Dexmedetomidine attenuates lipopolysaccharide-induced proinflammatory response in primary microglia

BackgroundNeuroinflammation mediated by microglia has been implicated in delirium. Suppression of microglial activation may therefore contribute to alleviate delirium. It has been reported that dexmedetomidine (DEX) has a potent anti-inflammatory property. In the present study, we investigated the effects of DEX on the production of proinflammatory mediators in lipopolysaccharide-stimulated microglia.Materials and methodsThe concentrations of DEX were chosen to correspond to 1, 10, and 100 times of clinically relevant concentration (i.e., 1, 10, and 100 ng/mL). The levels of proinflammatory mediators, such as inducible nitric oxide synthase or nitric oxide, prostaglandin E₂, interleukin 1β, and tumor necrosis factor α, were measured.ResultsDEX at 1 ng/mL did not affect the production of proinflammatory mediators. DEX at 10 and 100 ng/mL significantly inhibited the release of nitric oxide, prostaglandin E₂, interleukin 1β, and tumor necrosis factor α and the expression of inducible nitric oxide synthase messenger RNA.ConclusionsThese results suggest that DEX is a potent suppressor of lipopolysaccharide-induced inflammation in activated microglia and may be a potential therapeutic agent for the treatment of intensive care unit delirium.     

The effect of resuscitation strategy on the longitudinal immuno-inflammatory response to blunt trauma

IntroductionResuscitation strategies following blunt trauma have been linked to immuno-inflammatory complications leading to systemic inflammatory syndrome (SIRS), sepsis and multiple organ failure (MOF). The effect of resuscitation strategy on longitudinal inflammation marker trajectories is, however, unknown. We hypothesized that the effect of resuscitation strategy extends beyond the trauma-related coagulopathy, perhaps affecting the longitudinal immuno-inflammatory response to injury.MethodsWe analyzed data prospectively collected for the Inflammation and Host Response to Injury (Glue Grant) study. Blood sampling for inflammation marker analyses from blunt trauma patients was done on admission days 0, 1, 4, 7, 14, 21 and 28 where applicable.Total volume transfused of packed red blood cells (PRBC), fresh frozen plasma (FFP), platelets (PLT), and crystalloids during the initial 48 h was extracted, along with an analysis for an array of cytokines by Enzyme Linked Immunosorbent Assay (ELISA) technique. A within patient concentration change (WPCC) was calculated to quantify longitudinal alterations in cytokine levels, while controlling for potential confounders. To account for the multiple comparisons performed, p-values obtained from the multivariate regression model were post-hoc corrected by the false detection rate (FDR) q-value.ResultsNo longitudinal trajectories of inflammatory markers were found to be associated with PRBC- or PLT transfusion. Three proinflammatory cytokines (Il-1β, MIP-1β, and TNFR2) were negatively associated with volume of FFP transfused (q = 0.02, q < 0.001 and q = 0.007 respectively), and one proinflammatory cytokine (MIP-1β) was positively associated with crystalloid infusion (q = 0.005).ConclusionsResuscitation strategy employed following blunt trauma has limited association to longitudinal inflammation marker trajectories, with a potential association between the strategy employed and IL-1β, TNFR2, and MIP-1β trajectories, respectively.     

Inflammatory and growth factor response to continuous and intermittent exercise in youth with cystic fibrosis

BackgroundChildren with cystic fibrosis (CF) tend to suffer from chronic systemic inflammation and may have impaired growth associated with muscle catabolism. Therefore, investigating which type of exercise can elicit an anabolic response with minimal inflammation is of clinical value.MethodsTwelve children with CF (mean ± SD; age: 14.7 ± 2.3 years, predicted FEV₁: 90.0 ± 21.6%) and biological age-matched controls (age: 13.9 ± 2.1 years) completed moderate-intensity, continuous exercise (MICE) and high-intensity, intermittent exercise (HIIE) on separate days. During each exercise, blood was drawn at various time points and analyzed for immune cells, inflammatory cytokines, and growth mediators.ResultsAt rest, children with CF had higher concentrations of neutrophils and IL-6 compared with controls. In children with CF, HIIE did not affect immune cell subsets or cytokines: TNF-α, IL-6, and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). All immune cell subsets and IL-6 increased significantly with MICE in both groups. Growth hormone (GH) increased with both types of exercise, with a greater change from rest during MICE.ConclusionsHIIE was a sufficient stimulus to increase GH in children with CF, without affecting systemic inflammation.     

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.     

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.     

Impact of polyclonal anti-thymocyte globulins on the expression of adhesion and inflammation molecules after ischemia–reperfusion injury

BackgroundPolyclonal anti-thymocyte globulins (ATGs) are immunosuppressive agents used for the treatment and prevention of acute organ rejection after transplantation. ATGs induce apoptosis and complement-mediated cell death in peripheral T-lymphocytes and have shown a reduction of leukocyte adhesion after ischemia–reperfusion (IRI). We analyzed the impact of different ATGs upon the expression of adhesion and inflammation molecules after IRI.Materials and methodsThe major arteries and veins of the extremities of cynomolgus monkeys were surgically isolated and flushed with Ringer's lactate at 4 °C. After 60 min of ischemia the limbs were reperfused with matching human blood. ATGs were added to the blood 30 min prior to the reperfusion, forming four groups: Tecelac-ATG group (n = 16), Fresenius(S)-ATG group (n = 16), Thymoglobulin-ATG group (n = 12) and a control group (n = 16). Biopsies from muscular tissue were obtained after the experiments. The expression of adhesion (ICAM-1, VCAM, PECAM, CD11b, CD62E) and inflammation (IL-1, IL-6, TNF-α) molecules on endothelium, leukocytes, and reperfused tissue was analyzed by means of immunohistochemistry.ResultsThe expression of the studied adhesion molecules (ICAM-1, VCAM, PECAM, CD11b, and CD62E) was significantly increased in the control group when compared with the treated groups. The expression of IL-1, IL-6, and TNF-α was reduced in the ATG-groups in comparison to the control group.DiscussionOur results showed that ATGs caused a reduction of the expression of adhesion and inflammation molecules both in endothelium and reperfused tissue. The inhibition of the expression of molecules required for firm cellular adhesion, may contribute to decreasing cellular graft infiltration after post-ischemic reperfusion.     

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.     

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.     

A randomized controlled trial of inhaled l-Arginine in patients with cystic fibrosis

BackgroundCystic fibrosis (CF) airways are nitric oxide (NO) deficient. We studied safety and efficacy of repeated inhalations of nebulized l-arginine, the substrate for NO synthase (NOS), in patients with CF.MethodsDouble-blind, randomized, placebo-controlled crossover treatment trial of twice daily inhalation of 500 mg l-arginine for two weeks compared to inhalation of saline in 19 CF patients (ClinicalTrials.gov Identifier: NCT00405665).Resultsl-Arginine inhalation was well tolerated and resulted in a significant increase in exhaled NO. FEV₁ increased by an average of 56 ml compared to ? 8 ml after saline solution; but this difference did not reach statistical significance. Sputum concentrations of l-ornithine, the product of arginase activity, increased significantly while the l-ornithine derived polyamines did not. There was no change in inflammatory markers in sputum.ConclusionRepeated inhalation of l-arginine in CF patients was safe and well tolerated. Inhaled l-arginine increased NO production without evidence for changes in airway inflammation.     

Ancestral haplotype 8.1 and lung disease severity in European cystic fibrosis patients

BackgroundThe clinical course of cystic fibrosis (CF) lung disease varies between patients bearing identical CFTR mutations. This suggests that additional genetic modifiers may contribute to the pulmonary phenotype. The highly conserved ancestral haplotype 8.1 (8.1AH), carried by up to one quarter of Caucasians, comprises linked gene polymorphisms on chromosome 6 that play a key role in the inflammatory response: LTA + 252A/G; TNF −308G/A, HSP70-2 + 1267A/G and RAGE −429T/C. As inflammation is a key component inducing CF lung damage, we investigated whether the 8.1AH represents a lung function modifier in CF.MethodsWe analyzed the lung function of 404 European CF patients from France (n = 230), Germany (n = 95) and UK (n = 79). FEV₁ differences between 8.1AH carriers and non-carriers were calculated in each country and pooled using a random effects model.ResultsThe frequency of 8.1AH carriers was similar between French (22%), German (29%) and UK (27%) patients. We found that 8.1AH carriers had significantly lower FEV₁, adjusted for age classes and countries (P < 0.04, mean FEV₁ difference − 6.4% CI95% [− 12.4%, − 0.5%]). No difference was observed with respect to BMI Z-scores and chronic colonization with P. aeruginosa.ConclusionsThese findings support the concept that 8.1AH is an important genetic modifier of lung disease in CF. To conclude, multiple linked genes outside the CF locus might explain some of the variability in lung phenotype.     

Small macrophages are present in early childhood respiratory disease

BackgroundRecently, an established “small macrophage” phenotype has been observed in the sputum of patients with CF and COPD. However, little is known about the prevalence of this phenotype in the airways of young children. Since respiratory inflammation begins early in CF, we hypothesised that these small macrophages would be increased in paediatric CF bronchoalveolar lavage (BAL).MethodsMacrophage populations in CF and disease control BAL were assessed by multicolour flow cytometry. BAL inflammatory indices were collected as part of the AREST-CF programme.ResultsSmall macrophages were present in CF (n = 35, mean 36 ± 12% of BAL macrophages) but not significantly different to the respiratory disease controls (n = 7, mean 40 ± 21%). Number of small macrophages correlated significantly with number of BAL neutrophils (r = 0.44, p < 0.01) but not infection or IL-8.ConclusionsIn paediatric patients small macrophages are not unique to CF, but their establishment as the dominant phenotype in adults may be due to chronicity of inflammation and infection.     

Cytokine gene polymorphisms and severity of CF lung disease

BackgroundThe search for modifier genes to explain inconsistencies in cystic fibrosis (CF) genotype–phenotype relationships has yielded mixed results. In a previous cross-sectional study from our centre the clinical effect (as described by FEV₁, BMI z-score, admitted days and NIH score) of single nucleotide polymorphisms (SNPs) of four cytokine genes (IL-8, TNF-α, IL-1β and IL-10) was examined in 158 children with CF. No association between cytokine genotype and any biological outcome measure was found. In this present study a cross-sectional and longitudinal examination of this relationship was undertaken to test the hypothesis that pro-inflammatory SNPs would affect longitudinal changes in CF lung disease.MethodsUsing the cohort examined in our earlier study we performed both longitudinal and cross-sectional data analyses examining the relationship between SNPs (TNF-α, IL-8, IL-10 and IL-1β) and clinical outcome measurements. In the first part of this current study, lung function data (annual decline of FEV₁ percent predicted) was compared with the cytokine genotype over a 13 year period. In the second part of this current study multiple regression was used to assess associations between clinical outcomes (best FEV₁ percent predicted and BMI at the age of 10 years) and alleles of cytokine genes, adjusting for gender, CF genotype and lung infection status.ResultsA total of 152 patients with CF were analysed in the longitudinal study and data from 130 patients at the age of 10 years were analysed in the cross-sectional study. There was evidence for an association between pro-inflammatory SNPs of the IL-8, IL-10 and IL-1β genes and more severe lung disease. Multiple regression of the longitudinal data with a total of 10,956 lung function measurements showed an additional annual decline of the percentage predicted FEV₁ of − 1.15 (IL-8, p < 0.001), − 0.24 (IL-10, p = 0.049) and − 0.41 (IL-1β, p < 0.001) for patients with any of the pro-inflammatory alleles. None of the cross-sectional data showed a significant association between the cytokine genotypes and the clinical outcomes.ConclusionPro-inflammatory alleles of three cytokine genotypes, IL-8, IL-10 and IL-1β, appear to be associated with slightly more severe lung disease in patients with CF over a 13 year period. Further studies are required to exclude influence of confounders on the severity of lung disease.     

A novel neutrophil derived inflammatory biomarker of pulmonary exacerbation in cystic fibrosis

BackgroundThe focus of this study was to characterize a novel biomarker for cystic fibrosis (CF) that could reflect exacerbations of the disease and could be useful for therapeutic stratification of patients, or for testing of potential drug treatments. This study focused exclusively on a protein complex containing alpha-1 antitrypsin and CD16b (AAT:CD16b) which is released into the bloodstream from membranes of pro-inflammatory primed neutrophils.MethodsNeutrophil membrane expression and extracellular levels of AAT and CD16b were quantified by flow cytometry, Western blot analysis and by 2D-PAGE. Interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and AAT:CD16b complex were quantified in CF plasma (n = 38), samples post antibiotic treatment for 14 days (n = 10), chronic obstructive pulmonary disease (n = 10), AAT deficient (n = 10) and healthy control (n = 14) plasma samples by ELISA.ResultsCell priming with IL-8 and TNF-alpha caused release of the AAT:CD16b complex from the neutrophil cell membrane. Circulating plasma levels of IL-8, TNF-alpha and AAT:CD16b complex were significantly higher in patients with CF than in the other patient groups or healthy controls (P < 0.05). Antibiotic treatment of pulmonary exacerbation in patients with CF led to decreased plasma protein concentrations of AAT:CD16b complex with a significant correlation with improved FEV1 (r = 0.81, P = 0.003).ConclusionThe results of this study have shown that levels of AAT:CD16b complex present in plasma correlate to the inflammatory status of patients. The AAT:CD16b biomarker may become a useful addition to the clinical diagnosis of exacerbations in CF.     

A randomized double blind,placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis

BackgroundAirway inflammation, mediated in part by LTB₄, contributes to lung destruction in patients with cystic fibrosis (CF). LTB₄-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B₄ (LTB₄)-receptor antagonist BIIL 284 BS in CF patients.MethodsCF patients aged ≥ 6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV₁ and incidence of pulmonary exacerbation.ResultsAfter 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38).ConclusionsWhile the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events.     

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.     

Regional ventilation in cystic fibrosis measured by electrical impedance tomography

BackgroundThe feasibility of electrical impedance tomography (EIT) as an alternative examination tool in cystic fibrosis (CF) was examined.Methods14 CF patients and 14 healthy volunteers were studied. Spirometry and EIT measurements were performed simultaneously. The global inhomogeneity (GI) index was applied to assess the degree of ventilation homogeneity at different levels of maximum inspiratory volume. Ratios of maximum expiratory flow at 25% and 75% of vital capacity (MEF₂₅/MEF₇₅) were calculated for both global lung and regional areas in EIT images.ResultsSignificant differences among GI values at various lung volumes were found in CF patients (P < 0.01) but not in healthy subjects. Global MEF₂₅/MEF₇₅ measured with spirometry and with EIT were highly correlated for all subjects (r² = 0.69, P < 0.01). Significant difference in global MEF₂₅/MEF₇₅ was found between CF patients and healthy volunteers with both spirometer (CF: 0.15 ± 0.09; healthy: 0.46 ± 0.15; P < 0.001) and EIT (CF: 0.14 ± 0.09; healthy: 0.42 ± 0.08; P < 0.001). Regional airway obstruction was identified in the MEF₂₅/MEF₇₅ maps in CF patients.ConclusionsCompared to the global parameters provided by spirometry, EIT is able to deliver both global and regional information to assess the airway obstruction in CF patients.     

Low utility of serum 25–hydroxyvitamin D3 and 1, 25-dihydroxyvitamin D3 in predicting peripheral Treg and Th17 cell counts in ESRD and renal transplant patients

BackgroundVitamin D has shown an immune-modulatory effect in different studies. Vitamin D stimulates Tregs and inhibits Th17 cells. The immune-modulatory role of vitamin D in chronic kidney disease (CKD) and renal transplant patients is unclear. We measured whether different serum levels of vitamin D were associated with an increased or decreased presence of lymphocyte subsets including Treg and Th17 cells in end-stage renal disease (ESRD) and renal transplant recipients.MethodsEighty-seven renal transplant recipients and 53 end-stage renal disease (ESRD) patients were enrolled in this study. The absolute counts of CD4 + and CD8 + T, CD16 + CD56 + NK, CD19 + B, CD4 + CD25 + CD127- Foxp3 + (Tregs), Helios + Tregs, CD38 + Tregs, and CD4 + CD17 + (Th17) cells were analyzed in peripheral blood in both patient groups. In addition, serum 25 (OH) D₃, 1, 25 (OH)₂ D₃, IL-6, IL-17, IL-23, and TGF-β₁ were measured. The association between lymphocyte subset counts and 1, 25 (OH)₂ D₃ or 25 (OH) D₃ was studied, as was the association between serum IL-6, IL-17, IL-23, or TGF-β₁ and 1,25 (OH)₂ D₃ or 25 (OH) D₃.ResultsSerum 25 (OH) D₃ and 1,25 (OH)₂ D₃ levels were not independently associated with peripheral CD4 + T, CD19 + B, CD16 + CD56 + NK, Treg, or Th17 cell counts. In contrast to serum 25 (OH) D₃, serum1, 25 (OH)₂ D₃ was positively associated with CD8 + T cells counts in renal transplant recipients.ConclusionOur findings indicate low utility of serum 25 (OH) D₃ and 1, 25 (OH)₂ D₃ levels in predicting a change in lymphocyte subset counts in ESRD and renal transplant patients.     

Blood basophils from cystic fibrosis patients with allergic bronchopulmonary aspergillosis are primed and hyper-responsive to stimulation by aspergillus allergens

IntroductionFifteen to sixty percent of cystic fibrosis patients harbor Aspergillus fumigatus (Af) in their airways (CF-AC) and some will develop allergic bronchopulmonary aspergillosis (CF-ABPA). Since basophils play a key role in allergy, we hypothesized that they would display alterations in CF-ABPA patients compared to CF-AC or patients without Af colonization (CF).MethodsUsing flow cytometry, we measured CD203c, CD63 and CD123 levels on basophils from CF-ABPA (N = 11), CF-AC (N = 14), and CF (N = 12) patients before and after ex vivo stimulation with Af allergens.ResultsBaseline CD203c was increased in basophils from CF-ABPA compared to CF-AC and CF patients. Af extract and recombinant Aspf1 stimulated basophils from CF-ABPA patients to markedly upregulate CD203c, along with modest upregulation of CD63 and a CD123 downward trend. Plasma TARC/CCL17 at baseline and post-stimulation cell supernatant histamine levels were similar in the three groups.ConclusionsIn CF-ABPA, blood basophils are primed and hyperresponsive to Af allergen stimulation.     

Clinical utility of the oxygen uptake efficiency slope in cystic fibrosis patients

BackgroundThe present study investigated the validity and the reliability of the oxygen uptake efficiency slope (OUES) as a determinant of exercise tolerance in adults with cystic fibrosis (CF).Methods31 CF patients and 34 healthy controls performed a maximal incremental cycle test with respiratory gas-exchange measurements. OUES was calculated from data taken from different percentages of the entire exercise duration, including 80% (OUES₈₀) and 100% (OUES₁₀₀). Peak oxygen uptake (VO_2peak) and gas exchange threshold (GET) were also determined. The agreement between submaximal parameters and VO_2peak was assessed using Bland Altman plots. Test retest reliability was evaluated in CF patients using absolute (SEM) and relative indices (ICC).ResultsOn the contrary to the GET, which was undetectable in 16% of the CF patients, the OUES was easily determined in all patients. Among all the submaximal variables, OUES₈₀ had the best reliability (ICC = 0.94, SEM = 7.3%) and agreement with VO_2peak (r² = 0.83, P < 0.01; limits of agreement: ± 365 mL min^− 1) and did not differ from OUES₁₀₀.ConclusionsOUES₈₀ is a reliable and more useful submaximal parameter than the GET and may find use in the interpretation of exercise studies in CF patients who are unable to perform maximal exercise.     

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.