CF Patients Research Articles

P191 Is abnormal glucose tolerance driving lung inflammation in cystic fibrosis?

CF related diabetes (CFRD) is still one of the major comorbidities in CF and is affecting 30% of adult CF patients. CFRD leads to a poorer outcome with decline in lung function, increase lung infections and impaired nutritional status. In the decade of CFTR modulator therapy that will have great impact on life quality and life expectation it is even more important to understand the inflammatory pathways that lead to CFRD. In our study we want to investigate the connection between CFRD and impaired lung function. We want to examine if there are different expressions of cytokines and bacterial load in the airways of CF patients depending on their glucose tolerance.

Clinical, paraclinical, and genetic profile of patients with cystic fibrosis from Colombian Caribbean

BackgroundCystic fibrosis (CF) is a serious autosomal recessive disorder. Early diagnosis, comorbidity prevention, and control are cornerstones for a quality life and for improving life expectancy. In Colombian Caribbean, where there is a genetically admixed population, CF is an orphan disease affecting children and adults, and it remains a challenging issue to be addressed carefully. This work describes the genetic, clinical, and paraclinical profiles of CF patients from Cartagena de Indias, Colombia. MethodsThirty-six patients were included in the study. The subjects were identified and evaluated through the Regional Program for CF patients. CFTR gene mutations, anthropometric parameters, microbiological infections, and pulmonary function were analyzed. Data on demographic parameters, pharmacological treatments, and comorbidities were reported. Frequency and percentages were established for the categorical variables and mean or median for the quantitative variables. In addition, comparisons were made by sex. ResultsThe average age of the patients was 11.9 ± 5.3 years and the median age at diagnosis was 14 months. 55.5% were women and 44.5% were men. The mean values for weight, height, and body mass index were 35 ± 17.6 kg, 139.9 ± 28 cm, and 16.5 ± 2.9 kg/m2, respectively. The clinical manifestations that occurred more frequently were steatorrhea (65.4%) and recurrent pneumonia (46.2%). Chronic airway infection with Pseudomonas aeruginosa was identified in 71.4% of the cases and the p.F508del mutation was found in 47.2% of the subjects. ConclusionThe current profile of CF patients from the Colombian Caribbean showed some concerning features, such as nutritional status; however, progress in early diagnosis and clinical follow-up could contribute to improve the general conditions of patients. It is necessary to continue efforts to increase the life expectancy and quality of life of the patients.

P050 Elexacaftor/tezacaftor/ivacaftor for adult cystic fibrosis patients with preserved lung function: a case series

Introduction: Elexacaftor-tezacaftor-ivacaftor (ETI) significantly improves lung function in CF patients. Previous studies have estimated that a delay in ETI initiation could have a negative impact on long-term survival. ETI use has been approved for children aged ≥6 years fulfilling the genetic criteria independent of their lung function. However, there is still controversy regarding ETI use for adult patients with preserved lung function [defined as a percentage of predicted forced expiratory volume in the first second (ppFEV1)>90%] considering that this subgroup of patients was excluded in the screening period of phase III randomized clinical trials.

EPS3.05 Proximity Profiling of CFTR with Gating Mutations

Objectives: The prevalence of many Class III CFTR mutations are present in at least one allele in approximately 10% of the CF population. Type III mutations do not impact the surface quantity of CFTR at the cell surface but do cause defects in CFTR channel gating. The introduction of VX-770 has resulted in treated patients having a lower prevalence of CF-related complications and better-preserved lung function. VX-770 is currently the only CFTR potentiator approved for use in CF patients. Despite the many benefits this therapy has brought to the CF population, there are still patients who harbour mutations that lead to severe defects in CFTR channel conductance. Using proximity-dependent biotin identification (BioID), we can unveil novel interactions to determine how to better treat rarer forms of this disease.

P187 Small airways disease in cystic fibrosis patients

To evaluate small airways disease in CF patients with impulse oscillometry system (IOS) and multiple breath N2 washout (MBNW) and to assess relations between clinical score and indices of small airways dysfunction.

P024 Compound heterozygotes bearing the CFTRdup22 in trans with another cystic fibrosis-causing variant have a generally milder course of cystic fibrosis: analysis of 6 Czech cystic fibrosis cases

Introduction: Approx. 2.5% of CFTR gene variants are represented by large intragenic rearrangements with duplications (dup.) being less common than deletions. Although CFTR1 database includes 6 large dup., the CFTRdup7-11 (legacy nom. 6b-10) is the only one listed in CFTR2, thus far. Interestingly, the CFTRdup22 is not listed in either CFTR1 or CFTR2 databases and has been previously sporadically observed in Turkish and Hungarian CF patients. Thus far, we found this dup. in six Czech CF patients by routine MLPA examinations. We aimed to assess the course of CF in compound heterozygote cases bearing CFTRdup22 with another CF-causing variant in trans.

WS14.05 Effect of an agro-based compound (A-bC) on remodelling and regeneration of airway epithelium in cystic fibrosis

The CF airway epithelium (AE) exhibits large areas of remodelling such as basal or goblet cell hyperplasia, ciliated cell absence or epithelial desquamation, therefore leading to impaired mucociliary clearance (MCC). We have previously demonstrated that the regeneration of CF AE leads to a remodelled epithelium, the role of CF cell inflammatory memory in basal cell hyperplasia and increased CF AE height, the involvement of lung tissue inflammation in goblet cell hyperplasia, and the inflammationindependent default of ciliated cell differentiation. The identification of therapies favouring MCC through an improvement of CF AE regeneration is therefore crucial for CF patients. In this perspective, we examined the influence of an agro-based compound (A-bC) obtained by bacterial fermentation of wheat, on the regeneration of the human CF AE.

P204 Changes of lymphocyte susceptibility to glucocorticoids in cystic fibrosis patients with Burkholderia cepacia

Recently we have shown decreased IL-17F levels in blood and sputum samples of CF patients, chronically colonized with Burkholderia cepacia complex (Bcc) 1 Pukhalskaya D et al. ERJ. 2020; 56: 689DOI: 10.1183/13993003.congress-2020.689 Google Scholar . Since IL-17F is a cytokine upregulating the expression of cellular glucocorticoid β-receptors, its deficiency may change steroid sensitivity in various tissues and organs.

P231 Monitoring of respiratory tract infections of cystic fibrosis transplanted patients by means of a multiplex PCR assay

Molecular approach is widely used for the early diagnosis of difficult infections. Microbiological status of transplanted CF patients has been assessed by means of specific panels for lung pathogens.

P022 Elexacaftor/tezacaftor/ivacaftor restore the function of the CFTR channel in patients with the genetic variant 3272-16T>A (c.3140-16T>A)

Objectives: The splicing variant 3272-16T>A (c.3140-16T>A) according to the Russian CF Patients Registry, occurs with a frequency of 0.33% (21 place in Russian CF Patients Registry). This genetic variant is not specified in the instructions for the modulators. The aim was to study the effect of CFTR modulators on the CFTR protein function in patients with CF having the genetic variant 3272-16T>A.

P196 Use of nose clips for routine spirometry helps maximise forced expiratory outcome measures in cystic fibrosis clinics

Spirometry is used in CF patients to monitor progression of lung disease. Whilst nose clips (NC) are recommended by some guidelines there is no current consensus on their use during spirometry testing (Chavasse et al., 2003 European Respiratory Journal). The COVID-19 pandemic saw an escalation in the use of home monitoring including portable spirometers often resulting in reduced compliance with spirometry guidance. We examined the effect of NC on spirometry measurements in patients attending the CF clinic at Southampton Children’s Hospital.

WS18.05 Improved diagnosis of early aspergillus lung disease in cystic fibrosis (IDEAL) study design and first results

Objectives: Aspergillus fumigatus (Asp) is detected in up 70% of all CF patients. However, the role of Asp in the progression of structural lung damage (SLD) remains unclear. This study investigates the association of Asp with the SLD over time.

WS17.03 An alternative mutation agnostic therapy for cystic fibrosis with oligonucleotide antisense

Objectives: CFTR modulators have significantly changed the course of the disease in patients carrying drug-sensitive mutations. Unfortunately, those drugs cannot treat people with CF-carrying CFTR nonsense mutations. Hence, there is a growing interest in finding alternative strategies to treat all CF patients regardless of their mutations. An exciting alternative is to develop “mutation-agnostic” therapies by activating other anion channels. TMEM16A is one of the most promising alternative channels that could compensate for defective CFTR. However, previous studies demonstrated that miRNA-9 downregulates TMEM16A expression by binding to its 3′ UTR mRNA. To restore TMEM16A expression, our team has developed an oligonucleotide antisense (TMEM16A ASO) that binds to the TMEM16A 3’ UTR and prevents miRNA-9 binding, therefore, re-establishing TMEM16A expression and activity. Here we determine the effectiveness of the TMEM16A ASO on CF-dysregulated parameters and evaluate its toxicity and specificity.

WS07.06 CFTR impacts SARS-CoV-2 infection in cystic fibrosis

SARS-CoV-2 does not cause a more serious infection in CF patients compared to the general population, with better outcomes than initially predicted. The epidemiology raises the question of whether the determinants of CF pathophysiology might interfere with virus replication and COVID-19 disease.

P156 Treatment with the CFTR modulator [HB1] elexacafor/tezacaftor/ivacaftor reduces immunological response to airway Aspergillus in people with cystic fibrosis

Amongst people with Cystic Fibrosis, Aspergillus fumigatus is the most frequently cultured fungal pathogen in sputum samples. Elexacaftor/tezacaftor/ivacaftor (ETI) is a CFTR modulator which results in significant improvements in lung function. We investigated the effect of ETI therapy on the serological response to Aspergillus in adult CF patients prescribed ETI.

EPS1.09 Feasibility of cardiac magnetic resonance imaging in older cystic fibrosis patients

Objectives: Cardiac magnetic resonance (CMR) imaging technology allows for interrogation of cardiac structure and function. We examined stable CF patients aged ≥40 years via CMR to determine the prevalence and extent of myocardial disease in this population.

WS16.06 International disparities in access to highly effective modulator therapies

Objectives: The advent of CFTR modulator therapy represents an unparalleled opportunity to improve quality and length of life for over 90% of CF patients. Yet list prices for these drugs have been set at ~$300,000 per year, representing an enormous barrier to access. As such we sought to appraise international pricing and reimbursement of Kaftrio® to identify gaps in access, and to explore potential solutions to how wider treatment availability can be achieved.

P019 Complex CFTR allele [HB1] L467F-F508del is responsible for poor clinical response to elexacaftor/tezacaftor/ivacaftor CFTRm therapy in a cystic fibrosis female with the L467F-F508del/621+1 G > Tgenotype: a case report

Introduction: Over 50% of Czech CF patients are currently treated with the CFTRm (elexacaftor/tezacaftor/ivacaftor; ETI) combination. Our case report confirms the dependence of the clinical benefit of CFTRm on the “complex” CFTR genotype and the important role of sweat chloride concentration (SCC) monitoring.

EPS5.08 Elexacaftor/tezacaftor/ ivacaftor reduces need for pancreatic enzymes, enteral feeding and omeprazole use without causing excessive weight gain: a 2-year observational study

Introduction: Short term studies of Elexacaftor/tezacaftor/ivacaftor (ETI) have shown increasing weight gain and modest improvements in GI symptoms. Since August 2020, all CF patients aged >12 years attending our Paediatric Service have been treated with ETI according to UK licencing. In this real-world study, we assessed changes in nutritional status after starting ETI, effects on the need for enteral feeding, use of pancreatic enzymes (PERT), endocrine function and medication.

P014 Safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide cystic fibrosis therapeutic

The ASO field is an emerging area of drug development that targets the disease source at the RNA level, offering a promising alternative to therapies targeting downstream processes. SpliSense is developing SPL84, an inhaled ASO for the treatment of CF patients carrying the 3849 +10 kb C->T mutation. In order to move into the clinic, we performed a full battery of preclinical safety and toxicology studies with SPL84.