Theresa A. Laguna

Inflammation and Airway Microbiota during Cystic Fibrosis Pulmonary Exacerbations

Background Pulmonary exacerbations (PEx), frequently associated with airway infection and inflammation, are the leading cause of morbidity in cystic fibrosis (CF). Molecular microbiologic approaches detect complex microbiota from CF airway samples taken during PEx. The relationship between airway microbiota, inflammation, and lung function during CF PEx is not well understood. Objective To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx. Methods Expectorated sputum and blood were collected and lung function testing performed in CF subjects during early (0–3d.) and late treatment (>7d.) for PEx. Sputum was analyzed by culture, pyrosequencing of 16S rRNA amplicons, and quantitative PCR for total and specific bacteria. Sputum IL-8 and neutrophil elastase (NE); and circulating C-reactive protein (CRP) were measured. Results Thirty-seven sputum samples were collected from 21 CF subjects. At early treatment, lower diversity was associated with high relative abundance (RA) of Pseudomonas (r = −0.67, p<0.001), decreased FEV1% predicted (r = 0.49, p = 0.03) and increased CRP (r = −0.58, p = 0.01). In contrast to Pseudomonas, obligate and facultative anaerobic genera were associated with less inflammation and higher FEV1. With treatment, Pseudomonas RA and P. aeruginosa by qPCR decreased while anaerobic genera showed marked variability in response. Change in RA of Prevotella was associated with more variability in FEV1 response to treatment than Pseudomonas or Staphylococcus. Conclusions Anaerobes identified from sputum by sequencing are associated with less inflammation and higher lung function compared to Pseudomonas at early exacerbation. CF PEx treatment results in variable changes of anaerobic genera suggesting the need for larger studies particularly of patients without traditional CF pathogens.

Insulin Secretion Improves in Cystic Fibrosis Following Ivacaftor Correction of CFTR: A Small Pilot Study

To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector—ivacaftor.

Oral glucose tolerance testing in children with cystic fibrosis

Ode KL, Frohnert B, Laguna T, Phillips J, Holme B, Regelmann W, Thomas W, Moran A. Oral glucose tolerance testing in children with cystic fibrosis.

Recent trends in cystic fibrosis-related diabetes

Purpose of reviewTo provide an updated literature review highlighting important aspects of cystic fibrosis-related diabetes (CFRD) including epidemiology, pathogenesis, complications, screening, and management. Recent findingsAlthough CFRD continues to be associated with increased rates of mortality in the cystic fibrosis (CF) population, this has improved over the past several years, and the previous sex difference is no longer present. Recent studies support that CFRD is primarily caused by insulin deficiency due to loss of β cells, which may occur via a number of mechanisms including oxidative stress. Aggressive screening programs with oral-glucose tolerance testing and early treatment with insulin for patients with CFRD with or without fasting hyperglycemia have led to improvements in nutritional states and lung function. Oral agents do not appear to be effective in CFRD. SummaryCFRD is the most common comorbidity in the CF population and is associated with microvascular complications and protein catabolism leading to worse health outcomes. Recognition of glycemic abnormalities through aggressive screening has led to improvements in nutritional status, pulmonary function, and mortality rates.

The applicability of urinary creatinine as a method of specimen normalization in the cystic fibrosis population

BACKGROUND Urine specimens are commonly used in biomarker research. Urinary creatinine (UCr) is often used to adjust for urine analyte concentration. We aim to explore the applicability of UCr as a normalization method in a cystic fibrosis (CF) population during hospitalization. METHODS Multiple spot urine samples were collected from CF patients hospitalized for a pulmonary exacerbation. Single spot specimens were obtained from asthmatics and healthy children for comparison. The assumptions and implications from the use of UCr as a normalization factor for urinary desmosine measurements were investigated. RESULTS UCr differed significantly across disease groups and decreased significantly over time in the CF population. Differing results were obtained when contrasting normalization by UCr with specific gravity. CONCLUSIONS UCr levels are not completely attributable to simply variations in urine concentration. Analysis of urinary biomarker measurements should be initiated with an understanding of the relative effects of the normalization process on the results.

Impaired fasting glucose in cystic fibrosis.

OBJECTIVE While glucose tolerance abnormalities are common in cystic fibrosis (CF), impaired fasting glucose (IFG) has scarcely been explored. No studies have examined the relation between IFG and clinical status. RESEARCH DESIGN AND METHODS Data were retrieved from the University of Minnesota CF database on oral glucose tolerance tests (OGTTs) performed in 1996–2005. Subjects were identified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CF–related diabetes without fasting hyperglycemia (CFRD FH−). Patients with fasting hyperglycemia were excluded. The presence of IFG was assessed within each category. In a separate case-control cohort study, subjects with IFG were matched to CF control subjects by age, sex, and OGTT class to explore outcomes. RESULTS For the total population (n = 310), the prevalence of IFG was 22%, and by OGTT class was NGT 14%, IGT 31%, CFRD FH− 53%. Within the cohort study, mortality was significantly reduced in IFG (two vs. nine deaths, odds ratio [OR] = 0.2 [95% CI 0.04–0.9]). IFG did not confer increased risk of progression to diabetes (OR 0.66 [0.29–1.48]). Lung function was better in pediatric IFG subjects with IGT and not significantly worse in adults with IGT or adults and children with NGT and CFRD FH−. BMI was not significantly different in IFG subjects versus control subjects. CONCLUSIONS Contrary to expectations in patients with CF, IFG appeared to be associated with improved survival and was not associated with worse nutritional or pulmonary status or increased progression to fasting hyperglycemia.

Airway microbiota across age and disease spectrum in cystic fibrosis

Our objectives were to characterise the microbiota in cystic fibrosis (CF) bronchoalveolar lavage fluid (BALF), and determine its relationship to inflammation and disease status. BALF from paediatric and adult CF patients and paediatric disease controls undergoing clinically indicated bronchoscopy was analysed for total bacterial load and for microbiota by 16S rDNA sequencing. We examined 191 BALF samples (146 CF and 45 disease controls) from 13 CF centres. In CF patients aged <2 years, nontraditional taxa (e.g. Streptococcus, Prevotella and Veillonella) constituted ∼50% of the microbiota, whereas in CF patients aged ≥6 years, traditional CF taxa (e.g. Pseudomonas, Staphylococcus and Stenotrophomonas) predominated. Sequencing detected a dominant taxon not traditionally associated with CF (e.g. Streptococcus or Prevotella) in 20% of CF BALF and identified bacteria in 24% of culture-negative BALF. Microbial diversity and relative abundance of Streptococcus, Prevotella and Veillonella were inversely associated with airway inflammation. Microbiota communities were distinct in CF compared with disease controls, but did not differ based on pulmonary exacerbation status in CF. The CF microbiota detected in BALF differs with age. In CF patients aged <2 years, Streptococcus predominates, whereas classic CF pathogens predominate in most older children and adults. Bacterial taxa detected in cystic fibrosis bronchoalveolar lavage fluid differ by age and inflammatory response http://ow.ly/2uV230eFA0W

Sputum Desmosine During Hospital Admission for Pulmonary Exacerbation in Cystic Fibrosis

BACKGROUND Cystic fibrosis (CF) lung disease is characterized by structural changes in the airways and parenchyma. No sputum biomarker exists to measure the degree of active structural destruction during pulmonary exacerbation in patients with CF. The noninvasive measurement of desmosine, a breakdown product of elastin, may reflect ongoing lung injury and serve as a biomarker of short-term damage. Our objectives were to measure desmosine in the sputum of patients with CF hospitalized for treatment of a pulmonary exacerbation and to explore the correlation between desmosine levels and other markers of clinical improvement, including lung function and inflammatory mediators, following hospitalization. METHODS Sputum and blood samples collected and lung function measurements were made at multiple time points during hospitalization. We used a repeated measures model, adjusted for age and time between measurements, to compare log-transformed sputum desmosine levels across multiple time points and to correlate those levels with related variables. RESULTS Desmosine levels were measured by radioimmunoassay in 71 expectorated sputum samples from 19 patients with CF hospitalized for 26 pulmonary exacerbations (range of results, 0 to 200 pmol/L desmosine/mL). Sputum desmosine levels decreased significantly during the first week of hospitalization (p = 0.04). Desmosine levels were positively associated with plasma C-reactive protein (rho = 0.59; p = 0.03), sputum interleukin-8 (rho = 0.86; p < 0.01), and sputum neutrophil elastase (rho = 0.78; p < 0.01). CONCLUSIONS Sputum desmosine, a novel measure of acute structural lung injury, may serve as a marker of structural lung damage occurring during exacerbations of lung disease in CF.

Decreased Total Serum Coenzyme-Q10 Concentrations: A Longitudinal Study in Children with Cystic Fibrosis

OBJECTIVE To assess total serum levels of coenzyme Q(10) (Co-Q(10)), an important antioxidant, in children with cystic fibrosis (CF) and to investigate an association between Co-Q(10) level and clinical outcome. STUDY DESIGN Co-Q(10) levels were measured annually in a prospective cohort study of 381 children with CF. A total of 1092 serum levels of total Co-Q(10) were obtained by high-performance liquid chromatography and ultraviolet light detection. Associations of Co-Q(10) with demographic variables and clinical outcomes were investigated. RESULTS Of the 381 initial total serum Co-Q(10) measurements, 188 were in the deficient range. Low Co-Q(10) was significantly more prevalent in patients with pancreatic insufficiency (PI) (55%) compared with patients with pancreatic sufficiency (PS) (3%); 22% of the patients with PI exhibited persistently low Co-Q(10) levels. Low Co-Q(10) levels were significantly associated with Pseudomonas aeruginosa colonization in patients with PI and CF under age 24 months, but not with subsequent lung function or hospitalization rates. Low Co-Q(10) levels were related to other markers of nutritional status, including total lipids, beta-carotene, and alpha-tocopherol. CONCLUSIONS Persistently low total serum Co-Q(10) levels are common in children with CF and PI. A prospective study is indicated to determine whether Co-Q(10) supplementation in CF is beneficial.

Urinary desmosine: A biomarker of structural lung injury during CF pulmonary exacerbation†‡

Cystic fibrosis (CF) lung disease is characterized by structural changes and remodeling in airway architecture and lung parenchyma. Neutrophilic inflammation and infection lead to injury and breakdown of airway matrix constituents, including elastin. The non‐invasive measurement of urinary desmosine (UDes), a breakdown product of elastin, may be reflective of ongoing lung injury and may serve as a biomarker of active short‐term damage during pulmonary exacerbation. Our objectives were to measure desmosine in the urine of CF patients hospitalized for treatment of a pulmonary exacerbation and to explore the correlation between desmosine concentration and other markers of clinical improvement, including lung function and inflammatory mediators.