Forced Expiratory Volume in 1 Second Variability Helps Identify Patients with Cystic Fibrosis at Risk of Greater Loss of Lung Function

Cystic fibrosis is a chronic lung disease requiring frequent lung-function monitoring to track acute respiratory events (pulmonary exacerbations). The association between lung-function trajectory and time-to-first exacerbation can be characterized using joint longitudinal-survival modeling. Joint models specified through the shared parameter framework quantify the strength of association between such outcomes but do not incorporate latent sub-populations reflective of heterogeneous disease progression. Conversely, latent class joint models explicitly postulate the existence of sub-populations but do not directly quantify the strength of association. Furthermore, choosing the optimal number of classes using established metrics like deviance information criterion is computationally intensive in complex models. To overcome these limitations, we integrate latent classes in the shared parameter joint model through a fully Bayesian approach. To choose the optimal number of classes, we construct a mixture model assuming more latent classes than present in the data, thereby asymptotically “emptying” superfluous latent classes, provided the Dirichlet prior on class proportions is sufficiently uninformative. Model properties are evaluated in simulation studies. Application to data from the US Cystic Fibrosis Registry supports the existence of three sub-populations corresponding to lung-function trajectories with high initial forced expiratory volume in 1 s ( FEV1), rapid FEV1 decline, and low but steady FEV1 progression. The association between FEV1 and hazard of exacerbation was negative in each class, but magnitude varied.

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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 function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient

European Respiratory Journal ◽

10.1183/13993003.00326-2017 ◽

2017 ◽

Vol 50 (5) ◽

pp. 1700326 ◽

Cited By ~ 9

Author(s):

Gwyneth Davies ◽

Janet Stocks ◽

Lena P. Thia ◽

Ah-Fong Hoo ◽

Andrew Bush ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Early Life ◽

Treatment Protocol ◽

Forced Expiratory Volume ◽

Z Score ◽

Average Group ◽

Significant Difference ◽

Residual Capacity ◽

High Risk Infants

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45–1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify “high-risk” infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.

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P051 The bigger you are the harder you fall? Short term effects of LUM/IVA (Orkambi) on lung function in children with cystic fibrosis

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-nppc.60 ◽

2019 ◽

Vol 104 (7) ◽

pp. e2.57-e2

Author(s):

Emma O’ Grady ◽

Rebecca Finnegan ◽

Anna Smyth ◽

Stephanie Ryan ◽

Michael Williamson

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Pulmonary Function Tests ◽

Real Life ◽

Young Patients ◽

Forced Expiratory Volume ◽

List Type ◽

High Resolution Computed Tomography ◽

Air Trapping ◽

Female Ratio

AimCystic Fibrosis conductance Transmembrane Regulator (CFTR) protein modulators represent a major breakthrough in the pharmacological management of Cystic Fibrosis (CF). Previous studies report acute changes in lung function after first administration of lumacaftor/ivacaftor (LUM/IVA) without a clear underlying mechanism.1 2 Our aim was to explore links between changes in percent predicted forced expiratory volume in one second (ppFEV1) and a number of potentially influencing factors.MethodsWe conducted a retrospective review of all children with CF who were started on LUM/IVA treatment between September 2016 and August 2017 in our institution. Data was collected from patient charts, electronic laboratory and radiology records. CT Thorax images were reviewed for evidence of air trapping using the Brody score.3 Descriptive and statistical analyses were performed using SPSS. ResultsData was collected from 15 children with CF who were started on LUM/IVA treatment. The mean (±SD) age of starting treatment was 14 years (±1.7 years), with a mean weight of 47.3 kg (±8.9 kg) and male-to-female ratio of 9:6. Ninety-three percent of patients experienced an acute decline in ppFEV1 post initiation of LUM/IVA, with an absolute mean decline of -10.8% (0–20%). There is a statistically significant inverse relationship between absolute change in ppFEV1 (FEV1) and baseline ppFEV1. There is no correlation between FEV1 and weight, gender or air trapping score.ConclusionOur results suggest that a LUM/IVA related decline in lung function is more significant in CF children with higher baseline ppFEV1. This offers reassurance when initiating LUM/IVA as the patients who experience significant declines have a greater respiratory reserve with which to support this reduction. ReferencesRatjen F, Hug C, Marigowda G, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med 2017;5:557–567.Labaste A, Ohlmann C, Mainguy C, et al. Real-life acute lung function changes after lumacaftor/ivacaftor first administration in paediatric patients with cystic fibrosis. J Cyst Fibros 2017;16:709–712.Brody A, Klein J, Molina P, et al. High- resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests. Journal of Pediatrics 2004;145:32–38.

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Nocturnal hyperalimentation via a gastrostomy tube in children with cystic fibrosis

Voprosy praktičeskoj pediatrii ◽

10.20953/1817-7646-2021-2-22-34 ◽

2021 ◽

Vol 16 (2) ◽

pp. 22-34

Author(s):

I. Sokolov ◽

◽

E.A. Roslavtseva ◽

V.P. Chernevich ◽

N.I. Burkina ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Nutritional Status ◽

Body Weight Gain ◽

Forced Expiratory Volume ◽

Gastrostomy Tube ◽

Percutaneous Endoscopic Gastrostomy Tube ◽

Endoscopic Control ◽

Low Profile ◽

The Mean

Objective. To assess the efficacy of nocturnal hyperalimentation via a low-profile gastrostomy tube for in the improvement of nutritional status and lung function in children with severe cystic fibrosis (CF). Patients and methods. We used nocturnal hyperalimentation with a nutrient solution via a low-profile gastrostomy tube installed under endoscopic control to improve nutritional status of 16 CF children with severe protein-calorie malnutrition aged between 5.5 and 17.5 years. The mean duration of nocturnal hyperalimentation was 1.3 years (range: 7 months–54 months). The nutritional status was evaluated using the WHOAntho Plus software; pulmonary function was evaluated by assessing forced expiratory volume in 1 minute (FEV1) and the number of bronchopulmonary exacerbations per year. Results. All children demonstrated an improvement in their weight and height. After the first 12 months, the mean body weight gain was 5 kg; during the second and third years, children gained 4 kg and nearly 2 kg, respectively. The mean increase in height was 7 cm in the first year, 10 cm in the second year, and 4 cm in the third year. All patients except one had an increase in FEV1 and fewer exacerbations. Complications after gastrostomy were rare and easily addressed. Conclusion. Nocturnal hyperalimentation via a percutaneous endoscopic gastrostomy tube is an effective and safe method of improving nutritional status in children with CF, which delays the progression of bronchopulmonary lesions and lung function reduction, improves the prognosis and quality of life. Key words: cystic fibrosis, children, nutritional status, lung function, enteral nutrition, low-profile gastrostomy tube, nocturnal hyperalimentation

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The effect of age and genotype on lung function in children with cystic fibrosis

Russian Pulmonology ◽

10.18093/0869-0189-2021-31-2-159-166 ◽

2021 ◽

Vol 31 (2) ◽

pp. 159-166

Author(s):

V. V. Shadrina ◽

A. Yu. Voronkova ◽

M. A. Starinova ◽

O. I. Simonova ◽

D. F. Sergienko ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Russian Federation ◽

Age Groups ◽

Forced Expiratory Volume ◽

Functional Disorders ◽

Significant Difference ◽

The Russian Federation ◽

Effect Of Age ◽

Adolescent Period

Identifying the initial manifestations of pulmonary functional disorders associated with cystic fibrosis (CF) is essential for timely correction of the therapy and improvement of the prognosis.The aim of the study was to identify the age periods with the highest risk of a decrease in lung function in children with different CF genotypes.Methods. Lung function (LF) was analyzed using spirometry results in CF patients aged 6 to 18 years from the Registry of patients with cystic fibrosis in the Russian Federation 2018.Results. The forced expiratory volume in one second (FEV1) was statistically significantly lower in children aged 6 – 10 years with “severe” genotypes than in the children with “mild” genotypes. The lung function was reduced at 11 – 14 years of age in both “severe» and “mild” genotypes without any statistically significant difference. In general, the trend of a decrease in lung function in “severe” genotypes persists in the adolescent period from 15 to 18 years. The lung function is better in adolescents aged 15 – 18 with the “mild” variants of genotypes compared to the patients aged 11 – 14 years.Conclusion. The “severe” variants of CFTR negatively affect LF of CF patients in all age groups. The LF values in patients with “mild” genotypes at the age of 15 – 18 years were higher than in children aged 11 – 14 years with the same genotypes. There is a need for improved programs of medical care for adolescents with CF.

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The assessment of short- and long-term changes in lung function in cystic fibrosis using 129Xe MRI

European Respiratory Journal ◽

10.1183/13993003.00441-2020 ◽

2020 ◽

Vol 56 (6) ◽

pp. 2000441 ◽

Cited By ~ 3

Author(s):

Laurie J. Smith ◽

Alex Horsley ◽

Jody Bray ◽

Paul J.C. Hughes ◽

Alberto Biancardi ◽

...

Keyword(s):

Cystic Fibrosis ◽

Clinical Trials ◽

Lung Function ◽

Lung Disease ◽

Forced Expiratory Volume ◽

Longitudinal Change ◽

Response To Treatment ◽

Short Term Change ◽

Term Change ◽

Magnetic Resonance Imaging Mri

IntroductionXenon-129 (129Xe) ventilation magnetic resonance imaging (MRI) is sensitive to detect early cystic fibrosis (CF) lung disease and response to treatment. 129Xe-MRI could play a significant role in clinical trials and patient management. Here we present data on the repeatability of imaging measurements and their sensitivity to longitudinal change.Methods29 children and adults with CF and a range of disease severity were assessed twice, a median (interquartile range (IQR)) of 16.0 (14.4–19.5) months apart. Patients underwent 129Xe-MRI, lung clearance index (LCI), body plethysmography and spirometry at both visits. 11 patients repeated 129Xe-MRI in the same session to assess the within-visit repeatability. The ventilation defect percentage (VDP) was the primary metric calculated from 129Xe-MRI.ResultsAt baseline, mean±sd age was 23.0±11.1 years and forced expiratory volume in 1 s (FEV1) z-score was −2.2±2.0. Median (IQR) VDP was 9.5 (3.4–31.6)% and LCI was 9.0 (7.7–13.7). Within- and inter-visit repeatability of VDP was high. At 16 months there was no single trend of 129Xe-MRI disease progression. Visible 129Xe-MRI ventilation changes were common, which reflected changes in VDP. Based on the within-visit repeatability, a significant short-term change in VDP is >±1.6%. For longer-term follow-up, changes in VDP of up to ±7.7% can be expected, or ±4.1% for patients with normal FEV1. No patient had a significant change in FEV1; however, 59% had change in VDP >±1.6%. In patients with normal FEV1, there were significant changes in ventilation and in VDP.Conclusions129Xe-MRI is a highly effective method for assessing longitudinal lung disease in patients with CF. VDP has great potential as a sensitive clinical outcome measure of lung function and end-point for clinical trials.

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