2022 M – Z

Ryan MarshHelen GavilletLiam HansonChristabella NgMandisa Mitchell-WhyteGiles MajorAlan R SmythDamian RivettChristopher van der Gast.   Intestinal function and transit associate with gut microbiota dysbiosis in cystic fibrosis.  J Cyst Fibros 2022 May;21(3):506-513.doi.10.1016/j.jcf.2021.11.014. Epub 2021 Dec 8. [Pubmed]Free article

Ryan Marsh researchgate.net

Background: Most people with cystic fibrosis (pwCF) suffer from gastrointestinal symptoms and are at risk of gut complications. Gut microbiota dysbiosis is apparent within the CF population across all age groups, with evidence linking dysbiosis to intestinal inflammation and other markers of health. This pilot study aimed to investigate the potential relationships between the gut microbiota and gastrointestinal physiology, transit, and health.
Study design: 
Faecal samples from 10 pwCF and matched controls were subject to 16S rRNA sequencing. Results were combined with clinical metadata and MRI metrics of gut function to investigate relationships.
Results: 
pwCF had significantly reduced microbiota diversity compared to controls. Microbiota compositions were significantly different, suggesting remodelling of core and rarer satellite taxa in CF. Dissimilarity between groups was driven by a variety of taxa, including Escherichia coli, Bacteroides spp., Clostridium spp., and Faecalibacterium prausnitzii. The core taxa were explained primarily by CF disease, whilst the satellite taxa were associated with pulmonary antibiotic usage, CF disease, and gut function metrics. Species-specific ordination biplots revealed relationships between taxa and the clinical or MRI-based variables observed.

Conclusions: Alterations in gut function and transit resultant of CF disease are associated with the gut microbiota composition, notably the satellite taxa. Delayed transit in the small intestine might allow for the expansion of satellite taxa resulting in potential downstream consequences for core community function in the colon.

Ryan Marsh is a PhD student in the Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom.

Clémence Martin, Martine Reynaud-Gaubert, Rebecca Hamidfar, Isabelle Durieu, Marlène Murris-Espin, Isabelle Danner-Boucher, Raphaël Chiron, Sylvie Leroy, Benoit Douvry, Dominique Grenet. Laurent Mely, Sophie Ramel, Sylvie Montcouquiol, LydieLemonnier, Espérie Burnet, Jean-Louis Paillasseur, Jennifer Da Silva, Pierre-Régis Burgel. Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis.  J Cyst Fibros. 2022 Feb 2;S1569-1993(22)00032-7.doi: 10.1016/j.jcf.2022.01.012. Online ahead of print [Pubmed]

Clemence Martin researchgate.net

Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates.

Methods: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021.
Results: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV1) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation.

Conclusion: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

Clémence Martin is at the Université de Paris, Institut Cochin, InsermU1016, Paris, France; Respiratory Medicine and Cystic Fibrosis National Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; ERN-Lung CF network, Frankfurt, Germany.

Ernestina MelicoffFadel E RuizKathleen HosekGeorge B MalloryCystic Fibrosis Lung Transplant Recipients 10 years of age or Younger: Predisposing Factors for End-stage DiseasePediatr Pulmonol 2022 Mar 3.doi: 10.1002/ppul.25882. Online ahead of print. [Pubmed]

Ernestina Melicoff
bcm.edu

Background: The largest age group among children and adolescents referred for lung transplantation for cystic fibrosis (CF) have been those in the pubertal or post pubertal age range. However, over 100 younger patients with CF have undergone lung transplantation over the last three decades in the USA.
Methods: We performed a retrospective review of our experience with 18 children with CF who underwent lung transplantation in our center before the age of 11 years and compared them to our older CF lung transplant recipients and our larger CF Center population.
Results: The transplant population was demographically distinct from our CF center in terms of ethnicity, country of origin, and insurance status. Other notable findings were a high prevalence of methicillin-resistant Staphylococcus aureus, a high prevalence of CF-related diabetes mellitus and a high prevalence of consolidated lobar or whole lung disease. Post-transplant outcomes were comparable to those older than 10 years of age in our center until five years after transplant after which the younger cohort showed a superior enduring survival.
Conclusions: In an era of increasingly effective medications modifying the natural history of CF, identification of risk factors for early severe lung disease in CF remains relevant to permit interventions to prevent or postpone the time of future lung transplantation. This article is protected by copyright. All rights reserved.

Dr Enestina Melicoff is in the Section of Pediatric Pulmonology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital.

Xochitl MellorTerri SchindlerShahrazad SaabErica RoeschThomas SferraSenthilkumar Sankararaman. Eosinophilic esophagitis in cystic fibrosis: A case series with long-term follow-upPediatr Pulmonol 2022 Jun;57(6):1557-1561.doi: 10.1002/ppul.25912. Epub 2022 Apr 11. [Pubmed]
Challenging mealtime behaviors in young children and difficulties in meeting their dietary intake recommendations are sources of parenting stress and associated with negative quality of life. The gastrointestinal (GI) manifestations of cystic fibrosis (CF) can often present similarly to a GI pathology unrelated to CF. Specifically, this case series focuses on three toddlers with CF who presented with oral aversion and challenging mealtime behaviors and later were diagnosed with eosinophilic esophagitis (EoE). Though EoE often presents with dysphagia, younger patients commonly present with nonspecific GI symptoms such as regurgitation, emesis, abdominal pain, failure to thrive, food intolerance, and oral aversion. Given the overlap of GI manifestations in CF and EoE, it can be challenging for clinicians to diagnose the coexistent EoE in patients with CF. We describe the presenting symptoms, treatment, and successful outcomes of three pediatric patients with CF and EoE. To our knowledge, this is the second case series with a detailed description of EoE in CF.

Xochitl Mellor  is a paediatrician in the Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, US

Lina MerjanehSana HasanNader KasimKatie Larson Ode. The role of modulators in cystic fibrosis related diabetesJ Clin Transl Endocrinol  2021 Dec 7;27:100286.doi: 10.1016/j.jcte.2021.100286.eCollection 2022 Mar. Free PMC article   [Pubmed]

Lina Merjaneh seattlechildrens.org

The development and introduction of modulator therapies have completely shifted the paradigm for the treatment of cystic fibrosis (CF). Highly effective modulator therapies have driven marked improvements in lung function, exacerbation rate, weight and quality of life in CF patients. However, their effect on CF related diabetes (CFRD) is not well delineated. The role of CF transmembrane conductance regulator (CFTR) in CFRD pathogenesis is inadequately understood and research aimed at deciphering the underlying mechanisms of CFRD continues to evolve.

In this review, we summarize what is known regarding the effect of CFTR modulators on CFRD. Small studies using ivacaftor monotherapy in gating mutations have revealed improvement in insulin secretion, glucose tolerance and/or decrease in insulin requirement. However, lumacaftor/ivacaftor studies (primarily in delta F 508 homozygous) have not revealed significant improvement in CFRD or glucose tolerance. No studies are yet available regarding the effect of the highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) on CFRD or insulin secretion. CFTR modulators might affect development or progression of CFRD through many mechanisms including improving insulin secretion by correcting the CFTR defect directly, improving ductal function, reducing islet inflammation, and improving incretin secretion or by enhancing insulin sensitivity via reduced systemic inflammation and increased physical activity driven by improved lung function and quality of life. On the other hand, they can stimulate appetite and improve gastrointestinal function resulting in increased caloric intake and absorption, driving excessive weight gain and potentially increased insulin resistance. If the defect in insulin secretion is reversible then it is possible that initiation of CFTR modulators at a younger age might help prevent CFRD. Despite the advances in CF management, CFRD remains a challenge and knowledge continues to evolve. Future studies will drive better understanding of the role of highly effective CFTR modulators in CFRD.

Dr Lina Merjaneh is a pediatric endocrinologist and Assistant Professor at Seattle Children’s Hospital.

Julie Mésinèle Manon RuffinLoïc GuillotPierre-Yves BoëlleHarriet CorvolOn Behalf Of The French Cf Modifier Gene Study Investigators.  Factors predisposing the response to Lumacaftor/ivacaftor in people with cystic fibrosis. J Pers Med 2022 Feb 10;12(2):252.doi: 10.3390/jpm12020252.  35207740     Free PMC article
Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy.

A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years.

We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA.

Dr Julie Mésinèle is Post-Doctoral Researcher in Biostatistics at the Centre de Recherche Saint-Antoine (CRSA), Inserm, Sorbonne Université, 75012 Paris, France. and Hôpital Saint-Antoine, AP-HP, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Inserm, Sorbonne Université, 75012 Paris, France

Amir Moheet Antoinette MoranNew concepts in the pathogenesis of cystic fibrosis-related diabetes.  J Clin Endocrinol Metab. 2022 Feb 2;dgac020.doi: 10.1210/clinem/dgac020.Online ahead of print. [Pubmed]

Amir Moheet med.umn.edu

Context: Cystic fibrosis related diabetes (CFRD) is the most common extra pulmonary complication of cystic fibrosis (CF). Around 40% of people with CF above age 20 have CFRD. Presence of CFRD is associated with poor health outcomes in people with CF.
Objective: This review summarizes current knowledge on pathophysiology of CFRD.
Methods: A PubMed review of the literature was conducted, and search terms included CFRD, cystic fibrosis, cystic fibrosis related diabetes, and cystic fibrosis transmembrane conductance regulator (CFTR). Additional sources were identified through manual searches of reference lists. The pathophysiology underlying development of glucose tolerance abnormalities in CF is complex and not fully understood. β-cell loss and functional impairment of the remaining β-cell function results in progressive insulin insufficiency. Factors that may contribute to development in CFRD include local islet and systemic inflammation, alterations in the incretion hormone axis, varying degrees of insulin resistance and genetic factors related to type 2 diabetes
Conclusion: The prevalence of CFRD is expected to further increase with improving life expectancy of people with CF. Further research is needed to better understand the mechanisms underlying the development of CFRD and the impact of diabetes on clinical outcomes in CF.

Dr Amir Moheet is in the Department of Medicine, University of Minnesota, Minneapolis, Minnesota
Dr Antoinette Moran is in the Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota

Danya MuilwijkEyleen de PoelPeter van MourikSylvia W F SuenAnnelotte M Vonk Jesse E Brunsveld  et al.(please see PubMed abstract for full author list).  Forskolin-induced Organoid Swelling is Associated with Long-term CF Disease ProgressionEur Respir J 2022 Jan 27;2100508.doi: 10.1183/13993003.00508-2021. Online ahead of print.  3  [Pubmed]

Danya Muilwijk nl.linkedin.com

Rationale: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids (PDO) with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).
Methods: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed effect models and multivariable logistic regression to estimate the association of FIS with long-term FEV1pp decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.
Results: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95%CI: 0.11%-0.54%; p=0.004) per 1000-points change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR: 0.18, 95%CI: 0.07-0.46, p<0.001), CF-related liver disease (adjusted OR: 0.18, 95%CI: 0.06-0.54, p=0.002) and diabetes (adjusted OR: 0.34, 95%CI: 0.12-0.97, p=0.044). These associations were absent for SCC.

Conclusion: This study exemplifies the prognostic value of a PDO-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Dr Danya Muilwijk is a PhD candidate in the Department of Pediatric Respiratory Medicine, Wilhelmina Children’s Hospital, University Medical Center, Utrecht University, Utrecht, The Netherlands.

Eyleen de Poel  is in the Department of Regenerative Medicine Utrecht, University Medical Center, Utrecht University, Utrecht, The Netherlands.

David P NicholsAlex C PaynterSonya L HeltsheScott H DonaldsonCarla A FrederickSteven D Freedman and the other members of the PROMISE Study group. Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical TrialAm J Respir Crit Care Med. 2022 Mar 1;205(5):529-539 doi: 10.1164/rccm.202108-1986OC     Free PMC article [Pubmed

David Nichols seattle childrens.org

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF.
Objectives: PROMISE is a post-approval study to understand the broad effects of ETI through 30 months’ clinical use in a more diverse U.S. patient population with planned analyses after 6 months Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms.
Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV1 improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline.

Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Dr David P Nichols is at the Department of Pediatrics, and. Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children’s Research Institute, Seattle, Washington.

Nowak JK, Wykrętowicz A, Mądry E, Krauze T, Drzymała-Czyż S, Krzyżanowska-Jankowska P, Sobkowiak P, Schneider A, Goździk-Spychalska J, Kurek S, Kononets V, Kashirskaya N, Lisowska A, Walkowiak J.    Preclinical atherosclerosis in cystic fibrosis: Two distinct presentations are related to pancreatic status.     J Cyst Fibros. 2022 Jan;21(1):26-33. doi: 10.1016/j.jcf.2021.06.010. Epub 2021 Jul 10.  [Pubmed]
Background: Patients with cystic fibrosis (CF) are exposed to overlapping cardiovascular risk factors. We hypothesized that CF is characterized by increased arterial stiffness and greater intima-media thickness (IMT).
Methods: This cross-sectional study assessed the digital volume pulse arterial stiffness index (SIDVP) using photopletysmography, measured intima-media complex thickness (IMT) at the common carotid artery, and obtained an extended set of clinical and atherosclerosis-related laboratory parameters.
Results: Fifty-five patients with moderate-to-severe CF (mean age 26.3±8.6 years, BMI 20.3±3.1 kg/m2, FEV1 62±26%) and 51 healthy controls (25.1±4.4 years, BMI 21.7±3.0 kg/m2) entered the study. SIDVP was greater in pancreatic insufficient (PI), but not pancreatic sufficient (PS) CF patients compared with control (7.3±1.8 m/s vs 6.0±1.2 m/s; p=7.1 × 10-5). IMT was increased in PS (but not PI) participants relative to control (552±69 µm vs 456±95 µm, p=0.0011). SIDVP was also greater in PI than in PS patients (7.3±1.8 m/s vs 6.3±1.7 m/s, p=0.0232) and IMT was higher in PS compared with PI (552±69 µm vs 453±82 µm, p=0.0002). SIDVP independently associated with age, PI, the lack of liver cirrhosis, and with Pseudomonas aeruginosa colonization. PS was the only independent correlate of IMT in CF.

Conclusions: PI patients are at risk of developing general arterial stiffness. PS may relate to carotid IMT thickening, which underscores the need for further study that could lead to reconsideration of dietary guidance in PS CF.

JK Nowak is at the Poznan University of Medical Sciences, Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan, Poland.

Sophia Theres PallenbergSibylle JungeFelix C RingshausenAnnette Sauer-HeilbornGesine HansenAnna Maria DittrichBurkhard TümmlerManuel Nietert.  CFTR modulation with elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis assessed by the β-adrenergic sweat rate assay. J Cyst Fibros 2022 May;21(3):442-447.doi: 10.1016/j.jcf.2021.10.005. Epub 2021 Oct 29. Free article   [Pubmed]

Sophia There’s Pallenberg research gate.net

Background: The cystic fibrosis (CF) sweat gland is defective in β-adrenergically-stimulated sweat secretion in the coil and chloride reabsorption in the duct. Whereas chloride reabsorption is regularly assessed by quantitative pilocarpine iontophoresis (QPIT), the measurement of β-adrenergic sweat secretion is not yet established in clinical practice
Methods: A novel sweat bubble imaging protocol was developed that determines sweat secretion rates by automatic recording, processing and quality control of the kinetics of sweat droplet formation.
Results: Treatment of CF patients with the CFTR modulators elexacaftor, tezacaftor and ivacaftor reduced the sweat chloride concentration measured in QPIT in the majority of patients to values in the intermediate or normal range. In contrast, the β-adrenergically-stimulated sweat secretion rate assayed by the automated bubble sweat test was normalized in only 3 patients, slightly increased in 12 patients and remained undetectable in 8 patients.

Conclusions: β-adrenergic sweat stimulation in the coil is apparently rather stringent in its requirements for a wild type CFTR conformation whereas chloride reabsorption in the duct tolerates residual structural and functional deficits of native or pharmacologically rescued mutant CFTR in the apical membrane.

Sophia Theres Pallenberg is a clinical scientist in the Department of Pediatric Pneumology, Allergology and Neonatology in, Hannover Medical School, Hannover, Germany.

Petersen MC, Begnel L, Wallendorf M, Litvin M. Effect of elexacaftor-tezacaftor-ivacaftor on body weight and metabolic parameters in adults with cystic fibrosis. Journal of Cystic Fibrosis. 21(2):265-271, 2022 03.    [Pubmed]

Max C Petersen endocrinology.wustl.edu

Background: Though weight gain has been reported in some clinical trials of CFTR modulators, the effect of elexacaftor-tezacaftor-ivacaftor on body weight, body mass index (BMI), blood pressure, lipids and glycemic control in the real-world setting remains incompletely described.

Methods: We performed a single-center, retrospective, observational analysis of the effect of elexacaftor-tezacaftor-ivacaftor on body weight and cardiometabolic parameters in 134 adult CF patients of the Washington University Adult Cystic Fibrosis Center. Body weight, BMI, and blood pressure were extracted from outpatient clinic visits for the year preceding and the period following the initiation of elexacaftor-tezacaftor-ivacaftor. Other metabolic parameters were extracted at baseline and at latest available follow-up

Results: A mean of 12.2 months of follow-up data was available for analysis. The mean rate of change in BMI was 1.47 kg/m2/yr (95% CI, 1.08 to 1.87) greater after initiation of elexacaftor-tezacaftor-ivacaftor. Significant increases in blood pressure were observed. In those without CFRD, random blood glucose and hemoglobin A1c were decreased after elexacaftor-tezacaftor-ivacaftor initiation. In those with CFRD, elexacaftor-tezacaftor-ivacaftor increased serum total cholesterol, HDL-cholesterol, and LDL-cholesterol.

Conclusions: In this single-center, retrospective, observational study of 134 adults with CF, initiation of elexacaftor-tezacaftor-ivacaftor was associated with increases in BMI at a mean follow up of 12.2 months. Changes in other cardiometabolic risk factors were also observed. Widespread use of elexacaftor-tezacaftor-ivacaftor may be expected to increase the incidence of overnutrition in the CF population.

Max C Petersen is in the Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri, USA.

Poore TS, Taylor-Cousar JL, Zemanick ET.   Cardiovascular complications in cystic fibrosis: A review of the literature.J Cyst Fibros. 2022 Jan;21(1):18-25. doi: 10.1016/j.jcf.2021.04.016. Epub 2021 Jun 14.  [Pubmed] 

Thomas S Poore Childrens of Alabama

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to dysfunction of the CFTR protein. CFTR dysfunction leads to disease in the respiratory and gastrointestinal systems. Disorders of the cardiovascular system in individuals with CF are usually attributed to secondary effects from progressive lung disease. However, CFTR has been localized to vascular endothelium and smooth muscle, suggesting that CFTR dysfunction may directly impact cardiovascular function. As treatments for CF improve and life-expectancy increases, the risk of vascular disease may increase in prevalence related to primary and secondary CFTR dysfunction, chronic systemic inflammation, nutritional health and hyperglycemia in individuals with CF related diabetes. Here we review the available literature on CF and the cardiovascular system, examining the secondary effects and evidence for direct CFTR dysfunction in the heart, aorta, pulmonary vessels, and vasculature, as well as future directions and treatment options.

Thomas Spencer Poore is in the Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Magdalena PostekKatarzyna Walicka-SerzyskoJustyna MilczewskaDorota SandsWhat Is Most Suitable for Children With Cystic Fibrosis-The Relationship Between Spirometry, Oscillometry, and Multiple Breath Nitrogen WashoutFront Pediatr 2022 Jan 14;9:692949.doi: 10.3389/fped.2021.692949.eCollection 2021.Free PMC article   [Pubmed]

Dorota Sands szpitaldziekanow.pl

Magdalena Postek research gate.net

Introduction:In cystic fibrosis (CF), pathological lung changes begin early in life. The technological progress currently gives many diagnostic possibilities. However, pulmonary function testing in children remains problematic.
Objectives:Our study aimed to correlate the results of impulse oscillometry (IOS) with those of multiple breath nitrogen washout (MBNW) in our pediatric CF population. We also compared those parameters between the groups with and without spirometric features of obturation.
Methods:We collected 150 pulmonary function test sets, including spirometry, IOS, and MBNW in patients with CF aged 12.08 ± 3.85 years [6-18]. The study group was divided into two subgroups: IA (without obturation) and IB (with obturation). We also compared Sacin, Scond, and oscillometry parameters of 20 patients aged 14-18 years who reached the appropriate tidal volume (VT) during MBNW.
Results:Statistical analysis showed a negative correlation between lung clearance index (LCI) and spimoetric parameters. Comparison of subgroups IA (n = 102) and IB (n = 48) indicated a statistically significant difference in LCI (p < 0.001) and FEV1z-score (p < 0.001), FEV1% pred (p < 0.001), MEF25z-score (p < 0.001), MEF50 z-score (p < 0.001), MEF75 z-score (p < 0.001), R5% pred (p < 0.05), and R20% pred (p < 0.01). LCI higher than 7.91 was found in 75.33% of the study group, in subgroup IB-91.67%, and IA-67.6%.

Conclusions:LCI derived from multiple breath nitrogen washout (MBNW) may be a better tool than impulse oscillometry (IOS) for assessing pulmonary function in patients with CF, particularly those who cannot perform spirometry.

Dr Magdalena Postek is in the Cystic Fibrosis Department, Institute of Mother and Child, Warsaw, Poland and the Cystic Fibrosis Centre, Pediatric Hospital, Dziekanów Leśny, Poland.

Prof. Dorota Sands is a senior Paediatrician and coordinator at the Cystic Fibrosis Centre.

Marjolein MijndersSabine A FuchsEdward E S NieuwenhuisPossible applications of organoids in medicine. Ned TijdschrGeneeskd  2022 Jan 12;166:D6011.   35138705  [Article in Dutch]      [Pubmed]

Marjolein Mijnders uu.nl

With the development of organoids as three-dimensional model organs it is now possible to mimic the growth of human organs in a culture dish. As these model organs can be generated from patients’ (diseased) tissue and capture the (genetic) properties thereof, they are more representative disease models than cell lines and animal models. The use of organoids in pathophysiological research has already increased our understanding of many human diseases. Furthermore, organoids are used for patient-specific drug tests for cystic fibrosis, and this will soon be possible for other genetic diseases. Also, transplantation of (own genetically corrected) organoids could become a new treatment option. To fully employ the potential of organoids in medicine, cultures need to be standardized and further optimized for better organ/disease representation. With this, organoids hold the promise to quickly revolutionize personalized and regenerative medicine.

Dr Marjolein Mijndersis atUMC Utrecht, Wilhelmina Kinderziekenhuis, afd. Maag-, Darm- en Leverziekten, Utrecht.

Ernestina MelicoffFadel E RuizKathleen HosekGeorge B MalloryCystic Fibrosis Lung Transplant Recipients 10 years of age or Younger: Predisposing Factors for End-stage DiseasePediatr Pulmonol 2022 Mar 3.doi: 10.1002/ppul.25882. Online ahead of print. [Pubmed]

Ernestina Melicoff bcm.edu

Background:The largest age group among children and adolescents referred for lungtransplantation for cystic fibrosis (CF) have been those in the pubertal or post pubertal age range. However, over 100 younger patients with CF have undergone lung transplantation over the last three decades in the USA.
Methods:We performed a retrospective review of our experience with 18 children with CF who underwent lung transplantation in our center before the age of 11 years and compared them to our older CF lung transplant recipients and our larger CF Center population.
Results:The transplant population was demographically distinct from our CF center in terms of ethnicity, country of origin, and insurance status. Other notable findings were a high prevalence of methicillin-resistant Staphylococcus aureus, a high prevalence of CF-related diabetes mellitus and a high prevalence of consolidated lobar or whole lung disease. Post-transplant outcomes were comparable to those older than 10 years of age in our center until five years after transplant after which the younger cohort showed a superior enduring survival.
Conclusions:In an era of increasingly effective medications modifying the natural history of CF, identification of risk factors for early severe lung disease in CF remains relevant to permit interventions to prevent or postpone the time of future lung transplantation.

Dr Ernestina Melicoff is Assistant Professor in the the Section of Pediatric Pulmonology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital

Julie MésinèleManon RuffinLoïc GuillotPierre-Yves BoëlleHarriet CorvolOn Behalf Of The French Cf Modifier Gene Study Investigators.  Factors predisposing the response to Lumacaftor/ivacaftor in people with cystic fibrosis. J Pers Med 2022 Feb 10;12(2):252.doi: 10.3390/jpm12020252. [Pubmed]Free PMC article
Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy.

A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years.

We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA.

Dr Julie Mésinèle is Post-Doctoral Researcher in Biostatistics at the Centre de Recherche Saint-Antoine (CRSA), Inserm, Sorbonne Université, 75012 Paris, France. and Hôpital Saint-Antoine, AP-HP, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Inserm, Sorbonne Université, 75012 Paris, France

Aaron C MillerLogan M Harris ,Joseph E CavanaughMahmoud Abou AlaiwaDavid A StoltzDouglas B HornickPhilip M Polgreen. The rapid reduction of infection-related visits and antibiotic use among people with cystic fibrosis after starting Elexacaftor-Tezacaftor-Ivacaftor.  Clin Infect Dis 2022 Feb 10;ciac117.doi: 10.1093/cid/ciac117. Online ahead of print.  [Pubmed

Aaron C Miller informatics.grad.uiowa.edu

Background: People with cystic fibrosis (CF) routinely suffer from recurrent sino-pulmonary infections. Such infections require frequent courses of antimicrobials and often involve multidrug-resistant organisms. The goal of this study was to identify real-world evidence for the effectiveness of Elexacaftor-Tezacaftor-Ivacaftor (ELX/TEZ/IVA) at decreasing infection-related visits and antimicrobial use in people with CF.
Methods: Using IBM MarketScan data, we identified 389 enrollees with CF who began taking ELX/TEZ/IVA prior to 12/1/2019 and were enrolled from 7/1/2019-3/14/2020. We also identified a comparison population who did not begin ELX/TEZ/IVA during the study period. We compared the following outcomes in the 15 weeks before and after medication initiation: total healthcare visits, inpatient visits, infection-related visits, and antimicrobial prescriptions. We analyzed outcomes using both a case-crossover analysis and a difference-in-differences analysis, to control for underlying trends.
Results: For the case-crossover analysis, ELX/TEZ/IVA initiation was associated with 2.20 (95% CI: -3.26, -1.14) fewer overall healthcare visit-days, 0.16 (95% CI: -0.22, -0.11) fewer inpatient admissions, 0.33 (95% CI: -0.59, -0.07) fewer infection-related visit-days, and 0.78 (95% CI: -1.03, -0.54) fewer antibiotic prescriptions over a 15 week period. Results from the difference-in-differences approach were similar.

Conclusions: We show a rapid reduction of infection-related visits and antimicrobial use among people with CF after starting a therapy that was not explicitly designed to treat infections. Currently, there are over 30,000 people living with CF in the United States alone. Given that this therapy is effective for approximately 90% of people with CF, the impact on respiratory infections and antimicrobial use may be substantial.

Dr Aaron C Miller is at the Department ofInternal Medicine, University of Iowa, Iowa City, IA, USA.

Amir MoheetAntoinette Moran. New concepts in the pathogenesis of cystic fibrosis-related diabetes.  J Clin Endocrinol Metab. 2022 Feb 2;dgac020.doi: 10.1210/clinem/dgac020.Online ahead of print.    [Pubmed]

Amir Motet med.umn.edu

Context: Cystic fibrosis related diabetes (CFRD) is the most common extra pulmonary complication of cystic fibrosis (CF). Around 40% of people with CF above age 20 have CFRD. Presence of CFRD is associated with poor health outcomes in people with CF.
Objective: This review summarizes current knowledge on pathophysiology of CFRD.
Methods: A PubMed review of the literature was conducted, and search terms included CFRD, cystic fibrosis, cystic fibrosis related diabetes, and cystic fibrosis transmembrane conductance regulator (CFTR). Additional sources were identified through manual searches of reference lists. The pathophysiology underlying development of glucose tolerance abnormalities in CF is complex and not fully understood. β-cell loss and functional impairment of the remaining β-cell function results in progressive insulin insufficiency. Factors that may contribute to development in CFRD include local islet and systemic inflammation, alterations in the incretion hormone axis, varying degrees of insulin resistance and genetic factors related to type 2 diabetes
Conclusion: The prevalence of CFRD is expected to further increase with improving life expectancy of people with CF. Further research is needed to better understand the mechanisms underlying the development of CFRD and the impact of diabetes on clinical outcomes in CF.

Dr Amir Moheet is in the Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Dr Antoinette Moran is in the Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota

Danya Muilwijk nl.linkedin.com

Danya MuilwijkEyleen de PoelPeter van MourikSylvia W F SuenAnnelotte M VonkJesse E Brunsveld et al.(please see PubMed abstract for full author list).  Forskolin-induced Organoid Swelling is Associated with Long-term CF Disease Progression.  Eur Respir J 2022 Jan 27;2100508.doi: 10.1183/13993003.00508-2021. Online ahead of print.  [Pubmed
Rationale: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids (PDO) with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).
Methods: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed effect models and multivariable logistic regression to estimate the association of FIS with long-term FEV1pp decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.
Results: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95%CI: 0.11%-0.54%; p=0.004) per 1000-points change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR: 0.18, 95%CI: 0.07-0.46, p<0.001), CF-related liver disease (adjusted OR: 0.18, 95%CI: 0.06-0.54, p=0.002) and diabetes (adjusted OR: 0.34, 95%CI: 0.12-0.97, p=0.044). These associations were absent for SCC.

Conclusion: This study exemplifies the prognostic value of a PDO-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Dr Danya Muilwijk is a PhD candidate in the Department of Pediatric Respiratory Medicine, Wilhelmina Children’s Hospital, University Medical Center, Utrecht University, Utrecht, The Netherlands.

Eyleen de Poel is in the Department of Regenerative Medicine Utrecht, University Medical Center, Utrecht University, Utrecht, The Netherlands.

E NauwynckJ VanbesienJ De SchepperI GiesA Van LeynseeleE De WachterB HauserW Staels.  Everything in excess is opposed to nature, even vitamin D: a case reportEndocrinol Diabetes Metab Case Rep 2022 Feb 1;2022:21-0181.doi: 10.1530/EDM-21-0181.Online ahead of print. Free PMC article [Pubmed]
Summary:Vitamin D intoxication in children is rare but its incidence is increasing as vitamin D is supplemented more often and in higher doses. Children with cystic fibrosis (CF) are at risk for vitamin D intoxication due to incorrect compounded preparations of liposoluble vitamins. Here, we report a severe vitamin D intoxication in a 4-year-old girl with CF, due to an error in the compounded vitamin A, D, E, and K preparation, presenting clinically with weight loss, constipation, polydipsia, polyuria, and nycturia. The administered compounded preparation contained 10 000-fold the prescribed vititsiamin D dose. The patient was treated with hyperhydration, loop diuretics, and bisphosphonates. Serum calcium levels normalized after 4 days but serum 25-hydroxyvitamin D levels remained elevated even up to 2 months after treatment.

Learning points:Vitamin D intoxication should be ruled out when patients with cystic fibrosis (CF) present with acute polyuria, constipation, and weight loss. Prompt treatment is necessary to avert life-threatening complications. Regularly measuring serum calcium and 25-hydroxyvitamin D concentrations in children with CF receiving vitamin A, D, E, and K supplements is important during their follow-up.

Dr E Nauwynck is in the Division of Pediatric Endocrinolgy, KidZ Health Castle, UZ Brussel Vrije Universitiet, Brussels Belgium

Thi Tham NguyenGraham R JohnsonScott C BellLuke D Knibbs. A Systematic Literature Review of Indoor Air Disinfection Techniques for Airborne Bacterial Respiratory Pathogens. Int J Environ Res Public Health 2022 Jan 21;19(3):1197.doi: 10.3390/ijerph19031197    Free PMC article    [Pubmed]
Interrupting the transmission of airborne (<≈5 µm) respiratory pathogens indoors is not a new challenge, but it has attracted unprecedented interest due to the COVID-19 pandemic during 2020-2021. However, bacterial respiratory pathogens with known or potential airborne transmission account for an appreciable proportion of the communicable disease burden globally. We aimed to systematically review quantitative, laboratory-based studies of air disinfection techniques for airborne respiratory bacteria. Three databases (PubMed, Web of Science, Scopus) were searched, following PRISMA guidelines. A total of 9596 articles were identified, of which 517 were assessed in detail and of which 26 met the inclusion and quality assessment criteria. Seven air disinfection techniques, including UV-C light, filtration, and face masks, among others, were applied to 13 different bacterial pathogens. More than 80% of studies suggested that air disinfection techniques were more effective at inactivating or killing bacteria than the comparator or baseline condition. However, it was not possible to compare these techniques because of methodological heterogeneity and the relatively small number of the studies. Laboratory studies are useful for demonstrating proof-of-concept and performance under controlled conditions. However, the generalisability of their findings to person-to-person transmission in real-world settings is unclear for most of the pathogens and techniques we assessed.

Thi Tham Nguyen is at the School of Public Health, The University of Queensland, Herston, QLD 4006, Australia

 Qi Ni; Chen X; Zhang P; Yang L; Lu Y; Xiao F; Wu B; Wang H; Zhou W; Dong X.  Systematic estimation of cystic fibrosis prevalence in Chinese and genetic spectrum comparison to Caucasians.  Orphanet Journal Of Rare Diseases. 17(1):129, 2022 03 21. Free article [Pubmed]
Background: Cystic fibrosis (CF) is a common, life-threatening genetic disease in Caucasians but rarely reported in Chinese population. The prevalence and population-specific genetic spectrum of CF in China needs to be systematically estimated and compared with Caucasians.
Materials and methods: We reviewed 30,951 exome-sequencing samples, including 20,909 pediatric patient samples and 10,042 parent samples, from Chinese Children’s Rare Disease Genetic Testing Clinical Collaboration System (CCGT). After the in-lab filtration process, 477 candidate variants of CFTR gene were left and 53 variants were manually curated as pathogenic/likely-pathogenic (P/LP). These P/LP variants were adopted to estimate CF prevalence in three methods: the carrier frequency method, the permutation-combinations method and the Bayesian framework method. Allele frequencies of the 477 CFTR variants were compared with non-Finland European (NFE) and East Asian (EAS) from gnomAD database. To investigate the haplotype structure difference of CFTR, another 2067 whole-genome-sequencing samples from CCGT and 195 NFE from 1000 genome project were analyzed by Shapeit4 software.
Result: With the 53 manually curated P/LP variants in CFTR gene, we excluded individuals identified or suspected with CF and their parents in our cohorts and estimated the Chinese CF prevalence is approximately 1/128,434. Only 21 (39.6%) of the 53 variants were included in Caucasian specific CF screening panels, resulting in significantly under-estimation of CF prevalence in our children cohort (1/143,171 vs. 1/1,387,395, P = 5e-24) and parent’s cohort (1/110,127 vs. 1/872,437, P = 7e-10). The allele frequencies of six pathogenic variants (G970D, D979A, M469V, G622D, L88X, 1898+5G->T) were significantly higher in our cohorts compared with gnomAD-NFE population (all P-value < 0.1). Haplotype analysis showed more haplotype diversity in Chinese compared to Caucasians. In addition, G970D and F508del were founder mutation of Chinese and Caucasians with two SNPs (rs213950-rs1042077) identified as related genotype in exon region.

Conclusions: Chinese population showed significantly different genetic spectrum pattern in CFTR gene compared with Caucasian population, and thus a Chinese-specific CF screening panel is needed.

Qi Ni is at the Children’s Hospital and Institutes of Biomedical Sciences, Fudan University, National Children’s Medical Center, Shanghai, 201102, People’s Republic of China and the Center for Molecular Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China.

Katharina NiedermayrVerena GasserClaudia Rueckes-NilgesDorothea AppeltJohannes EderTeresa FuchsLutz NaehrlichHelmut Ellemunter.   Personalized medicine with drugs targeting the underlying protein defect in cystic fibrosis: is monitoring of treatment response necessary.  Ther Adv Chronic Dis   2022 Aug 5;13:20406223221108627.doi: 10.1177/20406223221108627.eCollection 2022.    Free PMC article  [Pubmed]
Cystic fibrosis (CF) is caused by two mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. In the last years, drugs targeting the underlying protein defect like lumacaftor/ivacaftor (LUM/IVA) or tezacaftor/ivacaftor (TEZ/IVA) and more recently elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) were admitted. Outcome parameters evaluating therapy response like forced expiratory pressure in 1 s (FEV1), body mass index (BMI) or the efficacy of CFTR function in sweat glands showed improvement in several cases. Other, CFTRbiomarkers were analysed rarely.
This prospective observational study was aimed at evaluating CFTR function in patients treated with different CFTR modulators together with common valid clinical outcome parameters at standardized appointments (day 0, week 2, 4, 16). We followed four patients with the same mutation (F508del-CFTR), sex, age and disease severity. Monitoring focused on lung function, gastrointestinal aspects and CFTR function of sweat glands, nasal and intestinal epithelium. Sweat tests were performed by pilocarpine iontophoresis. Nasal potential difference (NPD) measured transepithelial voltage in vivo and potential increased when CFTRfunction improved. Rectal biopsies were obtained for intestinal current measurements (ICM) ex vivo. Intestinal CFTR function was assessed by stimulating chloride secretion with different reagents.

Response to CFTR modulators regarding clinical outcome parameters was rather variable. A sweat chloride reduction of 35.3 mmol/L, nasal CFTR rescue of 4.4% and fivefold higher CFTR function in the intestine was seen at week 16 post-LUM/IVA. Due to our monitoring, we identified a non-responder to LUM/IVA and TEZ/IVA. In case of ELX/TEZ/IVA, clinical parameters and CFTR bioassays improved and were concordant. Although our cohort is small, results emphasize that non-responders exist and conclusions could not be drawn if patients were not monitored. Data on CFTR function can confirm or disprove ongoing CFTR dysfunction and might be helpful selectively. Non-responders need other alternative therapy options as demonstrated with ELX/TEZ/IVA.

Dr Katharina Niedermayr is in the Department for Child and Adolescent Health, University Clinic for Paediatrics III, Cystic Fibrosis Centre, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Tyrol, Austria.

Yifat S OrenOfra Avizur-BarchadEfrat Ozeri-GalaiRenana ElgrabliMeital R SchirelmanTehilla BlinderChava D StampferMerav OrdanOnofrio LaselvaMalena Cohen-CymberknohEitan KeremChristine E BearBatsheva KeremAntisense oligonucleotide splicing modulation as a novel Cystic Fibrosis therapeutic approach for the W1282X nonsense mutationJ Cyst Fibros 2022 Jul;21(4):630-636.doi: 10.1016/j.jcf.2021.12.012.Epub 2021 Dec 28.Free article Pubmed

Yifat Oren resarchgate.net

Background:Antisense oligonucleotide- based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to generate skipping over exon 23 of the CFTR transcript, to eliminate the W1282X nonsense mutation and avoid RNA degradation induced by the nonsense mediated mRNA decay mechanism, allowing production of partially active CFTR proteins lacking exon 23.
Methods:∼80 ASOs were screened in 16HBEge W1282X cells. ASO candidates showing significant exon skipping were assessed for their W1282X allele selectivity and the increase of CFTR protein maturation and function. The effect of a highly potent ASO candidates was further analyzed in well differentiated primary human nasal epithelial cells, derived from a W1282X homozygous patient.
Results:ASO screening led to identification of several ASOs that significantly decrease the level of CFTR transcripts including exon 23. These ASOs resulted in significant levels of mature CFTR protein and together with modulators restore the channel function following free uptake into these cells. Importantly, a highly potent lead ASOs, efficiently delivered by free uptake, was able to increase the level of transcripts lacking exon 23 and restore the CFTR function in cells from a W1282X homozygote patient.

Conclusion:The highly efficient exon 23 skipping induced by free uptake of the lead ASO and the resulting levels of mature CFTR protein exhibiting channel function in the presence of modulators, demonstrate the ASO therapeutic potential benefit for CF patients carrying the W1282X mutation with the objective to advance the lead candidate SPL23-2 to proof-of-concept clinical study.

Yifat S Oren is in with Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem, Israel; SpliSense Therapeutics, Jerusalem, Givat Ram, Israel.

Mette F OlsenMaria S Kjøller-SvarreGrith MøllerTerese L KatzensteinBibi U NielsenTacjana PresslerJack I LewisInger H MathiesenChristian MølgaardDaniel Faurholt-JepsenCorrelates of Pancreatic Enzyme Replacement Therapy Intake in Adults with Cystic Fibrosis: Results of a Cross-Sectional Study Nutrients 2022 Mar 22;14(7):1330. doi: 10.3390/nu14071330.  [Pubmed]

   Mette F Olsen

Most people with cystic fibrosis (pwCF) develop pancreatic insufficiency and are treated with pancreatic enzyme replacement therapy (PERT). We aimed to describe the use of PERT and assess the correlates of PERT dose in adult pwCF. In a cross-sectional study at the Copenhagen CF Centre, the participants reported PERT intake, gastrointestinal (GI) symptoms and the use of concomitant treatments. Demographic and clinical characteristics were extracted from the Danish CF Registry. We used linear regression to assess the correlates of PERT dose per kg bodyweight (U-lipase/kg). We included 120 pwCF with a median age of 32.9 years, 46% women and 72% F508delta homozygote. The PERT dose ranged from 0 to 6160 U-lipase/kg per main meal (mean 1828; SD 1115). The PERT dose was associated with participants’ sex (men vs. women: 661; 95% CI: 302; 1020 U-lipase/kg), age (-16; 95% CI: -31; -1 U-lipase/kg per year) and weight (-45; 95% CI: -58; -31 U-lipase/kg per kg). Having less frequent constipation and being lung transplanted were also associated with a higher PERT dose. A third of participants did not take PERT for snacks, and this was associated with the frequency of diarrhoea. These findings indicate that PERT intake may be improved to reduce GI symptoms.

Dr Mette F Olsen is Associate Professor at the Cystic Fibrosis Centre, Department of Infectious Diseases, Rigshospitalet, 2100 Copenhagen, Denmark and the Department of Nutrition, Exercise and Sports, University of Copenhagen, 1958 Frederiksberg, Denmark.

Annalisa Orenti Meir Mei-ZahavPatrizia BoracchiAnders LindbladMichal ShteinbergECFSPR Scientific Committee. Prevalence, trends and outcomes of long-term inhaled antibiotic treatment in people with cystic fibrosis without chronic Pseudomonas aeruginosa infection – A European cystic fibrosis patient registry data analysisJ Cyst Fibros 2022 Aug 28;S1569-1993(22)00647-6.doi: 10.1016/j.jcf.2022.08.010.Online ahead of print. [Pubmed]

    Annalisa Orenti researchgate.net

Background: Long-term treatment with inhaled antibiotics is recommended for people with cystic fibrosis (pwCF) chronically infected with Pseudomonas aeruginosa (PA). However, pwCF without chronic PA infection are also commonly treated with inhaled antibiotics. Using data from the European Cystic Fibrosis Patient Registry (ECFSPR) we aimed to determine the prevalence and factors associated with inhaled antibiotic treatment in pwCF without chronic PA infection, and long-term outcomes with inhaled antibiotics use.
Methods: The ECFSPR was searched for pwCF 6 years of age and older who were not chronically infected with PA at baseline. Factors associated with inhaled antibiotic use were first assessed through a logistic regression. From this model a propensity score was computed for each individual, providing the likelihood of being treated with inhaled antibiotics. Long-term outcomes with and without inhaled antibiotics were assessed separately for propensity scores tertiles.
Results: 7210 pwCF without chronic PA infection at baseline were included, with 2722 (37.75%) receiving long-term treatment with inhaled antibiotics. Treatment with inhaled antibiotics was more prevalent with severe genotype, diabetes, pancreatic insufficiency, and past infection with chronic PA (OR 3.8, 95% CI, 2.88-5.04). Treatment with inhaled antibiotics was not associated with a reduced risk for acquisition of PA or other resistant pathogens, or with improved lung function decline, mortality, or transplantation.

Conclusions: Many pwCF without chronic PA infection are receiving long-term treatment with inhaled antibiotics despite lack of support from clinical trials or practice guidelines. We did not observe improve outcomes with inhaled antibiotics. Our findings suggest controlled studies evaluating specific inhaled antibiotic regimens targeting specific pathogens or indications be performed to determine their effect.

Annalisa Orienti is a postdoctoral fellow in the Department of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology “G. A. Maccacaro”, University of Milan, Milan, Italy.

Lucy PerremSanja StanojevicMelinda SolomonHartmut GrasemannNeil SweezeyValerie WatersDon B SandersStephanie D DavisFelix RatjenEvaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controlsThorax. 2022 Apr 15;thoraxjnl-2021-218347.doi: 10.1136/thoraxjnl-2021-218347.Online ahead of print. [Pubmed]

Lucy Perem             researchgate.net

Background:The limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change.
Methods:In a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up.

Results:Clinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up.

Conclusion:The limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.

Dr Lucy Perrem is involved with the Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada, Postgraduate Medical Education, Royal College of Surgeons in Ireland, Dublin, Ireland. National Children’s Research Centre, Dublin, Ireland.   Department of Paediatrics, The University of Toronto, Toronto, Ontario, Canada. Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada.

Philip M PolgreenAlejandro P Comellas.  Clinical Phenotypes of Cystic Fibrosis CarriersAnnu Rev Med 2022 Jan 27;73:563-574.doi: 10.1146/annurev-med-042120-020148.

Philip Polgreen medicine.uiowa.edu

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in CFTR, the cystic fibrosis transmembrane conductance regulator gene. People with CF experience a wide variety of medical conditions that affect the pulmonary, endocrine, gastrointestinal, pancreatic, biliary, and reproductive systems.

Traditionally, CF carriers, with one defective copy of CFTR, were not thought to be at risk for CF-associated diseases. However, an emerging body of literature suggests that heterozygotes are at increased risk for many of the same conditions as homozygotes. For example, heterozygotes appear to be at increased risk for chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis. In the United States alone, there are almost 10 million CF carriers. Universal newborn screening and prenatal genetic screening will identify more. Thus, there is a critical need to develop more precise estimates of health risks attributable to the CF carrier state across the lifespan.

Philip M Polgreen is Professor of Internal Medicine and Infectious Diseases in the Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA

Poore TS, Taylor-Cousar JL, Zemanick ET.   Cardiovascular complications in cystic fibrosis: A review of the literature.J Cyst Fibros. 2022 Jan;21(1):18-25. doi: 10.1016/j.jcf.2021.04.016. Epub 2021 Jun 14.[Pubmed]

Spencer Poor  inside beds.org

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to dysfunction of the CFTR protein. CFTR dysfunction leads to disease in the respiratory and gastrointestinal systems. Disorders of the cardiovascular system in individuals with CF are usually attributed to secondary effects from progressive lung disease. However, CFTR has been localized to vascular endothelium and smooth muscle, suggesting that CFTR dysfunction may directly impact cardiovascular function. As treatments for CF improve and life-expectancy increases, the risk of vascular disease may increase in prevalence related to primary and secondary CFTR dysfunction, chronic systemic inflammation, nutritional health and hyperglycemia in individuals with CF related diabetes. Here we review the available literature on CF and the cardiovascular system, examining the secondary effects and evidence for direct CFTR dysfunction in the heart, aorta, pulmonary vessels, and vasculature, as well as future directions and treatment options.

T Spencer Poore is in the Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Eldar Priel Adil AdatiaMelanie KjarsgaardParameswaran Nair.  CFTR heterozygosity in severe asthma with recurrent airway infections: a retrospective reviewAllergy Asthma Clin Immunol 2022 Jun 6;18(1):46.doi: 10.1186/s13223-022-00684-   Free PMC article  [Pubmed]

Adil Adatia allergyfoundation.ca

Eldar Priel researchgate.net

Rationale:Patients with asthma who have neutrophilic bronchitis may have an underlying cause leading to increased susceptibility to airway infections.
Methods:Retrospective review of patients with asthma who had a previous history of recurrent exacerbations that had been associated with airway or sinus infections referred to a tertiary asthma center between 2005 and 2020. Demographics, clinical features, and airway inflammation type determined by sputum cytometry were compared between CFTR carriers and non-carriers. Multiple linear regression was used to identify clinical predictors of CFTR carrier status. Response to nebulized hypertonic saline was assessed by comparing the number of infective exacerbations before and after its initiation.
Results:75 patients underwent CFTR mutation testing. Of these, 13 (17%) were CFTR carriers. The most common mutation was [Formula: see text]F508. CFTR carriers were older (adjusted odds ratio 1.06 (CI 95% 1.01, 1.13)) and had more frequent flares requiring hospitalization (4.19 (1.34, 24.74)). Neutrophilic airway inflammation was the most common inflammatory subtype in CFTR carriers, though 8/13 also had eosinophilic bronchitis. Nebulized hypertonic saline was well tolerated by most and reduced the frequency of infective exacerbations.

Conclusions:The prevalence of CFTR heterozygosity in this cohort with recurrent neutrophilic bronchitis is higher than in the general population. Respiratory disease in CFTR carriers is associated with older age and may cause significant morbidity. Airway neutrophilia is the most common inflammatory subtype, but > 50% had eosinophilic bronchitis requiring treatment. Hypertonic saline appears to be well tolerated and effective in reducing the number of infective exacerbations.

Eldar Priel and Adil Adatia contributed equally and are both at the McMaster University Department of Medicine, Hamilton, Canada and the Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6, Canada.

Rathin PujariBhairavi BhatiaErika Marie DamatoPhilip AlexanderSuccessful non-surgical treatment of pseudomonas choroidal abscess in cystic fibrosis with previous double lung transplantationBMJ Case Rep 2022 Jan 13;15(1):e245238.doi: 10.1136/bcr-2021-245238.[Pubmed]
Pseudomonas aeruginosa choroidal abscess is a rare condition which tends to affect patients with cystic fibrosis (CF) who have undergone double lung transplantation. Various surgical treatment strategies have been described but almost universally have had a dismal prognosis. We present a case of pseudomonas choroidal abscess in a CF patient with previous double lung transplantation who was managed with medical treatment, with intravitreal and systemic antibiotics, without surgical intervention, which led to successful resolution of the choroidal abscess, preservation of the eye and retention of vision.

Rathin Pujariin the Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Hunter RaganElizabeth AutryTaryn BomersbackJennifer HewlettLauren KormelinkJulie SafirsteinLaura ShanleyLisa Lubsch.  The use of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis post-liver transplant: A case seriesPediatr Pulmonol 2022 Feb;57(2):411-417.doi: 10.1002/ppul.25779.Epub 2021 Dec 12.[Pubmed]
Introduction:Cystic fibrosis (CF)-related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator modulator that has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in liver function tests (LFTs) and drug-drug interactions with several immunosuppressant medications.
Objective:The purpose of this case series is to explore if the use of elx/tez/iva is safe and tolerable in patients with CF postliver transplantation.
Methods:A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed.
Results:Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and the median time from the transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in seven patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body mass index, and maintained or improved lung function.

Conclusion:Initiation of elx/tez/iva in patients with CF who received liver transplantation may be safe with clinical benefits.

Hunter Ragan is at the Goldfarb School of Nursing at Barnes-Jewish College, St. Louis, Missouri, USA.

Luc RakotoarisoaClothilde WagnerMarion MunchBenjamin Renaud PicardDominique GrenetAnne OllandMichel GregetIulian EnescuFlorence BouilloudPierre BonnetteAxel GuthDomenico BoscoCatherine MercierMuriel RabilloudThierry BerneyPierre Yves BenhamouGilbert MassardCoralie Camilo,Cyrille ColinCécile ArnoldRomain KesslerLaurence KesslerGRAGIL-TREPID group.   Feasibility and efficacy of combined pancreatic islet-lung transplantation in cystic fibrosis related diabetes -PIM study: a multicenter phase 1-2 trial. Am J Transplant 2022 Apr 11.doi: 10.1111/ajt.17058. Online ahead of print. [Pubmed]
Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), and restoring metabolic control in these patients may improve their management after lung transplantation. In this this multicenter, prospective, phase 1-2 trial, we evaluate the feasibility and metabolic efficacy of combined pancreatic islet-lung transplantation from a single donor in patients with CFRD, terminal respiratory failure and poorly controlled diabetes. Islets were infused via the portal vein under local anesthesia, one week after lung transplantation. At one year, the primary outcome was transplant success as evaluated by a composite score including four parameters (weight, fasting glycaemia, HbA1c, insulin requirements). 10 participants (age: 24 years [17-31], diabetes duration: 8 years [4-12]) received a combined islet-lung transplant with 2892 IEQ/kg [2293 – 6185]. Transplant success was achieved in 7/10 participants at one year post-transplant. Fasting plasma C-peptide increased from 0.91μg/L [0.56-1.29] to 1.15μg/L [0.77-2.2], HbA1c decreased from 7.8% [6.5-8.3] (62 mmol/mol [48-67]) to 6.7% [5.5-8.0] (50 mmol/mol [37-64]), with 38% decrease in daily insulin doses. No complications related to the islet injection procedure were reported. In this pilot study, combined pancreatic islet-lung transplantation restored satisfactory metabolic control and pulmonary function in patients with CF, without increasing the morbidity of lung transplantation.

Luc Rakotoarisoais in the Department of Endocrinology, Diabetes and Nutrition, Strasbourg University Hospital, France and Inserm UMR 1260, Regenerative Nanomedicine, Strasbourg, France

Kathleen J RamosJennifer S GuimbellotMaryam ValapourLauren E BartlettTravis Hee WaiChristopher H GossJoseph M PilewskiAlbert FaroJoshua M DiamondCFLTC Study GroupUse of elexacaftor/tezacaftor/ivacaftor among cystic fibrosis lung transplant recipientsJ Cyst Fibros 2022 Apr 23;S1569-1993(22)00098-4.doi: 10.1016/j.jcf.2022.04.009.Online ahead of print.[Pubmed]

Kathleen J Ramos uwmedicine.org

Background:Cystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes.
Methods:This was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests.
Results:There were 94 patients prescribed ETI; indications included sinus disease (68%), GI symptoms (39%), or low BMI (19%). Prescriptions were written by CF physicians (34%), LT physicians (27%), or physicians who practice both CF and LT (39%). Forty patients (42%) stopped ETI at a median of 56 days [IQR 26, 139] after start/prescription date. ETI was not associated with a significant change in BMI (0.2 kg/m2, 95% CI [-0.1, 0.6], p = 0.150), but was associated with decreased A1c (0.4%, 95% CI 0.2, 0.7, p = 0.003), and increased hemoglobin for patients with anemia (0.6 g/dL, 95% CI 0.2, 1.0, p = 0.007). Three people (3%) stopped ETI due to elevated transaminases.

Conclusions:ETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.

Kathleen J Ramos is in the Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, 1959 NE Pacific Street, Box 356522, Seattle, WA 98195, USA.

Mitchell L RamseyMichael R WellnerKyle PorterStephen E KirkbySusan S LiLuis F LaraSean G KellyA James HanjeLindsay A SobotkaCystic fibrosis patients on cystic fibrosis transmembrane conductance regulator modulators have a reduced incidence of cirrhosisWorld J Hepatol 2022 Feb 27;14(2):411-419.doi: 10.4254/wjh.v14.i2.411. Free PMC article    [Pubmed]

Mitchell Ramsey health.usnews.com

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol.
Aim: To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF.
Methods: A retrospective analysis was performed using Truven MarketScan from    January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups.
Results: A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients (P = 0.05), patients on Ursodiol (P < 0.001), and patients on dual therapy (P = 0.003). The highest incidence of cirrhosis was found among patients treated with Ursodiol alone, compared to untreated patients (P < 0.001) or patients on Ursodiol and CFTR modulators (P = 0.01).

Conclusion: CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

Dr Mitchell L Ramsey is in the Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States.

Mitchell L Ramsey, Susan S Li Luis F LaraYevgeniya GokunVenkata S AkshintalaDarwin L ConwellJohn HeintzStephen E KirkbyKaren S McCoyGeorgios I Papachristou  Alpa PatelVikesh K SinghPhil A Hart Cystic fibrosis transmembrane conductance regulator modulators and the exocrine pancreas: A scoping reviewJ Cyst Fibros  2022 Aug 22;S1569-1993(22)00644-0.doi: 10.1016/j.jcf.2022.08.008. Online ahead of print.  [Pubmed]
Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve pulmonary outcomes in subjects with cystic fibrosis (CF); however, the effects on pancreatic manifestations are not well characterized. We hypothesized that CFTR modulators would improve measures of exocrine pancreatic function and outcomes.
Methods: We performed a systematic search to identify studies reporting measures of the exocrine pancreas in humans treated with CFTR modulators. Only studies reporting baseline and on-treatment assessments were included.
Results: Of 630 identified studies, 41 met inclusion criteria. CFTR modulators reduced acute pancreatitis events by 85% overall (rate ratio 0.15, 95% confidence interval (CI) 0.04, 0.52), with a greater effect seen in the subgroup with pancreas sufficient CF (PS-CF) (rate ratio 0.13 (95% CI 0.03, 0.53). Among 293 subjects with baseline and on-treatment evaluation of pancreas sufficiency, 253 were pancreas insufficient at baseline and 54 (21.3%) converted to pancreas sufficiency. Of 32 subjects with baseline FE-1 values <200 mcg/g, 16 (50%) increased to ≥200 mcg/g. Serum trypsin decreased by a mean of 565.9 ng/mL (standard deviation (SD) 311.8), amylase decreased by 38.2 U/L (SD 57.6), and lipase decreased by 232.3 U/L (SD 247.7).

Conclusions: CFTR modulator use reduces acute pancreatitis frequency and improves indirect measures of exocrine pancreas function. Future interventional studies that evaluate the mechanism and impact of CFTR modulators on acute pancreatitis and pancreas sufficiency in patients with CFTR dysfunction are warranted.

Dr Mitchell L Ramsey  is in the Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Karen S RaraighMichelle H LewisJoseph M CollacoMary CoreyChristopher M PenlandAnne L StephensonJohanna M RommensCarlo CastellaniGarry R CuttingCaution advised in the use of CFTR modulator treatment for individuals harboring specific CFTR variantsJ Cyst Fibros 2022 May 5;S1569-1993(22)00108-4.doi: 10.1016/j.jcf.2022.04.019.Online ahead of print[Pubmed]

    Karen S Raraigh CFFPhiladelphia 2022

In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants.

Karen S Raraigh is a genetic counsellor at the McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States

Felix RatjenDonald R VanDevanter.  Retracing changes in cystic fibrosis understanding and management over the past twenty years.  J Cyst Fibros 2022 Jan;21(1):3-9.doi: 10.1016/j.jcf.2021.09.015.Epub 2021 Oct 1.[Pubmed]

Donald R VanDevanter researchgate.net

Felix Ratjen oirm.ca

I summarised the contents of this article as follows – This is an excellent review of the past 20 years describing the state of the art in 2002 through to 2022. Important milestone between 2002 and 2022 are described including the building of a clinical research structure, encounter based registries, the adoption of newborn screening, consensus guidelines and the Cochrane Database analysis, alternate measures of lung physiology and function, improved delivery of inhaled therapy, improved knowledge of airway microbiology, use of animal models, newer therapies and CFTR modulators, efficacy studies in paediatric CF populations with mild lung disease.
The authors conclude that CF is a multiorgan disease and CF research and care encompass a broad variety of disciplines, from basic science to epidemiology to drug development. They note the exponential rise of research at the same time as the Journal of Cystic Fibrosis was established and the importance of a journal dealing solely with cystic fibrosis.

The article puts to past 20 years nicely in perspective and can be firmly recommended, particularly to younger professionals who have not experienced to earlier part of the last 20 years.

Felix Ratjen is Professor in the Division of Respiratory Medicine, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Canada.

Donald VanDevanter Adjunct Professor in the Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH USA.

Jonathan H RaymentFadi AsfourMargaret RosenfeldMark HigginsLingyun LiuMolly MasciaHildegarde Paz-DiazSimon TianRachel ZahigianSusanna A McColleyVX16-809-122 Study Group. A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age With Cystic Fibrosis Homozygous for F508del-CFTR.  Am J Respir Crit Care Med 2022 Jun 30. doi: 10.1164/rccm.202204-0734OC.Online ahead of print.[Pubmed]              

Jonathan Rayment msfhr.org

Rationale: Previous phase 3 trials showed treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ≥2 years with cystic fibrosis homozygous for F508del-CFTR (F/F genotype).
Objectives: 
To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype.
Methods: This open-label, phase 3 study consisted of two parts (Part A [N = 14] and Part B [N = 46]) that enrolled two cohorts based on age (Cohort 1: 18 to <24 months and Cohort 2: 12 to <18 months). For the 15-day treatment period in Part A, lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from Part A were used to determine dose-based weight boundaries for Part B (24-week treatment period).
Measurements and main results: 
The primary endpoint of Part A was pharmacokinetics and the primary endpoint for Part B was safety and tolerability. Secondary endpoints for Part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from Part A confirmed the appropriateness of Part B dosing. In Part B, 44 children (95.7%) had adverse events which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of cystic fibrosis, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was ‒29.1 mmol/L (95% confidence interval, ‒34.8 to ‒23.4). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin were observed.
Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population

Dr Jonathan Rayment is paediatrician and researcher at the BC Children’s Hospital, 37210, Respiratory Medicine, Vancouver, British Columbia, Canada.

Emily E RicottaD Rebecca PrevotsKenneth N Olivier. CFTR modulator use and risk of nontuberculous mycobacteria positivity in cystic fibrosis, 2011-2018ERJ Open Res 2022 Apr 11;8(2):00724-2021.doi: 10.1183/23120541.00724-2021.eCollection 2022 Apr.   Free PMC article   [Pubmed]

Emily E Ricotta loop.frontiersin.org

Background: People with cystic fibrosis are at increased risk of pulmonary nontuberculous mycobacteria (NTM) disease. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are associated with reduced lung infection with pathogens like Pseudomonas aeruginosa and Staphylococcus aureus. This association has not been studied with NTM.
Methods:Using encounter-level data from the US Cystic Fibrosis Foundation Patient Registry from 2011 to 2018, we identified individuals aged >12 years with one or more NTM-negative sputum culture and information on receipt of ivacaftor therapy. We used a Cox proportional hazards model to assess the relationship between CFTR modulator usage (any and monotherapy versus combination therapy) and NTM sputum culture positivity, controlling for sex, least severe class of CFTR mutation, receipt of chronic macrolides, age, body mass index and percentage predicted forced expiratory volume.
Results:Out of 25 987 unique individuals, 17 403 individuals met inclusion criteria. During follow-up, 42% of individuals received CFTR modulator therapy, and 23% had incident NTM. The median (interquartile range) time to event was 6.1 (4.0-7.3) years for those ever receiving CFTR modulators compared to 4.0 (1.6-6.5) years in those never receiving CFTR modulators. CFTR modulator use was associated with a significantly reduced hazard of NTM culture positivity (hazard ratio (HR) 0.88, 95% CI 0.79-0.97); there was no significant difference in the hazard between those receiving ivacaftor monotherapy versus combination therapy (combination HR 1.01, 95% CI 0.79-1.23).

Conclusions:CFTR modulator therapy is associated with a decreased risk of NTM positivity in individuals with cystic fibrosis.

Dr Emily E Ricotta is an epidemiologist in the Dept of Epidemiology and Population Studies Unit, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.

Shan RikuHerman HedrianaJacqueline A CarozzaJennifer HoskovecReflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower costJ Med Econ Jan-Dec 2022;25(1):403-411. doi: 10.1080/13696998.2022.2053384. Free article [Pubmed]

Shan Riku github.com

Objective: To evaluate the clinical benefits and achievable cost savings associated with the adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care.
Method:A decision-analytic model was developed to compare carrier screen with reflex sgNIPT (maternal carrier status and fetal risk reported together) as first-line carrier screening to the traditional carrier screening workflow (positive maternal carrier screen followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and healthcare costs associated with the two screening methods. These results were used to simulate appropriate pricing for reflex sgNIPT.
Results:Reflex sgNIPT carrier screening-detected 108 of 110 affected pregnancies per 100,000 births (98.5% sensitivity), whereas traditional carrier screening-detected 46 of 110 affected pregnancies (41.5% sensitivity). The cost to identify one affected pregnancy was reduced by 62% in the reflex sgNIPT scenario compared to the traditional scenario. Adding together the testing cost savings and the savings from earlier clinical intervention made possible by reflex sgNIPT, the total cost savings was $37.6 million per 100,000 pregnancies. Based on these cost savings, we simulated appropriate reflex sgNIPT pricing range: if the cost to identify one affected pregnancy is the unit cost, carrier screening with reflex sgNIPT can be priced up to $1,859 per test (or $7,233 if sgNIPT is billed separately); if the cost per 100,000 pregnancies is the unit cost, carrier screening with sgNIPT can be priced up to $1,070 per test (or $2,336 if sgNIPT is billed separately).

Conclusion:Using the carrier screen with reflex sgNIPT as first-line screening improves the detection of affected fetuses by 2.4-fold and can save costs for the healthcare system. A real-life experience will be needed to assess the clinical utility and exact cost savings of carrier screen with reflex sgNIPT.

Shan Riku is SVP of Product at BillionToOne, Inc., Menlo Park, CA, USA.

Jobst F RoehmelFriederike J DoerflerCordula Koerner-RettbergFolke BrinkmannAnne SchlegtendalMartin WetzkeIsa RudolfSimone HelmsJoerg Große-OnnebrinkYin YuThomas NuessleinIrena Wojsyk-BanaszakSebastian BeckeOlaf EickmeierOlaf SommerburgHeymut OmranMirjam StahlMarcus A Mall     Comparison of the Lung Clearance Index in Preschool Children with Primary Ciliary Dyskinesia and Cystic Fibrosis     Chest. 2022 Mar 7;S0012-3692(22)00421-4.doi: 10.1016/j.chest.2022.02.052.Online ahead of print. [Pubmed]

        Jobst Roshmel

Background:Previous studies have shown that the lung clearance index (LCI) determined by multiple-breath washout (MBW) is sensitive to detect early lung disease in preschool children with cystic fibrosis (CF). In preschool children with primary ciliary dyskinesia (PCD), data on the onset and severity of lung disease and on the sensitivity of the LCI as a noninvasive quantitative outcome measure remain limited.
Research and study question:Is MBW feasible and sensitive to detect ventilation inhomogeneity in preschool children with PCD?
Study design and methods:This was a prospective cross-sectional multicenter study and included preschoolers with PCD and preschoolers with CF and healthy controls. LCI was determined using nitrogen MBW, and compared between the three groups.
Results:LCI was determined in 27 children with PCD, 34 children with CF and 30 healthy controls (mean age, 4.8 years; range, 2.2 – 6.9 years). The LCI in preschool children with PCD was increased (median, 9.1; CI 95%, 8.6-10.3) compared to healthy controls (median, 7.0; CI 95%, 6.7-7.1), (P < 0.0001), but did not differ from preschool children with CF (median, 8.6; CI 95%, 8.4-9.7), (P = 0.71). The feasibility in the PCD group was 93.1% and was similar to that in the CF group (91.9%) and in healthy controls (85.7%), (P = 0.55).
Interpretation:This study demonstrates early onset of lung disease in preschool children with PCD and indicates that lung disease severity in PCD may be similar to that in CF during preschool years. These data support a need for early diagnostic monitoring and therapy and suggest the LCI as a noninvasive diagnostic tool and as a potential endpoint in clinical trials testing early interventions in children with PCD.

Dr Jobst F Roehmel is consultant paediatrician in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Bhaswati RoyMarlyn S WooSusana VacasPatricia EshaghianAdupa P RaoRajesh KumarRegional brain tissue changes in patients with cystic fibrosis. J Transl Med 2021 Oct 9;19(1):419.doi: 10.1186/s12967-021-03092-x.[Pubmed]Free PMC article

Bhaswati Roy kumarlab.dgsom.ucla.edu

Background:Cystic fibrosis (CF) patients present with a variety of symptoms, including mood and cognition deficits, in addition to classical respiratory, and autonomic issues. This suggests that brain injury, which can be examined with non-invasive magnetic resonance imaging (MRI), is a manifestation of this condition. However, brain tissue integrity in sites that regulate cognitive, autonomic, respiratory, and mood functions in CF patients is unclear. Our aim was to assess regional brain changes using high-resolution T1-weighted images based gray matter (GM) density and T2-relaxometry procedures in CF over control subjects.
Methods:We acquired high-resolution T1-weighted images and proton-density (PD) and T2-weighted images from 5 CF and 15 control subjects using a 3.0-Tesla MRI. High-resolution T1-weighted images were partitioned to GM-tissue type, normalized to a common space, and smoothed. Using PD- and T2-weighted images, whole-brain T2-relaxation maps were calculated, normalized, and smoothed. The smoothed GM-density and T2-relaxation maps were compared voxel-by-voxel between groups using analysis of covariance (covariates, age and sex; SPM12, p < 0.001).
Results:Significantly increased GM-density, indicating tissues injury, emerged in multiple brain regions, including the cerebellum, hippocampus, amygdala, basal forebrain, insula, and frontal and prefrontal cortices. Various brain areas showed significantly reduced T2-relaxation values in CF subjects, indicating predominant acute tissue changes, in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum.

Conclusions:Cystic fibrosis subjects show predominant acute tissue changes in areas that control mood, cognition, respiratory, and autonomic functions and suggests that tissue changes may contribute to symptoms resulting from ongoing hypoxia accompanying the condition.

Dr Bhaswati Roy is a Post doc in the Department of Anesthesiology and Perioperative Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA.

Rajesh Kumar is Professor of Anesthesiology and Radiological Sciences; Director of Imaging Technology, University of California Los Angeles, Los Angeles

Francesca SaluzzoLuca RiberiBarbara MessoreNicola Ivan LoréIrene EspositoElisabetta BignaminiVirginia De Rose.   CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis.   Cells 2022 Apr 6;11(7):1243.doi: 10.3390/cells11071243  Free PMC article   [Pubmed]
Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown.

This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed.

Francesca Saluzzo is in the Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.

D B SandersU KhanS L HeltsheM SkallandN E WestD R VanDevanterC H GossP A FlumeSTOP2 Investigators.   Association of site of treatment with clinical outcomes following intravenous antimicrobial treatment of a pulmonary exacerbation. J Cyst Fibros 2022 Jul;21(4):574-580.doi: 10.1016/j.jcf.2021.11.009.Epub 2021 Nov 29.[Pubmed]

Don B Sanders medicine.iu.edu

Background: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital.
Methods: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location.
Results: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only.

Conclusions: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF

Don B Sanders is Associate Professor of Pediatrics at Indiana University School of Medicine, Indianapolis, IN, United States.

Adrienne P SavantCystic fibrosis year in review 2021Pediatr Pulmonol 2022 May 2.doi: 10.1002/ppul.25948.Online ahead of print.[Pubmed]

Adrienne P Savant icmchealth.org

People with cystic fibrosis (CF) have an amazing outlook with the treatment availability of highly effective modulators. Unfortunately, not all PwCF are eligible for modulators leading to continued pulmonary exacerbations and advanced lung disease. Additionally, optimizing diagnosis and evaluation for CF in the newborn period continues to be an area of focus for research. This review article will work to cover articles published in 2021 with high clinical relevance related to the above topics, however due to the extensive body of research published, this review will not be comprehensive. This article is protected by copyright. All rights reserved.

Adrienne P Savant is a paediatric pulmonologist at the Department of Pediatrics, Children’s Hospital of New Orleans, New Orleans, Louisiana, USA and the Department of Pediatrics, Tulane University, New Orleans, Louisiana, USA.

Gregory S SawickiMark ChilversJohn McNamaraLutz NaehrlichClare SaundersIsabelle Sermet-GaudelusClaire E WainwrightNeil AhluwaliaDaniel CampbellR Scott HarrisHildegarde Paz-DiazJudy L ShihJane C Davies.  A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variantJ Cyst Fibros 2022 Feb 18;S1569-1993(22)00033-9.doi: 10.1016/j.jcf.2022.02.003.Online ahead of print.[Pubmed]

Gregory Sawick doctors.childrenshospital

Background:Two previous Phase 3 studies (“parent studies”) showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study.
Methods:This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI).
Results:One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ‑R respiratory domain score, and BMI observed from parent study baseline to Week 96.

Conclusions:Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.

Dr Gregory Sawick is ta the Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA.

Nicholas J SimmondsC Kors van der EntCarla ColomboNils KinnmanCynthia DeSouzaTeja ThoratMarci L ChewKeval ChandaranaCarlo CastellaniVOCAL: An observational study of ivacaftor for people with cystic fibrosis and selected non-G551D-CFTR gating mutations. J Cyst Fibros 2022 May 22;S1569-1993(22)00141-2. doi: 10.1016/j.jcf.2022.05.007.Online ahead of print.[Pubmed]

Nicholas Simmonds rbht.nhs.uk

Background:VOCAL was an observational study of the effect of long-term ivacaftor on real-world clinical outcomes and healthcare resource utilization (HCRU) in people with cystic fibrosis (pwCF) in Italy, the Netherlands, and the UK.
Methods:pwCF aged ≥6 years with non-G551D-CFTR gating mutations were eligible. Prospective data were collected up to 48 months after enrollment; retrospective data were collected to ensure that 12 months of pre-ivacaftor data were available. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and measures of nutritional status. Pulmonary exacerbation (PEx) rates, HCRU, and respiratory microbiology during ivacaftor treatment were compared with data from the 12-month period before initiation.
Results:Seventy-three eligible pwCF were enrolled and received ivacaftor; 65 (89.0%) completed the study (48 [65.8%] completed ≥48 months of ivacaftor). During the first 6 months of ivacaftor, ppFEV1, body mass index (BMI), and BMI-for-age z-score showed least-squares mean absolute improvements of 10.8 percentage points, 0.79 kg/m2, and 0.54, respectively; improvements were maintained through 48 months. Rates of PEx, antibiotic use due to PEx, and hospitalization decreased by >50% during ivacaftor treatment compared with before ivacaftor. The number of respiratory cultures and sputum was lower post-ivacaftor, as was the percentage of pwCF with positive respiratory cultures for 3 of 9 pathogens evaluated (Pseudomonas aeruginosa, Aspergillus fumigatus, Stenotrophomonas maltophilia). Reported safety results were consistent with CF and ivacaftor’s known safety profile.

Conclusions:These results demonstrate the positive long-term effectiveness of ivacaftor on clinical outcomes and HCRU in pwCF with non-G551D-CFTR gating mutations in real-world settings.

Professor Nicholas Simmonds is at the Adult Cystic Fibrosis Centre, Royal Brompton Hospital, London, UK, and National Heart and Lung Institute, Imperial College London, London, UK.

Sherie SmithNicola J RowbothamChristopher T EdwardsShort-acting inhaled bronchodilators for cystic fibrosis. Cochrane Database Syst Rev 2022 Jun 24;6(6):CD013666.doi: 10.1002/14651858.CD013666.pub2..[Pubmed]
 A Cochrane Review looking at both short- and long-acting inhaled bronchodilators for CF was withdrawn from the Cochrane Library in 2016. That review has been replaced by two separate Cochrane Reviews: one on long-acting inhaled bronchodilators for CF, and this review on short-acting inhaled bronchodilators for CF. For this review ‘inhaled’ includes the use of pressurised metered dose inhalers (MDIs), with or without a spacer, dry powder devices and nebulisers.
Objectives:To evaluate short-acting inhaled bronchodilators in children and adults with CF in terms of clinical outcomes and safety.
Authors’ conclusions:All included trials in this review are small and of a cross-over design. Most trials looked at very short-term effects of inhaled bronchodilators, and therefore did not measure longer-term outcomes. The certainty of evidence across all outcomes was very low, and therefore we have been unable to describe any effects with certainty.

Sherie Smith is a researcher in the Academic Unit of Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham, UK.

– A disappointing conclusion. However, clinicians will presumably continue to try the effect of short acting bronchodilators on their patients and, depending on the change in respiratory function test(s) and the patient’s opinion, will continue to prescribe in a proportion of patients.

Stephen M StickAlexia FotiRobert S WareHarm A W M Tiddens Barry S ClementsDavid S ArmstrongHiran SelvaduraiAndrew TaiPeter J CooperCatherine A ByrnesYvonne BelessisClaire WainwrightAdam JaffePhilip RobinsonLisa SaimanPeter D SlyCOMBAT CF Study Group. The effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): a phase 3, randomised, double-blind, placebo-controlled clinical trialLancet Respir Med  2022 Aug;10(8):776-784.doi: 10.1016/S2213-2600(22)00165-5. Epub 2022 Jun 2. [Pubmed]

Stephen Stick thelimbic.com

Background: Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans.
Methods: A phase three, randomised, double-blind, placebo-controlled trial was done at eight paediatric cystic fibrosis centres in Australia and New Zealand. Infants (aged 3-6 months) diagnosed with cystic fibrosis following newborn screening were eligible. Exclusion criteria included prolonged mechanical ventilation in the first 3 months of life, clinically significant medical disease or comorbidities other than cystic fibrosis, or macrolide hypersensitivity. Participants were randomly assigned (1:1) to receive either azithromycin (10 mg/kg bodyweight orally three times per week) or matched placebo until age 36 months. Randomisation was done with a permuted block strategy and an interactive web-based response system, stratified by study site. Unblinding was done once all participants completed the trial. The two primary outcomes were the proportion of children with radiologically defined bronchiectasis, and the percentage of total lung volume affected by disease. Secondary outcomes included clinical outcomes and exploratory outcomes were inflammatory markers. Analyses were done with the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT01270074).
Findings: Between June 15, 2012, and July 10, 2017, 281 patients were screened, of whom 130 were enrolled, randomly assigned, and received first study dose. 68 participants received azithromycin and 62 received placebo. At 36 months, 88% (n=50) of the azithromycin group and 94% (n=44) of the placebo group had bronchiectasis (odds ratio 0·49, 95% CI 0·12 to 2·00; p=0·32), and total airways disease did not differ between groups (median difference -0·02%, 95% CI -0·59 to 0·56; p=0·96). Secondary outcome results included fewer days in hospital for pulmonary exacerbations (mean difference -6·3, 95% CI -10·5 to -2·1; p=0·0037) and fewer courses of inhaled or oral antibiotics (incidence rate ratio 0·88, 95% CI 0·81 to 0·97; p=0·0088) for those in the azithromycin group. For the pre-planned, exploratory analysis, concentrations of airway inflammation were lower for participants receiving azithromycin, including interleukin-8 (median difference -1·2 pg/mL, 95% CI -1·9 to -0·5; p=0·0012) and neutrophil elastase activity (-0·6 μg/mL, -1·1 to -0·2; p=0·0087) at age 36 months, although no difference was noted between the groups for interleukin-8 or neutrophil elastase activity at 12 months. There was no effect of azithromycin on body-mass index at age 36 months (mean difference 0·4, 95% CI -0·1 to 0·9; p=0·12), nor any evidence of pathogen emergence with the use of azithromycin. There were few adverse outcomes with no differences between the treatment groups.

Interpretation: Azithromycin treatment from diagnosis of cystic fibrosis did not reduce the extent of structural lung disease at 36 months of age; however, it did reduce airway inflammation, morbidity including pulmonary exacerbations in the first year of life and hospitalisations, and improved some clinical outcomes associated with cystic fibrosis lung disease. Therefore, we suggest thrice-weekly azithromycin is a strategy that could be considered for the routine early management of paediatric patients with cystic fibrosis.

Stephen M Stick is Clinical Professor at the Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA, Australia; Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia; Department of Respiratory and Sleep Medicine, Perth Children’s Hospital, Perth, WA, Australia.

Khalid M SumailyRefat NimerMaha AlzahraniMai Abdel JabarAhmad AlodibEssa M SabiImran NizamiAnas M Abdel RahmanCFTR protein quantification as a cystic fibrosis diagnostic biomarker in dried blood spots using multiple reaction monitoring tandem mass spectrometry. J Pharm Biomed Anal  2022 Apr 27;216:114801.doi: 10.1016/j.jpba.2022.114801.Online ahead of print[Pubmed]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel found on the apical surface of epithelial cells in the airway and gastrointestinal tract. A mutation in the CFTR protein is responsible for developing cystic fibrosis (CF) disease.
Therefore, circulating CFTR protein could be a promising biomarker of CF disease. Multiple methodological challenges are associated with CF’s available diagnostic and screening methods, such as low specificity and potential false discovery rate, mainly for ethnic groups whose CFTR mutations are not covered in the mutation panels.
Herein, we have developed an absolute quantification (AQUA) method based on two CFTR signature peptides (SPs). A liquid chromatography-tandem spectrometry (LC-MS/MS) method in multiple reaction monitoring (MRM) mode (MRM transitions 1168.90 > 85.929 and 707.19 > 85.93 of SP1 and SP2, respectively) enabled the accurate quantification of CFTR protein in a dried blood spot (DBS). The method was validated successfully based on international guidelines in terms of signal linearity, precision (within-run CV 3.37-8.54%; between-run CV 5.15-11.06% for the selected SPs), and accuracy (within-run 93.4-105.59%; between-run 97.45-103.28% for the selected SPs). The level of soluble CFTR protein was evaluated as a potential biomarker for CF using patients (n = 39) and healthy controls (n = 30), were found to be in CF patients lower than controls. For instant, the level of signature peptide 1 (SP1) was 2.09 ± 0.55 nM, 68.77 ± 1.40 nM in CF patients compared to Ctrl, respectively; p < 0.0001.

This study is the first to report CFTR levels in DBS using signature peptides by LC-MS/MS as a diagnostic marker for CF. The receiver operating characteristic (ROC) for CFTR SP1 and SP2 showed a significant area under the curves (AUC) 0.7714 (99% CI, p < 0.0001), and 0.8234 (99% CI, p < 0.0001), respectively. The presented MRM method provides a highly specific and sensitive approach to CFTR quantification in a DBS and could be applied in CF screening.

Khalid M Sumaily is in  the Clinical Biochemistry Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia; Clinical Biochemistry Unit, Laboratory Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia.

Birce SunmanNagehan EmiraliogluGülsen HazirolanBurçin ŞenerBeste OzsezenDilber A TuralHalime N BuyuksahinIsmail GuzelkasEbru YalcinDeniz DogruUğur ÖzçelikNural Kiper  Effectiveness of different eradication treatment protocols for new-onset Pseudomonas aeruginosa in children with cystic fibrosisPediatr Pulmonol 2022 Jun;57(6):1456-1465.doi: 10.1002/ppul.25876. Epub 2022 Apr 8.[Pubmed]

Birce Sunman researchgate.net

Objectives: While eradicating new-onset Pseudomonas aeruginosa in children with cystic fibrosis is an important issue, there is no clear evidence about the best treatment approach. This retrospective observational cohort study aims to compare the effectiveness of intravenous therapy versus inhalation with/without oral therapy in the eradication of new-onset P. aeruginosa, determine the factors affecting the treatment success and assess lung function at baseline and posttreatment.
Methods: Of 399 children, 110 (140 episodes) with either the first P. aeruginosa isolation or a new isolation after at least 1 year free of infection were included. Different eradication regimens (intravenous therapy or inhaled tobramycin or inhaled tobramycin plus oral ciprofloxacin) were compared. Eradication success was accepted as remaining free of infection with a negative culture for 12 months. Demographic, clinical, and microbiological characteristics of children, effectiveness of different eradication strategies, time to a new P. aeruginosa isolation, and the relationship between lung function and the type of eradication regimen were determined.
Results: Of 140 episodes, intravenous therapy was administered in 53 and inhalation therapy (in combination with or without oral ciprofloxacin) in 87. Total success rate of eradication was 60.7%. Eradication was achieved in 56.6% of children with intravenous therapy, 59.7% with inhaled tobramycin therapy, and 72% with inhaled tobramycin plus oral ciprofloxacin therapy. Success rates of different eradication regimens did not differ significantly (p = 0.419). Lung function by the end of the first year was worse in the intravenous group compared to the inhalation group (p = 0.017 for forced expiratory volume in 1 s, p = 0.015 for forced vital capacity).

Conclusion: No advantage of intravenous therapy was demonstrated compared to inhalation therapy in terms of eradication success© 2022

Dr Birce Sunman is in the Department of Pediatric Pulmonology, Ihsan Dogramaci Children’s Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Marcus SvedbergHenrik ImbergPer GustafssonMela BrinkHåkan CaisanderAnders LindbladChest X-rays are less sensitive than multiple breath washout examinations when it comes to detecting early cystic fibrosis lung diseaseActa Paediatr 2022 Jun;111(6):1253-1260.doi: 10.1111/apa.16302.Epub 2022 Feb 24.[Pubmed]

     Marcus Svedberg nuvoair.com

Aim:Annual chest X-ray is recommended as routine surveillance to track cystic fibrosis (CF) lung disease. The aim of this study was to investigate the clinical utility of chest X-rays to track CF lung disease.
Methods:Children at Gothenburg’s CF centre who underwent chest X-rays, multiple breath washouts and chest computed tomography examinations between 1996 and 2016 were included in the study. Chest X-rays were interpreted with Northern Score (NS). We compared NS to lung clearance index (LCI) and structural lung damage measured by computed tomography using a logistic regression model.
Results:A total of 75 children were included over a median period of 13 years (range: 3.0-18.0 years). The proportion of children with abnormal NS was significantly lower than the proportion of abnormal LCI up to the age of 4 years (p < 0.05). A normal NS and a normal LCI at age 6 years were associated with a median (10-90th percentile) total airway disease of 1.8% (0.4-4.7%) and bronchiectasis of 0.2% (0.0-1.5%).

Conclusion: Chest X-rays were less sensitive than multiple breath washout examinations to detect early CF lung disease. The combined results from both methods can be used as an indicator to perform chest computed tomography less frequently.

Marcus Svedberg is at the Department of Pediatrics, Institute of Clinical Science at The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden and the Department of Pediatrics, Queen Silvia’s Children Hospital, Gothenburg, Sweden.

Sylvia SzentpeteryKimberly FoilSara HendrixSue GrayChristina MingoraBarbara HeadDonna JohnsonPatrick A Flume.  A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetusJ Cyst Fibros 2022 Apr 11;S1569-1993(22)00095-9.doi: 10.1016/j.jcf.2022.04.005.Online ahead of print.[Pubmed]

Sylvia Szentpetery education.musc.edu

We report elexacaftor-tezacaftor-ivacaftor (ETI) treatment of a F508del carrier who was pregnant with a F508del homozygous fetus. At 23-weeks gestation meconium ileus (MI) was evident on ultrasound including dilated, hyperechoic bowel, which persisted on subsequent imaging. Through shared decision-making, the mother began ETI at 32 weeks with intent to treat fetal MI. The ultrasound findings persisted at treatment day 13, but bowel dilation had resolved by imaging on treatment day 27. A female infant was delivered vaginally at 36 weeks with no complications. The mother continued ETI while breastfeeding. Stool elastase at age 2 weeks was 240 mcg/g. Sweat chloride measurement was 64 and 62 mEq/L. Maternal and infant liver function testing have been normal. Maternal ETI treatment likely led to resolution of the MI and there is evidence supporting continued infant benefit through breastmilk. Logistical and ethical considerations regarding treatment of a carrier mother for infant benefit are discussed.

Dr Sylvia Szentpetery is a pediatric pulmonologist at the Medical University of South Carolina, Charleston, SC 29424, USA. Electronic address: szentpet@musc.edu.

Haluk TekerlekBilge Nur Yardımcı-LokmanoğluDeniz Inal-InceUğur ÖzçelikAkmer Mutlu.  Developmental Functioning Outcomes in Infants with Cystic Fibrosis: a 24- to 36-Month Follow-Up Study. Phys Ther  2022 Apr 6;pzac037.doi: 10.1093/ptj/pzac037. Online ahead of print 
[Pubmed] 

Haluk Tekerlek researchgate.net

This study aimed to follow the developmental functioning of infants, 3 to 5 months of age, with cystic fibrosis (CF), according to recent published results based on Prechtl General Movement Assessment (GMA).
Methods:Motor repertoire was evaluated using Prechtl GMA, and developmental function was assessed using Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) in infants with CF and their peers who were neurotypical.
Results:Twelve infants with CF clinically stable and 12 infants who were neurotypical, with respective median postterm ages of 14 and 13 weeks, were assessed using GMA. At 24 to 36 months, the Bayley-III was applied to the CF group (median postterm age = 27.5 months) and the control group (median post-term age = 27.0 months). Fidgety movements (FMs) were absent in 5 infants with CF, whereas all infants who were neurotypical had normal FMs. The Motor Optimality Score (MOS) was significantly lower in the CF group (median = 18.5) compared with the control group (median = 26). The CF group had significantly lower composite scores in the Bayley-III cognition, language, and motor domains compared to the control group.
Conclusions:Cognitive, language, and motor development was delayed in infants with CF. Developmental functioning of infants with CF should be assessed as early as possible and monitored, and age-specific early intervention programs should be considered when necessary.

Impact:Children with CF may have motor, cognitive, and language developmental delays compared with peers who are neurotypical during early childhood, and hospitalization was negatively correlated with motor development at 24 to 36 months of age. This study highlights the importance of early assessment of developmental functioning and age-specific, early intervention programs when necessary in infants with CF.

Dr Haluk Tekerlek is in the Faculty of Physical Therapy and Rehabilitation, Hacettepe University, Ankara, Turkey.

Harm A W M TiddensYuxin ChenEleni-Rosalina AndrinopoulouStephanie D DavisMargaret RosenfeldFelix RatjenRichard A KronmalKaren D Hinckley StukovskyAlison DasiewiczStephen Michael StickSHIP-CT Study Group Collaborators.  The effect of inhaled hypertonic saline on lung structure in children aged 3-6 years with cystic fibrosis (SHIP-CT): a multicentre, randomised, double-blind, controlled trial. Lancet Respir Med 2022 Mar 11;S2213-2600(21)00546-4.doi: 10.1016/S2213-2600(21)00546-4. Online ahead of print [Pubmed]

Harm Tiddens          erasmucmc.nl

Background: In the Saline Hypertonic in Preschoolers (SHIP) study, inhaled 7% hypertonic saline improved the lung clearance index in children aged 3-6 years with cystic fibrosis, but it remained unclear whether improvement is also seen in structural lung disease. We aimed to assess the effect of inhaled hypertonic saline on chest CT imaging in children aged 3-6 years with cystic fibrosis.
Methods: Children with cystic fibrosis were enrolled in this multicentre, randomised, double-blind, controlled study at 23 cystic fibrosis centres in Spain, Denmark, the Netherlands, Italy, France, Belgium, the USA, Canada, and Australia. Eligible participants were children aged 3-6 years who were able to cooperate with chest CT imaging and comply with daily nebuliser treatment. Participants were randomly assigned 1:1 to receive inhaled 2 puffs of 100 μg salbutamol followed by 4mL of either 7% hypertonic saline or 0·9% isotonic saline twice per day for 48 weeks. Randomisation was stratified by age in North America and Australia, and by age and country in Europe. Chest CTs were obtained at baseline and 48 weeks and scored using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF) method. The primary outcome was the difference between groups in the percentage of total lung volume occupied by abnormal airways (PRAGMA-CF %Disease) measured by chest CT at 48 weeks. Analysis was by intention-to-treat. This study is registered withClinicaltrials.gov, NCT02950883.

Findings: Between May 24, 2016, and Dec 18, 2019, 134 children were assessed for inclusion. 18 patients were excluded (nine had incomplete or unsuccessful chest CT at enrolment visit, two could not comply with CT training, two had acute respiratory infection, two withdrew consent, two for reasons unknown, and one was already on hypertonic saline). 116 participants were enrolled and randomly assigned to hypertonic saline (n=56) or isotonic saline (n=60). 12 patients dropped out of the study (seven in the hypertonic saline group and five in the isotonic saline group). Mean PRAGMA-CF %Disease at 48 weeks was 0·88% (95% CI 0·60-1·16) in the hypertonic saline group and 1·55% (1·25-1·84) in the isotonic saline group (mean difference 0·67%, 95% CI 0·26-1·08; p=0·0092) based on a linear regression model adjusted for baseline %Disease values and baseline age. Most adverse events in both groups were rated as mild, and the most common adverse event in both groups was cough.

Interpretation: Inhaled hypertonic saline for 48 weeks had a positive effect on structural lung changes in children aged 3-6 years with cystic fibrosis relative to isotonic saline. This is the first demonstration of an intervention that alters structural lung disease in children aged 3-6 years with cystic fibrosis.

Prof. Harm A W M Tiddens is in the Department of Paediatrics, Division of Respiratory Medicine and Allergology, Sophia Children’s Hospital, Erasmus MC, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands.

Monique TheberathDavid BauerWeizhi ChenManisha SalinasArya B MohabbatJuan YangTony Y ChonBrent A BauerDietlind L Wahner-RoedlerEffects of COVID-19 pandemic on mental health of children and adolescents: A systematic review of survey studies. SAGE Open Med.2022 Mar 30;10:20503121221086712.doi: 10.1177/20503121221086712.eCollection 2022.[Pubmed] Free PMC article
Objective:Mental health problems among children and adolescentsare increasingly observed during the outbreak of COVID-1   9, leading to significant healthcare concerns. Survey studies provide unique opportunities for research during this pandemic, while there are no existing systematic reviews in this setting. The objective was to summarize existing survey studies addressing the effects of the current COVID-19 pandemic on the mental health of children and adolescents.
Methods:For this systematic review, we performed an electronic search in multiple databases from December 2019 to December 2020. The quality appraisal of the included studies was performed with the Critical Appraisal Skills Programme Qualitative Checklist. Because of the high methodological heterogeneity between studies, a narrative synthesis of the qualitative data was used.
Results:In total, 35 survey studies with 65,508 participants, ranging from 4 to 19 years of age, are included in this review. Anxiety (28%), depression (23%), loneliness (5%), stress (5%), fear (5%), tension (3%), anger (3%), fatigue (3%), confusion (3%), and worry (3%) were the most common mental health issues reported. Children and adolescents with psychiatric and/or developmental disorders, such as severe obesity, chronic lung disease, attention deficit hyperactivity disorder, cystic fibrosis, and obsessive-compulsive disorders, were especially vulnerable to the mental health effects of the COVID-19 pandemic. Age, gender, psychological quality, and negative coping strategies were identified as risk factors for the development of mental health problems. Social and family support, along with a positive coping style, was associated with better outcomes.

Conclusion:The impact of the COVID-19 pandemic on mental health of children and adolescents is multifaceted and substantial. Survey studies regarding child and adolescent mental health amid COVID-19 indicated that anxiety, depression, loneliness, stress, and tension are the most observed symptoms. Positive coping strategies with family and social support may be important to achieving better outcomes. Due to limited available evidence, more well-designed studies in this area are urgently needed.

Monique Theberath is at St Olaf College, Northfield MN, USA

Christina ThorntonRanjani SomayajiAngel ChuMichael D Parkins Human papillomavirus (HPV) and cervical dysplasia in adult female cystic fibrosis (CF) lung transplant recipientsThorax 2022 Feb 4;thoraxjnl-2021-218461.doi: 10.1136/thoraxjnl-2021-218461.Online ahead of print.[Pubmed]

Christina Thornton cihr-irsc.gc.ca

Human papillomavirus (HPV) is the principal risk factor for cervical cancer. Transplant recipients are at a disproportionate risk of HPV complications. We conducted a single-centre, retrospective study of adult female cystic fibrosis (CF) lung transplant recipients between 2008 and 2021. We observed 12 of 34 (35.3%) with ≥1 abnormal pap smear (median age: 26.7 years). Complications included refractory anogenital warts (n=3), vulvectomy (n=2) and cervical cancer (n=4), with two deaths from metastatic disease. None with HPV morbidity was vaccinated. Lung transplant recipients had greater odds of cervical dysplasia relative to controls (OR, 3.98; 95% CI 1.17 to 11.82).

CF care providers must prioritise HPV vaccination to attenuate potential future morbidity and mortality.

Dr Christina Thornton is at the Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Lakshmi ViswanathanEric BachmanSimon TianNeil AhluwaliaYaohua ZhangHarold S BernsteinPaul Panorchan. Phase 1 Study to Assess the Safety and Pharmacokinetics of Elexacaftor/Tezacaftor/Ivacaftor in Subjects Without Cystic Fibrosis With Moderate Hepatic ImpairmentEur J Drug Metab Pharmacokinet 2022 Aug 29. doi: 10.1007/s13318-022-00791-8.Online ahead of print [Pubmed]
Background and objective: Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people with cystic fibrosis (pwCF) who have ≥ 1 responsive mutation. Liver disease occurs in approximately 10%-20% of pwCF. The objective of this study was to assess the safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in people with moderate hepatic impairment, which is necessary to inform on its use and guide dosing recommendations.
Methods: The safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor were evaluated in subjects without CF with moderate hepatic impairment versus matched healthy controls. Twenty-two subjects (11 with moderate hepatic impairment and 11 healthy subjects) received half the standard adult daily dose of elexacaftor/tezacaftor/ivacaftor (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 150 mg) orally for 10 days.
Results: Elexacaftor/tezacaftor/ivacaftor was safe and well tolerated in subjects with moderate hepatic impairment and healthy controls. On day 10, the mean values of the area under the curve during the dosing interval (AUCτ) for total (bound and unbound) elexacaftor and its major active metabolite M23-elexacaftor were increased 1.25-fold (95% CI 1.01, 1.54) and 1.73-fold (95% CI 1.27, 2.35), respectively, in subjects with moderate hepatic impairment compared with matched healthy subjects. The mean values of AUCτ for ivacaftor and tezacaftor were increased 1.50-fold (95% CI 1.09, 2.06) and 1.20-fold (95% CI 1.00, 1.43), respectively, while the mean value of AUCτfor the active metabolite M1-tezacaftor was 1.29-fold lower [ratio of moderate hepatic impairment to healthy subjects (95% CI): 0.778 (0.655, 0.924)] in subjects with moderate hepatic impairment.

Conclusions: A dose reduction of elexacaftor/tezacaftor/ivacaftor is warranted in people with moderate hepatic impairment.

Lakshmi Viswanathan is a clinical pharmacologist with Vertex Phamaceuticals in Boston USA

-I wonder if the non-CF patients were expected to improve. Were they informed it was not for their benefit?  This paper is available in full on publisher’s website

Nirmal VijayavelSung Woo KohElizabeth Leigh GoodmanCystic fibrosis associated with Wernicke’s encephalopathy in an older adultBMJ Case Rep 2022 Jul 27;15(7):e249727.doi: 10.1136/bcr-2022-249727.[Pubmed]

Nirmal Vijavavel doximetry.com

Here we report the first case of an association between cystic fibrosis and Wernicke’s encephalopathy. The patient had a history of cystic fibrosis diagnosed in her early 60s associated with pancreatitis and chronic lung disease. She presented with a traumatic hip fracture requiring operative repair. On examination, she was found to have bilateral nystagmus. MRI revealed enhancement of the mammillary bodies. Laboratory results were notable for thiamine deficiency, which in context of the radiographic and physical examination findings, confirmed a diagnosis of Wernicke’s encephalopathy. The cause of her low thiamine was thought to be poor dietary intake, weight loss and malabsorption associated with exocrine pancreatic insufficiency in the setting of a history of recurrent pancreatitis. The patient had complete resolution of her symptoms with the initiation of thiamine supplementation and pancreatic enzymes. Although classically associated with fat soluble vitamin deficiencies, there are increasing reports of water-soluble vitamin deficiencies associated with cystic fibrosis.

Nirmal Vijayavel is a resident in internal medicine at Internal Medicine, Harbor-UCLA Medical Center Department of Internal Medicine, Torrance, California, USA.

Anna Louise WatsonMarko MaticThomas RobertsonAlexandra Gabrielle Ann StewartMicrosporidial myositis, keratitis and hypercalcaemia in a cystic fibrosis lung transplant recipient.  BMJ Case Rep    2022 Jul 4;15(7):e250643.doi: 10.1136/bcr-2022-250643.Free PMC article includes an interest patient’s perspective. [Pubmed]
A man in his 50s was admitted with 4 months of myalgia, headaches, hypercalcaemia and declining renal function on a background of lung transplantation for cystic fibrosis 5 years prior. MRI confirmed myositis and a muscle biopsy revealed invasive muscular microsporidial infection. Positron emission tomography(PET)/CT revealed widespread dissemination of the infection. Albendazole was commenced and after a 1 week systemic inflammatory response syndrome, the patient made a significant recovery and was discharged home. PCR testing confirmed the species as Anncaliia algerae, which is known to infect mosquitoes, larvae and contaminate water supplies. This case highlights the need to relentlessly pursue a diagnosis and to consider atypical pathology in immune compromised patients. A tissue sample yielded highly beneficial and unexpected results. A multispecialty approach was essential given the varied infection manifestations, which included myositis, keratitis and possible central nervous system, vocal cord, parapharyngeal and renal involvement.

Anna Louise Watson is at the General Medicine & Infectious Diseases, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

Dirk Westhölter  FabianSchumacherNuria WülfinghoffSivagurunathanSutharsanSvenja StrassburgBurkhard KleuserPeter A HornSebastian ReuterErich GulbinsChristian TaubeMatthias Welsner.  CFTR modulator therapy alters plasma sphingolipid profiles in people with cystic fibrosis.  J Cyst Fibros 2022 Feb 12;S1569-1993(22)00037-6.doi: 10.1016/j.jcf.2022.02.005.Online ahead of print. [Pubmed]
Background: Sphingolipids, in particular ceramides, play an important role in the pathogenesis of cystic fibrosis (CF) lung disease. Ceramides seem to be dysregulated in people with CF (PWCF): An elevated ratio of ceramides C16Cer/ C24Cer has been linked to inflammation and disease severity. CFTR modulators might influence sphingolipid dysregulation in PWCF.
Methods: Sphingolipid profiles were retrospectively analyzed in serum from 112 PWCF and 96 healthy controls as well as in plasma from 25 PWCF before and after treatment with the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lipid data were correlated with clinical parameters.
Results: There were significantly higher levels of long-chain ceramides C18Cer and C20Cer and of the very long-chain ceramide C24:1Cer in PWCF versus healthy controls. Sphingosine levels were significantly reduced and accurately distinguished PWCF from healthy controls. Treatment with ELX/TEZ/IVA was associated with a decrease in levels of long-chain ceramides C16Cer, C18Cer and C20Cer and very long-chain ceramide C24:1Cer. Plasma levels of the most abundant very long-chain ceramide C24Cer as well as sphingosine-1-phosphate increased. Consequently, the ratio of ceramides C16Cer/ C24Cer decreased. Sphingolipid levels showed weak correlations with clinical parameters.

Conclusions: These findings highlight the existence of a distinctive sphingolipid profile in blood from PWCF, which appears to be altered by ELX/TEZ/IVA therapy. Thus, strategies for sphingolipid remodeling need to be reassessed and adjusted in the light of highly effective CFTR modulator therapies.

Dirk Westhölter is in the Department of Pulmonary Medicine, University Hospital Essen- Ruhrlandklinik, Tüschener Weg 40, Essen 45239, Germany.

Lena WucherpfennigSimon M F TriphanSabine WegeHans-Ulrich KauczorClaus P HeusselNiclas SchmittFelix WuennemannVictoria L MayerOlaf SommerburgMarcus A MallMonika EichingerMark O WielpützMagnetic resonance imaging detects improvements of pulmonary and paranasal sinus abnormalities in response to elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosisJ Cyst Fibros 2022 Apr 7;S1569-1993(22)00088-1.: 10.1016/j.jcf.2022.03.011.Online ahead of print.[Pubmed]

Lena Wucherpfennig researchgate.net

Background: Therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) was recently approved for adult cystic fibrosis (CF) patients with at least one F508del mutation. However, its effects on structural and functional lung abnormalities and chronic rhinosinusitis have not been studied by imaging.
Methods: 19 adults with CF (mean age 31±9y, range 19-55y) underwent standardized chest magnetic resonance imaging (MRI), and nine also same-session sinonasal MRI, before (MRI1) and after (MRI2) at least one month (mean duration 5 ± 3mon) on ETI. 24 control CF patients (30±7y, range 20-44y) without ETI underwent longitudinal chest MRI, and eleven also sinonasal MRI, twice (mean interval 40±15mon). MRI was assessed using the validated chest MRI score and chronic rhinosinusitis (CRS)-MRI score. Forced expiratory volume in 1 s percent predicted (FEV1%) was measured in all patients.
Results: In controls, the chest MRI global score and CRS-MRI sum score were stable from MRI1 to MRI2. In patients under ETI, the chest MRI global score improved (-11.4 ± 4.6, P<0.001), mainly due to reduction of bronchiectasis/wall thickening and mucus plugging subscores (-3.3 ± 2.2 and -5.2 ± 1.5, P<0.001, respectively). The improvement in chest MRI score correlated well with improved FEV1% (r=-0.703, P<0.001). The CRS-MRI sum score also improved in patients under ETI (-6.9 ± 3.0, P<0.001), mainly due to a reduction of mucopyoceles in the maxillary and ethmoid sinus (-50% and -39%, P<0.05, respectively).

Conclusions: MRI detects improvements of chest MRI and CRS-MRI scores in adult CF patients who first received ETI, demonstrating reversibility of structural lung and paranasal sinus abnormalities in patients with established disease.

Dr Lena Wucherpfennig is in the Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany; Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany.

John XuerebPatrick SammutChiara VellaIan M Balfour-Lynn.Resolution of lobe collapse in a child with cystic fibrosis with Mycobacterium abscessus using serial intrabronchial rhDNasePediatr Pulmonol 2022 Jun;57(6):1549-1551.doi: 10.1002/ppul.25902.Epub 2022 Mar 31.[Pubmed]

An eight-year-old girl with cystic fibrosis (CF) developed a left upper lobe collapse failing to resolve with initial conventional antibiotic treatment, mucolytics and intensified physiotherapy. Mycobacterium abscessus was isolated from her sputum. Bronchoscopy revealed thick viscous mucus plugging of the left upper lobe bronchus with complete obliteration.  Three bronchoscopies with saline lavage and Dornase alfa, a rhDNase, at the end of each procedure resulted in removal of this mucus plug and the re-inflation of the affected lobe, with clinical and radiological resolution. The use of flexible bronchoscopy as a ‘secondary’ treatment with 0.9% saline lavage and instillation of rhDNase is described sparsely in the literature. This is the first reported successful therapeutic resolution of a lung collapse in a CF patient with Mycobacterium abscessus, with sequential therapeutic bronchoscopies with instillation  of Dornase alfa. This should be considered for lobar collapse in CF not responding to the standard therapeutic regime.

Dr John Xuereb is in the Department of Paediatrics, Mater Dei Hospital, Msida, Malta.

Marco ZampoliNataliya KashirskayaBulent KaradagLuiz Vicente Ribeiro Ferreira da Silva FilhoGrace R Paul,Christine Noke.    Global access to affordable CFTR modulator drugs: Time for action! J Cyst Fibros 2022 Mar 24;S1569-1993(22)00083-2.doi: 10.1016/j.jcf.2022.03.006.Online ahead of print.

There is no abstract so the article is reproduced here

Marco Zampoli  news.uct.ac.za

Whilst the incredible advancements in CF treatment are to be applauded and celebrated, the reality is that only a minority of people with CF in the rich global North are benefiting from CFTRm therapy. We are therefore very grateful and encouraged by the timely and important article by Jonathan Guo et al. published recently in the Journal which highlights the stark reality and disparity that exists in CF diagnosis and treatment across the world. According to their estimates based on available data, there are 57,076 people with undiagnosed CF across the world with the highest burden likely to be in the Middle East and India. Furthermore, only 12% of estimated 105,352 people captured in global CF registries are receiving Trikafta®/Kaftrio® and the majority of them are living in North America or Western Europe. We agree with their view that paucity of epidemiological data and lack of CF diagnosis capacity in low and middle-income countries (LMICs) are major barriers to advocating for effective and equitable treatment in these regions. However, there are significant CF populations living in LMICs such as South Africa, India, the Middle East, eastern Europe, and South America who currently have no access nor pathway to registration of Trikafta®/Kaftrio® which will undoubtably lead to increasing disparity in CF outcomes between the rich global North and poor global South. In these countries, the main barrier to accessing triple CFTRm therapy is not lack of diagnosis capacity, but profit-driven global market forces which are accountable more to shareholders than the health needs of the global CF community.

Global distribution and sales of CFTRm drugs and patents are in place until 2037 in many LMICs that are signatories to the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights, effectively preventing manufacture and distribution of affordable generic alternatives in these countries. The current annual cost per patient of Trikafta®/Kaftrio® paid by countries with negotiated agreements is more than $250 000 which is prohibitive for governments and private health insurers in LMICs. Vertex Pharmaceuticals posted a net income of $5.7 billion in 2021 which is a bitter pill to swallow for CF communities in LMICs who are helpless and increasingly impatient with the injustice of their plight . Precedent exists where pharmaceutical companies holding patents have issued voluntary licenses to generic manufacturers to distribute, with profit, life-saving affordable generic drugs in LMICs for treatment of Human Immunodeficiency Virus, hepatitis-C and more recently COVID-19. It is time that the global CF community stand in solidarity in support of similar issuing of voluntary licenses for the manufacture and distribution of generic CFTRm drugs.

We appeal and urge that the Journal and CF patient organizations in the global North such as the Cystic Fibrosis Foundation and European CF Society adopt a stronger position and publish statements against the injustice of the disparity in access to CFTRm therapy for all people across the world living with CF who are eligible for this life-saving treatment. Cystic fibrosis clinicians, researchers and CF communities living in LMICs cannot endure and tolerate much longer reading and hearing about the ‘miracle’ outcomes of triple CFTRm drugs of the privileged minority in rich countries. In the meantime, we continue to patiently negotiate in good faith with Vertex Pharmaceuticals in the hope that CF communities in LMICs will soon have affordable access to this life saving treatment. But time is running out for many people slowly dying too early with CF.

Dr Marco Zampoli is Clinical Head: Cystic Fibrosis Clinic Red Cross War Memorial Children’s Hospital, National Director South African CF Registry Steering Committee, Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa

Claire E Wainwright  A New Era for Cystic Fibrosis and CFTR Modulator Trials in Infants.  Am J Respir Crit Care Med 2022 Jul 20.doi: 10.1164/rccm.202207-1356ED.Online ahead of print.[Pubmed]
(Summary as no abstract)

Claire Wainwright
Author’s photo

As CFTR modulator therapies becomes established in young children a new approach to clinical care is likely to evolve as people with CF live longer lives ensuring healthy ageing will become a priority
In open label trials nearly 11% of children had transaminases elevation more than 3x upper limit of normal. Details of trails in young infants remain to be decided – open label trials appear to be extending to infants. There may be unrecognised effects on the young developing child and will open label trials be adequate to recognise these problems?
As CFTR modulation becomes established clinically the window for randomised placebo-controlled trials has almost closed. Consumers, clinicians and researchers need to rapidly determine how we move forward in developing new CFTR modulator therapy for infants and decide whether infants are indeed “little adults” and whether benefits can be effectively inferred or whether they deserve the same degree of evidence as older people expect?

Claire E Wainwright is Professor of Paediatrics and Child Health University of Queensland, Brisbane, Australia