Lung function and disease severity in cystic fibrosis patients heterozygous for p.Arg117His

Expression of p.Arg117His cystic fibrosis (CF) transmembrane conductance regulator is influenced by a polythymidine (poly-T) tract and a thymidine–guanine (TG) repeat on intron 9, which vary in length and affect exon 10 skipping.We compared clinical characteristics and the rate of progression of lung disease of CF patients carrying the p.Arg117His mutation with different intron 9 varying sequences (poly-T) and mutation classes in trans.Data were collected from patients in Northern Ireland, UK, including diagnostic features, sweat chloride, nutritional status, sputum microbiology, CF-related complications and lung function. Poly-T and TG repeats were determined by PCR. Forced expiratory volume in 1 s (FEV1) decline was determined from linear regression of FEV1 measurements of patients over time.We identified 62 patients with p.Arg117His, 55 with a class I/II mutation in trans and six with p.Arg117His/p.Gly551Asp. 42 patients had 5T and 13 had 7T. All patients had 12 TG repeats. Patients with p.Arg117His-5T had greater lung function decline, sweat chloride concentrations, pancreatic insufficiency and prevalence of Pseudomonas aeruginosa infection compared with patients with p.Arg117His-7T.Lung function decline and disease severity in p.Arg117His is determined by the poly-T tract length and identity of the mutation in trans. Patients with p.Arg117His-5T and a second class I/II mutation have a severity similar to p.Phe508del homozygous patients, although lung function decline is delayed to an older age. There may be linkage disequilibrium between p.Arg117His and 12 TG repeats.

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Clinical Presentation of the c.3844T>C (p.Trp1282Arg, W1282R) Variant in Russian Cystic Fibrosis Patients

Genes ◽

10.3390/genes11101137 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1137

Author(s):

Nika V. Petrova ◽

Nataliya Y. Kashirskaya ◽

Stanislav A. Krasovskiy ◽

Elena L. Amelina ◽

Elena I. Kondratyeva ◽

...

Keyword(s):

Lung Function ◽

Severe Disease ◽

Pancreatic Insufficiency ◽

Clinical Manifestations ◽

Chloride Concentration ◽

Class I ◽

Sweat Test ◽

Microbial Infection ◽

Sweat Chloride ◽

In Trans

The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical manifestations and complications (the age at CF diagnosis, sweat test, pancreatic status, lung function, microbial infection, body mass index (BMI), the presence of meconium ileus (MI), diabetes, and severe liver disease) were compared in four groups: group 1—patients carrying c.3844T>C and severe class I or II variant in trans; group 2—3849+10kbC>T/F508del patients; group 3—F508del/F508del patients; and group 4—patients with W1282R and “mild” variant in trans. Based on the analyses, W1282R with class I or II variant in trans appears to cause at least as severe CF symptoms as F508del homozygotes as reflected in the early age of diagnosis, high sweat chloride concentration, insufficient pancreatic function, and low lung function, in contrast to 3849+10kbC-T/F508del compound heterozygotes having milder clinical phenotypes. The W1282R pathogenic variant is seemed to lead to severe disease phenotype with pancreatic insufficiency similarly to the F508del homozygous genotype.

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1014 Relationship Between Lung Function and Obstructive Sleep Apnea in Cystic Fibrosis

SLEEP ◽

10.1093/sleep/zsaa056.1010 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A385-A385

Author(s):

A Shakkottai ◽

S Z Nasr ◽

F Hassan ◽

L M O’Brien ◽

R D Chervin

Keyword(s):

Cystic Fibrosis ◽

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Lung Function ◽

Forced Expiratory Volume ◽

Apnea Hypopnea Index ◽

Lung Function Decline ◽

Obstructive Sleep ◽

Larger Sample ◽

Training Grant

Abstract Introduction The frequency of obstructive sleep apnea (OSA) may be high among patients with cystic fibrosis (CF), a life-shortening, genetic respiratory disease that affects approximately 30,000 Americans. Yet, the potential relationship between OSA and lung function has not been thoroughly explored. Methods Single-center retrospective review of polysomnography (PSG) results from 2009-2017 in referred patients with CF and available pulmonary function data (PFTs) obtained at time of PSG and at 3, 6, 9, and 12-months prior. Results Mean ages were 11.1±3.9 (sd) and 37.1±14.1 years, among 18 children and 16 adults, respectively. Mean body mass index (BMI) was normal in both groups (62.5±26.6% in children; 25.1±6.4 kg/m2 in adults). Twenty-six subjects (76%) had OSA (apnea-hypopnea index >1 in children, ≥5 in adults). Mean forced expiratory volume in 1 second percent predicted (FEV1 PPD) was higher among subjects with vs. without OSA at PSG and at each time-point in the year prior, independent of age and BMI at PSG (longitudinal mixed effects model, β=19.0, SE=8.1, p=0.028). While FEV1 PPD remained unchanged in the non-OSA group, FEV1 PPD at PSG was lower, in comparison to the year prior in subjects with OSA, with the greatest difference observed at 9-months prior to PSG (2-sample t-test, difference of -6.6% vs 0.6% in OSA vs. non-OSA groups respectively, p=0.078). Conclusion The PFTs, as daytime markers of CF lung disease severity, do not seem to reliably predict risk for OSA. In our sample, CF patients with vs. without OSA had better PFTs at baseline but they also showed a greater tendency for decline in PFTs over the year prior to OSA diagnosis. Larger sample size and longer duration of assessment may help, going forward, to assess any potential adverse impact of OSA on lung function decline. Support NIH Training Grant (T32NS007222, F32HL145915)

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Lung function over the life course of paediatric and adult patients with cystic fibrosis from a large multi-centre registry

Scientific Reports ◽

10.1038/s41598-020-74502-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Arul Earnest ◽

Farhad Salimi ◽

Claire E. Wainwright ◽

Scott C. Bell ◽

Rasa Ruseckaite ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Mixed Model ◽

Linear Mixed Model ◽

Pancreatic Insufficiency ◽

Forced Expiratory Volume ◽

Rate Of Change ◽

Data Registry ◽

Mortality Outcome ◽

The Impact

Abstract A key measure of lung function in people with Cystic Fibrosis (CF) is Forced Expiratory Volume in the first second FEV1 percent predicted (FEV1pp). This study aimed to address challenges in identifying predictors of FEV1pp, specifically dealing with non-linearity and the censoring effect of death. Data was obtained from a large multi-centre Australian Cystic Fibrosis Data Registry (ACFDR). A linear mixed model was used to study FEV1pp as the endpoint. There were 3655 patients (52.4% male) included in our study. Restricted cubic splines were used to fit the non-linear relationship between age of visit and FEV1pp. The following predictors were found to be significant in the multivariate model: age of patient at visit, BMI z-score, age interaction with lung transplantation, insulin dependent diabetes, cirrhosis/portal hypertension, pancreatic insufficiency, Pseudomonas aeruginosa infection and baseline variability in FEV1pp. Those with P. aeruginosa infection had a lower mean difference in FEV1pp of 4.7 units, p < 0.001 compared to those who did not have the infection. Joint modelling with mortality outcome did not materially affect our findings. These models will prove useful for to study the impact of CFTR modulator therapies on rate of change of lung function among patients with CF.

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Burkholderia dolosa phenotypic variation during the decline in lung function of a cystic fibrosis patient during 5.5 years of chronic colonization

Journal of Medical Microbiology ◽

10.1099/jmm.0.069849-0 ◽

2014 ◽

Vol 63 (4) ◽

pp. 594-601 ◽

Cited By ~ 9

Author(s):

Ana Sílvia Moreira ◽

Carla P. Coutinho ◽

Pilar Azevedo ◽

Luís Lito ◽

José Melo-Cristino ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Fungal Pathogens ◽

Forced Expiratory Volume ◽

Burkholderia Cenocepacia ◽

Epidemiological Surveillance ◽

Lung Function Decline ◽

Swarming Motility ◽

Systematic Assessment ◽

Chronic Colonization

Although rarely isolated from cystic fibrosis (CF) patients, Burkholderia dolosa is associated with accelerated lung function decline. During 18 years of epidemiological surveillance in the major Portuguese CF centre in Lisbon, only one patient was infected with B. dolosa. Pulmonary deterioration, associated with the evolution of forced expiratory volume in 1 s, occurred during 5.5 years of colonization with this B. dolosa clone (with the new sequence type ST-668). Transient co-colonization with Burkholderia cenocepacia and other bacterial and fungal pathogens occurred, but B. dolosa prevailed until the patient’s death. The systematic assessment of relevant phenotypes for the sequential clonal isolates examined in this retrospective study (14 of B. dolosa and four of B. cenocepacia) showed that they were variants, although in general no isolation time-dependent pattern of alteration was identified. However, the first B. dolosa isolate retrieved was more susceptible to gentamicin, imipenem and tobramycin, and exhibited a higher swarming motility compared with most of the isolates obtained during the later stages of disease progression and antimicrobial therapy.

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

Vojnosanitetski pregled ◽

10.2298/vsp171114005g ◽

2019 ◽

Vol 76 (11) ◽

pp. 1110-1114

Author(s):

Bojana Gojsina ◽

Milan Rodic ◽

Jelena Visekruna ◽

Goran Trajkovic ◽

Aleksandar Sovtic ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Burkholderia Cepacia ◽

Negative Impact ◽

Bacterial Colonization ◽

Forced Expiratory Volume ◽

Lung Function Decline ◽

Pulmonary Exacerbations ◽

Fev1 Decline

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.

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Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function

European Respiratory Journal ◽

10.1183/13993003.02529-2017 ◽

2018 ◽

Vol 52 (3) ◽

pp. 1702529 ◽

Cited By ~ 18

Author(s):

Karin M. de Winter-de Groot ◽

Hettie M. Janssens ◽

Rick T. van Uum ◽

Johanna F. Dekkers ◽

Gitte Berkers ◽

...

Keyword(s):

Cystic Fibrosis ◽

Disease Severity ◽

Gastrointestinal Disease ◽

Pancreatic Insufficiency ◽

Chloride Concentration ◽

Individual Level ◽

Outcome Parameters ◽

Sweat Chloride ◽

Intestinal Organoids ◽

Residual Capacity

Forskolin-induced swelling (FIS) of intestinal organoids from individuals with cystic fibrosis (CF) measures function of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in CF.We investigated whether FIS corresponds with clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF. Relationships with FIS were studied for indicators of pulmonary and gastrointestinal disease.Children with low FIS had higher levels of immunoreactive trypsinogen (p=0.030) and pancreatitis-associated protein (p=0.039), more often had pancreatic insufficiency (p<0.001), had more abnormalities on chest computed tomography (p=0.049), and had lower z-scores for maximal expiratory flow at functional residual capacity (p=0.033) when compared to children with high FIS values. FIS significantly correlated with sweat chloride concentration (SCC) and intestinal current measurement (ICM) (r= −0.82 and r=0.70, respectively; both p<0.001). Individual assessment of SCC, ICM and FIS suggested that FIS can help to classify individual disease severity.Thus, stratification by FIS identified subgroups that differed in pulmonary and gastrointestinal outcome parameters. FIS of intestinal organoids correlated well with established CFTR-dependent biomarkers such as SCC and ICM, and performed adequately at group and individual level in this proof-of-concept study.

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Cystic-fibrosis related-diabetes (CFRD) is preceded by and associated with growth failure and deteriorating lung function

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0005 ◽

2017 ◽

Vol 30 (8) ◽

Cited By ~ 13

Author(s):

Nicolas Terliesner ◽

Mandy Vogel ◽

Anna Steighardt ◽

Ruth Gausche ◽

Constance Henn ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Children And Adolescents ◽

Pancreatic Insufficiency ◽

Growth Failure ◽

Forced Expiratory Volume ◽

Exocrine Pancreatic Insufficiency ◽

Retrospective Case ◽

Poor Growth ◽

Impaired Lung Function

AbstractBackground:Impaired glucose metabolism and cystic fibrosis (CF)-related diabetes (CFRD) are associated with insufficient weight gain and impaired lung function in children and adolescents with CF. We have asked whether imminent CFRD may be a cause of poor growth in children and adolescents.Methods:A retrospective case control study including 32 patients with CF with or without diabetes was conducted. Sixteen pairs, matched according to age, gender and exocrine pancreatic insufficiency, were analysed. Standard deviation scores (SDS) of height, growth, weight, body mass index (BMI), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and forced expiratory flow at 75% of expired FVC (FEF75) were recorded during a mean observation period of 13 years per patient.Results:SDS of height and weight were reduced in CF patients with diabetes compared to those without, not only at the point of diagnosis (both p<0.05) but years before the evidence of diabetes. Afterwards there was a significant decline in height (p<0.001) and weight (p<0.01) SDS in CFRD patients and an increasing difference between the height and weight of CF patients with or without diabetes. In contrast, no significant reduction of BMI-SDS was observed in CFRD patients. All analysed lung function parameters showed a marked decline in CFRD patients starting 1 year prior to the diagnosis of diabetes.Conclusions:Deteriorating growth, reduced weight and impaired lung function are related to the development of CFRD and are obvious several years before the actual diagnosis of diabetes.

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Single nucleotide variants in Pseudomonas aeruginosa populations from sputum correlate with baseline lung function and predict disease progression in individuals with cystic fibrosis

10.1101/2021.10.04.21264421 ◽

2021 ◽

Author(s):

Morteza M Saber ◽

Jannik Donner ◽

Inès Levade ◽

Nicole Acosta ◽

Michael D Perkins ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Genetic Variation ◽

Lung Function ◽

Lung Disease ◽

Disease Severity ◽

Single Nucleotide Variants ◽

Lung Function Decline ◽

Single Nucleotide ◽

Lung Disease Severity

Complex polymicrobial communities inhabit the lungs of individuals with cystic fibrosis (CF) and contribute to the decline in lung function. However, the severity of lung disease and its progression in CF patients are highly variable and imperfectly predicted by host clinical factors at baseline, CFTR mutations in the host genome, or sputum polymicrobial community variation. The opportunistic pathogen Pseudomonas aeruginosa (Pa) dominates airway infections in the majority of CF adults. Here we hypothesized that genetic variation within Pa populations would be predictive of lung disease severity. To quantify Pa genetic variation within whole CF sputum samples, we used deep amplicon sequencing on a newly developed custom Ion AmpliSeq panel of 209 Pa genes previously associated with the host pathoadaptation and pathogenesis of CF infection. We trained machine learning models using Pa single nucleotide variants (SNVs), clinical and microbiome diversity data to classify lung disease severity at the time of sputum sampling, and to predict future lung function decline over five years in a cohort of 54 adult CF patients with chronic Pa infection. The models using Pa SNVs alone classified baseline lung disease with good sensitivity and specificity, with an area under the receiver operating characteristic curve (AUROC) of 0.87. While the models were less predictive of future lung function decline, they still achieved an AUROC of 0.74. The addition of clinical data to the models, but not microbiome community data, yielded modest improvements (baseline lung function: AUROC=0.92; lung function decline: AUROC=0.79), highlighting the predictive value of the AmpliSeq data. Together, our work provides a proof-of-principle that Pa genetic variation in sputum is strongly associated with baseline lung disease, moderately predicts future lung function decline, and provides insight into the pathobiology of Pa's effect on CF.

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Improving lung function in adolescents with CF by tracking annual rate of lung function decline

BMJ Open Quality ◽

10.1136/bmjoq-2020-001199 ◽

2021 ◽

Vol 10 (3) ◽

pp. e001199

Author(s):

Sydney Schiff ◽

Miah Starks ◽

Rachel W Linnemann

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Forced Expiratory Volume ◽

Rapid Decline ◽

Lung Function Decline ◽

Progressive Decline ◽

Individual Patient Level ◽

Proactive Approach ◽

Level Data ◽

Lung Health

BackgroundFor patients with cystic fibrosis (CF), sustaining lung function through the adolescent years is crucial to slow the progressive decline that leads to significant morbidity and early mortality. This holds true for patients with high per cent predicted forced expiratory volume in 1 s (ppFEV1), as they may receive less vigilant monitoring and treatment. Early identification of lung function decline followed by aggressive treatment can lead to preservation of lung function.InterventionThe Emory+Children’s Pediatric Cystic Fibrosis Program implemented multiple quality improvement (QI) initiatives to identify and aggressively treat adolescent patients with a rapid decline in lung function. These initiatives included (1) lung zones to categorise and highlight lung function decline, (2) individual lung decline tables for quick reference, (3) a lung health algorithm to encourage uniformity, (4) a rapid decliner checklist to identify potential reasons for individual decline and (5) an automated individual patient-level data report and centre scorecard. We tested these interventions with plan–do–study–act cycles and refined as needed.ResultsImplementation of these QI initiatives resulted in overall improvement in lung function and slowing of lung function decline among adolescents with CF . This improvement could be attributed to the more standardised and proactive approach to decreases in lung function and the increased clinician attention to patients with rapid decline, especially for patients with high baseline ppFEV1.

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Lung function decline is associated with serum uric acid in Korean health screening individuals

Scientific Reports ◽

10.1038/s41598-021-89678-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kyung-Min Ahn ◽

Suh-Young Lee ◽

So-Hee Lee ◽

Sun-Sin Kim ◽

Heung-Woo Park

Keyword(s):

Uric Acid ◽

Lung Function ◽

Serum Uric Acid ◽

Uric Acid Level ◽

Acid Level ◽

Serum Uric Acid Level ◽

Forced Expiratory Volume ◽

Linear Regression Models ◽

Lung Function Decline ◽

Health Screenings

AbstractWe performed a retrospective cohort study of 19,237 individuals who underwent at least three health screenings with follow-up periods of over 5 years to find a routinely checked serum marker that predicts lung function decline. Using linear regression models to analyze associations between the rate of decline in the forced expiratory volume in 1 s (FEV1) and the level of 10 serum markers (calcium, phosphorus, uric acid, total cholesterol, total protein, total bilirubin, alkaline phosphatase, aspartate aminotransferase, creatinine, and C-reactive protein) measured at two different times (at the first and third health screenings), we found that an increased uric acid level was significantly associated with an accelerated FEV1 decline (P = 0.0014 and P = 0.037, respectively) and reduced FEV1 predicted % (P = 0.0074 and P = 8.64 × 10–7, respectively) at both visits only in non-smoking individuals. In addition, we confirmed that accelerated forced vital capacity (FVC) and FEV1/FVC ratio declines were observed in non-smoking individuals with increased serum uric acid levels using linear mixed models. The serum uric acid level thus potentially predicts an acceleration in lung function decline in a non-smoking general population.

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