Development and initial validation of the bronchiectasis exacerbation and symptom tool (BEST).

Respir Res. 2020 Jan 13;21(1):18

Authors: Artaraz A, Crichton ML, Finch S, Abo-Leyah H, Goeminne P, Aliberti S, Fardon T, Chalmers JD

Abstract
BACKGROUND: Recurrent bronchiectasis exacerbations are related to deterioration of lung function, progression of the disease, impairment of quality of life, and to an increased mortality. Improved detection of exacerbations has been accomplished in chronic obstructive pulmonary disease through the use of patient completed diaries. These tools may enhance exacerbation reporting and identification. The aim of this study was to develop a novel symptom diary for bronchiectasis symptom burden and detection of exacerbations, named the BEST diary.
METHODS: Prospective observational study of patients with bronchiectasis conducted at Ninewells Hospital, Dundee. We included patients with confirmed bronchiectasis by computed tomography, who were symptomatic and had at least 1 documented exacerbation of bronchiectasis in the previous 12 months to participate. Symptoms were recorded daily in a diary incorporating cough, sputum volume, sputum colour, dyspnoea, fatigue and systemic disturbance scored from 0 to 26.
RESULTS: Twenty-one patients were included in the study. We identified 29 reported (treated exacerbations) and 23 unreported (untreated) exacerbations over 6-month follow-up. The BEST diary score showed a good correlation with the established and validated questionnaires and measures of health status (COPD Assessment Test, r = 0.61, p = 0.0037, Leicester Cough Questionnaire, r = - 0.52,p = 0.0015, St Georges Respiratory Questionnaire, r = 0.61,p < 0.0001 and 6 min walk test, r = - 0.46,p = 0.037). The mean BEST score at baseline was 7.1 points (SD 2.2). The peak symptom score during exacerbation was a mean of 16.4 (3.1), and the change from baseline to exacerbation was a mean of 9.1 points (SD 2.5). Mean duration of exacerbations based on time for a return to baseline symptoms was 15.3 days (SD 5.7). A minimum clinically important difference of 4 points is proposed.
CONCLUSIONS: The BEST symptom diary has shown concurrent validity with current health questionnaires and is responsive at onset and recovery from exacerbation. The BEST diary may be useful to detect and characterise exacerbations in bronchiectasis clinical trials.

PMID: 31931782 [PubMed - in process]

Biofabrication of personalised anatomical models and tools for the clinic.

J Cyst Fibros. 2019 03;18(2):161-162

Authors: Allenby MC, Woodruff MA

PMID: 30797725 [PubMed - indexed for MEDLINE]

Immunomodulatory function of the cystic fibrosis modifier gene BPIFA1.

PLoS One. 2020;15(1):e0227067

Authors: Saferali A, Tang AC, Strug LJ, Quon BS, Zlosnik J, Sandford AJ, Turvey SE

Abstract
BACKGROUND: Cystic fibrosis (CF) is characterized by a progressive decline in lung function due to airway obstruction, infection, and inflammation. CF patients are particularly susceptible to respiratory infection by a variety of pathogens, and the inflammatory response in CF is dysregulated and prolonged. BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are proteins expressed in the upper airways that may have innate immune activity. We previously identified polymorphisms in the BPIFA1/BPIFB1 region associated with CF lung disease severity.
METHODS: We evaluated whether the BPIFA1/BPIFB1 associations with lung disease severity replicated in individuals with CF participating in the International CF Gene Modifier Consortium (n = 6,365). Furthermore, we investigated mechanisms by which the BPIFA1 and BPIFB1 proteins may modify lung disease in CF.
RESULTS: The association of the G allele of rs1078761 with reduced lung function was replicated in an independent cohort of CF patients (p = 0.001, n = 2,921) and in a meta-analysis of the full consortium (p = 2.39x10-5, n = 6,365). Furthermore, we found that rs1078761G which is associated with reduced lung function was also associated with reduced BPIFA1, but not BPIFB1, protein levels in saliva from CF patients. Functional assays indicated that BPIFA1 and BPIFB1 do not have an anti-bacterial role against P. aeruginosa but may have an immunomodulatory function in CF airway epithelial cells. Gene expression profiling using RNAseq identified Rho GTPase signaling pathways to be altered in CF airway epithelial cells in response to treatment with recombinant BPIFA1 and BPIFB1 proteins.
CONCLUSIONS: BPIFA1 and BPIFB1 have immunomodulatory activity and genetic variation associated with low levels of these proteins may increase CF lung disease severity.

PMID: 31931521 [PubMed - in process]

Activity of Pulmonary Vancomycin Exposures versus Planktonic and Biofilm Methicillin-Resistant Staphylococcus aureus Isolated from Cystic Fibrosis Sputum.

Int J Antimicrob Agents. 2020 Jan 10;:105898

Authors: Britt NS, Hazlett DS, Horvat RT, Liesman RM, Steed ME

Abstract
Vancomycin is commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with cystic fibrosis (CF) lung disease; however, there are limited data to support the in vitro activity of this agent against MRSA isolated from CF sputum. The primary objective of this study was to evaluate the activity of vancomycin at pulmonary concentrations (intravenous and inhaled) against 4 clinical MRSA CF sputum isolates in planktonic and biofilm time-kill (TK) experiments. Vancomycin minimum inhibitory concentrations (MICs) were determined for these isolates at standard inoculum (SI; ∼106 colony-forming units [CFU]/mL) and high inoculum (HI; ∼108 CFU/mL), and in biofilms cultivated using physiologic media recapitulating the microenvironment of the CF lung. Vancomycin concentrations of 10, 25, 100, and 275 µg/mL were evaluated in TK experiments against planktonic MRSA at varying inocula and versus biofilm MRSA. Vancomycin MICs increased from 0.5 µg/mL at SI to 8-16 µg/mL when tested at HI. Vancomycin MICs were further increased to 16-32 µg/mL in biofilm studies. In TK experiments, vancomycin displayed bactericidal activity (≥ 3 log10 killing at 24 h) against 1/4 and 0/4 planktonic MRSA isolates at SI and HI, respectively. Against MRSA biofilms, vancomycin was bactericidal against 0/4 isolates. Based on these findings, vancomycin monotherapy appears unlikely to eradicate MRSA from the respiratory tract of patients with CF, even at high concentrations similar to those observed with inhaled therapy. Novel vancomycin formulations with enhanced biofilm penetration or combination therapy with other potentially synergistic agents should be explored.

PMID: 31931147 [PubMed - as supplied by publisher]

Evaluation of the exercise intensity generated by active video gaming in patients with cystic fibrosis and healthy individuals.

J Cyst Fibros. 2020 Jan 09;:

Authors: Campos NE, Heinzmann-Filho JP, Becker NA, Schiwe D, Gheller MF, de Almeida IS, Donadio MVF

Abstract
BACKGROUND: Adherence of patients with cystic fibrosis (CF) to exercise is challenging. Here we compared the physiological responses during the use of interactive video games (VG) with the cardiopulmonary exercise test (CPET) in healthy and CF subjects.
METHODS: Cross-sectional study including CF and healthy (CON) subjects older than 6 years. Individuals were evaluated in two visits. At visit one, anthropometric measures, spirometry and CPET were performed. In the second visit, a physical activity questionnaire was applied and gas analyses performed during the use (10 min) of both Nintendo Wii (Wii Fit Plus: (1) Obstacle Course, (2) Rhythm Boxing and (3) Free Run) and Xbox One (Just Dance 2015: (1) Love Me Again, (2) Summer and (3) Happy).
RESULTS: Twenty-five CON and 30 CF patients were included. The mean FEV1 (%) was significantly lower in the CF group compared to CON. There were no differences between groups at peak exercise (CPET) for heart rate (HR), oxygen consumption (VO2) and minute ventilation (VE). In the CON group, games 2 and 3 (Xbox) and game 3 (Nintendo) increased HR to values similar to the anaerobic threshold (AT), while for the CF group this occurred for games 2 (Xbox) and 3 (Nintendo). As for VO2 and VE, both groups obtained similar responses as compared to AT values in games 2 (Xbox) and 3 (Nintendo).
CONCLUSION: The use of VG generated a cardiorespiratory response similar to AT levels found during CPET, indicating that it may be an alternative for exercise training of CF individuals.

PMID: 31928975 [PubMed - as supplied by publisher]

Taking a look on fungi in cystic fibrosis: More questions than answers.

Rev Iberoam Micol. 2020 Jan 09;:

Authors: Martín-Gómez MT

Abstract
Cystic fibrosis (CF) is one of the most frequent recessive inherited diseases in western countries. Advances in medical care have led to a substantial increase in the life expectancy of CF patients. Survival beyond adolescence has permitted to see fungi not only as late colonizers, but also as potential pathogens responsible of allergic reactions and chronic infections related to lung function deterioration. The role of fungi, nevertheless, has been overlooked until recently. As a result, a number of questions on their epidemiology, clinical significance, or diagnosis, among others, remain unanswered. Besides more in depth studies about the extent of the deleterious effect of fungi on the CF host, new technologies may provide the key to understand its pathogenic role, its interaction with other microbial components of the respiratory microbiota, and should pave the way to define subsets of patients at risk who would benefit from specific therapy. This review is intended to provide a quick overview on what we know about the presence of fungi in the CF airway and its repercussion in the host, and to point out some of the many knowledge gaps needed to understand and advance in the management of fungi in the airway of CF subjects.

PMID: 31928888 [PubMed - as supplied by publisher]

Clinical Use and Barriers of Thoracic Ultrasound: A Survey of Italian Pulmonologists.

Respiration. 2020 Jan 10;:1-6

Authors: Zanforlin A, Tursi F, Marchetti G, Pellegrino GM, Vigo B, Smargiassi A, Inchingolo R, Centanni S, Gasparini S, Blasi F, Soldati G, Sferrazza Papa GF, AdET Study Group

Abstract
INTRODUCTION: Thoracic ultrasound is accurate in the diagnosis of a wide range of respiratory diseases. Yet the extent of its use is unknown. Through a national survey, we aimed to explore the clinical use of thoracic ultrasound and the barriers to the diffusion of the technique in Italy.
METHODS: Accademia di Ecografia Toracica (AdET) developed a self-administered survey which was sent by email to Italian pulmonologists via national scientific societies and networks.
RESULTS: Of the 2010 physicians invited, 514 completed the survey (26% response rate). According to 99% of responders, thoracic ultrasound had a relevant clinical role. Seventy-nine percent of the responders used thoracic ultrasound at least once a month. The main settings were: 53% pulmonology ward, 15% outpatient clinic, 15% interventional pulmonology room, 10% internal medicine ward, 4% respiratory intensive care units, and 9% other. Thoracic ultrasound was primarily used: (1) with both diagnostic and interventional aims (72%), (2) as diagnostic imaging (17%), and (3) as guidance for interventional procedures (11%). The main clinical applications were: (1) diagnosis and management of pleural effusion, (2) pneumothorax, (3) pneumonia, (4) cardiac failure, and (5) acute dyspnea. Twenty-one percent of the responders do not use thoracic ultrasound. The main reported bar-riers were: (1) availability of an ultrasound system (52%), (2) lack of protected time and training (22%), and (3) use of the technique by other specialists (15%).
CONCLUSION: Thoracic ultrasound is widely used by Italian pulmonologists and considered a clinically relevant tool. The availability of dedicated ultrasound systems seems to be a major limit of the use of the technique.

PMID: 31927551 [PubMed - as supplied by publisher]

Levels of pro- and anti-inflammatory cytokines in cystic fibrosis patients with or without gingivitis.

Cytokine. 2020 Jan 09;127:154987

Authors: Duruel O, Berker E, Özşin-Özler C, Gharibzadeh-Hızal M, Gürpınar Ö, Eryılmaz-Polat S, Ataman-Duruel ET, Tan Ç, Karabulut E, Tekçiçek M, Köseoğlu-Eser Ö, Kiper N, Tezcan İ

Abstract
BACKGROUND: Inflammatory periodontal diseases are caused by interaction between gram negative, anaerobic bacteria and host response. Persistent infection of Pseudomonas aeruginosa in cystic fibrosis (CF) patients also cause increased pro-inflammatory response and the imbalance of pro- and anti-inflammatory response in brochoalveolar lavage fluid which leads to destruction of lungs. The aim of this study is to evaluate periodontal status of CF patients, to measure level of cytokines and biochemical molecules in gingival crevicular fluid (GCF), and to detect presence of P. aeruginosa in dental plaque samples.
MATERIALS AND METHODS: GCF samples were collected from 41 CF patients and 39 healthy (non-CF) subjects. Interleukin (IL)-1ß, IL-17, IL-10, human neutrophil elastase (HNE), cystic fibrosis transmembrane regulator (CFTR) protein, and human β-defensin-1 (HBD1) in GCF were evaluated by ELISA method. Dental plaque samples were collected from 18 CF patients with history of P. aeruginosa colonization and 15 non-CF subjects. Presence of P. aeruginosa was evaluated by using conventional culture methods and molecular methods.
RESULTS: Levels of IL-1ß, HNE, and HBD1 in CF patients were significantly higher than non-CF subjects. However, IL-10 level was significantly lower in CF patients. Increased pro-inflammatory (IL-1ß) and decreased anti-inflammatory (IL-10) cytokine levels were observed in GCF samples from CF patients, irrespective of their periodontal status. P. aeruginosa were detected in four samples of 18 CF patients, and all were negative in non-CF group.
CONCLUSIONS: As a result of this study, CF coexists increasing pro-inflammatory and decreasing anti-inflammatory response locally. Due to increasing pro-inflammation, CF patients should be followed-up more often than non-CF children.

PMID: 31927460 [PubMed - as supplied by publisher]

Characteristics and Outcomes of Lung Transplant Candidates With Preexisting Renal Dysfunction.

Transplant Proc. 2020 Jan 08;:

Authors: Woll F, Mohanka M, Bollineni S, Joerns J, Kaza V, Torres F, Tanriover B, Banga A

Abstract
BACKGROUND: The proportion of lung transplant candidates with comorbid renal dysfunction (RD) may rise as sicker patients are being considered for lung transplant (LT). There is lack of data regarding the characteristics and outcome of patients with RD and the role of simultaneous lung-kidney transplant (SLuKi) among these patients.
METHODS: The United Network of Organ Sharing database was queried for adult patients (18 years or older) undergoing LT between 1995 and 2014. Pretransplant RD was defined as estimated glomerular filtration rate (eGFR), using the Chronic Kidney Disease Epidemiology Collaboration equation of <60 mL/min/1.73 m2 at the time of transplant listing. The recipient, donor, and procedure-related variables and survival were compared among patients with RD undergoing LT alone (split on the basis of eGFR impairment: 30-60 mL/min/1.73 m2 and ≤ 30 mL/min/1.73 m2) vs those with SLuKi.
RESULTS: The frequency of pretransplant RD was 5.42% (n = 1337). Patients with RD have significantly higher 1-year mortality (23.2% vs 15%; P < .001) and 3-year mortality (38.3% vs 28%; P < .001) than patients with eGFR > 60mL/min/1.73 m2. The proportion of patients with RD undergoing SLuKi was 2.84% (38 of 1337). Both the number and proportion of patients undergoing SLuKi progressively increased during the study period, especially in the lung allocation score era (30 of 38 SLuKi patients in the post lung allocation score era (linear R2 = 0.641, P < .001). The patients who underwent SLuKi were significantly younger, had lower body mass index, serum albumin, and listing eGFR (P < .001 for all comparisons). Patients with SLuKi were more likely to have cystic fibrosis or vascular diseases as the underlying diagnosis (29.7% vs 13.8%, P = .004). Despite higher need of early dialysis support after transplant, there was no difference in the 30-day, 1-year, or 3-year survival between the 2 groups.
CONCLUSIONS: A significant proportion of LT candidates have a pre-existing RD, and this comorbidity is associated with significantly worse 1- and 3-year survival. Despite being the sicker group at baseline, patients with RD who undergo SLuKi have 1-year outcomes similar to patients with LT alone.

PMID: 31926746 [PubMed - as supplied by publisher]

Lung inflammation and disease: A perspective on microbial homeostasis and metabolism.

IUBMB Life. 2019 02;71(2):152-165

Authors: Mendez R, Banerjee S, Bhattacharya SK, Banerjee S

Abstract
It is now well appreciated that the human microbiome plays a significant role in a number of processes in the body, significantly affecting its metabolic, inflammatory, and immune homeostasis. Recent research has revealed that almost every mucosal surface in the human body is associated with a resident commensal microbiome of its own. While the gut microbiome and its role in regulation of host metabolism along with its alteration in a disease state has been well studied, there is a lacuna in understanding the resident microbiota of other mucosal surfaces. Among these, the scientific information on the role of lung microbiota in pulmonary diseases is currently severely limited. Historically, lungs have been considered to be sterile and lung diseases have only been studied in the context of bacterial pathogenesis. Recently however, studies have revealed a resilient microbiome in the upper and lower respiratory tracts and there is increased evidence on its central role in respiratory diseases. Knowledge of lung microbiome and its metabolic fallout (local and systemic) is still in its nascent stages and attracting immense interest in recent times. In this review, we will provide a perspective on lung-associated metabolic disorders defined for lung diseases (e.g., chronic obstructive pulmonary disease, asthma, and respiratory depression due to infection) and correlate it with lung microbial perturbation. Such perturbations may be due to altered biochemical or metabolic stress as well. Finally, we will draw evidence from microbiome and classical microbiology literature to demonstrate how specific lung morbidities associate with specific metabolic characteristics of the disease, and with the role of microbiome in this context. © 2018 IUBMB Life, 71(1):152-165, 2019.

PMID: 30466159 [PubMed - indexed for MEDLINE]

No association between alpha-tocopherol levels with pulmonary function or exacerbations in cystic fibrosis.

Acta Paediatr. 2020 Jan 10;:

Authors: Loukou I, Moustaki M, Sardeli O, Plyta M, Douros K

Abstract
Most patients with cystic fibrosis (CF) need daily fat-soluble vitamins, but are not always able to achieve the optimal serum levels. The activity of vitamin E is the cumulative function of eight naturally occurring tocopherols. The most potent is alpha-tocopherol and vitamin E deficiency is diagnosed when the serum concentration of this tocopherol is less than 500 µg/dL. Due to its antioxidant properties, Vitamin E may play a protective role in the lungs and it has been associated with less pulmonary exacerbations and better lung function (1,2).

PMID: 31925826 [PubMed - as supplied by publisher]

SP-D attenuates LPS-induced formation of human neutrophil extracellular traps (NETs), protecting pulmonary surfactant inactivation by NETs.

Commun Biol. 2019 Dec 16;2(1):470

Authors: Arroyo R, Khan MA, Echaide M, Pérez-Gil J, Palaniyar N

Abstract
An exacerbated amount of neutrophil extracellular traps (NETs) can cause dysfunction of systems during inflammation. However, host proteins and factors that suppress NET formation (NETosis) are not clearly identified. Here we show that an innate immune collectin, pulmonary surfactant protein-D (SP-D), attenuates lipopolysaccharide (LPS)-mediated NETosis in human neutrophils by binding to LPS. SP-D deficiency in mice (Sftpd-/-) leads to excess NET formation in the lungs during LPS-mediated inflammation. In the absence of SP-D, NETs inhibit the surface-active properties of lung surfactant, essential to prevent the collapse of alveoli, the air breathing structures of the lungs. SP-D reverses NET-mediated inhibition of surfactant and restores the biophysical properties of surfactant. To the best of our knowledge, this study establishes for the first time that (i) SP-D suppresses LPS-mediated NETosis, (ii) NETs inhibit pulmonary surfactant function in the absence of SP-D, and (iii) SP-D can restore NET-mediated inhibition of the surfactant system.

PMID: 31925295 [PubMed - in process]

Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells.

Nat Commun. 2020 Jan 10;11(1):215

Authors: Mithal A, Capilla A, Heinze D, Berical A, Villacorta-Martin C, Vedaie M, Jacob A, Abo K, Szymaniak A, Peasley M, Stuffer A, Mahoney J, Kotton DN, Hawkins F, Mostoslavsky G

Abstract
Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, we report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, we follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or colonic epithelium. We employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modeling and therapeutic screening applications.

PMID: 31924806 [PubMed - in process]

Nanomedicine Approaches for the Pulmonary Treatment of Cystic Fibrosis.

Front Bioeng Biotechnol. 2019;7:406

Authors: Velino C, Carella F, Adamiano A, Sanguinetti M, Vitali A, Catalucci D, Bugli F, Iafisco M

Abstract
Cystic fibrosis (CF) is a genetic disease affecting today nearly 70,000 patients worldwide and characterized by a hypersecretion of thick mucus difficult to clear arising from the defective CFTR protein. The over-production of the mucus secreted in the lungs, along with its altered composition and consistency, results in airway obstruction that makes the lungs susceptible to recurrent and persistent bacterial infections and endobronchial chronic inflammation, which are considered the primary cause of bronchiectasis, respiratory failure, and consequent death of patients. Despite the difficulty of treating the continuous infections caused by pathogens in CF patients, various strategies focused on the symptomatic therapy have been developed during the last few decades, showing significant positive impact on prognosis. Moreover, nowadays, the discovery of CFTR modulators as well as the development of gene therapy have provided new opportunity to treat CF. However, the lack of effective methods for delivery and especially targeted delivery of therapeutics specifically to lung tissues and cells limits the efficiency of the treatments. Nanomedicine represents an extraordinary opportunity for the improvement of current therapies and for the development of innovative treatment options for CF previously considered hard or impossible to treat. Due to the peculiar environment in which the therapies have to operate characterized by several biological barriers (pulmonary tract, mucus, epithelia, bacterial biofilm) the use of nanotechnologies to improve and enhance drug delivery or gene therapies is an extremely promising way to be pursued. The aim of this review is to revise the currently used treatments and to outline the most recent progresses about the use of nanotechnology for the management of CF.

PMID: 31921811 [PubMed]

Use of mepolizumab in adult patients with cystic fibrosis and an eosinophilic phenotype: case series.

Allergy Asthma Clin Immunol. 2020;16:3

Authors: Zhang L, Borish L, Smith A, Somerville L, Albon D

Abstract
Background: Cystic fibrosis (CF) is characterized by inflammation, progressive lung disease, and respiratory failure. Although the relationship is not well understood, patients with CF are thought to have a higher prevalence of asthma than the general population. CF Foundation (CFF) annual registry data in 2017 reported a prevalence of asthma in CF of 32%. It is difficult to differentiate asthma from CF given similarities in symptoms and reversible obstructive lung function in both diseases. However, a specific asthma phenotype (type 2 inflammatory signature), is often identified in CF patients and this would suggest potential responsiveness to biologics targeting this asthma phenotype. A type 2 inflammatory condition is defined by the presence of an interleukin (IL)-4high, IL-5high, IL-13high state and is suggested by the presence of an elevated total IgE, specific IgE sensitization, or an elevated absolute eosinophil count (AEC). In this manuscript we report the effects of using mepolizumab in patients with CF and type 2 inflammation.
Results: We present three patients with CF (63, 34 and 24 year of age) and personal history of asthma, who displayed significant eosinophilic inflammation and high total serum IgE concentrations (type 2 inflammation) who were treated with mepolizumab. All three patients were colonized with multiple organisms including Pseudomonas aeruginosa and Aspergillus fumigatus and tested positive for specific IgE to multiple allergens. We examined the effect of mepolizumab on patients' lung function (FEV1), blood markers of type 2 inflammation, systemic corticosteroid use and frequency of CF exacerbations. One patient had a substantial increase in lung function after starting mepolizumab and all three patients had a substantial benefit in regards to reduced oral CCS use. While none of the patients showed significant changes in the exacerbation rates there was markedly reduced requirements for oral CCS with exacerbations. In addition, mepolizumab had a positive effect on type 2 inflammatory markers, reducing markers of allergic inflammation in all 3 patients.
Conclusions: Mepolizumab appears to have a positive effect on clinical course in patients with CF presenting with a type 2 phenotype characterized by allergic sensitization and hyper-eosinophilia.

PMID: 31921321 [PubMed]

Despite Antagonism in vitro, Pseudomonas aeruginosa Enhances Staphylococcus aureus Colonization in a Murine Lung Infection Model.

Front Microbiol. 2019;10:2880

Authors: Millette G, Langlois JP, Brouillette E, Frost EH, Cantin AM, Malouin F

Abstract
Staphylococcus aureus and Pseudomonas aeruginosa are prevalent lung pathogens in cystic fibrosis (CF). Whereas co-infection worsens the clinical outcome, prototypical strains are usually antagonistic in vitro. We sought to resolve the discrepancy between these in vitro and in vivo observations. In vitro, growth kinetics for co-cultures of co-isolates from CF patients showed that not all P. aeruginosa strains affected S. aureus viability. On solid media, S. aureus slow-growing colonies were visualized around some P. aeruginosa strains whether or not S. aureus viability was reduced in liquid co-cultures. The S. aureus-P. aeruginosa interactions were then characterized in a mouse lung infection model. Lung homogenates were plated on selective media allowing colony counts of either bacterium. Overall, 35 P. aeruginosa and 10 S. aureus strains (clinical, reference, and mutant strains), for a total of 200 co-infections, were evaluated. We observed that S. aureus colonization of lung tissues was promoted by P. aeruginosa and even by strains showing antagonism in vitro. Promotion was proportional to the extent of P. aeruginosa colonization, but no correlation was found with the degree of myeloperoxidase quantification (as marker of inflammation) or with specific virulence-associated factors using known mutant strains of S. aureus and P. aeruginosa. On the other hand, P. aeruginosa significantly increased the expression of two possible cell receptors for S. aureus, i.e., ICAM-1 and ITGA-5 (marker for integrin α5β1) in lung tissue, while mono-infections by S. aureus did not. This study provides insights on polymicrobial interactions that may influence the progression of CF-associated pulmonary infections.

PMID: 31921058 [PubMed]

Draft Genome Sequence of a Pseudomonas aeruginosa Sequence Type 3351 Strain Exhibiting High-Level Resistance to Polymyxins in a Pediatric Patient with Cystic Fibrosis in Mexico.

Microbiol Resour Announc. 2020 Jan 09;9(2):

Authors: Rosales-Reyes R, Esposito F, Fuga B, Cerdeira L, Gayosso-Vázquez C, Lezana-Fernández JL, Lascurain R, Valvano MA, Lincopan N, Santos-Preciado JI

Abstract
Here, we present the draft genome sequence of a Pseudomonas aeruginosa isolate (strain CF16053) belonging to a novel sequence type (ST), ST3351, isolated from a pediatric patient with cystic fibrosis (CF). CF16053 shows high-level resistance to polymyxins associated with mutations in the pmrB gene. Biofilm, pyoverdine, exotoxin A, and type III secretion system (T3SS) genes were identified.

PMID: 31919170 [PubMed]

Subacute TGFβ Exposure Drives Airway Hyperresponsiveness in CF Mice through the PI3K Pathway.

Am J Respir Cell Mol Biol. 2020 Jan 10;:

Authors: Kramer EL, Madala SK, Hudock KM, Davidson C, Clancy JP

Abstract
Cystic fibrosis (CF) is a lethal genetic disease characterized by progressive lung damage and airway obstruction. The majority of patients demonstrate airway hyperresponsiveness (AHR), which is associated with more rapid lung function decline. Recent studies in the neonatal CF pig demonstrated airway smooth muscle (ASM) dysfunction. These findings, combined with observed CFTR expression in ASM, suggest that a fundamental defect in ASM function contributes to lung function decline in CF. One established driver of AHR and ASM dysfunction is Transforming Growth Factor beta 1 (TGFβ), a genetic modifier of CF lung disease. Prior studies demonstrated that TGFβ exposure in CF mice drives features of CF lung disease, including goblet cell hyperplasia and abnormal lung mechanics. CF mice displayed aberrant responses to pulmonary TGFβ, with elevated PI3K signaling and greater increases in lung resistance compared to controls. Here, we show that TGFβ drives abnormalities in CF ASM structure and function through PI3K signaling that is enhanced in CFTR deficient lungs. CF and non-CF mice were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA, empty vector, or PBS only. We assessed methacholine-induced AHR, bronchodilator response, and ASM area in control and CF mice. Notably, CF mice demonstrated enhanced AHR and bronchodilator response with greater ASM area increases compared to non-CF mice. Further, therapeutic inhibition of PI3K signaling mitigated the TGFβ-induced AHR, as well as goblet cell hyperplasia, in CF mice. These results highlight a latent airway hyperresponsiveness phenotype in CFTR deficiency that is enhanced through TGFβ-induced PI3K signaling.

PMID: 31922900 [PubMed - as supplied by publisher]

The impact of Lactococcus lactis (probiotic nasal rinse) co-culture on growth of patient-derived strains of Pseudomonas aeruginosa.

Int Forum Allergy Rhinol. 2020 Jan 10;:

Authors: Cho DY, Skinner D, Lim DJ, Mclemore JG, Koch CG, Zhang S, Swords WE, Hunter R, Crossman DK, Crowley MR, Grayson JW, Rowe SM, Woodworth BA

Abstract
BACKGROUND: The Lactococcus strain of bacteria has been introduced as a probiotic nasal rinse for alleged salubrious effects on the sinonasal bacterial microbiome. However, data regarding interactions with pathogenic bacteria within the sinuses are lacking. The purpose of this study is to assess the interaction between L. lactis and patient-derived Pseudomonas aeruginosa, an opportunistic pathogen in recalcitrant chronic rhinosinusitis (CRS).
METHODS: Commercially available probiotic suspension containing L. lactis W136 was grown in an anaerobic chamber and colonies were isolated. Colonies were co-cultured with patient-derived P. aeruginosa strains in the presence of porcine gastric mucin (mimicking human mucus) for 72 hours. P. aeruginosa cultures without L. lactis served as controls. Colony forming units (CFUs) were compared.
RESULTS: Six P. aeruginosa isolates collected from 5 CRS patients (3 isolates from cystic fibrosis [CF], 1 mucoid strain) and laboratory strain PAO1 were co-cultured with L. lactis. There was no statistical difference in CFUs of 5 P. aeruginosa isolates grown with L. lactis compared to CFUs without presence of L. lactis. CFU counts were much higher when the mucoid strain was co-cultured with L. lactis (CFU+L.lactis = 1.9 × 108 ± 1.44 × 107, CFU-L.lactis = 1.3 × 108 ± 8.9 × 106, p = 0.01, n = 7). L. lactis suppressed the growth of 1 P. aeruginosa strain (CFU+L.lactis = 2.15 × 108 ± 2.9 × 107, CFU-L.lactis = 3.95 × 108 ± 4.8 × 106, p = 0.03, n = 7).
CONCLUSION: L. lactis suppressed the growth of 1 patient P. aeruginosa isolate and induced growth of another (a mucoid strain) in in vitro co-culture setting in the presence of mucin. Further experiments are required to assess the underlying interactions between L. lactis and P. aeruginosa.

PMID: 31922358 [PubMed - as supplied by publisher]

Patient acceptance and outcome of mental health screening in Swedish adults with cystic fibrosis.

Qual Life Res. 2020 Jan 09;:

Authors: Järvholm S, Ericson P, Gilljam M

Abstract
PURPOSE: Anxiety and depression are common among adults with cystic fibrosis (CF), and the International Committee on Mental Health in CF (ICMH) recommends annual screening for mental health problems. We implemented screening according to the recently published guidelines and assessed the results from the first year, as well as the patients' attitude to annual screening METHODS: Adult patients attending Gothenburg CF-center from Feb 2015 to Dec 2016 completed the GAD-7 (anxiety) and PHQ-9 (depression) forms at the time of their annual review. In addition, questions regarding the screening process and instruments used were asked.
RESULTS: All invited patients (n = 100, 52% males, 2% lung transplanted), with a median age of 28 years (range 18-65), agreed to participate. In general (83%), the patients were positive to screening on an annual basis. No significant differences in total GAD-7 and PHQ-9 scores were found when comparing men and women. Patients younger than 30 years of age reported more symptoms of anxiety compared to older patients (p = 0.02). There were 21 (21%) patients with scores > 10 for GAD-7 and/or PHQ-9 indicating at least moderate anxiety or depression. Scores > 10 were reported by 15 patients on GAD-7, 15 patients on PHQ-9, and 9 patients reported scores above 10 on both measures.
CONCLUSION: The patients considered annual check-ups for mental health issues important. Although the screening results are reassuring, the group is heterogenic and younger individuals should be given extra attention. Follow-up over longer time will provide more robust data.

PMID: 31919786 [PubMed - as supplied by publisher]