[Selection of lung transplant candidates in France in 2019].

Rev Mal Respir. 2019 Apr 18;:

Authors: Falque L, Gheerbrant H, Saint-Raymond C, Quétant S, Camara B, Briault A, Porcu P, Pirvu A, Durand M, Pison C, Claustre J, groupe coopératif COhort of Lung Transplantation - COLT

Abstract
INTRODUCTION: In 2015, the International Society for Heart and Lung Transplantation (ISHLT) published a consensus document for the selection of lung transplant candidates. In the absence of recent French recommendations, this guideline is useful in order to send lung transplant candidates to the transplantation centers and to list them for lung transplantation at the right time.
BACKGROUND: The main indications for lung transplantation in adults are COPD and emphysema, idiopathic pulmonary fibrosis and interstitial diseases, cystic fibrosis and pulmonary arterial hypertension (PAH). The specific indications for each underlying disease as well as the general contraindications have been reviewed in 2015 by the ISHLT. For cystic fibrosis, the main factors are forced expiratory volume in one second, 6-MWD, PAH and clinical deterioration characterized by increased frequency of exacerbations; for emphysema progressive disease, the BODE score, hypercapnia and FEV1; for PAH progressive disease or the need of specific intravenous therapy and NYHA classification. Finally, the diagnosis of fibrosing interstitial lung disease is usually a sufficient indication for lung transplantation assessment.
OUTLOOK AND CONCLUSION: These new recommendations, close to French practices, help clinicians to find the right time for referral of patients to transplantation centers. This is crucial for the prognosis of lung transplantation.

PMID: 31006579 [PubMed - as supplied by publisher]

Impact of CFTR-modulating drugs on GH-IGF-1 axis impairment in adult patients with cystic fibrosis.

J Endocrinol Invest. 2019 Apr 20;:

Authors: Pascucci C, De Biase RV, Savi D, Quattrucci S, Gnessi L, Lubrano C, Lenzi A

Abstract
INTRODUCTION: A new class of drugs in the treatment of cystic fibrosis (CF) includes two agents: lumacaftor, which corrects CFTR channel protein, and ivacaftor, which increases CFTR channel activity. In our previous study we recruited 50 stable adults with CF and 16 of them showed growth hormone deficit (GHD): 7 patients severe and 9 patients partial GHD.
MATERIAL AND METHODS: We decided to re-evaluate ten patients with the GHRH + arginine test of whom only five were treated with lumacaftor/ivacaftor.
RESULTS: All CF patients in therapy with lumacaftor/ivacaftor showed a marked improvement in GHD. Two patients moved from a severe GHD to a normal response to the GH/IGF-1 axis test, and three patients who had partial GHD moved to normal response.
CONCLUSION: The pituitary gland may be damaged by CF disease and could benefit of the action of correcting drugs.

PMID: 31006073 [PubMed - as supplied by publisher]

Adherence to nutritional supplementation in cystic fibrosis.

J Pediatr Nurs. 2019 Apr 18;47:18-22

Authors: Hommel KA, Rausch J, Towner EK, Schall J, Maqbool A, Mascarenhas M, Stallings V

Abstract
PURPOSE: The purpose of this study was to examine patterns of adherence to a novel dietary supplement in pediatric cystic fibrosis. Adherence to dietary supplementation in cystic fibrosis is challenging, and examination of patterns of adherence behavior over time is needed to better characterize subgroups of patients who need self-management support.
DESIGN AND METHODS: We prospectively examined adherence to Lym-X-Sorb™ (LXS), an organized lipid matrix dietary supplementation for patients with cystic fibrosis (CF) and pancreatic insufficiency (PI), over a 12-month period. Adherence for participants aged 5-17 years with CF and PI (N = 109) was monitored monthly via supplement packet counts. Group-based trajectory modeling was employed to examine patterns in adherence behavior over time.
RESULTS: Four distinct trajectories best characterized adherence in this sample, with 18% of participants demonstrating near perfect adherence, 42% demonstrating good adherence (at or above 80%), 16% demonstrating poor adherence that declined over time, and 24% demonstrating significant non-adherence (< 30%).
CONCLUSIONS: Some patients with CF and PI who are prescribed nutritional supplements will require intensive, individualized behavioral intervention to enhance adherence. Identifying patients who will have difficulty adhering to dietary interventions may result in better treatment-to-patient matching and improved adherence promotion efforts.
PRACTICE IMPLICATIONS: Assessment of adherence to dietary supplementation over time can identify patients at risk for continued difficulty with self-management and provide opportunities for early intervention.

PMID: 31005801 [PubMed - as supplied by publisher]

Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy.

J Cyst Fibros. 2019 Apr 17;:

Authors: Terlizzi V, Mergni G, Buzzetti R, Centrone C, Zavataro L, Braggion C

Abstract
OBJECTIVE: The implementation of cystic fibrosis (CF) newborn screening (NBS) has led to identification of infants with a positive NBS test but inconclusive diagnosis classified as "CF screen positive, inconclusive diagnosis" (CFSPID). We retrospectively evaluated the prevalence and clinical outcome of CFSPID infants diagnosed by 2 NBS algorithms in the period from 2011 to 2016 in the Tuscany region of Italy.
METHODS: In 2011-2016, we assessed the diagnostic impact of DNA analysis on the NBS 4-tier algorithm [immunoreactive trypsin (IRT) - meconium lactase - IRT2 - sweat chloride (SC)]. All CFSPID patients repeated SC testing every 6 months, and CFTR gene analysis was performed (detection rate 98%). We reclassified children as: CF diagnosis in presence of at least 2 pathological SC results; healthy carrier or healthy in presence of at least 2 normal SC results for age and either 1 or 0 CF-causing mutations, respectively.
RESULTS: We identified 32 CF and 50 CFSPID cases: 20/50 (40%) were diagnosed only by the IRT-DNA-SC algorithm and 16/50 (32%) only by IRT-meconium lactase-IRT2-SC. Both protocols identified the remaining 14 cases (28%). Thirty-seven of 50 (74%) CFSPID patients had a conclusive diagnosis on December 31, 2017:5 (10%) CF, 17 (34%) healthy and 15 (30%) healthy carriers; 13/50 (26%) cases were asymptomatic with persistent intermediate SC and followed as CFSPID (CF:CFSPID ratio 2.85:1).
CONCLUSIONS: In 6 years, the CF:CFSPID ratio modified from 0.64:1 to 2.85:1, and 10% of CFSPID cases progressed to CF. Genetic analysis improved positive predictive value and identified a higher number of CFSPID infants progressing to CF.

PMID: 31005549 [PubMed - as supplied by publisher]

A new IgE Western blot identifies Aspergillus fumigatus sensitization and may discriminate allergic bronchopulmonary aspergillosis.

Allergy. 2019 Apr 20;:

Authors: Piarroux R, Dubus JC, Reynaud-Gaubert M, Gouitaa M, Ranque S, Vitte J

PMID: 31004499 [PubMed - as supplied by publisher]

Addressing lung transplant with adults with cystic fibrosis: A qualitative analysis of patients' perspectives and experiences.

J Cyst Fibros. 2019 Apr 16;:

Authors: Ramos KJ, Hobler MR, Engelberg RA, Curtis JR, Zander MI, Howard SS, Goss CH, Aitken ML

Abstract
Referral for lung transplantation is a complex process that typically begins with a discussion in cystic fibrosis (CF) clinic. We performed a secondary analysis of interviews conducted at the University of Washington CF Clinic as part of a study of unmet palliative care needs, June 2015 - January 2016, among adults with moderate-to-severe CF-related lung disease. Content analysis methods were used to identify themes related to discussion of lung transplant in CF clinic. Thirty-two of 48 interviews (67%) addressed transplant. An individual's willingness to discuss transplant was not necessarily related to the degree of lung function impairment. Patients reported reliance on CF physicians as a source of accurate information about transplant. Individuals with CF sometimes reported feeling too old or not worthy of transplant. Many had apprehensive or ambivalent feelings towards transplant. Patient-identified barriers and facilitators to lung transplant discussions can inform physicians as they discuss transplant in CF clinic.

PMID: 31003953 [PubMed - as supplied by publisher]

"No-No" Head Tremor-A Nod to the Diagnosis.

Pediatr Neurol. 2019 Mar 19;:

Authors: Terry C, Forman EB, Gorman KM, King MD

PMID: 31003879 [PubMed - as supplied by publisher]

Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions.

Cochrane Database Syst Rev. 2019 Apr 19;4:CD011385

Authors: van Galen KP, Engelen ET, Mauser-Bunschoten EP, van Es RJ, Schutgens RE

Abstract
BACKGROUND: Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease (VWD). The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date. This is an update of a previously published Cochrane Review.
OBJECTIVES: Primarily, we aim to assess the efficacy of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or VWD undergoing oral or dental procedures.Secondary objectives are to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or VWD and to establish the effects of these agents on bleeding in oral or dental procedures for each of these patient populations.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched PubMed, Embase, Cinahl and the Cochrane Library. Additional searches were performed in ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP).Date of last search of the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 01 March 2019.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials in people with haemophilia or VWD undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid (EACA)) to prevent perioperative bleeding compared to no intervention or usual care with or without placebo.
DATA COLLECTION AND ANALYSIS: Two authors independently screened the titles and abstracts of all identified articles. Full texts were obtained for potentially relevant abstracts and two authors independently assessed these for inclusion based on the selection criteria. A third author verified trial eligibility. Two authors independently performed data extraction and risk of bias assessments using standardised forms.
MAIN RESULTS: While there were no eligible trials in people with VWD identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of EACA published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference (RD) of -0.64 (95% confidence interval (CI) -0.93 to - 0.36) and the EACA trial a RD of -0.50 (95% CI 0.77 to -0.22). The combined RD of both trials was -0.57 (95% CI -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping EACA (combined RD of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the EACA trial, but overall the risk of bias appeared to be low for both trials.
AUTHORS' CONCLUSIONS: Despite the discovery of a beneficial effect of systemically administered tranexamic acid and EACA in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with VWD.

PMID: 31002742 [PubMed - as supplied by publisher]

Roles, Actions, and Therapeutic Potential of Specialized Pro-resolving Lipid Mediators for the Treatment of Inflammation in Cystic Fibrosis.

Front Pharmacol. 2019;10:252

Authors: Recchiuti A, Mattoscio D, Isopi E

Abstract
Non-resolving inflammation is the main mechanism of morbidity and mortality among patients suffering from cystic fibrosis (CF), the most common life-threatening human genetic disease. Resolution of inflammation is an active process timely controlled by endogenous specialized pro-resolving lipid mediators (SPMs) produced locally in inflammatory loci to restrain this innate response, prevent further damages to the host, and permit return to homeostasis. Lipoxins, resolvins, protectins, and maresins are SPM derived from polyunsaturated fatty acids that limit excessive leukocyte infiltration and pro-inflammatory signals, stimulate innate microbial killing, and enhance resolution. Their unique chemical structures, receptors, and bioactions are being elucidated. Accruing data indicate that SPMs carry protective functions against unrelenting inflammation and infections in preclinical models and human CF systems. Here, we reviewed their roles and actions in controlling resolution of inflammation, evidence for their impairment in CF, and proofs of principle for their exploitation as innovative, non-immunosuppressive drugs to address inflammation and infections in CF.

PMID: 31001110 [PubMed]

Comparative risks of chronic inhaled corticosteroids and macrolides for bronchiectasis.

Eur Respir J. 2019 Apr 18;:

Authors: Henkle E, Curtis JR, Chen L, Chan B, Aksamit TR, Daley CL, Griffith DE, Winthrop KL

Abstract
INTRODUCTION: Non-cystic fibrosis bronchiectasis ("bronchiectasis") is a chronic airway disease for which little data exist to inform treatment decisions. We sought to compare the risks of respiratory infections in chronic users of inhaled corticosteroids (ICS) versus macrolide monotherapy.
METHODS: We identified a cohort of U.S. Medicare enrollees with a bronchiectasis diagnosis (494.0/494.1) between 2006 and 2014, excluding cystic fibrosis. We defined chronic new use as the first 28+ day prescription of ICS or macrolide monotherapy. We compared characteristics of the exposure cohorts using standardised mean differences (SMD) and computed a propensity score (PS) to account for treatment differences. The risks of acute exacerbation, hospitalised respiratory infection, all-cause hospitalisation, and mortality were compared using PS decile-adjusted Cox regression models.
RESULTS: We identified 83 589 new users of ICS and 6500 of macrolides from 285 043 included Medicare enrollees with bronchiectasis. The crude incidence of hospitalised respiratory infection was 12.6 (ICS) and 10.3 (macrolide) per 100 patient-years. The PS-adjusted hazard comparing ICS to macrolide new-users was 1.39 (95% CI 1.23-1.57) for hospitalised respiratory infection, 1.56 (1.49-1.64) for acute exacerbation, and 1.09 (0.95-1.25) for mortality.
INTERPRETATION: Among patients with bronchiectasis, the use of ICS was associated with an increased risk of hospitalised respiratory infections compared to macrolide monotherapy.

PMID: 31000676 [PubMed - as supplied by publisher]

The Potential of Self-Management mHealth for Pediatric Cystic Fibrosis: Mixed-Methods Study for Health Care and App Assessment.

JMIR Mhealth Uhealth. 2019 Apr 18;7(4):e13362

Authors: Martinez-Millana A, Zettl A, Floch J, Calvo-Lerma J, Sevillano JL, Ribes-Koninckx C, Traver V

Abstract
BACKGROUND: Remote care services and patient empowerment have boosted mobile health (mHealth). A study of user needs related to mHealth for pediatric cystic fibrosis (PCF) identified the set of preferred features mobile apps should support; however, the potential use of PCF apps and their suitability to fit into PCF clinical management remains unexplored.
OBJECTIVE: We examine whether PCF holds potential for the implementation of mHealth care.
METHODS: The study is based on a literature review and qualitative analysis of content and was conducted in two parts: (1) we reviewed scientific and gray literature to explore how European countries manage PCF and conducted a qualitative study of 6 PCF units and (2) we performed a systematic review of apps available in the myhealthapps.net repository searching for cystic fibrosis (CF) management and nutrition apps, which we analyzed for characteristics, business models, number of downloads, and usability.
RESULTS: European CF routine care guidelines are acknowledged in most European countries, and treatments are fully covered in almost all countries. The majority of teams in CF units are interdisciplinary. With respect to the systematic review of apps, we reviewed 12 apps for CF management and 9 for general nutrition management in the myhealthapps.net directory. All analyzed apps provided functionalities for recording aspects related to the disease and nutrition such as medication, meals, measurements, reminders, and educational material. None of the apps reviewed in this study supported pancreatic enzyme replacement therapy. CF apps proved to be less appealing and usable than nutrition apps (2.66 [SD 1.15] vs 4.01 [SD 0.90]; P<.001, z-value: -2.6). User needs detected in previous research are partially matched by current apps for CF management.
CONCLUSIONS: The health care context for PCF is a unique opportunity for the adoption of mHealth. Well-established clinical guidelines, heterogeneous clinical teams, and coverage by national health care systems provide a suitable scenario for the use of mHealth solutions. However, available apps for CF self-management do not cover essential aspects such as nutrition and education. To increase the adoption of mHealth for CF self-management, new apps should include these features.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2016-014931.

PMID: 30998222 [PubMed]

Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

Cochrane Database Syst Rev. 2019 Apr 18;4:CD009876

Authors: Regan KH, Bhatt J

Abstract
BACKGROUND: Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute infection with Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. This is an updated version of the review.
OBJECTIVES: To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Last search: 12 March 2019.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 12 March 2019.
SELECTION CRITERIA: Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics or alternative therapeutic agents used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed for inclusion in the review the eligibility of 52 studies (79 references) identified by the search of the Group's Trial Register and the other electronic searches.
MAIN RESULTS: No studies looking at the eradication of Burkholderia cepacia complex species were identified.
AUTHORS' CONCLUSIONS: The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.

PMID: 30997925 [PubMed - as supplied by publisher]

Prevalence of atopy and allergic rhinitis in patients with adult non-cystic fibrosis bronchiectasis

Turk J Med Sci. 2019 Apr 18;49(2):551-557

Authors: Niksarlıoğlu EY, Işık R, Uysal MA, Ünal D, Çamsarı G

Abstract
Background/aim: Non-cystic fibrosis bronchiectasis (non-CF BR) is common in developing countries.Limited data are available regarding the impact of atopy, and no data are available regarding allergic rhinitis in patients with adult bronchiectasis.The aim of this study was to evaluate the prevalence of atopy and allergic rhinitis in the clinical conditions of patients with BR.
Materials and methods: The study enrolled 101 patients who were diagnosed with non-CF BR using high-resolution computed chest tomography. Allergic rhinitis (AR) was defined by skin prick test (SPT) positivity and the presence of any nasal symptoms (watery runny nose, nasal obstruction, nasal itching, and sneezing).
Results: The mean age of patients was 48 ± 15 years (range 18–82); 55 (54.5%) patients were female. SPT positivity was detected in 37 (36.6%) cases. AR was detected in 32 (31.7%) patients with non-CF BR. AR was related to dyspnea (P = 0.04) and number of admissions to an emergency department in the previous year (P = 0.01). Forced expiratory volume in 1 s and forced vital capacity in patients with and without AR were different (P = 0.01 and P = 0.01, respectively). AR was correlated with number of admissions to an emergency department in the last year (r = 0.417, P = 0.005).
Conclusion: We concluded that atopy was detected in more than one-third of adult non-CF BR patients. This study demonstrated that non-CF BR patients might have AR; it might be important to be aware of nasal symptoms in non-CF BR patients.

PMID: 30997791 [PubMed - in process]

Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles.

Clin Case Rep. 2019 Apr;7(4):616-618

Authors: Chouchane I, Stremler-Lebel N, Reix P

Abstract
We report the initiation of CFTR modulator lumacaftor/ivacaftor combination (LUM/IVA) in two adolescents with cystic fibrosis who were treated with antifungal azoles (AZO) and tacrolimus (TCS) for liver transplantation. Despite multiple drug-drug interactions, maintaining therapeutic TCS levels was achievable. During the following year, LUM/IVA was well tolerated, providing clinical benefits.

PMID: 30997048 [PubMed]

Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools.

Sci Rep. 2019 Apr 17;9(1):6234

Authors: Pereira SV, Ribeiro JD, Ribeiro AF, Bertuzzo CS, Marson FAL

Abstract
Cystic fibrosis (CF) is caused by ~300 pathogenic CFTR variants. The heterogeneity of which, challenges molecular diagnosis and precision medicine approaches in CF. Our objective was to identify CFTR variants through high-throughput sequencing (HTS) and to predict the pathogenicity of novel variants through in 8 silico tools. Two guidelines were followed to deduce the pathogenicity. A total of 169 CF patients had genomic DNA submitted to a Targeted Gene Sequencing and we identified 63 variants (three patients had three variants). The most frequent alleles were: F508del (n = 192), G542* (n = 26), N1303K (n = 11), R1162* and R334W (n = 9). The screened variants were classified as follows: 41 - pathogenic variants [classified as (I) n = 23, (II) n = 6, (III) n = 1, (IV) n = 6, (IV/V) n = 1 and (VI) n = 4]; 14 - variants of uncertain significance; and seven novel variants. To the novel variants we suggested the classification of 6b-16 exon duplication, G646* and 3557delA as Class I. There was concordance among the predictors as likely pathogenic for L935Q, cDNA.5808T>A and I1427I. Also, Y325F presented two discordant results among the predictors. HTS and in silico analysis can identify pathogenic CFTR variants and will open the door to integration of precision medicine into routine clinical practice in the near future.

PMID: 30996306 [PubMed - in process]

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.

JCI Insight. 2019 Apr 18;4(8):

Authors: Fernandez-Petty CM, Hughes GW, Bowers HL, Watson JD, Rosen BH, Townsend SM, Santos C, Ridley CE, Chu KK, Li Y, Leung HM, Garcia BA, Evans TIA, Libby EF, Hathorne H, Hanes J, Tearney GJ, Engelhardt JF, Swords WE, Thornton DJ, Wiesmann WP, Baker SM, Rowe SM

Abstract
Cystic fibrosis (CF) is characterized by increased mucus viscosity and delayed mucociliary clearance that contributes to progressive decline of lung function. Mucus in the respiratory and GI tract is excessively adhesive in the presence of airway dehydration and excess extracellular Ca2+ upon mucin release, promoting hyperviscous, densely packed mucins characteristic of CF. Therapies that target mucins directly through ionic interactions remain unexploited. Here we show that poly (acetyl, arginyl) glucosamine (PAAG), a polycationic biopolymer suitable for human use, interacts directly with mucins in a Ca2+-sensitive manner to reduce CF mucus viscoelasticity and improve its transport. Notably, PAAG induced a linear structure of purified MUC5B and altered its sedimentation profile and viscosity, indicative of proper mucin expansion. In vivo, PAAG nebulization improved mucociliary transport in CF rats with delayed mucus clearance, and cleared mucus plugging in CF ferrets. This study demonstrates the potential use of a synthetic glycopolymer PAAG as a molecular agent that could benefit patients with a broad array of mucus diseases.

PMID: 30996141 [PubMed - in process]

A Live Salmonella Vaccine Delivering PcrV through the Type III Secretion System Protects against Pseudomonas aeruginosa.

mSphere. 2019 Apr 17;4(2):

Authors: Aguilera-Herce J, García-Quintanilla M, Romero-Flores R, McConnell MJ, Ramos-Morales F

Abstract
Pseudomonas aeruginosa is a common Gram-negative opportunistic pathogen that is intrinsically resistant to a wide range of antibiotics. The development of a broadly protective vaccine against P. aeruginosa remains a major challenge. Here, we used an attenuated strain of Salmonella enterica serovar Typhimurium as a vehicle to express P. aeruginosa antigens. A fusion between the S. enterica type III secretion effector protein SseJ and the P. aeruginosa antigen PcrV expressed under the control of the sseA promoter was translocated by Salmonella into host cells in vitro and elicited the generation of specific antibodies in mice. Mice immunized with attenuated Salmonella expressing this fusion had reduced bacterial loads in the spleens and lungs and lower serum levels of proinflammatory cytokines than control mice after P. aeruginosa infection. Importantly, immunized mice also showed significantly enhanced survival in this model. These results suggest that type III secretion effectors of S. enterica are appropriate carriers in the design of a live vaccine to prevent infections caused by P. aeruginosa IMPORTANCE The Gram-negative bacterium Pseudomonas aeruginosa is an important opportunistic pathogen that causes infections in cystic fibrosis and hospitalized patients. Therapeutic treatments are limited due to the emergence and spread of new antibiotic-resistant strains. In this context, the development of a vaccine is a priority. Here, we used an attenuated strain of Salmonella enterica serovar Typhimurium as a vehicle to express and deliver the Pseudomonas antigen PcrV. This vaccine induced the generation of specific antibodies in mice and protected them from lethal infections with P. aeruginosa This is an important step toward the development of an effective vaccine for the prevention of infections caused by P. aeruginosa in humans.

PMID: 30996108 [PubMed - in process]

Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis.

Sci Transl Med. 2019 Apr 17;11(488):

Authors: Burgener EB, Sweere JM, Bach MS, Secor PR, Haddock N, Jennings LK, Marvig RL, Johansen HK, Rossi E, Cao X, Tian L, Nedelec L, Molin S, Bollyky PL, Milla CE

Abstract
Filamentous bacteriophage (Pf phage) contribute to the virulence of Pseudomonas aeruginosa infections in animal models, but their relevance to human disease is unclear. We sought to interrogate the prevalence and clinical relevance of Pf phage in patients with cystic fibrosis (CF) using sputum samples from two well-characterized patient cohorts. Bacterial genomic analysis in a Danish longitudinal cohort of 34 patients with CF revealed that 26.5% (n = 9) were consistently Pf phage positive. In the second cohort, a prospective cross-sectional cohort of 58 patients with CF at Stanford, sputum qPCR analysis showed that 36.2% (n = 21) of patients were Pf phage positive. In both cohorts, patients positive for Pf phage were older, and in the Stanford CF cohort, patients positive for Pf phage were more likely to have chronic P. aeruginosa infection and had greater declines in pulmonary function during exacerbations than patients negative for Pf phage presence in the sputum. Last, P. aeruginosa strains carrying Pf phage exhibited increased resistance to antipseudomonal antibiotics. Mechanistically, in vitro analysis showed that Pf phage sequesters these same antibiotics, suggesting that this mechanism may thereby contribute to the selection of antibiotic resistance over time. These data provide evidence that Pf phage may contribute to clinical outcomes in P. aeruginosa infection in CF.

PMID: 30996083 [PubMed - in process]

Pharmacoeconomic Review Report: Lumacaftor/Ivacaftor (Orkambi): (Vertex Pharmaceuticals (Canada) Incorporated): Indication: For the treatment of cystic fibrosis in patients 6 years of age and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator gene

Book. 2018 10

Authors:

Abstract
Orkambi is a fixed-dose combination tablet containing 200 mg lumacaftor and 125 mg ivacaftor (LUM/IVA). It is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. This is most common CF-causing mutation worldwide and approximately half of all Canadian patients with CF are homozygous for the F508del mutation. LUM/IVA is the first treatment specifically indicated for the treatment of patients who are homozygous for the F508del mutation in the CFTR gene. The manufacturer has requested that LUM/IVA be listed in accordance with the Health Canada–approved indication. The recommended dose is lumacaftor 400 mg/ivacaftor 250 mg every 12 hours. This represents the lower of the dosages considered in both the TRANSPORT AND TRAFFIC trials. At the current marketed price of $170.54 per tablet, the daily cost of treatment per patient with LUM/IVA is $682, or $248,982 annually. CADTH reviewed LUM/IVA in 2015 for the treatment of CF in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. CDEC recommended that LUM/IVA not be reimbursed, based on the clinical findings. The price submitted for LUM/IVA in the original submission is the same as the current submission. The manufacturer submitted a cost-utility analysis to assess the cost-effectiveness of LUM/IVA + standard of care (SoC) compared with SoC alone in patients with CF who are 6 years of age or older and homozygous for the F508del-CFTR mutation.

PMID: 30998303

Transcriptomic responses to Ivacaftor and prediction of Ivacaftor clinical responsiveness.

Am J Respir Cell Mol Biol. 2019 Apr 17;:

Authors: Sun T, Sun Z, Jiang Y, Ferguson AA, Pilewski JM, Kolls JK, Chen W, Chen K

Abstract
Ivacaftor is a recently FDA-approved drug for the treatment of cystic fibrosis (CF) patients with at least one copy of the G511D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The transcriptomic effect of Ivacaftor in CF patients remains unclear. We aim to examine if and how the transcriptome of patients is influenced by Ivacaftor treatment and to determine if these data allow prediction of Ivacaftor responsiveness. Our data originate from the GOAL-G551D Observational Study. We performed RNA-sequencing (RNA-seq) on PBMCs from 56 patients and compared the transcriptomic changes before and after Ivacaftor treatments. Consensus clustering method was employed to stratify patients into sub-groups based on clinical responses post treatment and we determined differences between subgroups in baseline gene expressions. A random forest model was built to predict Ivacaftor responsiveness. We identified 239 genes (false discovery rate < 0.1) that were significantly influenced by Ivacaftor in PBMC. The functions of these genes relate to cell differentiation, microbial infection, inflammation, Toll-like receptor signaling, and metabolism. We classified patients into "good" and "moderate" responders based on clinical response to Ivacraftor. We identified a panel of signature genes and built a statistical model for predicting CFTR modulator responsiveness. Despite a limited sample size, adequate prediction performance was achieved with an accuracy of 0.92. In conclusion, for the first time, the present study demonstrates profound transcriptomic impacts of Ivafactor in CF patients PBMCs and built a pilot statistical model for predicting the clinical responsiveness to Ivacaftor prior to treatment.

PMID: 30995102 [PubMed - as supplied by publisher]