Am J Respir Crit Care Med. 2022 Mar 11. doi: 10.1164/rccm.202202-0337ED. Online ahead of print.

NO ABSTRACT

PMID:35275803 | DOI:10.1164/rccm.202202-0337ED

Curr Med Res Opin. 2022 Mar 11:1-9. doi: 10.1080/03007995.2022.2052514. Online ahead of print.

ABSTRACT

BACKGROUND: Many feeding strategies may be used in chronically ill children on enteral nutrition. Interest is currently growing in real food-based enteral nutrition. A new tube feeding formula with real food ingredients is currently commercially available in Europe.

CASE REPORTS: By focusing on four clinical cases, this article illustrates the use of a tube feeding formula with real food ingredients in pediatric patients with various complex conditions. The formula contains a milk-based mixture of peas, green beans, peaches, carrots, and chicken, and provides 1.2 kcal/ml. It was offered under medical supervision and after full consideration of all feeding options.

CONCLUSIONS: Formula choice appears to be based on clinical experience and must be individualized to patients' characteristics and needs. Real food-containing formulas seem to improve tolerance and feeding outcomes as well as promote family inclusion and mealtime engagement, but further studies are warranted.

PMID:35274578 | DOI:10.1080/03007995.2022.2052514

Indian Pediatr. 2022 Mar 10:S097475591600409. Online ahead of print.

ABSTRACT

OBJECTIVE: To study the frequency and spectrum of CFTR gene variants in different ethnic groups of Kazakhstan.

METHODS: The reviewed the records of 58 patients with cystic fibrosis. All the patients underwent molecular genetic analysis to reveal genotype-phenotype correlations.

RESULTS: The median (IQR) age of the patients was 5.4 year (7 months, 18 year); 40% were diagnosed at the age of 5-10 year. The study identified 28 specific variants: p.Phe508del, the variant most common in the European population, was detected in 30 patients (51.7%). Variants other than p.Phe508del were revealed in 31% (21 patients).

CONCLUSIONS: We found a number of specific variants characteristic of the Kazakhstani population. A pronounced regression of disease symptoms was detected in patients with mild mutations; whereas in patients with severe mutations, therapy produced very little effect.

PMID:35273129

Am J Physiol Lung Cell Mol Physiol. 2022 Mar 10. doi: 10.1152/ajplung.00152.2021. Online ahead of print.

ABSTRACT

Chronic illnesses rarely present in a vacuum, devoid of other complications, and chronic kidney disease is hardly an exception. Comorbidities associated with chronic kidney disease lead to faster disease progression, expedited dialysis dependency, and a higher mortality rate. Although chronic kidney disease is most commonly accompanied by cardiovascular diseases and diabetes, there is clear crosstalk between the lungs and kidneys pH balance, phosphate metabolism, and immune system regulation. Our present understanding of the exact underlying mechanisms that contribute to chronic kidney disease-related pulmonary disease are poorly understood. This review summarizes the current research on kidney-pulmonary interorgan crosstalk in the context of chronic kidney disease, highlighting various acute and chronic pulmonary diseases that lead to further complications in patient care. Treatment options for patients presenting with chronic kidney disease and lung disease are explored by assessing activated molecular pathways and the body's compensatory response mechanisms following homeostatic imbalance. Understanding the link between the lungs and kidneys will potentially improve health outcomes for patients and guide healthcare professionals to better understand how and when to treat each of the pulmonary comorbidities that can present with chronic kidney disease.

PMID:35272496 | DOI:10.1152/ajplung.00152.2021

Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666211070133. doi: 10.1177/17534666211070133.

ABSTRACT

BACKGROUND: Home monitoring (HM) is able to detect more pulmonary exacerbations (PEx) than routine care (RC) in individuals with cystic fibrosis (CF), but there is currently no evidence for benefits in health outcomes. Patient experiences of using HM and a health economics assessment have not been rigorously assessed to date. This study aimed to assess the effects of HM on hospital admissions, quality of life, antibiotic requirements, exacerbation frequency, lung function, nutritional outcomes, anxiety, depression, costs and health outcomes, as well as the qualitative effects on the patient experience.

METHODS: This randomised controlled mixed-methods pilot study recruited CF adults cared for in one large regional CF centre. Participants were randomly allocated 1:1 to the intervention cohort [twice-weekly HM of symptoms measured by the Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory Infection Symptom Score (CFRSD-CRISS) and forced expiratory volume in one second (FEV1)] or a control cohort (routine clinical care) for the 12-month study period. Measurements were recorded at study visits at baseline, 3, 6, 9 and 12 months. Spirometry, body weight, comorbidities, medications, hospital inpatient days, courses of antibiotics (oral and intravenous) and PEx (defined by the modified Fuchs criteria) were recorded at each study visit. Health status, capability and cost-effectiveness were measured at each study visit by the Hospital Anxiety and Depression Scale (HADS), the ICEpop CAPability measure for Adults (ICECAP-A), EuroQol 5 dimensions (EQ-5D-5L) questionnaire and an adapted resource use questionnaire. The patient experience of HM was assessed by semi-structured qualitative interviews at baseline and 12 months.

RESULTS: Eighty-eight participants were recruited, with 44 (50%) randomised to receive HM and 44 (50%) randomised to receive RC. Patient hospital inpatient bed days per annum and overall health-related quality of life were similar between the groups. Protocol-defined PEx requiring intravenous and oral antibiotics were detected more frequently in the HM group, with no other differences between the groups in the secondary outcomes. The total mean National Health Service (NHS) costs were approximately £1500 more per patient for the RC arm than the HM group. The qualitative analysis demonstrated that the patient experience of HM was generally positive and overall the intervention was well accepted.

CONCLUSION: The findings of this trial confirm that HM is effective in detecting PEx in adults with CF. There were no significant differences in hospital inpatient bed days and overall health-related quality of life between the groups. Despite the cost of the HM equipment and the salary of the research fellow to respond to the results, health economics analysis suggests the intervention was less expensive than RC. HM was generally well accepted, with most participants reporting that it resulted in them feeling more empowered and reassured.

TRIAL REGISTRATION: The study protocol was registered with Clinicaltrials.gov (NCT02994706) on 16 July 2014 and published in a peer reviewed journal.Data from this trial has been presented in abstract form at the ECFS Conference in Lyon in September 2020.

PMID:35274585 | PMC:PMC8921750 | DOI:10.1177/17534666211070133

Horm Metab Res. 2022 Mar 10. doi: 10.1055/a-1794-5496. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to compare continuous glucose monitoring (CGM) in cystic fibrosis (CF) according to pancreatic exocrine status.

METHODS: CGM and oral glucose tolerance testing (OGTT) were realized annually over five years in patients with CF (pwCF) aged ≥10 years without cystic fibrosis-related diabetes (CFRD). CGM parameters in patients with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and newly diagnosed CFRD were compared according to presence of pancreatic sufficiency (PS) or insufficiency (PI).

RESULTS: Overall, 547 OGTTs and 501 CGMs were performed in 147 CF patients, comprising 122 PI and 25 PS. In PS patients, 84% displayed NGT, 12% IGT, and 4% CFRD vs. 58%, 32%, and 10% (p=0.05) in PI. Among participants displaying normal OGTT, time in glucose range (70-140mg/dl) was significantly increased, 97% (93, 99) vs. 92% (85, 96), p<0.001, and time above glucose range significantly decreased, 1% (0, 2) % vs. 6% (2, 13), in patients with PS compared to those with PI. No significant differences were highlighted in patients with IGT.

CONCLUSION: CGM revealed significant different glucose tolerance abnormalities in PI versus PS, which were undetected by standard 2-hour OGTT glucose.

PMID:35272389 | DOI:10.1055/a-1794-5496

Chest. 2022 Mar 7:S0012-3692(22)00421-4. doi: 10.1016/j.chest.2022.02.052. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies have shown that the lung clearance index (LCI) determined by multiple-breath washout (MBW) is sensitive to detect early lung disease in preschool children with cystic fibrosis (CF). In preschool children with primary ciliary dyskinesia (PCD), data on the onset and severity of lung disease and on the sensitivity of the LCI as a noninvasive quantitative outcome measure remain limited.

RESEARCH AND STUDY QUESTION: Is MBW feasible and sensitive to detect ventilation inhomogeneity in preschool children with PCD?

STUDY DESIGN AND METHODS: This was a prospective cross-sectional multicenter study and included preschoolers with PCD and preschoolers with CF and healthy controls. LCI was determined using nitrogen MBW, and compared between the three groups.

RESULTS: LCI was determined in 27 children with PCD, 34 children with CF and 30 healthy controls (mean age, 4.8 years; range, 2.2 - 6.9 years). The LCI in preschool children with PCD was increased (median, 9.1; CI 95%, 8.6-10.3) compared to healthy controls (median, 7.0; CI 95%, 6.7-7.1), (P < 0.0001), but did not differ from preschool children with CF (median, 8.6; CI 95%, 8.4-9.7), (P = 0.71). The feasibility in the PCD group was 93.1% and was similar to that in the CF group (91.9%) and in healthy controls (85.7%), (P = 0.55).

INTERPRETATION: This study demonstrates early onset of lung disease in preschool children with PCD and indicates that lung disease severity in PCD may be similar to that in CF during preschool years. These data support a need for early diagnostic monitoring and therapy and suggest the LCI as a noninvasive diagnostic tool and as a potential endpoint in clinical trials testing early interventions in children with PCD.

PMID:35271842 | DOI:10.1016/j.chest.2022.02.052

Sensors (Basel). 2022 Feb 28;22(5):1902. doi: 10.3390/s22051902.

ABSTRACT

Physical training at home by making individuals play active video games is a new therapeutic strategy to improve the condition of patients with cystic fibrosis (CF). We reviewed studies on the use of video games and their benefits in the treatment of CF. We conducted a systematic review with data from six databases (PubMed, Medline, Scopus, Web of Science, PEDro, and Cochrane library plus) since 2010, according to PRISMA standards. The descriptors were: "Cystic Fibrosis", "Video Game", "Gaming Console", "Pulmonary Rehabilitation", "Physiotherapy", and "Physical Therapy". Nine articles with 320 participants met the inclusion criteria and the study objective. Patients who played active video games showed a high intensity of exercise and higher ventilatory and aerobic capacity compared to the values of these parameters in tests such as the cardiopulmonary stress test or the six-minute walk test. Adequate values of metabolic demand in these patients were recorded after playing certain video games. A high level of treatment adherence and satisfaction was observed in both children and adults. Although the quality of the included studies was moderate, the evidence to confirm these results was insufficient. More robust studies are needed, including those on evaluation and health economics, to determine the effectiveness of the treatment.

PMID:35271048 | DOI:10.3390/s22051902

Int J Environ Res Public Health. 2022 Mar 2;19(5):2912. doi: 10.3390/ijerph19052912.

ABSTRACT

BACKGROUND: Time spent in 24-h movement behaviors is important to health and wellbeing in childhood, but levels of these behaviors in children with chronic disease are unknown.

METHODS: A case-control-study included 80 children with chronic disease; 20 with type 1 diabetes mellitus (T1DM), 20 with juvenile idiopathic arthritis (JIA), 20 with congenital heart disease (CHD), 20 with cystic fibrosis (CF); pair-matched individually for age, sex, and timing of measures with 80 healthy children. Habitual time spent in movement behaviors and step counts were all measured with an activPAL accelerometer over 7 days. Comparisons against recommendations and differences between the groups were made.

RESULTS: Time spent in physical activity and step counts/day were significantly lower in T1DM and CHD groups compared to controls. Only 20/80 children with chronic disease and 29/80 controls met step count recommendations. Sedentary time was significantly higher in children with CF compared to controls. Time spent asleep was slightly greater in children with chronic disease, significant only for the JIA group. Sleep disruption was consistently greater in those with chronic disease, reaching significance for T1DM, CHD, and CF groups.

CONCLUSIONS: For some groups of children with chronic disease, 24-h movement behaviors may differ substantially from recommendations, and slightly but systematically from their healthy peers. Optimizing levels of 24-h movement behaviors should confer a number of benefits for child health, development, and wellbeing.

PMID:35270604 | DOI:10.3390/ijerph19052912

Int J Mol Sci. 2022 Feb 28;23(5):2688. doi: 10.3390/ijms23052688.

ABSTRACT

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, a cAMP regulated chloride (Cl-) and bicarbonate (HCO3-) ion channel expressed at the apical plasma membrane (PM) of epithelial cells. Reduced CFTR protein results in decreased Cl- secretion and excessive sodium reabsorption in epithelial cells, which consequently leads to epithelial dehydration and the accumulation of thick mucus within the affected organs, such as the lungs, pancreas, gastrointestinal (GI) tract, reproductive system and sweat glands. However, CFTR has been implicated in other functions besides transporting ions across epithelia. The rising number of references concerning its association to actin cytoskeleton organization, epithelial cell junctions and extracellular matrix (ECM) proteins suggests a role in the formation and maintenance of epithelial apical basolateral polarity. This review will focus on recent literature (the last 10 years) substantiating the role of CFTR in cell junction formation and actin cytoskeleton organization with its connection to the ECM.

PMID:35269829 | DOI:10.3390/ijms23052688

Int J Mol Sci. 2022 Feb 23;23(5):2442. doi: 10.3390/ijms23052442.

ABSTRACT

Deletion of phenylalanine 508 (∆F508) of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel protein is the leading cause of Cystic Fibrosis (CF). Here, we report the analysis of CFTR and ∆F508-CFTR interactomes using BioID (proximity-dependent biotin identification), a technique that can also detect transient associations. We identified 474 high-confidence CFTR proximity-interactors, 57 of which have been previously validated, with the remainder representing novel interaction space. The ∆F508 interactome, comprising 626 proximity-interactors was markedly different from its wild type counterpart, with numerous alterations in protein associations categorized in membrane trafficking and cellular stress functions. Furthermore, analysis of the ∆F508 interactome in cells treated with Orkambi identified several interactions that were altered as a result of this drug therapy. We examined two candidate CFTR proximity interactors, VAPB and NOS1AP, in functional assays designed to assess surface delivery and overall chloride efflux. VAPB depletion impacted both CFTR surface delivery and chloride efflux, whereas NOS1AP depletion only affected the latter. The wild type and ∆F508-CFTR interactomes represent rich datasets that could be further mined to reveal additional candidates for the functional rescue of ∆F508-CFTR.

PMID:35269585 | DOI:10.3390/ijms23052442

Cells. 2022 Feb 25;11(5):812. doi: 10.3390/cells11050812.

ABSTRACT

Obstructive lung diseases, such as chronic obstructive pulmonary disease, asthma, or non-cystic fibrosis bronchiectasis, share some major pathophysiological features: small airway involvement, dysregulation of adaptive and innate pulmonary immune homeostasis, mucus hyperproduction, and/or hyperconcentration. Mucus regulation is particularly valuable from a therapeutic perspective given it contributes to airflow obstruction, symptom intensity, disease severity, and to some extent, disease prognosis in these diseases. It is therefore crucial to understand the mucus constitution of our patients, its behavior in a stable state and during exacerbation, and its regulatory mechanisms. These are all elements representing potential therapeutic targets, especially in the era of biologics. Here, we first briefly discuss the composition and characteristics of sputum. We focus on mucus and mucins, and then elaborate on the different sample collection procedures and how their quality is ensured. We then give an overview of the different direct analytical techniques available in both clinical routine and more experimental settings, giving their advantages and limitations. We also report on indirect mucus assessment procedures (questionnaires, high-resolution computed tomography scanning of the chest, lung function tests). Finally, we consider ways of integrating these techniques with current and future therapeutic options. Cystic fibrosis will not be discussed given its monogenic nature.

PMID:35269434 | DOI:10.3390/cells11050812

J Clin Med. 2022 Feb 26;11(5):1283. doi: 10.3390/jcm11051283.

ABSTRACT

Cystic fibrosis is a life-threatening disease that affects at least 100,000 people worldwide. It is caused by a defect in the cystic fibrosis transmembrane regulator (CFTR) gene and presently, 360 CFTR-causing mutations have been identified. Since the discovery of the CFTR gene, the expectation of developing treatments that can substantially increase the quality of life or even cure cystic fibrosis patients is growing. Yet, it is still uncertain today which developing treatments will be successful against cystic fibrosis. This study addresses this gap by assessing the opinions of over 524 cystic fibrosis researchers who participated in a global web-based survey. For most respondents, CFTR modulator therapies are the most likely to succeed in treating cystic fibrosis in the next 15 years, especially through the use of CFTR modulator combinations. Most respondents also believe that fixing or replacing the CFTR gene will lead to a cure for cystic fibrosis within 15 years, with CRISPR-Cas9 being the most likely genetic tool for this purpose.

PMID:35268374 | DOI:10.3390/jcm11051283

Nutrients. 2022 Feb 28;14(5):1028. doi: 10.3390/nu14051028.

ABSTRACT

Cystic fibrosis (CF) is a chronic, multisystem disease with multiple comorbidities that can significantly affect nutrition and quality of life. Maintaining nutritional adequacy can be challenging in people with cystic fibrosis and has been directly associated with suboptimal clinical outcomes. Comorbidities of CF can result in significantly decreased nutritional intake and intestinal absorption, as well as increased metabolic demands. It is crucial to utilize a multidisciplinary team with expertise in CF to optimize growth and nutrition, where patients with CF and their loved ones are placed in the center of the care model. Additionally, with the advent of highly effective modulators (HEMs), CF providers have begun to identify previously unrecognized nutritional issues, such as obesity. Here, we will review and summarize commonly encountered comorbidities and their nutritional impact on this unique population.

PMID:35268004 | DOI:10.3390/nu14051028

Nutrients. 2022 Feb 22;14(5):933. doi: 10.3390/nu14050933.

ABSTRACT

BACKGROUND: Physical exercise is an important part of regular care for people with cystic fibrosis (CF). It is unknown whether such exercise has beneficial or detrimental effects on nutritional status (body composition). Thus, the objective of this review was to evaluate the effect of exercise on measures of nutritional status in children and adults with CF.

METHODS: Standardized reporting guidelines for systematic reviews were followed and the protocol was prospectively registered. Multiple databases were utilized (e.g., PubMed, Scopus, and CINHAL). Two reviewers independently reviewed titles/abstracts and then the full text for selected studies.

RESULTS: In total, 924 articles were originally identified; data were extracted from 4 eligible studies. These four studies included only children; pulmonary function ranged from severe to normal, and the majority of participants were at or below their recommended weight. Exercise training did not worsen nutritional status in any study; two studies that included resistance exercise reported an increase in fat-free mass. Three of the four studies also reported increased aerobic capacity and/or muscle strength.

CONCLUSIONS: Exercise training can produce positive physiologic changes in children with CF without impairing their nutritional status. In fact, resistance exercise can help improve body mass. Much less is known about how exercise may affect adults or those who are overweight.

PMID:35267909 | DOI:10.3390/nu14050933

J Cardiovasc Pharmacol. 2022 Mar 9. doi: 10.1097/FJC.0000000000001257. Online ahead of print.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the cells fate. To further understand its function in vascular remodeling, we examined whether CFTR directly regulates platelet-derived growth factor-BB(PDGF-BB)-stimulated vascular smooth muscle cells(VSMCs) proliferation and migration, as well as the balloon injury-induced neointimal formation. The CFTR adenoviral gene delivery was used to evaluate the effects of CFTR on neointimal formation in a rat model of carotid artery balloon injury. The roles of CFTR in PDGF-BB-stimulated VSMCs proliferation and migration was detected by MTT assay, wound healing assay, trsnswell chamber method, western blot and qPCR. We found that CFTR expression was declined in injured rat carotid arteries, while adenoviral overexpression of CFTR in vivo attenuated neointimal formation in carotid arteries. CFTR overexpression inhibited PDGF-BB-induced VSMCs proliferation and migration whereas CFTR silencing caused the opposite results. Mechanistically, CFTR suppressed the phosphorylation of PDGFRβ, SGK1, JNK, p38 and ERK induced by PDGF-BB, as well as the increased mRNA expression of MMP9 and MMP2 induced by PDGF-BB. In conclusion, our results indicated that CFTR may attenuate neointimal formation by suppressing PDGF-BB-induced activation of SGK1 and the JNK/p38/ERK signaling pathway.

PMID:35266910 | DOI:10.1097/FJC.0000000000001257

Open Forum Infect Dis. 2022 Feb 14;9(4):ofac082. doi: 10.1093/ofid/ofac082. eCollection 2022 Apr.

ABSTRACT

Inhaled antibiotics are a common and valuable therapy for patients suffering from chronic lung infection, with this particularly well demonstrated for patients with cystic fibrosis. However, in vitro tests to predict patient response to inhaled antibiotic therapy are currently lacking. There are indications that antimicrobial susceptibility testing (AST) may have a role in guidance of therapy, but which tests would correlate best still needs to be researched in clinical studies or animal models. Applying the principles of European Committee on Antimicrobial Susceptibility Testing methodology, the analysis of relevant and reliable data correlating different AST tests to patients' outcomes may yield clinical breakpoints for susceptibility, but these data are currently unavailable. At present, we believe that it is unlikely that standard determination of minimum inhibitory concentration will prove the best predictor.

PMID:35265731 | PMC:PMC8900927 | DOI:10.1093/ofid/ofac082

ERJ Open Res. 2022 Mar 7;8(1):00786-2020. doi: 10.1183/23120541.00786-2020. eCollection 2022 Jan.

ABSTRACT

INTRODUCTION: Bronchiectasis is an increasingly common chronic inflammatory airway disease. We evaluated secondary safety outcomes in a comparative effectiveness study of chronic inhaled corticosteroids (ICS) and macrolide monotherapy in bronchiectasis patients.

METHODS: We conducted a retrospective study using US Medicare Parts A, B and D (but not C) 2006-2014 datasets. Among those with a pulmonologist-associated bronchiectasis claim (ICD-9-CM 494.0 or 494.1), without cystic fibrosis, we identified the first new use of either chronic (>28 days) ICS or macrolide monotherapy. For each drug exposure, we calculated crude incidence rates of the secondary safety outcomes: arrhythmia, myocardial infarction, sensorineural hearing loss, hip fracture and opportunistic infections. We calculated a propensity score (PS) for ICS use using demographic, clinical and utilisation characteristics and compared risks of macrolides versus ICS for each outcome using PS decile-adjusted Cox regression models.

RESULTS: Of 285 043 Medicare patients with bronchiectasis, we identified 6500 (2%) macrolide and 83 589 (29%) ICS new users. Key covariates were balanced across exposure groups within decile. Myocardial infarction, hip fracture and opportunistic infection were not significantly associated with treatment. Macrolides were associated with a decreased risk of arrhythmia (adjusted hazard ratio (aHR) 0.87, 95% CI 0.80-0.94) and an increased risk of sensorineural hearing loss (aHR 1.38, 95% CI 1.56-1.22) compared to ICS.

CONCLUSIONS: Macrolides were not associated with an elevated risk of acute cardiac events compared to ICS. The increased risk of hearing loss in macrolide users compared to ICS users in older bronchiectasis patients should be balanced against known benefits of macrolides.

PMID:35265701 | PMC:PMC8899493 | DOI:10.1183/23120541.00786-2020

Front Cell Infect Microbiol. 2022 Feb 21;12:846828. doi: 10.3389/fcimb.2022.846828. eCollection 2022.

ABSTRACT

Cystic fibrosis (CF) lung disease is aggravated by recurrent and ultimately chronic bacterial infections. One of the key pathogens in adult CF lung disease is P. aeruginosa (PA). In addition to bacteria, respiratory viral infections are suggested to trigger pulmonary exacerbations in CF. To date, little is known on how chronic infections with PA influence susceptibility and response to viral infection. We investigated the interactions between PA, human rhinovirus (HRV) and the airway epithelium in a model of chronic PA infection using differentiated primary bronchial epithelial cells (pBECs) and clinical PA isolates obtained from the respiratory sample of a CF patient. Cells were repeatedly infected with either a mucoid or a non-mucoid PA isolate for 16 days to simulate chronic infection, and subsequently co-infected with HRV. Key cytokines and viral RNA were quantified by cytometric bead array, ELISA and qPCR. Proteolytic degradation of IL-6 was analyzed by Western Blots. Barrier function was assessed by permeability tests and transepithelial electric resistance measurements. Virus infection stimulated the production of inflammatory and antiviral mediators, including interleukin (IL)-6, CXCL-8, tumor necrosis factor (TNF)-α, and type I/III interferons. Co-infection with a non-mucoid PA isolate increased IL-1β protein concentrations (28.88 pg/ml vs. 6.10 pg/ml), but in contrast drastically diminished levels of IL-6 protein (53.17 pg/ml vs. 2301.33 pg/ml) compared to virus infection alone. Conditioned medium obtained from co-infections with a non-mucoid PA isolate and HRV was able to rapidly degrade recombinant IL-6 in a serine protease-dependent manner, whereas medium from individual infections or co-infections with a mucoid isolate had no such effect. After co-infection with HRV and the non-mucoid PA isolate, we detected lower mRNA levels of Forkhead box J1 (FOXJ1) and Cilia Apical Structure Protein (SNTN), markers of epithelial cell differentiation to ciliated cells. Moreover, epithelial permeability was increased and barrier function compromised compared to single infections. These data show that PA infection can influence the response of bronchial epithelial cells to viral infection. Altered innate immune responses and compromised epithelial barrier function may contribute to an aggravated course of viral infection in PA-infected airways.

PMID:35265536 | PMC:PMC8899922 | DOI:10.3389/fcimb.2022.846828

Front Microbiol. 2022 Feb 21;13:821820. doi: 10.3389/fmicb.2022.821820. eCollection 2022.

ABSTRACT

Non-tuberculosis Mycobacterium (NTM) is a group of opportunistic pathogens associated with pulmonary infections that are difficult to diagnose and treat. Standard treatment typically consists of prolonged combination antibiotic therapy. Antibiotic resistance and the role of biofilms in pathogen communities, such as NTM persister cells, is an important unmet challenge that leads to increased toxicity, frequent relapse, poor clinical management, and an extended treatment period. Infection recurrence and relapse are not uncommon among individuals with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD), where thick mucus supports bacterial biofilm production and impairs mucociliary clearance. The study evaluates a membrane-active cationic glycopolymer [poly (acetyl, arginyl) glucosamine (PAAG)] being developed to support the safe and effective treatment of NTM biofilm infections. PAAG shows antibacterial activity against a wide range of pathogenic bacteria at concentrations non-toxic to human epithelial cells. Time-kill curves demonstrated PAAG's rapid bactericidal potential at concentrations as low as 1X MIC against all NTM strains tested and compared to the standard of care. PAAG treatment prevents persister formation and eradicates antibiotic-induced persister cells in planktonic NTM cultures below the limit of detection (10 colony-forming unit (CFU)/ml). Further, PAAG showed the ability to penetrate and disperse NTM biofilms formed by both rapidly and slowly growing strains, significantly reducing the biofilm biomass (p < 0.0001) compared to the untreated NTM biofilms. Microscopical examination confirmed PAAG's ability to disrupt and disperse mycobacterial biofilms. A single PAAG treatment resulted in up to a 25-fold reduction in live-labeled NTM and a 78% reduction in biofilm thickness. Similar to other polycationic molecules, PAAG's bactericidal and antibiofilm activities employ rapid permeabilization of the outer membrane of the NTM strains, and subsequently, reduce the membrane potential even at concentrations as low as 50 μg/ml (p < 0.001). The outcomes of these in vitro analyses suggest the importance of this polycationic glycopolymer, PAAG, as a potential therapeutic agent for opportunistic NTM infections.

PMID:35265060 | PMC:PMC8900536 | DOI:10.3389/fmicb.2022.821820