The Impact of Airway Complications on Survival Among Lung Transplant Recipients.

Transplant Proc. 2020 Jun 09;:

Authors: Nęcki M, Pandel A, Urlik M, Antończyk R, Latos M, Gawęda M, Stącel T, Wajda-Pokrontka M, Zawadzki F, Okienica M, Przybyłowski P, Zembala M, Ochman M

Abstract
INTRODUCTION: Long-term outcomes of airway complications (AC) after lung transplantation are unknown. The incidence of AC varies from 1.6% to 32% with the related mortality rate of 2% to 4%. The management of most AC is based on endobronchial methods, including balloon bronchoplasty, endobronchial stent placement, and ablative techniques. The aim of the study was to assess the connection between airway complications treated by bronchial intervention (BI) and the survival of lung transplant recipients.
MATERIALS AND METHODS: The single-center retrospective study reviewed the cases of 165 patients (63 women [38.18%], 103 men [61, 82%]; median age at referral for lung transplantations (LTx), 41 years [range, 15-68 years]). The cohort was stratified into 2 groups comprising those whose procedures were complicated by ACs and those without. The primary outcome measured was mortality, with survival endpoints calculated at 6 months.
RESULTS: The comparison of the survival of recipients regarding underlying disease (cystic fibrosis [CF], chronic obstructive pulmonary disease [COPD], idiopathic pulmonary artery hypertension [IPAH], and others) with the use of the Kaplan-Meier estimator indicated that the only statistically significant (P = .0194) differences between patients who underwent BI and patients without BI performed were observed in CF patients (Fig 1). In any other diagnosis, the results were not statistically significant (P > .05).
CONCLUSIONS: Bronchoscopic intervention because of airway complications after lung transplantation are often-used procedures, but they have no impact on the survival of patients with cystic fibrosis.

PMID: 32532559 [PubMed - as supplied by publisher]

An 8 week open-label interventional multicenter study to explore the lung clearance index as endpoint for clinical trials in cystic fibrosis patients ≥8 years of age, chronically infected with Pseudomonas aeruginosa.

BMC Pulm Med. 2020 Jun 12;20(1):167

Authors: Sutharsan S, Naehrig S, Mellies U, Sieder C, Ziegler J

Abstract
BACKGROUND: Forced expiratory volume in 1 second (FEV1) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to explore the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF.
METHODS: This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV1, LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment.
RESULTS: All patients (n = 17) showed elevated LCI of > 11 despite 3 patients having normal FEV1 (> 90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV1 in 9 (53%) patients. At week 4, LCI improved by 0.88, FEV1 increased by 0.52%, and P. aeruginosa reduced by 30,481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity.
CONCLUSIONS: Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV1 for lung function. LCI can be hypothesized to be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling younger patients or patients with more milder lung disease and thus, limiting the ventilation inhomogeneities.
TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov, identifier: NCT02248922.

PMID: 32532226 [PubMed - as supplied by publisher]

Development of an Innovative, Carrier-Based Dry Powder Inhalation Formulation Containing Spray-Dried Meloxicam Potassium to Improve the In Vitro and In Silico Aerodynamic Properties.

Pharmaceutics. 2020 Jun 10;12(6):

Authors: Benke E, Farkas Á, Szabó-Révész P, Ambrus R

Abstract
Most of the marketed dry powder inhalation (DPI) products are traditional, carrier-based formulations with low drug concentrations deposited in the lung. However, due to their advantageous properties, their development has become justified. In our present work, we developed an innovative, carrier-based DPI system, which is an interactive physical blend of a surface-modified carrier and a spray-dried drug with suitable shape and size for pulmonary application. Meloxicam potassium, a nonsteroidal anti-inflammatory drug (NSAID), was used as an active ingredient due to its local anti-inflammatory effect and ability to decrease the progression of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The results of the in vitro and in silico investigations showed high lung deposition in the case of this new formulation, confirming that the interparticle interactions were changed favorably.

PMID: 32532040 [PubMed - as supplied by publisher]

Tracking of Infused Mesenchymal Stem Cells in Injured Pulmonary Tissue in Atm-Deficient Mice.

Cells. 2020 Jun 10;9(6):

Authors: Baer PC, Sann J, Duecker RP, Ullrich E, Geiger H, Bader P, Zielen S, Schubert R

Abstract
Pulmonary failure is the main cause of morbidity and mortality in the human chromosomal instability syndrome Ataxia-telangiectasia (A-T). Major phenotypes include recurrent respiratory tract infections and bronchiectasis, aspiration, respiratory muscle abnormalities, interstitial lung disease, and pulmonary fibrosis. At present, no effective pulmonary therapy for A-T exists. Cell therapy using adipose-derived mesenchymal stromal/stem cells (ASCs) might be a promising approach for tissue regeneration. The aim of the present project was to investigate whether ASCs migrate into the injured lung parenchyma of Atm-deficient mice as an indication of incipient tissue damage during A-T. Therefore, ASCs isolated from luciferase transgenic mice (mASCs) were intravenously transplanted into Atm-deficient and wild-type mice. Retention kinetics of the cells were monitored using in vivo bioluminescence imaging (BLI) and completed by subsequent verification using quantitative real-time polymerase chain reaction (qRT-PCR). The in vivo imaging and the qPCR results demonstrated migration accompanied by a significantly longer retention time of transplanted mASCs in the lung parenchyma of Atm-deficient mice compared to wild type mice. In conclusion, our study suggests incipient damage in the lung parenchyma of Atm-deficient mice. In addition, our data further demonstrate that a combination of luciferase-based PCR together with BLI is a pivotal tool for tracking mASCs after transplantation in models of inflammatory lung diseases such as A-T.

PMID: 32531978 [PubMed - as supplied by publisher]

Myeloid CFTR loss-of-function causes persistent neutrophilic inflammation in cystic fibrosis.

J Leukoc Biol. 2020 Jun 12;:

Authors: Ng HP, Jennings S, Wellems D, Sun F, Xu J, Nauseef WM, Wang G

Abstract
Persistent neutrophilic inflammation is a hallmark of cystic fibrosis (CF). However, the mechanisms underlying this outstanding pathology remain incompletely understood. Here, we report that CFTR in myeloid immune cells plays a pivotal role in control of neutrophilic inflammation. Myeloid CFTR-Knockout (Mye-Cftr-/-) mice and congenic wild-type (WT) mice were challenged peritoneally with zymosan particles at different doses, creating aseptic peritonitis with varied severity. A high-dose challenge resulted in significantly higher mortality in Mye-Cftr-/- mice, indicating an intrinsic defect in host control of inflammation in mice whose myeloid cells lack CF. The low-dose challenge demonstrated an impaired resolution of inflammation in Mye-Cftr-/- mice, reflected by a significant overproduction of proinflammatory cytokines, including neutrophil chemokines MIP-2 and KC, and sustained accumulation of neutrophils. Tracing neutrophil mobilization in vivo demonstrated that myeloid CF mice recruited significantly more neutrophils than did WT mice. Pulmonary challenge with zymosan elicited exuberant inflammation in the lung and recapitulated the findings from peritoneal challenge. To determine the major type of cell that was primarily responsible for the over-recruitment of neutrophils, we purified and cultured ex vivo zymosan-elicited peritoneal neutrophils and macrophages. The CF neutrophils produced significantly more MIP-2 than did the WT counterparts, and peripheral blood neutrophils isolated from myeloid CF mice also produced significantly more MIP-2 after zymosan stimulation in vitro. These data altogether suggest that CFTR dysfunction in myeloid immune cells, especially neutrophils, leads to hyperinflammation and excessive neutrophil mobilization in the absence of infection. Thus, dysregulated inflammation secondary to abnormal or absent CFTR in myeloid cells may underlie the clinically observed neutrophilic inflammation in CF.

PMID: 32531843 [PubMed - as supplied by publisher]

Elevated exopolysaccharide levels in Pseudomonas aeruginosa flagellar mutants have implications for biofilm growth and chronic infections.

PLoS Genet. 2020 Jun 12;16(6):e1008848

Authors: Harrison JJ, Almblad H, Irie Y, Wolter DJ, Eggleston HC, Randall TE, Kitzman JO, Stackhouse B, Emerson JC, Mcnamara S, Larsen TJ, Shendure J, Hoffman LR, Wozniak DJ, Parsek MR

Abstract
Pseudomonas aeruginosa colonizes the airways of cystic fibrosis (CF) patients, causing infections that can last for decades. During the course of these infections, P. aeruginosa undergoes a number of genetic adaptations. One such adaptation is the loss of swimming motility functions. Another involves the formation of the rugose small colony variant (RSCV) phenotype, which is characterized by overproduction of the exopolysaccharides Pel and Psl. Here, we provide evidence that the two adaptations are linked. Using random transposon mutagenesis, we discovered that flagellar mutations are linked to the RSCV phenotype. We found that flagellar mutants overexpressed Pel and Psl in a surface-contact dependent manner. Genetic analyses revealed that flagellar mutants were selected for at high frequencies in biofilms, and that Pel and Psl expression provided the primary fitness benefit in this environment. Suppressor mutagenesis of flagellar RSCVs indicated that Psl overexpression required the mot genes, suggesting that the flagellum stator proteins function in a surface-dependent regulatory pathway for exopolysaccharide biosynthesis. Finally, we identified flagellar mutant RSCVs among CF isolates. The CF environment has long been known to select for flagellar mutants, with the classic interpretation being that the fitness benefit gained relates to an impairment of the host immune system to target a bacterium lacking a flagellum. Our new findings lead us to propose that exopolysaccharide production is a key gain-of-function phenotype that offers a new way to interpret the fitness benefits of these mutations.

PMID: 32530919 [PubMed - as supplied by publisher]

Hyaluronic Acid for the Treatment of Airway Diseases in Children: Little Evidence for Few Indications.

Pediatr Pulmonol. 2020 Jun 12;:

Authors: Di Cicco M, Peroni D, Sepich M, Tozzi MG, Comberiati P, Cutrera R

Abstract
BACKGROUND: Hyaluronic acid (HA) is major physiological component of the extracellular matrix, which, in its high molecular weight form (HMW-HA) has anti-inflammatory properties. The diffusion of many different medical devices for inhalation therapy containing HA has led to an increase in their prescription, also in children. Here we systematically review the published evidence on the efficacy and safety of HA for the treatment of upper and lower airway diseases in childhood.
METHODS: Relevant published studies (randomized controlled trials) for the efficacy of hyaluronic acid inhalation in children with upper airways diseases, asthma, cystic fibrosis and non-CF bronchiectasis were searched in Pubmed, Scopus and Web of Knowledge databases by combining the adequate Medical Subject Headings terms and keywords, with no limit for the year of publication.
RESULTS: We identified 7 relevant publications for upper airways diseases, 1 for asthma and 5 for cystic fibrosis, while we found no clinical trial including children with non-CF bronchiectasis. Meta-analysis was not conducted due to the heterogeneity of the included studies.
CONCLUSIONS: The evidence of HA efficacy in the treatment of the upper and lower airways is still limited in children. Available data suggest that inhaled HMW-HA could be useful in the treatment of recurrent upper respiratory infections and chronic or recurrent inflammation of the middle ear and adenoids as well as of the lower airways in cystic fibrosis in association with hypertonic saline solution. Studies on larger populations and on the different formulations and nebulization methods, especially in pediatric age, are urgently needed. This article is protected by copyright. All rights reserved.

PMID: 32530559 [PubMed - as supplied by publisher]

Effect of the COVID-19 pandemic on anxiety among children with cystic fibrosis and their mothers.

Pediatr Pulmonol. 2020 Jun 12;:

Authors: Senkalfa BP, Eyuboglu TS, Aslan AT, Gursoy TR, Soysal AS, Yapar D, İlhan MN

Abstract
BACKGROUND: We aimed to evaluate anxiety among children with cystic fibrosis (CF) and their mothers related to the COVID-19 pandemic.
METHODS: A total of 45 patients with CF and their mothers were enrolled in the study together with 90 age-matched healthy children and their mothers as a control group. The State and Trait Anxiety Inventory (STAI) was administered by teleconference with children aged 13-18 years old and their mothers. The STAI for children was administered with children aged 9-12 years. Results were compared with age-matched healthy children and their mothers. The relationship between anxiety scores of children with CF and their mothers was evaluated by comparing with clinical data of children with CF. At the conclusion of the teleconference, mothers were asked whether their anxiety had changed as a result of the interview.
RESULTS: It was found that healthy children aged 13-18 years had higher state anxiety scores than age-matched children with CF. Mothers of children with CF had higher trait anxiety scores, especially those of children aged 0-12 years, than mothers of healthy children (p<0.05). For mothers of children with CF, state anxiety scores were higher among those whose children had chronic Pseudomonas infection (p<0.05). Most mothers of children with CF stated that their anxiety decreased following the interview.
CONCLUSION: The COVID-19 pandemic may increase anxiety among mothers of children with CF as well those with healthy children. However, COVID-19 had no effect on the anxiety of children with CF. Informing parents of children with CF about COVID-19 by teleconference may decrease anxiety. This article is protected by copyright. All rights reserved.

PMID: 32530552 [PubMed - as supplied by publisher]

Characterization of Burkholderia cepacia Complex Core Genome and the Underlying Recombination and Positive Selection.

Front Genet. 2020;11:506

Authors: Zhou J, Ren H, Hu M, Zhou J, Li B, Kong N, Zhang Q, Jin Y, Liang L, Yue J

Abstract
Recombination and positive selection are two key factors that play a vital role in pathogenic microorganisms' population adaptation and diversification. The Burkholderia cepacia complex (Bcc) represents bacterial species with high similarity, which can cause severe infections among cases suffering from the chronic granulomatous disorder and cystic fibrosis (CF). At present, no genome-wide study has been carried out focusing on investigating the core genome of Bcc associated with the two evolutionary forces. The general characteristics of the core genome of Bcc species remain scarce as well. In this study, we explored the core orthologous genes of 116 Bcc strains using comparative genomic analysis and studied the two adaptive evolutionary forces: recombination and positive selection. We estimated 1005 orthogroups consisting entirely of single copy genes. These single copy orthologous genes in some Cluster of Orthologous Groups (COG) categories showed significant differences in the comparison of several evolutionary properties, and the encoding proteins were relatively simple and compact. Our findings showed that 5.8% of the core orthologous genes strongly supported recombination; in the meantime, 1.1% supported positive selection. We found that genes involved in protein synthesis as well as material transport and metabolism are favored by selection pressure. More importantly, homologous recombination contributed more genetic variation to a large number of genes and largely maintained the genetic cohesion in Bcc. This high level of recombination between Bcc species blurs their taxonomic boundaries, which leads Bcc species to be difficult or impossible to distinguish phenotypically and genotypically.

PMID: 32528528 [PubMed]

Resolvin D1 Reduces Lung Infection and Inflammation Activating Resolution in Cystic Fibrosis.

Front Immunol. 2020;11:581

Authors: Isopi E, Mattoscio D, Codagnone M, Mari VC, Lamolinara A, Patruno S, D'Aurora M, Cianci E, Nespoli A, Franchi S, Gatta V, Dubourdeau M, Moretti P, Di Sabatino M, Iezzi M, Romano M, Recchiuti A

Abstract
Non-resolving lung inflammation and Pseudomonas aeruginosa infections are the underlying cause of morbidity and mortality in cystic fibrosis (CF). The endogenous lipid mediator resolvin (Rv) D1 is a potent regulator of resolution, and its roles, actions, and therapeutic potential in CF are of interest. Here, we investigated actions and efficacy of RvD1 in preclinical models of cystic fibrosis. Cftr knockout mice with chronic P. aeruginosa lung infection were treated with RvD1 to assess differences in lung bacterial load, inflammation, and tissue damage. Cells from volunteers with CF were treated with RvD1 during ex vivo infection with P. aeruginosa, and effects on phagocytosis and inflammatory signaling were determined. In CF mice, RvD1 reduced bacterial burden, neutrophil infiltration, and histological signs of lung pathology, improving clinical scores of diseases. Mechanistically, RvD1 increased macrophage-mediated bacterial and leukocyte clearance in vivo. The clinical significance of these findings is supported by actions in primary leukocytes and epithelial cells from volunteers with CF where RvD1 enhanced P. aeruginosa phagocytosis and reduced genes and proteins associated to NF-κB activation and leukocyte infiltration. Concentration of RvD1 in sputum from patients with CF was also inversely correlated to those of cytokines and chemokines involved in CF lung pathology. These findings demonstrate efficacy of RvD1 in enhancing resolution of lung inflammation and infections and provide proof of concept for its potential as a prototypic novel pro-resolutive therapeutic approach for CF.

PMID: 32528461 [PubMed - in process]

A Core Genome Multilocus Sequence Typing Scheme for Pseudomonas aeruginosa.

Front Microbiol. 2020;11:1049

Authors: de Sales RO, Migliorini LB, Puga R, Kocsis B, Severino P

Abstract
Pseudomonas aeruginosa is a ubiquitous microorganism and an important opportunistic pathogen responsible for a broad spectrum of infections mainly in immunosuppressed and critically ill patients. Molecular investigations traditionally rely on pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). In this work we propose a core genome multilocus sequence typing (cgMLST) scheme for P. aeruginosa, a methodology that combines traditional MLST principles with whole genome sequencing data. All publicly available complete P. aeruginosa genomes, representing the diversity of this species, were used to establish a cgMLST scheme targeting 2,653 genes. The scheme was then tested using genomes available at contig, chromosome and scaffold levels. The proposed cgMLST scheme for P. aeruginosa typed over 99% (2,314/2,325) of the genomes available for this study considering at least 95% of the cgMLST target genes present. The absence of a certain number gene targets at the threshold considered for both the creation and validation steps due to low genome sequence quality is possibly the main reason for this result. The cgMLST scheme was compared with previously published whole genome single nucleotide polymorphism analysis for the characterization of the population structure of the epidemic clone ST235 and results were highly similar. In order to evaluate the typing resolution of the proposed scheme, collections of isolates belonging to two important STs associated with cystic fibrosis, ST146 and ST274, were typed using this scheme, and ST235 isolates associated with an outbreak were evaluated. Besides confirming the relatedness of all the isolates, earlier determined by MLST, the higher resolution of cgMLST denotes that it may be suitable for surveillance programs, overcoming possible shortcomings of classical MLST. The proposed scheme is publicly available at: https://github.com/BioinformaticsHIAEMolecularMicrobiology/cgMLST-Pseudomonas-aeruginosa.

PMID: 32528447 [PubMed]

Fungal lung disease.

Paediatr Respir Rev. 2020 Apr 22;:

Authors: Koltsida G, Zaoutis T

Abstract
Fungal lung disease in the paediatric population occurs with distinct features in the immunocompetent, in immunocompromised patients and in people with cystic fibrosis. Pulmonary mycoses are the least prevalent in immunocompetent children, with the most common diseases being the endemic mycoses and Aspergillomas. Filamentous fungi such as Aspergillus and Scedosporium have been isolated with increased frequency in recent years from the respiratory secretions of individuals with cystic fibrosis. Undoubtedly, fungal respiratory infections are encountered with increased frequency and severity in patients with impaired immune systems, such as patients with malignancies, solid organ or bone marrow transplants and immunodeficiencies [1].

PMID: 32527608 [PubMed - as supplied by publisher]

Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders' consensus view.

J Cyst Fibros. 2020 Jun 08;:

Authors: De Boeck K, Lee T, Amaral M, Drevinek P, Elborn JS, Fajac I, Kerem E, Davies JC

Abstract
CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development. As part of its 'Strategic Plan to speed up Access to new Drugs', the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs.

PMID: 32527602 [PubMed - as supplied by publisher]

Healthcare reassessment in a pandemics time: challenges for CF.

J Cyst Fibros. 2020 Mar;19(2):194-195

Authors: Castellani C

PMID: 32527496 [PubMed - in process]

Appropriate age at solid introduction: is EFSA extending the individualised window on a sounding scientific evidence?

Int J Food Sci Nutr. 2020 Jun 12;:1-3

Authors: Dipasquale V, Agostoni C, Romano C

Abstract
The appropriate age at introduction of complementary foods (CFs) has always been a matter of debate. The Panel on Nutrition, Novel Foods and Food Allergens (NDA) of the European Food Safety Authority (EFSA) recently produced a Scientific Opinion based on a systematic literature search, supporting the existence of an age range for the introduction of CFs, which vary according to the characteristics of the individual. Furthermore, it concluded that the early introduction of CFs is not associated with either adverse or beneficial health effects at any age. The introduction of foods of age-appropriate texture and nutritional properties might be enough for reaching both developmental and nutritional goals. Accordingly, complementary feeding could be implemented as an infant-tailored approach, guided by the acquisition of the neuromotor skills necessary to progress from a liquid to a diversified diet.

PMID: 32527162 [PubMed - as supplied by publisher]

Evaluation of a New Culture Protocol for Enhancing Fungal Detection Rates in Respiratory Samples of Cystic Fibrosis Patients.

J Fungi (Basel). 2020 Jun 09;6(2):

Authors: Engel TGP, Tehupeiory-Kooreman M, Melchers WJG, Reijers MH, Merkus P, Verweij PE

Abstract
Cystic fibrosis (CF) can be complicated by fungal infection of the respiratory tract. Fungal detection rates in CF sputa are highly dependent on the culture protocol and incubation conditions and thus may lead to an underestimation of the true prevalence of fungal colonization. We conducted a prospective study to evaluate the additional value of mucolytic pre-treatment, increased inoculum (100 µL), additional fungal culture media (Sabouraud agar; SAB, Medium B+, Scedosporium selective agar; SceSel+ and Dichloran-Glycerol agar; DG18) and longer incubation time (3 weeks) compared with our current protocol. Using the new protocol, we prospectively analyzed 216 expectorated sputum samples from adult and pediatric CF patients (n = 77) and compared the culture yield to a three year retrospective cohort that used direct 10 µL loop inoculation on SAB with 5 days incubation (867 sputum samples/103 patients). Detection rates for molds increased from 42% to 76% (p < 0.0001). Twenty-six percent of cultures were polymicrobial in the prospective cohort as opposed to 4.7% in the retrospective cohort (p < 0.0001). Colonization rate with A. fumigatus increased from 36% to 57%. SAB and DG18 showed the highest detection rates for all molds (SAB 58.6%; DG18 56.9%) and DG18 had the best performance for molds other than A. fumigatus. The larger sample volume and longer incubation also contributed to the increased recovery of molds. The introduction of a modified fungal culture protocol leads to a major increase in detection rate and the diversity of molds, which influences fungal epidemiology and may have implications for treatment decisions.

PMID: 32526938 [PubMed]

Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19.

Eur Respir J. 2020 06;55(6):

Authors: Khoury M, Cuenca J, Cruz FF, Figueroa FE, Rocco PRM, Weiss DJ

Abstract
The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted urgent need for novel therapies. Cell-based approaches, primarily using mesenchymal stem (stromal) cells (MSCs), have demonstrated safety and possible efficacy in patients with acute respiratory distress syndrome (ARDS), although they are not yet well studied in respiratory virus-induced ARDS. Limited pre-clinical data suggest that systemic MSC administration can significantly reduce respiratory virus (influenza strains H5N1 and H9N2)-induced lung injury; however, there are no available data in models of coronavirus respiratory infection.There is a rapidly increasing number of clinical investigations of cell-based therapy approaches for COVID-19. These utilise a range of different cell sources, doses, dosing strategies and targeted patient populations. To provide a rational strategy to maximise potential therapeutic use, it is critically important to understand the relevant pre-clinical studies and postulated mechanisms of MSC actions in respiratory virus-induced lung injuries. This review presents these, along with consideration of current clinical investigations.

PMID: 32265310 [PubMed - indexed for MEDLINE]

The Association of Antibiotic Duration With Successful Treatment of Community-Acquired Pneumonia in Children.

J Pediatric Infect Dis Soc. 2020 Jun 11;:

Authors: Same RG, Amoah J, Hsu AJ, Hersh AL, Sklansky DJ, Cosgrove SE, Tamma PD

Abstract
BACKGROUND: National guidelines recommend 10 days of antibiotics for children with community-acquired pneumonia (CAP), acknowledging that the outcomes of children hospitalized with CAP who receive shorter durations of therapy have not been evaluated.
METHODS: We conducted a comparative effectiveness study of children aged ≥6 months hospitalized at The Johns Hopkins Hospital who received short-course (5-7 days) vs prolonged-course (8-14 days) antibiotic therapy for uncomplicated CAP between 2012 and 2018 using an inverse probability of treatment weighted propensity score analysis. Inclusion was limited to children with clinical and radiographic criteria consistent with CAP, as adjudicated by 2 infectious diseases physicians. Children with tracheostomies; healthcare-associated, hospital-acquired, or ventilator-associated pneumonia; loculated or moderate to large pleural effusion or pulmonary abscess; intensive care unit stay >48 hours; cystic fibrosis/bronchiectasis; severe immunosuppression; or unusual pathogens were excluded. The primary outcome was treatment failure, a composite of unanticipated emergency department visits, outpatient visits, hospital readmissions, or death (all determined to be likely attributable to bacterial pneumonia) within 30 days after completing antibiotic therapy.
RESULTS: Four hundred and thirty-nine patients met eligibility criteria; 168 (38%) patients received short-course therapy (median, 6 days) and 271 (62%) received prolonged-course therapy (median, 10 days). Four percent of children experienced treatment failure, with no differences observed between patients who received short-course vs prolonged-course antibiotic therapy (odds ratio, 0.48; 95% confidence interval, .18-1.30).
CONCLUSIONS: A short course of antibiotic therapy (approximately 5 days) does not increase the odds of 30-day treatment failure compared with longer courses for hospitalized children with uncomplicated CAP.

PMID: 32525203 [PubMed - as supplied by publisher]

Benchmarking service provision, scope of practice, and skill mix for physiotherapists in adult cystic fibrosis care delivery.

Physiother Theory Pract. 2020 Jun 11;:1-7

Authors: Hall K, Maxwell L, Cobb R, Chambers R, Roll M, Bell SC, Kuys S

Abstract
BACKGROUND: Increasing age, numbers, and complexity of care are potentially impacting physiotherapy service delivery for adults with cystic fibrosis (CF).
PURPOSE: This study aimed to describe physiotherapy service provision, scope of practice, and skill mix in a large tertiary adult CF center, and determine if services were meeting clinical practice recommendations.
METHODS: A prospective cross-sectional study examined inpatient and outpatient physiotherapy care across a three-month period in a tertiary adult CF center. Physiotherapy services were described by number and skill level of physiotherapists, total hours of activity, and number, type, and duration of each physiotherapy activity.
RESULTS: Twenty-two physiotherapists provided care. Respiratory (n = 1058, 38%), and exercise treatments (n = 338, 12%) were the most frequent. Exercise testing (n = 20, 1%), and detailed treatment reviews (n = 79, 3%) occurred infrequently. Time for research was limited. Junior physiotherapists undertook more exercise treatments per day (p < .01), with senior physiotherapists attending outpatient clinics (p < .01).
CONCLUSION: A large number of physiotherapists were involved in the delivery of services. Recommended respiratory and exercise treatments were frequently provided; however, other recommended activities occurred infrequently. The impact of increasing age, numbers of patients, and complexity of care may be contributing to demand exceeding supply for physiotherapy services. Future studies are required to determine innovative approaches to address the gaps in clinical practice recommendations.

PMID: 32524870 [PubMed - as supplied by publisher]

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

J Cyst Fibros. 2020 Jun 07;:

Authors: Mayer-Hamblett N, van Koningsbruggen-Rietschel S, Nichols DP, VanDevanter DR, Davies JC, Lee T, Durmowicz AG, Ratjen F, Konstan MW, Pearson K, Bell SC, Clancy JP, Taylor-Cousar JL, De Boeck K, Donaldson SH, Downey DG, Flume PA, Drevinek P, Goss CH, Fajac I, Magaret AS, Quon BS, Singleton SM, VanDalfsen JM, Retsch-Bogart GZ

Abstract
As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

PMID: 32522463 [PubMed - as supplied by publisher]