Respir Med. 2023 Apr 6:107237. doi: 10.1016/j.rmed.2023.107237. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy have resulted in longer life expectancies, yet pulmonary exacerbations remain a leading cause of morbidity. Intravenous antibiotics is the mainstay treatment, however achieving adequate concentrations remains challenging. The effect of therapeutic drug monitoring (TDM) of beta-lactams on exacerbations and lung function has not been studied.

METHODS: Patient demographics, antibiotic regimens, forced expiratory volume 1 second (FEV1), and exacerbation history was obtained from 32 patients with cystic fibrosis admitted for exacerbations. All patients were colonized with Pseudomonas aeruginosa, received CFTR therapy for at least one year, and had 3-month interval follow ups. Plasma concentrations, FEV1, and exacerbation history was obtained before and after therapeutic drug monitoring. This included peak and trough plasma concentrations of piperacillin-tazobactam and cefepime using liquid chromatography with mass spectrometry. T-test and Mann-Whitney U test were used to compare medians/means of FEV1 and pulmonary exacerbations pre and post-TDM as well as free trough-to-minimum inhibitory concentration ratio (fCmin/MIC) ≥1 and ≥ 4.

RESULTS: TDM was associated with decreased exacerbations/year from 1.91 to 1.31 (p = 0.04) and among the cohort with >/ = 2 exacerbations per year, there was a longer exacerbation free interval after TDM (196.2 vs 103.7 days, p = 0.02). The decline in FEV1% predicted after therapeutic drug monitoring to the first exacerbation was -4.9 compared to -9.7 prior (p = 0.03).

CONCLUSIONS: TDM for cystic fibrosis pulmonary exacerbations results in decreased pulmonary exacerbations, longer intervals to pulmonary exacerbation, and lower decline in FEV1% predicted.

PMID:37030586 | DOI:10.1016/j.rmed.2023.107237

Diabetes Metab. 2023 Apr 6:101444. doi: 10.1016/j.diabet.2023.101444. Online ahead of print.

ABSTRACT

The increase in life expectancy of patients with cystic fibrosis has come with new comorbidities, particularly diabetes. The gradual development of glucose tolerance abnormalities means that 30 to 40% of adults will be diabetic. Cystic fibrosis-related diabetes is a major challenge in the care of these patients because it is a morbidity and mortality factor at all stages of the disease. Early glucose tolerance abnormalities observed from childhood, before the stage of diabetes, are also associated with a poor pulmonary and nutritional outcome. The long asymptomatic period justifies systematic screening with an annual oral glucose tolerance test from the age of 10 years. However, this strategy does not take into account the new clinical profiles of patients with cystic fibrosis, recent pathophysiological knowledge of glucose tolerance abnormalities, and the emergence of new diagnostic tools in diabetology. In this paper, we summarise the challenges of screening in the current context of new patient profiles - patients who are pregnant, have transplants, or are being treated with fibrosis conductance transmembrane regulator modulators - and put forward an inventory of the various screening methods for cystic fibrosis-related diabetes, including their applications, limitations and practical implications.

PMID:37030530 | DOI:10.1016/j.diabet.2023.101444

Lancet Psychiatry. 2023 Apr 5:S2215-0366(23)00115-3. doi: 10.1016/S2215-0366(23)00115-3. Online ahead of print.

NO ABSTRACT

PMID:37030311 | DOI:10.1016/S2215-0366(23)00115-3

J Cyst Fibros. 2023 Apr 5:S1569-1993(23)00084-X. doi: 10.1016/j.jcf.2023.03.020. Online ahead of print.

ABSTRACT

INTRODUCTION: Following availability of the highly effective cystic fibrosis (CF) transmembrane conductance regulator modulator, elexacaftor/tezacaftor/ivacaftor, there was a near doubling of pregnancies reported in the United States (US) in people with CF. We sought to determine health impacts of planned (PP) versus unplanned pregnancies (UP).

METHODS: We collected retrospective pregnancy data from January 2010-December 2020 from 11 US CF centers. After adjusting for potential confounding effects, we conducted multivariable, multilevel longitudinal regression analysis using mixed effect modeling to assess whether changes in percent predicted forced expiratory volume in one second (ppFEV1), body mass index (BMI), and pulmonary exacerbations (PEx) 1-year-pre- to 1-year-post-pregnancy were associated with pregnancy planning.

RESULTS: Our analysis included 163 people with 226 pregnancies; the cohort had a mean age at conception of 29.6 years, mean pre-pregnancy ppFEV1 of 75.4 and BMI of 22.5 kg/m2. PpFEV1 declined in both PP (adjusted decline of -2.5 (95% CI: -3.8, -1.2)) and UP (adjusted decline of -3.0 (95% CI: -4.6, -1.4)) groups, they did not differ from each other (p = 0.625). We observed a difference in change in the annual number of PEx pre- to post-pregnancy (PP: 0.8 (0.7, 1.1); UP: 1.3 (1.0, 1.7); interaction effect p = 0.029). In a subset of people with available infant data, infants resulting from UP had more preterm births, lower APGAR scores, and more intensive care unit stays.

CONCLUSIONS: Following UP, there is an increased trajectory for PEx and potentially for infant complications compared to PP. Clinicians should consider increased surveillance in the setting of UP.

PMID:37029015 | DOI:10.1016/j.jcf.2023.03.020

Ann Am Thorac Soc. 2023 Apr 7. doi: 10.1513/AnnalsATS.202211-951OC. Online ahead of print.

ABSTRACT

RATIONALE: Cystic Fibrosis (CF) is a genetic disease leading to progressive lung function loss and early mortality. Many clinical and demographic variables are associated with lung function decline, but little is known about the effects of prolonged periods of missed care.

OBJECTIVES: To determine if missed care in the US Cystic Fibrosis Foundation Patient Registry (CFFPR) is associated with decreased lung function at follow-up visits.

METHODS: De-identified US Cystic Fibrosis Foundation Patient Registry (CFFPR) data for 2004-2016 was analyzed, with the exposure of interest being ≥ 12-month gap in CF registry data. We modeled percent predicted forced expiratory volume in one second (FEV1PP) using longitudinal semiparametric modeling with natural cubic splines for age (knots at quantiles) and with subject-specific random effects, adjusted for gender and cystic fibrosis transmembrane conductance regulator (CFTR) genotype, race, and ethnicity and included time-varying covariates for gaps in care, insurance type, underweight BMI, CF-related diabetes status, and chronic infections.

RESULTS: 24,328 individuals with 1,082,899 encounters in the CFFPR met inclusion criteria. 8,413 (35%) individuals in the cohort had at least a single ≥ 12-month episode of discontinuity, whereas 15,915 (65%) had continuous care. 75.8% of all encounters preceded by a 12-month gap occurred in patients 18 years or older. Compared to those with continuous care, those with a discontinuous care episode had a lower follow-up FEV1PP at the index visit (-0.81%; 95% CI -1.00, -0.61), after adjustment for other variables. The magnitude of this difference was much greater (-2.1%; 95% CI -1.5, -2.7) in young adult F508del homozygotes.

CONCLUSIONS: There was a high rate of ≥ 12-month gap in care, especially in adults, documented in the CFFPR. Discontinuous care identified in the US CFFPR was strongly associated with decreased lung function, especially in adolescents and young adults homozygous for the F508del CFTR mutation. This may have implications for identifying and treating people with lengthy gaps in care and have implications for CFF care recommendations.

PMID:37027571 | DOI:10.1513/AnnalsATS.202211-951OC

PLoS Pathog. 2023 Apr 7;19(4):e1010942. doi: 10.1371/journal.ppat.1010942. Online ahead of print.

ABSTRACT

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

PMID:37027441 | DOI:10.1371/journal.ppat.1010942

Front Pharmacol. 2023 Mar 21;14:1158207. doi: 10.3389/fphar.2023.1158207. eCollection 2023.

ABSTRACT

Triple combination therapy with the CFTR modulators elexacaftor (ELX), tezacaftor (TEZ) and ivacaftor (IVA) has been qualified as a game changer in cystic fibrosis (CF). We provide an overview of the body of literature on ELX/TEZ/IVA published between November 2019 and February 2023 after approval by the regulators. Recombinant ELX/TEZ/IVA-bound Phe508del CFTR exhibits a wild type conformation in vitro, but in patient's tissue a CFTR glyoisoform is synthesized that is distinct from the wild type and Phe508del isoforms. ELX/TEZ/IVA therapy improved the quality of life of people with CF in the real-life setting irrespective of their anthropometry and lung function at baseline. ELX/TEZ/IVA improved sinonasal and abdominal disease, lung function and morphology, airway microbiology and the basic defect of impaired epithelial chloride and bicarbonate transport. Pregnancy rates were increasing in women with CF. Side effects of mental status changes deserve particular attention in the future.

PMID:37025483 | PMC:PMC10072268 | DOI:10.3389/fphar.2023.1158207

BMC Palliat Care. 2023 Apr 6;22(1):36. doi: 10.1186/s12904-023-01151-2.

ABSTRACT

BACKGROUND: The COVID-19 pandemic impacts on working routines and workload of palliative care (PC) teams but information is lacking how resource use and associated hospital costs for PC changed at patient-level during the pandemic. We aim to describe differences in patient characteristics, care processes and resource use in specialist PC (PC unit and PC advisory team) in a university hospital before and during the first pandemic year.

METHODS: Retrospective, cross-sectional study using routine data of all patients cared for in a PC unit and a PC advisory team during 10-12/2019 and 10-12/2020. Data included patient characteristics (age, sex, cancer/non-cancer, symptom/problem burden using Integrated Palliative Care Outcome Scale (IPOS)), information on care episode, and labour time calculated in care minutes. Cost calculation with combined top-down bottom-up approach with hospital's cost data from 2019. Descriptive statistics and comparisons between groups using parametric and non-parametric tests.

RESULTS: Inclusion of 55/76 patient episodes in 2019/2020 from the PC unit and 135/120 episodes from the PC advisory team, respectively. IPOS scores were lower in 2020 (PCU: 2.0 points; PC advisory team: 3.0 points). The number of completed assessments differed considerably between years (PCU: episode beginning 30.9%/54.0% in 2019/2020; PC advisory team: 47.4%/40.0%). Care episodes were by one day shorter in 2020 in the PC advisory team. Only slight non-significant differences were observed regarding total minutes/day and patient (PCU: 150.0/141.1 min., PC advisory team: 54.2/66.9 min.). Staff minutes showed a significant decrease in minutes spent in direct contact with relatives (PCU: 13.9/7.3 min/day in 2019/2020, PC advisory team: 5.0/3.5 min/day). Costs per patient/day decreased significantly in 2020 compared to 2019 on the PCU (1075 Euro/944 Euro for 2019/2020) and increased significantly for the PC advisory team (161 Euro/200 Euro for 2019/2020). Overhead costs accounted for more than two thirds of total costs. Direct patient cost differed only slightly (PCU: 134.7 Euro/131.1 Euro in 2019/2020, PC advisory team: 54.4 Euro/57.3 Euro).

CONCLUSIONS: The pandemic partially impacted on daily work routines, especially on time spent with relatives and palliative care problem assessments. Care processes and quality of care might vary and have different outcomes during a crisis such as the COVID-19 pandemic. Direct costs per patient/day were comparable, regardless of the pandemic.

PMID:37024852 | DOI:10.1186/s12904-023-01151-2

Life Sci Alliance. 2023 Apr 5;6(6):e202201857. doi: 10.26508/lsa.202201857. Print 2023 Jun.

ABSTRACT

Highly effective drugs modulating the defective protein encoded by the CFTR gene have revolutionized cystic fibrosis (CF) therapy. Preclinical drug-testing on human nasal epithelial (HNE) cell cultures and 3-dimensional human intestinal organoids (3D HIO) are used to address patient-specific variation in drug response and to optimize individual treatment for people with CF. This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE. Furthermore, 2D HIO showed good correlation to clinical outcome markers. A larger measurable CFTR functional range and access to the apical membrane were identified as advantages of 2D HIO over HNE and 3D HIO, respectively. Our study thus expands the utility of 2D intestinal monolayers as a preclinical drug testing tool for CF.

PMID:37024122 | DOI:10.26508/lsa.202201857

Am J Respir Crit Care Med. 2023 Apr 6. doi: 10.1164/rccm.202303-0580ED. Online ahead of print.

NO ABSTRACT

PMID:37023264 | DOI:10.1164/rccm.202303-0580ED

Orphanet J Rare Dis. 2023 Apr 5;18(1):71. doi: 10.1186/s13023-023-02685-7.

ABSTRACT

BACKGROUND: In many countries worldwide orphan drug regulations are installed but only the United States of America and Japan have an orphan device regulation. For many years surgeons have used off-label or self-assembled medical devices for the prevention, diagnosis or treatment of rare disorders. Four examples are given: an external cardiac pacemaker, a metal brace for clubfoot in newborns, a transcutaneous nerve stimulator and a cystic fibrosis mist tent.

CONCLUSION: In this article we argue that we need authorized medical devices as well as medicinal products to prevent, diagnose and treat patients with life-threatening or chronically debilitating disorders with a low prevalence/incidence. Several arguments are given to support this statement.

PMID:37020310 | DOI:10.1186/s13023-023-02685-7

J Cyst Fibros. 2023 Apr 3:S1569-1993(23)00078-4. doi: 10.1016/j.jcf.2023.03.014. Online ahead of print.

NO ABSTRACT

PMID:37019745 | DOI:10.1016/j.jcf.2023.03.014

J Heart Lung Transplant. 2023 Mar 13:S1053-2498(23)01783-7. doi: 10.1016/j.healun.2023.03.003. Online ahead of print.

ABSTRACT

BACKGROUND: The French national protocol for controlled donation after circulatory determination of death (cDCD) includes normothermic regional perfusion (NRP) in case of abdominal organ procurement and additional ex-vivo lung perfusion (EVLP) before considering lung transplantation (LT).

METHODS: We made a retrospective study of a prospective registry that included all donors considered for cDCD LT from the beginning of the program in May 2016 to November 2021.

RESULTS: One hundred grafts from 14 donor hospitals were accepted by 6 LT centers. The median duration of the agonal phase was 20 minutes [2-166]. The median duration from circulatory arrest to pulmonary flush was 62 minutes [20-90]. Ten lung grafts were not retrieved due to prolonged agonal phases (n = 3), failure of NRP insertion (n = 5), or poor in situ evaluation (n = 2). The remaining 90 lung grafts were all evaluated on EVLP, with a conversion rate of 84% and a cDCD transplantation rate of 76%. The median total preservation time was 707 minutes [543-1038]. Seventy-one bilateral LTs and 5 single LTs were performed for chronic obstructive pulmonary disease (n = 29), pulmonary fibrosis (n = 21), cystic fibrosis (n = 15), pulmonary hypertension (n = 8), graft-versus-host disease (n = 2), and adenosquamous carcinoma (n = 1). The rate of PGD3 was 9% (n = 5). The 1-year survival rate was 93.4%.

CONCLUSION: After initial acceptance, cDCD lung grafts led to LT in 76% of cases, with outcomes similar to those already reported in the literature. The relative impacts of NRP and EVLP on the outcome following cDCD LT should be assessed prospectively in the context of comparative studies.

PMID:37019731 | DOI:10.1016/j.healun.2023.03.003

ACS Biomater Sci Eng. 2023 Apr 5. doi: 10.1021/acsbiomaterials.2c01460. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is one of the most frequent genetic diseases, caused by dysfunction of the CF transmembrane conductance regulator (CFTR) chloride channel. CF particularly affects the epithelium of the respiratory system. Therapies aim at rescuing CFTR defects in the epithelium, but CF genetic heterogeneity hinders the finding of a single and generally effective treatment. Therefore, in vitro models have been developed to study CF and guide patient therapy. Here, we show a CF model on-chip by coupling the feasibility of the human bronchial epithelium differentiated in vitro at the air-liquid interface and the innovation of microfluidics. We demonstrate that the dynamic flow enhanced cilia distribution and increased mucus quantity, thus promoting tissue differentiation in a short time. The microfluidic devices highlighted differences between CF and non-CF epithelia, as shown by electrophysiological measures, mucus quantity, viscosity, and the analysis of ciliary beat frequency. The described model on-chip may be a handy instrument for studying CF and setting up therapies. As a proof of principle, we administrated the corrector VX-809 on-chip and observed a decrease in mucus thickness and viscosity.

PMID:37019688 | DOI:10.1021/acsbiomaterials.2c01460

Chest. 2023 Apr 3:S0012-3692(23)00471-3. doi: 10.1016/j.chest.2023.03.043. Online ahead of print.

ABSTRACT

BACKGROUND: Peripherally inserted central catheter(s), PICC(s), are commonly used to administer antibiotics to people with cystic fibrosis (pwCF), but their use can be complicated by venous thrombosis and catheter occlusion.

RESEARCH QUESTION: Which participant-, catheter-, and catheter management-level attributes are associated with increased risk of complications of PICCs among pwCF?

STUDY DESIGN AND METHODS: This was a prospective observational study of adults and children with cystic fibrosis (CF) who received PICCs at ten CF care centers in the US. The primary endpoint was defined as occlusion of the catheter resulting in unplanned removal and/or symptomatic venous thrombosis in the extremity containing the catheter. There were three categories of composite secondary outcomes: difficult line placement, local soft tissue or skin reactions, and catheter malfunction. Data specific to the participant, catheter placement, and catheter management were collected in a centralized database. Risk factors for primary and secondary outcomes were analyzed by multivariate logistical regression.

RESULTS: Between June 2018 and July 2021, 157 adults and 103 children over six years of age with CF had 375 PICCs placed. There were 4,828 catheter-days of observation. Of the 375 PICCs, 334 (89%) were ≤4.5 Fr, 342 (91%) were single-lumen, and 366 (98%) were placed using ultrasound guidance. The primary outcome occurred in 15 PICCs for an event rate of 3.11 per 1,000 catheter-days. There were no cases of catheter related bloodstream infection (CRBSI). Other secondary outcomes developed in 147 of 375 (39%) catheters. Despite evidence of practice variation, no risk factors for the primary outcome and few risk factors for secondary outcomes were identified.

INTERPRETATION: This study affirms the safety of contemporary approaches to inserting and utilizing PICCs in pwCF. Given the low rate of complications in this study, observations may reflect a widespread shift to selecting smaller-diameter PICC and using ultrasound to guide placement.

PMID:37019356 | DOI:10.1016/j.chest.2023.03.043

Biomed Pharmacother. 2023 Apr 3;162:114628. doi: 10.1016/j.biopha.2023.114628. Online ahead of print.

ABSTRACT

Acquired cystic fibrosis transmembrane regulator (CFTR) dysfunctions have been associated with several conditions, including myocardial infarction (MI). Here, CFTR is downregulated in brain, heart, and lung tissue and associates with inflammation and degenerative processes. Therapeutically increasing CFTR expression attenuates these effects. Whether potentiating CFTR function yields similar beneficial effects post-MI is unknown. The CFTR potentiator ivacaftor is currently in clinical trials for treatment of acquired CFTR dysfunction associated with chronic obstructive pulmonary disease and chronic bronchitis. Thus, we tested ivacaftor as therapeutic strategy for MI-associated target tissue inflammation that is characterized by CFTR alterations. MI was induced in male C57Bl/6 mice by ligation of the left anterior descending coronary artery. Mice were treated with ivacaftor starting ten weeks post-MI for two consecutive weeks. Systemic ivacaftor treatment ameliorates hippocampal neuron dendritic atrophy and spine loss and attenuates hippocampus-dependent memory deficits occurring post-MI. Similarly, ivacaftor therapy mitigates MI-associated neuroinflammation (i.e., reduces higher proportions of activated microglia). Systemically, ivacaftor leads to higher frequencies of circulating Ly6C+ and Ly6Chi cells compared to vehicle-treated MI mice. Likewise, an ivacaftor-mediated augmentation of MI-associated pro-inflammatory macrophage phenotype characterized by higher CD80-positivity is observed in the MI lung. In vitro, ivacaftor does not alter LPS-induced CD80 and tumor necrosis factor alpha mRNA increases in BV2 microglial cells, while augmenting mRNA levels of these markers in mouse macrophages and differentiated human THP-1-derived macrophages. Our results suggest that ivacaftor promotes contrasting effects depending on target tissue post-MI, which may be largely dependent on its effects on different myeloid cell types.

PMID:37018991 | DOI:10.1016/j.biopha.2023.114628

J Gen Physiol. 2023 Jun 5;155(6):e202313336. doi: 10.1085/jgp.202313336. Epub 2023 Apr 5.

ABSTRACT

Light-controlled availability for phosphorylation reveals dominant roles of select R-domain serines in CFTR channel activation.

PMID:37017643 | DOI:10.1085/jgp.202313336

Cell Death Dis. 2023 Apr 5;14(4):238. doi: 10.1038/s41419-023-05740-0.

ABSTRACT

Many anticancer agents induce apoptosis, mitotic catastrophe or cellular senescence. Here, we report the functional characterization of an experimental inducer of tumor necrosis factor (TNF)-independent necrosis, necrocide-1 (NC1). NC1 (but not its stereoisomer) killed a panel of human cancer cells (but not normal cells) at nanomolar concentrations and with a non-apoptotic, necrotic morphotype, both in vitro and in vivo. NC1-induced killing was not inhibited by caspase blockers, anti-apoptotic BCL2 overexpression or TNFα neutralization, suggesting that NC1 elicits a bona fide necrotic pathway. However, pharmacological or genetic inhibition of necroptosis, pyroptosis and ferroptosis failed to block NC1-mediated cell death. Instead, NC1 elicited reactive oxygen species (ROS) production by mitochondria, and elimination of mitochondrial DNA, quenching of mitochondrial ROS, as well as blockade of mitochondrial permeability transition with cyclosporine A, interfered with NC1-induced cell death. NC1 induced hallmarks of immunogenic cell death incurring calreticulin (CALR) exposure, ATP secretion and high mobility group box 1 (HMGB1) release. Taken together, these data identify a previously uncharacterized signaling cascade leading to an immunogenic variant of mitochondrion-regulated necrosis, supporting the notion that eliciting regulated necrosis may constitute a valid approach for anticancer therapy.

PMID:37015922 | PMC:PMC10073102 | DOI:10.1038/s41419-023-05740-0

J Gen Physiol. 2023 May 1;155(5):e202313343. doi: 10.1085/jgp.202313343. Epub 2023 Apr 4.

ABSTRACT

CFTR, unique among ABC transporters, evolved to function as an ion channel in part by optimizing the stability of the open state.

PMID:37014352 | PMC:PMC10075223 | DOI:10.1085/jgp.202313343

Respir Care. 2023 Apr 4:respcare.10428. doi: 10.4187/respcare.10428. Online ahead of print.

ABSTRACT

BACKGROUND: Whereas pulmonary exacerbations and aerobic fitness play a key role in the prognosis of cystic fibrosis (CF), the use of ventilatory threshold data as markers of exacerbation risk has been scarcely addressed. This study sought to examine the association between aerobic fitness, assessed through ventilatory threshold variables recorded during cardiopulmonary exercise testing (CPET), and the risk of exacerbations in individuals with CF.

METHODS: Participants of this retrospective cohort study were subjects from 6 y of age. Over a 4-y period, the following data were recorded: lung function indicators, CPET variables, time to first exacerbation and antibiotic use, along with demographic, clinical, and anthropometric data.

RESULTS: The mean age of 20 subjects included was 16 ± 5.4 y. Univariate regression analysis revealed that lung function (FEV1: Cox hazard ratio [HR] 0.97, P = .03; and forced expiratory flow between 25-75% of vital capacity [FEF25-75]: Cox HR 0.98, P = .036) and aerobic fitness (oxygen consumption [V̇O2 ] at ventilatory threshold: Cox HR 0.94, P = .01; and ventilatory equivalent for carbon dioxide [V̇E/V̇CO2 ] at ventilatory threshold: Cox HR 1.13, P = .049) were associated with exacerbation risk, whereas in the multivariate model, only V̇O2 at the ventilatory threshold (%max) (Cox HR 0.92, P = .01) had a significant impact on this risk. Consistently, individuals experiencing exacerbation had significantly lower V̇O2 values (%max) at the ventilatory threshold (P = .050) and higher ventilatory equivalent for oxygen consumption (V̇E/V̇O2 ) (P = .040) and V̇E/V̇O2 (P = .037) values at the ventilatory threshold. Time to exacerbation was significantly correlated with V̇O2 at the ventilatory threshold (r = 0.50, P = .02), V̇E/V̇O2 (r = -0.48, P = .02), and V̇E/V̇CO2 (r = -0.50, P = .02).

CONCLUSIONS: Our results suggest an association between CPET variables at the ventilatory threshold and exacerbations. Percentage V̇O2 at the ventilatory threshold could serve as a complementary variable to monitor exacerbations in people with CF.

PMID:37015814 | DOI:10.4187/respcare.10428