Impact of surgical lung biopsy on lung function and survival in patients with idiopathic pulmonary fibrosis in a multi-centre registry cohort.

BACKGROUND AND OBJECTIVE: Establishing an accurate and timely diagnosis of idiopathic pulmonary fibrosis (IPF) is essential for appropriate management and prognostication. In some cases, surgical lung biopsy (SLB) is performed but carries non-negligible risk. The objective of this retrospective study was to determine if SLB is associated with accelerated lung function decline in patients with IPF using the Canadian Registry for Pulmonary Fibrosis. METHODS: Linear mixed models and Cox proportional hazards regression models were used to compare decline in forced vital capacity (FVC)%, diffusion capacity of the lung (DLCO%) and risk of death or lung transplantation between SLB and non-SLB patients. Adjustments were made for baseline age, sex, smoking history, antifibrotic use, and lung function. A similar analysis compared lung function changes 12 months pre- and post-SLB. RESULTS: A total of 81 SLB patients and 468 non-SLB patients were included. In the SLB group, the post-biopsy annual FVC% decline was 2.0% (±0.8) in unadjusted, and 2.1% (±0.8) in adjusted models. There was no difference in FVC% decline, DLCO% decline, or time to death or lung transplantation between the two groups, in adjusted or unadjusted models (all p-values >0.07). In the pre-post SLB group, no differences were identified in FVC% decline in unadjusted or adjusted models (p = 0.07 for both). CONCLUSION: No association between SLB and lung function decline or risk of death or lung transplantation was identified in this multi-centre study of patients with IPF.

Eligibility criteria from pharmaceutical randomised controlled trials of idiopathic pulmonary fibrosis: a registry-based study.

BACKGROUND: Little is known about generalisability of randomised controlled trials (RCTs) for idiopathic pulmonary fibrosis (IPF). We evaluated eligibility criteria for phase III IPF RCTs to determine their representativeness in clinical registries, and calculated forced vital capacity (FVC) changes according to eligibility criteria. METHODS: Common eligibility criteria used in >60% of IPF RCTs were identified from a literature search and applied to patients with IPF from prospective Australian and Canadian registries. Additional pre-specified criteria of 6-min walk distance (6MWD) and different measures of preceding disease progression were also evaluated. Joint longitudinal-survival modelling was used to compare FVC decline according to eligibility for individual and composite criteria. RESULTS: Out of 990 patients with IPF, 527 (53%) met all common RCT eligibility criteria at the first clinic visit, including 343 with definite IPF and 184 with radiological probable usual interstitial pneumonia pattern without histological confirmation (i.e. provisional IPF). The percentages of eligible patients for landmark RCTs of nintedanib and pirfenidone were 19-50%. Adding 6MWD ≥150 m and different measures of preceding disease progression to the composite common criteria reduced the percentages of patients meeting eligibility to 52% (n=516) and 4-18% (n=12-61), respectively. Patients meeting the composite common criteria had less-rapid 1-year FVC decline than those who did not (-90 versus -103 mL, p=0.01). Definite IPF generally had more-rapid 1-year FVC decline compared to provisional IPF. CONCLUSIONS: Eligibility criteria of previous IPF RCTs have limited generalisability to clinical IPF populations, with FVC decline differing between eligible and ineligible populations.

Validation and minimum important difference of the UCSD Shortness of Breath Questionnaire in fibrotic interstitial lung disease.

RATIONALE: The University of California, San Diego Shortness of Breath Questionnaire (UCSDSOBQ) is a frequently used domain-specific dyspnea questionnaire; however, there is little information available regarding its use and minimum important difference (MID) in fibrotic interstitial lung disease (ILD). We aimed to describe the key performance characteristics of the UCSDSOBQ in this population. METHODS: UCSDSOBQ scores and selected anchors were measured in 1933 patients from the prospective multi-center Canadian Registry for Pulmonary Fibrosis. Anchors included the St. George's Respiratory Questionnaire (SGRQ), European Quality of Life 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) and EQ visual analogue scale (EQ-VAS), percent-predicted forced vital capacity (FVC%), diffusing capacity of the lung for carbon monoxide (DLCO%), and 6-min walk distance (6MWD). Concurrent validity, internal consistency, ceiling and floor effects, and responsiveness were assessed, followed by estimation of the MID by anchor-based (linear regression) and distribution-based methods (standard error of measurement). RESULTS: The UCSDSOBQ had a high level of internal consistency (Cronbach's alpha = 0.97), no obvious floor or ceiling effect, strong correlations with SGRQ, EQ-5D-5L, and EQ-VAS (|r| > 0.5), and moderate correlations with FVC%, DLCO%, and 6MWD (0.3 < |r| < 0.5). The MID estimate for UCSDSOBQ was 5 points (1-8) for the anchor-based method, and 4.5 points for the distribution-based method. CONCLUSION: This study demonstrates the validity of UCSDSOBQ in a large and heterogeneous population of patients with fibrotic ILD, and provides a robust MID estimate of 5-8 points.

Functional ageing in fibrotic interstitial lung disease: the impact of frailty on adverse health outcomes.

BACKGROUND: Accelerated biological and functional ageing is common in fibrotic interstitial lung disease (ILD); however, their impact on adverse health outcomes has not been evaluated in this population. METHODS: Patients were prospectively recruited from a specialised ILD clinic. Functional ageing was determined by frailty index and biological age by measurement of absolute telomere length (aTL) from patients' peripheral blood leukocytes. Adverse health outcomes included health-related quality of life (St George's Respiratory Questionnaire), number and length of respiratory and non-respiratory hospitalisations, medication tolerability and time to death or lung transplantation. Multivariable models were used to determine the risks and rates of adverse health outcomes associated with the frailty index and aTL. RESULTS: 540 patients with fibrotic ILD, including 100 with idiopathic pulmonary fibrosis (IPF), provided 749 frailty index assessments, with 189 patients providing blood samples. The frailty index was strongly associated with quality of life, rate of hospitalisation, time to hospital discharge and mortality, including adjustment for age, sex, disease severity and IPF diagnosis. Mortality prognostication was improved by the addition of the frailty index to commonly used clinical parameters and previously validated composite indices. Conversely, aTL was not associated with most adverse health outcomes. The effect of chronological age on outcomes was mediated primarily by the frailty index, and to a lesser extent by aTL. CONCLUSIONS: Functional ageing is associated with adverse health outcomes in patients with fibrotic ILD, indicating the need for consideration of the individual functional age into clinical decision-making.

Short-term effects of Lumacaftor/Ivacaftor (Orkambi™) on exertional symptoms, exercise performance, and ventilatory responses in adults with cystic fibrosis.

RATIONALE: Lumacaftor/ivacaftor (LUM/IVA) modestly improves lung function following 1 month of treatment but it is unknown if this translates into improvements in exercise endurance and exertional symptoms. METHODS: Adult CF participants completed a symptom-limited constant load cycling test with simultaneous assessments of dyspnea and leg discomfort ratings pre- and 1 month post-initiation of LUM/IVA. RESULTS: Endurance time, exertional dyspnea and leg discomfort ratings at submaximal exercise did not change significantly. There was a significant inverse correlation between changes in leg discomfort and endurance time (r = - 0.88; p = 0.009) following 1-month of LUM/IVA. CONCLUSIONS: Overall, 1-month of LUM/IVA did not increase endurance time or modify exertional dyspnea or leg discomfort ratings. However, individuals who experienced a reduction in leg discomfort following LUM/IVA had an improvement in endurance time. Future studies with a larger sample size are needed to verify these findings and to assess the long-term effects of LUM/IVA on exercise outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02821130. Registered July 1, 2016.

A cluster-based analysis evaluating the impact of comorbidities in fibrotic interstitial lung disease.

BACKGROUND: Comorbidities are frequent and have been associated with poor quality of life, increased hospitalizations, and mortality in patients with interstitial lung disease (ILD). However, it is unclear how comorbidities lead to these negative outcomes and whether they could influence ILD disease progression. The goal of this study was to identify clusters of patients based on similar comorbidity profiles and to determine whether these clusters were associated with rate of lung function decline and/or mortality. METHODS: Patients with a major fibrotic ILD (idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, connective tissue disease-associated ILD, and unclassifiable ILD) from the CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) were included. Hierarchical agglomerative clustering of comorbidities, age, sex, and smoking pack-years was conducted for each ILD subtype to identify combinations of these features that frequently occurred together in patients. The association between clusters and change in lung function over time was determined using linear mixed effects modeling, with adjustment for age, sex, and smoking pack-years. Kaplan Meier curves were used to assess differences in survival between the clusters. RESULTS: Discrete clusters were identified within each fibrotic ILD. In IPF, males with obstructive sleep apnea (OSA) had more rapid decline in FVC %-predicted (- 11.9% per year [95% CI - 15.3, - 8.5]) compared to females without any comorbidities (- 8.1% per year [95% CI - 13.6, - 2.7]; p = 0.03). Females without comorbidities also had significantly longer survival compared to all other IPF clusters. There were no significant differences in rate of lung function decline or survival between clusters in the other fibrotic ILD subtypes. CONCLUSIONS: The combination of male sex and OSA may portend worse outcomes in IPF. Further research is required to elucidate the interplay between sex and comorbidities in ILD, as well as the role of OSA in ILD disease progression.

Demographic and clinical predictors of progression and mortality in connective tissue disease-associated interstitial lung disease: a retrospective cohort study.

BACKGROUND: Connective tissue disease-associated interstitial lung disease (CTD-ILD) is associated with reduced quality of life and poor prognosis. Prior studies have not identified a consistent combination of variables that accurately predict prognosis in CTD-ILD. The objective of this study was to identify baseline demographic and clinical characteristics that are associated with progression and mortality in CTD-ILD. METHODS: Patients were retrospectively identified from an adult CTD-ILD clinic. The predictive significance of baseline variables on serial forced vital capacity (FVC), diffusion capacity (DLCO), and six-minute walk distance (6MWD) was assessed using linear mixed effects models, and Cox regression analysis was performed to assess impact on mortality. RESULTS: 359 patients were included in the study. Median follow-up time was 4.0 (IQR 1.5-7.6) years. On both unadjusted and multivariable analysis, male sex and South Asian ethnicity were associated with decline in FVC. Male sex, positive smoking history, and diagnosis of systemic sclerosis (SSc) vs. other CTD were associated with decline in DLCO. Male sex and usual interstitial pneumonia (UIP) pattern predicted decline in 6MWD. There were 85 (23.7%) deaths. Male sex, older age, First Nations ethnicity, and a diagnosis of systemic sclerosis vs. rheumatoid arthritis were predictors of mortality on unadjusted and multivariable analysis. CONCLUSION: Male sex, older age, smoking, South Asian or First Nations ethnicity, and UIP pattern predicted decline in lung function and/or mortality in CTD-ILD. Further longitudinal studies may add to current clinical prediction models for prognostication in CTD-ILD.

Exertional hypoxemia is more severe in fibrotic interstitial lung disease than in COPD.

BACKGROUND AND OBJECTIVE: Despite its clinical and prognostic significance, few studies have evaluated the severity of exertional oxygen desaturation in fibrotic interstitial lung disease (ILD). Our objectives were to identify clinical and physiological variables that predict the extent of exertional oxygen desaturation in fibrotic ILD and to quantify the severity of desaturation compared to chronic obstructive pulmonary disease (COPD). METHODS: This retrospective study compared the results of 6-min walk test (6MWT) performed while breathing room air in fibrotic ILD patients and COPD patients eligible for pulmonary rehabilitation. Outcomes included the oxygen saturation (SpO2 ) nadir and the change in SpO2 from rest during a 6MWT. Predictor variables were identified on unadjusted analysis, followed by multivariate analysis to identify independent predictors of desaturation. RESULTS: The study included 134 patients with fibrotic ILD and 274 patients with COPD. The ILD and COPD cohorts had similar age, sex, frequency of major comorbidities, walk distance, baseline SpO2 and baseline Borg dyspnoea scores. DLCO was the strongest predictor of desaturation in both cohorts. Compared to patients with COPD, ILD patients had significantly lower SpO2 nadir values (88.1 ± 6.4 vs 91.0 ± 4.6) and greater decrease in SpO2 from baseline (7.4 ± 5.2 vs 4.5 ± 3.7) after adjusting for demographic features and pulmonary physiology (P < 0.0005), with greater between-group differences at lower DLCO values. CONCLUSION: Patients with fibrotic ILD have greater oxygen desaturation during 6MWT compared to patients with COPD when adjusting for demographic features and pulmonary physiology. These findings suggest the need for disease-specific studies to evaluate the potential utility of ambulatory oxygen in fibrotic ILD.

Oesophageal diameter is associated with severity but not progression of systemic sclerosis-associated interstitial lung disease.

BACKGROUND AND OBJECTIVE: It is unknown whether oesophageal disease is associated with systemic sclerosis-associated interstitial lung disease (SSc-ILD) severity, progression or mortality. METHODS: High-resolution computed tomography (HRCT) scans from 145 SSc-ILD patients were scored for fibrosis score, oesophageal diameter and presence of hiatal hernia. Fibrosis asymmetry was calculated as: (most affected side - least affected side)/(most affected side + least affected side). Mixed effects models were used for repeated measures analyses. RESULTS: Mean fibrosis score was 8.6%, and most patients had mild-to-moderate physiological impairment. Every 1 cm increase in oesophageal diameter was associated with 1.8% higher fibrosis score and 5.5% lower forced vital capacity (FVC; P ≤ 0.001 for unadjusted and adjusted analyses). Patients with hiatal hernia had 3.9% higher fibrosis score, with persistent differences on adjusted analysis (P = 0.001). Oesophageal diameter predicted worsening fibrosis score over the subsequent year (P = 0.02), but not when adjusting for baseline fibrosis score (P = 0.16). Oesophageal diameter was independently associated with mortality (P = 0.001). Oesophageal diameter was not associated with asymmetric disease or radiological features of gross aspiration. CONCLUSION: Oesophageal diameter and hiatal hernia are independently associated with SSc-ILD severity and mortality, but not with ILD progression or asymmetric disease. Oesophageal disease is unlikely to be a significant driver of ILD progression in SSc.

Cough is less common and less severe in systemic sclerosis-associated interstitial lung disease compared to other fibrotic interstitial lung diseases.

BACKGROUND AND OBJECTIVE: The objectives of this study were to determine the prevalence and characteristics of cough in idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP) and systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Cough severity was measured in consecutive patients with IPF (n = 77), HP (n = 32) and SSc-ILD (n = 67) using a 10-cm visual analogue scale (VAS). Dyspnoea and quality of life were measured using established questionnaires. Cough severity was compared across ILD subtypes and predictors of cough severity were determined using multivariate analysis. RESULTS: Cough was more common in IPF and chronic HP compared to SSc-ILD (87% and 83% vs 68%, P = 0.02). The median (interquartile range) VAS score was 39 (17-65) in the IPF cohort, 29 (11-48) in HP and 18 (0-33) in SSc-ILD (P < 0.0001). Cough was more often productive in chronic HP and IPF (63% and 43% vs 21%, P < 0.001). Cough severity was independently predicted only by ILD diagnosis and higher dyspnoea score. Cough severity was not associated with other common causes of cough. Cough was a significant predictor of quality of life in IPF and SSc-ILD with adjustment for age, sex, dyspnoea and ILD severity; however, cough was not associated with quality of life in chronic HP. CONCLUSION: Cough is more frequent, more severe and more often productive in IPF and chronic HP compared to SSc-ILD, despite similar ILD severity in these cohorts. Cough severity is strongly and independently associated with dyspnoea and pulmonary function, and is a significant contributor to reduced quality of life in both IPF and SSc-ILD.

Frailty is common and strongly associated with dyspnoea severity in fibrotic interstitial lung disease.

BACKGROUND AND OBJECTIVE: Frailty is the age-related accumulation of deficits that decrease the ability to respond to biological stress. Patients with fibrotic interstitial lung disease (ILD) may be frail due to consequences of ILD, age, co-morbidities and adverse effects of pharmacotherapies. The objective of this study was to examine the prevalence and predictors of frailty in fibrotic ILD. METHODS: Fibrotic ILD patients were recruited from a specialized clinic. Patients with ILD secondary to a systemic disease were excluded. Frailty was determined using the Frailty Index based on the presence or absence of multiple deficits, including co-morbidities, symptoms and functional limitations. The Frailty Index was based on the proportion of deficits present, with frailty defined as a score >0.21. Cronbach's alpha was used to estimate the internal consistency of the Frailty Index. Dyspnoea was measured using the University of California San Diego Shortness of Breath Questionnaire. Multivariate analysis was used to determine independent predictors of frailty. RESULTS: The definition of frailty was met in 50% of the 129 patients. Cronbach's alpha for the Frailty Index was 0.87. The Frailty Index was associated with forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1 ), diffusion capacity of the lung for carbon monoxide (DLCO ), ILD-gender, age and physiology (GAP) index, composite physiologic index and dyspnoea score. Dyspnoea severity was the strongest unadjusted predictor (r = 0.65, P < 0.001) and only independent predictor of the Frailty Index (0.034 increase in Frailty Index per 10-point increase in dyspnoea score; R2 = 0.37; P < 0.001). CONCLUSION: Frailty is highly prevalent and is strongly and independently associated with dyspnoea severity, demonstrating that dyspnoea is a more important determinant of frailty than pulmonary function.

Discovery of novel plasma protein biomarkers to predict imminent cystic fibrosis pulmonary exacerbations using multiple reaction monitoring mass spectrometry.

BACKGROUND: Despite the significant morbidity and mortality related to pulmonary exacerbations in cystic fibrosis (CF), there remains no reliable predictor of imminent exacerbation. OBJECTIVE: To identify blood-based biomarkers to predict imminent (<4 months from stable blood draw) CF pulmonary exacerbations using targeted proteomics. METHODS: 104 subjects provided plasma samples when clinically stable and were randomly split into discovery (n=70) and replication (n=34) cohorts. Multiple reaction monitoring mass spectrometry (MRM-MS) was used to measure 117 peptides (79 proteins) from plasma. Plasma proteins with differential abundance between subjects who did versus did not develop an imminent exacerbation were analysed and proteins with fold difference >1.5 between the groups were included in an MRM-MS classifier model to predict imminent exacerbations. Performance characteristics were compared with clinical predictors and candidate plasma protein biomarkers. RESULTS: Six proteins were included in the final MRM-MS protein panel. The area under the curve (AUC) for the prediction of imminent exacerbations was highest for the MRM-MS protein panel (AUC 0.74) in comparison to FEV1% predicted (AUC 0.55) and the top candidate plasma protein biomarkers, including C-reactive protein (AUC 0.61) and interleukin-6 (AUC 0.60). The MRM-MS protein panel performed similarly in the replication cohort (AUC 0.73). CONCLUSIONS: Using MRM-MS, a six-protein panel measured from plasma can distinguish individuals with versus without an imminent exacerbation. With further replication and assay development, this biomarker panel may be clinically applicable for prediction of exacerbations in individuals with CF.

Characteristics and risk factors of interstitial pneumonia with autoimmune features.

BACKGROUND: Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting criteria for a specific CTD. We compared baseline characteristics, survival, and response to treatment of IPAF to both CTD-ILD and unclassifiable ILD. METHODS: Measurements were extracted from a prospective registry. Baseline features and survival were compared in IPAF against both CTD-ILD and unclassifiable ILD. Linear trajectory of lung function decline (%-predicted forced vital capacity [FVC%] and diffusion capacity of the lung for carbon monoxide [DLCO%]) before and after initiation of mycophenolate or azathioprine were compared in IPAF against both CTD-ILD and unclassifiable ILD using linear mixed models. RESULTS: Compared to CTD-ILD (n = 1240), patients with IPAF (n = 128) were older, more frequently male, and had greater smoking history. Compared to unclassifiable ILD (n = 665), patients with IPAF were younger, more frequently female, and had worse baseline lung function. IPAF had higher mortality compared to CTD-ILD and similar risk of mortality compared to unclassifiable ILD. Mycophenolate initiation was associated with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% in patients with IPAF, and azathioprine initiation with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% decline in IPAF and DLCO% decline in CTD-ILD. CONCLUSION: Patients with IPAF had worse survival compared to those with CTD-ILD and similar mortality to unclassifiable ILD, with treatment being associated with stabilization in lung function in all three ILDs. It is uncertain whether IPAF should be considered a distinct ILD diagnostic subgroup.

Pulmonary exacerbation inflammatory phenotypes in adults with cystic fibrosis.

BACKGROUND: Adults with cystic fibrosis (CF) develop exuberant inflammatory responses during pulmonary exacerbations (PEx) but whether distinct systemic inflammatory profiles can be identified and whether these associate with disparate treatment outcomes are unclear. We conducted a pilot study to address this question and hypothesized that CF adults with a pauci-inflammatory phenotype might derive less clinical benefit from intravenous (IV) antibiotic treatment than patients with other systemic inflammatory phenotypes. METHODS: Six proteins reflective of systemic inflammation were examined in 37 PEx from 28 unique CF subjects. We applied exploratory factor analysis and cluster analysis to identify biological clusters. Levels of blood proteins at PEx and clinical outcomes following IV antibiotic treatment were compared between clusters. RESULTS: Three clusters of PEx were identified. The pauci-inflammatory phenotype was characterized by lower levels of interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor (TNF)-α, calprotectin, and C-reactive protein (CRP) (p < 0.05). Higher levels of IL-6 and IL-1ß were observed in the other 2 inflammatory clusters, but one of them was associated with higher calprotectin levels (p = 0.001) (neutrophil-predominant phenotype); whereas the other was associated with increased TNF-α and IL-10 levels (p < 0.001) (pro-inflammatory phenotype). A greater proportion of events from the neutrophil-predominant phenotype presented with acute respiratory symptoms and a larger decrease in ppFEV1 from baseline to hospital admission than the other two inflammatory phenotypes (p = 0.03). CONCLUSIONS: Three distinct inflammatory phenotypes were identified at PEx admission and each presented with unique clinical characteristics.

Predicting New-onset Exertional and Resting Hypoxemia in Fibrotic Interstitial Lung Disease.

Rationale: Hypoxemia in fibrotic interstitial lung disease (ILD) indicates disease progression and is of prognostic significance. The onset of hypoxemia signifies disease progression and predicts mortality in fibrotic ILD. Accurately predicting new-onset exertional and resting hypoxemia prompts appropriate patient discussion and timely consideration of home oxygen. Objectives: We derived and externally validated a risk prediction tool for both new-onset exertional and new-onset resting hypoxemia. Methods: This study used ILD registries from Canada for the derivation cohort and from Australia and the United States for the validation cohort. New-onset exertional and resting hypoxemia were defined as nadir oxyhemoglobin saturation < 88% during 6-minute-walk tests, resting oxyhemoglobin saturation < 88%, or the initiation of ambulatory or continuous oxygen. Candidate predictors included patient demographics, ILD subtypes, and pulmonary function. Time-varying Cox regression was used to identify the top-performing prediction model according to Akaike information criterion and clinical usability. Model performance was assessed using Harrell's C-index and goodness-of-fit (GoF) likelihood ratio test. A categorized risk prediction tool was developed. Results: The best-performing prediction model for both new-onset exertional and new-onset resting hypoxemia included age, body mass index, a diagnosis of idiopathic pulmonary fibrosis, and percent predicted forced vital capacity and diffusing capacity of carbon monoxide. The risk prediction tool exhibited good performance for exertional hypoxemia (C-index, 0.70; GoF, P = 0.85) and resting hypoxemia (C-index, 0.77; GoF, P = 0.27) in the derivation cohort, with similar performance in the validation cohort except calibration for resting hypoxemia (GoF, P = 0.001). Conclusions: This clinically applicable risk prediction tool predicted new-onset exertional and resting hypoxemia at 6 months in the derivation cohort and a diverse validation cohort. Suboptimal GoF in the validation cohort likely reflected overestimation of hypoxemia risk and indicated that the model is not flawed because of underestimation of hypoxemia.

Mucoid and nonmucoid Burkholderia cepacia complex bacteria in cystic fibrosis infections.

RATIONALE: infection with Burkholderia cepacia complex (BCC) bacteria in cystic fibrosis (CF) is associated with an unpredictable rate of pulmonary decline. Some BCC, but not others, elaborate copious mucoid exopolysaccharide, endowing them with a gross mucoid phenotype, the clinical significance of which has not been described. OBJECTIVES: to determine whether there was a correlation between bacterial mucoid phenotype, as assessed in a semiquantitative manner from plate culture, and severity of disease as assessed by the rate of decline in lung function. METHODS: we performed a retrospective clinical review of 100 patients with CF attending the Vancouver clinics between 1981 and 2007 and analyzed the rate of lung function decline (% predicted FEV(1)). MEASUREMENTS AND MAIN RESULTS: patients infected exclusively with nonmucoid BCC had a more rapid decline in lung function (annual FEV(1) change, -8.51 ± 2.41%) than those infected with mucoid bacteria (-3.01 ± 1.09%; P < 0.05). Linear mixed-effects data modeling revealed a statistically significant inverse association between semiquantitative mucoid exopolysaccharide production and rate of decline of lung function. In vitro incubation of BCC with ceftazidime and ciprofloxacin but not meropenem caused conversion of BCC from mucoid to nonmucoid. CONCLUSIONS: our data suggest an inverse correlation between the quantity of mucoid exopolysaccharide production by BCC bacteria and rate of decline in CF lung function. Certain antibiotics may induce a change in bacterial morphology that enhances their virulence. A simple in vitro test of bacterial mucoidy may be useful in predicting the rate of decline of respiratory function in CF.

The relationship of systemic inflammation to prior hospitalization in adult patients with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF) patients, it has been suggested that systemic inflammation may be an important risk factor for poor health outcomes. The relationship of plasma inflammatory biomarkers to lung function and hospitalization history remains largely unexplored. METHODS: This cross-sectional study included 58 consecutive, clinically stable adults from the CF Clinic at St. Paul's Hospital (Vancouver, Canada). Blood levels of interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), interleukin (IL)-6, IL-1ß, granzyme B (GzmB), chemokine C-C motif ligand 18 (CCL18/PARC), surfactant protein D (SP-D), lipopolysaccharide (LPS)-binding protein, and soluble cluster of differentiation 14 (sCD14) were measured using enzyme-linked immunosorbent assays, and LPS levels were measured using a Limulus amebocyte lysate assay. Spirometry was also performed. Multivariable linear regression analysis was used to assess relationships of the blood biomarkers to lung function. RESULTS: Lung function impairment was independently associated with elevated plasma levels of CRP (P < 0.01), IL-6 (P = 0.04), IL-1ß (P < 0.01), and LBP (P < 0.01). Increasing age (P < 0.01), reduced body mass index (P = 0.02), prior hospitalizations (P = 0.03), and presence of Pseudomonas aeruginosa in sputum cultures (P < 0.01) were also associated with reduced lung function. Elevated concentrations of LPS in plasma were associated with a previous history of hospitalization (P < 0.05). There was a trend towards an increase in plasma IL-6 (P = 0.07) and IL-1ß (P = 0.06) levels in patients who were previously hospitalized. CONCLUSIONS: IL-6 and IL-1ß are promising systemic biomarkers for lung function impairment and history of hospitalization in adult patients with CF.

Experience to date with CFTR modulators during pregnancy and breastfeeding in the British Columbia Cystic Fibrosis clinic.

The introduction and rapid uptake of CFTR modulator therapy, in addition to other treatments, has significantly increased life expectancy in CF and provided more women the opportunity to consider and successfully be managed throughout pregnancy. There is however limited evidence to guide patient management and enable informed decision making. Here we report the experience to date from a large multidisciplinary Cystic Fibrosis quaternary referral center in managing patients on CFTR modulators in the peri- and post-partum periods. While women in this case series were advised to discontinue CFTR modulators during pregnancy, they would likely receive a very different message today.

Association between elevated peripheral blood eosinophil count and respiratory outcomes in adults with cystic fibrosis.

BACKGROUND: Elevated blood eosinophil counts are linked to worse outcomes in asthma and COPD, but have yet to be well characterized in CF. We hypothesized that higher stable visit blood eosinophil counts are associated with increased rates of lung function decline and pulmonary exacerbations (PEx). METHODS: We performed a retrospective analysis of adult CF patients (≥19 years) enrolled from 2012 to 2018 in a prospective cohort study focused on blood biomarkers. We included individuals with at least one year of follow-up post-stable visit blood draw and compared clinical characteristics by blood eosinophil count (<300 cells/µL vs. ≥300 cells/µL). We used multivariate mixed-effects linear regression to estimate annual change in ppFEV1. Multivariable poisson and linear regression models were used to estimate rate of PEx requiring IV antibiotics and to compare CF Respiratory Symptom Diary-Chronic Respiratory Infection Symptom Scores (CFRSD-CRISS), respectively. RESULTS: Of 109 patients, 17 (15.6%) had eosinophil counts ≥300 cells/µL. After adjustment for age, sex, BMI, and baseline ppFEV1, there was no association between high vs. low eosinophil group and rates of lung function decline (difference in slope -0.04%/y; 95% CI -1.5 to +1.4) or rates of PEx requiring IV antibiotics (IRR 1.46; 95% CI 0.75 to 2.65). The high eosinophil group had a higher mean CFRSD-CRISS score at stable visit (adjusted mean difference 9.3; 95% CI 2.9 to 16.0). CONCLUSIONS: The high eosinophil group experienced increased respiratory symptoms, but the rates of lung function decline and PEx were comparable between groups.