Clinical Course Of Cystic Fibrosis Research Articles

P030 Features of clinical course of cystic fibrosis in patients from Chechen Republic

Objectives: The population of Chechens is one of the oldest ethnic groups in North Caucasus. In some previous articles it has been shown that these patients have a high frequency of two pathogenic variants c.1545_1546del and c.274G>A. However, clinical course of disease in these patients have not been described at the moment.

P360 Mental health in cystic fibrosis patients: predictive factors and psychopathology

Defining the characteristics of temperament that predispose to the onset of mood disorders and anxiety disorders in patients with Cystic Fibrosis (pwCF). Identifying personality factors and attachment styles that influence the medication adherence. Consequently, evaluating longitudinally the impact of the perception of disease and the dissociative symptoms on the clinical course of Cystic Fibrosis (CF).

Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy.

In the cohort of Russian patients with cystic fibrosis, the p.[Leu467Phe;Phe508del] complex allele (legacy name [L467F;F508del]) of the CFTR gene is understudied. In this research, we present the results of frequency evaluation of the [L467F;F508del] complex allele in the Russian Federation among patients with a F508del/F508del genotype, its effect on the clinical course of cystic fibrosis, the intestinal epithelium ionic channel function, and the effectiveness of target therapy. The frequency of the [L467F;F508del] complex allele among patients with homozygous F508del was determined with multiplex ligase-dependent probe amplification followed by polymerase chain reaction and fragment analysis. The function of ionic channels, including the residual CFTR function, and the effectiveness of CFTR modulators was analyzed using intestinal current measurements on rectal biopsy samples and the forskolin-induced swelling assay on organoids. The results showed that the F508del/[L467F;F508del] genotype is present in 8.2% of all Russian patients with F508del in a homozygous state. The clinical course of the disease in patients with the F508del/[L467F;F508del] genotype is severe and does not vary from the course in the cohort with homozygous F508del, although the CFTR channel function is significantly lower. For patients with the F508del/[L467F;F508del] genotype, we can recommend targeted therapy using a combined ivacaftor + tezacaftor + elexacaftor medication.

Клинические особенности патогенного варианта нуклеотидной последовательности L138ins в гене CFTR при муковисцидозе

In this study, we analyzed phenotypic manifestations and clinical course of cystic fibrosis (CF) in patients with the pathogenic variant L138ins of the CFTR gene. The L138ins variant is rarely detected in CF patients worldwide, but is quite common in different regions of the Russian Federation, particularly in the Middle Urals. Before the neonatal screening implementation, the majority of CF patients with the L138ins variant were diagnosed late because of the mild disease course and dubious results of sweat tests. Such patients usually have elevated levels of immunoreactive trypsinogen (IRT) in the neonatal period, which enables early diagnosis; however, false-negative results in CF patients have also been reported. There were cases of male infertility among CF patients with the L138ins variant, while women had their reproductive function preserved. There were also cases of asymptomatic pancreatic hyperenzymemia in children. Respiratory infections caused by Pseudomonas aeruginosa are not very common in this group of patients. However, adult patients have more severe respiratory manifestations (even with a fatal outcome) than children. Thus, despite the mild disease phenotype in patients with the L138ins variant, the residual function of the protein is not sufficient to ensure normal functioning of lungs. Key words: cystic fibrosis, pathogenic CFTR variants, L138ins

Diabetes and Prediabetes in Children With Cystic Fibrosis: A Systematic Review of the Literature and Recommendations of the Italian Society for Pediatric Endocrinology and Diabetes (ISPED).

Cystic fibrosis related diabetes (CFRD) is a comorbidity of cystic fibrosis (CF) that negatively impacts on its clinical course. Prediabetes is an important predictor of either CFRD development and unfavorable prognosis of CF in both pediatric and adult patients. International guidelines recommend insulin only in case of CFRD diagnosis. Whether early detection and treatment of prediabetes may contribute to improve the clinical course of CF is still debated. A subgroup of pediatric diabetologists of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED) performed a systematic review of the literature based on predefined outcomes: impact of pre-diabetes on clinical outcomes and on the risk of developing CFRD; diagnosis of diabetes and pre-diabetes under 10 years of age; effectiveness of therapy on glycemic control, impact of therapy on pulmonary function and nutritional status. Thirty-one papers were selected for the analysis data presented in these papers were reported in tables sorted by outcomes, including comprehensive evidence grading according to the GRADE approach. Following the grading of the quality of the evidence, the entire ISPED diabetes study group achieved consensus for the Italian recommendations based on both evidence and clinical experience. We concluded that in patients with CF, prediabetes should be carefully considered as it can evolve into CFRD. In patients with CF and prediabetic conditions, after complete evaluation of the OGTT trend, glucometrics, glycemic values measured during pulmonary exacerbations and/or steroid therapy, early initiation of insulin therapy could have beneficial effects on clinical outcomes of patients with CF and prediabetes.

Clinical course of cystic fibrosis in children

Annotation. This study is devoted to evaluation of clinical course of cystic fibrosis (CF) in children. The study involved 84 children who were diagnosed with cystic fibrosis. All participants were asked about complaints, life history, physical examination was made, and the results of objective testing and instrumental examination were assessed. The statistical system “IBM SPSS Statistics” version 12 (20) was used using parametric and non-parametric methods of descriptive statistics. Student's criterion was used to assess the significance of the difference between the independent samples, and the Fisher's factor was used for the percentage data. It was shown that 86.91% of subjects had severe or moderate course of CF. Major mutation of CFRT gene F508del/F508del was found in 45.2% children. Common complaints were productive cough (92.9%; р<0.01), failure to thrive (61.9%; р<0.01) and shortness of breath during exercise (40.5%; р<0.01). Results of bacteriologic test of sputum showed significant prevalence of St. aureus (54.0%; р<0.01) and Ps. aeruginosa (38.10%; р<0.01). Patients with severe course of CF had lower rates of FVC, FEV1, PEF, FEF 25%, FEF 50%, FEF 75% than children with moderate and mild course. At the age of 3 years, the diagnosis of cystic fibrosis was established in time by only 76.92% of respondents, which aims to further efforts to improve the quality of its diagnosis.

Cystic fibrosis in Canadian Hutterites.

The Hutterite Brethren are a communal group of Anabaptists who live in the Western regions of North America, predominantly in the Western Canadian provinces. Due to a founder effect, Hutterites have a high rate of cystic fibrosis (CF) with genotypes limited to only two CFTR mutations. One-third of Hutterite patients with CF are pancreatic sufficient. Previously we found an unexplained younger age at death in Hutterites compared with nonHutterites homozygous for the common F508del mutation. The present study expanded the data collection and analysis for confirmation and further exploration. Anonymized information, based on Hutterite surnames, was extracted from the Canadian CF Registry. Summary data on nonHutterite patients with CF homozygous for F508del served as control. Statistical analyses explored the effects of genotype within Hutterites and compared nutritional status, lung function, and microbiologic findings between the groups. The younger average age at death in Hutterites compared with controls was confirmed, but there was no suggestion of a generally shortened life expectancy. While the nutritional status in Hutterite children was better than that of controls, their lung function was slightly but significantly lower. Staphylococcus aureus was more frequent in Hutterites while there was no difference between the groups regarding Pseudomonas aeruginosa. Despite less pancreatic insufficiency, better nutrition, communal life in socioeconomic stability, and without exposure to environmental tobacco smoke, the clinical course of CF appears to be more severe in a significant number of Hutterites. Investigations of gene-environment interactions and of CF disease gene modifiers may help to explain this conundrum.

P007 Features of the clinical course of cystic fibrosis due to the severity of the genotype (according to the Cystic Fibrosis Patient Registry of the Russian Federation (2017))

P007 Features of the clinical course of cystic fibrosis due to the severity of the genotype (according to the Cystic Fibrosis Patient Registry of the Russian Federation (2017))

Pulmonary exacerbations as a risk factor for lung function decline-experiences of the National Cystic Fibrosis Center

Background/Aim. Pulmonary exacerbations have negative impact on clinical course of cystic fibrosis (CF) lung disease being associated with a steeper decline in the lung function, unfavorable prognosis and impaired quality of life. The aim of this study was to determine whether an increased number of exacerbations had influence on the lung function in the patients with CF, as well as to estimate the nutritional status, gender, presence of comorbid conditions and bacterial colonization of airways as predictive factors for pulmonary exacerbations. Methods. This retrospective cohort study included 83 pediatric and adult patients, treated from 2011? 2015 in the Mother and Child Health Institute of Serbia ?Dr Vukan Cupic?. The best result of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) in each year of follow-up was taken into account to calculate the five-year trend values of these indicators. The number of exacerbations per year of follow-up and its impact on the FEV1 decline was evaluated. Results. Mean annual decline of FEV1 and FVC were 2.4% and 1.7% respectively. The malnourished patients had the lower initial values of FEV1 and FVC, and more frequent exacerbations in comparison with the normal weight and overweight patients. The frequency of exacerbations was significantly higher in the patients chronically colonized with Burkholderia cepacia (p = 0.023). The increased number of exacerbation was proved to be the most important factor in a prediction of FEV1 decline over time (p = 0.013). Conclusion. Pulmonary exacerbations lead to the more progressive lung function decline in the patients with CF. Malnourishment and chronic airway colonization with Burkholderia cepacia result in more frequent pulmonary exacerbations.

Improving Detection of Rapid Cystic Fibrosis Disease Progression-Early Translation of a Predictive Algorithm Into a Point-of-Care Tool.

The clinical course of cystic fibrosis (CF) lung disease is marked by acute drops of lung function, defined clinically as rapid decline. As such, lung function is monitored routinely through pulmonary function testing, producing hundreds of measurements over the lifespan of an individual patient. Point-of-care technologies aimed at improving detection of rapid decline have been limited. Our aim in this early translational study is to develop and translate a predictive algorithm into a prototype prognostic tool for improved detection of rapid decline. The predictive algorithm was developed, validated and checked for 6-month, 1-year, and 2-year forecast accuracies using data on demographic and clinical characteristics from 30 879 patients aged 6 years and older who were followed in the U.S. Cystic Fibrosis Foundation Patient Registry from 2003 to 2015. Predictions of rapid decline based on the algorithm were compared to a detection algorithm currently being used at a CF center with 212 patients who received care between 2012–2017. The algorithm was translated into a prototype web application using RShiny, which resulted from an iterative development and refinement based on clinician feedback. The study showed that the algorithm had excellent predictive accuracy and earlier detection of rapid decline, compared to the current approach, and yielded a prototype platform with the potential to serve as a viable point-of-care tool. Future work includes implementation of this clinical prototype, which will be evaluated prospectively under real-world settings, with the aim of improving the pre-visit planning process for CF point of care. Likely extensions to other point-of-care settings are discussed.

Flexible semiparametric joint modeling: an application to estimate individual lung function decline and risk of pulmonary exacerbations in cystic fibrosis

BackgroundEpidemiologic surveillance of lung function is key to clinical care of individuals with cystic fibrosis, but lung function decline is nonlinear and often impacted by acute respiratory events known as pulmonary exacerbations. Statistical models are needed to simultaneously estimate lung function decline while providing risk estimates for the onset of pulmonary exacerbations, in order to identify relevant predictors of declining lung function and understand how these associations could be used to predict the onset of pulmonary exacerbations.MethodsUsing longitudinal lung function (FEV1) measurements and time-to-event data on pulmonary exacerbations from individuals in the United States Cystic Fibrosis Registry, we implemented a flexible semiparametric joint model consisting of a mixed-effects submodel with regression splines to fit repeated FEV1 measurements and a time-to-event submodel for possibly censored data on pulmonary exacerbations. We contrasted this approach with methods currently used in epidemiological studies and highlight clinical implications.ResultsThe semiparametric joint model had the best fit of all models examined based on deviance information criterion. Higher starting FEV1 implied more rapid lung function decline in both separate and joint models; however, individualized risk estimates for pulmonary exacerbation differed depending upon model type. Based on shared parameter estimates from the joint model, which accounts for the nonlinear FEV1 trajectory, patients with more positive rates of change were less likely to experience a pulmonary exacerbation (HR per one standard deviation increase in FEV1 rate of change = 0.566, 95% CI 0.516–0.619), and having higher absolute FEV1 also corresponded to lower risk of having a pulmonary exacerbation (HR per one standard deviation increase in FEV1 = 0.856, 95% CI 0.781–0.937). At the population level, both submodels indicated significant effects of birth cohort, socioeconomic status and respiratory infections on FEV1 decline, as well as significant effects of gender, socioeconomic status and birth cohort on pulmonary exacerbation risk.ConclusionsThrough a flexible joint-modeling approach, we provide a means to simultaneously estimate lung function trajectories and the risk of pulmonary exacerbations for individual patients; we demonstrate how this approach offers additional insights into the clinical course of cystic fibrosis that were not possible using conventional approaches.

A semiquantitative MRI-Score can predict loss of lung function in patients with cystic fibrosis: Preliminary results.

To evaluate the applicability of a semiquantitative MRI scoring system (MR-CF-S) as a prognostic marker for clinical course of cystic fibrosis (CF) lung disease. This observational study of a single-centre CF cohort included a group of 61 patients (mean age 12.9 ± 4.7years) receiving morphological and functional pulmonary MRI, pulmonary function testing (PFT) and follow-up of 2years. MRI was analysed by three raters using MR-CF-S. The inter-rater agreement, correlation of score categories with forced expiratory volume in 1s (FEV1) at baseline, and the predictive value of clinical parameters, and score categories was assessed for the whole cohort and a subgroup of 40 patients with moderately impaired lung function. The inter-rater agreement of MR-CF-S was sufficient (mean intraclass correlation coefficient 0.92). MR-CF-S (-0.62; p < 0.05) and most of the categories significantly correlated with FEV1. Differences between patients with relevant loss of FEV1 (>3%/year) and normal course were only significant for MR-CF-S (p < 0.05) but not for clinical parameters. Centrilobular opacity (CO) was the most promising score category for prediction of a decline of FEV1 (area under curve: whole cohort 0.69; subgroup 0.86). MR-CF-S is promising to predict a loss of lung function. CO seems to be a particular finding in CF patients with an abnormal course. • Lung imaging is essential in the diagnostic work-up of CF patients • MRI serves as a powerful, radiation-free modality in paediatric CF patients • Observational single-centre study showed significant correlation of MR-CF score and FEV 1 • MR-CF score is promising in predicting a loss of lung function.

Molecular Epidemiology of Nontuberculous Mycobacteria in a German CF Center and Clinical Course of NTM Positive Patients

Goal of this study was to analyse the clinical course of cystic fibrosis (CF) patients with nontuberculous mycobacteria (NTM) in their respiratory secretions and to investigate the molecular epidemiology of the most prevalent NTM species by multilocus sequence analysis (MLSA). The respiratory specimen and the clinical parameters forced expiratory volume in one second (FEV1), body-mass-index (BMI), erythrocyte sedimentation rate (ESR) 1 h and immunoglobulin G (IgG) of 357 CF patients, 0 - 52.4 years, mean FEV1 2009 81.5% pred were analysed between 1998 and 2010. In 13 patients NTM were detected. 12 of 13 patients carried M. abscessus, for one patient the NTM species was not characterized. 4 patients carried a second NTM species (M. avium, M. chelonae (2x), M. intracellulare). 6 patients exhibited a significant decline in FEV1, however changes in BMI, IgG and ESR were discordant. Molecular genotyping of M. abscessus isolates revealed a unique MLSA pattern in 6 patients. 2 patients harboured identical strains, and one patient a closely related strain. Whether the presence of identical strains is attributed to the acquisition of NTM clones from common environmental sources or to patient-to-patient transmission cannot be definitely clarified. Although cross-in- fection of the three patients with identical/closely related strains in the present cohort is highly unlikely, we recommend strict hygiene measures for all CF patients harbouring NTM.

Reference percentiles for FEV1 and BMI in European children and adults with cystic fibrosis

BackgroundThe clinical course of Cystic Fibrosis (CF) is usually measured using the percent predicted FEV1 and BMI Z-score referenced against a healthy population, since achieving normality is the ultimate goal of CF care. Referencing against age and sex matched CF peers may provide valuable information for patients and for comparison between CF centers or populations. Here, we used a large database of European CF patients to compute CF specific reference equations for FEV1 and BMI, derived CF-specific percentile charts and compared these European data to their nearest international equivalents.Methods34859 FEV1 and 40947 BMI observations were used to compute European CF specific percentiles. Quantile regression was applied to raw measurements as a function of sex, age and height. Results were compared with the North American equivalent for FEV1 and with the WHO 2007 normative values for BMI.ResultsFEV1 and BMI percentiles illustrated the large variability between CF patients receiving the best current care. The European CF specific percentiles for FEV1 were significantly different from those in the USA from an earlier era, with higher lung function in Europe. The CF specific percentiles for BMI declined relative to the WHO standard in older children. Lung function and BMI were similar in the two largest contributing European Countries (France and Germany).ConclusionThe CF specific percentile approach applied to FEV1 and BMI allows referencing patients with respect to their peers. These data allow peer to peer and population comparisons in CF patients.

AGER -429T/C Is Associated with an Increased Lung Disease Severity in Cystic Fibrosis

The clinical course of cystic fibrosis (CF) varies between patients bearing identical CFTR mutations, suggesting the involvement of modifier genes. We assessed the association of lung disease severity with the variant AGER -429 T/C, coding for RAGE, a pro-inflammatory protein, in CF patients from the French CF Gene Modifier Study. We analyzed the lung function of 967 CF patients p.Phe508del homozygous. FEV1 was analyzed as CF-specific percentile adjusted on age, height and mortality. AGER -429T/C polymorphism was genotyped and its function was evaluated in vitro by measurement of the luciferase activity. AGER -429 minor allele (C) was associated with poorer lung function (p = 0.03). In vitro, the promoter activity was higher in cells transfected with AGER -429C compared to cells transfected with the AGER -429T allele (p = 0.016 in BEAS-2B cells). AGER seems to be a modifier gene of lung disease severity in CF, and could be an interesting biomarker of CF airway inflammation. The functional promoter AGER -429C variant is associated with an increased RAGE expression that can lead to an increased lung inflammation and a more severe lung disease.

The impact of newborn screening and earlier intervention on the clinical course of cystic fibrosis

Cystic fibrosis is a life-limiting condition which is readily diagnosed in the vast majority of cases on newborn screening [NBS]. A diagnosis made on newborn screening translates into earlier initiation of therapies, improved growth, better lung function into the adult years and culminates in better survival.

Mutações do gene cystic fibrosis transmembrane conductance regulator e deleções dos genes glutationa S-transferase em pacientes com fibrose cística no Brasil

OBJETIVO: Determinar os efeitos que a mutação do gene cystic fibrosis transmembrane conductance regulator (CFTR) e da deleção dos genes glutationa S-transferase (GST) mu-1 (GSTM1) e teta-1 (GSTT1) têm na evolução clínica da fibrose cística (FC) em pacientes da região sudeste do Brasil. MÉTODOS: Entre março de 2002 e março de 2005, incluímos no estudo todos os pacientes com FC atendidos consecutivamente no Departamento de Pediatria do Hospital de Clínicas da Faculdade de Ciências Médicas da Universidade Estadual de Campinas. O DNA genômico de 66 pacientes com FC foi analisado por PCR e digestão com endonuclease de restrição para a identificação dos genótipos. RESULTADOS: A mutação ΔF508 do gene CFTR foi identificada em 44 (66,7%) pacientes. As deleções dos genes GSTM1, GSTT1 e da combinação nula GSTM1/GSTT1 foram identificadas em 40,9%, 15,2% e 3,0% dos pacientes, respectivamente. A mutação ΔF508 do gene CFTR foi mais comum em pacientes diagnosticados com FC antes dos 2,5 anos de idade que naqueles diagnosticados mais tarde (75,5% vs. 41,2%; p = 0,008). CONCLUSÕES: Foram observadas frequências similares da mutação ΔF508 do gene CFTR e dos genótipos GSTM1 e GSTT1 nos pacientes, independentemente do sexo, etnia ou status da doença pulmonar ou pancreática. Quando os pacientes foram estratificados por aspectos clínicos e epidemiológicos, as frequências dos genótipos GSTM1 e GSTT1 nulos foram semelhantes, sugerindo que a ausência herdada dessas vias enzimáticas não altera o curso da FC. Em contraste, a alta frequência da mutação ΔF508 no gene CFTR encontrada em pacientes mais jovens sugere que essa mutação influencia a idade no momento do diagnóstico de FC nessa região do país.

Clinical course of cystic fibrosis on adult patients carrying "mild" mutations

Clinical course of cystic fibrosis on adult patients carrying "mild" mutations

Therapeutic approaches to chronic cystic fibrosis respiratory infections with available, emerging aerosolized antibiotics

Chronic airway infection and inflammation are key events in the clinical course of cystic fibrosis (CF). The most relevant, best investigated strain of bacteria in these circumstances is Pseudomonas aeruginosa. Since pulmonary infection with P. aeruginosa is localized in the lower conducting airways, treatment is accessible with the use of inhaled aerosolized antibiotics. Tobramycin inhalation solution was the first antibiotic to be developed and approved (in 1998) for use as an aerosolized antibiotic in patients with CF. The only other aerosolized antibiotic indicated for this use is aztreonam lysine solution for inhalation, which has been approved by both European and US authorities. In prospective, randomized, controlled trails, both agents exhibited a very acceptable safety profile, along with an increase in forced expiratory volume in 1 second and other clinically relevant endpoints. New developments focus on such components as reducing the treatment burden by using dry power inhalers, decreasing inhalation frequency to once daily, penetrating P. aeruginosa biofilms, and combining two antibiotics in one solution for inhalation. However, the ideal aerosolized antibiotic regimen for the treatment of chronic P. aeruginosa infection has yet not been selected.

Nongenetic influences on cystic fibrosis outcomes

Despite dramatic improvements over the last several decades, tremendous variation exists in cystic fibrosis (CF) health outcomes. Genetic explanations for variations in disease progression are a promising source of information regarding disease biology and pathophysiology, but an understanding of nongenetic factors provides more immediate tools for improving disease outcomes. The clinical course of CF for any individual with CF is determined by the interaction of genetic endowment (including CFTR and modifier genes), the physical environment (including environmental tobacco smoke, outdoor pollution, and pathogenic microorganisms), the sociodemographic, cultural, and family context (which mediates stress, social support, and disease self-management skills), and variations in delivery and acceptance of healthcare treatments. The evidence linking socioeconomic status (SES) with CF outcomes continues to be strong, and appears to be primarily due to associations with environmental and sociocultural stressors and disease-management behaviors rather than barriers in access to healthcare. Attempts to eliminate detrimental environmental exposures, improve disease self-management skills, and ensure consistently optimal healthcare practices will likely decrease variations in outcomes including SES-related disparities. Low SES is an important marker of adverse exposures and outcomes which are present throughout the CF population.