J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S13-S22. doi: 10.1093/jpids/piac036.

ABSTRACT

Chronic lower respiratory tract infections are a leading contributor to morbidity and mortality in persons with cystic fibrosis (pwCF). Traditional respiratory tract surveillance culturing has focused on a limited range of classic pathogens; however, comprehensive culture and culture-independent molecular approaches have demonstrated complex communities highly unique to each individual. Microbial community structure evolves through the lifetime of pwCF and is associated with baseline disease state and rates of disease progression including occurrence of pulmonary exacerbations. While molecular analysis of the airway microbiome has provided insight into these dynamics, challenges remain including discerning not only "who is there" but "what they are doing" in relation to disease progression. Moreover, the microbiome can be leveraged as a multi-modal biomarker for both disease activity and prognostication. In this article, we review our evolving understanding of the role these communities play in pwCF and identify challenges in translating microbiome data to clinical practice.

PMID:36069903 | DOI:10.1093/jpids/piac036

J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S46-S52. doi: 10.1093/jpids/piac040.

ABSTRACT

Antimicrobial susceptibility testing (AST) has been used to guide therapy of airway infection in persons with cystic fibrosis (CF) for decades. However, evidence that AST adds benefit to treatment outcomes in CF is lacking. In fact, the routine use of AST has potential to exacerbate inappropriate antibiotic use. Several features of airway infection in CF contribute to the limitations of AST in predicting treatment outcomes, providing rationale for abandoning this practice altogether. Other features of CF infection suggest, however, that select use of AST can provide worthwhile guidance to antibiotic selection.

PMID:36069902 | DOI:10.1093/jpids/piac040

J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S32-S39. doi: 10.1093/jpids/piac061.

ABSTRACT

Airway infections have remained a prominent feature in persons living with cystic fibrosis (CF) despite the dramatic improvements in survival in the past decades. Antimicrobials are a cornerstone of infection management for both acute and chronic maintenance indications. Historic clinical trials of antimicrobials in CF have led to the adoption of consensus guidelines for their use in clinical care. More recently, however, there are efforts to re-think the optimal use of antimicrobials for care with the advent of novel and highly effective CF transmembrane conductance regulator modulator therapies. Encouragingly, however, drug development has remained active concurrently in this space. Our review focuses on the evidence for and perspectives regarding antimicrobial use in both acute and maintenance settings in persons with CF. The therapeutic innovations in CF and how this may affect antimicrobial approaches are also discussed.

PMID:36069901 | DOI:10.1093/jpids/piac061

J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S40-S45. doi: 10.1093/jpids/piac062.

ABSTRACT

Cystic fibrosis (CF) pulmonary exacerbations (PEx) are clinical events that commonly result in increased treatment burden, decreased quality of life, and accelerated lung disease progression. CF PEx have historically been approached as though dealing with acute infections, and antibiotic treatments have been associated with improved outcomes. In this review, we discuss data supporting a causal role of CF airway infection in PEx as well studies that highlight our knowledge gaps in regard to PEx definitions, pathophysiology, and optimal treatment approaches. In the era of highly effective cystic fibrosis transmembrane conductance regulator modulator therapy, and the continually increasing health and longevity of persons with CF, a better understanding of PEx and further optimization of PEx antibiotic treatment approaches are needed.

PMID:36069900 | DOI:10.1093/jpids/piac062

J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S53-S61. doi: 10.1093/jpids/piac071.

ABSTRACT

The chronic airway infection and inflammation characteristic of cystic fibrosis (CF) ultimately leads to progressive lung disease, the primary cause of death in persons with CF (pwCF). Despite many recent advances in CF clinical care, efforts to preserve lung function in many pwCF still necessitate frequent antimicrobial use. Incorporating antimicrobial stewardship (AMS) principles into management of pulmonary exacerbations (PEx) would facilitate development of best practices for antimicrobial utilization at CF care centers. However, AMS can be challenging in CF given the unique aspects of chronic, polymicrobial infection in the CF airways, lack of evidence-based guidelines for managing PEx, limited utility for antimicrobial susceptibility testing, and increased frequency of adverse drug events in pwCF. This article describes current evidence-based antimicrobial treatment strategies for pwCF, highlights the potential for AMS to beneficially impact CF care, and provides practical strategies for integrating AMS programs into the management of PEx in pwCF.

PMID:36069899 | DOI:10.1093/jpids/piac071

J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S23-S31. doi: 10.1093/jpids/piac073.

ABSTRACT

As opposed to acute respiratory infections, the persistent bacterial infections of the lung that characterize cystic fibrosis (CF) provide ample time for bacteria to evolve and adapt. The process of adaptation is recorded in mutations that accumulate over time in the genomes of the infecting bacteria. Some of these mutations lead to obvious phenotypic differences such as antibiotic resistance or the well-known mucoid phenotype of Pseudomonas aeruginosa. Other mutations may be just as important but harder to detect such as increased mutation rates, cell surface changes, and shifts in metabolism and nutrient acquisition. Remarkably, many of the adaptations occur again and again in different patients, signaling that bacteria are adapting to solve specific challenges in the CF respiratory tract. This parallel evolution even extends across distinct bacterial species. This review addresses the bacterial systems that are known to change in long-term CF infections with a special emphasis on cross-species comparisons. Consideration is given to how adaptation may impact health in CF, and the possible evolutionary mechanisms that lead to the repeated parallel adaptations.

PMID:36069898 | DOI:10.1093/jpids/piac073

J Pediatric Infect Dis Soc. 2022 Sep 7;11(Supplement_2):S1-S2. doi: 10.1093/jpids/piac077.

NO ABSTRACT

PMID:36069897 | DOI:10.1093/jpids/piac077

Microbiology (Reading). 2022 Sep;168(9). doi: 10.1099/mic.0.001237.

ABSTRACT

Mycobacterium abscessusis an opportunistic human pathogen of increasing concern, due to its ability to cause aggressive pulmonary infections (especially in cystic fibrosis patients), as well as skin and soft tissue infections. M. abscessus is intrinsically drug resistant and treatment regimens are lengthy, consisting of multiple antibiotics with severe side effects and poor patient success rates. New and novel strategies are urgently required to combat these infections. One such strategy thus far overlooked for mycobacteria is manuka honey. For millennia manuka honey has been shown to have wide ranging medicinal properties, which have more recently been identified for its broad spectrum of antimicrobial activity. Here we demonstrate that manuka honey can be used to inhibit M. abscessus and a variety of drug resistant clinical isolates in vitro. We also demonstrate using a microbroth dilution checkerboard assay that manuka honey works synergistically with amikacin, which is one of the current front line antibiotics used for treatment of M. abscessus infections. This was further validated using an in vitro inhalation model, where we showed that with the addition of manuka honey, the amikacin dosage can be lowered whilst increasing its efficacy. These findings demonstrate the utility of manuka honey for incorporation into nebulised antibiotic treatment for respiratory infections, in particular M. abscessus. These results pave the way for a change of strategy for M. abscessus management, offering new therapeutic options for this deadly infection.

PMID:36069786 | DOI:10.1099/mic.0.001237

J Physiol. 2022 Sep 6. doi: 10.1113/JP282308. Online ahead of print.

ABSTRACT

KEY POINTS: Human genome information can help finding drugs for human diseases. 'Omics' allow unbiased identification of novel drug targets. High-throughput (HT) approaches provide a global view on disease mechanisms. As a monogenic disease CF has led the way in multiple 'Omic' studies. 'Multi-omics' integration will generate maximal biological significance.

ABSTRACT: Today Biomedicine faces one of its greatest challenges, i.e. treating diseases through their causative dysfunctional processes and not just their symptoms. However, we still miss a global view of mechanisms and pathways involved in pathophysiology of most diseases. In fact, disease mechanisms and pathways can be achieved by holistic studies provided by 'Omic' approaches. Cystic Fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which encodes an anion channel, is paradigmatic for monogenic disorders, namely channelopathies. A high number of 'omics studies' have focussed on CF, namely several cell-based high-throughput (HT) approaches were developed and applied towards a global mechanistic characterization of CF pathophysiology and the identification of novel and 'unbiased' drug targets. Notwithstanding, it is likely that, through the integration of all these 'layers' of large datasets into comprehensive disease maps that biological significance can be extracted so that the enormous potential of these approaches to identifying dysfunctional mechanisms and novel drugs may become a reality. Abstract figure legend Schematic overview of the 3 main approaches to discovery of new drugs/drug targets. This article is protected by copyright. All rights reserved.

PMID:36068724 | DOI:10.1113/JP282308

Indian J Pediatr. 2022 Sep 7. doi: 10.1007/s12098-022-04353-3. Online ahead of print.

NO ABSTRACT

PMID:36068401 | DOI:10.1007/s12098-022-04353-3

J Cyst Fibros. 2022 Sep 3:S1569-1993(22)00653-1. doi: 10.1016/j.jcf.2022.08.016. Online ahead of print.

ABSTRACT

INTRODUCTION: In patients with cystic fibrosis (CF), it is still unclear to which extent glucose abnormalities - preceding the diagnosis of cystic fibrosis related diabetes (CFRD) - are associated with pulmonary and nutritional outcome parameters. This study related circadian glycemic patterns to clinical outcomes in a group of CF patients not previously diagnosed with diabetes.

METHODS: Continuous glucose monitoring (CGM) readings (7 days) of 47 CF patients (26 children, 21 adults) with an impaired oral glucose tolerance test (OGTT) (n = 25) and/or increased Hb1Ac (> 5.5%) were analyzed. Biometric, pulmonary function and clinical parameters were retrospectively collected over a period of 1 year before (T-1) and 1 year after (T + 1) CGM (T0).

RESULTS: 96% (45/47) of CGM readings showed glucose values > 140 mg/dL ≥ 4.5% of the time and at least one ≥ 200 mg/dL. In the pediatric cohort, no significant associations were found between CGM parameters and pulmonary and nutritional outcome parameters. In the adult cohort, an area under the curve (AUC) > 140 mg/dL and%-time > 140 mg/dL during the night were associated with a lower forced expiratory volume in 1 s (FEV1)% predicted (pp) at time of evaluation but not with change in FEV1pp.

CONCLUSION: This is the first study reporting the circadian glycemic pattern in children and adults at risk for CFRD. In the adult cohort an association between detection of abnormal glucose exposure and a lower FEV1pp was found. Our results support continued screening for glucose intolerance in patients with CF.

PMID:36068119 | DOI:10.1016/j.jcf.2022.08.016

Chron Respir Dis. 2022 Jan-Dec;19:14799731221121670. doi: 10.1177/14799731221121670.

ABSTRACT

BACKGROUND: The roles of physical activity (PA) and exercise within the management of cystic fibrosis (CF) are recognised by their inclusion in numerous standards of care and treatment guidelines. However, information is brief, and both PA and exercise as multi-faceted behaviours require extensive stakeholder input when developing and promoting such guidelines.

METHOD: On 30th June and 1st July 2021, 39 stakeholders from 11 countries, including researchers, healthcare professionals and patients participated in a virtual conference to agree an evidence-based and informed expert consensus about PA and exercise for people with CF. This consensus presents the agreement across six themes: (i) patient and system centred outcomes, (ii) health benefits, iii) measurement, (iv) prescription, (v) clinical considerations, and (vi) future directions. The consensus was achieved by a stepwise process, involving: (i) written evidence-based synopses; (ii) peer critique of synopses; (iii) oral presentation to consensus group and peer challenge of revised synopses; and (iv) anonymous voting on final proposed synopses for adoption to the consensus statement.

RESULTS: The final consensus document includes 24 statements which surpassed the consensus threshold (>80% agreement) out of 30 proposed statements.

CONCLUSION: This consensus can be used to support health promotion by relevant stakeholders for people with CF.

PMID:36068015 | DOI:10.1177/14799731221121670

Stem Cell Res. 2022 Aug 18;64:102896. doi: 10.1016/j.scr.2022.102896. Online ahead of print.

ABSTRACT

Induced pluripotent stem cells (iPSCs) was successfully generated from skin fibroblast obtained from patient with cystic fibrosis by using non-integrating, viral CytoTune™-iPS 2.0 Sendai Reprogramming Kit, which contain three vectors preparation: polycistronic Klf4-Oct3/4-Sox2, cMyc, and Klf4. Created iPSC lines showed a normal karyotype, expressed pluripotency markers and demonstrated the potential to differentiate into three germ layers in spontaneous differentiation assay.

PMID:36067639 | DOI:10.1016/j.scr.2022.102896

J Exp Med. 2022 Nov 7;219(11):e20220551. doi: 10.1084/jem.20220551. Epub 2022 Sep 6.

ABSTRACT

Human adaptive-like natural killer (NK) cells express low levels of FcεRIγ (FcRγ-/low) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcRγ expression in NK cells has yet to be fully defined. We observed lower FcRγ protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcRγ-/low NK cell subsets from healthy donors displayed reduced mTOR activity. We discovered that FcRγ upregulation is dependent on cell proliferation progression mediated by IL-2, IL-15, or IL-12, is sensitive to mTOR suppression, and is inhibited by TGFβ or IFNα. Accordingly, the accumulation of adaptive-like FcRγ-/low NK cells in COVID-19 patients corresponded to increased TGFβ and IFNα levels and disease severity. Our results show that an adaptive-like NK cell phenotype is induced by diminished cell proliferation and has an early prognostic value for increased TGFβ and IFNα levels in COVID-19 infection associated with disease severity.

PMID:36066491 | DOI:10.1084/jem.20220551

Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221122572. doi: 10.1177/17534666221122572.

ABSTRACT

BACKGROUND: Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy.

OBJECTIVES: To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF.

DESIGN AND METHODS: A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required.

RESULTS: No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified.

DISCUSSION AND CONCLUSION: This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essential.

REGISTRATION: This systematic review was registered on the PROSPERO database (CRD42020206033).

PMID:36066081 | DOI:10.1177/17534666221122572

J Cell Physiol. 2022 Sep 5. doi: 10.1002/jcp.30867. Online ahead of print.

ABSTRACT

Extracellular vehicles (EVs) are nanoscale lipid bilayer vesicles that carry biologically active biomolecule cargos like proteins, lipids, and nucleic acids (DNA, RNA) outside of the cell. Blood (serum/plasma), urine, and bronchoalveolar lavage fluid are all examples of biofluids from which they may be collected. EVs play a vital role in intracellular communication. The molecular signature of EVs largely depends on the parental cell's status. EVs are classified into two groups, (1) exosomes (originated by endogenous route) and (2) microvesicles (originated from the plasma membrane, also known as ectosomes). The quantity and types of EV cargo vary during normal conditions compared to pathological conditions (chronic inflammatory lung diseases or lung cancer). Consequently, EVs contain novel biomarkers that differ based on the cell type of origin and during lung diseases. Small RNAs (e.g., microRNAs) are transported by EVs, which is one of the most rapidly evolving research areas in the field of EVs biology. EV-mediated cargos transport small RNAs that can result in reprograming the target/recipient cells. Multiple chronic inflammatory lung illnesses, such as chronic obstructive pulmonary disease, asthma, pulmonary hypertension, pulmonary fibrosis, cystic fibrosis, acute lung injury, and lung cancer, have been demonstrated to be regulated by EV. In this review, we will consolidate the current knowledge and literature on the novel role of EVs and their small RNAs concerning chronic lung diseases (CLDs). Additionally, we will also provide better insight into the clinical and translational impact of mesenchymal stem cells-derived EVs as novel therapeutic agents in treating CLDs.

PMID:36063496 | DOI:10.1002/jcp.30867

Pediatr Pulmonol. 2022 Sep 5. doi: 10.1002/ppul.26137. Online ahead of print.

ABSTRACT

OBJECTIVE: To develop diagnostic algorithm for cystic fibrosis (CF) in setting of unavailability of sweat chloride, based on clinical features and basic laboratory investigations.

METHODS: In a prospective observational study, we enrolled children with recurrent/persistent pneumonia with either malabsorption or poor growth, undergoing sweat chloride test, between January 2019 and December 2020. They were simultaneously evaluated for aquagenic wrinkling of hands, stool fat globules, sputum for bacterial culture, blood gas and serum electrolytes. Sensitivity and specificity were calculated for parameters having significant difference between CF and non-CF group. Scoring systems and algorithm for diagnosis of CF were developed.

RESULTS: Of 134 children enrolled, 46 (34%) had CF. The sensitivity and specificity of various parameters to diagnose CF was: sibling death due to respiratory illness (30.43%, 96.59%), aquagenic wrinkling (76.74%, 47.67%), metabolic alkalosis (17.78%, 94.12%), hyponatremia (28.89%, 89.41%), stool fat globules (38.46%, 81.18%), and presence of Pseudomonas in sputum culture (23.68%, 98.80%). Using coefficients of significant parameters on stepwise logistic regression, composite score for diagnosis of CF were calculated as: 3X sibling death due to respiratory illness + 1.5X hyponatremia + 1.5X metabolic alkalosis + 1.5X aquagenic wrinkling + 1X stool fat globules + 2.5X presence of Pseudomonas in sputum culture (each of the variables score 0 or 1 for absence and presence, respectively). Cut-off of ≥2.5 had sensitivity and specificity of 81.82% and 76.83%, respectively.

CONCLUSIONS: In resource limited settings, the proposed diagnostic algorithm can be used for diagnosis of presumptive CF with fair sensitivity and specificity. This article is protected by copyright. All rights reserved.

PMID:36062940 | DOI:10.1002/ppul.26137

Am J Physiol Cell Physiol. 2022 Sep 5. doi: 10.1152/ajpcell.00248.2022. Online ahead of print.

ABSTRACT

Disordered sleep experienced by people with cystic fibrosis (CF) suggest a possible disruption in circadian regulation being associated with the loss of cystic fibrosis transmembrane conductance regulator (Cftr) function. To test this hypothesis, circadian regulation was assessed in a F508del/F508del CF mouse model. CF mice exhibited significant alterations in both timing of locomotor activity and in mean activity per hour in both light-dark (LD) and dark-dark (DD) photoperiods compared to wild type (WT) controls. It was also noted that in DD, periodicity increased in CF mice, while shortening in WT mice as is expected. CF mice also exhibited altered timing of circadian gene expression and a reduction of melatonin production at all time points. Mechanistically, the role of microtubules in regulating these outcomes was explored. Mice lacking expression of tubulin polymerization promoting protein (Tppp) effectively mimicked CF mouse phenotypes with each measured outcome. Depleting expression of the microtubule regulatory protein histone deacetylase 6 (Hdac6) from CF mice (CF/Hdac6) resulted in the reversal of each phenotype to WT profiles. These data demonstrate an innate disruption of circadian regulation in CF mice and identify a novel microtubule-related mechanism leading to this disruption that can be targeted for therapeutic intervention.

PMID:36062879 | DOI:10.1152/ajpcell.00248.2022

Am J Physiol Cell Physiol. 2022 Sep 5. doi: 10.1152/ajpcell.00319.2022. Online ahead of print.

ABSTRACT

We previously identified potentiators of KCa3.1 (DCEBIO) that stimulate Cl- secretion across HBEs expressing wild type (WT) CFTR. However, these compounds failed to stimulate Cl- secretion in F508del CFTR HBEs. Drug discovery efforts identified CFTR potentiators (VX-770) and correctors (VX-445, VX-661) for CF disease causing mutations, including F508del and G551D. Herein, we evaluated the effect of KCa3.1 potentiation on Cl- equivalent current (ICl) across primary HBEs expressing WT, F508del and G551D CFTR. Transepithelial impedance analysis was used to obtain estimates of apical (Ra) and basolateral membrane (BLM; Rb) resistances. In WT CFTR HBEs, DCEBIO stimulated ICl, which was increased by forskolin. Similarly, forskolin stimulated ICl, and this was increased by DCEBIO. The KCa3.1 blocker, TRAM-34 inhibited ICl. DCEBIO decreased Rb, whereas TRAM-34 increased Rb, consistent with BLM localization of KCa3.1. Following correction of F508del CFTR with VX-445+VX-661, DCEBIO failed to stimulate ICl, although the subsequent addition of forskolin+VX-770 increased ICl. Importantly, following stimulation of ICl with forskolin+VX-770, DCEBIO induced a further significant increase in ICl. As above, DCEBIO reduced Rb, whereas TRAM-34 increased Rb, consistent with BLM localized KCa3.1. Finally, we assessed KCa3.1 potentiation on ICl in G551D/F508del CFTR HBEs in the absence or presence of VX-445+VX-661. In both cases, DCEBIO failed to stimulate ICl. However, following stimulation with forskolin+VX-770, DCEBIO nearly doubled ICl. Our results demonstrate, following correction/potentiation of F508del and G551D CFTR, potentiation of KCa3.1 increases the Cl- secretory response, suggesting this class of compounds may represent a novel means of further increasing Cl- secretion across CF airway.

PMID:36062876 | DOI:10.1152/ajpcell.00319.2022

Front Artif Intell. 2022 Aug 18;5:948313. doi: 10.3389/frai.2022.948313. eCollection 2022.

ABSTRACT

Social media has become an important resource for discussing, sharing, and seeking information pertinent to rare diseases by patients and their families, given the low prevalence in the extraordinarily sparse populations. In our previous study, we identified prevalent topics from Reddit via topic modeling for cystic fibrosis (CF). While we were able to derive/access concerns/needs/questions of patients with CF, we observed challenges and issues with the traditional techniques of topic modeling, e.g., Latent Dirichlet Allocation (LDA), for fulfilling the task of topic extraction. Thus, here we present our experiments to extend the previous study with an aim of improving the performance of topic modeling, by experimenting with LDA model optimization and examination of the Top2Vec model with different embedding models. With the demonstrated results with higher coherence and qualitatively higher human readability of derived topics, we implemented the Top2Vec model with doc2vec as the embedding model as our final model to extract topics from a subreddit of CF ("r/CysticFibrosis") and proposed to expand its use with other types of social media data for other rare diseases for better assessing patients' needs with social media data.

PMID:36062265 | PMC:PMC9433987 | DOI:10.3389/frai.2022.948313