Factors in childhood associated with lung function decline to adolescence in cystic fibrosis

BackgroundDespite improvements in general health and life expectancy in people with cystic fibrosis (CF), lung function decline continues unabated during adolescence and early adult life.MethodsWe examined factors present at age 5-years that predicted lung function decline from childhood to adolescence in a longitudinal study of Australasian children with CF followed from 1999 to 2017.ResultsLung function trajectories were calculated for 119 children with CF from childhood (median 5.0 [25%-75%=5.0–5.1]) years) to early adolescence (median 12.5 [25%-75%=11.4–13.8] years). Lung function fell progressively, with mean (standard deviation) annual change -0.105 (0.049) for forced vital capacity (FVC) Z-score (p<0.001), -0.135 (0.048) for forced expiratory volume in 1-second (FEV₁) Z-score (p<0.001), -1.277 (0.221) for FEV₁/FVC% (p<0.001), and -0.136 (0.052) for forced expiratory flow between 25% and 75% of FVC Z-score (p<0.001). Factors present in childhood predicting lung function decline to adolescence, in multivariable analyses, were hospitalisation for respiratory exacerbations in the first 5-years of life (FEV₁/FVC p = 0.001, FEF_25–75 p = 0.01) and bronchoalveolar lavage neutrophil elastase activity (FEV₁/FVC% p = 0.001, FEV₁ p = 0.05, FEF_25–75 p = 0.02). No examined factor predicted a decline in the FVC Z-score.ConclusionsAction in the first 5-years of life to prevent and/or treat respiratory exacerbations and counteract neutrophilic inflammation in the lower airways may reduce lung function decline in children with CF, and these should be targets of future research.     

Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis

BackgroundIn cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLPs) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TLP activity and clinical outcome has not been studied.MethodsWe analysed supernatant (sol) prepared from CF sputum from adult CF patients in two study cohorts (29 and 33 samples, respectively). Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV₁). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis.ResultsTLP activity inversely correlated with percent predicted FEV₁ (r = −0.4, p = 0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p = 0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 per log unit TLP activity (p = 0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in the second study cohort.ConclusionsSputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease.     

Chronic Stenotrophomonas maltophilia infection and exacerbation outcomes in cystic fibrosis

BackgroundChronic Stenotrophomonas maltophilia infection is a risk factor for pulmonary exacerbation in cystic fibrosis (CF) but its impact on subsequent clinical outcomes is unknown. The aim of this study was to determine the effect of chronic S. maltophilia infection and associated antimicrobial therapy on the recovery of forced expiratory lung volume in 1 s (FEV₁) following pulmonary exacerbation.MethodsThis was a retrospective cohort study of patients with CF followed at The Hospital for Sick Children and St. Michael's Hospital from 1997 to 2008. The primary outcome was the difference in FEV₁ percent predicted from baseline to follow up after a pulmonary exacerbation. Secondary outcomes for the effect of antimicrobial therapy included time to subsequent exacerbation.ResultsThere were 1667 pulmonary exacerbations in 440 CF patients. Patients with chronic S. maltophilia infection did not recover their baseline FEV₁ following 31% of exacerbations and had an overall mean FEV₁ decline of 1.84% predicted after exacerbation. Older (p = 0.02), female (p = 0.02) patients with lower BMI z score (p = 0.002) and Burkholderia cepacia complex infection (p = 0.005), but not chronic S. maltophilia infection (p = 0.86), had a greater decrease in follow up FEV₁% pred compared to baseline. The number of days of antibiotic therapy against S. maltophilia during a pulmonary exacerbation was not associated with a significant difference in the FEV₁ recovery (p = 0.69) or with a longer time to subsequent pulmonary exacerbation (p = 0.56).ConclusionsAlthough CF patients experience a significant decline in lung function following exacerbation, chronic S. maltophilia infection and associated antimicrobial therapy do not affect subsequent lung function recovery.     

Strong toll-like receptor responses in cystic fibrosis patients are associated with higher lung function

BackgroundCystic fibrosis (CF) airways disease varies widely among patients with identical cystic fibrosis transmembrane conductance regulator (CFTR) genotypes. Robust airway inflammation is thought to be deleterious in CF; inter-individual variation in Toll-like receptor (TLR)-mediated innate immune inflammatory responses (TMIIR) might account for a portion of the phenotypic variation. We tested if TMIIR in people with CF are different than those of healthy controls, and whether higher TMIIR in people with CF are associated with reduced lung function.MethodsWe cultured whole blood from clinically stable subjects with CF (n = 76) and healthy controls (n = 45) with TLR agonists, and measured cytokine production and expression of TLR-associated genes. We tested for differences in TLR-stimulated cytokine levels between subjects with CF and healthy subjects, and for associations between cytokine and gene expression levels with baseline lung function (forced expiratory volume in one second percent predicted (FEV₁%)) and decline in FEV₁% over time.ResultsTMIIR in blood from subjects with CF were lower than in healthy controls. Expression of TLR regulators SARM1, TOLLIP, and AKT1 were downregulated in CF. In subjects with CF we found that lower TLR4-agonist-induced IL-8 was associated with lower FEV₁% at enrollment (p<0.001) and with greater five year FEV₁% decline (p<0.001).ConclusionsTMIIR were lower in people with CF relative to healthy controls; however, unexpectedly, greater whole blood TMIIR were positively associated with lung function in people with CF. These findings suggest a complex interaction between inflammation and disease in people with CF.     

Expression of the inflammatory regulator A20 correlates with lung function in patients with cystic fibrosis

BackgroundA20 and TAX1BP1 interact to negatively regulate NF-κB-driven inflammation. A20 expression is altered in F508del/F508del patients. Here we explore the effect of CFTR and CFTR genotype on A20 and TAX1BP1 expression. The relationship with lung function is also assessed.MethodsPrimary nasal epithelial cells (NECs) from CF patients (F508del/F508del, n = 7, R117H/F508del, n = 6) and controls (age-matched, n = 8), and 16HBE14o- cells were investigated. A20 and TAX1BP1 gene expression was determined by qPCR.ResultsSilencing of CFTR reduced basal A20 expression. Following LPS stimulation A20 and TAX1BP1 expression was induced in control NECs and reduced in CF NECs, broadly reflecting the CF genotype: F508del/F508del had lower expression than R117H/F508del. A20, but not TAX1BP1 expression, was proportional to FEV₁ in all CF patients (r = 0.968, p < 0.001).ConclusionsA20 expression is reduced in CF and is proportional to FEV₁. Pending confirmation in a larger study, A20 may prove a novel predictor of CF inflammation/disease severity.     

Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international,randomized controlled study

Background: Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults.Methods: This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV₁) 40–90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV₁ averaged over the 26-week treatment period.Results: Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV₁ averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV₁ averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively.Conclusions: In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV₁) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353.     

Health-related quality-of-life in children with cystic fibrosis aged 5-years and associations with health outcomes

BackgroundThe impact of early cystic fibrosis (CF) on health-related quality-of-life (HRQOL) in preschool children is poorly characterised, and data on relationships between HRQOL and health outcomes in young children with CF are limited. We aimed to characterise and compare parent-proxy and child-reported HRQOL and evaluate relationships with clinical outcomes at age 5-years.MethodsSubjects were participating in the multi-centre Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial investigating BAL-directed versus standard CF therapy. Children aged 5-years and their parents rated HRQOL using the Pediatric Quality of Life Inventory (PedsQL™) and Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaires.ResultsPedsQL and CFQ-R questionnaires were completed by 141 primary caregivers and 135 and 130 children, respectively. There were no differences in HRQOL between children randomised to BAL-directed versus standard CF therapy. Children with CF rated worse HRQOL than healthy children and there was poor parent-child concordance across HRQOL domains. Nutritional status, CF-CT scan score, forced expiratory volume in 1-second (FEV₁), and pulmonary exacerbations correlated with HRQOL at age 5-years. FEV₁ z-scores positively correlated with parent-proxy HRQOL in CFQ-R Respiratory (p = 0.018), Physical (<0.001), Emotional (p = 0.007) subscales and PedsQL Total-score (p = 0.021), Physical (p = 0.019) domains. Pulmonary exacerbation rates were inversely associated with parent-proxy CFQ-R Respiratory (p = 0.004), Physical (p = 0.022), PedsQL Total (p = 0.009) and Physical (p = 0.009) scores.ConclusionParent-reported HRQOL is a meaningful clinical endpoint to evaluate interventions in young children. Parent and child HRQOL reports provide different, complementary information. A preschool version of the CFQ-R is needed to assess relationships between HRQOL and clinical outcomes in young children.     

Pulmonary artery pressure in cystic fibrosis adults: Characteristics,clinical correlates and long-term follow-up

BackgroundWe examined pulmonary artery pressure (PAP) characteristics of CF adults, studied clinical correlates and long-term survival.MethodsComprehensive clinical data were collected and Doppler echocardiography was used to estimate PAP in 109 stable CF adults and 50 healthy controls.ResultsCF patients had lower day and night-time oxygen status, elevated CRP and BNP, and elevated PAP (27.7(13.2, 62.8) mmHg patients v 17.9(11.3, 30.9) mmHg controls, p < 0.001). Even patients with mild pulmonary disease had raised PAP. PAP measurements strongly correlated with arterial partial pressure of oxygen (PaO₂, r = − 0.673, p < 0.001), and FEV₁ percentage predicted (FEV₁%, r = − 0.642, p < 0.001) which were both independent predictors of PAP. At 10 year follow up PAP measurements were related to survival but FEV₁% and PaO₂ were both stronger predictors of death.ConclusionsPAP is raised in CF adults and correlates with pulmonary disease severity. Unlike PaO₂ and FEV₁%, it does not appear to be an independent prognostic marker.     

Prevalence and risk factors for recovery of filamentous fungi in individuals with cystic fibrosis

BackgroundFilamentous fungi are frequently recovered from respiratory cultures of individuals with CF.MethodsA CF cohort database was utilized to determine filamentous fungal prevalence and risk factors.ResultsThe prevalence of filamentous fungal isolation increased from 2.0% in 1997 to 28.7% in 2007. The odds of isolating filamentous fungi during a quarter was greater in CF adults [p < 0.001], during chronic oral antibiotic use [p = 0.002] and increased with each 10% drop in FEV₁ percent predicted [p = 0.005], while inhaled corticosteroids surprisingly decreased the likelihood [p = 0.012]. The direction of these effects persisted after excluding individuals with ABPA. A sub-analysis determined older age [p = 0.019] and use of inhaled antibiotics [p = 0.011] were independent risk factors for onset of fungal colonization.ConclusionsThis study suggests that isolation of filamentous fungi in CF at JHH has increased and risk factors include older age, decreased lung function, and chronic oral antibiotics.     

Carfilzomib versus rituximab for treatment of de novo donor-specific antibodies in lung transplant recipients

IntroductionDe novo donor-specific antibodies (DSAs) increase the risk of chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Both carfilzomib (CFZ) and rituximab (RTX) lower the mean fluorescent intensity (MFI) of DSAs, but comparative data are lacking. We compared CLAD-free survival and the degree and duration of DSA depletion after treatment of LTRs with CFZ or RTX.MethodsLTRs that received CFZ or RTX for DSA depletion between 08/01/2015 and 08/31/2020 were included. The primary outcome was CLAD-free survival. Secondary outcomes were change in MFI at corresponding loci within 6 months of treatment (ΔMFI), time to DSA rebound, and change in % predicted FEV₁ 6 months after treatment (ΔFEV₁).ResultsForty-four LTRs were identified, 7 of whom had ≥2 drug events; therefore, 53 drug events were divided into 2 groups, CFZ (n = 17) and RTX (n = 36). Use of plasmapheresis, immunoglobulin, and mycophenolate augmentation was equivalent in both groups. CLAD-free survival with a single RTX event was superior to that after ≥2 drug events (p = 0.001) but comparable to that with a single CFZ event (p = 0.399). Both drugs significantly lowered the MFI at DQ locus, and the median ΔMFI was comparable. Compared to the RTX group, the CFZ group had a shorter median interval to DSA rebound (p = 0.015) and a lower ΔFEV₁ at 6 months (p = 0.014).ConclusionAlthough both CFZ and RTX reduced the MFI of circulating DSAs, RTX prolonged the time to DSA rebound. Despite more pronounced improvement in FEV₁ with RTX, comparable CLAD-free survival between the 2 groups suggests that both drugs offer a reasonable treatment strategy for DSAs in LTRs.     

Withdrawal of dornase alfa increases ventilation inhomogeneity in children with cystic fibrosis

BackgroundThe lung clearance index (LCI) is increasingly used as an outcome in clinical trials of patients with mild cystic fibrosis (CF) lung disease. Yet, understanding the impact of standard CF respiratory therapy on LCI is needed. We assessed to what degree withdrawal of nebulised dornase alfa affected LCI in school-age children with CF not receiving CFTR modulators or hydrator therapy.MethodsA single-centre, randomised, controlled, parallel group study to determine effects of one month's withdrawal of nebulised dornase alfa (intervention) in 5-18 years old children with CF. Remaining chronic maintenance therapy stayed unchanged. Outcome measures were assessed at two visits one month apart. Primary outcome was absolute change in LCI. Secondary outcomes were FEV₁, FEF_25–75 and CF Questionnaire-revised (CFQ-R) respiratory symptom score. Possible harmful effects were assessed by comparing the occurrence of pulmonary exacerbations between groups.ResultsTwenty-eight children (median age 10.4 [interquartile range: 7.6; 13.5] years) with CF received standard care (n = 14) or intervention (n = 14). Compared with the control group, LCI increased (worsened) 1.74 (95% confidence interval: 0.62; 2.86) during withdrawal of dornase alfa, while FEV₁ (-6.8% predicted) and FEF_25–75 (-13.1% predicted) decreased significantly. Change in CFQ-R respiratory symptom score and the occurrence of pulmonary exacerbations did not differ significantly between groups.ConclusionsOne month's withdrawal of dornase alfa caused increasing ventilation inhomogeneity and deteriorating FEV₁ and FEF_25–75 in school-age children with mild CF. Hence, adherence to dornase alfa optimally needs to be addressed when using LCI and spirometric parameters as endpoints, even in short-term clinical trials.     

Limb muscle size and contractile function in adults with cystic fibrosis: A systematic review and meta-analysis

BackgroundThere is conflicting evidence regarding the presence of limb muscle impairments in adults with cystic fibrosis (CF), and the factors associated with these muscle impairments. The objectives of this study were to compare limb muscle size and function between adults with CF and healthy controls; and to examine their associations with demographic and clinical variables in adults with CF.MethodsThe systematic review was performed using PRISMA guidelines. Studies were included if they measured any aspect of limb muscle size or function in adults with CF. Meta-analyses were performed to compare muscle variables between CF and healthy controls; and to examine their associations with demographic and clinical variables.ResultsTwenty-eight studies were included, with 747 adults with CF. The meta-analyses showed that adults with CF have smaller thigh muscles [standardized mean difference (SMD) = 0.57, p<.0011, I²=0%], and lower handgrip strength (SMD = 0.89, p=.0034, I²=74.03%), which was weakly correlated with forced expiratory volume in one second (FEV₁) (r=0.24, p=.035, I²=0%) and lower in females with CF (SMD = 2.05, p<.0001, I²=0%). There is no significant difference between adults with CF and controls in knee extensor strength (SMD = 0.25, p=.095, I²=42.79%).ConclusionsLeg muscle atrophy and lower handgrip strength were noted. There may be a subgroup of adults with CF with knee extensor (quadriceps) weakness. Future studies are needed to better understand muscle impairments in people with CF; to explore the factors that can predict these muscle impairments; and to investigate their clinical significance in people with CF.     

An observational study of matrix metalloproteinase (MMP)-9 in cystic fibrosis

BackgroundIn cystic fibrosis (CF), cross-sectional studies have reported sputum matrix metalloproteinase (MMP)-9 to be elevated and negatively correlated with FEV₁. This longitudinal study examined the association between MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) to prognostic parameters in CF.MethodA cross-sectional survey of CF and control subjects; CF patients were followed up for a median of 49 months. MMP-9 and TIMP-1 and TIMP-2 were quantified in sputum and plasma.ResultsSeventy-three patients with CF, median age 22 years, and 40 controls were recruited. Fifty-three of these CF patients were followed up. Prospectively, in CF subjects, plasma MMP-9 activity was adversely associated with FEV₁ (β − 1.15 (95% CI − 2.10, − 0.20), p = 0.019) and rate of FEV₁ decline, and plasma TIMP-1 was adversely associated with mortality: hazard ratio 3.66 (1.91–7.04), p < 0.001.ConclusionsThese associations further justify investigation of MMP-9 and TIMP-1 as biomarkers for short- to medium-term FEV₁ decline and mortality in patients with CF.     

Infant spirometry as a predictor of lung function at early childhood in cystic fibrosis patients

BackgroundInfant pulmonary function testing using the raised volume rapid thoracoabdominal compression (RVRTC) technique requires sedation and is time consuming. Many cystic fibrosis (CF) centers do not have access to equipment and the utility of routine testing remains to be determined. We aimed to assess whether RVRTC tests performed during infancy predict spirometry at early school age.MethodsThe RVRTC-based forced expiratory flow measures in infants were compared to the first adequately performed spirometry at school age. All tests were carried out during routine clinic visits and expressed as age related z-scores; only test occasions where patients were considered stable were included in the analysis.Results47 patients had useable infant RVRTC as well as matching school age spirometry data. There was weak correlation between infant FEV_0.5 and early school age FEV₁ (R = 0.29, p = 0.05). Four infants had significantly low zFEV_0.5 (zFEV_0.5 < -1.96), of which one of those remained under that limit at childhood. Changes in spirometry between infancy and early childhood were negatively correlated to baseline FEV_0.5 (R = 0.61 p<0.001) reflecting that the change was driven by where individuals started off with. There was no difference in clinical characteristics between those improving, those with stable or deteriorating in lung function.ConclusionInfant RVRTC measures were not predictive of pulmonary function in early school age, likely due to the high proportion of measures of forced expiratory flows within the normal range at both time points.     

Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis

ObjectivesTobacco smoke exposure reduces CFTR functional expression in vitro and contributes to acquired CFTR dysfunction. We investigated whether it also inhibits the clinical benefit of CFTR modulators, focusing on tezacaftor/ivacaftor, approved in February 2018 for individuals with CF age ≥12 years.MethodsA retrospective longitudinal analysis of encounter-based data from the CF Foundation Patient Registry (2016–2018) compared the slope of change in lung function (GLI FEV₁% predicted) before and after tezacaftor/ivacaftor initiation in smoke-exposed vs unexposed age-eligible pediatric patients. Tobacco smoke exposure (Ever/Never) was determined from caregiver self-report. Statistical analyses used hierarchical linear mixed modeling and fixed effects regression modeling.ResultsThe sample included 6,653 individuals with a total of 105,539 person-period observations. Tezacaftor/ivacaftor was prescribed to 19% (1,251) of individuals, mean age 17 years, mean baseline ppFEV₁ 83%, 28% smoke-exposed. Tezacaftor/ivacaftor users who were smoke-exposed had a lower baseline ppFEV₁ and experienced a greater lung function decline. Over two years, the difference in ppFEV₁ by smoke exposure among tezacaftor/ivacaftor users increased by 1.2% (7.6% to 8.8%, p<0.001). In both mixed effects and fixed effects regression models, tezacaftor/ivacaftor use was associated with improved ppFEV₁ among unexposed individuals (1.2% and 1.7%, respectively; p<0.001 for both) but provided no benefit among smoke-exposed counterparts (0.3%, p = 0.5 and 0.6%, p = 0.07, respectively).ConclusionTobacco smoke exposure nullifies the therapeutic benefit of tezacaftor/ivacaftor among individuals with CF aged 12–20 years old. To maximize the therapeutic opportunity of CFTR modulators, every effort must be taken to eliminate smoke exposure in CF.     

Lung clearance index during hospital admission in school-age children with cystic fibrosis

BackgroundThere is currently limited information regarding lung clearance index (LCI) and its response to treatment of pulmonary exacerbations in CF. We aimed to examine the utility of LCI for assessing short term clinical response to IV antibiotic therapy in school-age children with CF.MethodsSubjects experiencing exacerbations and hospitalised for IV antibiotics performed both multiple breath nitrogen washout (MBNW) and spirometry on admission to hospital and prior to discharge.Results27 patients (aged 6–20 years) had paired data for MBNW and spirometry. Mean LCI reduced from 12.18 to 11.65 (4.4%) by time of discharge and FEV₁ z-score improved from − 3.05 to − 2.86 (6.2%). Overall, LCI improved in n = 15 (55%) patients compared with n = 18 (67%) where FEV₁ improved.ConclusionsIn summary, these findings do not support the use of LCI (or indeed, FEV₁) to gauge the short term clinical response to IV antibiotic therapy in school-age children with cystic fibrosis.     

Low body mass index as a barrier to lung transplant in cystic fibrosis

RationaleLow body mass index (BMI) may influence lung transplant decisions for patients with advanced cystic fibrosis (CF) lung disease.ObjectiveDetermine whether patients with advanced CF lung disease and BMI ≤17 kg/m² are less likely to be listed for lung transplant or have a higher risk of death without listing compared to those with higher BMI.MethodsUsing merged United Network for Organ Sharing and CF Foundation Patient Registries, we identified adults with onset of advanced lung disease (FEV₁ ≤ 40% predicted) between May-2005 and December-2016. We analyzed survival using competing risks regression with cause-specific risks of listing for lung transplant and death without listing. BMI ≤ 17 kg/m² was our predictor.Measurements and main resultsAmong 5,121 CF patients with advanced lung disease, 23% were listed for lung transplant (n = 1,201), 23% died without listing (n = 1,190), and 44% were alive without listing (n = 2,730) as of December-2016. Patients with BMI ≤ 17 kg/m² were less likely to be listed for transplant (HR 0.69; 95% CI 0.57, 0.83) and more likely to die without listing (HR 1.63; 95% CI 1.41, 1.88). We identified important regional variations in the likelihood of referral and listing, based on BMI.ConclusionsPatients with advanced CF lung disease and BMI ≤ 17 kg/m² are less likely to be listed for lung transplant and have a higher risk of dying without listing, compared to those with higher BMI. Regional differences suggest access to transplant for malnourished CF patients may be limited by location.     

Evidence of diminished FEV1 and FVC in 6-year-olds followed in the European cystic fibrosis patient registry, 2007–2009

BackgroundMany infants with cystic fibrosis (CF) exhibit airway inflammation, gas trapping, bronchiectasis, and/or reduced flow, but by age 6 years have forced vital capacities (FVC) and expiratory volumes in 1 second (FEV₁) within the variability range of the normal population. We sought evidence of diminished FVC and FEV₁ in 6-year-olds with CF.MethodsGLI 2012 FVC and FEV₁ Z-scores for 6-year-olds from the European CF Patient Registry were plotted against theoretical values from the Normal distribution.ResultsMean FVC and FEV₁ Z-scores for 681 patients (322 females) were ? 0.43 (SD = 1.41) and ? 0.65 (1.40). Z-scores were consistently lower than expected for the normative population by quantile–quantile plot.ConclusionsDiminished FEV₁, and to a lesser extent FVC, is found in a large majority of this population, consistent with an established body of evidence that loss of lung function begins early in life for most, if not all, children with CF.     

Molecular analysis of changes in Pseudomonas aeruginosa load during treatment of a pulmonary exacerbation in cystic fibrosis

BackgroundIntravenous antibiotics for pulmonary exacerbations (PEs) of cystic fibrosis (CF) usually target Pseudomonas aeruginosa. Insights into the CF lung microbiome have questioned this approach. We used RT-qPCR to determine whether intravenous antibiotics reduced P. aeruginosa numbers and whether this correlated with improved lung function. We also investigated antibiotic effects on other common respiratory pathogens in CF.MethodsSputa were collected from patients when stable and again during a PE. Sputa were expectorated into a RNA preservation buffer for RNA extraction and preparation of cDNA. qPCR was used to enumerate viable P. aeruginosa as well as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Burkholderia cepacia complex and Aspergillus fumigatus.ResultsFifteen CF patients were followed through 21 PEs. A complete set of serial sputum samples was unavailable for two patients (three separate PEs). P. aeruginosa numbers did not increase immediately prior to a PE, but numbers during intravenous antibiotic treatment were reduced ≥ 4-log in 6/18 and ≥ 1-log in 4/18 PEs. In 7/18 PEs, P. aeruginosa numbers changed very little with intravenous antibiotics and one patient demonstrated a ≥ 2-log increase in P. aeruginosa load. H. influenzae and S. pneumoniae were detected in ten and five PEs respectively, but with antibiotic treatment these bacteria rapidly became undetectable in 6/10 and 4/5 PEs, respectively. There was a negative correlation between P. aeruginosa numbers and FEV₁ during stable phase (r_s = 0.75, p < 0.05), and reductions in P. aeruginosa load with intravenous antibiotic treatment correlated with improved FEV₁ (r_s = 0.52, p < 0.05).ConclusionsExacerbations are not due to increased P. aeruginosa numbers in CF adults. However, lung function improvements correlate with reduced P. aeruginosa burden suggesting that current antibiotic treatment strategies remain appropriate in most patients. Improved understanding of PE characterised by unchanged P. aeruginosa numbers and minimal lung function improvement following treatment may allow better targeted therapies.     

Prevalence of unmet palliative care needs in adults with cystic fibrosis

BackgroundPhysical and emotional burdens impair quality of life (QoL) in many adults with cystic fibrosis (CF). Palliative care (PC) improves QoL in other serious illnesses, yet the full array of palliative needs amenable to PC are unknown in CF.MethodsWe surveyed 164 adults with CF using the Supportive Care Needs Survey 34 (SCNS-34) to assess unmet PC needs across five domains, the Edmonton Symptom Assessment System (ESAS) to assess symptom burden, and the Cystic Fibrosis Questionnaire—Revised (CFQ-R) to assess CF-specific QoL. We assessed associations between SCNS-34 domain scores and respondent characteristics, including symptom burden and FEV₁.ResultsMedian age was 29 years; 56% of respondents were male. Median FEV₁ was 57% predicted. 78% of respondents reported ≥1 unmet PC need; physical and daily living (72%) and psychological (66%) needs were most prevalent. Symptom burden was correlated with all SCNS-34 domains scores, and strongly correlated with the physical (r = 0.79) and psychological (r = 0.72) domain scores. FEV₁ was moderately inversely correlated with the physical domain score (r = −0.41). Forty-four of the 45 inverse correlations between SCNS-34 domain scores and CFQ-R domain scores were significant. Patient-reported depressive and anxiety symptoms were significantly associated with higher scores in five and four SCNS-34 domains, respectively.ConclusionsAdults with CF have substantial unmet PC needs. Patient-reported symptom burden is more strongly associated with reporting unmet PC needs than FEV₁. Routine screening of unmet PC needs, using tools such as the SCNS-34, may enable CF care teams to optimize the provision of primary and specialist PC.