Longitudinal changes and regional variation of incident infection rates at cystic fibrosis centers,United States 2010-2016

BackgroundMultiple factors affect incident infection rates (IIR) for Pseudomonas aeruginosa (PA) and methicillin resistant Staphylococcus aureus (MRSA) at CF care centers. We assessed changes in IIR across CF centers temporally associated with the 2013 Infection/Prevention & Control guidelines controlling for center-specific factors.MethodsUsing the CF Foundation Patient Registry we defined and measured changes in IIR between 2010-2012 and 2014-2016. Data were compared to non-CF rates of MRSA and resistant PA in geographically similar regions. Characteristics of each CF center (n centers: Adult 54 in 2010 to 82 in 2016. Pediatric ～106) and their respective population were evaluated for associations with IIR and with changes in IIR between the study periods.ResultsAcross the years 35613 patients were included. Incident-infection rates for PA (mean 19.2±0.04% Pediatric, 21.2±0.07% Adult centers) were higher than for MRSA (mean 9.4±0.03% Pediatric, 7.8±0.03% Adult). The IIR decreased for MRSA (-1.54±0.54%, p<0.001) and PA (-4.77±0.63%, p<0.001) at Pediatric but only for PA (-3.20±1.31, p=0.02) at Adult centers. Except for Adult CF, MRSA rates (CF and non-CF) were highest in the South. In 2014-2016, private insurance and a higher proportion of LatinX patients at a center were associated with lower MRSA IIR while larger center size, higher proportion of LatinX, and lower mean center-wide lung function were associated with higher PA IIR. Higher IIR in 2010-2012, were predictive of a more pronounced decrease in IIR in 2014-2016 for MRSA and PA (p<0.001). Different factors indicative of lower social status (smoking, insurance, education) in 2010-2012 predicted decreases in MRSA or PA IIR.ConclusionComparisons of IIR across U.S. CF centers should consider location, ethnic background and socio-economic variables of a center's population.     

AR-13 reduces antibiotic-resistant bacterial burden in cystic fibrosis phagocytes and improves cystic fibrosis transmembrane conductance regulator function

BackgroundThere are no effective treatments for Burkholderia cenocepacia in patients with cystic fibrosis (CF) due to bacterial multi-drug resistance and defective host killing. We demonstrated that decreased bacterial killing in CF is caused by reduced macrophage autophagy due to defective cystic fibrosis transmembrane conductance regulator (CFTR) function. AR-12 is a small molecule autophagy inducer that kills intracellular pathogens such as Francisella. We evaluated the efficacy of AR-12 and a new analogue AR-13 in reducing bacterial burden in CF phagocytes.MethodsHuman CF and non-CF peripheral blood monocyte-derived macrophages, neutrophils, and nasal epithelial cells were exposed to CF bacterial strains in conjunction with treatment with antibiotics and/or AR compounds.ResultsAR-13 and not AR-12 had growth inhibition on B. cenocepacia and methicillin-resistantStaphylococcus aureus (MRSA) in media alone. There was a 99% reduction in MRSA in CF macrophages, 71% reduction in Pseudomonas aeruginosa in CF neutrophils, and 70% reduction in non-CF neutrophils using AR-13. Conversely, there was no reduction in B. cenocepacia in infected CF and non-CF macrophages using AR-13 alone, but AR-13 and antibiotics synergistically reduced B. cenocepacia in CF macrophages. AR-13 improved autophagy in CF macrophages and CF patient-derived epithelial cells, and increased CFTR protein expression and channel function in CF epithelial cells.ConclusionsThe novel AR-12 analogue AR-13, in combination with antibiotics, reduced antibiotic-resistant bacterial burden in CF phagocytes, which correlated with increased autophagy and CFTR expression. AR-13 is a novel therapeutic for patients infected with B. cenocepacia and other resistant organisms that lack effective therapies.     

Upper and lower airway cultures in children with cystic fibrosis: Do not neglect the upper airways

BackgroundAirways of cystic fibrosis (CF) patients are colonised with bacteria early in life. We aimed to analyse differences between results of simultaneously taken upper airway (UAW) and lower airway (LAW) cultures, to describe clinical characteristics of patients with positive versus negative cultures and to follow up the patients with P. aeruginosa positive UAW cultures.MethodsBacteriological and clinical data from 157 children were collected during annual check up. The number of positive UAW and LAW cultures and correspondence between these results and clinical characteristics were analysed.ResultsPositive LAW and UAW cultures were found in 79.6% and 43.9% of patients respectively (p < 0.001). Patients with positive LAW cultures were significantly older (11.9 vs. 9.8 years, p < 0.05) and had more LAW symptoms (73.6% vs. 46.7%, p < 0.05), especially when P. aeruginosa was found. Patients with positive UAW cultures (especially S. aureus) had more nasal discharge (50.7% vs. 25.0%, p < 0.001). In 65% of patients with positive UAW and negative LAW culture for P. aeruginosa the next LAW became P. aeruginosa positive.ConclusionUAW cultures and LAW cultures differ in children with CF and there are differences in clinical characteristics between patients with positive versus negative culture results. P. aeruginosa positive UAW cultures appeared to precede positive LAW cultures in a substantial part of patients, suggesting some kind of cross-infection between the UAW and LAW.     

Neutrophil elastase-mediated increase in airway temperature during inflammation

BackgroundHow elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection.MethodsWe determined the temperature in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq.ResultsHere we show a temperature of ~ 38 °C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α₁-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa, under anaerobic conditions at 38 °C vs 30 °C revealed increased virulence traits and characteristic cell wall changes.ConclusionNeutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF.     

The fungal airway microbiome in cystic fibrosis and non-cystic fibrosis bronchiectasis

BackgroundThe prevalence of fungal disease in cystic fibrosis (CF) and non-CF bronchiectasis is increasing and the clinical spectrum is widening. Poor sensitivity and a lack of standard diagnostic criteria renders interpretation of culture results challenging. In order to develop effective management strategies, a more accurate and comprehensive understanding of the airways fungal microbiome is required. The study aimed to use DNA sequences from sputum to assess the load and diversity of fungi in adults with CF and non-CF bronchiectasis.MethodsNext generation sequencing of the ITS2 region was used to examine fungal community composition (n = 176) by disease and underlying clinical subgroups including allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, non-tuberculous mycobacteria, and fungal bronchitis. Patients with no known active fungal disease were included as disease controls.ResultsITS2 sequencing greatly increased the detection of fungi from sputum. In patients with CF fungal diversity was lower, while burden was higher than those with non-CF bronchiectasis. The most common operational taxonomic unit (OTU) in patients with CF was Candida parapsilosis (20.4%), whereas in non-CF bronchiectasis sputum Candida albicans (21.8%) was most common. CF patients with overt fungal bronchitis were dominated by Aspergillus spp., Exophiala spp., Candida parapsilosis or Scedosporium spp.ConclusionThis study provides a framework to more accurately characterize the extended spectrum of fungal airways diseases in adult suppurative lung diseases.     

IL-17A as a regulator of neutrophil survival in nasal polyp disease of patients with and without cystic fibrosis

Nasal polyps in adults are characterized by a chronic inflammation of the upper airways and by the preferential activation of Th2 cells. In contrast, IL-17 producing Th17 cells dominate the inflammation in nasal polyps of cystic fibrosis (CF) patients.MethodIL-17A, IL-5, IL-6, IL-8, IL-1β, ECP, MCP-1 and myeloperoxidase expression was determined in tissue homogenates of nasal polyps of non-CF and CF patients and controls. The cellular source of IL-17A was determined by immuno-histochemistry and FACS analysis. The functional role of IL-17A in the survival of neutrophils from CF and non-CF patients was tested.ResultsA significant upregulation of IL-17A and myeloperoxidase could be observed in nasal polyps from CF-patients. The cellular sources of IL-17A in nasal polyps were mainly T-lymphocytes. IL-17A was able to modulate the survival of neutrophils in nasal polyps from non-CF patients; however the survival of neutrophils in CF patients was independent of IL-17A.ConclusionThe present study shows that IL-17A has an impact on neutrophil survival in adult nasal polyp disease, but not in nasal polyps from CF patients.     

Alveolar inflammation in cystic fibrosis

BackgroundIn infected lungs of the cystic fibrosis (CF) patients, opportunistic pathogens and mutated cystic fibrosis transmembrane conductance regulator protein (CFTR) contribute to chronic airway inflammation that is characterized by neutrophil/macrophage infiltration, cytokine release and ceramide accumulation. We sought to investigate CF lung inflammation in the alveoli.MethodsLung tissue from 14 CF patients and four healthy individuals was analyzed for numbers of effector cells, elastin and collagen concentrations, inflammatory markers and density of Pseudomonas aeruginosa. Additionally, desmosine and isodesmosine concentrations were determined in 52 urine specimens from CF patients to estimate the burden of elastase activities in respiratory secretions.ResultsElastin concentration was significantly decreased and collagen significantly increased in CF alveolar tissues as compared to age-matched, healthy individuals. Elastin split products were significantly increased in urine samples from patients with CF and correlated inversely with age, indicating local tissue remodelling due to elastin degradation by unopposed proteolytic enzymes. Alveolar inflammation was also characterized by a significant cell infiltration of neutrophils, macrophages and T cells, extensive nuclear factor-κB and insulin-like growth factor-1 activation in various cell types and increased intercellular adhesion molecule-1 expression, and increased numbers of myofibroblasts. Additionally, ceramide accumulated in type II alveolar epithelial cells, lacking CFTR. P. aeruginosa organisms were rarely present in inflamed alveoli.ConclusionsChronic inflammation and remodeling is present in alveolar tissues of the CF lung and needs to be addressed by anti-inflammatory therapies.     

Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis

BackgroundChildren with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation.MethodsWe assessed 18 children (5 females) with median age of 3.2 years (range 0·9–5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level.ResultsPeak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG r_s = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, β = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015).ConclusionChildren with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.     

Outcomes of cystic fibrosis pulmonary exacerbations treated with antibiotics with activity against anaerobic bacteria

BackgroundObligate and facultative anaerobic bacteria are prevalent in cystic fibrosis (CF) airways. Increases in anaerobe relative abundance have been associated with CF pulmonary exacerbations (PEx); however, the impact of antibiotic treatment of anaerobes during PEx is unknown. We hypothesized that PEx treated with antibiotics with activity against anaerobes would improve outcomes compared to antibiotics without anaerobic activity.MethodsThis was a single-center, retrospective study of people with CF, ages 6 years and older, treated with intravenous (IV) antibiotics for PEx. IV antibiotics were classified as either broad or minimal anaerobic activity. PEx treated with broad anaerobe coverage were propensity-score matched to PEx treated with minimal anaerobic coverage. The primary outcome, % of baseline % predicted forced expiratory volume in one second (ppFEV₁) recovered, was compared between antibiotic categories with a linear mixed model. The secondary outcome, time to next PEx, was assessed using a Prentice Williams Petersen model.Results514 PEx from 182 patients were included. Broad anaerobe coverage was used in 27% of PEx, and was used more often for older patients (p < 0.001) with worse baseline ppFEV₁ (p < 0.001), and with Achromobacter (p < 0.001) or Burkholderia infections (p = 0.002). In the matched PEx, broad anaerobe coverage was not a significant predictor of % of baseline ppFEV₁ recovered (∆ppFEV₁ = -2.4, p = 0.09). Broad anaerobe coverage was also not a significant predictor of time to next PEx (HR 0.89, 95% CI 0.7-1.13, p = 0.35).ConclusionsIn this single center, retrospective study, antibiotics with broad activity against anaerobes were not associated with improved outcomes of CF PEx.     

Cessation of smoke exposure improves pediatric CF outcomes: Longitudinal analysis of CF Foundation Patient Registry data

BackgroundTobacco smoke exposure is a major risk factor for the health of children and adolescents with CF. In this study, we assess whether cessation of smoke exposure is associated with improved outcomes in this population.MethodsWe used annualized and encounter-based data from the U.S. CF Foundation Patient Registry (2006-2018) on all individuals born 1998-2010. The analytical sample included those who ever reported second-hand smoke exposure (daily or weekly), ever lived with a smoker, or ever reported smoking themselves. We used non-linear mixed models for pulmonary exacerbations and linear mixed models for ppFEV₁ and BMI as a function of ceased exposure.ResultsThe sample included 3,633 individuals contributing 19,629 person-years. Cessation of smoke exposure reduced the odds of a pulmonary exacerbation in 12 months by 17% (OR 0.83, p < 0.001) in the first year of cessation, with an additional 6% decrease (OR 0.94, p = 0.003) for each additional year of cessation. Cessation was associated with improvements in ppFEV₁ and BMI: 0.7% ppFEV₁ increase (p < 0.001) in the first year of cessation and 0.4% increase (p = 0.001) for each additional year of cessation; 1% increase in BMI percentile (p < 0.001) in the first year of cessation plus 0.4% increase (p = 0.009) for each additional year. Three years of cessation reduce the predicted probability of a pulmonary exacerbation in 12 months by 8% and improve ppFEV₁ and BMI by 2%.ConclusionEliminating smoke exposure may reduce pulmonary exacerbations and improve respiratory and nutritional outcomes in children and adolescents with CF. Both smoking cessation and exposure prevention should be prioritized in pediatric CF care.     

Neonates with cystic fibrosis have a reduced nasal liquid pH; A small pilot study

BackgroundDisrupted HCO₃^– transport and reduced airway surface liquid (ASL) pH in cystic fibrosis (CF) may initiate airway disease. We hypothesized that ASL pH is reduced in neonates with CF.MethodsIn neonates with and without CF, we measured pH of nasal ASL. We also measured nasal pH in older children and adults.ResultsIn neonates with CF, nasal ASL (pH 5.2 ± 0.3) was more acidic than in non-CF neonates (pH 6.4 ± 0.2). In contrast, nasal pH of CF children and adults was similar to values measured in people without CF.ConclusionsAt an age when infection, inflammation and airway wall remodeling are minimal, neonates with CF had an acidic nasal ASL compared to babies without CF. The CF:non-CF pH difference disappeared in older individuals, perhaps because secondary manifestations of disease increase ASL pH. These results aid understanding of CF pathogenesis and suggest opportunities for therapeutic intervention and monitoring of disease.     

Anti-inflammatory effects of DX-890, a human neutrophil elastase inhibitor

BackgroundNeutrophil elastase (NE)-mediated inflammation contributes to lung damage in cystic fibrosis (CF). We investigated if DX-890, a small-protein NE inhibitor, could reduce neutrophil trans-epithelial migration and reduce activity released from neutrophils and NE-induced cytokine expression in airway epithelial cells.MethodsActivated blood neutrophils (CF and healthy) treated ± DX-890 were assayed for NE activity. Transmigration of calcein-labeled neutrophils was studied using a 16HBE14o⁻ epithelial monolayer. IL-8 release from primary nasal epithelial monolayers (CF and healthy) was measured after treatment ± DX-890 and NE or CF sputum.ResultsDX-890 reduced NE activity from neutrophils (CF and healthy) and reduced neutrophil transmigration. DX-890 pre-treatment reduced IL-8 release from epithelial cells of healthy or CF subjects after stimulation with NE and CF sputum sol. All improvements with DX-890 were statistically significant (p < 0.05).ConclusionsDX-890 reduces NE-mediated transmigration and inflammation. NE inhibition could be useful in managing neutrophilic airway inflammation in CF.     

Early assessment of glucose abnormalities during continuous glucose monitoring associated with lung function impairment in cystic fibrosis patients

BackgroundCystic fibrosis-related diabetes (CFRD) is correlated with a decline in lung function. Under certain circumstances, oral glucose tolerance test (OGTT) screening, used to diagnose CFRD, fails to reveal early glucose tolerance abnormalities. In this situation, continuous glucose monitoring (CGM) could be a useful tool for evaluating early abnormalities of glucose tolerance in CF patients. We aimed to study the CGM glucose profile in CF patients with normal OGTT screening results and to evaluate lung function and nutritional status according to the CGM glucose profile.MethodsWe assessed glycemic control, the CGM glucose profile, nutritional status, lung function antibiotic courses and colonization (P. aeruginosa and S. aureus) in CF patients, aged 10 years and over, with normal screening OGTT results (blood glucose at T120 min < 7.8 mmol/l). Two groups were identified according to the max CGM glucose value: Group 1 < 11 mmol/l and Group 2 ≥ 11 mmol/l.ResultsAmong the 38 patients with normal OGTT, 12 (31.6%) were in Group 2. Compared to Group 1, Group 2 patients exhibited a significant impairment in lung function: FEV₁, 68.2 ± 25.6% vs. 87.3 ± 17%, p = 0.01 and FVC, 86.1% ± 19.4% vs. 99.3% ± 13.4%, p = 0.021, as well as a higher rate of colonization by P. aeruginosa: 83.3% vs. 44%, p = 0.024. Nevertheless, there were no differences in nutritional status (BMI standard deviation score: p = 0.079; prealbumin: p = 0.364).ConclusionsCGM reveals early abnormalities of glucose tolerance that remain undiagnosed by OGTT screening and are associated with worse lung function and a higher prevalence of P. aeruginosa colonization in patients with CF.Clinical trial registration number: NCT00476281.     

Soluble squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients

BackgroundThe bacterial contamination of nebulizers represents a major problem for cystic fibrosis (CF) patients that can lead to reduced nebulizer performance and increase the risk of patient reinfection by the contaminating bacteria.ObjectiveWe investigated the potential use of squalamine, a broad-spectrum antimicrobial compound, as a nebulizer disinfectant.MethodsPari LC nebulizers were artificially contaminated with a suspension of bacteria (Staphylococcus aureus and Pseudomonas aeruginosa; 10⁸ CFU/mL) and fungi (Candidida albicans and Aspergilus niger; 10⁷ CFU/mL) and then disinfected by immersion in squalamine solution for 20 min. Glutaraldehyde and Korsolex peracetic acid were used as disinfectant controls.ResultWe found that 0.5 g/L squalamine reduced the levels of viable S. aureus and P. aeruginosa by 5 log₁₀ and the level of viable C. albicans by 4 log₁₀ after 20 min. A concentration of 2 g/L was needed to reduce the level of A. niger cells by 4 log₁₀ in 6 hours. Finally, a formulation of squalamine in the form of a soluble disinfecting tablet containing 2.5% (w/w) squalamine was developed and successfully applied for nebulizer disinfection.ConclusionOur results suggest that aminosterol derivatives may be used by CF patients for rapid and easy home nebulizer disinfection and that soluble tablets may be developed for this purpose.     

Impact of airway Exophiala spp. on children with cystic fibrosis

IntroductionIsolation of Exophiala species from sputum samples has become increasingly reported in Cystic Fibrosis (CF). However, the clinical significance of Exophiala spp. with regards to the paediatric CF population is unknown.MethodsA case control study was undertaken to compare CF children with and without chronic Exophiala spp. in their sputum samples. Demographic and clinical data were collected retrospectively for each case from the date of Exophiala isolation and for 12 months preceding isolation. Each case was compared to three age and year-matched controls. To determine the effect of Exophiala on clinical course, patients were then followed for 12 months post isolation.ResultsIn total, 27 of 244 eligible paediatric CF patients (11%) isolated Exophiala spp. on more than one occasion. There were no significant differences in the key clinical parameters: spirometry, mean number of intravenous (IV) antibiotic days and body mass index (BMI), between cases and controls (p = 0.91, p = 0.56 and p = 0.63 respectively). A higher proportion of cases isolated Candida spp. (67% vs 21%, p < 0.0001) and Aspergillus fumigatus (37% vs 26%, p = 0.37). There was no clinically significant difference in spirometry, mean number of IV antibiotic days and BMI in cases pre and post Exophiala spp. isolation. Posaconazole was the only drug used that successfully eradicated Exophiala.ConclusionDespite the frequent isolation of Exophiala spp. in this cohort, in most patients it is not associated with significant clinical deterioration. It does however seem to be associated with isolation of other fungi.     

The application of neutrophil gelatin-related lipid delivery protein in evaluation of renal function,nutrition, anemia and inflammation in patients with CKD

ObjectiveTo investigate the role of neutrophil gelatinase-associated lipocalin in the evaluation of renal function, nutrition, anemia and inflammation in patients with chronic kidney diseases.Materials and methodsA total of 302 patients with chronic kidney diseases were selected, and their clinical data, blood neutrophil gelatinase-associated lipocalin levels, renal function, nutrition, anemia, inflammation and calcium, and phosphorus metabolism were analyzed.ResultSerum neutrophil gelatinase-associated lipocalin level increased with the progression of chronic kidney diseases. Higher neutrophil gelatinase-associated lipocalin levels were observed in patients with chronic kidney diseases stage 3b compared with healthy individuals (P < 0.05), while the patients with chronic kidney diseases stage 5 showed higher levels compared with other chronic kidney diseases stages (P < 0.01). Moreover, the ROC curve showed that neutrophil gelatinase-associated lipocalin had a better diagnostic performance from the chronic kidney diseases stage 3b to 5 (P < 0.05). In addition, the serum neutrophil gelatinase-associated lipocalin levels in patient with chronic kidney diseases were negatively correlated with body mass index, number of red blood cells, hemoglobin, transferrin, the estimatedglomerular filtration rate (eGFR), serum calcium (P < 0.01); and were positively correlated with mean arterial blood pressure, blood BUN, SCr and alpha 1 microglobulin, beta 2 microglobulin, urinary inhibition C, homocysteine, PTH levels, neutrophils ratio, free serum ferritin and c-reactive protein (P < 0.01); while no significant correlation was found with gender, and age (P > 0.05).ConclusionSerum neutrophil gelatinase-associated lipocalin levels are closely related to renal function injury, inflammatory response and anemia-related indicators in patients with chronic kidney diseases, and thus could be used as a diagnostic biomarker for evaluating the degree of renal injury and related complications in patients with chronic kidney diseases.     

Pseudomonas aeruginosa infection,but not mono or dual-combination CFTR modulator therapy affects circulating regulatory T cells in an adult population with cystic fibrosis

BackgroundChronic infection and an exaggerated inflammatory response are key drivers of the pathogenesis of cystic fibrosis (CF), especially CF lung disease. An imbalance of pro- and anti-inflammatory mediators, including dysregulated Th2/Th17 cells and impairment of regulatory T cells (Tregs), maintain CF inflammation. CF transmembrane conductance regulator (CFTR) modulator therapy might influence these immune cell abnormalities.MethodsPeripheral blood mononuclear cells and serum samples were collected from 108 patients with CF (PWCF) and 40 patients with non-CF bronchiectasis. Samples were analysed for peripheral blood lymphocytes subsets (Tregs; Th1-, Th1/17-, Th17- and Th2-effector cells) and systemic T helper cell-associated cytokines (interleukin [IL]-5, IL-13, IL-2, IL-6, IL-9, IL-10, IL-17A, IL-17F, IL-4, IL-22, interferon-γ, tumour necrosis factor-α) using flow cytometry.Results51% of PWCF received CFTR modulators (ivacaftor, ivacaftor/ lumacaftor or tezacaftor/ ivacaftor). There were no differences in proportions of analysed T cell subsets or cytokines between PWCF who were versus were not receiving CFTR modulators. Additional analysis revealed lower percentages of Tregs in PWCF and chronic pulmonary Pseudomonas aeruginosa infection; this difference was also present in PWCF treated with CFTR modulators. Patients with non-CF bronchiectasis tended to have higher percentages of Th2- and Th17-cells and higher levels of peripheral cytokines versus PWCF.ConclusionsChronic P. aeruginosa lung infection appears to impair Tregs in PWCF (independent of CFTR modulator therapy) but not those with non-CF bronchiectasis. Moreover, our data showed no statistically significant differences in major subsets of peripheral lymphocytes and cytokines among PWCF who were versus were not receiving CFTR modulators.     

Antibacterial properties of the CFTR potentiator ivacaftor

BackgroundIvacaftor increases CFTR channel activity and improves pulmonary function for individuals bearing a G551D mutation. Because ivacaftor structurally resembles quinolone antibiotics, we tested the hypothesis that ivacaftor possesses antibacterial properties.MethodsBioluminescence, colony forming unit, and minimal inhibitory concentration assays were used to assess viability of Staphylococcus aureus, Pseudomonas aeruginosa and multiple clinical microbial isolates.ResultsIvacaftor induced a dose-dependent reduction in bioluminescence of S. aureus and decreased the number of colony forming units. We observed a similar but less robust effect in P. aeruginosa following outer membrane permeabilization. Ivacaftor inhibited the growth of respiratory isolates of S. aureus and Streptococcus pneumoniae and exhibited positive interactions with antibiotics against lab and respiratory strains of S. aureus and S. pneumoniae.ConclusionThese data indicate that ivacaftor exhibits antibacterial properties and raise the intriguing possibility that ivacaftor might have an antibiotic effect in people with CF.     

Pseudomonas aeruginosa serology and risk for re-isolation in the EPIC trial

BackgroundThe prognostic value of Pseudomonas aeruginosa serology for antibiotic therapy in cystic fibrosis patients is not well understood.MethodsUsing five antigens from two ELISAs, we assessed whether positive serology in CF patients participating in the multi-center Early Pseudomonas Infection in Children (EPIC) trial would predict treatment failure, time to pulmonary exacerbation and risk for recurrent P. aeruginosa isolation post eradication.ResultsBaseline positive P. aeruginosa serology was not significantly associated with failure of initial P. aeruginosa eradication measured at week 10 (adjusted for baseline culture) but seropositivity to the antigens alkaline protease and exotoxin A was significantly associated with increased risk for recurrent P. aeruginosa isolation during the 60 week post eradication follow-up period (p = 0.003 and p = 0.001 respectively). There was no association between baseline seropositivity and time to pulmonary exacerbation.ConclusionP. aeruginosa serology may complement culture results in clinicians' efforts to successfully monitor recurrence of early P. aeruginosa in CF patients.