J Antimicrob Chemother. 2021 Mar 13:dkab068. doi: 10.1093/jac/dkab068. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary infections associated with Pseudomonas aeruginosa can be life-threatening for patients suffering from chronic lung diseases such as cystic fibrosis. In this scenario, the formation of biofilms embedded in a mucus layer can limit the permeation and the activity of anti-infectives.

OBJECTIVES: Native human pulmonary mucus can be isolated from endotracheal tubes, but this source is limited for large-scale testing. This study, therefore, aimed to evaluate a modified artificial sputum medium (ASMmod) with mucus-like viscoelastic properties as a surrogate for testing anti-infectives against P. aeruginosa biofilms.

METHODS: Bacterial growth in conventional broth cultures was compared with that in ASMmod, and PAO1-GFP biofilms were imaged by confocal microscopy. Transport kinetics of three antibiotics, tobramycin, colistin, and ciprofloxacin, through native mucus and ASMmod were studied, and their activity against PAO1 biofilms grown in different media was assessed by determination of metabolic activity and cfu.

RESULTS: PAO1(-GFP) cultured in human pulmonary mucus or ASMmod showed similarities in bacterial growth and biofilm morphology. A limited permeation of antibiotics through ASMmod was observed, indicating its strong barrier properties, which are comparable to those of native human mucus. Reduced susceptibility of PAO1 biofilms was observed in ASMmod compared with LB medium for tobramycin and colistin, but less for ciprofloxacin.

CONCLUSIONS: These findings underline the importance of mucus as a biological barrier to antibiotics. ASMmod appears to be a valuable surrogate for studying mucus permeation of anti-infectives and their efficacy against PAO1 biofilms.

PMID:33712824 | DOI:10.1093/jac/dkab068

Cell Death Discov. 2021 Mar 12;7(1):45. doi: 10.1038/s41420-021-00430-2.

ABSTRACT

Celiac disease (CD) is a complex immune-mediated chronic disease characterized by a consistent inflammation of the gastrointestinal tract induced by gluten intake in genetically predisposed individuals. Although initiated by the interaction between digestion-derived gliadin, a gluten component, peptides, and the intestinal epithelium, the disorder is highly complex and involving other components of the intestine, such as the immune system. Therefore, conventional model systems, mainly based on two- or three-dimension cell cultures and co-cultures, cannot fully recapitulate such a complex disease. The development of mouse models has facilitated the study of different interacting cell types involved in the disorder, together with the impact of environmental factors. However, such in vivo models are often expensive and time consuming. Here we propose an organ ex vivo culture (gut-ex-vivo system) based on small intestines from gluten-sensitive mice cultivated in a dynamic condition, able to fully recapitulate the biochemical and morphological features of the mouse model exposed to gliadin (4 weeks), in 16 h. Indeed, upon gliadin exposure, we observed: i) a down-regulation of cystic fibrosis transmembrane regulator (CFTR) and an up-regulation of transglutaminase 2 (TG2) at both mRNA and protein levels; ii) increased intestinal permeability associated with deregulated tight junction protein expression; iii) induction and production of pro-inflammatory cytokines such as interleukin (IL)-15, IL-17 and interferon gamma (IFNγ); and iv) consistent alteration of intestinal epithelium/villi morphology. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of CD, test new or repurposed molecules to accelerate the search for new treatments, and to study the impact of the microbiome and derived metabolites, in a time- and cost- effective manner.

PMID:33712560 | DOI:10.1038/s41420-021-00430-2

Thorax. 2021 Mar 12:thoraxjnl-2020-216370. doi: 10.1136/thoraxjnl-2020-216370. Online ahead of print.

ABSTRACT

To explore the role of extracellular vesicles (EVs) in chronic lung diseases.EVs are emerging as mediators of intercellular communication and possible diagnostic markers of disease. EVs harbour cargo molecules including RNA, lipids and proteins that they transfer to recipient cells. EVs are intercellular communicators within the lung microenvironment. Due to their disease-specific cargoes, EVs have the promise to be all-in-one complex multimodal biomarkers. EVs also have potential as drug carriers in chronic lung disease.Descriptive discussion of key studies of EVs as contributors to disease pathology, as biomarkers and as potential therapies with a focus on chronic obstructive pulmonary disorder (COPD), cystic fibrosis (CF), asthma, idiopathic pulmonary fibrosis and lung cancer.We provide a broad overview of the roles of EV in chronic respiratory disease. Recent advances in profiling EVs have shown their potential as biomarker candidates. Further studies have provided insight into their disease pathology, particularly in inflammatory processes across a spectrum of lung diseases. EVs are on the horizon as new modes of drug delivery and as therapies themselves in cell-based therapeutics.EVs are relatively untapped sources of information in the clinic that can help further detail the full translational nature of chronic lung disorders.

PMID:33712504 | DOI:10.1136/thoraxjnl-2020-216370

BMC Health Serv Res. 2021 Mar 12;21(1):222. doi: 10.1186/s12913-021-06208-7.

ABSTRACT

BACKGROUND: Innovative orphan drugs often have an incremental cost-effectiveness ratio (ICER) which is higher than the maximum threshold for reimbursement. Payers have limited budgets and often cannot pay the full price of a new product, but pharmaceutical and biotechnology companies require a minimum price to satisfy their investors. The objective of this study was to present a possible solution to bridge this pricing gap by having early phase price agreements, which reduce the risk for investors.

METHODS: We used a Pricing Model, which determines the minimum (break-even) price of an innovative drug from an investor's perspective. This model is based on economic valuation theory, which uses the expected free cash flows and the required cost of capital. We selected two orphan drugs with a positive clinical assessment and an ICER higsher than the Dutch maximum threshold of €80,000 per QALY gained to use as examples in the model: Spinraza for spinal muscular atrophy and Orkambi for cystic fibrosis.

RESULTS: The results show that early pricing agreements before phase III trials can substantially lower the drug price resulting from a lower cost of capital. The minimum price for orphan drugs can be reduced by 27.4%, when cost of capital decreases from 12 to 9%. An additional adjustment of other critical parameters due to early pricing agreements (lower probabilities of phase III failure and lower research and development (R&D) costs) can further reduce the minimal price by 62.8%.

CONCLUSION: This study shows that earlier timing of price negotiations resulting in an agreement on drug price can substantially lower the minimal price of orphan drugs for the investor.

PMID:33711994 | DOI:10.1186/s12913-021-06208-7

Cell Physiol Biochem. 2021 Mar 13;55(S1):106-118. doi: 10.33594/000000341.

ABSTRACT

More than three decades after their first biophysical description, Volume Regulated Anion Channels (VRACs) still remain challenging to understand. Initially, VRACs were identified as the main pathway for the cell to extrude Cl- ions during the regulatory volume decrease (RVD) mechanism contributing in fine to the recovery of normal cell volume. For years, scientists have tried unsuccessfully to find their molecular identity, leading to controversy within the field that only ended in 2014 when two independent groups demonstrated that VRACs were formed by heteromers of LRRC8 proteins. This breakthrough gave a second breath to the research field and was followed by many publications regarding LRRC8/VRACs structure/ function, physiological roles and 3D structures. Nevertheless, far from simplifying the field, these discoveries have instead exponentially increased its complexity. Indeed, the channel's biophysical properties seem to be dependent on the LRRC8 subunits composition with each heteromer showing different ion/molecule permeabilities and regulatory mechanisms. One clear example of this complexity is the intricate relationship between LRRC8/VRACs and the redox system. On one hand, VRACs appear to be directly regulated by oxidation or reduction depending on their subunit composition. On the other hand, VRACs can also impact the redox balance within the cells, through their permeability to reduced glutathione or through other as yet uncharacterized pathways. Unravelling this issue is particularly crucial as LRRC8/VRACs play an important role in a wide variety of physiological processes involving oxidative stress signaling. In this regard, we have tried to systematically identify in the literature both preand post-LRRC8 discovery as well as the interplay between VRACs and the redox system to provide new insights into this complex relationship.

PMID:33711227 | DOI:10.33594/000000341

Ann Surg Oncol. 2021 Mar 12. doi: 10.1245/s10434-021-09752-y. Online ahead of print.

ABSTRACT

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride (Cl-) anion conducting channel, and its role in esophageal squamous cell carcinoma (ESCC) was examined in the present study.

METHODS: Overexpression experiments were conducted on human ESCC cell lines following the transfection of a CFTR plasmid, and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. A microarray analysis was performed to examine gene expression profiles. Fifty-three primary tumor samples collected from ESCC patients during esophagectomy were subjected to an immunohistochemical analysis.

RESULTS: Transfection of the CFTR plasmid into the ESCC KYSE 170 and KYSE 70 cell lines suppressed cell proliferation, migration, and invasion and induced apoptosis. The microarray analysis showed the up-regulated expression of genes involved in the p38 signaling pathway in CFTR plasmid-transfected KYSE 170 cells. Immunohistochemical staining revealed a relationship between the CFTR expression pattern at the invasive front and the pN category. A relationship was also observed between the weak expression of CFTR at the invasive front and a shorter postoperative survival in a prognostic analysis.

CONCLUSIONS: The overexpression of CFTR in ESCC activated the p38 signaling pathway and was associated with a good patient prognosis. These results indicate the potential of CFTR as a mediator of and/or a biomarker for ESCC.

PMID:33710504 | DOI:10.1245/s10434-021-09752-y

J Food Biochem. 2021 Mar 12:e13684. doi: 10.1111/jfbc.13684. Online ahead of print.

ABSTRACT

Respiratory diseases are the prime cause of death and disability worldwide. The majority of lung-based diseases are resistant to treatment. Hence, research on unique drugs/compounds with a more efficient and minimum side effect for treating lung diseases is urgent. Punica granatum L (pomegranate) fruit has been used in the prevention and treatment of various respiratory disorders in recent times. In vivo and in vitro studies have demonstrated that pomegranate fruit, as well as its juice, extract, peel powder, and oil, exert anti-proliferative, anti-oxidant, anti-microbial, anti-inflammatory, anti-cancer, and anti-tumorigenic properties by attenuating various respiratory conditions such as asthma, lung fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), and alveolar inflammation via modulating various signaling pathways. The current review summarizes the potential properties and medical benefits of pomegranate against different lung-based diseases, also highlighting its possible role in the lung fibrinolytic system. The available data suggest that pomegranate is effective in controlling the disease progressions and could be a potential therapeutic target benefiting human health status. Furthermore, this review also outlines the preclinical and clinical studies highlighting the role of pomegranate in lung diseases further evoking future studies to investigate the effect of intake of this anti-oxidant fruit in larger and well-defined human clinical trials. PRACTICAL APPLICATIONS: This review outlines the putative pharmacologic benefits of P. granatum L (pomegranate) in treating various chronic lung-based diseases such as lung cancer, COPD, ARDS, asthma, lung fibrosis, and cystic fibrosis. This review also highlights the possible inhibitory role of P. granatum L (pomegranate) in the lung fibrinolytic system triggering the fibrinolytic markers. This review summarizes the preclinical and clinical studies using in vitro, in vivo, and human models highlighting the potential role of P. granatum L (pomegranate) in lung diseases. This review evokes future research to investigate the effect of intake of pomegranate fruit in well-defined human clinical trials.

PMID:33709449 | DOI:10.1111/jfbc.13684

Mycopathologia. 2021 Mar 11. doi: 10.1007/s11046-021-00539-z. Online ahead of print.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) and bronchiectasis represent chronic airway diseases associated with significant morbidity and mortality. Bacteria and viruses are commonly implicated in acute exacerbations; however the significance of fungi in these airways remains poorly defined. While COPD and bronchiectasis remain recognized risk factors for the occurrence of Aspergillus-associated disease including chronic and invasive aspergillosis, underlying mechanisms that lead to the progression from colonization to invasive disease remain uncertain. Nonetheless, advances in molecular technologies have improved our detection, identification and understanding of resident fungi characterizing these airways. Mycobiome sequencing has revealed the complex varied and myriad profile of airway fungi in COPD and bronchiectasis, including their association with disease presentation, progression, and mortality. In this review, we outline the emerging evidence for the clinical importance of fungi in COPD and bronchiectasis, available diagnostic modalities, mycobiome sequencing approaches and association with clinical outcomes.

PMID:33709335 | DOI:10.1007/s11046-021-00539-z

Eur J Clin Microbiol Infect Dis. 2021 Mar 12. doi: 10.1007/s10096-021-04218-1. Online ahead of print.

ABSTRACT

Management of cystic fibrosis (CF) patients colonized with Pseudomonas aeruginosa is challenging due to its virulence and multi-drug resistance. Ceftolozane/tazobactam (C/T) is a promising new antipseudomonal agent, and clinical data on CF are limited. We describe our experience in the use of C/T for P. aeruginosa-related pulmonary exacerbations (PE) in CF adults admitted within 2016 and 2019 at Careggi Hospital, Florence, Italy. PE was diagnosed as deterioration of respiratory function, worsening cough, and increasing of sputum. C/T was given at the dose of 3 g every 8 h. C/T was used in ten patients. Mean length of C/T treatment was 16.3 days, and tobramycin was the most frequently combined antipseudomonal agent. All patients were successfully treated although susceptibility testing on sputum sample showed C/T resistance in two cases. No adverse effects related to C/T were reported. To our knowledge this is the largest case series on CF patients treated with C/T. Clinical responses were encouraging even where C/T resistant P. aeruginosa was isolated, probably due to multiple phenotypes colonizing CF lungs. C/T could play a promising role in combination therapy against P. aeruginosa as a part of a colistin-sparing regime.

PMID:33709301 | DOI:10.1007/s10096-021-04218-1

J Orthop Case Rep. 2020 Nov;10(8):19-22. doi: 10.13107/jocr.2020.v10.i08.1840.

ABSTRACT

INTRODUCTION: Simultaneous bilateral neck of femur fracture is rare. Majority of them are due to low energy incidents with underlying conditions such as malnutrition, chronic renal failure, cystic fibrosis, celiac disease, seizures, steroid abuse, or osteomalacia.

CASE REPORT: A 68-year-old woman was referred with a 1-year history of bilateral hip pain and a 9-month history of inability to bear weight. She was diagnosed as a displaced bilateral femoral neck fracture secondary to osteomalacia. Due to the long duration of this condition and associated comorbidities, staged bilateral hip hemiarthroplasty was done. A good function was noted after surgery to 4-month follow-up.

CONCLUSION: Osteomalacia should be suspected in any patient with long-standing bone pain and muscle weakness regardless of age. Numerous options in the form of percutaneous screws, bipolar hemiarthroplasty, and total hip arthroplasty have been mentioned in the literature regarding the management of simultaneous bilateral femoral neck fractures. Staged bipolar hemiarthroplasty was done due to the associated comorbidities.

PMID:33708703 | PMC:PMC7933646 | DOI:10.13107/jocr.2020.v10.i08.1840

Front Immunol. 2021 Feb 23;12:599133. doi: 10.3389/fimmu.2021.599133. eCollection 2021.

ABSTRACT

Sixteen monozygotic cystic fibrosis (CF) twin pairs of whom 14 pairs were homozygous for the most common p.Phe508del CFTR mutation were selected from the European Cystic Fibrosis Twin and Sibling Study Cohort. The monozygotic twins were examined in their T cell receptor (TCR) repertoire in peripheral blood by amplicon sequencing of the CDR3 variable region of the ß-chain. The recruitment of TCR J and V genes for recombination and selection in the thymus showed a strong genetic influence in the CF twin cohort as indicated by the shortest Jensen-Shannon distance to the twin individual. Exceptions were the clinically most discordant and/or most severely affected twin pairs where clonal expansion probably caused by recurrent pulmonary infections overshadowed the impact of the identical genomic blueprint. In general the Simpson clonality was low indicating that the population of TCRß clonotypes of the CF twins was dominated by the naïve T-cell repertoire. Intrapair sharing of clonotypes was significantly more frequent among monozygotic CF twins than among pairs of unrelated CF patients. Complete nucleotide sequence identity was observed in about 0.11% of CDR3 sequences which partially should represent persisting fetal clones derived from the same progenitor T cells. Complete amino acid sequence identity was noted in 0.59% of clonotypes. Of the nearly 40,000 frequent amino acid clonotypes shared by at least two twin siblings 99.8% were already known within the immuneACCESS database and only 73 had yet not been detected indicating that the CDR3ß repertoire of CF children and adolescents does not carry a disease-specific signature but rather shares public clones with that of the non-CF community. Clonotypes shared within twin pairs and between unrelated CF siblings were highly abundant among healthy non-CF people, less represented in individuals with infectious disease and uncommon in patients with cancer. This subset of shared CF clonotypes defines CDR3 amino acid sequences that are more common in health than in disease.

PMID:33708199 | PMC:PMC7940196 | DOI:10.3389/fimmu.2021.599133

Sci Rep. 2021 Mar 11;11(1):5624. doi: 10.1038/s41598-021-85222-5.

ABSTRACT

Burkholderia cenocepacia is known for its capacity of adherence and interaction with the host, causing severe opportunistic lung infections in cystic fibrosis patients. In this work we produced Giant Plasma Membrane Vesicles (GPMVs) from a bronchial epithelial cell line and validated their use as a cell-like alternative to investigate the steps involved in the adhesion process of B. cenocepacia. RNA-sequencing was performed and the analysis of the B. cenocepacia K56-2 transcriptome after the first contacts with the surface of host cells allowed the recognition of genes implicated in bacterial adaptation and virulence-associated functions. The sensing of host membranes led to a transcriptional shift that caused a cascade of metabolic and physiological adaptations to the host specific environment. Many of the differentially expressed genes encode proteins related with central metabolic pathways, transport systems, cellular processes, and virulence traits. The understanding of the changes in gene expression that occur in the early steps of infection can uncover new proteins implicated in B. cenocepacia-host cell adhesion, against which new blocking agents could be designed to control the progression of the infectious process.

PMID:33707642 | DOI:10.1038/s41598-021-85222-5

Sci Rep. 2021 Mar 11;11(1):5729. doi: 10.1038/s41598-021-85100-0.

ABSTRACT

Pseudomonas aeruginosa uses quorum sensing (QS) to modulate the expression of several virulence factors that enable it to establish severe infections. The QS system in P. aeruginosa is complex, intricate and is dominated by two main N-acyl-homoserine lactone circuits, LasRI and RhlRI. These two QS systems work in a hierarchical fashion with LasRI at the top, directly regulating RhlRI. Together these QS circuits regulate several virulence associated genes, metabolites, and enzymes in P. aeruginosa. Paradoxically, LasR mutants are frequently isolated from chronic P. aeruginosa infections, typically among cystic fibrosis (CF) patients. This suggests P. aeruginosa can undergo significant evolutionary pathoadaptation to persist in long term chronic infections. In contrast, mutations in the RhlRI system are less common. Here, we have isolated a clinical strain of P. aeruginosa from a CF patient that has deleted the transcriptional regulator RhlR entirely. Whole genome sequencing shows the rhlR locus is deleted in PA80 alongside a few non-synonymous mutations in virulence factors including protease lasA and rhamnolipid rhlA, rhlB, rhlC. Importantly we did not observe any mutations in the LasRI QS system. PA80 does not appear to have an accumulation of mutations typically associated with several hallmark pathoadaptive genes (i.e., mexT, mucA, algR, rpoN, exsS, ampR). Whole genome comparisons show that P. aeruginosa strain PA80 is closely related to the hypervirulent Liverpool epidemic strain (LES) LESB58. PA80 also contains several genomic islands (GI's) encoding virulence and/or resistance determinants homologous to LESB58. To further understand the effect of these mutations in PA80 QS regulatory and virulence associated genes, we compared transcriptional expression of genes and phenotypic effects with isogenic mutants in the genetic reference strain PAO1. In PAO1, we show that deletion of rhlR has a much more significant impact on the expression of a wide range of virulence associated factors rather than deletion of lasR. In PA80, no QS regulatory genes were expressed, which we attribute to the inactivation of the RhlRI QS system by deletion of rhlR and mutation of rhlI. This study demonstrates that inactivation of the LasRI system does not impact RhlRI regulated virulence factors. PA80 has bypassed the common pathoadaptive mutations observed in LasR by targeting the RhlRI system. This suggests that RhlRI is a significant target for the long-term persistence of P. aeruginosa in chronic CF patients. This raises important questions in targeting QS systems for therapeutic interventions.

PMID:33707533 | DOI:10.1038/s41598-021-85100-0

Biophys J. 2021 Mar 8:S0006-3495(21)00204-6. doi: 10.1016/j.bpj.2021.01.041. Online ahead of print.

ABSTRACT

Impaired mucociliary clearance (MCC) is a key feature of many airway diseases, including asthma, bronchiectasis, chronic obstructive pulmonary disease, cystic fibrosis, and primary ciliary dyskinesia. To improve MCC and develop new treatments for these diseases requires a thorough understanding of how mucus concentration, mucus composition, and ciliary activity affect MCC, and how different therapeutics impact this process. Although differentiated cultures of human airway epithelial (HAE) cells are useful for investigations of MCC, the extent of ciliary coordination in these cultures varies, and the mechanisms controlling ciliary orientation are not completely understood. By introducing a pattern of ridges/grooves into the underlying collagen substrate, we demonstrate for the first time that changes in the extracellular matrix can induce ciliary alignment. Remarkably, 90% of HAE cultures achieved continuous directional mucociliary transport (MCT) when grown on the patterned substrate. These cultures maintain transport for months, allowing carefully controlled investigations of MCC over a wide range of normal and pathological conditions. To characterize the system, we measured the transport of bovine submaxillary gland mucin (BSM) under several conditions. Transport of 5% BSM was significantly reduced compared to that of 2% BSM, and treatment of 5% BSM with the reducing agent tris(2-carboxyethyl)phosphine (TCEP) reduced viscosity and increased the rate of MCT by ∼2-fold. Addition of a small amount of high molecular weight DNA increased mucus viscosity and reduced MCT by ∼75%, demonstrating that the composition of mucus, as well as the concentration, can have significant effects on MCT. Our results demonstrate that a simple patterning of the collagen substrate results in highly coordinated ciliated cultures that develop directional MCT, and can be used to investigate the mechanisms controlling the regulation of ciliary orientation. Further, the results demonstrate that this method provides an improved system for studying the effects of mucus composition and therapeutic agents on MCC.

PMID:33705757 | DOI:10.1016/j.bpj.2021.01.041

Am J Respir Cell Mol Biol. 2021 Mar 11. doi: 10.1165/rcmb.2021-0060ED. Online ahead of print.

NO ABSTRACT

PMID:33705685 | DOI:10.1165/rcmb.2021-0060ED

Pediatr Pulmonol. 2021 Mar 11. doi: 10.1002/ppul.25371. Online ahead of print.

ABSTRACT

BACKGROUND: Normal values (>80%) of Forced Expiratory Volume in one second (FEV1 ) in patients with Cystic fibrosis (CF) may lead to the interpretation that there is no lung disease. This study is a comprehensive analysis of lung involvement in CF patients having normal FEV1 .

METHODS: Patients were recruited from two CF Centers: Hadassah Medical Center, Jerusalem and Vall d' Hebron Hospital, Barcelona. Lung disease was assessed by lung clearance index (LCI), chest CT-Brody Score, respiratory cultures, number of pulmonary exacerbations (PEx) and days of antibiotic treatment in the year prior to the assessment.

RESULTS: Of the 247 patients, 89 (36%) had FEV1 ≥80% and were included in the study (mean age 17.6 range 4.25-49 years). Chronic P. aeruginosa infection was found in 21%, and 31% had at least one major PEx in the year prior to the study. Abnormally elevated LCI was found in 86% of patients, ranging between 7.52-18.97, and total Brody score (TBS) was abnormal in 92% (range 5.0-96.5). Patients with chronic P. aeruginosa had significantly higher LCI (p=0.01) and TBS (p=0.02) which were associated with more major PEx (p<0.01 and p=0.01, respectively) and more days of intravenous (IV) antibiotic treatment in the preceding year (p=0.03 and p=0.001, respectively).

CONCLUSIONS: Most CF patients with normal FEV1 have already physiological and structural lung abnormalities which were associated with more PEx and IV antibiotic treatment. Further studies are needed in order to determine if better adherence to the currently used therapies and the new CFTR modulators will prevent the progression of lung disease. This article is protected by copyright. All rights reserved.

PMID:33704929 | DOI:10.1002/ppul.25371

Diabetologia. 2021 Mar 11. doi: 10.1007/s00125-021-05423-5. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis (CF) and its presence is associated with adverse effects on nutritional status and pulmonary function. Early diagnosis could minimise CFRD morbidity, yet current methods of an OGTT at 0 and 2 h yield unreliable results. Our aim was to determine which indices from a 2 h OGTT with sampling every 30 min might improve prediction of CFRD.

METHODS: Cross-sectional analysis at baseline (n = 293) and observational prospective analysis (n = 185; mean follow-up of 7.5 ± 4.2 years) of the Montreal Cystic Fibrosis Cohort were performed. Blood glucose and insulinaemia OGTT variables were studied in relation to lung function (forced expiratory volume in 1 s [FEV1]), BMI and risk of developing CFRD.

RESULTS: At baseline, maximum OGTT glucose (Gmax) was negatively associated with FEV1 (p = 0.003). Other OGTT values, including classical 2 h glucose, were not. A higher Gmax was associated with lower insulin secretory capacity, delayed insulin peak timing and greater pancreatic insufficiency (p < 0.01). Gmax was positively associated with the risk of developing CFRD (p = 0.0029); no individual with a Gmax < 8 mmol/l developed CFRD over the following decade. No OGTT variable correlated to the rate of change in BMI or FEV1.

CONCLUSIONS/INTERPRETATION: In adults with CF, Gmax is strongly associated with the risk of developing CFRD; Gmax < 8 mmol/l could identify those at very low risk of future CFRD. Gmax is higher in individuals with pancreatic insufficiency and is associated with poorer insulin secretory capacity and pulmonary function.

PMID:33693987 | DOI:10.1007/s00125-021-05423-5

Med Mycol. 2021 Mar 10:myab010. doi: 10.1093/mmy/myab010. Online ahead of print.

ABSTRACT

We conducted a pilot study of patients with cystic fibrosis (CF) to assess intra-family transmission of P. jirovecii and compare it with data on other prevalent pathogens such as P. aeruginosa and S. pneumoniae, in which respiratory transmission has already been documented. Oral swab samples from 10 patients with CF and 15 household members were collected at baseline and 2 weeks later. P. aeruginosa and S. pneumoniae were assessed using standardized culture methods and PCR, and P. jirovecii was assessed using real and nested PCR, genotyping the positive samples by direct sequencing. P. aeruginosa cultures were positive for 7/10 (70%) of patients with CF at baseline and was identified by PCR in 8/10 (80%) of cases at baseline and 2 weeks later. S. pneumoniae cultures were negative for all patients, but the microorganism was identified by PCR in two cases. P. jirovecii was detected by real time and nested PCR in 5/10 (50%) of the patients at the two time points. In the household members, P. aeruginosa and P. jirovecii were identified in 7/15 (46.7%), and S. pneumoniae was identified in 8/15 (53,3%). The concordance of positive or negative pairs of patients with CF and their household members was 33.3% (5/15) for P. aeruginosa, 46.7% (7/15) for S. pneumonia and 93.3% (14/15) for P. jirovecii. The concordance for P. jirovecii genotypes among five pairs with available genotype was 100%. This study suggests for the first time the possible transmission of Pneumocystis in the home of patients with CF, indicating that patients and their household members are reservoirs and possible sources of infection.

LAY SUMMARY: This study suggests for the first time the possible transmission of Pneumocystis in the family environment of patients with cystic fibrosis, indicating that patients and their household members are reservoirs and possible sources of this infection.

PMID:33693837 | DOI:10.1093/mmy/myab010

Clin Infect Dis. 2021 Mar 6:ciab208. doi: 10.1093/cid/ciab208. Online ahead of print.

ABSTRACT

BACKGROUND: While Pseudomonas aeruginosa (Pa) eradication regimens have contributed to a decline in Pa prevalence in people with cystic fibrosis (CF), this antibiotic exposure might increase the risk of acquisition of drug-resistant organisms. This study evaluated the association between antipseudomonal antibiotic exposure intensity and acquisition risk of drug-resistant organisms among children with CF and new Pa infection.

METHODS: We utilized data from the Early Pseudomonas Infection Control Clinical Trial (EPIC CT), a randomized controlled trial comparing Pa eradication strategies in children with CF and new Pa. The exposure was the number of weeks of oral or inhaled antipseudomonal antibiotics, or ever vs. never treatment with intravenous antipseudomonal antibiotics, during the 18 months of EPIC CT participation. The primary outcomes were risks of acquisition of several respiratory organisms during five years of follow up after EPIC CT estimated using Cox proportional hazards models separately for each specific organism.

RESULTS: Among 249 participants, there was no increased acquisition risk of any organism associated with greater inhaled antibiotic exposure. With each additional week of oral antibiotics, there was an increased hazard of Achromobacter xylosoxidans acquisition (HR=1.24, 95% CI: 1.02-1.50; p=0.03). Treatment with intravenous antibiotics was associated with an increased hazard of acquisition of multidrug-resistant Pa (HR=2.47; 95% CI 1.28-4.78; p=0.01) and MRSA (HR=1.57; 95% CI 1.03-2.40); p=0.04).

CONCLUSIONS: Results from this study illustrate the importance of making careful antibiotic choices to balance the benefits of antibiotics in people with CF while minimizing the risk of acquisition of drug-resistant organisms.

PMID:33693586 | DOI:10.1093/cid/ciab208

ERJ Open Res. 2020 Nov 10;6(4):00190-2019. doi: 10.1183/23120541.00190-2019. eCollection 2020 Oct.

ABSTRACT

The inter-relationship between chronic respiratory disease and reflux disease in the airway reflux paradigm is extremely complex and remains poorly characterised. Reflux disease is reported to cause or contribute to the severity of a number of respiratory tract diseases including laryngeal disorders, sinusitis, chronic cough, asthma, COPD, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis and bronchiolitis obliterans post lung transplant. It is now appreciated that reflux disease is not simply caused by liquid acid reflux but rather by a variety of chemical refluxates originating from the stomach and duodenum due to a number of different mechanisms. Reflux disease can be challenging to diagnose, particularly proving its role in the causation of direct respiratory epithelial damage. Significant advances in oesophageal assessment and gastric biomarkers have emerged in recent years as our understanding increases. There are a number of treatments available for reflux disease, both medical and surgical, but there is a paucity of large randomised trials to evaluate their efficacy in the setting of chronic respiratory disease. Everyday clinical practice, however, informs us that treatment failure in reflux disease is common. This clinical review summarises associations between reflux disease in the setting of chronic respiratory diseases and examines available evidence regarding potential therapeutic strategies.

PMID:33693049 | PMC:PMC7927787 | DOI:10.1183/23120541.00190-2019