History - 2021 A to L


H L BarrT BihoueeA M ZwitserlootA year in review: Real world evidence, functional monitoring and emerging therapeutics in 2021J Cyst Fibros 2022 Mar;21(2):191-196.doi: 10.1016/j.jcf.2022.02.014.Epub 2022 Mar 7.   Free PMC article   [Pubmed]

Fig. 1 Helen Barr ResearchGate


This is a comprehensive and  extensively referenced review of significant areas of change and new knowledge during 2021. The Free PMC article is available and strongly recommended.

There are joint first authors. The correspondiing author is Dr Helen Barr (fig.1) consultant respiratory physician at the Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Nottingham Respiratory Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom.

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

Fig.2 Adrienne P Savant LCMC Health

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 (fig.2) 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.


A M Akkerman-Nijland J E MöhlmannO W AkkermanH Vd VaartC J MajoorB L RottierJ G M BurgerhofE HakG H KoppelmanD J Touw The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heartExpert Opin Drug Saf 2021 May 25. doi: 10.1080/14740338.2021.1932814.Online ahead of print. [Pubmed]

Fig. 3 Anne Akkerman-Nijland UMCG

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.
Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.
Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.

Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Anne M Akkerman-Nijland  (Fig. 3) is at the University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, Groningen, the Netherlands, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.

Gianfranco AlicandroValeria DaccóLisa CarianiMartina ContariniLetizia Corinna MorlacchiChiara RosazzaCalogero Sathya SciarrabbaFederica FerraroBeatrice Silvia OrenaAndrea GramegnaFrancesco BlasiCarla Colombo.   SARS-CoV-2 antibodies among people with cystic fibrosis prior to the vaccination campaign: A seroprevalence study in two specialized centres in Northern ItalyJ Cyst Fibros 2021 Dec 13;S1569-1993(21)02170-6.doi: 10.1016/j.jcf.2021.12.011.Online ahead of print. Free PMC article    [Pubmed]

Fig. 4 Gianfranco Alicandro

The prevalence of anti-SARS-CoV-2 antibodies in people with cystic fibrosis (CF) is largely unknown. We carried out a cross-sectional study between March and June 2021 with the aim of estimating the seroprevalence of anti-SARS-CoV-2 antibodies in two CF centres in Northern Italy. Total serum anti-SARS-CoV-2 (spike) antibodies levels were measured and values ≥0.8 U/mL were considered positive. Among 434 patients aged >12 years, 64 patients had a positive result (14.7%, 95% CI: 11.5-18.4), 36 (56.3%) without experiencing any COVID-19-related symptoms. Three out of 49 transplanted patients tested positive with an odds ratio for a positive result among transplanted as compared to non-transplanted patients of 0.35 (95% CI: 0.07-1.14).
No significant differences were observed between sexes, age groups, socioeconomic status and lung disease severity. In conclusion, SARS-CoV-2 has infected a relatively high proportion of our patients but in most cases the infection was asymptomatic.

Gianfranco Alicandro (fig.4) is in the Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Centre, Milan, Italy.

Margarida D Amaral  How to determine the mechanism of action of CFTR modulator compounds: A gateway to theranostics. Eur J Med Chem 2021 Jan 15;210:112989.doi: 10.1016/j.ejmech.2020.112989.Epub 2020 Nov 5.  [Pubmed]

Fig. 5 Margarida Amaral

The greatest challenge of 21st century biology is to fully understand mechanisms of disease to drive new approaches and medical innovation. Parallel to this is the huge biomedical endeavour of treating people through personalised medicine. Until now all CFTR modulator drugs that have entered clinical trials have been genotype-dependent. An emerging alternative is personalized/precision medicine in CF, i.e., to determine whether rare CFTR mutations respond to existing (or novel) CFTR modulator drugs by pre-assessing them directly on patient's tissues ex vivo, an approach also now termed theranostics. To administer the right drug to the right person it is essential to understand how drugs work, i.e., to know their mechanism of action (MoA), so as to predict their applicability, not just in certain mutations but also possibly in other diseases that share the same defect/defective pathway. Moreover, an understanding the MoA of a drug before it is tested in clinical trials is the logical path to drug discovery and can increase its chance for success and hence also approval. In conclusion, the most powerful approach to determine the MoA of a compound is to understand the underlying biology. Novel large datasets of intervenients in most biological processes, namely those emerging from the post-genomic era tools, are available and should be used to help in this task.

Dr Margarida D Amaral (fig.5) is at BioISI - Biosystems & Integrative Sciences Institute, Lisboa, Faculty of Sciences, University of Lisboa, Portugal.

Elena L AmelinaStanislav A KrasovskyNina E Akhtyamova-GivirovskayaNataliya Yu KashirskayaDiana I AbdulganievaIrina K AsherovaIlya E ZilberLiliya S Kozyreva Lubov M KudelyaNatalya D PonomarevaNataliya P Revel-MurozElena M ReutskayaTatiana A StepanenkoGulnara N Seitova  Olga P Ukhanova Olga V MagnitskayaDmitry A KudlayOksana A MarkovaElena V Gapchenko Comparison of biosimilar Tigerase and Pulmozyme in long-term symptomatic therapy of patients with cystic fibrosis and severe pulmonary impairment (subgroup analysis of a Phase III randomized open-label clinical trial (NCT04468100))PLoS One  2021 Dec 23;16(12):e0261410.doi: 10.1371/journal.pone.0261410. eCollection 2021. [Pubmed]  Free PMC article

Background: Patients with cystic fibrosis (CF) need costly medical care and adequate therapy with expensive medicinal products. Tigerase® is the first biosimilar of dornase alfa, developed by the lead Russian biotechnology company GENERIUM. The aim of the manuscript to present post hoc sub-analysis of patients' data with cystic fibrosis and severe pulmonary impairment of a larger comparative study (phase III open label, prospective, multi-centre, randomized study (NCT04468100)) of a generic version of recombinant human DNase Tigerase® to the only comparable drug, Pulmozyme®.
Methods: In the analyses included subgroup of 46 severe pulmonary impairment patients with baseline FEV1 level 40-60% of predicted (23 patients in each treatment group) out of 100 patients registered in the study phase III open label, prospective, multi-center, randomized study (NCT04468100), and compared efficacy endpoints (FEV1, FVC, number and time of exacerbations, body weight, St.George's Respiratory Questionnaire) as well as safety parameters (AEs, SAEs, anti-drug antibody) within 24 treatment weeks.
Results: All outcomes were comparable among the studied groups. In the efficacy dataset, the similar mean FEV1 and mean FVC changes for 24 weeks of both treatment groups were observed. The groups were also comparable in safety, all the secondary efficacy parameters and immunogenicity.

Conclusions: The findings from this study support the clinical Tigerase® biosimilarity to Pulmozyme® administered in CF patients with severe impairment of pulmonary function.

Elena L Amelina   is a paediatrician and Head of the Pulmonary Research Institute Moscow.Russia

Justin D AndersonZhongyu LiuL Victoria OdomLatona KershJennifer S Guimbellot. CFTR Function and Clinical Response to Modulators Parallel Nasal Epithelial Organoid SwellingAm J Physiol Lung Cell Mol Physiol 2021 May 19.doi: 10.1152/ajplung.00639.2020.Online ahead of print. [Pubmed]
Rationale: In vitro biomarkers to assess Cystic Fibrosis Transmembrane Conductance Regulator activity are desirable for precision modulator selection and as a tool for clinical trials.
Objectives: We describe an organoid swelling assay derived from human nasal epithelia using commercially available reagents and equipment and an automated imaging process.
Methods: Cells were collected in nasal brush biopsies, expanded in vitro, and cultured as spherical organoids or as monolayers. Organoids were used in a functional swelling assay with automated measurements and analysis, while monolayers were used for short-circuit current measurements to assess ion channel activity. Clinical data was collected from patients on modulators. Relationships between swelling data and short-circuit current, as well as between swelling data and clinical outcome measures, were assessed.
Main results: The organoid assay measurements correlate with short-circuit current measurements for ion channel activity. The functional organoid assay distinguished individual responses as well as differences between groups. The organoid assay distinguished incremental drug responses to modulator monotherapy with ivacaftor and combination therapy with ivacaftor, tezacaftor, and elexacaftor. The swelling activity paralleled clinical response.
Conclusions: An in vitro biomarker derived from patients' cells can be used to predict responses to drugs and is likely to be useful as a pre-clinical tool to aid in development of novel treatments, and as a clinical trial outcome measure for a variety of applications, including gene therapy or editing.

Dr Justin D Anderson  is at the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, and the Department of Pediatrics, Division of Pulmonary and Sleep Medicine, grid.265892.2University of Alabama at Birmingham, Birmingham, AL, USA.

Nicholas J AntosAdrienne P Savant. Cystic fibrosis year in review 2020: Section 2 pulmonary disease, infections, and inflammation. Pediatr Pulmonol. 2021 May 25.doi: 10.1002/ppul.25459. Online ahead of print. [Pubmed]

Fig. 7 Adrienne Savant

Fig. 6 Nicholas Antos mcw.edu

The outlook for those with cystic fibrosis (CF) has never been brighter with ever increasing life expectancy and the approval of the highly effective CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor. With that being said, the progressive pulmonary decline and importance of lung health, infection, and inflammation in CF remains.

This review is the second part in a three-part CF Year in Review 2020. Part one focused on the literature related to CFTR modulators while part three will feature the multisystem effects related to CF. This review focuses on articles from Pediatric Pulmonology, including articles from other journals that are of particular interest to clinicians. Herein, we highlight studies published during 2020 related to CF pulmonary disease, infection, treatment, and diagnostics.

Dr Nicholas J Antos (fig.6) is in the Department of Pediatrics, Division of Pulmonary and Sleep Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. & the Department of Pediatric Pulmonology, Children's Wisconsin, Milwaukee, Wisconsin, USA.

Dr Adrienne P Savant (fig.7) is in the Department of Pediatrics, Children's Hospital of New Orleans, New Orleans, Louisiana, USA & the Department of Pediatrics, Tulane University, New Orleans, Louisiana, USA.

Olga ArchangelidiPaul CullinanNicholas J SimmondsEmmanouil MentzakisDaniel PeckhamDiana BiltonSiobhán B Carr Incidence and risk factors of cancer in individuals with cystic fibrosis in the UK; a case-control study. J Cyst Fibros 2021 Aug 1;S1569-1993(21)01302-3.doi: 10.1016/j.jcf.2021.07.004.Online ahead of print.     [Pubmed]


 Fig. 8 Olga Archangelidi LinkedIn

To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients with CF, registered with the UK CF Registry. Each case with a first reported cancer between 1999 and 2017 was matched with up to 4 controls: by age (±2-years) and year of cancer diagnosis.

From 12,886 registered patients, 146 (1.1%) cases of malignancy were identified with 14.3% of cases occurring post solid organ transplant. Site of primary cancer was available for 98 patients: 22% were gastro-intestinal in origin (77% lower, 23% upper GI), 13% skin, 13% breast and 11% lymphomas/leukaemia. In univariable analysis, transplantation increased the odds of reporting any cancer by 2.46 times (95%CI: 1.3-4.6). CFRD also increased the odds of reporting any cancer (OR 2.35; CI: 1.37-4.0) and PPI use (OR 2.0; CI 1.28-3.19). In the multivariable models significant associations with CFRD and transplant remained, while PA infection, PPI use and being overweight showed increased, but statistically insignificant risks. The incidence of GI cancer was strongly associated with CFRD (OR=4.04; 1.47-11.1).

Conclusions: We observed a high incidence of lower GI cancers in our cohort which was significantly affected by the presence of CFRD. Screening for gastrointestinal cancers could benefit patients at higher risk.

Dr Olga Archangelidi (fig.8) a post-doctoral research associate at the National Heart and Lung Institute, Imperial College, London; Amgem Ltd.

Varinder S AthwalJennifer A ScottEmer FitzpatrickMarion RowlandEmerging clinical perspectives in cystic fibrosis liver diseaseCurr Opin Pulm Med  2021 Sep 1.doi: 10.1097/MCP.0000000000000824. Online ahead of print. [Pubmed]

Fig. 9 Varinder Athwal guts charity.org.uk

Purpose of review: Liver disease (CFLD) as a complication of cystic fibrosis is recognized as a more severe disease phenotype in both children and adults. We review recent advances in understanding the disease mechanism and consider the implications of new strategies for the diagnosis and management of cystic fibrosis in those with evidence of clinically significant liver disease.
Recent findings: Evidence suggests that the prevalence of CFLD has not declined with the introduction of newborn screening. Furthermore, children with CFLD, who have been diagnosed with cystic fibrosis following newborn screening continue to have a much higher mortality rate compared with those with no liver disease. There is further data suggesting noncirrhotic obliterative portal venopathy as the predominant pathological mechanism in the majority of children and young adults receiving a liver transplantation. Little progress has been made in developing an accurate noninvasive test for early diagnosis or monitoring disease progression in CFLD. The benefit of new modulator therapies is not well understood in those with established CFLD, whereas the risk of hepatotoxicity as a complication of treatment must be carefully monitored.

Summary: Better understanding of the pathophysiology of CFLD would allow a standardized approach to diagnosis, with the potential to improve outcomes for those with CFLD.

Dr Varinder S Athwal (fig.9) is Senior Clinical Lecturer and Consultant in Gastroenterology and Hepatology, Manchester University NHS Foundation Trust

Laura AtzoriCaterina FerreliFranco RongiolettiAquagenic (pseudo) keratoderma (aquagenic palmoplantar keratoderma, aquagenic wrinkling of palms)Clin Dermatol Mar-Apr 2021;39(2):256-260.doi: 10.1016/j.clindermatol.2020.10.003.Epub 2020 Oct 16. [Pubmed]

Fig.10 Laura Atzori

Aquagenic palmoplantar keratoderma (APK) is an uncommon hereditary or sporadic condition that is characterized by edematous flat-topped papules appearing on palmar skin with wrinkling after brief water exposure. APK has been associated with cystic fibrosis (CF), presenting with the same mutations found in CF (usually ΔF508 of the CFTR gene), either homozygous or heterozygous. APK may be idiopathic or drug-induced. The diagnosis is easily made if one is aware of this entity. Topical aluminum hydroxide and botulinum toxin injections are the most commonly used treatments. The sporadic form may have a shorter course compared with the hereditary one, resolving spontaneously after a few years. The condition should no longer be considered a true keratoderma but rather a pseudo keratoderma, and in spite of the many different names found in the literature, the term "aquagenic (pseudo) keratoderma" seems to be the most appropriate one.

Laura Atzori (Fig 10) is at the Dermatology Clinic, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy.

Margherita BaldassarriFrancesca Fava Chiara FalleriniSergio Daga Elisa Benetti Kristina Zguroet al.  On Behalf Of The Gen-Covid Multicenter StudySevere COVID-19 in Hospitalized Carriers of Single CFTRPathogenic VariantsJ Pers Med. 2021 Jun 15;11(6):558.doi: 10.3390/jpm11060558. Free PMC article [Pubmed]
The clinical presentation of COVID-19 is extremely heterogeneous, ranging from asymptomatic to severely ill patients. Thus, host genetic factors may be involved in determining disease presentation and progression. Given that carriers of single cystic fibrosis (CF)-causing variants of the CFTR gene-CF-carriers-are more susceptible to respiratory tract infections, our aim was to determine their likelihood of undergoing severe COVID-19. We implemented a cohort study of 874 individuals diagnosed with C https://www.google.com/OVID-19, during the first pandemic wave in Italy. Whole exome sequencing was performed and validated CF-causing variants were identified. Forty subjects (16 females and 24 males) were found to be CF-carriers. Among mechanically ventilated patients, CF-carriers were more represented (8.7%) and they were significantly (p < 0.05) younger (mean age 51 years) compared to noncarriers (mean age 61.42 years). Furthermore, in the whole cohort, the age of male CF-carriers was lower, compared to noncarriers (p < 0.05). CF-carriers had a relative risk of presenting an abnormal inflammatory response (CRP ≥ 20 mg/dL) of 1.69 (p < 0.05) and their hazard ratio of death at day 14 was 3.10 (p < 0.05) in a multivariate regression model, adjusted for age, sex and comorbidities. In conclusion, CF-carriers are more susceptible to the severe form of COVID-19, showing also higher risk of 14-day death.

Dr Margherita Baldassarri    is in the Department of Medical Genetics, University of Siena, 53100 Siena, Italy.  Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.

Bardin E, Pastor A, Semeraro M, Golec A, Hayes K, Chevalier B, Berhal F, Prestat G, Hinzpeter A, Gravier-Pelletier C, Pranke I, Sermet-Gaudelus I.   Modulators of CFTR. Updates on clinical development and future.  Eur J Med Chem. 2021 Mar 5;213:113195.doi: 10.1016/j.ejmech.2021.113195. Epub 2021 Jan 16. [Pubmed]

Fig.11 Emmanuelle Bardin LinkedIn.com

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

Dr Emmanuelle Bardin (fig.11) is a post-doctoral researcher at the Institut Necker Enfants Malades. INSERM U1151, Paris, France. in 2020 she was awarded a European Cystic Fibrosis Society and Cystic Fibrosis Europe Post-Doctoral Research Fellowship to research into "Novel insights into the impact of CFTR modulators on the response of the cystic fibrosis respiratory epithelium to S. aureus infection".

Peter J BarryMarcus A MallAntonio Álvarez1Carla ColomboKarin M de Winter-de GrootIsabelle Fajac  et al. VX18-445-104 Study Group Collaborators,  Triple Therapy for Cystic Fibrosis Phe508del-Gating and -Residual Function Genotypes. N Engl J Med  2021 Aug 26;385(9):815-825.doi: 10.1056/NEJMoa2100665. [Pubmed]

Fig. 12  Peter J Barry

Background: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508delallele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.
Methods: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group
Results: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.

Conclusions: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).

Dr Peter J Barry (fig.12) is at the Manchester University NHS Foundation Trust, Manchester, United Kingdom.

Rosara BassJefferson N BrownellVirginia A StallingsThe Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status. Nutrients 2021 Aug 24;13(9):2907. doi: 10.3390/nu13092907   free article [Pubmed]

Fig. 13 Rosara Bass chop.edu

Dysfunctional CFTR contributes to increased energy expenditure, exocrine pancreatic insufficiency causing impaired dietary macronutrient digestion and absorption, intestinal dysbiosis, and impaired bile acid homeostasis. Poor nutritional status as a result of these mechanisms is associated with decreased lung function, worse clinical outcomes, and ultimately, increased mortality. Nutritional interventions addressing these mechanisms, such as pancreatic enzyme-replacement therapy and enteral caloric supplementation, have improved nutritional status and, by association, clinical outcomes. In the last decade, the advent of medications targeting defective CFTR proteins has revolutionized the care of patients with CF by reducing the overall impact of CFTR dysfunction. Below, we summarize the effects of highly effective CFTR modulators on nutritional status overall as well as specific factors including bile acid metabolism, pancreatic function, energy expenditure, and intestinal dysbiosis. The authors suggest the future of CF nutrition care will require a paradigm shift away from focusing on methods addressing CFTR dysfunction such as excess calorie provision and toward an individualized, holistic approach in the context of specific mutations and CFTR-directed therapy.

Table 1 (from full paper available via PubMed)  Summary of the effects of highly effective CFTR modulators on markers of growth, nutritional status and gastrointestinal health.

Outcome Ivacaftor ELEX-TEZ-IVA
Weight-Z Increased Increased
Height-Z Increased in youth To be determined
BMI-Z Increased Increased
Fat Mass Increased To be determined
Fat-Free Mass Unchanged to increased To be determined
Bile Acid Metabolism Increased FGF-19 and decreased C4 To be determined
CF Liver Disease To be determined, case reports of improved steatosis To be determined
Exocrine Pancreatic Insufficiency Increased fecal elastase at younger ages To be determined
Bicarbonate Secretion Decreased time to reach pH 5.5 To be determined
Energy Expenditure Decreased To be determined
GI Microbiome Changes in intestinal flora and decreased calprotectin To be determined

Dr Rosara Bass (fig.13) is attending physician with the Division of Gastroenterology, Hepatology and Nutrition at the Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.

--- This is an excellent comprehensive review of the general effects of CFTR modulators on wide variety of factors relevant to nutrition

Sarah E BauerMelissa WessonSylwia K OlesClement L Ren.      Outcomes of Repeat Sweat Testing in Cystic Fibrosis Newborn Screen Positive Infants. Pediatr Pulmonol 2021 Jan 29.doi: 10.1002/ppul.25296. Online ahead of print.[Pubmed]

Fig. 14 Sarah Bauer medicine.iu.edu

Infants with a positive cystic fibrosis (CF) newborn screen, only one identified CFTR mutation (NBS+/1mut), and an initial intermediate sweat chloride (30-59 mmol/L) should have repeat sweat chloride testing (SCT). However, the outcome of repeat SCT and the relationship between initial sweat Cl and subsequent CF diagnosis have not been reported.   The objective of this study was to analyze the outcomes of repeat SCT and subsequent CF diagnosis in NBS+/1mut infants based on their initial sweat chloride concentration.We retrospectively identified all infants born in Indiana from 2007 through 2017 with NBS+/1mut and initial SCT in the intermediate range. For each infant, we recorded the initial and repeat SCT results and/or a final CF diagnosis.
Results: From 2007 through 2017 there were 2,822 NBS+/1mut infants of which 2,613 (82%) had at least one SCT result. No infants with an initial SCT of 30-39 mmol/L were subsequently diagnosed with CF. Of the 31 infants with an initial SCT of 40-49 mmol/L, only 1 was subsequently diagnosed with CF. In contrast, 61% of those with SCTs of 50-59 mmol/L were later diagnosed with CF.
Conclusion: These results suggest that infants with a positive NBS for CF and 1 CFTR mutation whose initial sweat chloride concentration is 50-59 mmol/L need to be monitored more closely for CF with strong consideration for earlier repeat SCTs and immediate genotyping.

Dr Sarah E Bauer (fig.14)  is a Fellow at Pediatrics, Indiana University, Indianapolis, IN, United States. Subsequently Assistant Professor.

Sarah E BauerHuiChuan J LaiCatherine M McDonaldFadi AsfourJames E SlavenClement L Ren. Zinc status and growth in infants and young children with cystic fibrosisPediatr Pulmonol. 2021 Sep 9.doi: 10.1002/ppul.25666. Online ahead of print. [Pubmed]
Background: Zinc deficiency is associated with poor growth in children without cystic fibrosis (CF), but its impact on growth in children with CF is unknown.
Objective: To determine the prevalence of low serum Zn (sZn) and its relationship with growth in the first 3 years of life in children with CF.
Methods: We utilized data from infants with CF who were enrolled in a longitudinal study of nutrition and lung health and had sZn measured as part of clinical care. Cross-sectional correlations between sZn levels and growth z scores were assessed by Pearson's correlation coefficient. To identify factors associated with sZn status and its association to longitudinal growth patterns, multiple regression analysis with repeated measures were performed using generalized estimating equations.
Results: A total of 106 sZn measurements from 53 infants were identified. Seventeen infants (32%) had intermittent Zn insufficiency, defined as at least one sZn <70 mcg/dl in their first 3 years of life. There were no significant cross-sectional associations between sZn and growth z scores. However, analysis of longitudinal growth patterns revealed that weight- and length-for-age z scores in children with intermittent Zn insufficiency were lower during early infancy and their weight-for-length z scores at age 3 years were also lower compared to those who were always Zn sufficient.

Conclusion: Low sZn occurs in one-third of children with CF in the first 3 years of life. Cross-sectional and longitudinal analyses revealed discrepant associations between sZn and growth. Therefore, prospective studies are needed to understand the role of Zn in growth in CF.

Dr Sarah E Bauer (fig.14) is a paediatric pulmonologist in the Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA

Katie J Bayfield Tonya A Douglas Tim RosenowJane Carolyn DaviesStuart J ElbornMarcus MallAnthony PaprokiFelix RatjenPeter D SlyAlan Robert SmythStephen StickClaire E WainwrightPaul D Robinson Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis.Thorax. 2021 Apr 29;thoraxjnl-2020-216085.doi: 10.1136/thoraxjnl-2020-216085. Online ahead of print. [Pubmed]    

Fig. 16  Tonya Douglas breathrightsleeptight.com.au

Fig. 15 Katie Bayfield ResearchGate

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV1≥90% predicted) and 'mild lung disease' (FEV1 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques.

The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.   Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups.
Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.
To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.

Dr Katie J Bayfield (fig.15) is in the Department of Respiratory Medicine, Children's Hospital at Westmead, Westmead, New South Wales, Australia.

Dr Tonya A Douglas (fig.16) is staff specialist and co-director of paediatric CF services, Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, South Brisbane, Queensland, Australia and the Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia.

Frédéric BecqSandra MirvalThomas CarrezManuella LévêqueArnaud BilletChristelle CorauxEdouard SageAnne Cantereau. The rescue of F508del-CFTR by elexacaftor/tezacaftor/ivacaftor (Trikafta) in human airway epithelial cells is underestimated due to the presence of ivacaftor. Eur Respir J 2021 Jul 15;2100671.doi: 10.1183/13993003.00671-2021.Online ahead of print. [Pubmed]

Fig. 17 Frederic Becq      Loop (Frontiers)

Trikafta, currently the leading therapeutic in Cystic Fibrosis (CF), has demonstrated a real clinical benefit. This treatment is the triple combination therapy of two folding correctors elexacaftor/tezacaftor (VX445/VX661) plus the gating potentiator ivacaftor (VX770). In this study, our aim was to compare the properties of F508del-CFTR in cells treated with either lumacaftor (VX809), tezacaftor, elexacaftor, elexacaftor/tezacaftor with or without ivacaftor. We studied F508del-CFTR function, maturation and membrane localisation by Ussing chamber and whole-cell patch clamp recordings, Western blot and immunolocalization experiments. With human primary airway epithelial cells and the cell lines CFBE and BHK expressing F508del, we found that, whereas the combination elexacaftor/tezacaftor/ivacaftor was efficient in rescuing F508del-CFTR abnormal maturation, apical membrane location and function, the presence of ivacaftor limits these effects. The basal F508del-CFTR short-circuit current was significantly increased by elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor compared to other correctors and non-treated cells, an effect dependent on ivacaftor and cAMP. These results suggest that the level of the basal F508del-CFTR current might be a marker for correction efficacy in CF cells. When cells were treated with ivacaftor combined to any correctors, the F508del-CFTR current was unresponsive to the subsequently acute addition of ivacaftor unlike the CFTR potentiators genistein and Cact-A1 which increased elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor-corrected F508del-CFTR currents. These findings show that ivacaftor reduces the correction efficacy of Trikafta. Thus, combining elexacaftor/tezacaftor with a different potentiator might improve the therapeutic efficacy for treating CF patients.

 Professor Frédéric Becq  (Fig. 17) is at the Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, France.

Marina M BelletMonica BorghiMarilena ParianoGiorgia RengaClaudia StincardiniFiorella D'OnofrioStefano BrancorsiniEnrico GaraciClaudio CostantiniLuigina Romani.  Thymosin alpha 1 exerts beneficial extrapulmonary effects in cystic fibrosis Eur J Med Chem 2021 Jan 1;209:112921.doi: 10.1016/j.ejmech.2020.112921. Epub 2020 Oct 9. [Pubmed]

Fig. 18 Marina M Bellet Loop (Frontiers)

We have previously demonstrated that thymosin alpha1 (Tα1), a naturally occurring immunomodulatory peptide, displays multi-sided beneficial effects in CF that concur in ameliorating the lung inflammatory pathology. In the present study, by resorting to murine models of gut inflammation with clinical relevance for CF patients, we demonstrate that Tα1 can also have beneficial effects in extrapulmonary pathology. Specifically, Tα1 restored barrier integrity and immune homeostasis in the inflamed gut of CF mice as well as in mice with the metabolic syndrome, a disorder that may arise in CF patients with high caloric intake despite pancreatic sufficiency. The protective effects of Tα1 also extended to pancreas and liver, further emphasizing the beneficial effects of Tα1 in extra-pulmonary complications of CF. By performing wide-ranging multi-organ anti-inflammatory effects, Tα1 could potentially integrate current therapeutic approaches to tackle the complex symptomatology of CF diseas

Marina M Bellet (fig.18) is in the Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.

KA McBennett, Pamela B Davis Michael W Konstan.  Increasing life expectancy in cystic fibrosis: Advances and challenges. Pediatr Pulmonol 2021 Oct 21.doi: 10.1002/ppul.25733. Online ahead of print. [Pubmed]

Fig.19 Kimberly A McBennett
Case Western Reserve

Based on data from 2019, the Cystic Fibrosis Foundation Registry Report from the United States calculated the predicted median survival age of a child born that year with cystic fibrosis to be 48.4 years1 , a remarkable achievement.

Kimberley A McBennett (fig.19) is at  Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.

 Lauryn A BenningerCesar TrilloJorge LascanoCFTR modulator use in post lung transplant recipientsJ Heart Lung Transplant  2021 Aug 26;S1053-2498(21)02482-7.doi: 10.1016/j.healun.2021.08.009. Online ahead of print.   [Pubmed]

Fig. 20 Lauryn Benninger ResearchGate

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy has previously been contraindicated in solid organ transplant recipients. This was due to lack of data and concern for interactions with immunosuppressive drug regimens. However, in post-lung transplant recipients, CFTR modulators may improve extrapulmonary manifestations of cystic fibrosis without impacting graft function or immunosuppressive drug levels. Herein, we present our single center experience with the use of elexacaftor/tezacaftor/ivacaftor, Trikafta, in adult post-lung transplant recipients.

Dr Lauryn A Benninger (fig. 20)  is a pulmonologist in the Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida

Amelia BercussonGeorge JarvisAnand Shah CF Fungal Disease in the Age of CFTR ModulatorsMycopathologia   2021 Apr 4.doi: 10.1007/s11046-021-00541-5.Online ahead of print. [Pubmed]

Fig. 21 Amelia Bercusson

Fungi are increasingly recognised to have a significant role in the progression of lung disease in Cystic fibrosis with Aspergillus fumigatus the most common fungus isolated during respiratory sampling. The emergence of novel CFTR modulators has, however, significantly changed the outlook of disease progression in CF. In this review we discuss what impact novel CFTR modulators will have on fungal lung disease and its management in CF. We discuss how CFTR modulators affect antifungal innate immunity and consider the impact of Ivacaftor on fungal disease in individuals with gating mutations. We further review the increasing complication of drug-drug interactions with concurrent use of azole antifungal medication and highlight key unknowns that require addressing to fully understand the impact of CFTR modulators on fungal disease.

Dr Amelia Bercusson (fig.21) is a consultant at the Cystic Fibrosis Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK. Co-authors are from the Royal Brompton in London.

Peder BergMajbritt JeppesenJens Leipziger  Cystic fibrosis in the kidney: new lessons from impaired renal HCO3- excretion. Curr Opin Nephrol Hypertens 2021 Jul 1;30(4):437-443.doi: 10.1097/MNH.0000000000000725. [Pubmed]

Fig. 22 Peder Berg

Purpose of review: A key role of cystic fibrosis transmembrane conductance regulator (CFTR) in the kidney has recently been uncovered. This needs to be integrated into the understanding of the developed phenotypes in cystic fibrosis (CF) patients.
Recent findings: In the beta-intercalated cells of the collecting duct , CFTR functions in very similar terms as established in the exocrine pancreatic duct and both CFTR and SLC26A4 (pendrin) orchestrate regulated HCO3- secretion. Like in the pancreas, the hormone secretin is a key agonist to activate renal HCO3- secretion. In mice lacking CFTR or pendrin, acute and chronic base challenges trigger marked metabolic alkalosis because collecting duct base secretion is defective. Also in CF patients, the ability to acutely increase renal HCO3- excretion is markedly reduced.

Summary: The now much enlarged understanding of CFTR in the kidney may permit the measurement of challenged urine HCO3- excretion as a new biomarker for CF. We suggest a new explanation for the electrolyte disorder in CF termed Pseudo-Bartter Syndrome. The hallmark electrolyte disturbance features of this can be well explained by a reduced function of collecting duct Cl-/HCO3- exchange. Eventually, we suggest the diagnostic term distal renal tubular alkalosis to cover those disturbances that causes metabolic alkalosis by a reduced collecting duct base secretion.

Dr Peder Berg (fig.22)  is in the Department of Biomedicine, Physiology, Health, Aarhus University, Aarhus, Denmark. For this work he was awarded the Gerd Döring award of the ECFS in 2021

Wolfgang BernhardAnna ShunovaJürgen MachannMona GrimmelTobias B HaackPhilipp UtzUte Graepler-Mainka. Resolution of severe hepatosteatosis in a cystic fibrosis patient with multifactorial choline deficiency: A case reportNutrition. 2021 May 24;89:111348. doi: 10.1016/j.nut.2021.111348.Online ahead of print.  [Pubmed

Fig.23 Wolfgang Bernhard medizin.uni-tuebingen.de/

In cystic fibrosis (CF), 85% to 90% of patients develop exocrine pancreatic insufficiency. De le phosphatidylcholine and choline deficiency. We report on a female patient who has C F and progressive hepatosteatosis from 4.5 y onward. At 22.3 y, the liver comprised 27% fat (2385 mL volume) and transaminases were strongly increased. Plasma choline was 1.9 µmol/L (normal: 8-12 mol/L). Supplementation with 3 × 1g/d choline chloride decreased liver fat and volume (3 mo: 8.2%; 1912 mL) and normalized transaminases. Plasma choline increased to only 5.6 µmol/L upon supplementation, with high trimethylamine oxide levels (12-35 µmol/L; normal: 3 ± 1 mol/L) proving intestinal microbial choline degradation. The patient was homozygous for rs12325817, a frequent single-nucleotide polymorphism in the PEMT gene, associated with severe hepatosteatosis in response to choline deficiency. Resolution of steatosis required 2 y (4.5% fat). Discontinuation/resumption of choline supplementation resulted in rapid relapse/resolution of steatosis, increased transaminases, and abdominal pain.

Prof. Wolfgang Bernhard (fig.23) is in the Department of Neonatology, Children's Hospital, Eberhard-Karls-University, Tübingen, Germany.

 Diana BiltonIsabelle FajacTacjana PresslerJohn Paul ClancyDorota SandsPredrag MinicMarco CipolliIvanka GalevaAmparo SoléAlexandra L QuittnerZhanna JumadilovaMonika CiesielskaMichael W KonstanCLEAR-110 Study Group. Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infectionJ Cyst Fibros 2021 Jun 15;S1569-1993(21)00164-8. doi: 10.1016/j.jcf.2021.05.013.Online ahead of print.  [Pubmed]

Fig.24  Di Bilton LinkedIn

Background: In CLEAR-108-a phase 3, randomised, open-label study-once-daily amikacin liposome inhalation suspension (ALIS) was noninferior to twice-daily tobramycin inhalation solution (TIS) in improving lung function in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection after 3 treatment cycles (28 days on/28 days off). The CLEAR-110 extension study (ClinicalTrials.gov: NCT01316276; EudraCT: 2011-000443-24) assessed long-term safety, tolerability, and efficacy of ALIS in eligible patients who completed CLEAR-108.
Methods: . Patients received once-daily ALIS 590 mg for 12 treatment cycles (96 weeks). Patients were grouped by prior treatment: the "prior-ALIS" cohort received ALIS in CLEAR-108, and the "ALIS-naive" cohort received TIS in CLEAR-108.
Results: . Overall, 206 patients (prior-ALIS, n=92; ALIS-naive, n=114) entered CLEAR-110 and received ≥1 dose of ALIS. Most patients (88.8%) experienced ≥1 treatment-emergent adverse event (TEAE) through day 672 (end of year 2). Most TEAEs (72.3%) were mild or moderate in severity. Severe TEAEs were reported in 31 patients (15.0%). Two life-threatening TEAEs (haemoptysis; intestinal obstruction) and 1 death (cardiac failure) were reported. Twenty-one patients (10.2%) discontinued treatment due to a TEAE (mostly infective pulmonary exacerbation of CF). Mean change from baseline in forced expiratory volume in 1 second percent predicted at day 672 was -3.1% (prior-ALIS, -4.0%; ALIS-naive, -2.3%). Mean change from baseline in sputum density of P. aeruginosa at day 672 was 0.02 (prior-ALIS, -0.16; ALIS-naive, 0.19) log CFU/g

Conclusions: . Long-term treatment with ALIS was well tolerated with a favourable adverse event profile and demonstrated continued antibacterial activity in CF patients with chronic P. aeruginosa infection.

Dr Diana Bilton,(fig.24)  before her retirement, was Director of the Adult CF Unit at the Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom.

Clark T Bishop Case report: Three adult brothers with cystic fibrosis (delF508-delF508) maintain unusually preserved clinical profile in the absence of standard CF careRespir Med Case Rep 2021 Apr 15;33:101413.doi: 10.1016/j.rmcr.2021.101413. eCollection 2021.    Free PMC article    [Pubmed]

Fig. 25 Clark T Bishop

We present three cases in this report. Three adult brothers, homozygous for the delF508 cystic fibrosis mutation, have maintained an unusually preserved clinical condition even though they did not attend a CF Clinic during their childhood, do not attend a CF Clinic now, and do not follow standard CF care guidelines. The brothers use an alternative CF treatment regimen on which they have maintained normal lung function, height/weight, and bloodwork, and they utilize less than half the recommended dosage of pancreatic enzymes. The brothers culture only methicillin-sensitive Staphylococcus aureus, and have never cultured any other bacteria. Highly effective modulator therapies, such as elexacaftor/tezacaftor/ivacaftor, do not substantially reduce infection and inflammation in vivo in CF patients, and thus these three case reports are of special note in terms of suggesting adjunct therapeutic approaches. Finally, these three cases also raise important questions about standard CF care guideline

Advise read the Free article where the detailed treatment of these patients is described.  Dr Clark has long time been an advocate of importance of glutathione'

Clark Bishop(fig.25)  is at the Utah Valley Regional Medical Center, Provo, UT, 84602, United States.

Bouzek DC, Abou Alaiwa MH, Adam RJ, Pezzulo AA, Reznikov LR, Cook DP, et al. Early Lung Disease Exhibits Bacterial-Dependent and -Independent Abnormalities in Cystic Fibrosis Pigs. Am J Respir Crit Care Med [online ahead of print] 25 June 2021 [Pubmed]

Fig. 26 Drake C Bouzek Doximetry

Rationale: While it is clear that cystic fibrosis airway disease begins at a very young age, the early and subsequent steps in disease pathogenesis and the relative contribution of infection, mucus, and inflammation are not well understood.
Objectives: As one approach to assessing the early contribution of infection, we tested the hypothesis that early and continuous antibiotics would decrease the airway bacterial burden. We thought that, if it does, it might reveal aspects of the disease that are more or less sensitive to decreasing infection.
Methods: Three groups of pigs were studied from birth until ~3 weeks of age: 1) wild-type, 2) cystic fibrosis, and 3) cystic fibrosis pigs treated continuously with broad-spectrum antibiotics from birth until study completion. Disease was assessed with chest computed tomography, histopathology, microbiology, and bronchoalveolar lavage.
Measurements and Main Results: Disease was present by 3 weeks of age in cystic fibrosis pigs. Continuous antibiotics from birth improved chest computed tomography imaging abnormalities and airway mucus accumulation, but not airway inflammation in the cystic fibrosis pig model. However, reducing bacterial infection did not improve two disease features already present at birth in cystic fibrosis pigs, air trapping and submucosal gland duct plugging. In the cystic fibrosis sinuses, antibiotics did not prevent the development of infection, disease, or the number of bacteria but did alter the bacterial species.
Conclusions: These findings suggest that cystic fibrosis airway disease begins immediately following birth, and that early and continuous antibiotics impact some, but not all, aspects of CF lung disease development

Dr Drake C Bouzek (fig.26) is a pediatric pulmonologist at the University of Iowa Roy J and Lucille A Carver College of Medicine, 12243, Iowa City, Iowa, United States

Shiping LuJay K KollsEarly Antibiotics in Cystic Fibrosis: Lessons from the CF Pig Model. Am J Respir Crit Care Med. 2021 Aug 3.doi: 10.1164/rccm.202106-1383ED.Online ahead of print. Pubmed

(Commentary on  the above article by Bouzek et al.)

Fig. 28 Jay K Kolls Tulane School of Medicine

Fig. 27 Shipping Lu

Cystic fibrosis (CF) is caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR), which results in defects in ion transport. The leading causes of morbidity and mortality are respiratory symptoms and progressive pulmonary failure. Three hallmarks of this pathogenesis identified to date are abnormal mucus accumulation/tethering, chronic sinopulmonary inflammation, and recurrent infections(1). But there has been continued debate about what comes first: infection or inflammation akin to the chicken or the egg argument.

This is a detailed referenced commentary on the relationship between  inflammation and infection in the CF infant. The main text finishes  - "As the clinical studies continue to be performed in younger individuals, it will be critical to understand how these drugs impact both mucous clearance, airways inflammation, and infection. Although, this paper focused on the contributions of bacterial infection, we know there is a complex interplay between viral infection and bacterial infection and specifically bacterial biofilm formation and this will be an important area to model in pre-clnical models. This paper highlights the potential need to target inflammation independent of infection to have the greatest impact in preserving lung function in patients with CF".

Dr Jay K Kolls, (fig.28)  the corresponding author, is Professor of Medicine and Pediatrics at Tulane University School of Medicine, 12255, Medicine, New Orleans, Louisiana, United States.

Dr Shiping Lu (Fig. 27) is a Faculty Member, Center for Translational Research in Infection and Inflammation, Tulane University Health Sciences Center34511391

Kevin E BoveAnas BerniehJennifer PicarsicJoseph P CoxEdmund YangPhilip C MantorAmeet ThakerLauren LazarMeghana SatheStephen Megison. Hypoplasia of Extrahepatic Biliary Tree and Intrahepatic Cholangiolopathy in Cystic Fibrosis Imperfectly Mimic Biliary Atresia in 4 Infants With Cystic Fibrosis and Kasai PortoenterostomyAm J Surg Pathol. 2021 Sep 13 doi: 10.1097/PAS.0000000000001803. Online ahead of print.  [Pubmed]

Fig.29 Kevin Bove Cincinati Children's

Four male infants with cystic fibrosis and prolonged neonatal jaundice underwent Kasai procedure to relieve biliary obstruction due to apparent biliary atresia. The excised remnants had viscid mucus accumulation in hypoplastic gallbladders and distended peribiliary glands. Main hepatic ducts were narrow and/or malformed. Microscopic differences between the gallbladder and extrahepatic bile ducts in cystic fibrosis and sporadic biliary atresia were unequivocal, despite some histologic overlap; no erosive or fibro-obliterative lesions typical of biliary atresia were seen. Common in liver, biopsies were small duct cholangiopathy with intense focal cholangiolitis and massive accumulation of ceroid pigment within damaged cholangiocytes, and in portal macrophages, portal fibrosis, and unequivocal features of large duct obstruction were inconspicuous compared with biliary atresia. Plugs of bile in small ducts tended to be pale and strongly periodic acid-Schiff-reactive in cystic fibrosis. Distinguishing the liver lesion from that of biliary atresia is challenging but possible. Liver biopsies from 2 additional infants with cystic fibrosis and prolonged jaundice that spontaneously resolved showed a similar small duct cholangiopathy. Small gallbladders and extrahepatic ducts challenge surgical judgment as findings in liver biopsies challenge the pathologist. The decision to perform a Kasai procedure is reasonable when mimicry of biliary atresia is grossly complete. We hypothesize that a disorder of bile volume/flow during development and/or early infancy linked to the CFTR mutation alone or in combination with the stresses of neonatal intensive care causes destructive cholangiolitis and intrahepatic reduction of bile flow with secondary hypoplasia of extrahepatic biliary structures.

Dr Kevin E Bove (fig.29)  is a paediatric staff pathologist and professor in the Division of Pathology Department of Pediatric Surgery, Cincinnati Children's Hospital, Cincinnati,

Molly Bozic Christopher H Goss Rabindra M TirouvanziamArthur BainesMargaret KlosterLiebe AntoineDrucy BorowitzSarah Jane SchwarzenbergGROW study group. Oral Glutathione and Growth in Cystic Fibrosis: A Multicenter, Randomized, Placebo-controlled, Double-blind Trial J Pediatr Gastroenterol Nutr 2020 Dec;71(6):771-777.doi: 10.1097/MPG.0000000000002948. [Pubmed]

 Fig. 30 Molly Bozic Riley Children's Health

Objectives: The nutritional status of children with cystic fibrosis (CF) is associated with mortality and morbidity. Intestinal inflammation may contribute to impaired digestion, absorption, and nutrient utilization in patients with CF and oral glutathione may reduce inflammation, promoting improved nutritional status in patients with CF.
Methods: The GROW study was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase II clinical trial in pancreatic insufficient patients with CF between the ages of 2 and 10 years. Patients received reduced glutathione or placebo orally daily for 24 weeks. The primary endpoint was the difference in change in weight-for-age z-scores from baseline through week 24 between treatment groups. Secondary endpoints included other anthropometrics, serum, and fecal inflammatory markers in addition to other clinical outcomes.
Results: Fifty-eight participants completed the study. No significant differences were seen between glutathione (n = 30) and placebo (n = 28) groups in the 6-month change in weight-for-age z-score (-0.08; 95% CI: -0.22 to 0.06; P = 0.25); absolute change in weight (kg) (-0.18; 95% CI: -0.55 to 0.20; P = 0.35); or absolute change in BMI kg/m (-0.06; 95% CI: -0.37 to 0.25; P = 0.69). There were no significant differences in other secondary endpoints. Overall, glutathione was safe and well tolerated.

Conclusions: Oral glutathione supplementation did not impact growth or change serum or fecal inflammatory markers in pancreatic insufficient children with CF when compared with placebo.

 Dr Molly Bozic Fig. 30  is Associate Professor of Pediatrics at the Indiana University School of Medicine, Indianapolis, IN.

Kubra M BozkanatNatalie E WestSigrid LadoresKristina MontemayorMaria Gabriela Tupayachi OrtizMindy ChristiansonRaksha Jain Catamenial haemoptysis in females with cystic fibrosis: a case series with review of management strategies. Respirol Case Rep 2021 May 7;9(6):e00755.doi: 10.1002/rcr2.755.eCollection 2021 Jun. [Pubmed]

Fig. 31 Kubra Bozkanat LinkedIn

Catamenial haemoptysis, the expectoration of blood during menses, has not been extensively reported in the cystic fibrosis (CF) literature. We describe four cases (age range: 25-34 years) of catamenial haemoptysis across four CF centres in the United States. These cases may represent thoracic endometriosis versus hormonal fluctuations in airway inflammation or infection resulting in bronchial artery bleeding. We identify common and nuanced management strategies including use of pro-coagulants, hormone contraceptives, anti-inflammatories, bronchial artery embolization, and use of the newer cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

Kubra M Bozkanat, (fig.31) is a paediatrician in the Department of Pediatrics University of Texas, Southwestern Medical Center, Dallas TX USA.

Oded BreuerDavid ShoseyovShifra KoretzNadia AlyanJoel ReiterMalena Cohen-CymberknohIsaiah WexlerEitan Kerem. Ethical dilemma: ELX/TEZ/IVA or Lung Transplantation in Cystic Fibrosis and End Stage Lung Disease? Chest 2021 Sep 7;S0012-3692(21)03846-0.doi: 10.1016/j.chest.2021.08.073.Online ahead of print. [Pubmed]

Fig. 32 Oded Breuer

Cystic fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of the disease. We present an ethical dilemma involving an 11-year-old child with CF and end stage lung disease. Shortly after starting treatment with Elexacaftor-Tezacaftor-Ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other is limited. A survey of CF center team members was conducted for the purpose of this manuscript. Ethical principles that may guide us in these situations are discussed.

Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared to other team members, are more likely to provide a specific recommendation vs. to present the information and let the family decide (odds ratio (95% confidence interval)=4.0 (1.2-12.8), p=0.021). A shared decision-making model, stressing our moral obligation as clinicians to respect autonomy by appreciating family values while offering to participate in the decision-making process and ensuring non-maleficence, is presented.
In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. Current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making which is focused on respecting autonomy is our preferred approach in these situations.

Dr Oded Brueris (Fig 32)is a paediatric pulmonologist in the Department of Pediatrics; Pediatric Pulmonology and CF Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel.

 Birimberg-Schwartz L; Wilschanski M.  Cystic Fibrosis Related Gastrointestinal Manifestations - Moving Forward. Journal of Cystic Fibrosis. 20(4):562-563, 2021 07.[Pubmed]
(No abstract so I have summarised some of the main points of the full version- JML)

Fig. 33 Liron Birimberg Schwartz gastro.on.ca

With the increase in life expectancy new disease-related manifestations are emerging such as an increased risk of colorectal cancer. Hepato-biliary GI manifestations are quite variable and include exocrine pancreatic disease, meconium ileus, constipation, distal intestinal obstruction syndrome, CF related liver disease, small intestinal bacterial overgrowth and intestinal inflammation.
The authors comment that CF related GI symptoms are not always properly addressed, and patients hesitate to report them to their pulmonologist. They stress the need for a dedicated gastroenterologist to work as part of the CF centre team.
The paucity of high-quality CF-GI studies prompted the CF Foundation to declare recently such studies are a priority. Current knowledge suggests that altered intestinal fluid secretions, dysbiosis and inflammation contribute to gut dysfunction. They also note the lack of GI clinical outcome measures which will be needed with CFTR modulator drug trials.
Nonetheless, the authors are encouraged to see “sprouting of research in the field which will lead the way to improved patient GF-GI disease outcomes”.

Dr Liron Birimberg-Schwartz (Fig. 33) and Dr Michael Wilschanski are in the  Department of Pediatric Gastroenterology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of  Jerusalem, Israel.

 Josephine M BryantKaren P BrownSophie BurbaudIsobel Everall Juan M Belardinelli Daniela Rodriguez-Rincon et al. Stepwise pathogenic evolution of Mycobacterium abscessus.   Science 2021 Apr 30;372(6541):eabb8699. doi:10.1126/science.abb8699.  [Pubmed]

Fig. 44 Josephine Bryant. infectious disease.cam.ac.uk

Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones.

Dr Josephine M Bryant (fig.44) is a researcher at the Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC Laboratory of Molecular Biology, Cambridge, UK, and the University of Cambridge Centre for AI in Medicine, Cambridge, UK.

[“saltational”= “a sudden and large mutational change from one generation to the next, potentially causing single-step speciation]

Buqing YiAlexander H DalpkeSébastien Boutin.  Changes in the Cystic Fibrosis Airway Microbiome in Response to CFTR Modulator Therapy.  Front Cell Infect Microbiol 2021 Mar 17;11:548613.doi: 10.3389/fcimb.2021.548613. eCollection 2021.Free PMC article   [Pubmed]

 Fig. 45 Buqing Yi ResearchGate

The development of CFTR modulator therapies significantly changed the treatment scheme of people with cystic fibrosis. However, CFTR modulator therapy is still a life-long treatment, which is not able to correct the genetic defect and cure the disease. Therefore, it becomes crucial to understand the effects of such modulation of CFTR function on the airway physiology, especially on airway infections and inflammation that are currently the major life-limiting factors in people with cystic fibrosis. In this context, understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections. Whether and how the newly available therapies affect the airway microbiome is still at the beginning of being deciphered. We present here a brief review summarizing the latest information about microbiome alterations in light of modern cystic fibrosis modulator therapy.

Dr Buqing Yi (fig.45) is at the Medical Faculty, Institute of Medical Microbiology and Virology, Technische Universität Dresden, Dresden, Germany

Pierre-Régis BurgelChristopher Goss.  COVID-19 outcomes in people with cystic fibrosisCurr Opin Pulm Med  2021 Nov 1;27(6):538-543.doi: 10.1097/MCP.0000000000000823. [Pubmed]

Fig. 46 Pierre-Regis Burgel

Purpose of review: The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a dramatic impact that is still ongoing around the world. Cystic fibrosis (CF) has been identified as a possible risk factor of poor outcome.
Recent findings: Data collected by multiple National CF registries around the world have indicated that persons with CF (PwCF) are not more likely to be affected by SARS-CoV-2 than the general population. The course of SARS-CoV-2 is usually mild in PwCF who are relatively young. Severe outcomes have been described in patients with low lung function and in those with immune suppression (i.e. solid organ transplantation). Indirect impact of the pandemic on the CF community has also been observed, including difficulties in the organization of CF care, leading to a dramatic increase in telehealth for PwCF. The pandemic has further affected clinical research by complicating ongoing clinical trials. Vaccination appears important to all PwCF, with special priority on developing adequate vaccination scheme for transplant recipients. Long-term effects of COVID-19 on the CF population remains unknown.

Summary: The COVID-19 pandemic has caused significant impacts on PwCF and on healthcare professionals who provide specialized CF c

Dr Pierre-Régis Burgel (fig.46) is at Université de Paris, Institut Cochin, Inserm U1016. Respiratory Medicine and Cystic Fibrosis National Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.

Diego A CalvopinaPeter J LewindonLouise E RammCharlton Noble Gunter F HartelDaniel H LeungGrant A Ramm. Gamma-glutamyl transpeptidase-to-platelet ratio as a biomarker of liver disease and hepatic fibrosis severity in paediatric Cystic Fibrosis. J Cyst Fibros 2021 Dec 22;S1569-1993(21)02171-8. doi: 10.1016/j.jcf.2021.10.014.Online ahead of print.[Pubmed]

Fig. 47 Diego Calvopina The Org

Background: Cystic fibrosis (CF)-associated liver disease (CFLD) causes significant morbidity and mortality in children with CF. Diagnosis of liver disease prior to development of cirrhosis or portal hypertension (PHT) is challenging. While imaging modalities using Elastography show great promise they are still not widely available to all clinicians. This study investigated gamma-glutamyl transpeptidase-to-platelet ratio (GPR) as a non-invasive biomarker to detect liver disease and stage fibrosis severity in children with CF.
Results: GPR was significantly increased in CFLD versus CFnoLD (0.33 [0.19-0.96] vs. 0.15 [0.11-0.21], P<0.0001). GPR demonstrated good diagnostic utility for detecting CFLD with an area under the curve (AUC) of 0.81 (95% confidence Interval [CI] [0.75-0.87]; P<0.0001), with sensitivity of 74% and specificity of 73%, using a cut-off of 0.20. GPR increased with increasing hepatic fibrosis stage. GPR discriminated both moderate-advanced (F2-F4) fibrosis vs. F0-F1 (AUC=0.82; 95%CI [0.71-0.94]; P<0.0001) and advanced (F3-F4) fibrosis vs. F0-F2 (AUC=0.77; 95%CI [0.64-0.90]; P = 0.004), with a cut-off 0.32 and 0.61, respectively. An elevated GPR of >0.84 was predictive of PHT at diagnosis of CFLD (AUC=0.81; 95%CI [0.67-0.95]; P = 0.0003).
Conclusions: GPR demonstrates good diagnostic utility for assessing the presence of liver disease, PHT and hepatic fibrosis severity in children with CF. These findings will aid in better identification of patients at risk for CF-related liver involvement and the potential for more targeted and timely follow-up and treatment.

Diego A Calvopina (fig.47) is a research scientist in the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia

A CapalboM FabianiS CaroselliM PoliL GirardiC PatassiniF FaveroD CimadomoA VaiarelliC SimonL F RienziF M Ubaldi Clinical validity and utility of preconception expanded carrier screening for the management of reproductive genetic risk in IVF and general population. Hum Reprod 2021 May 22;deab087.doi: 10.1093/humrep/deab087. Online ahead of print.[Pubmed]

 Fig. 48 Antonio Capalbo Igenomix

Study question: What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents?
Summary answer: The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population.
What is known already: About 2-4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds    the potential to significantly improve couple's genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring.
Study design, size, duration: A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples.
Participants/materials, setting, methods: A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making.
Main results and the role of chance: A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby.
Limitations, reasons for caution: The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene-disease associations

Wider implications of the findings: These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF.

Dr Antonio  Capalbo (fig.48) is Laboratory Manager  at Igenomix, Italy.

Vincenzo CarnovalePaola IacotucciVito TerlizziCarmela ColangeloPietro MedioLorenza FerrilloFabiola De Gregorio Michela FrancalanciGiovanni TaccettiSerena BuonaurioMarcella d'IppolitoGiovanni MarsicovetereMichele D'AndriaNicola FerraraDonatello Salvatore Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease with the Phe508del/minimal function genotypeRespir Med2021 Oct 12;189:106646.doi: 10.1016/j.rmed.2021.106646. Online ahead of print.     Pubmed

Fig. 49 Vincenzo Carnovale X.com

Background: Elexacaftor/tezacaftor/ivacaftor (E/T/I) is a cystic fibrosis transmembrane conductance regulator (CFTR) triple combination therapy used for the treatment of cystic fibrosis (CF) in patients aged ≥12 years who have at least one copy of the Phe508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with E/T/I. This study determined the effectiveness and safety of E/T/I treatment in a cohort of CF patients.
Methods: This retrospective cohort study collected data from the first 6 months of treatment of patients with CF, compound heterozygotes for the F and a minimal function (MF) mutations, enrolled in an E/T/I compassionate use program only available to patients having ppFEV1<40 or who are considered for lung transplantation. Forty-seven patients were included. Follow-up was performed after 1, 3, and 6 months from the beginning of therapy, assessing lung function, body mass index (BMI), sweat chloride concentration (SCC), quality of life (QoL), and safety.
Results: After 6 months of treatment, the mean (standard deviation (SD)) SCC decreased from 91.1 (19.3) mmol/L to 46.2 (24.2) mmol/L. The decrease of SCC was accompanied by improvement of lung function (mean (95% Confidence Interval (CI) absolute increase in ppFEV1 was 10.69 (8.05,13.33) after 1 month and 14.16 (11.43, 16.89) after 6 months of treatment), nutrition (mean (SD) BMI increased from 20.7 (3.0) kg/m2 at baseline to 22.6 (3.1) after 6 months), and QoL. No safety concerns were observed.

Conclusions: E/T/I was clinically effective and safe in patients with advanced CF lung disease with an F/MF genotype.

Vincenzo Carnovale (fig.49) is at the Department of Translational Medical Science, Cystic Fibrosis Center, Adult Unit, University of Naples "Federico II", Italy.

June C CarrollRobin Z HayeemsFiona A MillerCarolyn J Barg. Yvonne BombardPranesh ChakrabortyBeth K PotterJessica Peace BytautasKaren TamLouise TaylorElizabeth KerrChristine DaviesJennifer MilburnFelix RatjenAstrid GuttmannNewborn screening for cystic fibrosis: Role of primary care providers in caring for infants with positive screening resultsCan Fam Physician 2021 Jun;67(6):e144-e152.doi: 10.46747/cfp.6706e144.  Free article   [Pubmed]

Fig. 50 June Carrol lunenfield.ca

A mailed questionnaire in Ontario to explore primary care providers' (PCPs') preferred roles and confidence in caring for infants receiving a positive cystic fibrosis (CF) newborn screening (NBS) result, as well as management of CF family planning issues, given that expanded NBS has resulted in an increase in positive results.
Overall, 321 of 628 (51%) completed surveys (208 FPs, 68 pediatricians, 45 midwives). For well-baby care for infants confirmed to have CF, 77% of PCPs indicated they would not provide total care (ie, 68% would share care with other specialists and 9% would refer to specialists completely); for infants with an inconclusive CF diagnosis, 50% of PCPs would provide total care, 45% would provide shared care, and 5% would refer to a specialist; for CF carriers, 89% of PCPs would provide total care, 9% would provide shared care, and 2% would refer. Half (54%) of PCPs were extremely or very confident in providing reassurance about CF carriers' health. Only 25% knew how to order parents' CF carrier testing; 67% knew how to refer for prenatal diagnosis. Confidence in reassuring parents about the health of CF carrier children was associated with providing total well-baby care for CF carriers (risk ratio of 1.50; 95% CI 1.14 to 1.97) and infants with an inconclusive diagnosis (risk ratio of 3.30; 95% CI 1.34 to 8.16).

Conclusion: Most PCPs indicated willingness to treat infants with a range of CF NBS results in some capacity. It is concerning that some indicated CF carriers should have specialist involvement and only half were extremely or very confident about reassuring families about carrier status. This raises issues about possible medicalization of those with carrier status, prompting the need for PCP education about genetic disorders and the meaning of genetic test results.

Dr June C Carroll (fig 50) is a family physician and clinician scientist, Professor, and Sydney G. Frankfort Chair in Family Medicine in the Department of Family and Community Medicine with the Sinai Health System and the University of Toronto in Ontario.

Sara W CarsonKevin PsoterKirsten KoehlerKaren R SiklosiKristina MontemayorAlexandra ToporekNatalie E WestNoah LechtzinNadia N HanselJoseph M CollacoChristian A Merlo   Indoor air pollution exposure is associated with greater morbidity in cystic fibrosisJ Cyst Fibros 2021 Sep 13;S1569-1993(21)01356-4.doi: 10.1016/j.jcf.2021.08.015.Online ahead of print    [Pubmed]

Fig. 51 Sara Carson
Kootenai Health

Background: Exposure to higher levels of outdoor air pollution is associated with increased morbidity in individuals with cystic fibrosis. Limited information exist regarding the potential adverse effects of indoor air pollution on those with cystic fibrosi
Results: Of 1432 participants with data on secondhand smoke exposure, 362 (25.3%) were exposed. Of 765 individuals with data on forced hot air exposure, 491 (64.2%) were exposed. Of 1247 participants with data on wood stove exposure and 830 with data on fireplace exposure, 182 (14.6%) and 373 (44.9%) were exposed, respectively. In longitudinal analysis, pediatric individuals either exposed to secondhand smoke or to forced hot air had a 0.60% predicted/year decrease in FEV1% predicted (P=0.002) or a 0.46% predicted/year decrease in FEV1% predicted (P=0.048), respectively compared to individuals who were not exposed. Adults exposed to secondhand smoke had a 42% increased yearly risk of hospitalization compared to those who were not exposed (P=0.045).
Conclusions: Our questionnaire-based data suggest that exposure to sources of indoor air pollution increase morbidity in both the pediatric and adult cystic fibrosis populations. Future studies with quantitative indoor air quality assessments are needed.

Dr Sara W Carson (fig.51) is a Pulmonary and Critical Care Fellow at the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, USA.

Rosemary Carzino Katherine B Frayman Louise King Suzanna Vidmar Sarath Ranganathan AREST CF.  Regional differences in infection and structural lung disease in infants and young children with cystic fibrosisJ Cyst Fibros 2020 Nov;19(6):917-922.doi: 10.1016/j.jcf.2019.10.018.Epub 2019 Nov 7. [Pubmed]

Fig. 52 Rosemary Carzino Kalyan Respiratory Research Centre

Background: Both infection and inflammation are critical to the progression of cystic fibrosis (CF) lung disease. Potential anatomical differences in lower airway infection, inflammation and bronchiectasis in young children with CF raise questions regarding the pathogenesis of early structural lung disease.
Methods: A longitudinal multi-centre birth cohort study of infants newly diagnosed with CF was conducted. Paired bronchoalveolar lavage (BAL) samples were obtained from the right middle lobe (RML) and lingula bronchi. Chest computed tomography (CT) was performed biennially and analysed using the modified CF-CT scoring system.
Results: One hundred and twenty-four children (0.11 - 7.0 years) contributed 527 BAL samples and underwent 388 CT chest scans. Pro-inflammatory microbes were detected in 279 BAL samples (53%), either in both lingula and RML samples (69%), in the lingula alone (24%), or in the RML alone in only 7% of samples. Overall, the prevalence of structural lung disease was greater in the setting of pro-inflammatory microbes. Although infection was less commonly isolated in the right lung, bronchiectasis was more commonly detected in the right lung compared with the left. No anatomical differences in the presence of air trapping were detected.

Conclusion: Overall, the detection of pro-inflammatory microbes in the lower airways was associated with increased risk of both air trapping and bronchiectasis. However, the apparent discordance between commonest sites of isolation of pro-inflammatory microbes and the anatomical site of early bronchiectasis warrants further exploration.

Dr Rosemary Carzino (fig.52) is the Senior Research Assistant in the Respiratory Diseases Group, Murdoch Children's Research Institute, Victoria, Australia.

Helen K ChadwickJanice AbbottMargaret Anne HurleyLouise DyeClare L LawtonMichael W MansfieldDaniel Peckham Cystic fibrosis-related diabetes (CFRD) and cognitive function in adults with cystic fibrosis. J Cyst Fibros  2021 Jun 13;S1569-1993(21)00124-7.doi: 10.1016/j.jcf.2021.04.014.Online ahead of print.  [Pubmed]

Fig. 53  Helen Chadwick leeds.academia.edu

Background: Being able to function cognitively is imperative for successful achievement in school, working life, and disease self-management. Diabetes is known to cause changes in brain structure and long-term cognitive dysfunction. This work investigated cystic fibrosis-related diabetes (CFRD) as a mechanism for cognitive impairment in people with CF. It was hypothesised that cognition would be poorer in adults with CFRD than in those with CF without diabetes (CFND) or in healthy controls
Methods: Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery which provides a comprehensive cognitive assessment with tests mapping onto specific brain regions. Demographic, clinical and self-reported health data were documented for all participants. CF specific clinical variables were recorded for the two CF groups.
   Results: Ninety-eight people with CF (49CFRD,49CFND) and 49 healthy controls were recruited. People with CF demonstrated deficits in aspects of verbal and spatial memory, processing speed and cognitive flexibility compared with healthy controls, with all areas of the brain implicated. Those with CFRD had additional difficulties with higher-level processes known collectively as 'executive function', which demand greater cognitive load and recruit the prefrontal cortex. Compared with healthy controls, those with CFND and CFRD had an estimated 20% and up to 40% reduction in processing speed respectively.
Conclusion: Managing CF requires higher order executive function. Impairments may be sufficient to interfere with self-care and the ability to perform everyday tasks efficiently. At which point in the CF disease trajectory these difficulties begin, and what may attenuate them, has yet to be determined.

Dr Helen Chadwick (Fig. 53) is in the School of Psychology, University of Leeds, the Leeds Institute of Medical Research at St James's, University of Leeds, and the Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds UK

Ernest G ChanEric J HyznyJohn P RyanMatthew R MorrellJoseph PilewskiPablo G SanchezOutcomes following lung re-transplantation in patients with cystic fibrosisJ Cyst Fibros 2021 Dec 20;S1569-1993(21)02162-7.doi: 10.1016/j.jcf.2021.12.002.Online ahead of print.[Pubmed

Fig. 54 Ernest Chan Loop (frontiers)

Purpose: We examined cystic fibrosis (CF) patients and compared their clinical status at the time of primary versus double lung re-transplantation (re-DLTx) in order to better understand lung retransplant practice patterns.
Methods: We performed a retrospective analysis of the UNOS Database identifying CF patients ≥18 years old undergoing re-DLTx (5/4/2005 and 12/4/2020). Baseline and clinical variables at the primary and re-DLTx were compared utilizing the paired student t-test. Graft survival was defined as time from surgery to retransplant and analyzed using Kaplan-Meier estimates.

Results: 277 CF patients who underwent re-DLTx experienced a significantly worse 5-year survival when compared to the primary DLTx cohort (47.9% vs 58.8%, p = 0.00012). The following differences were observed comparing CF re-DLTx group to their primary DLTx: higher LAS score at the time of listing (50.66 vs 42.15, p < 0.001) and transplant (62.19 vs 48.20, p < 0.001), and increase LAS from the time of listing to transplant (+12.22 vs +7.23, p = 0.002). While serum albumin and total bilirubin were similar, CF patients had a higher creatinine (1.05 vs 0.74, p < 0.001), dialysis (4.4% vs 0.6%, p < 0.001), ECMO bridge to transplant rates (7.6% vs 4.0%, p < 0.001), and higher oxygen requirements (5.95 vs 3.93, p < 0.001) at the time of listing for a re-DLTx.

Conclusion: Compared to their initial transplant, CF patients experience significant clinical decline in renal, cardiac, and pulmonary function at the time of lung re-transplantation. This may indicate that an earlier evaluation and rehabilitation process may be necessary to identify patients earlier for lung re-transplantation prior significant clinical decline.

Ernest G Chan (Fig. 54)is a thoracic surgeon in the Division of Thoracic Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

Chilvers MA, Davies JC, Milla C, Tian S, Han Z, Cornell AG, Owen CA, Ratjen F. Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study.    Lancet Respir Med. 2021 Jan 28:S2213-2600(20)30517-8. doi: 10.1016/S2213-2600(20)30517-8. Online ahead of print. [Pubmed]

 Fig. 55 Mark Chilvers.  LinkedIn

Background: The safety and efficacy of 24 weeks of lumacaftor-ivacaftor combination therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data.
Methods: In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor-ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109). The study was conducted at 61 clinics in the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK. Children with cystic fibrosis homozygous for the F508del-CFTR mutation who had received lumacaftor-ivacaftor or placebo in the parent studies were treated with lumacaftor-ivacaftor for up to 96 weeks; those who had received the combination therapy in the parent studies (the treatment-to-treatment group) received up to 120 weeks of treatment in total. Participants aged 6-11 years at the start of the parent study received lumacaftor 200 mg-ivacaftor 250 mg orally once every 12 h; those aged 12 years or older received lumacaftor 400 mg-ivacaftor 250 mg orally once every 12 h. The primary endpoint was safety and tolerability in all children who had received at least one dose of the study drug. Secondary endpoints included change from baseline in lung clearance index 2·5% (LCI2·5), sweat chloride concentration, body-mass index, and Cystic Fibrosis Questionnaire-Revised respiratory domain score. This extension study is registered with ClinicalTrials.gov, NCT02544451, and has been completed.
Findings: The extension study ran from Aug 13, 2015, to Aug 17, 2018. Of 239 children who enrolled in the study and received at least one dose of lumacaftor-ivacaftor, 215 (90%) completed 96 weeks of treatment. Most children (236 [99%] of 239 children) had adverse events that were mild (49 [21%] of 239) or moderate (148 [62%] of 239) in severity, and there was a low rate of adverse events leading to treatment discontinuation. The most frequently reported adverse events were common manifestations or complications of cystic fibrosis, such as cough and pulmonary exacerbation, or were consistent with the known safety profile of lumacaftor-ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor-ivacaftor treatment. Children in the placebo-to-treatment group had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in children treated with lumacaftor-ivacaftor in the parent study were generally maintained in the extension study.
Interpretation: Lumacaftor-ivacaftor therapy in children homozygous for F508del-CFTR who initiated treatment at age 6-11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks. These data support the long-term use of lumacaftor-ivacaftor to treat children aged 6 years and older who are homozygous for the F508del-CFTR mutation.

Dr Mark Chilvers (fig.55) is Clinical Associate Professor, Division of Respiratory Medicine, Department of Pediatrics, Faculty of Medicine, University of British Columbia

Yajuan ChuJinfeng ShuaiKunling HuangJianhua LiuWenshan LvBaochi Li. Analysis of Clinical Manifestations, Imaging Features, and Gene Mutation Characteristics of 6 Children with Cystic Fibrosis in China.  Evid Based Complement Alternat Med. 2021 Nov 2;2021:7254391.doi: 10.1155/2021/7254391.eCollection 2021.[Pubmed] Free PMC article 
Objective: To explore the clinical manifestations, imaging features, and gene mutation characteristics of 6 children with cystic fibrosis (CF) so as to improve the understanding and diagnosis awareness of CF in children and reduce the missed diagnosis and misdiagnosis.   Methods: The clinical manifestations, imaging, and gene mutation data of six children with CF were collected and retrospectively analyzed.
Results: Among the 6 cases of CF, there were 4 males and 2 females. Among the 6 children with CF, 5 cases presented with recurrent respiratory tract infection. Etiology suggested 3 cases of Pseudomonas aeruginosa and 2 cases of Staphylococcus aureus. 3 cases had pancreatic exocrine dysfunction, manifested as diarrhea and aliphatic diarrhea, of which 1 case had high lipase in blood examination, and pancreatic ultrasound showed rough and enhanced pancreatic echo, considering pancreatic cystic fibrosis. 2 cases of CF combined with pseudo-Bartter syndrome (PBS); 1 case involved only the biliary tract and started with cholestasis without other systemic involvement. In 2 cases of sweat test, sweat chloride ions were all >60 mmol/L. 3 cases underwent fiberoptic bronchoscopy, and a large number of sticky secretions were visible under the bronchoscopy. CT of the chest revealed thickening of the bronchial wall (3 cases), bronchiectasis (1 case), atelectasis (1 case), and thin bronchial lumen (2 cases). 1 patient was found to have small airway lesions and mosaic perfusion during follow-up. All 6 children with CF underwent genetic testing. A total of 12 CF transmembrane conductance regulator (CFTR) gene mutations were found, of which 4 mutations were not reported in the literature.

Conclusion: CF is a disease caused by CFTR mutation. The incidence of this disease in China is low, and the clinical manifestations have great differences. The main symptoms are respiratory symptoms. Some children have gastrointestinal symptoms and/or PBS, and some children only show a single systemic lesion.

All the authors are in the Department of Respiratory Medicine, Hebei Children's Hospital, Shijiazhuang, Hebei 050031, China.

C CimbaloA ToscoV TerlizziA SepeA CastaldoL SalvadoriV Raia. Elevated sweat chloride test: is it always cystic fibrosis? Ital J Pediatr 2021 May 14;47(1):112. doi: 10.1186/s13052-021-01060-1. Free PMC article [Pubmed]
Background: The sweat chloride test (ST) is the gold standard for cystic fibrosis (CF) diagnosis in symptomatic patients, within the newborn screening and in the follow-up of CF patients during molecular therapies. However, false positives have been reported in patients with different diseases. We describe and discuss 4 cases due to different clinical conditions in which we recorded false positive ST, and the test remained altered for a period of varying length.

Cases presentation: Case 1: Eight months old female child suffering from constipation, recurrent vomiting and failure to thrive, family history of recurrent pancreatitis without mutations in the PRSS1 and SPINK1 genes. Both ST and fecal elastase were altered although no CFTR gene mutations were found. Due to rapid clinical deterioration, celiac disease was suspected and diagnosed by laboratory tests and intestinal biopsy. After 2 weeks of gluten-free diet ST and fecal elastase normalized. Case 2: 14 months old male suffering from bilateral renal dysplasia, episodes of metabolic alkalosis, recurrent respiratory infections and recurrent vomiting. The child had more ST positives, but no CFTR mutations were found. During follow-up, he developed sensorineural hearing loss and an atrial septic defect was found. Finally, a diagnosis of Klinefelter was made, but the ST normalized several years later. Case 3 and 4: Two boys with stubborn constipation and fecal occlusion treated with Poly Ethylene Glycol (PEG) with salts showed pathological ST. The test returned normal a few days after stopping treatment.
Conclusions: We hypotesized the possible causes of ST alteration in these conditions: in celiac disease it could be due to a transient dysregulation of the aquaporins, rapidly reversed by the diet; in Klinefelter, it may be due to stable pubertal hypoandrogenism; while, the PEG formulation itself contains salts that can temporarily alter ST.

Dr C Cimbalo  is at the Department of Translational Medical Sciences, Cystic Fibrosis Center, University Federico II, Naples, Italy.

James M CleggKelsey W MalloyRebekah F Brown, Alison G GrissoAndrew G SokolowIvacaftor withdrawal syndrome: A potentially life-threatening consequence from a life-saving medicationJ Cyst Fibros. 2021 Aug 11;S1569-1993(21)01340-0. doi: 10.1016/j.jcf.2021.07.021.Online ahead of print. Pubmed

Fig. 56  James Clegg pediatricsvumc.org

In 2018, a case series of three adult patients with cystic fibrosis (CF) suggested an ivacaftor withdrawal syndrome (IWS) perpetuated by abrupt cessation of ivacaftor treatment . An additional case published that year proposed IWS in the setting of rifampin use, demonstrating this may also be induced by drug-drug interactions . While this syndrome is a rare complication of highly effective modulator therapy (HEMT), it is     important to recognize as increasing numbers of patients are prescribed HEMT. Adult patients are not solely affected, as demonstrated by a pediatric patient's recent hospitalization.

A 12-year-old patient with CF (delF508/G1244E), who had been receiving ivacaftor therapy for four months, presented to the emergency room with fever, malaise, vomiting, productive cough, pleuritic chest pain, and dyspnea for three days. Physical exam showed tachypnea, hypoxemia, decreased breath sounds and respiratory crackles. Laboratory studies revealed leukocytosis and a negative PCR of common respiratory pathogens via nasal swab. Sputum culture grew chronic methicillin-resistant  Staphylococcus aureus and  Pseudomonas aeruginosa without a change in antibiotic resistance from previous cultures. Blood culture was negative. Chest radiograph was stable without acute changes. Spirometry on admission revealed all-time low pulmonary function for this patient with a forced expiratory volume in one second (FEV 1 ) of 27% predicted value (%pv) and forced vital capacity (FVC) of 32%pv, decreased from recent baseline values of 77%pv and 83%pv, respectively. The patient was admitted for aggressive airway clearance, intravenous antibiotics, and supplemental oxygen up to four liters per minute for hypoxemia. Secondary to her degree of distress, bronchoalveolar lavage was not possible at the time of presentation. She had required 12 prior CF-related hospitalizations, during which she presented with a decline of FEV 1 by 25%pv or less and displayed no hypoxemia or requirement for respiratory support.

Her family informed the medical team of a two-week lapse in taking her ivacaftor due to a combination of language barrier, difficulty in reaching the family by pharmacy, and miscommunication amongst her numerous caregivers regarding dosages given. IWS was suspected given severity of symptoms and lack of other likely precipitating factors. Sweat chloride testing was obtained and resulted elevated. Ivacaftor was reinitiated on hospital day two with the arrival of the patient's home supply. One day after reinitiating ivacaftor, she defervesced, and tachypnea and hypoxemia resolved. Five days after reinitiation, repeat sweat chloride was within normal range. Eight weeks post-discharge, FEV  1 was 76%pv. She transitioned to elexacaftor/tezacaftor/ivacaftor (elex/tez/iva) therapy leading to further improvement in pulmonary function.

While the potential of HEMT should be celebrated, complications such as IWS must also heighten awareness of the possible deleterious effects of withdrawal. With the increased eligibility for HEMT through elex/tez/iva, the number of patients potentially affected by withdrawal increases as well. Provider-patient communication regarding barriers to adherence is important to mitigate these consequences. Suspicion of this uncommon clinical entity should be considered in CF patients on HEMT with similar presentations.

Ivacaftor redefined the vision of CF treatment and prognosis. Less understood are the equally important, potentially deleterious effects of abrupt withdrawal from this medication.

Dr James Clegg (fig.56) is resident Physician at Nashville Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, 2200 Children's Way, TN 37232, USA.

Carla ColomboGianfranco AlicandroMark OliverPeter J LewindonGrant A RammChee Y OoiFederico AlghisiNataliya KashirskayaElena KondratyevaFabiola CortiRita PadoanIrina AsherovaHelen EvansIsabelle de MonestrolBirgitta StrandvikAnders LindbladCF UDCA study group.   Ursodeoxycholic acid and liver disease associated with cystic fibrosis: A multicenter cohort study.  J Cyst Fibros  2021 Apr 1;S1569-1993(21)00090-4.doi: 10.1016/j.jcf.2021.03.014.Online ahead of print.[Pubmed]

Fig. 57 Carla Colombo ResearchGate

Background: The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA.
Methods: We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model.
Results: Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12).
Conclusions: CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF.

Professor Carla Colombo (fig.57) is at IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan,

---  This is surprising and disappointing. Suggest you read the Liver section in TOPICS where Carla Colombo's earlier work in 1990 and subsequently is described.

Marika Comegna Vito TerlizziDonatello SalvatoreCarmela ColangeloAntonella Miriam Di LulloImmacolata Zollo Giovanni TaccettiGiuseppe CastaldoFelice Amato Elexacaftor-Tezacaftor-Ivacaftor Therapy for Cystic Fibrosis Patients with The F508del/Unknown Genotype. Antibiotics (Basel)2021 Jul 7;10(7):828.doi: 10.3390/antibiotics10070828.  Free PMC article   [Pubmed]

Fig. 58   Marika Comegna
Loop (Frontiers)

The new CFTR modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta) was approved by the FDA in October 2019 for treatment of Cystic Fibrosis in patients 6 years of age or older who have at least one F508del mutation in one allele and a minimal-function or another F508del mutation in the other allele. However, there is a group of patients, in addition to those with rare mutations, in which despite the presence of a F508del in one allele, it was not possible to identify any mutation in the other allele. To date, these patients are excluded from treatment with Trikafta in Italy, where the CF patients carrying F508del/unknown represent about 1.3% (71 patients) of the overall Italian CF patients. In this paper we show that the Trikafta treatment of nasal epithelial cells, derived from F508del/Unknown patients, results in a significant rescue of CFTR activity. Based on our findings, we think that the F508del/Unknown patients considered in this study could obtain clinical benefits from Trikafta treatment, and we strongly suggest their eligibility for this type of treatment. This study, adding further evidence in the literature, once again confirms the validity of functional studies on nasal cells in the cystic fibrosis theratyping and personalized medicine.

Dr Marika Comegna (fig.58)  is in the Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Pansini, 5, 80131 Naples, Italy.

J CrowleyK CroininD MullaneM Ní ChróinínRestoration of exocrine pancreatic function in child with lumacaftor/ivacaftor therapy in cystic fibrosisJ Cyst Fibros 2021 Sep 9;S1569-1993(21)01373-4.doi: 10.1016/j.jcf.2021.08.032.Online ahead of print. [Pubmed]

Fig 60 John Crowley

Fig. 59 Muireann Ni Chroinin Cork Beo

Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Ivacaftor therapy has resulted in exocrine pancreatic function restoration in young children and also in older children after more prolonged use.  We report a 3 year 6 months old girl with genotype homozygote p.Phe508del diagnosed on newborn screening with cystic fibrosis. She was noted to be pancreatic insufficient at birth and commenced on pancreatic enzyme replacement. Her baseline faecal elastase was 33 ug/g aged 8 months and < 15 ug/g at 22 months with normal reference >200ug/g.
She commenced on orkambi (lumacaftor/ ivacacftor) aged 24 months in February 2020. She was noted to have constipation and reduced enzyme replacement requirements with no symptoms of pancreatic insufficiency. A repeat faecal elastase at 3 years 4 months was 489ug/g showing evidence of restoration of exocrine pancreatic function.

This is the first report of exocrine pancreatic function restoration in a CF patient homozygous for p.Phe508del receiving lumaftor/ ivacaftor therapy. Consideration should be given to repeating faecal elastase in the population of CF children receiving orkambi where symptoms of pancreatic insufficiency have resolved and growth and weight are satisfactory. The prospect of restoration of pancreatic function in this group of young patients is very exciting.

Dr J Crowley (fig.60) is at the Cork University Hospital, Wilton, Cork, Ireland.

Dr Muireann Ni Chroinin (Fig.59) is a consultant in Respiratory Medicine at Cork University Hospital

Cori L DainesWayne J Morgan  The Future of Highly Effective Modulator Therapy in Cystic Fibrosis.. Am J Respir Crit Care Med 2021 Jun 15;203(12):1453-1455.doi: 10.1164/rccm.202104-0850ED.  Free PMC article  [Pubmed]

Fig 62  Wayne J Morgan. University of Arizona

 Fig.61 Cori Daines uappc.peds.arizona.edu

 There is no abstract, but the Free PMC article is a clear and recommended commentary on the article of Zemanick ET et al, Am J Respir Crit Care Med 2021;203:1522-1532. The other important references in this article are all abstracted in the appropriate date sections of this history.

The success of highly effective modulator therapy (HEMT) in cystic fibrosis (CF) now illustrates two areas of deficiency: the lack of HEMT for younger children and for approximately 10% of the CF population without a qualifying mutation.

The article concludes - At this point, the previous modulators IVA, lumacaftor/IVA, and TEZ/IVA have all been approved for younger ages than the original phase III qualifying studies IVA has recently been approved down to 4 months, whereas lumacaftor/IVA is approved to 2 years and TEZ/IVA is approved to 6 years. Longer-term data from these extensions show ongoing safety and efficacy even in the youngest patients. Previous modulators have been shown to be safe, both in the short and long term, in young children. This knowledge should reaffirm the safety findings in the current study and should prove the appropriateness of moving ELX/TEZ/IVA to the 6- to 11-year-old age group. The CF community has been waiting for the results of this study and to have ELX/TEZ/IVA for children. The goal and expectation will be much better long-term outcomes for people living with CF.

Both authors are in the Department of Pediatrics University of Arizona Tucson, Arizona.
Cori L Daines (fig.61)  is a professor of Pediatric Pulmonary Medicine, CF Centre Director.
Wayne J Morgan (fig. 62)  is Professor of Pediatrics and Physiology Arizona Elks Foundation Chair for Statewide Pediatric Research, Program Director, Pediatric Pulmonary Fellowship Pediatric Pulmonary and Sleep Medicine

Jérémy DanaDominique Debray ,Aurélie BeaufrèreSophie Hillaire Monique Fabre Caroline ReinholdThomas BaumertLaureline BertelootValérie Vilgrain Cystic fibrosis-related liver disease: clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapiesJ Hepatol 2021 Oct 19;S0168-8278(21)02115-2 doi: 10.1016/j.jhep.2021.09.042.Online ahead of print. [Pubmed]

Fig. 63 Jéremy Dana

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. Cystic Fibrosis-related Liver Disease (CFLD) is defined by the pathogenesis related to the underlying CFTR defect in biliary epithelial cells. CFLD needs to be distinguished from other liver manifestations that may not have any pathological significance. The clinical and histological presentation as well as the severity of CFLD varies. The main histological presentation of CFLD is focal biliary fibrosis, which is usually asymptomatic. Portal hypertension develops in a minority of cases (about 10%) and may require specific management including liver transplantation for end-stage liver disease. Portal hypertension is usually the result of the progression of focal biliary fibrosis to multilobular cirrhosis during childhood. Nevertheless, non-cirrhotic portal hypertension as a result of porto-sinusoidal vascular disease is now identified increasingly more frequently in these patients, mainly in young adults. To evaluate the effect of new CFTR modulator therapies on the liver, the spectrum of hepatobiliary involvement must first be precisely classified. This paper discusses the phenotypical features of CFLD, its underlying physiopathology and relevant diagnostic and follow-up approaches with a special focus on imaging.

Jérémy Dana (fig.63) is in the Department of Radiology, Beaujon Hospital, Université de Paris, Clichy, France; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur Les Maladies Virales et Hépatiques, Strasbourg, France; IHU-Strasbourg (Institut Hospitalo-Universitaire), Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.

Amy DarukhanavalaFilia Van H~ospital DesselJannifer HoMegan HansenTed KremerDavid Alfego   Use of hemoglobin A1c to identify dysglycemia in cystic fibrosis. PLoS One 2021 Apr 21;16(4):e0250036.doi: 10.1371/journal.pone.0250036. eCollection 2021  Free article   [Pubmed]   (Please see PubMed for full abstract details)

Fig. 64 Amy Darukhanaval Find a Doctor

Cystic fibrosis (CF) leads to pancreatic endocrine dysfunction with progressive glycemic disturbance. Approximately 30%-50% of people with CF eventually develop CF-related diabetes (CFRD). Pre-CFRD states progress from indeterminant glycemia (INDET) to impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Screening guidelines recommend inconvenient annual 2-hour oral glucose tolerance tests (OGTTs), beginning at age 10 years. More efficient methods, such as hemoglobin A1C (HbA1c), have been evaluated, but only limited, relatively small studies have evaluated the association between HbA1c and pre-CFRD dysglycemic states.
This study to determine whether HbA1c is an appropriate screening tool for identifying patients with pre-CFRD dysglycemia to minimize the burden of annual OGTTs.
Results: Mean HbA1c was not significantly different between patients with normal glucose tolerance and those in the INDET (p = 0.987), IFG (p = 0.690), and IGT (p = 0.874) groups. Analysis of variance confirmed the lack of association between HbA1c and glycemia, as mean HbA1c was not significantly different amongst the four categories (p = 0.250).
The authors concluded there is increasing awareness of the impact of pre-CFRD states, including reduced pulmonary function and nutritional status. Unfortunately, our results do not support using HbA1c as a screening tool for pre-CFRD dysglycemia, specifically INDET, IFG, and IGT. Further studies are warranted to evaluate more efficient screening methods to reduce the burden of annual OG

Dr Amy Darukhanavala Fig.64) is a paediatric endocrinologist and Assistant Professor at the Department of Pediatric Endocrinology, University of Massachusetts Medical Center, Worcester, MA, United States of America.

Alejandro Da Silva SanchezKalina PaunovskaAna CristianJames E Dahlman. Treating Cystic Fibrosis with mRNA and CRISPR. Hum Gene Ther 2020 Sep;31(17-18):940-955.doi: 10.1089/hum.2020.137.Epub 2020 Sep 8.    [Pubmed

Fig. 66 James Dahlman. Winship Cancer Institute

Fig. 65 Alejandro Da Silva Sanchez ResearchGate

Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory, they can silence or edit any gene by encoding CRISPR nucleases, or alternatively, produce any missing protein. Yet not all mRNA therapies are equally likely to succeed.

Over the past several years, an increasing number of clinical trials with siRNA- and antisense oligonucleotide-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by nonviral systems. First, scientists have come to understand that some genes make better targets for RNA therapies than others. Second, scientists have learned that the type and position of chemical modifications made to an RNA drug can alter its therapeutic window, toxicity, and bioavailability. Third, scientists have found that safe and targeted drug delivery vehicles are required to ferry mRNA therapies into diseased cells.

n this study, we apply these learnings to cystic fibrosis (CF). We also describe lessons learned from a subset of CF gene therapies that have already been tested in patients. Finally, we highlight the scientific advances that are still required for nonviral mRNA- or CRISPR-based drugs to treat CF successfully in patients.

Alejandro Da Silva Sanchez (fig.65)  is a graduate research assistant at the Petit Institute for Bioengineer and Biosciences, Georgia Institute of Technology, Atlanta, Georgia, USA and the School of Chemical & Biomolecule Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.

Dr. James E Dahlman (fig.66) is a chemical and bioengineer whose work lies at the interface of nanotechnology, genomics, and gene editing.  He is Associate Professor and holds the McCamish Foundation Early Career Professorship in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech Universit

Kavita Dave Rebecca Dobra Sandra Scott Clare Saunders Jess Matthews Nicholas J Simmonds Jane C Davies.   Entering the era of highly effective modulator therapies.   Pediatr Pulmonol 2021 Feb;56 Suppl 1:S79-S89. doi: 10.1002/ppul.24968.      [Pubmed]

Fig. 67  Kavita Dave LinkedIn

Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF

Dr Kavita Dave (fig.67) is the UK CF Trust Clinical Fellow at Departments of Cystic Fibrosis and Paediatric Respiratory Medicine, Royal Brompton & Harefield Foundation Trust, London, UK

Gwyneth DaviesLena P Thia Janet Stocks Andrew Bush Ah-Fong Hoo Angie Wade The Thanh Diem Nguyen Alan S Brody Alistair Calder Nigel J Klein Siobhán B CarrColin WallisRanjan SuriCaroline S PaoGary Ruiz Ian M Balfour-Lynn London Cystic Fibrosis Collaboration (LCFC) Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year. J Cyst Fibros 2020 Nov;19(6):896-901.doi: 10.1016/j.jcf.2020.01.006. Epub 2020 Feb 7. [Pubmed] 

Fig 68 Gwyneth Davies University College London

Background: With the widespread introduction of newborn s creening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age.
Methods: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs.
Results: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT.
Conclusions: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes.

Dr Gwyneth Davies (fig.68)  is at the Respiratory, Critical Care and Anaesthesia section, UCL Great Ormond Street Institute of Child Health (GOS ICH), London, United Kingdom; Department of Respiratory Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Jane C DaviesClaire E Wainwright Gregory S SawickiMark N Higgins Daniel Campbell Christopher HarrisPaul PanorchanEric HaseltineSimon TianMargaret RosenfeldIvacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial. Am J Respir Crit Care Med   2021 Mar 1;203(5):585-593.doi: 10.1164/rccm.202008-3177OC. [Pubmed]

 Fig. 69 Jane Davies Imperial College London

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.
Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.
Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.
Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.
Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.

Further detail abstracted from the full text - This study of CFTR modulation in the first year of life suggests that ivacaftor can be safely administered to infants ≥4 months of age. Our findings are consistent with observations in older children and support treating the underlying cause of CF in children ≥4 months. Ivacaftor has a favourable safety profile; it was well tolerated at both doses tested, with no new safety concerns. Results of this study suggest improvements in CFTR function, no adverse effects on growth, and reductions in lipase concentrations with ivacaftor. Improvements in FE-1 and IRT concentrations (together with lipase data) support the potential of ivacaftor to delay or possibly minimize progressive exocrine pancreatic dysfunction. Studies evaluating a larger number of children for longer periods of time are needed to further test this hypothesis. Studies of pharmacokinetics and safety in younger infants are planned.
Substantial decreases in sweat chloride concentration were seen, which is a measure of CFTR function. Although the sample sizes were small, the mean improvement in sweat chloride concentration of −55.7 (SD, 16.2) mmol/L in these infants aged 4 to <12 months appears comparable with what has been reported in older children
Improvements in concentrations of FE-1, a biomarker of exocrine pancreatic function, were seen from baseline to 24 weeks (mean [SD] increases of 164.7 [151.9] μg/g and 99.8 [138.4] μg/g in ARRIVAL and KIWI, respectively).  Similarly, in the current report, mean (SD) improvement in FE-1 concentrations at Week 24 was 166.0 (140.6) μg/g. Eleven infants had baseline FE-1 concentrations of ≤200 μg/g, indicating pancreatic insufficiency, among whom seven of nine with paired data had regained pancreatic sufficiency at Week 24.
Although the clinical relevance of improvements in biomarkers of pancreatic function is unknown, the combined findings in children aged 4 to <24 months in ARRIVAL and aged 2–5 years in KIWI suggest a possible positive and protective effect of ivacaftor on pancreatic exocrine function early in life.

Jane Davies (fig.69) is Professor in Paediatric Respirology & Experimental Medicine at the National Heart and Lung Institute and an Honorary Consultant in Paediatric Respiratory Medicine at the Royal Brompton & Harefield NHS Foundation Trust.

E de PoelS SpelierS W F SuenE KruisselbrinkS Y GraeberM A Mall E J M Weersink M M van der EerdenG H KoppelmanC K van der EntJ M Beekman.   Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids. J Cyst Fibros 2021 Oct 16;S1569-1993(21)01425-9.doi: 10.1016/j.jcf.2021.09.020.Online ahead of print. [Pubmed]

 Fig. 70  Eyleen de Poel

Background: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-     actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation.   Methods: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs.

Results: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome.
Conclusions: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

Eyleen de Poel  (Fig 70)  is in the Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584 EA Utrecht, The Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584 CT Utrecht, The Netherlands; Center for Living Technologies, Eindhoven-Wageningen-Utrecht Alliance, The Netherlands.

Kris De BoeckJ Stuart ElbornIsabelle FajacNiels Hoiby. The journal of cystic fibrosis' 20th anniversary. J Cyst Fibros 2021 Dec 11;S1569-1993(21)02157-3.doi: 10.1016/j.jcf.2021.11.016. Online ahead of print.    [Pubmed]

Fig. 71 Kris De Boeck ECFS

A very interesting account of the outstanding success of first 20 years of the Journal of Cystic Fibrosis. The Journal of Cystic Fibrosis (JCF) celebrates 20 years since its first edition and has gone from strength to strength under the leadership of exceptional Editors-in-Chief and their editorial boards. The JCF was first published in January 2002 and was the result of many discussions within the board of the relatively newly constituted European Cystic Fibrosis Society (ECFS). The vision for the journal came from then President, Prof Gerd Döring, and Prof Harry Heijerman, an ECFS board member at that time. Their vision is deeply appreciated.

--- The full text of the editorial is very informative including a large table listing the Journal of Cystic Fibrosis published guidelines and consensus statements: Search on archives of the Journal (January 2002-October 2021) for ‘guideline’ or ‘consensus’ in title.

Dimitri DeclercqLieselot PeremansMichiel Glorieus Yannick Vande WeygaerdeHeidi SchaballieEva Van BraeckelEveli Urinary sodium/creatinine ratio is a predictor for fractional sodium excretion and related to age in patients with cystic fibrosis. en SnauwaertSabine Van DaeleStephanie Van Biervliet. J Cyst Fibros. 2021 Nov 18;S1569-1993(21)02130-5.doi: 10.1016/j.jcf.2021.11.002.Online ahead of print. [Pubmed]

Fig 72  Dimitri Declercq

Electrolyte disturbances are common in patients with cystic fibrosis (CF). Current guidelines on monitoring sodium status are based on research in a small group of infants and require blood sampling. The aim of this study was to evaluate urinary salt parameters as a surrogate for sodium-status in different age-groups. Blood and urine samples for electrolytes were collected from 222 patients followed at the Ghent University Hospital CF-center. Fractional sodium excretion (FENa) and several urinary parameters were calculated. Clinical characteristics did not differ according to sodium status, defined as FENa <0.5%. ROC analysis demonstrated that sodium/creatinine ratio (UNa/Creat) predicted the sodium status most accurately with high sensitivity and specificity (97 and 91% respectively). The UNa/Creat cut-off predicting a FENa <0.5% differed significantly according to age. The UNa/Creat is an excellent marker for the sodium status defined as a FENa <0.5%. However, different cut-offs according to age category should be applied.

Dimitri Declercq (Fig. 72) is CF Dietitian and Diabetes Educator at the Cystic Fibrosis Reference Center, Ghent University Hospital, C. Heymanslaan 10, Belgium; Center for Nutrition and Dietetics, Ghent University Hospital, C. Heymanslaan 10, Gent, Belgium

David DrummondJérémy DanaLaureline BertelootElena K Schneider-FutschikFrédérique Chedevergne, Céline Bailly-BotuhaThao Nguyen-KhoaMathieu CornetMuriel Le BourgeoisDominique DebrayMuriel GirardIsabelle Sermet-Gaudelus.   Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTRJ Cyst Fibros. 2021 Aug 25;S1569-1993(21)01337-0.doi: 10.1016/j.jcf.2021.07.018. Online ahead of print. [Pubmed]

Fig. 73 David Drummond         HeKA team

Background: The effects of lumacaftor-ivacaftor on cystic fibrosis transmembrane conductance regulator (CFTR)-associated liver disease remain unclear. The objective of the study was to describe the effect of this treatment on features of liver involvement in a cystic fibrosis (CF) adolescent population homozygous for F508del.
Methods: Clinical characteristics, liver blood tests, abdominal ultrasonography (US), and pancreas and liver proton density fat fraction (PDFF) by magnetic resonance imaging, were obtained at treatment initiation and at 12 months for all patients. Biomarkers of CFTR activity (sweat chloride test, nasal potential difference, and intestinal current measurement) were assessed at initiation and at 6 months therapy.
Results: Of the 37 patients who started ivacaftor/lumacaftor treatment, 28 were eligible for analysis. In this group, before treatment initiation, 4 patients were diagnosed with multinodular liver and portal hypertension, 19 with other forms of CF liver involvement, and 5 with no signs of liver involvement. During treatment, no hepatic adverse reactions were documented, and no patient developed liver failure. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) decreased significantly following initiation of lumacaftor-ivacaftor, and remained so after 12 months treatment. This was not correlated with changes in clinical status, liver and pancreas US and PDFF, fecal elastase, or lumacaftor-ivacaftor serum levels. The most "responsive" patients demonstrated a significant increase in biomarkers of CFTR activity.

Conclusions: These results may suggest a potential beneficial effect of CFTR modulators on CF liver disease and warrant further investigation in larger, prospective studies.

Dr David Drummond (fig.73) is a paediatrician at Service de Pneumologie et Allergologie Pédiatriques, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Centre de Ressources et de Compétences pour la Mucoviscidose, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)-Centre, Université de Paris, Paris, France; Université de Paris, Paris, France.

Jamie DuckersBeth LesherTeja ThoratEleanor LucasLisa J McGarryKeval ChandaranaFosca De Iorio. Real-World Outcomes of Ivacaftor Treatment in People with Cystic Fibrosis: A Systematic Review. J Clin Med 2021 Apr 6;10(7):1527.doi: 10.3390/jcm10071527. free PMC article [Pubmed]        

 Fig. 74  Jamie Duckers cavuhb.nhs.wales

Cystic fibrosis (CF) is a rare, progressive, multi-organ genetic disease. Ivacaftor, a small-molecule CF transmembrane conductance regulator modulator, was the first medication to treat the underlying cause of CF. Since its approval, real-world clinical experience on the use of ivacaftor has been documented in large registries and smaller studies. Here, we systematically review data from real-world observational studies of ivacaftor treatment in people with CF (pwCF). Searches of MEDLINE and Embase identified 368 publications reporting real-world studies that enrolled six or more pwCF treated with ivacaftor published between January 2012 and September 2019. Overall, 75 publications providing data from 57 unique studies met inclusion criteria and were reviewed. Studies reporting within-group change for pwCF treated with ivacaftor consistently showed improvements in lung function, nutritional parameters, and patient-reported respiratory and sino-nasal symptoms. Benefits were evident as early as 1 month following ivacaftor initiation and were sustained over long-term follow-up. Decreases in pulmonary exacerbations, Pseudomonas aeruginosa prevalence, and healthcare resource utilization also were reported for up to 66 months following ivacaftor initiation. In studies comparing ivacaftor treatment to modulator untreated comparator groups, clinical benefits similarly were reported as were decreases in mortality, organ-transplantation, and CF-related complications. The safety profile of ivacaftor observed in these real-world studies was consistent with the well-established safety profile based on clinical trial data.

Our systematic review of real-world studies shows ivacaftor treatment in pwCF results in highly consistent and sustained clinical benefit in both pulmonary and non-pulmonary outcomes across various geographies, study designs, patient characteristics, and follow-up durations, confirming and expanding upon evidence from clinical trials.

Dr Jamie Duckers (fig.74) is a consultant in the All Wales Adult Cystic Fibrosis Centre University Hospital Llandough Cardiff

J DuckersR FitzgeraldD ProudC AddyD Datta Forewarned is forearmed: The cardiovascular time bomb in Cystic FibrosisJ Cyst Fibros. 2021 Dec 10;S1569-1993(21)02142-1.doi: 10.1016/j.jcf.2021.11.008.Online ahead of print. [Pubmed]
More than a third of adult CF patients develop CF related diabetes (CFRD) and over 60% of CF patients in one study were shown to have dyslipidaemia.  Both rates of dyslipidaemia and diabetes are shown to increase with age. Considering the increasing age of the CF population, cardiovascular disease prevention is an important factor to consider.

QRISK3 is a widely used online tool as part of cardiovascular disease primary prevention in the UK. It is used in adults (25–84 years) to predict cardiovascular risk. Using algorithms based on age, sex, smoking status, deprivation score, diagnosed medical conditions, drug history, cholesterol/HDL ratio, blood pressure and BMI it derives a healthy heart age score. The healthy heart age is the age at which a person of same sex and ethnicity with normal parameters would have the same QRISK3 score.
We used the QRISK3 calculator to estimate the healthy heart age score of the 207 adults aged 25–84 years (mean age 37 years SD10) attending the All Wales Adult CF Centre using annual review data.   The figure demonstrates the QRISK3 healthy heart age of all patients in the CF cohort compared with their actual age. Most patients in the CF cohort are above their control thresholds and their healthy heart age score ranged from 30 to >85 years (mean 45 years SD 14). This mean healthy heart age of patients with CF was 8 years more than the mean actual age (37 years) of the patients (  p <0.001).

People living with CF appear to be at increased cardiovascular risk based upon current known risk factors. Understanding and predicting the impacts of CF disease manifestations and CFTR on the cardiovascular system will become increasingly important in an ageing CF population. This increased understanding will enable more accurate prediction of cardiovascular risk. Forewarned with the improved prediction of risk we can be forearmed and develop routine monitoring and screening of risk factors within best practice guidelines.

Dr Jamie Duckers ( Fig  74) is a consultant in the All Wales Adult Cystic Fibrosis Centre University Hospital Llandough Cardiff

Rachel DunkSusan MadgeSARS-CoV-2 driving rapid change in adult cystic fibrosis services: the role of the clinical nurse specialistBMJ Open Qual 2021 Oct;10(4):e001427. doi: 10.1136/bmjoq-2021-001427. [Pubmed]

 Fig. 75 Rachel Dunk

Cystic fibrosis (CF) is a genetic, life-limiting disease without a cure; Coronavirus disease (COVID-19) rapidly changed healthcare services across the globe, including redeployment of healthcare professionals. This adult CF service was challenged to continue a patient facing service within severe staffing and structural limitations.Not only were many members of the CF multidisciplinary team (MDT) redeployed at the start of the first wave, but also both the CF and ambulatory care wards were closed. Fortunately, the CF clinical nurse specialists (CF-CNSs) remained in their role. Rapid change and adaptation of the CF service was required to ensure that patients did not feel abandoned and access to treatment remained available. The role of the CF-CNS was therefore pivotal in this change.The aim of this project was to use quality improvement methodology to plan an emergency service allowing a reintroduction of ambulatory care services. Success was measured by the number of patients clinically reviewed with or without intervention, and the reasons for patients contacting the CF-CNS via email and phone were recorded.In weeks 1 and 2 of the emergency service, the CF-CNSs triaged patients by phone, then reviewed face-to-face when necessary. This first step allowed the CF-CNSs to start two patients on home intravenous antibiotics. This service continued to be developed over the following 12 weeks, leading to a total of 36 patient attendances. In March 2020, n=1187 patients made contact (mostly COVID-19, unwell and medication related), in April n=904 and May n=870 (blood test results, unwell and medication related).The motivation of the CF-CNSs was pivotal to the success of this initiative with the CF MDT available to provide some support and advice. It concluded at week 12, which then saw the opening of the formal ambulatory care ward and returning redeployed ward staff.

Rachel Dunk (fig.75) and Sue Madge are in the Adult Cystic Fibrosis Department, Royal Brompton Hospital, London.

Gabrielle DuretteValérie JompheNathalie J BureauCharles PoirierPasquale FerraroLarry C LandsGeneviève Mailhot. Long-term bone mineral density changes and fractures in lung transplant recipients with cystic fibrosisJ Cyst Fibros. 2021 May;20(3):525-532.doi: 10.1016/j.jcf.2020.09.012. Epub 2020 Oct 21.[Pubmed

 Fig. 76 Gabrielle Durette LinkedIn

Background: Little is known about long-term bone mineral density (BMD) changes and fractures in lung transplant recipients with cystic fibrosis (CF). We examined femur and lumbar spine (LS) BMD changes in men and women with CF up to 10 years post-transplant and documented post-transplant fracture prevalence.
Methods: Retrospective study of individuals who had undergone a lung transplant (2000-2015) and had a pre-transplant and at least one BMD measurement after transplant. Vertebral fractures were assessed on chest computed tomography scans and other fractures abstracted from medical records.
Results: The cohort consisted of 131 individuals; 53% males, median age: 28 years [interquartile range: 24-35] and 31% having pre-transplant low bone mass. Most recipients were given bisphosphonates after transplant with proportion reaching 94% at 10 years. Up to 10 years post-transplant, men experienced positive or little change in LS BMD, indicating minimal loss from pre-transplant values. In contrast, women displayed negative changes in BMD up to 5 years post-transplant before recovering pre-transplant BMD values by 10 years. Similar patterns were observed at the femur BMD where men demonstrated a lower bone loss and faster recovery towards pre-transplant values than women. After transplant, 88% of recipients maintained their pre-transplant bone status, 3% experienced an improvement, mostly progressing from low bone mass to normal status whereas 9% had a deterioration of their pre-transplant bone status. Twenty-seven recipients suffered fractures in the post-transplant period.

Conclusions: These findings underline that lung recipients with CF remain at risk of skeletal fragility despite prompt initiation of post-transplant anti-osteoporosis therapy.

Dr Gabrielle Durette (fig. 76) is a nutritionist, conseillère scientifique at the l'Institut national de santé publique du Québec, Greater Montreal Metropolitan Area.

Oluwaseun B Esan,Daniela K SchlüterRhiannon PhillipsRebecca CosgriffShantini ParanjothyDenitza WilliamsRachel NormanSiobhán B Carr Jamie DuckersDavid Taylor-Robinson. Pregnancy rates and outcomes amongst women with cystic fibrosis in the UK: comparisons with the general population before and after the introduction of disease modifying treatment, 2003-17. BJOG 2021 Oct 1.doi: 10.1111/1471-0528.16957. Online ahead of print.     [Pubmed

Fig.77 Oluwaseun B Esan University of Liverpool

Objective: To compare pregnancy rates and outcomes for women with cystic fibrosis in the UK with the general population and assess the effect of introduction of disease modifying treatment
Design: A population-based longitudinal study, 2003-17 SETTING: United Kingdom POPULATION: Women aged 15-44 years in the UK CF Registry compared to women in England and Wales.
Methods: We calculated pregnancy and live birth rates for the CF and England and Wales (E&W) populations. For women with CF we compared pregnancy rates before and after ivacaftor was introduced in 2013. We further used CF registry data to assess pregnancy outcomes for mothers with CF, and to assess the relationship between maternal pre-pregnancy lung function and nutritional status and child gestational age.
Main outcome measures: Pregnancy and live birth rates; and child gestational age.
Results: Of 3,831 women with CF, 661 reported 818 pregnancies. Compared E&W the pregnancy rate was 3.3 times lower in the CF population (23.5 vs. 77.7 per 1,000 women years); the live birth rate was 3.5 times lower (17.4 vs. 61.4 per 1,000 women years) with 70% of pregnancies in CF women resulting in live births; abortion rates were also lower (9% vs. 22%). Pregnancy rates increased post-ivacaftor for eligible women with CF, from 29.7 to 45.7 per 1,000 women years. There was no association between pre-pregnancy lung function/nutrition status and gestational age.

Conclusions: Pregnancy rates in women with CF are about a third of the rates in E&W with favourable outcomes and increased for eligible women post-ivacaftor.

Dr Oluwaseun B Esan (fig.77) is a Post-doctoral Research Associate at the Institute of Population Health Liverpool.

Marie E EganEmerging technologies for cystic fibrosis transmembrane conductance regulator restoration in all people with CFPediatr Pulmonol 2021 Feb;56 Suppl 1:S32-S39.doi: 10.1002/ppul.24965.  [Pubmed]

 Fig 78  Marie Egan Yale School of medicine

Although effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has the potential to change the lives of many patients with cystic fibrosis (CF), it is unlikely that these drugs will be a game changing therapy for all. There are about 10% of patients with CF who don't produce a mutant protein tomodulate, potentiate, or optimize and for these patients such therapies are unlikely to be of significant benefit. There is a need to develop new therapeutic approaches that can work for this patient population and can advance CF therapies. These new therapies will be genetic-based therapies and each approach will result in functional CFTR protein inpreviously affected CF cells. In this review we will examine the potential of RNA therapies, gene transfer therapies, and gene editing therapies for the treatment of CF as well as the challenges that will need to be faced as we harness the power of these emerging therapies towards a one-time cure.

Marie Egan (fig.78) is Professor of Pediatrics and of Cellular and Molecular Physiology: Director, Cystic Fibrosis Center; Vice Chair for Research Department of Pediatrics, Yale School of Medicine.

Carlos M FarinhaMartina Gentzsch.  Revisiting CFTR Interactions: Old Partners and New Players. Int J Mol Sci 2021 Dec 7;22(24):13196.doi:10.3390/ijms222413196.  [Pubmed]   Free PMC article

 Fig. 79  Carlos Farinha LinkedIn

Remarkable progress in CFTR research has led to the therapeutic development of modulators that rescue the basic defect in cystic fibrosis. There is continuous interest in studying CFTR molecular disease mechanisms as not all cystic fibrosis patients have a therapeutic option available. Addressing the basis of the problem by comprehensively understanding the critical molecular associations of CFTR interactions remains key. With the availability of CFTR modulators, there is interest in comprehending which interactions are critical to rescue CFTR and which are altered by modulators or CFTR mutations. Here, the current knowledge on interactions that govern CFTR folding, processing, and stability is summarized. Furthermore, we describe protein complexes and signal pathways that modulate the CFTR function. Primary epithelial cells display a spatial control of the CFTR interactions and have become a common system for preclinical and personalized medicine studies. Strikingly, the novel roles of CFTR in development and differentiation have been recently uncovered and it has been revealed that specific CFTR gene interactions also play an important role in transcriptional regulation. For a comprehensive understanding of the molecular environment of CFTR, it is important to consider CFTR mutation-dependent interactions as well as factors affecting the CFTR interactome on the cell type, tissue-specific, and transcriptional levels.

Carlos M Farinha (Fig 79) is Associate Professor at BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, 1749-016 Lisboa, Portugal.

Clara Fernandez ElviroSylvain BlanchonSylke HoehnelUrs SchumacherAlain Sauty Nathalie Brandenberg Nicolas Regamey.  Diagnostic tools and CFTR functional assays in cystic fibrosis: utility and availability in SwitzerlandSwiss Med Wkly 2021 Apr 13;151:w20496.doi: 10.4414/smw.2021.20496.eCollection 2021 Apr 12.  [Pubmed]
Cystic fibrosis (CF) is a genetic disease caused by a bi-allelic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. When the diagnosis cannot be confirmed by a positive sweat test or/and the identification of two CF-causing variants, international guidelines recommend the use of CFTR functional assays. These tests assess whether CFTR activity is normal or diminished/absent through measurement of CFTR-mediated chloride secretion/absorption. CFTR functional assays are not only useful for diagnostic purposes but can also serve as a surrogate outcome for clinical trials of CFTR modulators, which are emerging therapeutic agents designed to correct the malfunctioning protein. In the near future they could also be used as precision-medicine techniques, to help guidance and optimisation of treatment. Until now, sweat testing has been the only CFTR functional assay available in Switzerland.

Since 2020, the Centre Hospitalier Universitaire Vaudois (CHUV) at Lausanne and the Lucerne Children’s Hospital perform nasal potential difference measurement. Moreover, The Ecole Polytechnique Fédérale de Lausanne (EPFL) established a reliable procedure to generate adult intestinal organoids, i.e., stem cell-derived in-vitro grown mini tissues, extracted from rectal biopsies, which can be used to assess CFTR function in vitro. This narrative review describes the most popular CFTR functional assays, as well as their indications, limitations and availability in Switzerland.

Clara Fernandez Elviro is in the Department Woman-Mother-Child, Service of Paediatrics, Paediatric Pulmonology and Cystic Fibrosis Unit, University Hospital of Lausanne and Faculty of Biology and Medicine, University of Lausanne, Switzerland.

Patrick A FlumeElena AmelinaCori L DainesBrett Charlton, Joanna LeadbetterAlessandro Guasconi Moira L Aitken. Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study.  J Cyst Fibros 2021 Mar 11;S1569-1993(21)00046-1.doi: 10.1016/j.jcf.2021.02.011.Online ahead of print. [Pubmed]Free article

Fig. 80 Patrick Flume

Background: Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults.
Methods: This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV1) 40-90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV1 averaged over the 26-week treatment period.
Results: Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV1averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively.

Conclusions: In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV1) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353.

Dr Patrick Flume (fig.80) is at the Medical University of South Carolina, Charleston, SC, United States.

--- In UK, where inhaled mannitol has been available for some years, the use is very modest. Only 5.9% of patients were taking regular mannitol - most were adult patients over 16 years of age.

Patrick A FlumeReta Fischer BinerDamian G DowneyCynthia BrownManu JainRainald Fischer, et al and the  VX14-661-110 study group.  Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study. Lancet Respir Med 2021 Jul;9(7):733-746.doi: 10.1016/S2213-2600(20)30510-5. Epub 2021 Feb 10. [Pubmed]
Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation.
Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914).
Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls.

Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes.

Deane J, Fouhy F, Ronan NJ, Daly M, Fleming C, Eustace JA, Shanahan F, Flanagan ET, Dupont L, Harrison MJ, Haworth CS, Floto A, Rea MC, Ross RP, Stanton C, Plant BJ.   A multicentre analysis of Clostridium difficile in persons with Cystic Fibrosisdemonstrates that carriage may be transient and highly variable with respect to strain and level: Cystic Fibrosis and Clostridium difficile. J Infect. 2021 Jan 11:S0163-4453(20)30788-X. doi:10.1016/j.jinf.2020.12.027. Online ahead of print [Pubmed]

Fig.81  Jennifer Deane ResearchGate

Clostridium difficile has been reported to occur in the gastrointestinal tract of 50% of Cystic Fibrosis (CF) subjects, however, clinical C. difficile infection (CDI) is a rare occurrence in this cohort despite the presence of toxigenic and hypervirulent ribotypes. Here, we present the first longitudinal, multicentre analysis of C. difficile prevalence among adult CF subjects.
Faecal samples were collected from adults with CF (selected based on confirmed Pseudomonas aeruginosa pulmonary colonisation) from Ireland, UK and Belgium as part of the CFMATTERS clinical research trial (grant No.603038) and from non-CF controls. Faecal samples were collected on enrolment, at three monthly intervals, during pulmonary exacerbation and three months post exacerbation. C. difficile was isolated from faecal samples by ethanol shocking followed by culturing on cycloserine cefoxitin egg yolk agar. Isolates were characterised in terms of ribotype, toxin type and antibiotic susceptibility to antibiotics routinely used in the treatment of CDI (metronidazole and vancomycin) and those implicated in induction of CDI (ciprofloxacin and moxifloxacin).
Results: Prevalence of C. difficile among CF subjects in the three sites was similar ranging from 47-50% at baseline, while the healthy control cohort had a carriage rate of 7.1%. Including subjects who were positive for C. difficile at any time point there was a higher carriage rate of 71.4%, 66.7% and 63.2% in Ireland, UK, and Belgium, respectively. Ribotyping of 80 isolates from 45 CF persons, over multiple time points revealed 23 distinct ribotypes with two ribotypes (046 and 078) shared by all centres. The proportion of toxigenic isolates varied across the sites, ranging from 66.7% in Ireland to 52.9% in Belgium and 100% in the UK. Antibiotic susceptibility rates to vancomycin, metronidazole, ciprofloxacin and moxifloxacin was 100%, 97.5%, 1.3% and 63.8%, respectively.
Conclusions: This study demonstrates the highest carriage rate of C. difficile to date in a CF cohort. Longitudinal data shows that C. difficile can be a transient inhabitant of the CF gut, changing both in terms of strain and excretion rates

Jennifer Deane (Fig. 81) is a PhD researcher at Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland; HRB Clinical Research Facility, University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland.

Amir Reza DjavidAlison E ThompsonAlexandria L IraceElen GusmanKimberly AltmanEmily A DiMangoClaire L Keating.  Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Advanced Cystic Fibrosis Lung DiseaseAnn Am Thorac Soc. 2021 May 17.doi: 10.1513/AnnalsATS.202102-220RL.Online ahead of print.  [Pubmed]

Fig 82 Claire Keating

No text available at time of writing

Dr Amir Reza Djavid is at Columbia University Vagelos College of Physicians and Surgeons, 12294, New York, New York, United States.

Dr Claire Keating (fig.82) is Associate Professor of Medicine at Columbia University Medical Center, Associate Director, Gunnar Esaison Adult Cystic Fibrosis and Lung Center is the corresponding author

Helmut EllemunterMarkus DumkeGratiana Steinkamp. Reference Values Matter: Fewer Patients with Malnutrition using American Compared to more Recent German Growth Charts. J Pediatr Gastroenterol Nutr 2021 Feb 24.doi: 10.1097/MPG.0000000000003095.Online ahead of print. [Pubmed]

Fig 83 Helmut Ellemunter

Reference values are important for patient care as well as for comparisons between different centres or countries. We investigated two anthropometric reference datasets, the US Centers for Disease Control (CDC) growth charts and the German Health Interview and Examination Survey for Children and Adolescents Study (KiGGS) percentiles, which were established in Germany between 2003 and 2006. A smaller proportion of children with cystic fibrosis had decreased z-scores <-2 with CDC (5.0% for weight and 3.0% for height) compared to KiGGS (7.4% for weight and 6.3% for height) values (p<0.0001). Median z-scores were higher using the CDC reference data. Thus, the choice of growth reference is important, may influence clinical management and must be considered when comparing outcomes of different institutions.

 Dr Helmut Ellemunter (fig.83)  is Assistant  Professor at the Cystic Fibrosis Centre at the Medical University of Innsbruck, Department of Child and Adolescent Health, Paediatrics III, Austria.  STAT-UP Statistical Consulting & Services, Munich, Germany Clinical Research and Medical Scientific Writing, Schwerin, Germany.

Nagehan EmiraliogluDilber Ademhan TuralHayriye Hizarcioglu GulsenYasin Maruf ErgenBeste OzsezenBirce Sunman İncinur Saltık TemizelEbru YalcinDeniz DogruUğur OzcelikNural Kiper  Does cystic fibrosis make susceptible to celiac disease? Eur J Pediatr 2021 Mar 25.doi: 10.1007/s00431-021-04011-4. Online ahead of print. [Pubmed]

Fig. 84 Nagehan Emiralioglu

The incidence of CD in 515 patients with CF was 1.4%. The median age at the time of CF diagnosis was 2 months (1-6 months). CD was diagnosed in six patients with poor weight gain, fatty stools, and low z score for BMI and one patient with poor weight gain despite a high protein and calorie diet and pancreatic enzyme replacement. The median age of CD diagnosis was 8 years (2-12 years). Except for one patient who was recently diagnosed, the other six patients gained weight and their accompanying symptoms resolved after starting a gluten-free diet.
Conclusion: CD should be investigated in patients with CF in the presence of inadequate weight and/or height gain or poor control of malabsorption symptoms despite appropriate and adequate nutritional and enzyme replacement treatment.
What is Known: • CFTR dysfunction may be a risk factor for CD, due to increased intestinal permeability and intestinal inflammation, pancreatic exocrine insufficiency that results in higher antigen load and increased antibodies against to nutritional antigens such as anti-gliadin IgA antibodies.
• Although coexistence of CF and CD are rare in the same patient; there is still no consensus on when children with CF should be screened for CD.
What is New: • Physicians should consider the investigation of CD in patients with CF, in the presence of inadequate weight and/or height gain or i control of malabsorption symptoms despite appropriate and adequate nutritional and enzyme replacement treatment
• CFTR dysfunction has been emphasized to develop susceptibility to CD, and patients with CF who have persistent gastrointestinal symptoms despite appropriate and adequate nutritional and enzyme replacement treatment should be screened for CD.

Dr Nagehan Emiralioglu (Fig 84) is in the Department of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Isabelle Fajac Isabelle Sermet.  Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators. Cells 2021 Oct 19;10(10):2793.doi: 10.3390/cells10102793. Free PMC article [Pubmed]

Fig 85 Isabelle Fajac Kitherbiotech.com

Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function, and they will benefit many patients with cystic fibrosis in the near future.
However, some patients bear rare mutations that are not yet    eligible for CFTR modulators, although they might be amenable to these new disease-modifying drugs. Moreover, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon.
The purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations ineligible for CFTR modulators. One approach is to broaden the numbers of mutations eligible for CFTR modulators. This requires developing strategies to evaluate drugs in populations bearing very rare genotypes. Other approaches aiming at correcting the CFTR defect develop new mutation-specific or mutation-agnostic therapies for mutations that do not produce a CFTR protein: readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA- or DNA-based, and cell-based therapies. Most of these approaches are in pre-clinical development or, for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.

Prof. Isabelle Fajac (Fig 85)  is at the Physiology Department at the AP-HP. Centre-Université de Paris, Hôpital Cochin, Centre de Référence Maladie Rare-Mucoviscidose, 75014 Paris, France and the  Faculté de Médecine, Université de Paris, 75006 Paris, France.

Philip M FarrellElinor Langfelder-SchwindMichael H Farrell Challenging the dogma of the healthy heterozygote: Implications for newborn screening policies and practices. Mol Genet Metab. 2021 Aug 21;S1096-7192(21)00772-1.doi: 10.1016/j.ymgme.2021.08.008. Online ahead of print.[Pubmed]

 Fig. 86 Philip Farrell

Heterozygous (carrier) status for an autosomal recessive condition is traditionally considered to lack significance for an individual's health, but this assumption has been challenged by a growing body of evidence. Carriers of several autosomal recessive disorders and some X-linked diseases are potentially at risk for the pathology manifest in homozygotes. This minireview provides an overview of the literature regarding health risks to carriers of two common autosomal recessive conditions on the Recommended Uniform Screening Panel: sickle cell disease [sickle cell trait (SCT)] and cystic fibrosis (CF). We also consider and comment on bioethical and policy implications for newborn blood screening (NBS). Health risks for heterozygotes, while relatively low for individuals, are often influenced by intrinsic (e.g., other genomic variants or co-morbidities) and extrinsic (environmental) factors, which present opportunities for personalized genomic medicine and risk counseling. They create a special challenge, however, for developing screening/follow-up policies and for genetic counseling, particularly after identification and reporting of heterozygote status through NBS. Although more research is needed, this minireview of the SCT and CF literature to date leads us to propose that blanket terms such as "healthy heterozygotes" or "unaffected carriers" should be superseded in communications about NBS results, in favor of a more nuanced paradigm of setting expectations for health outcomes with "genotype-to-risk." In the molecular era of NBS, it remains clear that public health needs to become better prepared for the full range of applied genetics.

Prof. Philip Farrell (fig. 86) is in the Departments of Pediatrics and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Clinical Sciences Center (K4/948), Madison, WI 53792, USA

---   Prof. Philip Farrell and his team were responsible for the introduction of neonatal CF screening in the USA. One particular publications from his department were sufficient to provide evidence of long term benefit for the UK government to approve nationwide CF screening (Farrell PM, et al.Pediatrics. 2001 Jan;107(1):1-13.[Pubmed]

Gunter FlemmingUlrich BaumannRichter NicolasVondran FlorianBurkhard TümmlerAnna-Maria DittrichCarsten MüllerMandy VogelPfister Eva-DoreenSurvival Benefits Following Liver Transplantation - A Matched-Pair Analysis in Pediatric Patients with Cystic FibrosisJ Pediatr Gastroenterol Nutr  2021 Jun 1.doi: 10.1097/MPG.0000000000003194.Online ahead of print.  [Pubmed]
Objectives and study: Cystic fibrosis related liver disease (CFLD) with consecutive cirrhosis is the third most common cause of death in CF patients (3). The aim of this study is to identify the potential long-term benefits of liver transplantation (LTx) in a match-control comparison.
Methods: Retrospective single-center data analysis of all pediatric LTx for CFLD between 1998 and 2014. A control group was selected from the local CF patient registry. Data were collected from case report forms and included clinical and laboratory data, lung function tests, the indication for LTx and details of surgical procedures.
Results: At our institution 23 patients with severe CFLD median age 13.8 years (range 8.7-17.4; 16 boys) underwent LTx between 1998 and 2014. In all patients, normalization of hepatic CF manifestations were achieved after LTx. But obviously there was no significant positive influence on nutritional status. Signs of post-transplant liver steatosis were documented by ultrasound in 17 patients. Liver biopsies after LTx were performed in 19 patients, in 42% (n = 8) of these biopsies a fatty degeneration was observed. 5 patients died after LTx, none because of primary hepatic dysfunction (1 due to post-transplant proliferative disorder, 4 due to infection).Analysis of matched control pairs revealed that liver function, anthropometry, pulmonary function and life expectancy of CFLD patients with LTx are comparable to matched CF peers without CFLD.
Conclusion: Isolated LTx normalizes the hepatic manifestation of CF disease. LTx enables children and adolescents with severe CFLD to have a comparable prognosis in terms of growth, life expectancy and lung function as CF patients without advanced liver involvement. Our data clarifies the long-term perspectives of affected patients.

Gunter Matthias Christian Flemming is at the Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany Hospital for Children and Adolescents, University of Leipzig, Germany Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany Pediatric Pneumology, Allergology, and Neonatology, Hannover Medical School, Hannover, Germany

Loretta FerreraFloriana Cappiello Maria Rosa LoffredoElena PuglisiBruno CasciaroBruno BottaLuis J V GaliettaMattia MoriMaria Luisa Mangoni.  Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides.  Cell Mol Life Sci 2021 Dec 31;79(1):67.doi: 10.1007/s00018-021-04030-2.  Free PMC article   [Pubmed]

Fig. 87    Loretta Ferrera

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease.

Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity. In this study, by means of electrophysiological techniques and computational studies we discovered their ability to increase the CFTR-controlled ion currents, by direct interaction with the F508del-CFTR mutant. Remarkably, this property was not explored previously with any AMPs or peptides in general. More interestingly, in contrast with clinically used CFTR modulators, Esc peptides would give particular benefit to CF patients by combining their capability to eradicate lung infections and to act as promoters of airway wound repair with their ability to ameliorate the activity of the channel with conductance defects.

Overall, our findings not only highlighted Esc peptides as the first characterized AMPs with a novel property, that is the potentiator activity of CFTR, but also paved the avenue to investigate the functions of AMPs and/or other peptide molecules, for a new up-and-coming pharmacological approach to address CF lung disease.

Lorreta Ferrera (fig.87)  is at U.O.C. Genetica Medica, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, 16147, Genoa, Italy

Fortner CN, Seguin JM, Kay DM. Normal pancreatic function and false-negative CF newborn screen in a child born to a mother taking CFTR modulator therapy during pregnancy. J Cyst Fibros. 2021;20:835-6. DOI:10.1016/j.jcf.2021.03.018 https://pubmed.ncbi.nlm.nih.gov/33846105/

Jonathan A FridellMolly A BozicBenjamin J UlrichAndrew J LutzJohn A Powelson.  Pancreas transplantation for Cystic Fibrosis: A Frequently Missed Opportunity. Clin Transplant. 2021 May 25;e14371.doi: 10.1111/ctr.14371. Online ahead of print.  [Pubmed]

Fig. 88 Jonathan Fridell Webmd Doctor

As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency, and CF related diabetes (CFRD). Both of these can be managed through pancreas transplantation. Pancreas transplantation is usually performed in combination with another organ, most often with a kidney transplant for end-stage diabetic nephropathy. In the CF patient population, the two settings where inclusion of a pancreas transplant should be considered would be in combination with a lung transplant for CF pulmonary disease, or in combination with a liver for CF related liver disease with cirrhosis. This report will discuss this topic in detail, including a review of the literature regarding combinations of lung/pancreas and liver/pancreas transplant.

Jonathan A Fridel  (fig. 88)  is professor of Surgery in the Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

Eva FurstovaTereza DousovaJakub BeranekMalgorzata LibikLibor FilaMartin ModrakOndrej CinekMilan Macek JrPavel Drevinek    Response to elexacaftor/tezacaftor/ivacaftor in intestinal organoids derived from people with cystic fibrosis. J Cyst Fibros 2021 Aug 1;S1569-1993(21)01304-7.doi: 10.1016/j.jcf.2021.07.006.Online ahead of print.[Pubmed]

Fig. 88 Eva Furstova

Superior efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) over tezacaftor/ivacaftor (TEZ/IVA) in people with cystic fibrosis (CF) and Phe508del/Phe508del genotype was shown in clinical trials. We utilized intestinal organoid approach to compare in vitro responses to these 2 CFTR modulator drug combinations and to check potential inter-individual variability in therapeutic response to the triple combination.

Organoids from 17 subjects with Phe508del/Phe508del were screened with forskolin induced swelling assay. Significantly larger swelling, when exposed to ELX/TEZ/IVA as compared to TEZ/IVA, was observed in 16 of them. However, 1 sample showed no additional effect of ELX. The finding of unique CFTR variants in this sample indicates that genetic traits other than CF-causing CFTR mutation are worth exploring as they may have an impact on the definitive modulator drug response.

Dr Eva Furstovaig.(fig 88)  a medical doctor and PhD researcher in the Department of Paediatrics, 2nd Faculty of Meicine, Charles University and Motol University Hospital, Prague, Czech Republic; Department of Medical Microbiology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

Megan E GabelClaudia K FoxRachel A GrimesJohn D LowmanCatherine M McDonaldVirginia A StallingsSuzanne H MichelOverweight and cystic fibrosis: An unexpected challenge.  Pediatr Pulmonol 2021 Nov 5.doi: 10.1002/ppul.25748. Online ahead of print. [Pubmed]

Fig.89 Megan E Gabel University of Rochester

Achieving a healthy weight balance has been a central focus of care for people who have cystic fibrosis (CF). Over the years, the emphasis has primarily been on promoting weight gain to optimize pulmonary outcomes. With continued improvements in CF care, including highly effective CF modulators available for many people, the CF community is now experiencing a new challenge: addressing the concern that some people are gaining weight excessively. While at this time, we do not know to what extent overweight and obesity will affect health outcomes for people with CF, it is likely that excessive weight gain may have negative health impacts similar to those seen in the general population. In this paper, we review the history of nutritional guidelines for people with CF, as well as more recent trends toward overweight and obesity for some. A multidisciplinary approach is needed to collaboratively start the oftentimes difficult conversation regarding excessive weight gain, and to identify resources to help people achieve and maintain a healthy weight through diet, exercise, and behavioral modification.

Dr Megan E Gabel (fig.89)  is Associate Professor in the Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA.

Luke W GarrattOded BreuerCraig J SchofieldSamantha A McLeanDaniel R LauciricaRabindra TirouvanziamBarry S ClementsAnthony KicicSarath RanganathanStephen M Stick, CF.  Changes in airway inflammation with pseudomonas eradication in early cystic fibrosisJ Cyst Fibros 2021 Jan 15;S1569-1993(20)30947-4.doi: 10.1016/j.jcf.2020.12.015.Online ahead of print.   [Pubmed]

Fig 90 Luke Garratt

The authors aimed to evaluate how neutrophil elastase (NE) activity changes after P. aeruginosa eradication and influences early disease outcomes. They assessed participants in the AREST CF cohort between 2000 and 2018 who had P. aeruginosa cultured from their routine annual bronchoalveolar lavage (BAL) fluid and who underwent eradication treatment and a post eradication BAL. Factors associated with persistent P. aeruginosa infection, persistent neutrophilic inflammation following eradication and worse structural lung disease one-year post-eradication were evaluated.
Results: Eighty-eight episodes (3 months to 6 years old) of P. aeruginosa infection were studied. Eradication was successful in 84.1% of episodes. Median activity of NE was significantly reduced post-eradication from 9.15 to 3.4 nM (p = 0.008) but persisted in 33 subjects. High post-eradication NE levels were associated with an increased risk for P. aeruginosa infection in the next annual visit (odds ratio=1.7, 95% confidence interval 1.1-2.7, p = 0.014). Post-eradication NE levels (difference, 0.8; 95% confidence interval, 0.1-1.5) and baseline bronchiectasis computed tomography (CT) score (difference, 0.4; 95% confidence interval, 0.1-0.8) were the best predictors of bronchiectasis progression within 1 year (backward stepwise linear regression model, R2= 0.608, P<0.001), independent of eradication.
Conclusion: In children with CF, NE activity may persist following successful P. aeruginosa eradication and is significantly associated with bronchiectasis progression. Evaluating strategies to diminish neutrophilic inflammation is essential for improving long-term outcomes.

Dr Luke W Garratt (Fig 90)is an airway cell biologist and biomedical scientist at the Wal-yan Respiratory Research Centre, Telethon Kids Institute, University of Western Australia, Nedlands, Australia.

Emrah GeciliSiva SivaganesanOzgur AsarJohn P ClancyAssem ZiadyRhonda D Szczesniak.  Bayesian regularization for a nonstationary Gaussian linear mixed effects model Stat Med 2022 Feb 20;41(4):681-697.doi: 10.1002/sim.9279. Epub 2021 Dec 12. [Pubmed]

Fig 90 Emrah Gecili LinkedIn

In omics experiments, estimation and variable selection can involve thousands of proteins/genes observed from a relatively small number of subjects. Many regression regularization procedures have been developed for estimation and variable selection in such high-dimensional problems. However, approaches have predominantly focused on linear regression models that ignore correlation arising from long sequences of repeated measurements on the outcome. Our work is motivated by the need to identify proteomic biomarkers that improve the prediction of rapid lung-function decline for individuals with cystic fibrosis (CF) lung disease. We extend four Bayesian penalized regression approaches for a Gaussian linear mixed effects model with nonstationary covariance structure to account for the complicated structure of longitudinal lung function data while simultaneously estimating unknown parameters and selecting important protein isoforms to improve predictive performance. Different types of shrinkage priors are evaluated to induce variable selection in a fully Bayesian framework. The approaches are studied with simulations. We apply the proposed method to real proteomics and lung-function outcome data from our motivating CF study, identifying a set of relevant clinical/demographic predictors and a proteomic biomarker for rapid decline of lung function. We also illustrate the methods on CD4 yeast cell-cycle genomic data, confirming that the proposed method identifies transcription factors that have been highlighted in the literature for their importance as cell cycle transcription factors.

Dr Emrah Gecili (fig. 90) is post-doctoral research fellow at Cincinnati Children's Hospital Medical Center and Cystic Fibrosis Foundation Fellow.

Panagiotis GiannakourasMenelaos KanakisFilia DiamanteaMaria TzetisChrysanthi KoutsandreaDimitrios PapaconstantinouIlias Georgalas.   Ophthalmologic manifestations of adult patients with cystic fibrosisEur J Ophthalmol 2021 Apr 8;11206721211008780. doi: 10.1177/11206721211008780.Online ahead of print. pubmed.ncbi.nlm.nih.gov/33832348/
Introduction: Cystic fibrosis (CF) is the most common life-shortening recessive genetic disease in Caucasians, affecting primarily the lungs. The objective of our study was to investigate potential ophthalmologic involvement in adult patients with CF.
Methods: Fifty adult patients with cystic fibrosis and 60 age- and sex-matched controls underwent complete ophthalmologic examination including tear-film Break-Up Time (BUT), Macular Thickness, and peripapillary Retinal Nerve Fiber Layer (pRNFL) thickness measurements using Spectral Domain-OCT.
Results: CF patients had significantly lower nasal-inferior pRNFL thickness (median 82 IQR 67-102 vs 92.5 IQR 82-107, p = 0.005) and lower percentage of normal tear Break-Up Time (56.0% vs 96.7%, p = 0.001) than healthy controls. All CF patients with BUT <10 s were diagnosed with blepharitis at the time of our assessement. The subgroup of patients homozygous for the most common CF mutation, F508del, had lower nasal-inferior pRNFL thickness (p = 0.014) and lower percentage of normal tear Break-Up Time (p = 0.001) compared to the control group. Additional findings, present in the CF group only, were punctuate retinal hemorrhages (four patients), vessel tortuosity (four patients), snail-track degeneration, and retinal tufts (two patients without refractive error). There were no significant differences in visual acuity, refractive errors, gonioscopic findings, or intraocular pressure between the groups.
Conclusions: Our study is, to the best of our knowledge, the largest ophthalmologic study of patients with cystic fibrosis. We found that CF patients had significantly decreased inferior-quadrant peripapillary retinal nerve fiber layer thickness and decreased tear-film break-up time compared to controls. We highlight the importance of careful regular ophthalmologic assessment and follow-up of these patients.

Panagiotis Giannakouras  is in the First Department of Ophthalmology, G. Gennimatas General Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Daniella GinsburgChoo Phei WeeMaria Carmen ReyesJohn J BrewingtonDanieli B Salinas. When CFSPID becomes CF.  J Cyst Fibros 2021 Oct 28;S1569-1993(21)01296-0.doi: 10.1016/j.jcf.2021.06.012.Online ahead of print.  [Pubmed]

Fig.91 Daniella Ginsburg UCLA Health

There has been a growing number of infants identified as CRMS/CFSPID in countries applying genetic testing as part of cystic fibrosis (CF) newborn screening. Currently there are neither standardized protocols for follow up beyond infancy, nor established predictors to stratify this population as high or low risk of reclassification to CF or CFTR-related disorder.
We report a series of 10 children who reclassified, including eight carrying CFTR variants of varying clinical consequence and seven with initial sweat chloride measurements <30 mmol/L. The overall increase in sweat chloride concentration was 5.8 mmol/L/year. Pseudomonas aeruginosa was isolated from respiratory cultures in five subjects, and reclassification was aided by human nasal epithelial cultures in two cases.
In this centre’s experience, 6% of all CRMS/CFSPID referrals reclassified to CF over a 12-year period. The rate of sweat chloride increase, genotype, and CFTR functional assay can potentially be used as prognostic tools in the CRMS/CFSPID population.

Dr Daniella K Ginsburg (fig.91)  is paediatric Pulmonogist at the Department of Pediatrics, Division of Pediatric Pulmonology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California.

Karl A GlenIain L Lamont.  β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects. Pathogens. 2021 Dec 18;10(12):1638   doi: 10.3390/pathogens10121638. Free PMC article    [Pubmed]

Fig. 92 Iain Lamont University of Otago 

Pseudomonas aeruginosa is a major opportunistic pathogen, causing a wide range of acute and chronic infections. β-lactam antibiotics including penicillins, carbapenems, monobactams, and cephalosporins play a key role in the treatment of P. aeruginosa infections. However, a significant number of isolates of these bacteria are resistant to β-lactams, complicating treatment of infections and leading to worse outcomes for patients.
In this review, we summarize studies demonstrating the health and economic impacts associated with β-lactam-resistant P. aeruginosa. We then describe     how β-lactams bind to and inhibit P. aeruginosa penicillin-binding proteins that are required for synthesis and remodelling of peptidoglycan. Resistance to β rotein 3, that is essential for cell division; reduced uptake or increased efflux of β-lactams; degradation of β-lactam antibiotics by increased expression or altered substrate specificity of an AmpC β-lactamase, or by the acquisition of β-lactamases through horizontal gene transfer; and changes to biofilm formation and metabolism.
The current understanding of these mechanisms is discussed. Lastly, important knowledge gaps are identified, and possible strategies for enhancing the effectiveness of β-lactam antibiotics in treating P. aeruginosa infections are considered.

Iain Lamont (fig.92) is Professor in the Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.

 Sophie GohyAlexandra MoeremansCharles PiletteAmandine Collin.   Immunoglobulin A Mucosal Immunity and Altered Respiratory Epithelium in Cystic FibrosisCells 2021 Dec 20;10(12):3603.doi: 10.3390/cells10123603  Free PMC article [Pubmed]

Fig. 93 Sophie Gohy
Le Soir

The respiratory epithelium represents the first chemical, immune, and physical barrier against inhaled noxious materials, particularly pathogens in cystic fibrosis. Local mucus thickening, altered mucociliary clearance, and reduced pH due to CFTR protein dysfunction favour bacterial overgrowth and excessive inflammation. We aimed in this review to summarize respiratory mucosal alterations within the epithelium and current knowledge on local immunity linked to immunoglobulin A in patients with cystic fibrosis.

There are detailed colour figures in the free PMC article

Dr Sophie Gohy (Fig. 93)  is with the Department of Pneumology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 2, 1200 Brussels, Belgium;Pole of Pneumology, ENT and Dermatology, Institute of Experimental & Clinical Research, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium; Cystic Fibrosis Reference Center, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium.

Rebecca H GoldbergNatalie H MatthewsAlexandra C HristovFrank Wang Urticaria multiforme-like eruption due to a novel agent elexacaftor/tezacaftor/ivacaftor in a pediatric patient with cystic fibrosisJAAD Case Rep. 2021 Oct 25;18:71-73.doi: 10.1016/j.jdcr.2021.10.018.eCollection 2021 Dec.Free article pubmed.ncbi.nlm.nih.gov/34841028/
Enter free article via this pubmed link - contains excellent illustrations.

Fig. 94 Rebecca Goldberg

Rebecca H Goldberg (fig 94) is at the University of Michigan Medical School, Ann Arbor, Michigan.

Tanja GonskaKatherine KeenanJacky AuAnnie DupuisMark A ChilversCaroline Burgess et al. Outcomes of Cystic Fibrosis Screening-Positive Infants With Inconclusive Diagnosis at School Age. Pediatrics 2021 Nov 16;e2021051740.doi: 10.1542/peds.2021-051740. Online ahead of print.   [Pubmed]

Fig. 95 Tanja Gonska

Background and objectives: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children.
Methods: Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive-screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes.
Results: The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls.
Conclusions: Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

Tanja Gonska (fig. 95) is Associate Professor Endocrine, Gastroenterology in the Divisions of Gastroenterology, Hepatology and Translational Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

Emily GrangerGwyneth DaviesRuth H Keogh. Treatment patterns in people with cystic fibrosis: have they changed since the introduction of ivacaftor?    J Cyst Fibros. 2021 Sep 5;S1569-1993(21)01355-2.doi: 10.1016/j.jcf.2021.08.014.Online ahead of print.   34497037    [Pubmed]

Fig.96 Emily Granger

Background: In late 2012, ivacaftor became available in the UK for people with cystic fibrosis (CF) aged 6 years and over with a G551D mutation. Long-term changes in treatment patterns have not previously been reported. We investigated long-term treatment patterns in people with CF with a G551D mutation who took ivacaftor and compared these with non-ivacaftor-treated cohorts using the UK Cystic Fibrosis Registry.
Methods: Using 2007-2018 data we compared treatment patterns between four cohorts: 1: ivacaftor-treated; 2: ivacaftor era (2013-2018), ineligible genotype (no G551D mutation); 3: pre-ivacaftor era (2007-2012), eligible genotype (G551D mutation); 4: pre-ivacaftor era, ineligible genotype. Treatments included: inhaled antibiotics, dornase alfa, hypertonic saline, chronic oral antibiotics and supplementary feeding.
Results: Up to 2012 the percentages of people taking each treatment were similar between the two cohorts defined by genotype and tended to increase by year with a similar slope. Once ivacaftor was introduced, the use of other treatments tended to decrease or remain stable by year for the ivacaftor-treated cohort, whereas it remained stable or increased in the non-ivacaftor-treated cohort. This led to differences in treatment use between the two cohorts in the ivacaftor-era, which became more marked over time.

Conclusions: We have shown a clear divergence in treatment patterns since the introduction of ivacaftor in a number of key treatments widely used in CF. Further research is needed to investigate whether the differences in treatment patterns are associated with changes in health outcomes.

Dr Emily Granger (fig.96) is a research fellow in the Department of Medical Statistics, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St, Bloomsbury, London.

Christopher H GossIsabelle FajacRaksha Jain 3Wolfgang Seibold Abhya Gupta Ming-Chi Hsu Sivagurunathan SutharsanJane C Davies Marcus A Mall. Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE-CF™ 1 - a randomised, Phase II study   [Pubmed]

Fig. 97 Christopher H Goss       iths.org

Background: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans.
Objective: We present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF.
Results: Initially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of -0.8% (95%CI -6.6, 4.9) in ppFEV1 and +2.1 units (95%CI -2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers.
Conclusion: BI 1265162 was safe but did not demonstrate a potential for clinical benefit. Development has been terminated.

Dr Christopher H Goss (Fig.97) is Professor at Department of Medicine, Department of Pediatrics, University of Washington; Seattle Children's Hospital & Research Institute, Seattle, WA, USA

Christopher H Goss Sonya L HeltsheNatalie E WestMichelle SkallandDon B SandersRaksha JainTara L BartoBarbra FogartyBruce C MarshallDonald R VanDevanterPatrick A Flume,  STOP2 Investigators  A Randomized Trial of Antimicrobial Duration for Cystic Fibrosis Pulmonary Exacerbation Treatment.  Am J Respir Crit Care Med 2021 Sep 1.doi: 10.1164/rccm.202102-0461OC.Online ahead of print. [Pubmed]
 People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration.
Methods: STOP2 was a multi-center, randomized, controlled, clinical trial in exacerbation among adults with CF. After 7-10-days of treatment, participants exhibiting pre-defined lung function and symptom improvements were randomized to 10- or 14-days total antimicrobial duration; all others were randomized to 14- or 21-days.
Measurements: The primary outcome was percent predicted forced expiratory volume in 1 second (ppFEV1) change from treatment initiation to two weeks after cessation. Among early responders non-inferiority of 10-days to 14-days was tested; superiority of 21-days compared to 14-days was compared for the others. Symptoms, weight, and adverse events were secondary.
Results: Among 982 randomized, 277 met improvement criteria and were randomized to 10- or 14-days treatment; the remaining 705 received 21- or 14-days. Mean ppFEV1 change was 12.8 and 13.4 for 10- and 14-days, respectively, a ‒0.65 difference [95%CI ‒3.3, 2.0], excluding the pre-defined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV1 changes, a difference of ‒0.10 [‒1.3, 1.1]. Secondary endpoints and sensitivity analyses were supportive.

Conclusions: Among CF adults with early treatment improvement during exacerbation, ppFEV1 after 10-days of intravenous antimicrobials is not inferior to 14-days. For those with less improvement after one week, 21-days is not superior to 14-days. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02781610.

Dr Christopher H Goss (fig.97 above) is at University of Washington, 7284, Medicine and Pedaitrics, Seattle, Washington, and Seattle Children's Research Institute, 145793, CF Therapeutics Development Network Coordinating Center, Seattle, Washington, United States.

--- This is an interesting study but I suspect many experienced clinicians will use their own judgement taking into account the many factors relating to the particular patient.

Michelle J GouldHaley SmithJonathan H RaymentHelen MachidaTanja GonskaGary J Galante. CFTR modulators increase risk of acute pancreatitis in pancreatic insufficient patients with cystic fibrosis.  J Cyst Fibros 2021 Oct 31;S1569-1993(21)01415-6.doi: 10.1016/j.jcf.2021.09.010.Online ahead of print.    [Pubmed]

Fig. 98 Michelle Gould  X.com

Patients with pancreatic insufficient cystic fibrosis rarely develop acute pancreatitis due to insufficient acinar reserve. We describe a series of five patients under the age of 18 (range 8-16 years) with pancreatic insufficient cystic fibrosis who developed a phenotype in keeping with acute pancreatitis following initiation of CFTR modulator therapy. This occurred at a median of 30 months following CFTR modulator initiation. 3/5 of these patients also developed pancreatic sufficiency or at least an intermediary pancreas status, indicated by fecal elastases above 100 μg/g. This series highlights a mostly unrecognized potential side effect of this therapy as well as the potential of CFTR modulator therapies to improve exocrine pancreatic function, even in adolescent patients.

Michelle J Gould (Fig.98) is in the Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.

Emily GrangerGwyneth DaviesRuth H Keogh. Treatment patterns in people with cystic fibrosis: have they changed since the introduction of ivacaftor?    J Cyst Fibros. 2021 Sep 5;S1569-1993(21)01355-2.doi: 10.1016/j.jcf.2021.08.014.Online ahead of print. [Pubmed]

  Fig.99 Emily Granger

Background: In late 2012, ivacaftor became available in the UK for people with cystic fibrosis (CF) aged 6 years and over with a G551D mutation. Long-term changes in treatment patterns have not previously been reported. We investigated long-term treatment patterns in people with CF with a G551D mutation who took ivacaftor and compared these with non-   ivacaftor-treated cohorts using the UK Cystic Fibrosis Registry.

Methods: Using 2007-2018 data we compared treatment patterns between four cohorts: 1: ivacaftor-treated; 2: ivacaftor era (2013-2018), ineligible genotype (no G551D mutation); 3: pre-ivacaftor era (2007-2012), eligible genotype (G551D mutation); 4: pre-ivacaftor era, ineligible genotype. Treatments included: inhaled antibiotics, dornase alfa, hypertonic saline, chronic oral antibiotics and supplementary feeding.
Results: Up to 2012 the percentages of people taking each treatment were similar between the two cohorts defined by genotype and tended to increase by year with a similar slope. Once ivacaftor was introduced, the use of other treatments tended to decrease or remain stable by year for the ivacaftor-treated cohort, whereas it remained stable or increased in the non-ivacaftor-treated cohort. This led to differences in treatment use between the two cohorts in the ivacaftor-era, which became more marked over time.

Conclusions: We have shown a clear divergence in treatment patterns since the introduction of ivacaftor in a number of key treatments widely used in CF. Further research is needed to investigate whether the differences in treatment patterns are associated with changes in health outcomes.

Dr Emily Granger (fig.99) is a research fellow in the Department of Medical Statistics, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St, Bloomsbury, London.

Morgan GreenNatalie R LindgrenAlexander G Henderson Johnathan D Keith Ashley M Oden Susan E Birket.  Ivacaftor partially corrects airway inflammation in a humanized G551D rat. Am J Physiol Lung Cell Mol Physiol. 2021 Apr 7.doi: 10.1152/ajplung.00082.2021.Online ahead of print. [Pubmed]

Fig. 100 Morgan Green

Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when CFTR activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus.
Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.

Dr Morgan Green (fig. 100) is in the Department of Medicine, University of Alabama at Birmingham, United States

Simon Y GraeberConstanze VitzthumMarcus A MallPotential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic FibrosisJ Pers Med. 2021 May 8;11(5):384.doi: 10.3390/jpm11050384.[Pubmed]Free PMC article

Fig.101 Simon Graeber ResearchGate

Refinement of personalized treatment of cystic fibrosis (CF) with emerging medicines targeting the CF basic defect will likely benefit from biomarkers sensitive to detect improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function in individual patients. Intestinal current measurement (ICM) is a technique that enables quantitative assessment of CFTR chloride channel function in rectal tissues or other intestinal epithelia. ICM was originally developed to study the CF ion transport defect in the intestine and has been established as a sensitive biomarker of CFTR function and diagnostic test for CF. With the emergence of CFTR-directed therapeutics, ICM has become an important tool to estimate the level of rescue of CFTR function achieved by approved CFTR modulators, both at the level of CFTR genotype groups, as well as individual patients with CF. In combination with preclinical patient-derived cell culture models, ICM may aid the development of targeted therapies for patients with rare CFTR mutations. Here, we review the principles of ICM and examine how this CFTR biomarker may be used to support diagnostic testing and enhance personalized medicine for individual patients with common as well as rare CFTR mutations in the new era of medicines targeting the underlying cause of CF.

Dr Simon Y Graeber (fig101)  is at the Charité-Universitätsmedizin Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, 13353 Berlin, Germany.

Anthony R GreggMahmoud AarabiSusan KlugmanNatalia T LeachMichael T BashfordTamar GoldwaserEmily ChenTeresa N SparksHoney V ReddiAleksandar RajkovicJeffrey S DunganACMG Professional Practice and Guidelines Committee.Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)Genet Med 2021 Jul 20.doi: 10.1038/s41436-021-01203-z. Online ahead of print. [Pubmed]

Fig 102 Anthony R Gregg
Inside Precision Medicine

Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay-Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase "expanded carrier screening" is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency.
This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.

Dr Anthony R Gregg (Fig 102) s at the Department of Obstetrics and Gynecology, Prisma Health, Columbia, SC, USA.

Claudia GrehnA-M DittrichJ WosniokF HolzS HafkemeyerL NaehrlichC SchwarzRegistry working group of the German CF Registry. Risk factors for cystic fibrosis arthropathy: Data from the German cystic fibrosis registry. J Cyst Fibros 2021 May 22;S1569-1993(21)00130-2.doi: 10.1016/j.jcf.2021.05.003.Online ahead of print. [Pubmed]

 Fig. 103 Claudia Grehn ResearchGate

Background: Epidemiology and potential risk factors for cystic fibrosis arthropathy (CFA) were studied in a relevant cystic fibrosis (CF) patient cohort.
Methods: Cohort study of patients included in the German CF registry in 2016-2017. Descriptive analysis, exploratory tests and multivariable logistic regression were used to assess prevalence of CFA and associated potential risk factors for adult patients with/without chronic Pseudomonas aeruginosa infection.
Results: 6069 CF patients aged from 0 to 78 years were analysed. CFA was observed in 4.9% of the patients. Prevalence was significantly higher in adult patients (8.4%) compared to patients <18 years (0.7%; p<0.0001). Logistic regression analyses in adult patients (n=3319) showed that CFA was significantly associated with increasing age (OR=1.04; 95% CI: 1.02-1.05; p<0.0001), female gender (OR=2.10; 95%CI:1.52-2.90; p<0.0001), number of hospitalizations (OR=1.24; 95%CI:1.12-1.36; p<0.0001), chronic P. aeruginosa infection (OR=1.83; 95%CI:1.28-2.61; p=0.0009), CF-related diabetes (OR=1.69; 95%CI:1.23-2.33; p=0.0013), pancreatic insufficiency (OR=2.39; 95%CI:1.28-4.46; p=0.0060) and sinusitis/polyps (OR=1.91; 95%CI:1.39-2.62; p<0.0001). In a subgroup analysis of adults without chronic P. aeruginosa infection (n=1550) CFA was also significantly associated with increasing age, female gender, increasing number of hospitalizations, pancreatic insufficiency as well as sinusitis/polyps; antimycotic treatment associated only in this subgroup while association with CF-related diabetes was not significant.

Conclusion: CFA is a frequent and clinically relevant co-morbidity particularly in adult CF patients. CFA is significantly more common in patients with chronic P. aeruginosa colonization but associations with other indicators for a more severe disease course were identified regardless of P. aeruginosa colonization status.

Dr Claudia Grehn (fig.103) is in the Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin, Berlin, Germany. Electronic address: claudia.grehn@charite.de.

G GrimaltM CarbonellR Grimalt. Aquagenic wrinkling of the palms and cystic fibrosis diagnosisJ Eur Acad Dermatol Venereol 2021 Aug;35(8):1608.doi: 10.1111/jdv.17445. [Pubmed]

Fig 104 Ramon Grimalt  ResearchGate

Aquagenic wrinkling of the palms (AWP) is an exaggerated and early wrinkling occurring after brief immersion to water, AWP is also called aquagenic palmoplantar keratoderma, transient reactive papulo translucent acrokeratoderma, aquagenic syringeal keratoderma or transient aquagenic hyperwrinkling. It is a transitory condition which occurs 2–3 min after exposure to water and patients in addition to hyper wrinkling might also show white papules, oedema, and feel a tingling sensation and even pain as the water exposure time increases. Its association with cystic fibrosis (CF) is well-known and it is a common practice to run out tests for CF in patients complaining of AWP.

The pathophysiology of AWP is not clear, although a few theories have been proposed, indicating the increased tonicity of the sweat of people with CF and the upregulation of aquaporins in the keratinocytes of CF patients as the main causes for it.   The article published by Alexopoulos et al.6 in this issue of the J Eur Acad Dermatol Venereol 2021; 35: 1717-1724 has turned the idea back sides and they propose to use the brief immersion to water (BIW) test as a screening tool for CF.

The article clearly demonstrated that in the occasions of dealing with patients with the clinical suspicion of CF one fast and easy test to perform is the BIW test.  In the study by Alexopoulos, they showed for the first time that the use of BIW test as a screening method in a large cohort of children with CF can be a valuable, fast and unexpensive tool.   The conclusions from the paper are clear: There is a strong association between AWP and CF. AWP after BIW could be easily used as a screening tool to assess if an individual with symptoms and signs that raise the likelihood of CF is a CF patient.
Brief immersion to water could be implemented in resource-limited scenarios, as a quick and easy, low-cost, risk-free test for initial screening that could guide further clinical decisions for confirmatory tests like sweat test and/or molecular DNA analysis

Dr G Grimalt (fig.104),  presumably the senior author, is Associate Professor of Dermatology at the Facultat de Medicina i Ciències de la Salut, Universitat Internacional de Catalunya, Barcelona, Spain.

Jing GuoRong HeZhi-Qin Mao. Case Report: White Colored Stool: An Early Sign of Cystic Fibrosis in Infants. Front Pediatr 2021 Apr 14;9:656584. doi: 10.3389/fped.2021.656584.eCollection 2021.Free PMC article [Pubmed]
A 2-month-old male infant presented with white colored stools 1 month after birth. There was no jaundice of the skin, mucous membrane, or sclera; his liver was enlarged (4 cm below the ribs), and his liver function tests showed slightly elevated total bilirubin (TB), direct bilirubin (DB), and total bile acid (TBA). An abdominal doppler ultrasound showed no signs of biliary atresia. Genetic testing revealed a CFTR hemizygous mutation site (c.223C>T) in exon 3 and exon 2-3 heterozygous deletion mutation. The infant's stool turned yellow after oral administration of pancreatic tablets. Finally, the infant was diagnosed with cystic fibrosis (CF).

Review of literature revealed five children (including the infant in this case study) with CF who presented with white stool. All five children had anaemia, four had oedema and hypoproteinemia, five had changes in stool colour (it was pistachio-green colour in two patients, pale coloured in one, acholic stool in one, and white stool in one), two had cholestasis, one infant had delayed meconium discharge, and three children had delayed growth and hepatomegaly. Two children had an abnormal sweat test, one had a F508del compound heterozygous mutation, and one had three mutation sites (C.214G>G/A, P.A72T; C.650A>A/G, P.E217G, and C.3406G>G/A, P. A1136T), which was a compound heterozygous mutation.

So, CF could be included in the differential diagnosis of infants with white stool. Genetic testing could confirm an early diagnosis of CF. Pancreatic replacement therapy has been shown to be beneficial for improving the digestive function.

Jing Guo is in the Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

 Katharina HablerAnne-Sophie KallaMichael RychlikMathias BruegelDaniel TeupserSusanne NährigMichael VogeserMichael Paal.  Isotope dilution LC-MS/MS quantification of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their major metabolites in human serumClin Chem Lab Med 2021 Oct 19.doi: 10.1515/cclm-2021-0724. Online ahead of print pubmed.ncbi.nlm.nih.gov/34668357/

Fig. 105 Katharina Habler  MSACL 2023

Objectives: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have revolutionized the therapeutic landscape in CF treatment. These vital drugs are extensively metabolized via CYP3A, so caution must be exercised in multimodal CF therapy because of the risk of adverse drug interactions. Our goal was to develop a highly sensitive assay for the purpose of therapeutic drug monitoring (TDM) in diagnostic laboratories
Methods: After protein precipitation, the CFTR modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their metabolites ivacaftor-M1, ivacaftor-M6, and tezacaftor-M1 were separated with a two-dimensional chromatography setup within 5 min, and quantified with stable isotope-labeled internal standards. The method was validated according to the European Medicines Agency (EMA) guideline on bioanalytical method validation and applied to CF patient samples.
Results: Inaccuracy was ≤7.0% and the imprecision coefficient of variation (CV) was ≤8.3% for all quality controls (QCs). The method consistently compensated for matrix effects, recovery, and process efficiency were 105-115 and 96.5-103%, respectively. Analysis of CF serum samples provided concentrations comparable to the pharmacokinetic profile data reported in the EMA assessment report for the triple combination therapy Kaftrio.

Conclusions: We hereby present a robust and highly selective isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) assay for the simultaneous quantification of the so far approved CFTR modulators and their metabolites in human serum. The assay is suitable for state-of-the-art pharmacovigilance of CFTR modulator therapy in CF patients, in order to maximize safety and efficacy, and also to establish dose-response relationships in clinical trials.

Katharina Habler (Fig 105) is a food chemist at the Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany.

Yousaf B HadiDhairya A Lakhani Syeda F NaqviNida Ul FatimaArif R Sarwari.     Outcomes of SARS-CoV-2 infection in patients with cystic fibrosis: A multicenter retrospective research network study. Respir Med 2021 Sep 8;188:106606.doi: 10.1016/j.rmed.2021.106606. Online ahead of print. Free PMC article [Pubmed]

 Fig.106 Yousaf Hadi West Virginia University Health Sciences Directory

Background: In this study, we report clinical outcomes in COVID-19 infection in a large cohort of people with cystic fibrosis (pwCF) and compare these outcomes to a propensity score matched cohort of people without CF.
Methods: Analysis of a multicenter research network TriNETX was performed including patients more than 16 years of age diagnosed with COVID-19. Outcomes in COVID-19 positive pwCF were compared with a propensity-matched cohort of people without CF.
Results: A total of 507,810 patients with COVID-19 were included (422 patients, 0.08% with CF; 507,388 patients, 99.92% without CF. Mean age at COVID-19 diagnosis in CF cohort was 46.6 ± 19.3 years, with female predominance (n = 225, 53.32%). Majority of the participants were Caucasian (n = 309, 73.22%). In the crude, unmatched analysis, mortality, hospitalization, critical care need, mechanical ventilation, acute kidney injury and composite (combination of intubation and mortality) outcome at 30 days was higher in the pwCF. Following robust propensity matching, pwCF had higher hospitalization rate (RR 1.56, 95% CI 1.20-2.04), critical care need (RR 1.78, 95% CI 1.13-2.79), and acute renal injury (RR 1.60, 95% CI 1.07-2.39) as compared to patients without CF.

Conclusion: People with CF are at risk of poor outcomes with COVID-19.5.2% of these patients died within one month of COVID-19 diagnosis, and more than one in 10 patients required critical care. Therefore, the relatively young median age of cystic fibrosis patients, and lower prevalence of obesity do not protect these patients from severe disease contrary to prior reports.

Dr Yousaf B Hadi (fig 106)is a gastroenterology fellow in the Department of Internal Medicine, West Virginia University, Morgantown, WV, 26506, USA.

Patrick O HanafinIsabelle Sermet-GaudelusMatthias GrieseMatthias KapplerHelmut EllemunterCarsten SchwarzJohn WilsonMarsha TanTony VelkovGauri G RaoElena K Schneider-Futschik Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis. Front Pharmacol 2021 Aug 2;12:577263.doi: 10.3389/fphar.2021.577263.eCollection 2021. Free PMC article [Pubmed]

Fig. 107 Patrick Hanafin

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited.
Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV).
Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman's rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients.
Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.

Patrick O Hanafin (Fig. 107) is in the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Sana HasanSarah SoltmanColleen WoodScott M Blackman The role of genetic modifiers, inflammation and CFTR in the pathogenesis of Cystic fibrosis related diabetes. J Clin Transl Endocrinol 2021 Dec 10;27:100287.doi: 10.1016/j.jcte.2021.100287.eCollection 2022 Mar [Pubmed]Free PMC article

Fig. 108 Sana Hasan

Cystic fibrosis related diabetes (CFRD) generally reflects insufficient and/or delayed production of insulin, developing slowly over years to decades. Multiple mechanisms have been implicated in the pathogenesis of CFRD. CFTR function itself is a strong determinant of CFRD risk. Variants in CFTR that result in residual CFTR function and exocrine pancreatic sufficiency reduce the risk of CFRD by ten to twenty-fold.
Two groups of hypotheses have been proposed for the mechanism of CFTR impairing insulin secretion in CFRD: (1) β-cell dysfunction results from β cell intrinsic CFTR-dependent mechanisms of insulin secretion. (2) β-cell dysfunction results from factors outside the β cell.
Genome-wide association studies have identified multiple susceptibility genes for type 2 diabetes, including TCF7L2, CDKN2A/B, CDKAL1, and IGF2BP2, as containing genetic modifiers of CFRD. These findings support the presence of intrinsic β cell defects playing a role in CFRD pathogenesis. Oxidative stress and inflammation are β cell-extrinsic mechanisms involved with CFRD. CFTR mutations render β cells more susceptible to oxidative stress and also leads to defects in α-cell function, resulting in reduced suppression of glucagon secretion. Furthermore, CFRD is characterized by β cell loss secondary to intra-islet inflammation. Recent studies have demonstrated the presence of multiple inflammatory mediators within the human CF islet.

This review presents a concise overview of the current understanding of genetic modifiers of CFRD, oxidative stress, islet inflammation, and the controversies about the role of CFTR in the islet.

Dr Sana Hasan (fig.108) is an endocrinologist in the Department of Endocrinology and Metabolism, Cleveland Clinic Foundation, Cleveland, OH, USA.

Aurelie HattonAnne BergougnouxKatarzyna ZybertBenoit ChevalierMyriam MesbahiJean Pierre Altéri Katarzyna Walicka-Serzysko Magdalena Postek Magali Taulan-Cadars Aleksander Edelman Alexandre Hinzpeter Mireille Claustres Emmanuelle Girodon Caroline Raynal Isabelle Sermet-Gaudelus Dorota Sands  Reclassifying innclusive diagnosis after newborn screening for cystic fibrosis. Moving forward.  J Cyst Fibros 2021 Dec 20;S1569-1993(21)02169-X.doi:10.1016/j.jcf.2021.12.010.Online ahead of print   [Pubmed]

Fig. 109 Auriele Hatton LinkedIn

Background: Newborn screening for Cystic Fibrosis (CF) is associated with situations where the diagnosis of CF or CFTR related disorders (CFTR-RD) cannot be clearly ruled out.
Materials/patients and methods: We report a case series of 23 children with unconclusive diagnosis after newborn screening for CF and a mean follow-up of 7.7 years (4-13). Comprehensive investigations including whole CFTR gene sequencing, in vivo intestinal current measurement (ICM), nasal potential difference (NPD), and in vitro functional studies of variants of unknown significance, helped to reclassify the patients.
Results: Extensive genetic testing identified, in trans with a CF causing mutation, variants with varying clinical consequences and 3 variants of unknown significance (VUS). Eighteen deep intronic variants were identified by deep resequencing of the whole CFTR gene in 13 patients and were finally considered as non-pathogenic. All patients had normal CFTR dependent chloride transport in ICM. NPD differentiated 3 different profiles: CF-like tracings qualifying the patients as CF, such as F508del/D1152H patients; normal responses, suggesting an extremely low likelihood of developing a CFTR-RD such as F508del/TG11T5 patients; partial CFTR dysfunction above 20% of the normal, highlighting a remaining risk of developing CFTR-RD such as F508del/F1052V patients. The 3 VUS were reclassified as variant with defective maturation (D537N), defective expression (T582I) or with no clinical consequence (M952T).

Conclusion: This study demonstrates the usefulness of combining genetic and functional investigations to assess the possibility of evolving to CF or CFTR-RD in babies with inconclusive diagnosis at neonatal screening.

Aurelie Hatton  (fig.109)  is at INSERM U1151, Institut Necker Enfants Malades, Université de Paris, 149 rue de Sévres, Paris 75015, France; Université de Paris, Paris, France.

Sophie HerbertNicola Jane RowbothamSherie SmithPatrick WilsonZoe C ElliottPaul A LeightonAlistair Duff Alan Robert Smyth. Exploring the challenges of accessing medication for patients with cystic fibrosis.  Thorax. 2021 Sep 23;thoraxjnl-2021-217140.doi: 10.1136/thoraxjnl-2021-217140.Online ahead of print. [Pubmed]

Fig 110  Sophie Herbert. ResearchGate 

Reducing treatment burden in cystic fibrosis (CF) is the top research priority for patients and clinicians. Difficulty accessing medication is one aspect of treatment burden. We investigated this with an online survey available globally for patients with CF and healthcare professionals. Almost three quarters of patients with CF in our survey report difficulty getting repeat prescriptions on time, and most community pharmacists experience interrupted supplies of CF-specific medications. These barriers affect emotional and physical health of people with CF. Two-thirds of people with CF would like to get all their CF medication from one place, their CF centre.

Dr Sophie Herbert (fig.110)  is with the Evidence Based Child Health Group, University of Nottingham School of Medicine, Nottingham, UK..

Anna Engell HolmHans Henrik Lawaetz SchultzHelle Krogh JohansenTania PresslerThomas Kromann LundMartin IversenMichael PerchBacterial Re-Colonization Occurs Early after Lung Transplantation in Cystic Fibrosis Patients, J Clin Med 2021 Mar 19;10(6):1275.doi: 10.3390/jcm10061275. Free PMC article  [Pubmed]

Fig. 111  Anna Engell Holm

Most cystic fibrosis (CF) patients referred for lung transplantation are chronically infected with Gram-negative opportunistic pathogens. It is well known that chronic infections in CF patients have a significant impact on lung-function decline and survival before transplantation. The rate and timing of re-colonization after transplantation have been described, but the impact on survival after stratification of bacteria is not well elucidated. We did a single-center retrospective analysis of 99 consecutive CF patients who underwent lung transplantation since the beginning of the Copenhagen Lung Transplant program in 1992 until October 2014. Two patients were excluded due to re-transplantation. From the time of CF diagnosis, patients had monthly sputum cultures. After transplantation, CF-patients had bronchoscopy with bronchoalveolar lavage at 2, 4, 6 and 12 weeks and 6, 12, 18 and 24 months after transplantation, as well as sputum samples if relevant. Selected culture results prior to and after transplantation were stored. We focused on colonization with the most frequent bacteria: Pseudomonas aeruginosa (PA), Stenotrophomonas maltophilia(SM), Achromobacter xylosoxidans (AX) and Burkholderia cepacia complex (BCC). Pulsed-field gel electrophoresis (PFGE) was used to identify clonality of bacterial isolates obtained before and after lung transplantation.

Time to re-colonization was defined as the time from transplantation to the first positive culture with the same species. Seventy-three out of 97 (75%) had sufficient culture data for analyses with a median of 7 (1-91) cultures available before and after transplantation.
Median colonization-free survival time was 23 days until the first positive culture after transplantation. After 2 years, 59 patients (81%) were re-colonized, 33 (48.5%) with PA, 7 (10.3%) with SM, 12 (17.6%) with AX, and 7 (10.3%) with BCC. No difference in survival was observed between the patients colonized within the first 2 years and those not colonized. Re-colonization of bacteria in the lower airways occurred at a median of 23 days after transplantation in our cohort. In our patient cohort, survival was not influenced by re-colonization or bacterial species.

Dr Anna Engell Holm (Fig. 111) s in the Department of Cardiology, Section for Lung Transplantation, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.

Jordana E HoppeMark ChilversFelix RatjenJohn J McNamaraCaroline A OwenSimon TianRachel ZahigianAlexandra G CornellSusanna A McColley. Long-term safety of lumacaftor-ivacaftor in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study. Lancet Respir Med 2021 May 6;S2213-2600(21)00069-2.doi: 10.1016/S2213-2600(21)00069-2. Online ahead of print. [Pubmed]

Fig. 112 Jordana Hoppe Children's Hospital Colorado

[Background: A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study.
Methods: In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395.
Findings: This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI.
Interpretation: Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation

Jordana Hoppe (fig.112) is in the Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.

Alex R HorsleyJohn BelcherKatie BayfieldBrooke BiancoSteve CunninghamCatherine FullwoodAndrew JonesAnna ShawcrossJaclyn A SmithAnirban MaitraFrancis J Gilchrist.    Longitudinal assessment of lung clearance index to monitor disease progression in children and adults with cystic fibrosisThorax 2021 Jul 22;thoraxjnl-2021-216928.doi: 10.1136/thoraxjnl-2021-216928.Online ahead of print. [Pubmed]

 Fig. 113   Alex Horsley

Background: Lung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change.   In order to help inform clinical practice, this study aimed to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease.
Methods: Prospective, 3-year, multicentre, observational study of repeated LCI measurement at time of clinical review in patients with CF >5 years, delivered using a rapid wash-in system.
Results: 112 patients completed at least one LCI assessment and 98 (90%) were still under follow-up at study end. The median (IQR) age was 14.7 (8.6-22.2) years and the mean (SD) FEV1 z-score was -1.2 (1.3). Of 81     subjects with normal FEV1 (>-2 z-scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within 6 months, the mean (limits of agreement) change in LCI was 0.9% (-18.8% to 20.7%). A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. The median total test time was under 19 min.
Conclusions: Most patients with CF with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.

Dr Alex Horsley (Fig. 113) is in the Division of Infection, Immunity and Respiratory Medicine, The University of Manchester Faculty of Biology, Medicine and Health, Manchester, UK and Manchester Adult Cystic Fibrosis Centre, Manchester University NHS Foundation Trust, Manchester, UK.

Deanne H Hryciw Courtney A JacksonNirajan ShresthaDavid ParsonsMartin DonnelleyAndrew J McAinch. Role for animal models in understanding essential fatty acid deficiency in cystic fibrosis. Cell Mol Life Sci. 2021 Nov 5.doi: 10.1007/s00018-021-04014-2.Online ahead of print. [Pubmed]

Fig.114  Deanne H Hryciw Loop (Frontiers)

Essential fatty acid deficiency has been observed in most patients with Cystic Fibrosis (CF); however, pancreatic supplementation does not restore the deficiency, suggesting a different pathology independent of the pancreas. At this time, the underlying pathological mechanisms are largely unknown. Essential fatty acids are obtained from the diet and processed by organs including the liver and intestine, two organs significantly impacted by mutations in the cystic fibrosis transmembrane conductance regulator gene (Cftr). There are several CF animal models in a variety of species that have been developed to investigate molecular mechanisms associated with the CF phenotype. Specifically, global and systemic mutations in Cftr which mimic genotypic changes identified in CF patients have been generated in mice, rats, sheep, pigs and ferrets. These mutations produce CFTR proteins with a gating defect, trafficking defect, or an absent or inactive CFTR channel. Essential fatty acids are critical to CFTR function, with a bidirectional relationship between CFTR and essential fatty acids proposed. Currently, there are limited analyses on the essential fatty acid status in most of these animal models. Of interest, in the mouse model, essential fatty acid status is dependent on the genotype and resultant phenotype of the mouse. Future investigations should identify an optimal animal model that has most of the phenotypic changes associated with CF including the essential fatty acid deficiencies, which can be used in the development of therapeutics.

Dr Deanne H Hryciw  (fig.114)  is a Senior Lecturer at the School of Environment and Science, Griffith University, Nathan, QLD, Australia.   Centre for Planetary Health and Food Security, Griffith University, Nathan, QLD, Australia.  Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.

Dominique HubertChristophe MarguetJacques BenichouCynthia DeSouzaCatherine Payen-ChampenoisNils KinnmanKeval ChandaranaAnne MunckIsabelle Fajac BRIO Study Group.  Real-World Long-Term Ivacaftor for Cystic Fibrosis in France: Clinical Effectiveness and Healthcare Resource Utilization. Pulm Ther 2021 Jun 8.doi: 10.1007/s41030-021-00158-5. Online ahead of print. [Pubmed]

 Fig. 116  Isabelle Fajac

 Fig. 115  Dominique Hubert

Introduction: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has demonstrated clinical benefits in phase 3 trials. We report results from a real-world study (BRIO) to assess the effectiveness of ivacaftor in people with cystic fibrosis (pwCF) in France.
Methods: BRIO was an observational study conducted at 35 centers in France. Both pwCF initiating ivacaftor treatment and those already taking ivacaftor were included and prospectively followed for 24 months. The primary objective was to evaluate the effect of ivacaftor on percent predicted forced expiratory volume in 1 s (ppFEV1); secondary objectives were evaluating the effect of ivacaftor on clinical effectiveness, healthcare resource utilization (HCRU), and safety.
Results: A total of 129 pwCF were enrolled; 58.9% were aged < 18 years; 64.3% had a G551D-CFTR allele. Mean age at ivacaftor initiation was 19.1 years (range, 2-64 years); ppFEV1 increased by a least squares mean of 8.49 percentage points in the first 6 months and was sustained through 36 months of ivacaftor use. Growth metrics increased during the first 12 months post-ivacaftor and remained stable. The rate of pulmonary exacerbations (PEx) decreased during the 12 months post-fivacaftor compared with the 12 months pre-ivacaftor; estimated rate ratios (95% CI) were 0.57 (0.43-0.75) for PEx events and 0.25 (0.13-0.48) for PEx requiring hospitalization. No new safety concerns were identified; no deaths occurred.
Conclusions: The results from this real-world study of ivacaftor usage in France were consistent with prior clinical trial outcomes, confirming the clinical effectiveness of ivacaftor, as well as an associated reduction in health care resource utilization.

 Dr Dominique Hubert (fig.115) is at the Respiratory Medicine and National Cystic Fibrosis Reference Center, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Dr Isabelle Fajac (Fig. 116)  is at the Respiratory Medicine and National Cystic Fibrosis Reference Center, Cochin Hospital, Assistance Publique-Hôpitaux de Paris; the Physiology Department, AP-HP Centre-Université de Paris, Hôpital Cochin and the Université de Paris, Paris, France.


Dominic A HughesOlga ArchangelidiMatthew CoatesDarius Armstrong-JamesStuart J ElbornSiobhán B CarrJane C Davies. Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study. J Cyst Fibros 2021 May 3;S1569-1993(21)00117-X.doi: 10.1016/j.jcf.2021.04.007.Online ahead of print. [Pubmed]

Fig. 117  Dominic Hughes   Cystic Fibrosis Trust

Background: Pseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection using the UK CF Registry.Full details on PubMed.

Conclusions: Co-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.

Dr Dominic A Hughes (fig.117) is a researcher at the National Heart & Lung Institute, Imperial College London, UK; Royal Brompton and Harefield Hospitals, London, UK

Aesha JobanputraSugeet JagpalPaula MarulandaMaya RamagopalTeodoro SantiagoSreelatha Naik .  An overview of non-invasive ventilation in cystic fibrosis.  Pediatr Pulmonol 2021 Nov 9.doi: 10.1002/ppul.25753. Online ahead of print. [Pubmed]

Noninvasive ventilation (NIV) use was initially reported in cystic fibrosis (CF) in 1991 as a bridge to lung transplantation, and over the decades, the use of NIV has increased in the CF population. Individuals with CF are prone to various physiologic changes as lung function worsens, and they benefit from NIV for advanced lung disease. As life expectancy in CF has been increasing due to advances such as highly effective modulator therapy, people with CF may also benefit from NIV for other diagnosis beyond advanced lung disease. NIV can improve gas exchange, quality of sleep, exercise tolerance, and augment airway clearance in CF. CF providers can readily become comfortable with this therapeutic modality.In this review, we will summarize the physiologic basis for NIV use in CF, describe indications for initiation, and discuss how to order and monitor patients on NIV. We will discuss aspects unique to people with CF and the use of NIV, as well as suggestions on how to reduce risks such as infection. We hope that this serves as a resource for CF providers, in particular those who do not have dedicated training in sleep medicine as we all continue to care for the CF patient population.

Dr Aesha Jobanputra (fig. 118) is Assistant Professor of Medicine in the Division of Pulmonary, Critical Care and Sleep Medicine, Rutgers the State University of New Jersey, New Brunswick, New Jersey, USA.

Ajay S KasiChoo Phei WeeThomas G KeensDanieli B SalinasAbnormal Lung Clearance Index in Cystic Fibrosis Children with Normal FEV 1 and Single-Breath Nitrogen Washout TestLung 2021 Jan 3.doi: 10.1007/s00408-020-00412-8. Online ahead of print. [Pubmed]

Fig.119 Ajay S Kasi Webmd Doctor

Single- and multiple-breath washout tests (SBW and MBW) measure ventilation inhomogeneity, but the relationship between them is unclear.
Forty-three subjects with cystic fibrosis (CF) and healthy controls (HC) 8-21 years of age were recruited (CF = 30 and HC = 13) and performed nitrogen MBW, vital capacity SBW, spirometry, and plethysmography. Mean phase III slope from SBW (SIII) and lung clearance index (LCI) were significantly different between CF and HC (p = 0.017 and p < 0.0001, respectively). Based on Pearson correlation, SIII and LCI showed strong correlation (ρ = 0.81, p < 0.0001). Both SIII and LCI significantly correlated with spirometry (all p < 0.05). Among CF subjects with normal FEV1 (≥ 80%; n = 17), 76% (n = 13) had normal SIII but abnormal LCI.
We conclude that LCI can be abnormal despite normal SIII and FEV1 in CF children. Although LCI and SIII showed strong correlation, our results suggest that LCI is a better test to detect ventilation inhomogeneity in CF children with normal FEV1.

Dr Ajay S Kasi (fig 119) is in the Division of Pediatric Pulmonology, Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Duncan E KeeganJohn J Brewington. Nasal Epithelial Cell-Based Models for Individualized Study in Cystic FibrosisInt J Mol Sci 2021 Apr 24;22(9):4448.doi: 10.3390/ijms22094448. Free article [Pubmed]
The emergence of highly effective CFTR modulator therapy has led to significant improvements in health care for most patients with cystic fibrosis (CF). For some, however, these therapies remain inaccessible due to the rarity of their individual CFTR variants, or due to a lack of biologic activity of the available therapies for certain variants. One proposed method of addressing this gap is the use of primary human cell-based models, which allow preclinical therapeutic testing and physiologic assessment of relevant tissue at the individual level. Nasal cells represent one such tissue source and have emerged as a powerful model for individual disease study. The ex vivo culture of nasal cells has evolved over time, and modern nasal cell models are beginning to be utilized to predict patient outcomes. This review will discuss both historical and current state-of-the art use of nasal cells for study in CF, with a particular focus on the use of such models to inform personalized patient care.

Dr Duncan Elliott Keegan is a Pulmonary Fellow in the Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center USA.and the Department of Pediatrics, University of Cincinnati College of Medicine.

Dr John Brewington is a pediatric pulmonologist at Cincinnati-Children’s-Hospital-Medical-Center with an interest in CF and other airway disorders.

Anthony M KendleJared T RoeknerElsa C SantillanaLilla E KisMary A Cain.  Cystic Fibrosis Transmembrane Conductance Regulator Modulators During Pregnancy: A Case Series. Cureus 2021 Aug 25;13(8):e17427.doi: 10.7759/cureus.17427.eCollection 2021 Aug.   Free PMC article [Pubmed]

Fig 120  Anthony Michael Kendle
USF Health

We present a series of pregnant patients taking novel CF transmembrane conductance regulator (CFTR) modulators and summarize pertinent clinical considerations. All women conceived within four months after starting elexacaftor-ivacaftor-tezacaftor. Pulmonary function was stable before and during pregnancy. One patient developed transaminitis necessitating discontinuation of the medication mid-trimester.

All patients delivered healthy neonates between 36-38 weeks of gestation with uncomplicated postpartum courses. No birth defects were encountered. Given that newly introduced CFTR modulators may increase fertility among CF patients, contraception counselling, pulmonary function monitoring, liver function monitoring, and multi-disciplinary care are important pillars of management.

Anthony M Kendle (fig 120) is at Department of Obstetrics and Gynaecology, University of South Florida, Tampa, USA.

Ruth H KeoghRebecca CosgriffEleni-Rosalina AndrinopoulouKeith G BrownleeSiobhán B CarrKarla Diaz-OrdazEmily GrangerNicholas P JewellAlex LewinClemence LeyratDaniela K SchlüterMaarten van SmedenRhonda D SzczesniakGary J Connett. Projecting the impact of triple CFTR modulator therapy on intravenous antibiotic requirements in cystic fibrosis using patient registry data combined with treatment effects from randomised trials Thorax 2021 Sep 23;thoraxjnl-2020-216265.doi: 10.1136/thoraxjnl-2020-216265.Online ahead of print.  [Pubmed]

 Fig. 121  Ruth Keogh  PubPub

Background: Cystic fibrosis (CF) is a life-threatening genetic disease, affecting around 10 500 people in the UK. Precision medicines have been developed to treat specific CF-gene mutations. The newest, elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), has been found to be highly effective in randomised controlled trials (RCTs) and became available to a large proportion of UK CF patients in 2020. Understanding the potential health economic impacts of ELEX/TEZ/IVA is vital to planning service provision.
Methods: We combined observational UK CF Registry data with RCT results to project the impact of ELEX/TEZ/IVA on total days of intravenous (IV) antibiotic treatment at a population level. Registry data from 2015 to 2017 were used to develop prediction models for IV days over a 1-year period using several predictors, and to estimate 1-year population total IV days based on standards of care pre-ELEX/TEZ/IVA. We considered two approaches to imposing the impact of ELEX/TEZ/IVA on projected outcomes using effect estimates from RCTs: approach 1 based on effect estimates on FEV1% and approach 2 based on effect estimates on exacerbation rate.
Results: ELEX/TEZ/IVA is expected to result in significant reductions in population-level requirements for IV antibiotics of 16.1% (~17 800 days) using approach 1 and 43.6% (~39 500 days) using approach 2. The two approaches require different assumptions. Increased understanding of the mechanisms through which ELEX/TEZ/IVA acts on these outcomes would enable further refinements to our projections.
Conclusions: This work contributes to increased understanding of the changing healthcare needs of people with CF and illustrates how Registry data can be used in combination with RCT evidence to estimate population-level treatment impacts.

Professor Ruth H Keogh (fig 121) is at the Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK

Swapnil KhareMarisa DesimoneNader KasimChristine L Chan.  Cystic fibrosis-related diabetes: Prevalence, screening, and diagnosis. J Clin Transl Endocrinol 2021 Dec 7;27:100290.doi: 10.1016/j.jcte.2021.100290.eCollection 2022 Mar Free PMC article [Pubmed]

Fig. 122 Swapnil Khare IU Health

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in patients with cystic fibrosis (CF). Prevalence of CFRD increases with age and is greater with severe mutations. Other risk factors associated with CFRD are female sex, pancreatic insufficiency, liver disease, need for gastrostomy tube feedings, history of bronchopulmonary aspergillosis, and poor pulmonary function. CFRD is related to worse clinical outcomes and increased mortality. Early diagnosis and treatment have been shown to improve clinical outcomes. Screening for CFRD is recommended with an annual oral glucose tolerance test (OGTT) starting at age 10 years. Diagnosis of CFRD is made by standard American Diabetes Association (ADA) criteria during baseline health. CFRD can also be diagnosed in individuals with CF during acute illness, while on enteral feeds, and after transplant. In this review we will discuss the epidemiology of CFRD and provide an overview of the advantages and pitfalls of current screening and diagnostic tests for CFRD.

 Dr Swapnil Khare (fig.122)is Assistant Professor of Clinical Medicine in the Division of Endocrinology, Diabetes and Metabolism, Indiana University-Purdue University, Indianapolis, IN, United States.

Elisabeth KieningerCorin WillersKatrin RöthlisbergerSophie YammineOrso PusterlaGrzegorz BaumanEnno StranzingerOliver Bieri Philipp LatzinCarmen Casaulta Effect of Salbutamol on Lung Ventilation in Children with Cystic Fibrosis: Comprehensive Assessment Using Spirometry, Multiple-Breath Washout, and Functional Lung Magnetic Resonance ImagingRespiration 2021 Nov 22;1-10.doi: 10.1159/000519751. Online ahead of print. [Pubmed]

Fig. 123  Elisabeth Kieninge kinderklinik.insel.ch

Background: Inhalation therapy is one of the cornerstones of the daily treatment regimen in patients with cystic fibrosis (CF). Recommendations regarding the addition of bronchodilators, especially salbutamol are conflicting due to the lack of evidence. New diagnostic measures such as multiple-breath washout (MBW) and functional magnetic resonance imaging (MRI) have the potential to reveal new insights into bronchodilator effects in patients with CF.

Objective: The objective of the study was to comprehensively assess the functional response to nebulized inhalation with salbutamol in children with CF.
Methods: Thirty children aged 6-18 years with stable CF performed pulmonary function tests, MBW, and matrix pencil-MRI before and after standardized nebulized inhalation of salbutamol.
Results: Lung clearance index decreased (improved) by -0.24 turnover (95% confidence interval [CI]: -0.53 to 0.06; p = 0.111). Percentage of the lung volume with impaired fractional ventilation and relative perfusion decreased (improved) by -0.79% (CI: -1.99 to 0.42; p = 0.194) and -1.31% (CI: -2.28 to -0.35; p = 0.009), respectively. Forced expiratory volume (FEV1) increased (improved) by 0.41 z-score (CI: 0.24-0.58; p < 0.0001). We could not identify specific clinical factors associated with a more pronounced effect of salbutamol.
Conclusions: There is a positive short-term effect of bronchodilator inhalation on FEV1 in patients with CF, which is independent of ventilation inhomogeneity. Heterogeneous response between patients suggests that for prediction of a therapeutic effect this should be tested by spirometry in every patient individually.

Elisabeth Kieninger (fig.123) is in the Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Namho KimGijung KwakJason Rodriguez Alessandra Livraghi-ButricoXinyuan ZuoValentina SimonEric HanSiddharth Kaup ShenoyNikhil PandeyMarina Mazur, Susan E BirketAnthony KimSteven M RoweRichard BoucherJustin HanesJung Soo Suk Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier. Thorax 2021 Oct 25;thoraxjnl-2020-215185. doi: 10.1136/thoraxjnl-2020-215185.Online ahead of print.[Pubmed]

Fig. 124 Nambo Kim ResearchGate

Introduction: Inhaled gene therapy of muco-obstructive lung diseases requires a strategy to achieve therapeutically relevant gene transfer to airway epithelium covered by particularly dehydrated and condensed mucus gel layer. Here, we introduce a synthetic DNA-loaded mucus-penetrating particle (DNA-MPP) capable of providing safe, widespread and robust transgene expression in in vivo and in vitro models of muco-obstructive lung diseases.
Methods: We investigated the ability of DNA-MPP to mediate reporter and/or therapeutic transgene expression in lung airways of a transgenic mouse model of muco-obstructive lung diseases (ie, Scnn1b-Tg) and in air-liquid interface cultures of primary human bronchial epithelial cells harvested from an individual with cystic fibrosis. A plasmid designed to silence epithelial sodium channel (ENaC) hyperactivity, which causes airway surface dehydration and mucus stasis, was intratracheally administered via DNA-MPP to evaluate therapeutic effects in vivo with or without pretreatment with hypertonic saline, a clinically used mucus-rehydrating agent.
Results: DNA-MPP exhibited marked greater reporter transgene expression compared with a mucus-impermeable formulation in in vivo and in vitro models of muco-obstructive lung diseases. DNA-MPP carrying ENaC-silencing plasmids provided efficient downregulation of ENaC and reduction of mucus burden in the lungs of Scnn1b-Tg mice, and synergistic impacts on both gene transfer efficacy and therapeutic effects were achieved when DNA-MPP was adjuvanted with hypertonic saline.

Discussion: DNA-MPP constitutes one of the rare gene delivery systems providing therapeutically meaningful gene transfer efficacy in highly relevant in vivo and in vitro models of muco-obstructive lung diseases due to its unique ability to efficiently penetrate airway mucus.

Namho Kim (fig 124) is at the Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Medicine, Baltimore, Maryland, USA.and the Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Whiting School of Engineering, Baltimore, Maryland, USA.

Carmen Ribes Koninckx Ester Donat Marc A BenningaIlse J BroekaertFrederic Gottrand, et al.  The Use of Fecal Calprotectin Testing in Paediatric Disorders: A Position Paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee.  J Pediatr Gastroenterol Nutr 2021 Apr 1;72(4):617-640.doi: 10.1097/MPG.0000000000003046. [Pubmed]

Fig. 125  Carmen Ribes Koninckx. eMedEvents

Objectives: The aim of the study was to review the evidence regarding the clinical use and value of fecal calprotectin (FC) measurements in different gastrointestinal disorders in children.
Methods: A literature search was conducted in the PubMed, MEDLINE, EMBASE, and Cochrane databases until October 31, 2019. Subtopics were identified and each assigned to individual authors.
Results: A total of 28 recommendations were voted on using the nominal voting technique. Recommendations are given related to sampling, measurement methods, and results interpretation. The 14 authors anonymously voted on each recommendation using a 9-point scale (1 strongly disagree to 9 fully agree). Consensus was considered achieved if at least 75% of the authors voted 6, 7, 8, or 9.

Conclusions: Consensus was reached for all recommendations. Limitations for the use of FC in clinical practice include variability in extraction methodology, performance of test kits as well as the need to establish local reference ranges because of the influence of individual factors, such as age, diet, microbiota, and drugs. The main utility of FC measurement at present is in the diagnosis and monitoring of inflammatory bowel disease (IBD) as well as to differentiate it from functional gastrointestinal disorders (FAPDs). FC, however, has neither utility in the diagnosis of infantile colic nor to differentiate between functional and organic constipation. A rise in FC concentration, may alert to the risk of developing necrotizing enterocolitis and help identifying gastrointestinal involvement in children with Henoch-Schönlein purpura. FC measurement is of little value in Cow's Milk Protein Allergy, coeliac disease (CD), and cystic fibrosis. FC does neither help to distinguish bacterial from viral acute gastroenteritis (AGE), nor to diagnose Helicobacter Pylori infection, small intestinal bacterial overgrowth (SIBO), acute appendicitis (AA), or intestinal polyps.

Dr Carmen Ribes Koninckx (Fig 125) is head of the Department of Paediatric Gastroenterology, Hepatology and Nutrition, La Fe University Hospital Valencia, Spain.

---  A useful summary of the situations in which estimation of fecal calprotectin may be of use and this appears to be mainly for monitoring of inflammatory bowel disease and differentiating IBD from functional bowel disorders.

Michael W KonstanDavid J PastaDonald R VanDevanterJeffrey S WagenerWayne J MorganScientific Advisory Group and the Investigators and Coordinators of ESCF.  Epidemiologic Study of Cystic Fibrosis: 25 years of observational research. Pediatr Pulmonol 2021 May;56(5):823-836.doi: 10.1002/ppul.25248.Epub 2021 Jan 12. [Pubmed}

Fig. 126  Michael Konstan

The Epidemiologic Study of Cystic Fibrosis (ESCF) was a prospective observational study of over 32,000 people with cystic fibrosis (CF) from 250 clinical care sites in North America from 1994 to 2005. Begun as a pharmacovigilance study in connection with the approval of dornase alfa in 1993, ESCF was open to all people with CF treated at any participating site in the United States or Canada. In addition to obtaining safety and effectiveness data on dornase alfa, ESCF collected encounter-based data to characterize the natural history and management of CF with a special focus on lung disease. During the study, 32,178 patients reported at least one encounter, contributing 869,136 encounters, 622,592 pulmonary function tests, 432,896 cultures, and 118,563 pulmonary exacerbations treated with intravenous antibiotics. Although ESCF data collection concluded in 2005, through a collaboration with the U.S. Cystic Fibrosis Foundation Patient Registry, additional follow-up data through 2017 was available for two-thirds of patients. This allowed for updating of CF genotype and survival information. Fifty-six peer-reviewed publications (cited over 3600 times) resulted from this study. In this manuscript we summarize the published ESCF manuscripts in thematic groups with key study findings and brief comments, and speculate on how ESCF findings will inform future data registries and patient care practice

Dr Michael W Konstan  (Fig. 126) is at the Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA and the UH Rainbow Children’s Hospital, Cleveland , Ohio..

Insa KortenMarc-Alexander OestreichUrs FreyAlexander MoellerAndreas JungRenate SpinasDominik Mueller-SuterDaniel TrachselIsabelle RochatBen SpycherPhilipp LatzinCarmen CasaultaKathryn RamseySCILD, and BILD, study groupRespiratory symptoms do not reflect functional impairment in early CF lung diseaseJ Cyst Fibros    2021 Jun 1;S1569-1993(21)00116-8.doi: 10.1016/j.jcf.2021.04.006.Online ahead of print.  [Pubmed]

Fig. 127 Insa Korten kinderklinik.insel.ch/

Background: Lung disease can develop within the first year of life in infants with cystic fibrosis (CF). However, the frequency and severity of respiratory symptoms in infancy are not known.
Methods: We assessed respiratory symptoms in 50 infants with CF and 50 healthy matched controls from two prospective birth cohort studies. Respiratory symptoms and respiratory rate were documented by standardized weekly interviews throughout the first year. Infants performed multiple breath washout in the first weeks of life.
Results: We analyzed 4552 data points (2217 in CF). Respiratory symptoms (either mild or severe) were not more frequent in infants with CF (OR:1.1;95% CI:[0.76, 1.59]; p=0.6). Higher lung clearance index and higher respiratory rate in infants with CF were not associated with respiratory symptoms.
Conclusions: We found no difference in respiratory symptoms between healthy and CF infants. These data indicate that early CF lung disease may not be captured by clinical presentation alone

Dr Insa Korten (fig 127) is in the Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern Unviersity Hospital, University of Bern, Switzerland.

Sateesh KrishnamurthySoumba TraoreAshley L CooneyChristian M BrommelKatarina KulhankovaPatrick L SinnGregory A NewbyDavid R LiuPaul B McCray. Functional correction of CFTR mutations in human airway epithelial cells using adenine base editorsNucleic Acids Res. 2021 Sep 14;gkab788.doi: 10.1093/nar/gkab788. Online ahead of print.  [Pubmed]

Fig. 128 Sateesh Krishnamurthy,

Mutations in the CFTR gene that lead to premature stop codons or splicing defects cause cystic fibrosis (CF) and are not amenable to treatment by small-molecule modulators. Here, we investigate the use of adenine base editor (ABE) ribonucleoproteins (RNPs) that convert A•T to G•C base pairs as a therapeutic strategy for three CF-causing mutations. Using ABE RNPs, we corrected in human airway epithelial cells premature stop codon mutations (R553X and W1282X) and a splice-site mutation (3849 + 10 kb C > T). Following ABE delivery, DNA sequencing revealed correction of these pathogenic mutations at efficiencies that reached 38-82% with minimal bystander edits or indels. This range of editing was sufficient to attain functional correction of CFTR-dependent anion channel activity in primary epithelial cells from CF patients and in a CF patient-derived cell line.

These results demonstrate the utility of base editor RNPs to repair CFTR mutations that are not currently treatable with approved therapeutics.

Dr Sateesh Krishnamurthy (fig.128) is a research scientist in the McCray Lab and the Department of Pediatrics, University of Iowa, Iowa City, IA, USA.

Jochen G MainzChristin ArnoldKara WittstockUta-Christina HiplerThomas LehmannCarlos ZagoyaFranziska DucksteinHelmut EllemunterJulia Hentschel.   Ivacaftor Reduces Inflammatory Mediators in Upper Airway Lining Fluid From Cystic Fibrosis Patients With a G551D Mutation: Serial Non-Invasive Home-Based Collection of Upper Airway Lining FluidFront Immunol 2021 May 5;12:642180.doi: 10.3389/fimmu.2021.642180. eCollection 2021.   Free PMC article [Pubmed]

 Fig. 129 Jochen Mainz   EVB Gruppe

In cystic fibrosis (CF) therapy, the recent approval of CF-transmembrane conductance regulator (CFTR) channel modulators is considered to be the major breakthrough. However, the current first-line approach based mainly on pulmonary function to measure effects of the novel therapy, tested by forced expiratory volumes in one second (FEV1), provides restricted sensitivity to detect early structural damages. Accordingly, there is a need for new sensitive surrogate parameters. Most interestingly, these should quantify inflammation that precedes a decline of pulmonary function.
We present a novel method assessing inflammatory markers in the upper airways' epithelial lining fluid (ELF) obtained by nasal lavage (NL). In contrast to broncho-alveolar lavage, ELF sampling by NL is an attractive method due to its limited invasiveness which allows repeated analyses, even performed in a home-based setting. In a longitudinal cohort study (ClinicalTrials.gov, Identifier: NCT02311140), we assessed changes of inflammatory mediators in 259 serially obtained nasal lavages taken up to every second day before and during therapy with ivacaftor from ten CF patients carrying a G551D mutation. Patients were trained to sample NL-fluid at home, to immediately freeze and transfer chilled secretions to centers. Neutrophil Elastase, Interleukins IL-1β, IL-6 and IL-8 in NL were quantified. During 8-12 weeks of ivacaftor-treatment, median values of IL-1β and IL-6 significantly declined 2.29-fold (2.97→1.30 pg/mL), and 1.13-fold (6.48→5.72 pg/mL), respectively. In parallel, sweat tests and pulmonary function improved considerably.

This is the first study assessing changes of airway inflammation on a day-to-day basis in CF patients receiving a newly administered CFTR-modulator therapy. It proves a decline of airway inflammation during ivacaftor-therapy.

Dr Jochen G Mainz (fig 129) is Professor at the Cystic Fibrosis Center, Brandenburg Medical School (MHB) University, Klinikum Westbrandenburg, Brandenburg an der Havel,, the CF-Center, Jena University Hospital, Jena and the Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus -Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Cottbus, Brandenburg an der Havel and Potsdam, Germany.

C MartinE BurnetA Ronayette-PreiraP de CarliJ MartinL DelmasB PrieurP-R Burgel.  Patient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung diseaseRespir Med Res. 2021 May 17;80:100829.doi: 10.1016/j.resmer.2021.100829.Online ahead of print.  [Pubmed]

Fig. 130 Clemence Martin

Backgound: Elexacaftor-tezacaftor-ivacaftor partially restores cystic fibrosis transmembrane conductance regulator function, and has been shown to induce significant clinical improvement in patients with at least one Phe508del allele. Yet little data exist on patient perspectives following elexacaftor-tezacaftor-ivacaftor initiation.
Methods: A mixed methods study was conducted using an online 13-item questionnaire (including 9 closed questions and 4 open questions), submitted from July 10th to August 21th2020 to French patients aged 12 years and older with advanced CF who were treated with elexacaftor-tezacaftor-ivacaftor. Their responses were summarized as numbers (%), and free-text items were analysed using a grounded theory approach.
Results: Of 245 patients who started elexacaftor-tezacaftor-ivacaftor in France, 101 (41%) participated. Median [IQR] age was 35 [28-41] years and duration of elexacaftor-tezacaftor-ivacaftor treatment was 4.3 [3.0-5.6] months. Patients generally reported a rapid impact on respiratory symptoms, sleep quality, general well-being and physical self-esteem, and a reduction in overall treatment burden. The majority of patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation before elexacaftor-tezacaftor-ivacaftor, to renewed and unexpected physical strength, leading to greater self-confidence, autonomy and long-term planning, after treatment initiation. A small number of patients expressed concerns, mainly regarding changes in body representation and/or the fear of becoming dependent on the treatment.
Conclusion: After initiation of elexacaftor-tezacaftor-ivacaftor, CF patients with advanced disease reported rapid and positive physical, psychological and social effects, which translated into improved quality of life and the formulation of new life goals.

 Dr Clemence Martin (Fig. 130)  is at the Université de Paris, Institut Cochin, Inserm U1016, Paris, France; Respiratory Medicine and National Reference Cystic Fibrosis Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; ERN-Lung CF network.

Ida MartinelliAlessandro CiavarellaMaria AbbattistaStefano AlibertiValentina De ZanChristian FolliMauro Panigada  Andrea Gori Andrea ArtoniAnna Maria IerardiGianpaolo Carrafiello  Valter MonzaniGiacomo Grasselli  Francesco Blasi Flora PeyvandiIncreasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19. Intern Emerg Med 2021 Jan 3. doi: 10.1007/s11739-020-02585-9. Online ahead of print. [Pubmed]

Fig. 131 Ida Martinelli

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleedi

Ida Martinelli (Fig. 131) is at the A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy

Matthew P Moore Iain L LamontDavid WilliamsSteve PatersonIrena Kukavica-IbruljNicholas P Tucker et al.   Transmission, adaptation and geographical spread of the Pseudomonas aeruginosa Liverpool epidemic strain. Microb Genom 2021 Mar 15.doi: 10.1099/mgen.0.000511. Online ahead of print.[Pubmed] Free article

Fig. 132 Matthew P Moore
Google Scholar

The Liverpool epidemic strain (LES) is an important transmissible clonal lineage of Pseudomonas aeruginosa that chronically infects the lungs of people with cystic fibrosis (CF). Previous studies have focused on the genomics of the LES in a limited number of isolates, mostly from one CF centre in the UK, and from studies highlighting identification of the LES in Canada.
Here we significantly extend the current LES genome database by genome sequencing 91 isolates from multiple CF centres across the UK, and we describe the comparative genomics of this large collection of LES isolates from the UK and Canada. Phylogenetic analysis revealed that the 145 LES genomes analysed formed a distinct clonal lineage when compared with the wider P. aeruginosa population. Notably, the isolates formed two clades (a group of organisms believed to comprise all the evolutionary descendants of a common ancestor) : one associated with isolates from Canada, and the other associated with UK isolates.
Further analysis of the UK LES isolates revealed clustering by clinic geography. Where isolates clustered closely together, the association was often supported by clinical data linking isolates or patients. When compared with the earliest known isolate, LESB58 (from 1988), many UK LES isolates shared common loss-of-function mutations, such as in genes gltR and fleR. Other loss-of-function mutations identified in previous studies as common adaptations during CF chronic lung infections were also identified in multiple LES isolates. Analysis of the LES accessory genome (including genomic islands and prophages) revealed variations in the carriage of large genomic regions, with some evidence for shared genomic island/prophage complement according to clinic location. Our study reveals divergence and adaptation during the spread of the LES, within the UK and between continents.

Dr Matthew Moore  (fig 132)   Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.     Present address: Nuffield Department of Health, University of Oxford, UK.

Zumi MehtaKhalid M KamalRichard MillerJordan R CovveyVincent GiannettiAdherence to cystic fibrosis transmembrane conductance regulator (CFTR) modulators: analysis of a national specialty pharmacy database, J Drug Assess. 2021 Apr 5;10(1):62-67.doi: 10.1080/21556660.2021.1912352. Free PMC article   [Pubmed]                                 

 Fig. 133  Zumi Mehta LinkedIn

Objective: To calculate the medication adherence in patients taking CFTR modulators using a national specialty pharmacy database.
Methods: This retrospective observational cohort study utilized de-identified specialty pharmacy data from September 2017 to August 2018 to assess medication adherence for three CFTR modulators: ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor & ivacaftor. The primary outcome was proportion of days covered (PDC) for each medication, with mean PDC values compared across age groups and insurance characteristics. All analyses were performed using the SAS 9.4 University Edition (SAS Institute, Cary, NC).
Results: A total of 2,548 patients were analyzed, including 1,289 (50.59%) patients on lumacaftor/ivacaftor, 784 (30.77%) on ivacaftor, and 475 (18.64%) on tezacaftor/ivacaftor & ivacaftor. The mean PDC value for all CFTR modulators was above 0.80. Tezacaftor/ivacaftor & ivacaftor had the highest overall PDC of 0.92, while PDC values for both lumacaftor/ivacaftor and ivacaftor were 0.84. Children/adolescents on lumacaftor/ivacaftor (p = 0.0001) and tezacaftor/ivacaftor & ivacaftor (p = 0.001) had significantly higher mean PDC values compared to adults but not for ivacaftor (p = 0.3744). No statistical differences were seen in PDC across insurance characteristics.
Conclusion: To the best of our knowledge, this is the first study to assess the adherence of three CFTR modulators using a large nationwide specialty database. With high acquisition costs of CFTR modulator therapies, there is a need to improve rates of adherence in patients with  CF

Dr Zumi Mehta (Fig.133) is graduate student in the Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA.

Joseph MoryousefJustin KwongTeruko KishibeMichael Ordon. Systematic Review of the Prevalence of Kidney Stones in Cystic Fibrosis. J Endourol 2021 Apr 28. doi: 10.1089/end.2021.0151. Online ahead of print.[Pubmed]

Fig. 134 Joseph Moryousef

A study to investigate the prevalence of urolithiasis in cystic fibrosis (CF) and to summarize the available clinical features within this unique population. [for full details please see PubMed abstract)
The overall prevalence of stone formation in the CF population was 4.6% (137/2,982). The mean age of diagnosis was 25.1 ± 9.6 and ranged from 0.25 - 47. Ultrasound was the most common imaging modality for kidney stone diagnosis. There was no apparent sex difference, with a female to male ratio of 1:1. Surgical intervention was required in 37.8% (34/90) of cases. Stone recurrence was reported in 42.9% (33/77) of stone formers

Joseph Moryousef  (fig. 134) of the Faculty of Medicine, McGill University, Montreal, Canada. University, Montreal, Quebec, Canada

Heather N MustonJames E SlavenChristina TillerCharles ClemThomas W FerkolSarath RanganathanStephanie D DavisClement L Ren.     Hyperinflation is Associated with Increased Respiratory Rate and is a More Sensitive Measure of Cystic Fibrosis Lung Disease During Infancy Compared to Forced Expiratory Measures. Pediatr Pulmonol 2021 Jun 18.doi: 10.1002/ppul.25538. Online ahead of print. [Pubmed]

Fig. 135  Heather Muston Riley Children's health 

Background: The goal of this study was to identify clinical features associated with abnormal infant pulmonary function tests (iPFTs), specifically functional residual capacity (FRC), in infants with cystic fibrosis (CF) diagnosed via newborn screen (NBS). We hypothesized that poor nutritional status in the first 6-12 months would be associated with increased FRC at 12-24 months.
Methods: This study utilized a combination of retrospectively and prospectively collected data from ongoing research studies and iPFTs performed for clinical indications. Demographic and clinical features were obtained from the electronic medical record. Forced expiratory flows and volumes were obtained using the raised volume rapid thoracoabdominal technique (RVRTC) and FRC was measured via plethysmography.
Results: A total of 45 CF NBS infants had iPFTs performed between 12-24 months. Mean forced vital capacity, forced expiratory volume in 0.5 second, and forced expiratory flows were all within normal limits. In contrast, the mean FRC z-score was 2.18 (95%CI=1.48, 2.88) and the mean respiratory rate (RR) z-score was 1.42 (95%CI=0.95, 1.89). There was no significant association between poor nutritional status and abnormal lung function. However, there was a significant association between higher RR and increased FRC, and a RR cut off of 36 breaths/min resulted in 92% sensitivity to detect hyperinflation with 32% specificity.
Conclusions: These results suggest that FRC is a more sensitive measure of early CF lung disease than RVRTC measurements and that RR may be a simple, non-invasive clinical marker to identify CF NBS infants with hyperinflation. This article is protected by copyright. All rights reserved.

Heather N Muston  (Fig 135) is Assistant Professor of Pediatrics in the Division of Pediatric Pulmonology, Allergy and Sleep Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN. 

--- This is an interesting and practically useful article confirming the value of a simple clinical sign, a raised respiratory rate, with functional residual capacity – an early measure of infant lung disease

Thomas LahiriJillian S Sullivan.  Recent advances in the early treatment of cystic fibrosis: Bridging the gap to highly effective modulator therapyPediatr Pulmonol. 2021 Sep 2.doi: 10.1002/ppul.25660. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/34473419/

Fig.136 Thomas Lahiri NACFC

Highly effective modulator therapy (HEMT) for cystic fibrosis (CF) has been touted as one of the greatest advances to date in CF care. As these therapies are now available for many older children and adults with CF, marked improvement of their nutritional status, pulmonary and gastrointestinal symptoms has been observed. However, most infants and younger children are not current candidates for HEMT due to age and/or cystic fibrosis transmembrane conductance regulator (CFTR) mutation. For these young children, it is essential to provide rigorous monitoring and care to avoid potential disease sequelae while awaiting HEMT availability. The following article highlights recent advances in the care of infants and young children with CF with regard to surveillance and treatment of nutritional, pulmonary, and gastrointestinal disorders. Recent clinical trials in this population are also reviewed.

Dr Thomas Lahiri (fig 136) Divisions of Pediatric Pulmonology and Gastroenterology, University of Vermont Children's Hospital, Burlington, Vermont, USA. Professor and  paediatric pulmonologist.

Elinor Langfelder-SchwindKaren S RaraighRichard B ParadCF newborn screening genetic counseling workgroup Genetic counseling access for parents of newborns who screen positive for cystic fibrosis: consensus guidelinesPediatr Pulmonol 2021 Dec 29.doi: 10.1002/ppul.25806. Online ahead of print. [Pubmed

Fig. 137  Elinor Langfelder-Schwind NACFC

Introduction: A risk associated with cystic fibrosis newborn screening (CFNBS) is parental misunderstanding of genetic information generated by the over 6,600 positive screens reported annually in the US. CFNBS algorithms incorporating DNA analysis can generate genetic information that requires clinical interpretation and has significance for the newborn, parents, and other relatives. Engagement between CF care centers and trained genetic counseling providers, such as licensed and/or certified genetic counselors (GCs), is variable and limited in providing information to CFNBS positive (CFNBS+) families.
Methods: Using a modified Delphi process, a workgroup of CFNBS experts developed recommendations for engagement of genetic counseling services in CF care centers where CFNBS+ diagnostic evaluations are performed. Statements were assessed over three rounds of surveys, one face-to-face meeting, and through public feedback.
Results: Seventeen statements achieved >80% consensus (range: 82-100%). The workgroup affirmed prior CFF policy statements recommending genetic counseling for parents of infants with CFNBS+. The remaining statements addressed infrastructure and logistics of genetic counseling services, including defining appropriate training for genetic counseling providers and counseling content, establishing a path to equal access to genetic counseling providers across CF care centers, and setting a standard for client-centered CFNBS genetic counseling that is respectful of diverse patient needs and autonomy.

Conclusions: Implementation of client-centered genetic counseling for CFNBS+ families in CF care centers by providers with expertise in both CF and genetic counseling will require efforts to further define core concepts, enhance education of providers, and develop opportunities for access via telemedicine.

Elinor Langfelder-Schwind (Fig.137) is a genetic counselor at the Cystic Fibrosis Center, Mount Sinai Beth Israel, Department of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, 1st Ave at 16th Street, S403, New York, NY, 10003, USA

Beth L LaubeKathryn A CarsonChristopher M Evans, Melis A Aksit Joseph M CollacoVanessa L RichardsonGail Sharpless, Pamela L ZeitlinGarry R CuttingPeter J Mogayzel. Characterizing mucociliary clearance in young children with cystic fibrosis. Pediatr Res 2021 Mar 22.doi: 10.1038/s41390-021-01453-2. Online ahead of print. [Pubmed]

Fig 137 Beth L Laube LinkedIn

Background: This research characterized mucociliary clearance (MCC) in young children with cystic fibrosis
Methods: Fourteen children (5-7 years old) with CF underwent: two baseline MCC measurements (Visits 1 and 2); one MCC measurement approximately 1 year later (Visit 3); and measurements of lungTwo shirts as well clearance index (LCI), a measure of ventilation inhomogeneity.
Results: Median (range) percent MCC through 60 min (MCC60) was similar on Visits 1 and 2 with 11.0 (0.9-33.7) and 12.8 (2.7-26.8), respectively (p = 0.95), and reproducible (Spearman Rho = 0.69; p = 0.007). Mucociliary clearance did not change significantly over 1 year with median percent MCC60 on Visit 3 [12.8 (3.7-17.6)] similar to Visit 2 (p = 0.58). Lower percent MCC60 on Visit 3 was significantly associated with higher LCI scores on Visit 3 (N = 14; Spearman Rho = -0.56; p = 0.04).
Conclusions: Tests of MCC were reproducible and reliable over a 2-week period and stable over a 1-year period in 5-7-year-old children with CF. Lower MCC values were associated with increased ventilation inhomogeneity. These results suggest that measurements of MCC could be used in short-term clinical trials of interventions designed to modulate MCC and as a new, non-invasive test to evaluate early lung pathology in children with CF.
Impact: This is the first study to characterize mucociliary clearance (MCC) in children with cystic fibrosis (CF) who were 5-7 years old. Measurements of mucociliary clearance were reproducible and reliable over a 2-week period and stable over a 1-year period. Variability in MCC between children was associated with differences in ventilation homogeneity, such that children with lower MCC values had increased ventilation inhomogeneity.
These results suggest that measurements of MCC could be used in short-term clinical trials of interventions designed to modulate MCC and as a new, non-invasive test to evaluate early lung pathology in children with CF.

Dr Beth L Laube (Fig. 137) is a professor of pediatrics in the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. She is an aerosol scientist.

Thomas W LaudoneLauren GarnerCharissa W Kam Charles R Esther Jr Cameron J McKinzie.  Novel therapies for treatment of resistant and refractory nontuberculous mycobacterial infections in patients with cystic fibrosis. Pediatr Pulmonol 2021 Feb;56 Suppl 1:S55-S68.doi: 10.1002/ppul.24939.[Pubmed]

Fig. 138 Thomas Laudone

Respiratory infections caused by non-tuberculous mycobacteria (NTM) are a major cause of morbidity for patients living with cystic fibrosis (CF), as NTM pulmonary disease (NTM-PD) is challenging to both diagnose and eradicate. Despite the lengthy courses of the established regimens recommended by the Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) consensus guidelines, only about 50% to 60% of patients achieve culture conversion, and treatment regimens are often complicated by antibiotic resistance and toxicities. Since publication of the CFF/ECFS guidelines, several new or alternative antibiotic regimens have been described for patients with CF who have NTM-PD. These regimens offer new options for patients who do not clear NTM with standard therapies or cannot utilize the usual regimens due to toxicities or drug-drug interactions.

Thomas W Laudone (fig 138)  Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, North Carolina. Now works at University of Maryland Medical Center.

Eline LauwersAnnemiek Snoeckx Kris Ides Kim Van HoorenbeeckMaarten Lanclus Wilfried De BackerJan De BackerStijn Verhulst Functional respiratory imaging in relation to classical outcome measures in cystic fibrosis: a cross-sectional studyBMC Pulm Med 2021 Aug 4;21(1):256.doi: 10.1186/s12890-021-01622-3. Free PMC article   [Pubmed]

Fig. 139 Eline Lauwers. www.uantwerpen.be

Background: Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population.
Methods: CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations.
Results: 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV1 ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV1 < 70%) when comparing FRI to CF-CT scores.

Conclusions: Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research.

Dr Eline Lauwers (fig. 139) is a PhD researcher at the Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2160, Wilrijk, Belgium and the Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium.

Vincent Le MoigneAnne-Laure RouxHélène MahoudoGaëtan ChristienAgnès FerroniOana DumitrescuGérard LinaJean-Philippe BoucharaPatrick PlésiatJean-Louis GaillardStéphane CanaanGeneviève Héry-ArnaudJean-Louis Herrmann.  Serological biomarkers for the diagnosis of Mycobacterium abscessus infections in cystic fibrosis patientsJ Cyst Fibros 2021 Sep 9;S1569-1993(21)01360-6.doi: 10.1016/j.jcf.2021.08.019.Online ahead of print.

Fig 140 Vincent Le Moigne

Background: Culture conditions sometimes make it difficult to detect non-tuberculous mycobacteria (NTM), particularly Mycobacterium abscessus, an emerging cystic fibrosis (CF) pathogen. The diagnosis of NTM positive cases not detected by classical culture methods might benefit from the development of a serological assay.
Methods: As part of a diagnostic accuracy study, a total of 173 sera CF-patients, including 33 patients with M. abscessus positive cultures, and 31 non-CF healthy controls (HC) were evaluated. Four M. abscessus antigens were used separately, comprising two surface extracts (Interphase (INP) and a TLR2 positive extract (TLR2eF)) and two recombinant proteins (rMAB_2545c and rMAB_0555 also known as the phospholipase C (rPLC)).
Results: TLR2eF and rPLC were the most efficient antigens to discriminate NTM-culture positive CF-patients from NTM-culture negative CF-patients. The best clinical values were obtained for the detection of M. abscessus-culture positive CF-patients; with sensitivities for the TLR2eF and rPLC of 81.2% (95% CI:65.7-92.3%) and 87.9% (95% CI:71.9-95.6%) respectively, and specificities of 88.9% (95% CI:85.3-94.8%) and 84.8% (95% CI:80.6-91.5%) respectively. When considering as positive all sera, giving a positive response in at least one of the two tests, and, as negative, all sera negative for both tests, we obtained a sensitivity of 93.9% and a specificity of 80.7% for the detection of M. abscessus-culture positive CF-patients.

Conclusion: High antibody titers against TLR2eF and rPLC were obtained in M. abscessus-culture positive CF-patients, allowing us to consider these serological markers as potential tools in the detection of CF-patients infected with M. abscessus.

Dr Vincent Le Moigne  (fig 140)  is a post doctorant at the Université Paris Saclay, UVSQ, Inserm, Infection et Inflammation, Montigny-le-Bretonneux,France

Eline LauwersDennis BelmansBenjamin MignotKris Ides Kim Van HoorenbeeckAnnemiek SnoeckxCedric Van Holsbeke Vicky NowéEva Van Braeckel  Wilfried De BackerJan De BackerStijn Verhulst. The short-term effects of ORKAMBI (lumacaftor/ivacaftor) on regional and distal lung structures using functional respiratory imaging. Ther Adv Respir Dis Jan-Dec 2021;15:17534666211046774.doi:10.1177/17534666211046774.[Pubmed]Free PMC article

Fig. 141  Eline Lauwers ResearchGate

Background: Lumacaftor/ivacaftor (LUM/IVA) has shown modest benefits in previous research, but the exact effects in the cystic fibrosis (CF) lung remain unclear. This study aims to offer novel information on the mode of action of the cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drug by assessing lung structure and function using functional respiratory imaging (FRI).
Methods: CF patients aged ⩾12 years homozygous for F508del were recruited in an open-label study. Before and after 12 weeks of treatment with LUM/IVA, FRI was used to visualize regional information, such as air trapping, lobar volume and airway wall volume. Secondary outcomes included the CF-CT scoring system, spirometry, the Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaire, exercise tolerance and nutritional status.
Results: Of the 12 patients enrolled in the study, 11 completed all study visits. Concerning the FRI parameters, hyperinflation of the lung decreased, indicated by a reduction in air trapping and lobar volume at expiration. Also, a decrease in airway wall volume and a redistribution of pulmonary blood volume were noted, which might be related to a decrease in mucus impaction. Airway resistance, airway volume, internal airflow distribution and aerosol deposition pattern did not show significant changes. No significant improvements were found in any of the CF-CT scores or in the spirometric parameters. Other secondary outcomes showed similar results compared with previous research. Correlations at baseline were found between FRI and conventional outcomes, including physical functioning, spirometry and CF-CT scores.
Conclusions: LUM/IVA decreased lung hyperinflation in combination with a potential decrease in mucus impaction, which can be related to an improved mucociliary transport. These results indicate that several FRI parameters, reflecting regional and distal lung structures, are more sensitive to changes caused by LUM/IVA than conventional respiratory outcomes.

Eline Lauwers  (fig 141) is PhD student at the Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp and with the Infla-Med Research Consortium of Excellence, University of Antwerp, Belgium

Jin-A Lee, Alex ChoElena N HuangYiming XuHenry QuachJim Hu Amy P WongGene therapy for cystic fibrosis: new tools for precision medicine. J Transl Med. 2021 Oct 30;19(1):452.doi: 10.1186/s12967-021-03099-4.   Free PMC article   [Pubmed]

Fig 142 Jin-A Lee

The discovery of the Cystic fibrosis (CF) gene in 1989 has paved the way for incredible progress in treating the disease such that the mean survival age of individuals living with CF is now ~58 years in Canada. Recent developments in gene targeting tools and new cell and animal models have re-ignited the search for a permanent genetic cure for all CF. In this review, we highlight some of the more recent gene therapy approaches as well as new models that will provide insight into personalized therapies for CF.

Jin-A Lee (fig 142) is a research fellow, Program in Developmental and Stem Cell Biology, Hospital for Sick Children,  86 Bay Street, PGCRL 16-9420, Toronto, ON,  Canada.

Michael A LensinkSarah N BoersVincent A M GulmansKarin R JongsmaAnnelien L Bredenoord.  Mini-gut feelings: perspectives of people with cystic fibrosis on the ethics and governance of organoid biobanking.  Per Med 2021 Apr 7.doi: 10.2217/pme-2020-0161. Online ahead of print. [Pubmed]

Fig. 143 Michael Lensink

Aim: Organoid technology has enormous potential for precision medicine, such as has recently been demonstrated in the field of cystic fibrosis. However, storage and use of organoids has been associated with ethical challenges and there is currently a lack of harmony in regulation and guidelines to govern the rapid emergence of 'organoid medicine'. Developing sound governance demands incorporation of the perspectives of patients as key stakeholders.
Materials & methods: We conducted 17 semi-structured interviews with people with cystic fibrosis to explore their perspectives on the ethics and governance of organoid biobanking.
Results: We identified three themes: prioritization of research and trust, ambivalent views on commercial involvement and transparency and control.
Conclusion: Our study offers important insights for ethically robust governance of 'organoid medicine'.

Plain Language Summary
Lay abstract Organoids are living tissues that can be grown in a lab out of stem cells, which can replicate some features of actual organs in the body. They can be used to study diseases or develop drugs, but also to test the effectiveness of therapy for a specific patient (which is called precision medicine). Organoid technology is promising for the treatment of cystic fibrosis. At the same, storing and using organoids raises ethical and practical challenges. In order to ensure that the interests of those who provide the cells are respected, we interviewed people with cystic fibrosis. Their motivation to participate in organoid research was high, but at the same time they wanted to know how their organoids are used. In addition, while they did not feel the need to be directly involved in decisions about how their tissue is used, they valued ongoing communication from biobanks about its activities.

Michael A Lensink (fig. 143) is a PhD student at the Julius Center for Health Sciences & Primary Care, Department of Medical Humanities, University Medical Center Utrecht,

Kelsey LeonhardtElizabeth B AutryRobert J KuhnMark A Wurth CFTR modulator drug desensitization: preserving the hope of long term improvement. Pediatr Pulmonol. 2021 Apr 29.doi: 10.1002/ppul.25437. Online ahead of print. [Pubmed]

Fig 144  Kelsey Leonhardt UK College of Pharmacy

The development of modulator therapy has, for the first time, allowed direct targeting of the underlying cause of cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator (CFTR). Patients treated with CFTR modulators have improvement in lung function and decreased rates of pulmonary exacerbations. In 2019, elexacaftor/tezacaftor/ivacaftor was approved for use in the United States, opening these therapies to 90% of patients with CF.

Intolerable adverse drug reactions (ADRs) to CFTR modulators results in discontinuation of therapy, which can be devastating to our patients. We describe our approach to two cases, not previously reported, of rash to elexacaftor/tezacaftor/ivacaftor in patients with a previous history of cutaneous adverse reactions to dual modulator therapy that had been addressed by desensitization. Case 1 was able to tolerate elexacaftor/tezacaftor/ivacaftor after desensitization to the triple combination therapy, while in case 2 tolerance was obtained by treating through the reaction. The loss of tolerance in these patients was unexpected, and may be a common finding in patients with history of cutaneous adverse reactions to these drugs. We hope reporting our experience, including our desensitization protocol, may benefit CF patients for whom these drug reactions may be limiting access to powerful disease altering therapies.

Dr Kelsey Leonhardt (fig 144) in Clinical Pharmacist in the Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, Kentucky.

 Marco L LeungSallie McAdoo Deborah Watson Kallyn Stumm Margaret Harr Xiang Wang Christine H ChungFernanda MafraAddie I NesbittHakon HakonarsonAvni Santani  A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening.   J Mol Diagn 2021 Jan;23(1):91-102. doi: 10.1016/j.jmoldx.2020.10.009.   

 Fig. 145  Marco L Leung nationwidehildrens.org 

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis cof the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature
As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these da

Marco L Leung (fig.145) at the Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;

Barry Linnane Aaron M WalshCalum J WalshFiona CrispieOrla O'SullivanPaul D CotterMichael McDermottJulie RenwickPaul McNally.  The Lung Microbiome in Young Children with Cystic Fibrosis: A Prospective Cohort Study. Microorganisms 2021 Feb 26;9(3):492.doi: 10.3390/microorganisms9030492. Free article        [Pubmed]

 Fig. 147 Julie Renwick

Fig. 146 Barry Linnane

The objective of this study was to thoroughly characterise the lower airway microbiome in pre-school children with CF. Bronchoalveolar lavage (BAL) samples were collected annually from children attending the three clinical centres. Clinical and demographic data were collated on all subjects alongside BAL inflammatory markers.  Data on 292 sequenced BALs from 101 children with CF and 51 without CF show the CF lung microbiome, while broadly similar to that in non-CF children, is distinct. Alpha diversity between the two cohorts was indistinguishable at this early age. The CF diagnosis explained only 1.1% of the variation between the cohort microbiomes.

However, several key genera were significantly differentially abundant between the groups. While the non-CF lung microbiome diversity increased with age, diversity reduced in CF with age. Pseudomonas and Staphylococcus were more abundant with age, while genera such as Streptococcus, Porphyromonas and Veillonella were less abundant with age.

There was a negative correlation between alpha diversity and interleukin-8 and neutrophil elastase in the CF population. Neither current flucloxacillin or azithromycin prophylaxis, nor previous oral or IV antibiotic exposure, was correlated with microbiome diversity. Consecutive annual BAL samples over 5 years from a subgroup of children demonstrated diverse patterns of development in the first years of life.

 Dr Barry Linnane (Fig. 146) is at the Centre for Interventions in Infection, Inflammation and Immunity (4i) and Graduate Entry Medical School, University of Limerick, Limerick V94 T9PX, Ireland. Director of the Paediatric CF Programme. Limerick

Corresponding author is Dr Julie Renwick (Fig. 147) Assistant Professor of Clinical Microbiology, School of Medicine, Trinity College, Dublin. She cofounded the Airway Microbiome in Cystic Fibrosis project

---  There is a detailed full version available. There are no definite suggestions as to the practical implications of the findings.

Jia LiuAllison P BergYiting WangWalailak Jantarajit Katy J SutcliffeEdward B StevensLishuang CaoMarko J PregelDavid N Sheppard. A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR. Br J Pharmacol 2021 Oct 13.doi: 10.1111/bph.15709. Online ahead of print. [Pubmed]

Fig. 148  David Sheppard

Background and purpose: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators are small molecules developed to treat the genetic disease cystic fibrosis (CF). They interact directly with CFTR Cl- channels at the plasma membrane to enhance channel gating. Here, we investigate the action of a new CFTR potentiator, CP-628006 with a distinct chemical structure.
Experimental approach: Using electrophysiological assays with CFTR-expressing heterologous cells and CF patient-derived human bronchial epithelial (hBE) cells, we compared the effects of CP-628006 with the marketed CFTR potentiator ivacaftor.
Key results: CP-628006 efficaciously potentiated CFTR function in epithelia from cultured hBE cells. Its effects on the predominant CFTR variant F508del-CFTR were larger than those with the gating variant G551D-CFTR. In excised inside-out membrane patches, CP-628006 potentiated wild-type, F508del- and G551D-CFTR by increasing the frequency and duration of channel openings. CP-628006 increased the affinity and efficacy of F508del-CFTR gating by ATP. In these respects, CP-628006 behaved like ivacaftor. CP-628006 also demonstrated notable differences with ivacaftor. Its potency and efficacy were lower than those of ivacaftor. CP-628006 conferred ATP-dependent gating on G551D-CFTR, whereas the action of ivacaftor was ATP-independent. For G551D-CFTR, but not F508del-CFTR, the action of CP-628006 plus ivacaftor was greater than ivacaftor alone. CP-628006 delayed, but did not prevent, the deactivation of F508del-CFTR at the plasma membrane, whereas ivacaftor accentuated F508del-CFTR deactivation
Conclusions and implications: CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.

Jia Liu is at the Neuroscience and Pain Research Unit, Pfizer Inc., Granta Park, Great Abington, Cambridge, UK. and the School of Physiology, Pharmacology Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK.

Professor David Sheppard (fig148) is professor in the School of Physiology and Pharmacology University of Bristol and his group have been involved with basic CF research for many years.

Anna-May LongIan H JonesMarian KnightJanet McNallyBAPS-CASS Early management of meconium ileus in infants with cystic fibrosis: A prospective population cohort studyJ Pediatr Surg 2021 Feb 24;S0022-3468(21)00181-0.doi: 10.1016/j.jpedsurg.2021.02.047.Online ahead of print. [Pubmed]

Fig. 149 Anna-May Long

Background: Contemporary early outcome data of meconium Ileus (MI) in cystic fibrosis (CF) are lacking on a population level. We describe these and explore factors associated with successful non-operative management.
Methods: A prospective population-cohort study using an established surveillance system (BAPS-CASS) was conducted October 2012-September 2014. Live-born infants with bowel-obstruction from inspissated meconium in the terminal ileum and CF were reported. Data are described as median (interquartile range, IQR).
Results: 56 infants were identified. 14/56(25%) had primary laparotomy (13/23 complicated MI, 1/33 simple), the remainder underwent contrast enema. Twelve, (12/33 (36%) with simple MI) achieved decompression. 8/12 (67%) who decompressed had >1 enema vs 3/20 (15%) with simple MI who had laparotomy after enema. The number of enemas per infant (1-4), contrast agents and their concentration, were highly variable. Enterostomy was formed at 24/44(55%) of laparotomies. In infants with simple MI, time to full enteral feeds was 6 (2-10) days in those decompressing with enema vs 15 (9-19) days with laparotomy after enema. Case fatality was 4% (95% CI 0.4-12%). Two infants, both preterm died, both in the second month after birth.
Conclusions: Infants with simple MI achieving successful enema decompression were more likely to have had repeat enemas than those who proceeded to laparotomy. Successful non-operative management was associated with a shorter time to full feeds. The early management of infants with MI is highly variable and not standardised across the UK and Ireland.

Miss Anna-May Long  (fig.149) is a consultant paediatric surgeon in the Department of Paediatric Surgery, Cambridge University Hospitals, Cambridge, United Kingdom; she is taking three years off her surgical training to work at  the National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford.