Transcriptional consequences of impaired immune cell responses induced by cystic fibrosis plasma characterized via dual RNA sequencing.

BMC Med Genomics. 2019 May 22;12(1):66

Authors: Ideozu JE, Rangaraj V, Abdala-Valencia H, Zhang X, Kandpal M, Sala MA, Davuluri RV, Levy H

Abstract
BACKGROUND: In cystic fibrosis (CF), impaired immune cell responses, driven by the dysfunctional CF transmembrane conductance regulator (CFTR) gene, may determine the disease severity but clinical heterogeneity remains a major therapeutic challenge. The characterization of molecular mechanisms underlying impaired immune responses in CF may reveal novel targets with therapeutic potential. Therefore, we utilized simultaneous RNA sequencing targeted at identifying differentially expressed genes, transcripts, and miRNAs that characterize impaired immune responses triggered by CF and its phenotypes.
METHODS: Peripheral blood mononuclear cells (PBMCs) extracted from a healthy donor were stimulated with plasma from CF patients (n = 9) and healthy controls (n = 3). The PBMCs were cultured (1 × 105 cells/well) for 9 h at 37 ° C in 5% CO2. After culture, total RNA was extracted from each sample and used for simultaneous total RNA and miRNA sequencing.
RESULTS: Analysis of expression signatures from peripheral blood mononuclear cells induced by plasma of CF patients and healthy controls identified 151 genes, 154 individual transcripts, and 41 miRNAs differentially expressed in CF compared to HC while the expression signatures of 285 genes, 241 individual transcripts, and seven miRNAs differed due to CF phenotypes. Top immune pathways influenced by CF included agranulocyte adhesion, diapedesis signaling, and IL17 signaling, while those influenced by CF phenotypes included natural killer cell signaling and PI3K signaling in B lymphocytes. Upstream regulator analysis indicated dysregulation of CCL5, NF-κB and IL1A due to CF while dysregulation of TREM1 and TP53 regulators were associated with CF phenotype. Five miRNAs showed inverse expression patterns with three target genes relevant in CF-associated impaired immune pathways while two miRNAs showed inverse expression patterns with two target genes relevant to a dysregulated immune pathway associated with CF phenotypes.
CONCLUSIONS: Our results indicate that miRNAs and individual transcript variants are relevant molecular targets contributing to impaired immune cell responses in CF.

PMID: 31118097 [PubMed - in process]

Next-generation sequencing for identifying a novel/de novo pathogenic variant in a Mexican patient with cystic fibrosis: a case report.

BMC Med Genomics. 2019 May 22;12(1):68

Authors: Martínez-Hernández A, Larrosa J, Barajas-Olmos F, García-Ortíz H, Mendoza-Caamal EC, Contreras-Cubas C, Mirzaeicheshmeh E, Lezana JL, Orozco L

Abstract
BACKGROUND: Mexico is among the countries showing the highest heterogeneity of CFTR variants. However, no de novo variants have previously been reported in Mexican patients with cystic fibrosis (CF).
CASE PRESENTATION: Here, we report the first case of a novel/de novo variant in a Mexican patient with CF. Our patient was an 8-year-old male who had exhibited the clinical onset of CF at one month of age, with steatorrhea, malabsorption, poor weight gain, anemia, and recurrent respiratory tract infections. Complete sequencing of the CFTR gene by next generation sequencing (NGS) revealed two different variants in trans, including the previously reported CF-causing variant c.3266G > A (p.Trp1089*, W1089*), that was inherited from the mother, and the novel/de novo CFTR variant c.1762G > T (p.Glu588*).
CONCLUSION: Our results demonstrate the efficiency of targeted NGS for making a rapid and precise diagnosis in patients with clinically suspected CF. This method can enable the provision of accurate genetic counselling, and improve our understanding of the molecular basis of genetic diseases.

PMID: 31118044 [PubMed - in process]

Salivary thiocyanate as a biomarker of Cystic Fibrosis Transmembrane Regulator function.

Anal Chem. 2019 May 22;:

Authors: Malkovskiy AV, Yacob AA, Dunn CE, Zirbes JM, Ryan SP, Bollyky PL, Rajadas J, Milla CE

Abstract
Improved methods are needed to reliably assess CFTR function in vivo in light of recent therapeutic developments targeting the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Saliva from patients with cystic fibrosis (CF) and healthy controls (HC) was studied using colorimetry and non-resonant Raman spectroscopy. Colorimetry experiments showed only a 36% decrease in thiocyanate (SCN-) concentration, but a sharp Raman peak at 2068 cm-1, attributable to (SCN-) vibrations, normalized to C-H peak, was on average 18 times higher for HC samples. Samples from patients under-going treatment with CFTR modulators including ivacaftor, lumacaftor and tezacaftor, showed a high normalized peak in response to therapy. The peak intensity was consistent in longitudinal samples from single donors and in stored samples. The Raman peak ratio is a more sensitive, convenient, non-invasive biomarker for assessments of the therapeutic efficacy of drugs targeting CFTR and provides a value that is in much better agreement with theoretical expectations of saliva SCN- concentrations, compared to colorimetry. Moreover, samples from patients can be collected remotely, as they are stable and can be shipped in dry state. This insight may greatly facilitate assessments of CFTR modulator efficacy in individual pa-tients as well as development of new ones.

PMID: 31117414 [PubMed - as supplied by publisher]

Lsr2 Is an Important Determinant of Intracellular Growth and Virulence in Mycobacterium abscessus.

Front Microbiol. 2019;10:905

Authors: Le Moigne V, Bernut A, Cortès M, Viljoen A, Dupont C, Pawlik A, Gaillard JL, Misguich F, Crémazy F, Kremer L, Herrmann JL

Abstract
Mycobacterium abscessus, a pathogen responsible for severe lung infections in cystic fibrosis patients, exhibits either smooth (S) or rough (R) morphotypes. The S-to-R transition correlates with inhibition of the synthesis and/or transport of glycopeptidolipids (GPLs) and is associated with an increase of pathogenicity in animal and human hosts. Lsr2 is a small nucleoid-associated protein highly conserved in mycobacteria, including M. abscessus, and is a functional homolog of the heat-stable nucleoid-structuring protein (H-NS). It is essential in Mycobacterium tuberculosis but not in the non-pathogenic model organism Mycobacterium smegmatis. It acts as a master transcriptional regulator of multiple genes involved in virulence and immunogenicity through binding to AT-rich genomic regions. Previous transcriptomic studies, confirmed here by quantitative PCR, showed increased expression of lsr2 (MAB_0545) in R morphotypes when compared to their S counterparts, suggesting a possible role of this protein in the virulence of the R form. This was addressed by generating lsr2 knock-out mutants in both S (Δlsr2-S) and R (Δlsr2-R) variants, demonstrating that this gene is dispensable for M. abscessus growth. We show that the wild-type S variant, Δlsr2-S and Δlsr2-R strains were more sensitive to H2O2 as compared to the wild-type R variant of M. abscessus. Importantly, virulence of the Lsr2 mutants was considerably diminished in cellular models (macrophage and amoeba) as well as in infected animals (mouse and zebrafish). Collectively, these results emphasize the importance of Lsr2 in M. abscessus virulence.

PMID: 31114557 [PubMed]

Genotypic characterization of Pseudomonas aeruginosa isolates from Turkish children with cystic fibrosis.

Infect Drug Resist. 2019;12:675-685

Authors: Sener Okur D, Yuruyen C, Gungor O, Aktas Z, Erturan Z, Akcakaya N, Camcioglu Y, Cokugras H, Koksalan K

Abstract
Objective: To identify epidemic and other transmissible Pseudomonas aeruginosa strains, genotypic analyses are required. The aim of this study was to assess the distribution of P. aeruginosa strains within the Turkish pediatric cystic fibrosis (CF) clinic population. Methods: Eighteen patients attending the pediatric CF clinic of Cerrahpasa Medical Faculty were investigated in the study. Throat swab and/or sputum samples were taken from each patient at 3-month intervals. The isolates of patients were analyzed by pulsed-field gel electrophoresis (PFGE). The intra- and interpatient genotypic heterogeneity of isolates was examined to determine the clonal isolates of P. aeruginosa within the cohort. Results: A total of 108 clinical isolates of P. aeruginosa were obtained from 18 patients between May 2013 and May 2014. The pulsotypes of the first patient's isolates could not be obtained by PFGE. From the remaining 17 patients and 101 isolates, 55 distinct pulsotypes were detected. The number of pulsotypes observed in more than one patient (minor clonal strains, cluster strains) was 8 (14.5%), and one of them colonized three patients. However, none of them was detected in more than three patients. These pulsotypes were composed of 20 isolates. In addition, with the PFGE analysis of 81 isolates, we detected 47 (85.6%) pulsotypes, which belonged to only one patient. Over different periods of this study, only 2 (11.8%) patients were colonized with the same pulsotype. Conclusion: Our study indicates that there was considerable genomic diversity among the P. aeruginosa isolates in our clinic. The presence of shared pulsotypes supports cross-transmission between patients.

PMID: 31114258 [PubMed]

Cyclic compression increases F508 Del CFTR expression in ciliated human airway epithelium.

Am J Physiol Lung Cell Mol Physiol. 2019 May 22;:

Authors: Marozkina N, Bosch J, Cotton CU, Smith L, Seckler JV, Zaman K, Rehman S, Periasamy A, Gaston H, Altawallbeh G, Davis M, Jones DR, Schilz R, Randell SH, Gaston B

Abstract
Mechanisms by which transepithelial pressure changes observed during exercise and airway clearance can benefit lung health are challenging to study. Here, we have studied 117 mature, fully ciliated airway epithelial cell filters grown at air liquid interface grown from 10 cystic fibrosis (CF) and 19 control subjects. These were exposed to cyclic increases in apical air pressure of 15 cm H2O for varying times. We measured the effect on proteins relevant to lung health, with a focus on the CF transmembrane regulator (CFTR). Immunoflourescence and immunoblot data were concordant in demonstrating that air pressure increased F508Del CFTR expression and maturation. This effect was in part dependent on the presence of cilia, on Ca2+ influx and on formation of nitrogen oxides. These data provide a mechanosensory mechanism by which changes in luminal air pressure, like those observed during exercise and airway clearance, can affect epithelial protein expression and benefit patients with diseases of the airways.

PMID: 31116581 [PubMed - as supplied by publisher]

Nanocarriers in effective pulmonary delivery of siRNA: current approaches and challenges.

Ther Deliv. 2019 May 01;10(5):311-332

Authors: Bardoliwala D, Patel V, Javia A, Ghosh S, Patel A, Misra A

Abstract
Research on siRNA is increasing due to its wide applicability as a therapeutic agent in irreversible medical conditions. siRNA inhibits expression of the specific gene after its delivery from formulation to cytosol region of a cell. RNAi (RNA interference) is a mechanism by which siRNA is silencing gene expression for a particular disease. Numerous studies revealed that naked siRNA delivery is not preferred due to instability and poor pharmacokinetic performance. Nanocarriers based delivery of siRNA has the advantage to overcome physiological barriers and protect the integrity of siRNA from degradation by RNAase. Various diseases like lung cancer, cystic fibrosis, asthma, etc can be treated effectively by local lung delivery. The selective targeted therapeutic action in diseased organ and least off targeted cytotoxicity are the key benefits of pulmonary delivery. The current review highlights recent developments in pulmonary delivery of siRNA with novel nanosized formulation approach with the proven in vitro/in vivo applications.

PMID: 31116099 [PubMed - in process]

High-Content Screening Identifies Vanilloids as a Novel Class of Inhibitors of NET Formation.

Front Immunol. 2019;10:963

Authors: Sondo E, Bertelli R, Pesce E, Ghiggeri GM, Pedemonte N

Abstract
Neutrophils migrate to sites of infection where they phagocytose, degranulate, and/or, in the presence of appropriate stimuli, release decondensed chromatin strands (called neutrophil extracellular traps, NETs) for trapping and possibly killing microorganisms. NET formation is characterized by marked morphological cell changes, in particular within the nucleus. Lytic NET formation can be observed in neutrophils undergoing cell death, which is referred to as NETosis. Dysregulation of NET production and/or degradation can exert pathogenic effects, contributing to the pathogenesis of various diseases, including cystic fibrosis, autoimmune diseases and inflammatory conditions. By employing a phenotypic assay based on high-content imaging and analysis, we screened a library of biologically active compounds and identified vanilloids as a novel class of chemical compounds able to hinder NETosis induction and NET release. Vanilloids also markedly decrease cytosolic ROS production. The identification of novel vanilloid NET inhibitors, able to stop excessive or aberrant NET production might offer new therapeutic options for those disorders displaying NET overproduction.

PMID: 31114589 [PubMed - in process]

Cystic fibrosis in ferrets.

Lab Anim (NY). 2019 Jun;48(6):165

Authors: Le Bras A

PMID: 31114052 [PubMed - in process]

Put to the test: Organoid-based testing becomes a clinical tool.

Nat Med. 2017 07 11;23(7):796-799

Authors: Chakradhar S

PMID: 28697178 [PubMed - indexed for MEDLINE]

In support of point-of-care social needs screening: The effects of five social determinants on the health of children with chronic diseases in British Columbia.

Paediatr Child Health. 2019 Jun;24(3):200-208

Authors: Seear M, Amed S, Dionne J, Yang C, Tourigny K, De Mello A, Hamilton Z, Garcia Espinosa B

Abstract
Background: Prior to introducing social needs screening into our subspecialty clinics, we first wanted to understand the health effects of the major social challenges facing children with chronic diseases in British Columbia.
Methods: Using a strict prospective methodology, avoiding use of health databases and proxy end points, we studied the effects of five social health determinants (distance from care, family income, gender, ethnicity, caregiver education), on health outcomes in three groups of children with chronic diseases: cystic fibrosis (CF), type 1 diabetes (T1D), chronic kidney disease (CKD). Social determinant data were collected at a face-to-face interview during a clinic visit. These were correlated with diagnosis-specific health outcomes, measured at the same visit. Main outcomes were: forced expired volume in 1 second (FEV1) (CF group), HbA1c (T1D group), estimated glomerular filtration rate (CKD group).
Results: We studied 270 children: 85 CF, 89 T1D and 96 CKD. In all three groups, children from families with annual income less than $45,000 had significantly worse health than those from families above this cut-off. Lower caregiver education was related to worse health in the CKD and T1D groups. We found no adverse health effects associated with distance from subspecialty care, patient ethnicity or gender.
Conclusion: Even in a prosperous province, family poverty and lack of caregiver education still impose measurable adverse effects on the health of children with chronic diseases. We hope these results help support the integration of social needs screening into routine multidisciplinary outpatient clinics. Early detection of social problems and targeted interventions will hopefully help to equalize health outcomes between children from different social groups.

PMID: 31110462 [PubMed]

Vibrating Mesh Nebulisation of Pro-Antimicrobial Peptides for Use in Cystic Fibrosis.

Pharmaceutics. 2019 May 17;11(5):

Authors: Forde É, Kelly G, Sweeney L, Fitzgerald-Hughes D, MacLoughlin R, Devocelle M

Abstract
BACKGROUND: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung by a vibrating mesh nebuliser (VMN) and whether the pro-AMP modification has any effect on delivery.
METHODS: Physical characteristics of the peptides (AMP and pro-AMP) and antimicrobial activity were compared before and after nebulisation. Droplet size distribution was determined by laser diffraction and cascade impaction. Delivery to a model lung was determined in models of spontaneously-breathing and mechanically-ventilated patients.
RESULTS: The physical characteristics and antimicrobial activities were unchanged after nebulisation. Mean droplet size diameters were below 5 μm in both determinations, with the fine particle fraction approximately 67% for both peptides. Approximately 25% of the nominal dose was delivered in the spontaneously-breathing model for both peptides, with higher deliveries observed in the mechanically-ventilated model. Delivery times were approximately 170 s per mL for both peptides and the residual volume in the nebuliser was below 10% in nearly all cases.
CONCLUSIONS: These results demonstrate that the delivery of (pro-)AMPs to the lung using a VMN is feasible and that the prodrug modification is not detrimental. They support the further development of pro-AMPs as therapeutics in CF.

PMID: 31108949 [PubMed]

Pharmacokinetics and safety of tobramycin nebulization with the I-neb® and PARI-LC Plus® in children with cystic fibrosis: a randomized, crossover study.

Br J Clin Pharmacol. 2019 May 21;:

Authors: van Velzen AJ, Uges JWF, Heijerman HGM, Arets HGM, Nuijsink M, van der Wiel-Kooij EC, van Maarseveen EM, van Zanten GA, Pullens B, Touw DJ, Janssens HM

Abstract
AIMS: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC® Plus nebulizer in children with cystic fibrosis (CF).
METHODS: A randomized, open-label, crossover study was performed. In two separate study visits blood samples from 22 children were collected following TIS nebulization with the I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by one month, in which one of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian pharmacokinetic modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard eGFR values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed.
RESULTS: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and eGFR revealed no abnormalities. Increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest, however, TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb.
CONCLUSIONS: Nebulization of 75 mg TIS with the I-neb in children with CF resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.

PMID: 31112621 [PubMed - as supplied by publisher]

Noninvasive Ventilatory Support for Acute Hypercapnic Respiratory Failure.

Respir Care. 2019 Jun;64(6):647-657

Authors: Hill NS, Spoletini G, Schumaker G, Garpestad E

Abstract
Noninvasive ventilation is well established as the ventilatory modality of first choice to treat acute or acute-on-chronic hypercapnic respiratory failure in patients with COPD by improving dyspnea and gas exchange, avoiding the need for intubation, and reducing morbidity and mortality rates. Noninvasive ventilation also offers benefit for patients with COPD and with accompanying pneumonia or with hypercapnic respiratory failure in postextubation, postoperative, and do not intubate settings. Noninvasive ventilation, in addition, offers benefit in other forms of acute hypercapnic respiratory failure, including those caused by asthma, cystic fibrosis, and obesity hypoventilation. A newer form of noninvasive ventilatory assistance, high-flow nasal cannula, has emerged in recent years as a technique to not only oxygenate effectively but also to improve ventilatory efficiency and reduce the work of breathing in patients with severe COPD. Results of recent studies indicate that high-flow nasal cannula therapy can benefit some patients with acute hypercapnic respiratory failure, either instead of or in combination with noninvasive ventilation, but more study is needed.

PMID: 31110034 [PubMed - in process]

Ethanol decreases Pseudomonas aeruginosa flagellar motility through the regulation of flagellar stators.

J Bacteriol. 2019 May 20;:

Authors: Lewis KA, Baker AE, Chen AI, Harty CE, Kuchma SL, O'Toole GA, Hogan DA

Abstract
Pseudomonas aeruginosa frequently encounters microbes that produce ethanol. Low concentrations of ethanol reduced P. aeruginosa swim zone area by up to 45% in soft agar. The reduction of swimming by ethanol required the flagellar motor proteins MotAB and two PilZ-domain proteins (FlgZ and PilZ). PilY1 and the type-4 pilus alignment complex (comprised of PilMNOP) have been previously implicated in MotAB regulation in surface associated cells and were required for ethanol-dependent motility repression. As FlgZ requires the second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) to represses motility, we screened mutants lacking genes involved in c-di-GMP metabolism and found that mutants lacking diguanylate cyclases SadC and GcbA were less responsive to ethanol. The double mutant was resistant to its effects. As published previously, ethanol also represses swarming motility, and the same genes required for ethanol effects on swimming motility were required for its regulation of swarming. Microscopic analysis of single cells in soft agar found that ethanol effects on swim zone area correlated with ethanol effects on the portion of cells that paused or stopped during the time interval analyzed. Ethanol increased c-di-GMP in planktonic wild-type cells, but not in ΔmotAB or ΔsadCΔgcbA mutants suggesting c-di-GMP plays a role in the response to ethanol in planktonic cells. We propose that ethanol produced by other microbes induces a regulated decrease in P. aeruginosa motility, thereby promoting P. aeruginosa co-localization with ethanol-producing microbes. Furthermore, some of the same factors involved in the response to surface contact are involved in the response to ethanol.ImportanceEthanol is an important, biologically active molecule produced by many bacteria and fungi. It has also been identified as a potential marker for disease state in cystic fibrosis. In line with previous data that show that ethanol promotes biofilm formation by Pseudomonas aeruginosa, here we report that ethanol reduces swimming motility using some of the same proteins involved in surface sensing. We propose that these data may provide insight into how microbes, via their metabolic byproducts, can influence P. aeruginosa co-localization in the context of infection and in other polymicrobial settings.

PMID: 31109994 [PubMed - as supplied by publisher]

Stenotrophomonas maltophilia differential gene expression in synthetic cystic fibrosis sputum reveals shared and cystic fibrosis strain-specific responses to the sputum environment.

J Bacteriol. 2019 May 20;:

Authors: Willsey GG, Eckstrom K, LaBauve AE, Hinkel LA, Schutz K, Meagher RJ, LiPuma JJ, Wargo MJ

Abstract
Stenotrophomonas maltophilia is a Gram-negative opportunistic pathogen that can infect the lungs of people with cystic fibrosis (CF). The highly viscous mucus in the CF lung, expectorated as sputum, serves as the primary nutrient source for microbes colonizing this site and induces virulence-associated phenotypes and gene expression in several CF pathogens. Here, we characterized the transcriptional responses of three S. maltophilia strains during exposure to synthetic CF sputum media (SCFM2) to gain insight into how this organism interacts with the host in the CF lung. These efforts led to the identification of 881 transcripts differentially expressed by all three strains, many of which reflect the metabolic pathways used by S. maltophilia in sputum, as well as altered stress responses. The latter correlated with increased resistance to peroxide exposure after pre-growth in SCFM2 for two of the strains. We also compared the SCFM2 transcriptomes of two S. maltophilia CF isolates to that of the acute infection strain, S. maltophilia K279a, allowing us to identify CF isolate-specific signatures in differential gene expression. Expression of genes from the accessory genomes was also differentially altered in response to SCFM2. Finally, a number of biofilm-associated genes were differentially induced in SCFM2, particularly in K279a, which corresponded to increased aggregation and biofilm formation in this strain relative to both CF strains. Collectively, this work details the response of S. maltophilia to an environment that mimics important aspects of the CF lung, identifying potential survival strategies and metabolic pathways used by S. maltophilia during infections.Importance Stenotrophomonas maltophilia is an important infecting bacterium in the airways of people with cystic fibrosis (CF). However, compared to the other CF pathogens, S. maltophilia has been relatively understudied. The significance of our research is to provide insight into the global transcriptomic changes of S. maltophilia in response to a medium that was designed to mimic important aspects of the CF lung. This work allows us to understand the overall metabolic changes that occur when S. maltophilia encounters the CF lung, and generates a roadmap of candidate genes to test using in vitro and in vivo models of CF.

PMID: 31109991 [PubMed - as supplied by publisher]

[The most ancestral mycobacterial ESX-4 secretion system is essential for intracellular growth of Mycobacterium abscessus within environmental and human phagocytes].

Med Sci (Paris). 2018 Oct;34(10):795-797

Authors: Girard-Misguich F, Laencina L, Dubois V, Le Moigne V, Kremer L, Maljessi L, Brosch R, Herrmann JL

PMID: 30451667 [PubMed - indexed for MEDLINE]

Assessing the impact of program volume and composition on waiting list outcomes in pediatric lung transplantation.

J Heart Lung Transplant. 2017 11;36(11):1180-1182

Authors: Sweet SC

PMID: 28705645 [PubMed - indexed for MEDLINE]

Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease.

Cochrane Database Syst Rev. 2019 May 20;5:CD001287

Authors: Poole P, Sathananthan K, Fortescue R

Abstract
BACKGROUND: Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume or purulence of sputum, or both. Personal and healthcare costs associated with exacerbations indicate that therapies that reduce the occurrence of exacerbations are likely to be useful. Mucolytics are oral medicines that are believed to increase expectoration of sputum by reducing its viscosity, thus making it easier to cough it up. Improved expectoration of sputum may lead to a reduction in exacerbations of COPD.
OBJECTIVES: Primary objective• To determine whether treatment with mucolytics reduces exacerbations and/or days of disability in patients with chronic bronchitis or COPDSecondary objectives• To assess whether mucolytics lead to improvement in lung function or quality of life• To determine frequency of adverse effects associated with use of mucolytics SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of articles on 12 separate occasions, most recently on 23 April 2019.
SELECTION CRITERIA: We included randomised studies that compared oral mucolytic therapy versus placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis.
DATA COLLECTION AND ANALYSIS: This review analysed summary data only, most derived from published studies. For earlier versions, one review author extracted data, which were rechecked in subsequent updates. In later versions, review authors double-checked extracted data and then entered data into RevMan 5.3 for analysis.
MAIN RESULTS: We added four studies for the 2019 update. The review now includes 38 trials, recruiting a total of 10,377 participants. Studies lasted between two months and three years and investigated a range of mucolytics, including N-acetylcysteine, carbocysteine, erdosteine, and ambroxol, given at least once daily. Many studies did not clearly describe allocation concealment, and we had concerns about blinding and high levels of attrition in some studies. The primary outcomes were exacerbations and number of days of disability.Results of 28 studies including 6723 participants show that receiving mucolytics may be more likely to be exacerbation-free during the study period compared to those given placebo (Peto odds ratio (OR) 1.73, 95% confidence interval (CI) 1.56 to 1.91; moderate-certainty evidence). However, more recent studies show less benefit of treatment than was reported in earlier studies in this review. The overall number needed to treat with mucolytics for an average of nine months to keep an additional participant free from exacerbations was eight (NNTB 8, 95% CI 7 to 10). High heterogeneity was noted for this outcome (I² = 62%), so results need to be interpreted with caution. The type or dose of mucolytic did not seem to alter the effect size, nor did the severity of COPD, including exacerbation history. Longer studies showed smaller effects of mucolytics than were reported in shorter studies.Mucolytic use was associated with a reduction of 0.43 days of disability per participant per month compared with use of placebo (95% CI -0.56 to -0.30; studies = 9; I² = 61%; moderate-certainty evidence). With mucolytics, the number of people with one or more hospitalisations was reduced, but study results were not consistent (Peto OR 0.68, 95% CI 0.52 to 0.89; participants = 1788; studies = 4; I² = 58%; moderate-certainty evidence). Investigators reported improved quality of life with mucolytics (mean difference (MD) -1.37, 95% CI -2.85 to 0.11; participants = 2721; studies = 7; I² = 64%; moderate-certainty evidence). However, the mean difference did not reach the minimal clinically important difference of -4 units, and the confidence interval includes no difference. Mucolytic treatment was associated with a possible reduction in adverse events (OR 0.84, 95% CI 0.74 to 0.94; participants = 7264; studies = 24; I² = 46%; moderate-certainty evidence), but the pooled effect includes no difference if a random-effects model is used. Several studies that could not be included in the meta-analysis reported high numbers of adverse events, up to a mean of five events per person during follow-up. There was no clear difference between mucolytics and placebo for mortality, but the confidence interval is too wide to confirm that treatment has no effect on mortality (Peto OR 0.98, 95% CI 0.51 to 1.87; participants = 3527; studies = 11; I² = 0%; moderate-certainty evidence).
AUTHORS' CONCLUSIONS: In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics leads to a small reduction in the likelihood of having an acute exacerbation, in days of disability per month and possibly hospitalisations, but is not associated with an increase in adverse events. There appears to be limited impact on lung function or health-related quality of life. Results are too imprecise to be certain whether or not there is an effect on mortality. Our confidence in the results is reduced by high levels of heterogeneity in many of the outcomes and the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies. This may be a result of greater risk of selection or publication bias in earlier trials, thus benefits of treatment may not be as great as was suggested by previous evidence.

PMID: 31107966 [PubMed - as supplied by publisher]

FDG PET/CT of Gardnerella vaginalis infection.

Clin Nucl Med. 2019 May 03;:

Authors: Foret T, Dhomps A, Dauwalder O, Skanjeti A, Tordo J

Abstract
We report the case of a 23-year-old woman with a history of cystic fibrosis and bilung transplantation, who presented clinically cervical swollen lymph nodes with alteration of her general state. F-FDG PET/CT was performed because of lymphoma suspicion and showed cervical and pelvic hypermetabolic lymphadenopathies, with linear vaginal hypermetabolism. There was an increase of lactate dehydrogenase, and Epstein-Barr virus detection was negative. A right cervical lymph node biopsy was performed, with no lymphoma involvement. Complementary microbiological investigations showed positive results for Gardnerella vaginalis. F-FDG PET/CT lymphatic node hypermetabolism is not specific to lymphoma, particularly in immunocompromised patients.

PMID: 31107755 [PubMed - as supplied by publisher]