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Identification of novel blood biomarkers of treatment response in cystic fibrosis pulmonary exacerbations by label-free quantitative proteomics.

ABSTRACT: Pulmonary exacerbations (PEx) are clinically impactful events for individuals with CF. Unfortunately, many CF individuals with PEx fail to regain their baseline lung function despite treatment. The objective of this study was to use unbiased proteomic technology to identify novel blood protein biomarkers that change following intravenous (IV) antibiotic treatment and to explore if changes correlate with clinical response by the end of treatment. Blood samples from 25 PEx events derived from 22 unique CF adults were collected within 24?hours of hospital admission, day 5, day 10, and IV antibiotic completion. Three-hundred and forty-six blood proteins were evaluated with label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitative proteomics and immunoassays. Forty-seven plasma proteins changed significantly following 5 days of IV antibiotic treatment (q-value???0.10). Early change in IGF2R from hospital admission to day 5 correlated with overall change in symptom score (CFRSD-CRISS) by the end of treatment (r?=?-0.48, p-value?=?0.04). Several plasma proteins identified and quantified by label-free LC-MS/MS changed early following treatment with IV antibiotics and many of these proteins are involved in complement activation and inflammatory/immune-related pathways. Early change in IGF2R correlated with symptom response following IV antibiotic treatment and requires further validation as a predictive biomarker of symptom response.

SUBMITTER: Dong K

PROVIDER: S-EPMC6868239 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Identification of novel blood biomarkers of treatment response in cystic fibrosis pulmonary exacerbations by label-free quantitative proteomics.

Dong Kang K Moon Kyung-Mee KM Chen Virginia V Ng Raymond R Foster Leonard J LJ Tebbutt Scott J SJ Quon Bradley S BS

Scientific reports 20191120 1

Pulmonary exacerbations (PEx) are clinically impactful events for individuals with CF. Unfortunately, many CF individuals with PEx fail to regain their baseline lung function despite treatment. The objective of this study was to use unbiased proteomic technology to identify novel blood protein biomarkers that change following intravenous (IV) antibiotic treatment and to explore if changes correlate with clinical response by the end of treatment. Blood samples from 25 PEx events derived from 22 u ...[more]

PMID: 31748618

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Project description:The lack of effective differential diagnostic methods for active tuberculosis (TB) and latent infection (LTBI) is still an obstacle for TB control. Furthermore, the molecular mechanism behind the progression from LTBI to active TB has been not elucidated. Therefore, we performed label-free quantitative proteomics to identify plasma biomarkers for discriminating pulmonary TB (PTB) from LTBI. A total of 31 overlapping proteins with significant difference in expression level were identified in PTB patients (n = 15), compared with LTBI individuals (n = 15) and healthy controls (HCs, n = 15). Eight differentially expressed proteins were verified using western blot analysis, which was 100% consistent with the proteomics results. Statistically significant differences of six proteins were further validated in the PTB group compared with the LTBI and HC groups in the training set (n = 240), using ELISA. Classification and regression tree (CART) analysis was employed to determine the ideal protein combination for discriminating PTB from LTBI and HC. A diagnostic model consisting of alpha-1-antichymotrypsin (ACT), alpha-1-acid glycoprotein 1 (AGP1), and E-cadherin (CDH1) was established and presented a sensitivity of 81.2% (69/85) and a specificity of 95.2% (80/84) in discriminating PTB from LTBI, and a sensitivity of 81.2% (69/85) and a specificity of 90.1% (64/81) in discriminating PTB from HCs. Additional validation was performed by evaluating the diagnostic model in blind testing set (n = 113), which yielded a sensitivity of 75.0% (21/28) and specificity of 96.1% (25/26) in PTB vs. LTBI, 75.0% (21/28) and 92.3% (24/26) in PTB vs. HCs, and 75.0% (21/28) and 81.8% (27/33) in PTB vs. lung cancer (LC), respectively. This study obtained the plasma proteomic profiles of different M.TB infection statuses, which contribute to a better understanding of the pathogenesis involved in the transition from latent infection to TB activation and provide new potential diagnostic biomarkers for distinguishing PTB and LTBI.

Project description:Pulmonary exacerbations lead to significant morbidity and mortality in patients with cystic fibrosis (CF). National consensus guidelines exist, but few studies report current practice in the treatment and monitoring of pulmonary exacerbations. The goal of this study was to characterize consistency and variability in the inpatient management of CF-related pulmonary exacerbations. We focused on the use of guideline-recommended maintenance therapies, antibiotic selection and treatment regimens, use of systemic corticosteroids, and frequency of lung function testing. We hypothesized that significant variability in these treatment practices exists nationally. This trial was a retrospective cross-sectional study. It included patients with CF aged ≤18 years hospitalized for pulmonary exacerbations between July 1, 2010, and June 30, 2015, at hospitals within the US Pediatric Health Information System database that are also Cystic Fibrosis Foundation-accredited care centers. One exacerbation per patient was randomly selected over the 5-year study period. From 38 hospitals, 4827 individual pulmonary exacerbations were examined. Median length of stay was 10.0 days (interquartile range, 6-14.0 days). Significant variation was seen among centers in the use of hypertonic saline (11%-100%), azithromycin (5%-83%), and systemic corticosteroids (3%-61%) and in the frequency of lung function testing. Four different admission antibiotic regimens were used >10% of the time, and the most commonly used admission antibiotic regimen comprised 2 intravenous antibiotics with no additional oral or inhaled antibiotics (29%). Significant variation exists in the treatment and monitoring of pulmonary exacerbations across Pediatric Health Information System-participating, Cystic Fibrosis Foundation-accredited care centers. Results from this study can inform future research working toward standardized inpatient pulmonary exacerbation management to improve CF care for children and adolescents.

Project description:IntroductionMetabolomics is an emerging area of research and has the potential to identify clinical biomarkers for predicting or diagnosing cystic fibrosis (CF) pulmonary exacerbations (PEx).ObjectiveTo identify clinically promising metabolites across different sample sources that can be used to predict or diagnose PEx in CF.Evidence reviewSearches for original literature were completed through EMBASE, MEDLINE, and all databases on the Web of Science with no restrictions on language or publication date. Gray literature was collected through Google Scholar. Additional studies were obtained by contacting authors and searching reference lists of candidate papers. The patient population included individuals with CF. Studies involving patients who underwent lung transplantation were excluded. The outcome was the prediction or diagnosis of pulmonary exacerbations from metabolites directly measured from biological samples. Search results were downloaded and imported into Covidence and duplicates were removed automatically. Any remaining duplicates were manually tagged and excluded. Two independent reviewers screened each abstract for eligibility and repeated this process for full texts. Risk of bias was conducted using QUADAS-2 by two independent reviewers. A third author resolved any remaining conflicts.ResultsA combined 3974 relevant abstracts were identified and 115 full texts were assessed for eligibility. The final 25 studies underwent data extraction for study design, patient demographics, studied metabolites, concentration values, and diagnostic accuracy values. Included studies differed considerably in methodologies, sample specimen types (exhaled breath condensate [EBC], sputum, saliva, plasma, urine), and disease states. We identified 19 unique metabolites that were measured by two or more studies of which 2 have the potential to predict PEx (EBC 4-hydroxycyclohexylcarboxylic acid [4-HCHC] and lactic acid) and 6 to diagnose PEx (EBC 4-HCHC and lactic acid, sputum lactic acid and nitrate, and plasma arginine and methionine).Conclusion and relevanceThis systematic review has identified promising metabolites for further study in CF. Certain metabolites may provide clinical potential in predicting or diagnosing PEx, but further validation studies are required. With better tools to aid in the earlier identification of PEx, clinicians can implement preventative measures to mitigate airway damage.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/.

Project description:Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis. The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We aimed to assess the association between pulmonary artery enlargement (defined as pulmonary artery diameter to ascending aorta diameter [PA:A] ratio >1), a marker of pulmonary vascular disease, and exacerbations.In this cohort study, we used clinical, CT imaging, and prospective exacerbation data from a previous prospective clinical trial (derivation cohort) and from The Prince Charles Hospital (TPCH; Brisbane, QLD, Australia) cystic fibrosis registry (validation cohort). In our derivation cohort, we included adults aged 18 years or older with cystic fibrosis and at least one CFTR nonsense mutation, who were enrolled in the trial between Sept 8, 2009, and Nov 30, 2010, randomly assigned to receive placebo, and had baseline CT imaging. Our validation cohort included adult patients with cystic fibrosis who had CT imaging performed between Jan 1, 2002, and Dec 31, 2014. We measured the PA:A ratio at the level of the pulmonary artery bifurcation on CT scans. Patients in each cohort were separated into two groups on the basis of PA:A ratio (>1 or ?1) and were followed up for 1 year in the derivation cohort and 2 years in the validation cohort. The primary endpoint was the development of one or more acute pulmonary exacerbations during follow-up. We used linear and logistic regression models to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine the time to first exacerbation in the validation cohort.37 (50%) of 74 patients in the derivation cohort and 89 (47%) of 190 patients in the validation cohort had enlarged pulmonary arteries (PA:A>1). 50 (68%) patients in the derivation cohort had one or more exacerbations at 1 year and 133 (70%) patients in the validation cohort had one or more exacerbations at 2 years. At baseline, patients with pulmonary artery enlargement were younger than those without enlargement in both cohorts and had elevated sweat chloride concentrations in the derivation cohort (100·5 mmol/L [SD 10·9] vs 90·4 mmol/L [19·9]; difference 10·1 mmol/L [95% CI 2·5-17·7], p=0·017). Pulmonary artery enlargement was associated with exacerbations in the derivation cohort (odds ratio 3·49 [95% CI 1·18-10·3], p=0·023) when adjusted for sex, body-mass index (BMI), forced expiratory volume in 1 s (FEV1), and PA:A greater than 1, and in the validation cohort (2·41 [1·06-5·52], p=0·037) when adjusted for sex, BMI, chronic Pseudomonas aeruginosa infection, FEV1/FVC (forced vital capacity), PA:A greater than 1, and previous exacerbation. The time to first exacerbation was shorter in patients with enlarged pulmonary arteries than in those with normal-sized pulmonary arteries in the validation cohort (hazard ratio 1·66 [95% CI 1·18-2·34], p=0·0038) in unadjusted analysis, but not when adjusted for sex, BMI, exacerbations within 1 year before index CT scan, FEV1/FVC, and chronic P aeruginosa infection (1·14 [0·80-1·62], p=0·82).Pulmonary artery enlargement is prevalent in adult patients with cystic fibrosis and was associated with acute pulmonary exacerbation risk in two well characterised cohorts. The PA:A ratio could be a predictive marker in cystic fibrosis.US National Heart, Lung, and Blood Institute/National Institutes of Health, Cystic Fibrosis Foundation, the University of Alabama at Birmingham, and the Queensland Health Fellowship.

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Identification of novel blood biomarkers of treatment response in cystic fibrosis pulmonary exacerbations by label-free quantitative proteomics.

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Identification of novel blood biomarkers of treatment response in cystic fibrosis pulmonary exacerbations by label-free quantitative proteomics.

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