequencing were performed on DNA extracts to determine total bacterial load, species-specific load and taxa relative abundance. Quantification of pre-specified pathogens was performed by culture-based methods. Bacteriological data were related to neutrophil counts, interleukin-8, lung function, and two computed-tomography based measures, CF-CT (as the primary measure) and PRAGMA.
Of all bacteriological measures assessed, total bacterial load determined by qPCR correlated most strongly with structural disease (CF-CT total score, rs=0.30, P=0.0095). Specifically, total bacterial load correlated with bronchiectasis, airway wall thickening, mucus plugging and parenchymal disease sub-scores. In contrast, culture-based quantification, microbiota-derived measures, and pathogen-specific qPCR-based quantification were weakly associated with total CF-CT. Regression analyses supported correlation findings, with total bacterial load explaining the greatest variance in total CF-CT (R2=0.097, P=0.0061). Correlations with PRAGMA score were comparable to CF-CT total score.
the authors concluded within the ACFBAL trial, culture-independent quantification of total bacteria provided the most clinically informative bacteriological measure in 5-year-old CF patients.
Steven Taylor is at the SAHMRI Microbiome Research Laboratory, Flinders University College of Medicine and Public Health, Adelaide, SA, Australia; Microbiome and Host Health, South Australia Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia
Turkovic L, Caudri D, Rosenow T, Breurer O, Murray C, Tiddens HAWM, Ramanauskas F, Ranganathan SC, Hall GL, Stick SM; AREST CF. Structural determinants of long term functional outcomes in young children with cystic fibrosis. Eur Respir J. 2020 Mar 5. pii: 1900748. doi: 10.1183/13993003.00748-2019. [Epub ahead of print] [Pubmed]
Accelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients.
Annual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of AREST CF cohort for children aged 3-months to 6-years. Annual spirometry measurements were available for 89.77% of the cohort (n=167 children at age 5-6 years) from ages 5 to 15 years through outpatient clinics at Perth Children’s Hospital and The Royal Children’s Hospital in Melbourne. (n=697 measurements, age 9.3 (2.1) years).
Findings: Children with a total CT score at 5-6 years above the median were more likely to have abnormal FEV1 (aHR 2.67 (1.06, 6.72) p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV1 Z scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change -0.17 (-0.26, -0.07) p<0.001 and -0.09 (-0.14, -0.04) p<0.001 respectively).
The authors observe that this study shows that chest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success.
Dr Lidijat Turkovic was at Telethon Kids Institute, Perth, Australia and now Principal Biostatistician, IQVIA Human Data Science Company, Melbourne, Australia
– This excellent long-term data from AREST CF study provides further hard evidence that what happens in very early childhood determines the situation many years later. Once damage occurs progress is downhill even though considerably slowed by treatment during childhood.
van Heusden C, Button B, Anderson WH, Ceppe A, Morton LC, O’Neal WK, Dang H, Alexis NE, Donaldson S, 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. 2020 Feb 1;318(2):L356-L365. doi: 10.1152/ajplung.00449.2019. Epub 2019 Dec 4[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.
Dr C van Heusden of the Marsico Lung Institute/UNC CF Research Center, University of North Carolina, Chapel Hill, North Carolina.
Waterer G, Lord J, Hofmann T, Jouhikainen T. A Phase I, dose-escalating study of safety and pharmacokinetics of inhaled dry powder vancomycin (AeroVanc) in volunteers and patients with cystic fibrosis: a new approach to therapy for methicillin-resistant Staphylococcus aureus.
Antimicrob Agents Chemother. 2020 Jan 21. pii: AAC.01776-19. doi: 10.1128/AAC.01776-19. [Epub ahead of print] [Pubmed]
Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, the authors developed a dry powder formulation suitable for inhalation (AeroVanc).
They report a Phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.
Dr Grant Waterer is Professor of Medicine, University of Western Australia is a respiratory physician at Royal Perth Hospital and is a professor of medicine at the University of Western Australia and professor of medicine at Northwestern University, Chicago, USA.
Yeung JC, Machuca TN, Chaparro C, Cypel M, Stephenson AL, Solomon M, Saito T, Binnie M, Chow CW, Grasemann H, Pierre AF, Yasufuku K, de Perrot M, Donahoe LL, Tikkanen J, Martinu T, Waddell TK, Tullis E, Singer LG, Keshavjee S. Lung transplantation for cystic fibrosis.
J Heart Lung Transplant. 2020 Feb 20. pii: S1053-2498(20)31404-2. doi: 10.1016/j.healun.2020.02.010. [Epub ahead of print] [Pubmed]
The contribution of lung transplantation to the treatment of patients with end-stage cystic fibrosis (CF) has been debated. The authors aimed to describe achievable outcomes from high-volume CF and lung transplant programs. This study reports on the largest single-center experience of lung transplantation for adult and pediatric patients with CF. It also highlights the evolution of practice and outcomes over time. A retrospective analysis of the prospectively collected Toronto Lung Transplant database was carried out. Post-transplant survival in CF was calculated using the Kaplan-Meier method and analyzed with log-rank tests.
From 1983 to 2016, a total of 1,885 transplants were performed at our institution, where 364 (19.3%) were CF recipients and another 39 (2.1%) were CF re-transplants. The mean age at first transplant was 29.5 ± 9.7 years where 56.6% were males and 91.5% were adults. Pre-transplantation, 88 patients (24.2%) were Burkholderia cepacia complex (BCC)-positive, 143 (39.3%) had diabetes mellitus, and the mean forced expiratory volume in one second was 26.0 ± 7.2%, as predicted at listing. The 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively. Pediatric, BCC-positive, and re-transplant recipients had worse survival than adult patients who were BCC-negative. Strategies to improve the donor pool did not affect survival but possibly reduced waitlist mortality. For the entire cohort, the most common causes of death after lung transplant were infection and chronic lung allograft dysfunction.
The authors consider lung transplantation for CF provides excellent short- and long-term outcomes. These results strongly support lung transplantation as the standard of care for patients with CF having advanced lung disease.
Dr Jonathan Yeung, Thoracic surgeon and members of the Toronto Lung Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada; Division of Thoracic Surgery, Toronto General Hospital, Toronto, Ontario, Canada.
Zhang D, Li S, Wang N, Tan HY, Zhang Z, Feng Y. The Cross-Talk Between Gut Microbiota and Lungs in Common Lung Diseases.
Front Microbiol. 2020 Feb 25;11:301. doi: 10.3389/fmicb.2020.00301. eCollection 2020. Free PMC Article [Pubmed]
Emerging findings indicate there is a vital cross-talk between gut microbiota and the lungs, which is known as gut-lung axis. The gut disturbances in lung diseases including allergy, asthma, chronic obstructive pulmonary disease, cystic fibrosis and lung cancer were observed by extensive studies. Investigating how gut microbiota impact other distant organs is of great interest in recent years. Although it has not been fully understood whether the disturbance is the cause or effect of lung diseases, alterations in the gut microbial species and metabolites have been linked to changes in immune responses and inflammation as well as the disease development in the lungs. In this article, we systemically review the role and mechanisms underlying the changes in the constituent of gut microbiota and metabolites in lung diseases. In particular, the roles of gut-lung axis in mediating immune responses and reshaping inflammation are highlighted. Furthermore, we discuss the potential of strategies to manipulate the gut microbiota and metabolites as the therapeutic approach for lung diseases.
D Zhang is at the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.