Controlling Extra- and Intramacrophagic Mycobacterium abscessus by Targeting Mycolic Acid Transport.

Front Cell Infect Microbiol. 2017;7:388

Authors: Viljoen A, Herrmann JL, Onajole OK, Stec J, Kozikowski AP, Kremer L

Abstract
Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) causing serious infections especially among cystic fibrosis patients. Extremely limited therapeutic options against M. abscessus and a rise in infections with this mycobacterium require novel chemotherapies and a better understanding of how the bacterium causes infection. Different from most RGM, M. abscessus can survive inside macrophages and persist for long durations in infected tissues. We recently delineated differences in the infective programs followed by smooth (S) and rough (R) variants of M. abscessus. Unexpectedly, we found that the S variant behaves like pathogenic slow growing mycobacteria, through maintaining a block on the phagosome maturation process and by inducing phagosome-cytosol communications. On the other hand, R variant infection triggers autophagy and apoptosis, reminiscent of the way that macrophages control RGM. However, the R variant has an exquisite capacity to form extracellular cords, allowing these bacteria to rapidly divide and evade phagocytosis. Therefore, new chemotherapeutic interventions against M. abscessus need to efficiently deal with both the reservoir of intracellular bacilli and the extracellular cords. In this context, we recently identified two chemical entities that were very effective against both M. abscessus populations. Although being structurally unrelated these two chemotypes inhibit the activity of the essential mycolic acid transporter, MmpL3. In this Perspective, we aimed to highlight recent insights into how M. abscessus interacts with phagocytic cells and how the inhibition of mycolic acid transport in this pathogenic RGM could be an efficient means to control both intracellular and extracellular populations of the bacterium.

PMID: 28920054 [PubMed - in process]

Body Weight and Body Mass Index in Patients with End-Stage Cystic Fibrosis Stabilize After the Start of Enteral Tube Feeding.

J Acad Nutr Diet. 2017 Sep 11;:

Authors: Hollander FM, de Roos NM, Belle van Meerkerk G, Teding van Berkhout F, Heijerman HGM, van de Graaf EA

Abstract
BACKGROUND: Enteral tube feeding (ETF) is widely used in patients with cystic fibrosis (CF) and end-stage lung disease, but previous studies have been limited to investigating whether ETF improves outcomes in patients with moderately or mildly impaired pulmonary function.
OBJECTIVE: This study investigated body weight, body mass index (BMI; calculated as kg/m(2)), pulmonary function, and the presence of CF-related diabetes before and after the start of ETF.
DESIGN: This was a retrospective observational study.
PARTICIPANTS/SETTING: Data from 26 adult patients in an outpatient setting who had end-stage CF (19 women) and had been using ETF for at least 6 months between 2000 and 2014 were analyzed.
MAIN OUTCOME MEASURES: Body weight, BMI, pulmonary function (forced expiratory volume in 1 second as percent of predicted) and incidence of CF-related diabetes from 6 months before to 6 months after starting ETF.
STATISTICAL ANALYSES PERFORMED: Time effects were tested with one-way analysis of variance for data that were normally distributed and the Friedman test for non-parametric data. Correlations were tested with Pearson's r or Spearman's ρ, depending on the distribution of the data.
RESULTS: Mean body weight increased by 3.5 kg (95% CI 2.2 to 4.8 kg) after patients started ETF. In women, mean BMI decreased by 0.7 in the 6 months before the start of ETF (P<0.05) and increased by 1.4 in the 6 months thereafter (P<0.05). In men, BMI changes were similar (-0.8 and +1.1), but not statistically significant. Forced expiratory volume in 1 second as percent of predicted significantly decreased in time from a median of 28% to 26% at the start of ETF to 25% after 6 months (P=0.0013), with similar trends in women and men. There was no correlation between changes in weight and lung function. CF-related diabetes was already present in 12 patients and developed in 1 more patient after the start of ETF.
CONCLUSIONS: ETF improved body weight and BMI but not pulmonary function in 26 patients with end-stage CF. Clinical outcomes were similar in women and men, but the sample size of men was too small to determine statistical significance.

PMID: 28919081 [PubMed - as supplied by publisher]

Gene Editing with Helper-Dependent Adenovirus Can Efficiently Introduce Multiple Changes Simultaneously over a Large Genomic Region.

Mol Ther Nucleic Acids. 2017 Sep 15;8:101-110

Authors: Palmer DJ, Grove NC, Turner DL, Ng P

Abstract
Helper-dependent adenoviral vectors (HDAds) possess long homology arms that mediate high-efficiency gene editing. These long homology arms may permit simultaneous introduction of multiple modifications into a large genomic region or may permit a single HDAd to correct many different individual mutations spread widely across a gene. We investigated this important potential using an HDAd bearing 13 genetic markers in the region of homology to the target CFTR locus in human iPSCs and found that all markers can be simultaneously introduced into the target locus, with the two farthest markers being 22.2 kb apart. We found that genetic markers closer to the HDAd's selectable marker are more efficiency introduced into the target locus; a marker located 208 bp from the selectable marker was introduced with 100% efficiency. However, even markers 11 kb from the selectable marker were introduced at a relatively high frequency of 21.7%. Our study also revealed extensive heteroduplex DNA formation of up to 10 kb with no bias toward vector or chromosomal repair. However, mismatches escape repair at a frequency of up to 15%, leading to a genetically mixed colony and emphasizing the need for caution, especially if the donor and target sequences are not 100% homologous.

PMID: 28918012 [PubMed]

End-of-life practice patterns at U.S. adult cystic fibrosis care centers: A national retrospective chart review.

J Cyst Fibros. 2017 Sep 13;:

Authors: Chen E, Homa K, Goggin J, Sabadosa KA, Hempstead S, Marshall BC, Faro A, Dellon EP

Abstract
BACKGROUND: There are many challenges to providing end-of-life care (EOLC) to people with cystic fibrosis (CF).
METHODS: Chart abstraction was used to examine EOLC in adults with CF who died between 2011 and 2013.
RESULTS: We reviewed 248 deaths from 71 CF care centers. Median age at death was 29years (range 18-73). While median FEV1 was in the severe lung disease category (FEV1<40%), 38% had mild or moderate lung disease in the year preceding death. The most common location of death was the intensive care unit (ICU, 39%), and 12% of decedents were listed for lung transplant. Fewer of those dying in the ICU personally participated in advance care planning or utilized hospice or Palliative Care Services (p<0.05).
CONCLUSIONS: Adults dying with CF in the United States most commonly die in an ICU, with limited and variable use of hospice and Palliative Care Services. Palliative care and advance care planning are recommended as a routine part of CF care.

PMID: 28917611 [PubMed - as supplied by publisher]

Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis.

Thorax. 2017 Sep 15;:

Authors: Gray RD, Hardisty G, Regan KH, Smith M, Robb CT, Duffin R, Mackellar A, Felton JM, Paemka L, McCullagh BN, Lucas CD, Dorward DA, McKone EF, Cooke G, Donnelly SC, Singh PK, Stoltz DA, Haslett C, McCray PB, Whyte MKB, Rossi AG, Davidson DJ

Abstract
BACKGROUND: Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation.
METHODS: Blood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR.
RESULTS: CF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF.
CONCLUSIONS: CF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.

PMID: 28916704 [PubMed - as supplied by publisher]

Therapeutic approaches to CFTR dysfunction: From discovery to drug development.

J Cyst Fibros. 2017 Sep 12;:

Authors: Li H, Pesce E, Sheppard DN, Singh AK, Pedemonte N

Abstract
Cystic fibrosis (CF) mutations have complex effects on the cystic fibrosis transmembrane conductance regulator (CFTR) protein. They disrupt its processing to and stability at the plasma membrane and function as an ATP-gated Cl(-) channel. Here, we review therapeutic strategies to overcome defective CFTR processing and stability. Because CF mutations have multiple impacts on the assembly of CFTR protein, combination therapy with several pharmacological chaperones is likely to be required to rescue mutant CFTR expression at the plasma membrane. Alternatively, proteostasis regulators, proteins which regulate the synthesis, intracellular transport and membrane stability of CFTR might be targeted to enhance the plasma membrane expression of mutant CFTR. Finally, we consider an innovative approach to bypass CFTR dysfunction in CF, the delivery of artificial anion transporters to CF epithelia to shuttle Cl(-) across the apical membrane. The identification of therapies or combinations of therapies, which rescue all CF mutations, is now a priority.

PMID: 28916430 [PubMed - as supplied by publisher]

Integrated Behavioral Health Care in Pediatric Subspecialty Clinics.

Child Adolesc Psychiatr Clin N Am. 2017 Oct;26(4):785-794

Authors: Samsel C, Ribeiro M, Ibeziako P, DeMaso DR

Abstract
Comorbid behavioral and physical health conditions are accompanied by troubling symptom burden, functional impairment, and treatment complexity. Pediatric subspecialty care clinics offer an opportunity for the implementation of integrated behavioral health (BH) care models that promote resiliency. This article reviews integrated BH care in oncology, palliative care, pain, neuropsychiatry, cystic fibrosis, and transplantation. Examples include integrated care mandates, standards of care, research, and quality improvement by child and adolescent psychiatrists (CAPs) and allied BH clinicians. The role of CAPs in integrated BH care in subspecialty care is explored, focusing on cost, resource use, financial support, and patient and provider satisfaction.

PMID: 28916014 [PubMed - in process]

New perspectives in nanotherapeutics for chronic respiratory diseases.

Biophys Rev. 2017 Sep 15;:

Authors: da Silva AL, Cruz FF, Roccco PRM, Morales MM

Abstract
According to the World Health Organization (WHO), hundreds of millions of people of all ages and in all countries suffer from chronic respiratory diseases, with particular negative consequences such as poor health-related quality of life, impaired work productivity, and limitations in the activities of daily living. Chronic obstructive pulmonary disease, asthma, occupational lung diseases (such as silicosis), cystic fibrosis, and pulmonary arterial hypertension are the most common of these diseases, and none of them are curable with current therapies. The advent of nanotechnology holds great therapeutic promise for respiratory conditions, because non-viral vectors are able to overcome the mucus and lung remodeling barriers, increasing pharmacologic and therapeutic potency. It has been demonstrated that the extent of pulmonary nanoparticle uptake depends not only on the physical and chemical features of nanoparticles themselves, but also on the health status of the organism; thus, the huge diversity in nanotechnology could revolutionize medicine, but safety assessment is a challenging task. Within this context, the present review discusses some of the major new perspectives in nanotherapeutics for lung disease and highlights some of the most recent studies in the field.

PMID: 28914424 [PubMed - as supplied by publisher]

Immunogenicity and antimicrobial effectiveness of Pseudomonas aeruginosa specific bacteriophage in a human lung in vitro model.

Appl Microbiol Biotechnol. 2017 Sep 15;:

Authors: Shiley JR, Comfort KK, Robinson JB

Abstract
The rise of antibiotic resistant bacteria is posing a serious threat to human health. For example, resistant strains of Pseudomonas aeruginosa have resulted in untreatable and potentially lethal infections in both cystic fibrosis and immunocompromised patients. Due to the growing need for alternative treatment options, bacteriophage, or phage, therapy is gaining considerable attention. While previous studies have demonstrated the effectiveness of phage in combating persistent bacterial infections, there is currently a lack of knowledge regarding the host immunological response following phage exposure. In the present study, the bioresponses of an enhanced in vitro model were characterized following exposure to either DMS3 or PEV2, P. aeruginosa targeting phages. Results demonstrated a PEV2-dependent increase in IL-6 and TNF-α production, but no changes associated with DMS3 exposure. Additionally, following the establishment of an in vitro infection model, DMS3 was found to successfully protect mammalian lung cells from P. aeruginosa. Taken together, the biocompatibility and antibacterial effectiveness distinguish DMS3 bacteriophage as a strong candidate for phage therapy. However, as DMS3 is pilin dependent and bacterial receptor expression varies significantly, this work highlights the necessity of generating phage cocktails.

PMID: 28914348 [PubMed - as supplied by publisher]

Editorial: A Multidisciplinary Look at Stenotrophomonas maltophilia: An Emerging Multi-Drug-Resistant Global Opportunistic Pathogen.

Front Microbiol. 2017;8:1511

Authors: Brooke JS, Di Bonaventura G, Berg G, Martinez JL

PMID: 28912755 [PubMed]

Draft Genome Sequence of the Human-Pathogenic Fungus Scedosporium boydii.

Genome Announc. 2017 Sep 14;5(37):

Authors: Duvaux L, Shiller J, Vandeputte P, Dugé de Bernonville T, Thornton C, Papon N, Le Cam B, Bouchara JP, Gastebois A

Abstract
The opportunistic fungal pathogen Scedosporium boydii is the most common Scedosporium species in French patients with cystic fibrosis. Here we present the first genome report for S. boydii, providing a resource which may enable the elucidation of the pathogenic mechanisms in this species.

PMID: 28912311 [PubMed]

Erratum of "Hearing thresholds at high frequency in patients with cystic fibrosis: a systematic review".

Braz J Otorhinolaryngol. 2017 Sep - Oct;83(5):608

Authors: Caumo DTM, Geyer LB, Teixeira AR, Barreto SSM

PMID: 28911954 [PubMed - in process]

Data that empower: The success and promise of CF patient registries.

Pediatr Pulmonol. 2017 Sep 14;:

Authors: Fink AK, Loeffler DR, Marshall BC, Goss CH, Morgan WJ

Abstract
In this article, we describe existing CF registries with a focus on US registry data collected through the CF Foundation Patient Registry (CFFPR) and the Epidemiologic Study of CF (ESCF); highlight what registries have taught us regarding epidemiology of CF; showcase the impact of registries on research and clinical care; and discuss future directions. This manuscript complements the plenary address given by Dr Wayne Morgan at the 2016 North American CF Conference by summarizing the key points from the presentation and providing additional detail and information.

PMID: 28910520 [PubMed - as supplied by publisher]

Pharmacokinetics of single-dose ceftaroline fosamil in children with cystic fibrosis.

Pediatr Pulmonol. 2017 Sep 14;:

Authors: Le J, Bradley JS, Hingtgen S, Skochko S, Black N, Jones RN, Lim M, Capparelli EV

Abstract
BACKGROUND: Single-dose pharmacokinetics (PK) and safety of ceftaroline fosamil with population pharmacokinetic/pharmacodynamic (PK/PD) modeling for staphylococcal pneumonia was performed in children with CF.
METHODS: Subjects between 6 and 18 years old were evaluated in this phase 1, open-label, single-dose, prospective study using 10 mg/kg (up to 600 mg). Non-compartmental analysis and population-based PK analyses with Monte Carlo simulation (for doses 8-20 mg/kg every 8 h, infused over 1-4 h) were conducted.
RESULTS: A total of 20 subjects were enrolled. The median age and weight were 12 yr (range 6.3-17.4) and 38.7 kg (range 17.8-94.3), respectively. A 3-compartment linear model incorporating age and weight provided the best fit for the data. Comparing children 6 to <12 years to those 12 to <18 years, the mean posthoc Bayesian parameter estimates for total volume of distribution (VT ) were 0.32 ± 0.05 L/kg versus 0.32 ± 0.04 L/kg, P = 0.7; and total Clearance (CLT ), 0.50 ± 0.10 L/h/kg versus 0.30 ± 0.07 L/h/kg, P = 0.001. Using susceptibility data from pediatric MRSA lower respiratory tract isolates, 8 mg/kg (maximum of 1000 mg per dose) infused over 1 h every 8 h achieved free-drug plasma concentrations above the minimum inhibitory concentration for ≥60% of the dosing interval in at least 95% of virtual subjects.
CONCLUSIONS: Since children with CF have increased ceftaroline CL compared with published data from non-CF children; greater dosages may be required in children with CF to achieve adequate exposure in the treatment of MRSA pneumonia. Pharmacodynamic-based dosing predicts that dosing should also be based on the patient's MRSA MIC.

PMID: 28910514 [PubMed - as supplied by publisher]

Shining new light on newborn screening of cystic fibrosis in the province of Quebec.

Can J Public Health. 2017 Sep 14;108(3):e335-e337

Authors: Khendek L

Abstract
Newborn screening of cystic fibrosis, a severe genetic disease with high treatment burden, is offered in all of North America with the exception of the province of Quebec. This condition, when diagnosed on symptomatic presentation, is marked by chronic infections and progressive lung function decline leading to eventual respiratory failure. Patients continue to have a median age of survival notably below the Canadian average. Despite prevalence rates of cystic fibrosis almost three times the national average in certain regions of Quebec, the province still does not offer screening to its newborns. However, the results of newly published research comparing patients from Quebec with those of other provinces has shown that screening is associated with better nutritional status and overall growth, lower hospitalization rates as well as fewer episodes of infection, hence contributing to the prevention of lung damage in the long term. This research appears to confirm the benefits and pertinence of implementing a neonatal screening program for patients with cystic fibrosis in the province.

PMID: 28910260 [PubMed - in process]

Variceal Hemorrhage and Adverse Liver Outcomes in Patients With Cystic Fibrosis Cirrhosis.

J Pediatr Gastroenterol Nutr. 2017 Sep 12;:

Authors: Ye W, Narkewicz MR, Leung DH, Karnsakul W, Murray KF, Alonso EM, Magee JC, Schwarzenberg SJ, Weymann A, Molleston JP, CFLDnet research group

Abstract
OBJECTIVES: Cirrhosis occurs in 5-10% of CF (cystic fibrosis) patients, often accompanied by portal hypertension. We analyzed three adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver death (LD), and risk factors for these in CF Foundation Patient Registry (CFFPR) subjects with reported cirrhosis.
METHODS: We determined 10-year incidence rates for VB, LT, LD, and all-cause mortality (ACM), and examined risk factors using competing risk models and Cox-proportional hazard regression.
RESULTS: From 2003-2012, 943 participants (41% female, mean age 18.1 years) had newly reported cirrhosis; 24.7% required insulin, 85% had prior pseudomonas. Seventy-three subjects had reported VB; 38 with first VB and new cirrhosis reported simultaneously and 35 with VB after cirrhosis report. 10-year cumulative VB, LT, and LD rates were 6.6% (95% Confidence Interval (CI): 4.0, 9.1%), 9.9% (95% CI: 6.6%, 13.2%), and 6.9% (95% CI: 4.0%, 9.8%), respectively, with an ACM of 39.2% (95% CI: 30.8, 36.6%). ACM was not increased in subjects with VB compared to those without (HR 1.10, 95% CI: 0.59, 2.08). CF related diabetes (CFRD (hazard ratio (HR): 3.141, 95% CI:1.56, 6.34) and VB (HR: 4.837, 95% CI: 2.33, 10.0) were associated with higher LT risk while only worse lung function was associated with increased LD in multivariate analysis. Death rate among subjects with VB was 24% with LT and 20.4% with native liver.
CONCLUSIONS: VB is an uncommon complication of CF cirrhosis and can herald the diagnosis, but does not affect ACM. Adverse liver outcomes and ACM are frequent by 10 years after cirrhosis report.

PMID: 28906321 [PubMed - as supplied by publisher]

Gastro-intestinal manifestations in cystic fibrosis patients.

Acta Gastroenterol Belg. 2016 Sep-Dec;79(4):481-486

Authors: Van Biervliet S, de Clercq C, Declercq D, Van Braeckel E, Van Daele S, De Baets F, De Looze D

Abstract
Cystic fibrosis (CF) is a life-limiting disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). This defective chloride channel, present in different organ systems such as respiratory system, gastrointestinal tract, reproductive system and sweat glands, disturbs the ion and water transport over the membranes leading to the well known CF symptoms. CF has outgrown paediatric care, as half of CF patients are currently adults. The CF gastrointestinal tract has its own particularities. Some gastrointestinal manifestations are the direct consequence of the CFTR defect whilst others are secondary to treatment. The gastrointestinal diseases are classified according to the way they usually present in symptoms at diagnosis, acute and chronic abdominal pain and silently evolving conditions. (Acta gastroenterol. belg., 2016, 79, 481-486).

PMID: 28906218 [PubMed - in process]

Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene.

Gene Ther. 2017 Sep 14;:

Authors: Staber JM, Pollpeter MJ, Anderson CG, Burrascano M, Cooney AL, Sinn PL, Rutkowski DT, Raschke WC, McCray PB

Abstract
Current therapies for hemophilia A include frequent prophylactic or on-demand intravenous factor treatments which are costly, inconvenient and may lead to inhibitor formation. Viral vector delivery of factor VIII (FVIII) cDNA has the potential to alleviate the debilitating clotting defects. Lentiviral-based vectors delivered to murine models of hemophilia A mediate phenotypic correction. However, a limitation of lentiviral-mediated FVIII delivery is inefficient transduction of target cells. Here, we engineer a feline immunodeficiency virus (FIV) -based lentiviral vector pseudotyped with the baculovirus GP64 envelope glycoprotein to mediate efficient gene transfer to mouse hepatocytes. In anticipation of future studies in FVIII-deficient dogs, we investigated the efficacy of FIV-delivered canine FVIII (cFVIII). Codon-optimization of the cFVIII sequence increased activity and decreased blood loss as compared to the native sequence. Further, we compared a standard B-domain deleted FVIII cDNA to a cDNA including 256 amino acids of the B-domain with 11 potential asparagine-linked oligosaccharide linkages. Restoring a partial B-domain resulted in modest reduction of endoplasmic reticulum (ER) stress markers. Importantly, our optimized vectors achieved wild-type levels of phenotypic correction with minimal inhibitor formation. These studies provide insights into optimal design of a therapeutically relevant gene therapy vector for a devastating bleeding disorder.Gene Therapy advance online publication, 14 September 2017; doi:10.1038/gt.2017.67.

PMID: 28905885 [PubMed - as supplied by publisher]

Rescue therapy within the UK Cystic Fibrosis Registry: An exploration of predictors of intravenous antibiotic use amongst adults with CF.

Respirology. 2017 Sep 14;:

Authors: Hoo ZH, Wildman MJ, Curley R, Walters SJ, Campbell MJ

Abstract
BACKGROUND AND OBJECTIVE: Intravenous (i.v.) antibiotics are needed for rescue when preventative therapy fails to achieve stability among adults with cystic fibrosis (CF). Understanding the distribution of i.v. days can provide insight into the care that adults with CF need. We aim to determine the baseline characteristics that are associated with higher i.v. use, in particular to test the hypothesis that prior-year i.v. use is associated with future-year i.v. use.
METHODS: This is a cross-sectional analysis of the 2013-2014 UK CF registry data. Stepwise logistic regression was performed using current-year i.v. days as the dependent variable, and demographic variables including prior-year i.v. days as the covariates. Based on these results, study sample was divided into clinically meaningful subgroups using analysis similar to tree-based method.
RESULTS: Data were available for 4269 adults in 2013 and 4644 adults in 2014. Prior-year i.v. use was the strongest predictor for current-year i.v. use followed by forced expiratory volume in 1 s (FEV1 ). Adults with high prior-year i.v. use (>14 days) continued to require high levels of i.v., regardless of FEV1 . Those with high prior-year i.v. use and FEV1 ≥70% had higher current-year i.v. days compared to adults with low prior-year i.v. use and FEV1 <40% (28 days, interquartile range (IQR): 11-41 days vs 14 days, IQR: 0-28 days; Mann-Whitney P-value <0.001 in 2013).
CONCLUSION: CF people with prior high levels of rescue often continue to need high levels of rescue even if they have good FEV1 . The reasons for this require further investigations.

PMID: 28905459 [PubMed - as supplied by publisher]

Toll-like receptor 2 induced cytotoxic T-lymphocyte-associated protein 4 regulates Aspergillus-induced regulatory T-cells with pro-inflammatory characteristics.

Sci Rep. 2017 Sep 13;7(1):11500

Authors: Raijmakers RPH, Sprenkeler EGG, Aleva FE, Jacobs CWM, Kanneganti TD, Joosten LAB, van de Veerdonk FL, Gresnigt MS

Abstract
Patients with cystic fibrosis, chronic obstructive pulmonary disease, severe asthma, pre-existing pulmonary lesions, and severely immunocompromised patients are susceptible to develop infections with the opportunistic pathogenic fungus Aspergillus fumigatus, called aspergillosis. Infections in these patients are associated with persistent pro-inflammatory T-helper (TH)2 and TH17 responses. Regulatory T-cells, natural suppressor cells of the immune system, control pro-inflammatory T-cell responses, but can also contribute to disease by shifting to a pro-inflammatory TH17-like phenotype. Such a shift could play an important role in the detrimental immunopathology that is seen in aspergillosis. Our study demonstrates that Aspergillus fumigatus induces regulatory T-cells with a TH17-like phenotype. We also demonstrate that these regulatory T-cells with a pro-inflammatory TH17-like phenotype can be reprogrammed to their "classical" anti-inflammatory phenotype by activating Toll-like receptor 2 (TLR2), which regulates the induction of cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Similarly, soluble CTLA4 could reverse the pro-inflammatory phenotype of Aspergillus-induced regulatory T-cells. In conclusion, our results suggest a role for regulatory T-cells with a pro-inflammatory TH17-like phenotype in Aspergillus-associated immunopathology, and identifies key players, i.e. TLR2 and CTLA4, involved in this mechanism.

PMID: 28904353 [PubMed - in process]