Exp Lung Res. 2021 Oct 11:1-9. doi: 10.1080/01902148.2021.1989523. Online ahead of print.

ABSTRACT

Current gene therapy delivery protocols for small animal lungs typically utilize indirect dose delivery via the nasal airways, or bolus delivery directly into the trachea. Both methods can result in variable transduction throughout the lung, as well as between animals, and cannot be applied in a targeted manner. To minimize variability and improve lung coverage we previously developed and validated a method to visualize and dose gene vectors into pre-selected lobes of rat lungs using a mini-bronchoscope. Lentiviral (LV) vectors are known to be fragile and can be inactivated easily by temperature or the application of shear stresses. There are several ways that the bronchoscope could be configured to deliver the LV vector, and these could result in different amounts of functional LV vector being delivered to the lung. This study evaluated several methods of LV vector delivery through the bronchoscope, and how flow rates and LV vector stabilizing diluents impact LV vector delivery. NIH-3T3 cells were exposed to LV vector containing the green fluorescent protein (GFP) reporter gene using various bronchoscopic delivery techniques and the number of GFP-positive cells produced by each was quantified by flow cytometry. The results showed that directly drawing the LV vector into the bronchoscope tip resulted in 80-90% recovery of viable vector, and was also the simplest method of delivery. The fluid delivery rate and the use of stabilizing serum in the vector diluent had no effect on the viability of the LV vector delivered. These findings can be used to optimize LV vector dose delivery into individual lung lobes of small animal models.

PMID:34632894 | DOI:10.1080/01902148.2021.1989523

Lancet Microbe. 2021 Oct;2(10):e498-e507. doi: 10.1016/S2666-5247(21)00128-2.

ABSTRACT

BACKGROUND: Mycobacterium abscessus has emerged as a significant clinical concern following reports that it is readily transmissible in health-care settings between patients with cystic fibrosis. We linked routinely collected whole-genome sequencing and health-care usage data with the aim of investigating the extent to which such transmission explains acquisition in patients with and without cystic fibrosis in England.

METHODS: In this retrospective observational study, we analysed consecutive M abscessus whole-genome sequencing data from England (beginning of February, 2015, to Nov 14, 2019) to identify genomically similar isolates. Linkage to a national health-care usage database was used to investigate possible contacts between patients. Multivariable regression analysis was done to investigate factors associated with acquisition of a genomically clustered strain (genomic distance <25 single nucleotide polymorphisms [SNPs]).

FINDINGS: 2297 isolates from 906 patients underwent whole-genome sequencing as part of the routine Public Health England diagnostic service. Of 14 genomic clusters containing isolates from ten or more patients, all but one contained patients with cystic fibrosis and patients without cystic fibrosis. Patients with cystic fibrosis were equally likely to have clustered isolates (258 [60%] of 431 patients) as those without cystic fibrosis (322 [63%] of 513 patients; p=0·38). High-density phylogenetic clusters were randomly distributed over a wide geographical area. Most isolates with a closest genetic neighbour consistent with potential transmission had no identifiable relevant epidemiological contacts. Having a clustered isolate was independently associated with increasing age (adjusted odds ratio 1·14 per 10 years, 95% CI 1·04-1·26), but not time spent as an hospital inpatient or outpatient. We identified two sibling pairs with cystic fibrosis with genetically highly divergent isolates and one pair with closely related isolates, and 25 uninfected presumed household contacts with cystic fibrosis.

INTERPRETATION: Previously identified widely disseminated dominant clones of M abscessus are not restricted to patients with cystic fibrosis and occur in other chronic respiratory diseases. Although our analysis showed a small number of cases where person-to-person transmission could not be excluded, it did not support this being a major mechanism for M abscessus dissemination at a national level in England. Overall, these data should reassure patients and clinicians that the risk of acquisition from other patients in health-care settings is relatively low and motivate future research efforts to focus on identifying routes of acquisition outside of the cystic fibrosis health-care-associated niche.

FUNDING: The National Institute for Health Research, Health Data Research UK, The Wellcome Trust, The Medical Research Council, and Public Health England.

PMID:34632432 | PMC:PMC8481905 | DOI:10.1016/S2666-5247(21)00128-2

FASEB Bioadv. 2021 Aug 2;3(10):841-854. doi: 10.1096/fba.2021-00043. eCollection 2021 Oct.

ABSTRACT

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The F508del and G542X are the most common mutations found in US patients, accounting for 86.4% and 4.6% of all mutations, respectively. The F508del causes deletion of the phenylalanine residue at position 508 and is associated with impaired CFTR protein folding. The G542X is a nonsense mutation that introduces a stop codon into the mRNA, thus preventing normal CFTR protein synthesis. Here, we describe the generation of CFTRF508del / F508del and CFTRG542X / G542X lambs using CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). First, we introduced either F508del or G542X mutations into sheep fetal fibroblasts that were subsequently used as nuclear donors for SCNT. The newborn CF lambs develop pathology similar to CFTR -/- sheep and CF patients. Moreover, tracheal epithelial cells from the CFTRF508del / F508del lambs responded to a human CFTR (hCFTR) potentiator and correctors, and those from CFTRG542X / G542X lambs showed modest restoration of CFTR function following inhibition of nonsense-mediated decay (NMD) and aminoglycoside antibiotic treatments. Thus, the phenotype and electrophysiology of these novel models represent an important advance for testing new CF therapeutics and gene therapy to improve the health of patients with this life-limiting disorder.

PMID:34632318 | PMC:PMC8493969 | DOI:10.1096/fba.2021-00043

Front Cell Infect Microbiol. 2021 Sep 22;11:718213. doi: 10.3389/fcimb.2021.718213. eCollection 2021.

ABSTRACT

Pseudomonas aeruginosa is a major opportunistic human pathogen which employs a myriad of virulence factors. In people with cystic fibrosis (CF) P. aeruginosa frequently colonises the lungs and becomes a chronic infection that evolves to become less virulent over time, but often adapts to favour persistence in the host with alginate-producing mucoid, slow-growing, and antibiotic resistant phenotypes emerging. Cysteamine is an endogenous aminothiol which has been shown to prevent biofilm formation, reduce phenazine production, and potentiate antibiotic activity against P. aeruginosa, and has been investigated in clinical trials as an adjunct therapy for pulmonary exacerbations of CF. Here we demonstrate (for the first time in a prokaryote) that cysteamine prevents glycine utilisation by P. aeruginosa in common with previously reported activity blocking the glycine cleavage system in human cells. Despite the clear inhibition of glycine metabolism, cysteamine also inhibits hydrogen cyanide (HCN) production by P. aeruginosa, suggesting a direct interference in the regulation of virulence factor synthesis. Cysteamine impaired chemotaxis, lowered pyocyanin, pyoverdine and exopolysaccharide production, and reduced the toxicity of P. aeruginosa secreted factors in a Galleria mellonella infection model. Thus, cysteamine has additional potent anti-virulence properties targeting P. aeruginosa, further supporting its therapeutic potential in CF and other infections.

PMID:34631600 | PMC:PMC8494450 | DOI:10.3389/fcimb.2021.718213

World J Gastrointest Endosc. 2021 Sep 16;13(9):371-381. doi: 10.4253/wjge.v13.i9.371.

ABSTRACT

BACKGROUND: Symptomatic biliary and gallbladder disorders are common in adults with cystic fibrosis (CF) and the prevalence may rise with increasing CF transmembrane conductance regulator modulator use. Cholecystectomy may be considered, but the outcomes of cholecystectomy are not well described among modern patients with CF.

AIM: To determine the risk profile of inpatient cholecystectomy in patients with CF.

METHODS: The Nationwide Inpatient Sample was queried from 2002 until 2014 to investigate outcomes of cholecystectomy among hospitalized adults with CF compared to controls without CF. A propensity weighted sample was selected that closely matched patient demographics, patient's individual comorbidities, and hospital characteristics. The propensity weighted sample was used to compare outcomes among patients who underwent laparoscopic cholecystectomy. Hospital outcomes of open and laparoscopic cholecystectomy were compared among adults with CF.

RESULTS: A total of 1239 inpatient cholecystectomies were performed in patients with CF, of which 78.6% were performed laparoscopically. Mortality was < 0.81%, similar to those without CF (P = 0.719). In the propensity weighted analysis of laparoscopic cholecystectomy, there was no difference in mortality, or pulmonary or surgical complications between patients with CF and controls. After adjusting for significant covariates among patients with CF, open cholecystectomy was independently associated with a 4.8 d longer length of stay (P = 0.018) and an $18449 increase in hospital costs (P = 0.005) compared to laparoscopic cholecystectomy.

CONCLUSION: Patients with CF have a very low mortality after cholecystectomy that is similar to the general population. Among patients with CF, laparoscopic approach reduces resource utilization and minimizes post-operative complications.

PMID:34630887 | PMC:PMC8474692 | DOI:10.4253/wjge.v13.i9.371

Arch Bronconeumol. 2021 Jan;57:92-94. doi: 10.1016/j.arbres.2020.09.017. Epub 2020 Oct 22.

NO ABSTRACT

PMID:34629680 | PMC:PMC7577873 | DOI:10.1016/j.arbres.2020.09.017

J Cyst Fibros. 2021 Oct 7:S1569-1993(21)01422-3. doi: 10.1016/j.jcf.2021.09.017. Online ahead of print.

ABSTRACT

Background Cystic fibrosis (CF) lung disease is characterised by recurrent Pseudomonas aeruginosa (Pa) infections, leading to structural lung damage and decreased survival. The epidemiology of Pa infection and its impact on lung function in people with CF (pwCF), especially in recent birth cohorts, remain uncertain. Methods We included 1,231 French pwCF under 18 years of age. Age at initial acquisition (Pa-IA), chronic colonisation (Pa-CC), and duration from Pa-IA to Pa-CC were estimated using the Kaplan-Meier method. Demographic, clinical, and genetic characteristics were analysed as risk factors for Pa infection using Cox regression models. Lung function decline was assessed by modelling percent-predicted forced expiratory volume in 1 s (ppFEV1) before Pa infection, after Pa-IA, and after Pa-CC. Results Among the 1,231 pwCF, 50% had Pa-IA by the age of 5.1 years [95% confidence interval (CI) 3.8-6.2] and 25% had Pa-CC by the age of 14.7 years (95% CI 12.1 to ∞). We observed that CF-related diabetes and liver disease were risk factors for Pa, while gender, CFTR variants, and CF centre size were not. Genetic variants of TNF, DCTN4, SLC9A3, and CAV2 were confirmed to be associated with Pa. The annual rate of ppFEV1 decline before Pa was -0.38% predicted/year (95% CI -0.59 to -0.18), which decreased significantly after Pa-IA to -0.93% predicted/year (95% CI -1.14 to -0.71) and after Pa-CC to -1.51% predicted/year (95% CI -1.86 to -1.16). Conclusions We identified and replicated several risk factors associated with Pa infection and showed its deleterious impact on lung function in young pwCF. This large-scale study confirmed that Pa airway infection is a major determinant of lung disease severity.

PMID:34629287 | DOI:10.1016/j.jcf.2021.09.017

ISME J. 2021 Oct 9. doi: 10.1038/s41396-021-01130-6. Online ahead of print.

ABSTRACT

The efficacy of antibiotic treatments targeting polymicrobial communities is not well predicted by conventional in vitro susceptibility testing based on determining minimum inhibitory concentration (MIC) in monocultures. One reason for this is that inter-species interactions can alter the community members' susceptibility to antibiotics. Here we quantify, and identify mechanisms for, community-modulated changes of efficacy for clinically relevant antibiotics against the pathogen Pseudomonas aeruginosa in model cystic fibrosis (CF) lung communities derived from clinical samples. We demonstrate that multi-drug resistant Stenotrophomonas maltophilia can provide high levels of antibiotic protection to otherwise sensitive P. aeruginosa. Exposure protection to imipenem was provided by chromosomally encoded metallo-β-lactamase that detoxified the environment; protection was dependent upon S. maltophilia cell density and was provided by S. maltophilia strains isolated from CF sputum, increasing the MIC of P. aeruginosa by up to 16-fold. In contrast, the presence of S. maltophilia provided no protection against meropenem, another routinely used carbapenem. Mathematical ordinary differential equation modelling shows that the level of exposure protection provided against different carbapenems can be explained by differences in antibiotic efficacy and inactivation rate. Together, these findings reveal that exploitation of pre-occurring antimicrobial resistance, and inter-specific competition, can have large impacts on pathogen antibiotic susceptibility, highlighting the importance of microbial ecology for designing successful antibiotic treatments for multispecies communities.

PMID:34628478 | DOI:10.1038/s41396-021-01130-6

Microbiol Res. 2021 Oct 5;253:126887. doi: 10.1016/j.micres.2021.126887. Online ahead of print.

ABSTRACT

Mycobacterium abscessus complex (MABC) infections cause significant morbidity and mortality among patients with chronic lung disease, like cystic fibrosis. MABC exists in smooth (S) and rough (R) morphotypes, but triggers of morphotype switching and associated pathogenicity or antimicrobial susceptibility are poorly understood. We demonstrate that M. abscessus subspecies abscessus (Mab), massiliense (Mms), and bolletii (Mbl) cultured in Middlebrook (MB) broth exhibit S morphotype, whereas the bacteria grown in Luria Bertani (LB) broth adopt the R morphotype, characterized by low glycopeptidolipid (GPL) expression. The components of broth that mediate this selection are complex, with albumin supplementation promoting growth of S morphotype, but not sufficient for complete selection. Consistent with the findings of other groups, R forms of Mab, Mms and Mbl selected by LB broth were internalized in RAW 264.7 macrophages with higher efficiency than S. Intracellular survival of broth-selected organisms was variable and was higher for S Mab, but lower for S Mms and Mbl. It is proposed that growth in R morphotype is induced during stress conditions, such as nutrient poor environments or during inflammation. One key component of inflammation is release of nitric oxide. We demonstrated that a nitric oxide donor (DETA-NONOate) appears to induce growth in an R morphotype, as indicated by reduced GPL expression of Mab. Mab treated with DETA-NONOate also enhanced susceptibility to azithromycin at sub-MIC concentrations. In conclusion, morphotype and macrophage intracellular bacterial load of MABC subspecies can be manipulated by growing the bacteria in different culture conditions. Nitric oxide may also drive morphotype selection and enhanced azithromycin activity against Mab and macrophage killing.

PMID:34628130 | DOI:10.1016/j.micres.2021.126887

Lancet Respir Med. 2021 Oct 7:S2213-2600(21)00383-0. doi: 10.1016/S2213-2600(21)00383-0. Online ahead of print.

ABSTRACT

BACKGROUND: The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes.

METHODS: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107).

FINDINGS: We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9-6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40-59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity.

INTERPRETATION: We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care.

FUNDING: UK Research and Innovation and National Institute for Health Research.

PMID:34627560 | DOI:10.1016/S2213-2600(21)00383-0

J Transl Med. 2021 Oct 9;19(1):419. doi: 10.1186/s12967-021-03092-x.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) patients present with a variety of symptoms, including mood and cognition deficits, in addition to classical respiratory, and autonomic issues. This suggests that brain injury, which can be examined with non-invasive magnetic resonance imaging (MRI), is a manifestation of this condition. However, brain tissue integrity in sites that regulate cognitive, autonomic, respiratory, and mood functions in CF patients is unclear. Our aim was to assess regional brain changes using high-resolution T1-weighted images based gray matter (GM) density and T2-relaxometry procedures in CF over control subjects.

METHODS: We acquired high-resolution T1-weighted images and proton-density (PD) and T2-weighted images from 5 CF and 15 control subjects using a 3.0-Tesla MRI. High-resolution T1-weighted images were partitioned to GM-tissue type, normalized to a common space, and smoothed. Using PD- and T2-weighted images, whole-brain T2-relaxation maps were calculated, normalized, and smoothed. The smoothed GM-density and T2-relaxation maps were compared voxel-by-voxel between groups using analysis of covariance (covariates, age and sex; SPM12, p < 0.001).

RESULTS: Significantly increased GM-density, indicating tissues injury, emerged in multiple brain regions, including the cerebellum, hippocampus, amygdala, basal forebrain, insula, and frontal and prefrontal cortices. Various brain areas showed significantly reduced T2-relaxation values in CF subjects, indicating predominant acute tissue changes, in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum.

CONCLUSIONS: Cystic fibrosis subjects show predominant acute tissue changes in areas that control mood, cognition, respiratory, and autonomic functions and suggests that tissue changes may contribute to symptoms resulting from ongoing hypoxia accompanying the condition.

PMID:34627274 | DOI:10.1186/s12967-021-03092-x

J Allergy Clin Immunol Pract. 2021 Oct 6:S2213-2198(21)01060-6. doi: 10.1016/j.jaip.2021.09.033. Online ahead of print.

ABSTRACT

BACKGROUND: Addition of a long-acting muscarinic antagonist (LAMA) is recommended for patients with asthma uncontrolled on inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy. This is the first large-scale, real-world study examining multiple-inhaler triple-therapy (MITT) use in asthma.

OBJECTIVE: To describe real-world prevalence, outcomes and treatment patterns associated with MITT.

METHODS: This retrospective cohort study used medical and pharmacy claims from the Optum Research Database. Patients were diagnosed with asthma between January 01, 2013-July 31, 2018 with evidence of MITT use (≥1 overlapping days' supply of ICS, LABA and LAMA). Annual MITT prevalence (primary endpoint) was assessed in the prevalent population; eligible patients were ≥18 years with ≥2 asthma diagnoses during the study period, and continuous enrollment for the entire year. Secondary outcomes (adherence [proportion of days covered [PDC]], MITT persistence, healthcare resource utilization [HCRU], costs) were assessed in the incident MITT population; eligible patients were ≥18 years, with ≥2 asthma diagnoses and continuous enrollment during both the 12-month baseline and 12-month follow-up periods. Patients with chronic obstructive pulmonary disease or cystic fibrosis were excluded.

RESULTS: MITT prevalence was low but increased from 0.35% (95% confidence interval [CI]: 0.32, 0.37) in 2014/2015 to 1.00% (95% CI: 0.96, 1.04) in 2017/2018. Among 1,831 incident MITT users there was a substantial disease burden, demonstrated by high HCRU and exacerbation rates. Adherence and persistence to MITT was low (mean [SD] PDC: 0.31 [0.27]) and 12% (n=216) remained on MITT 12 months post-initiation.

CONCLUSIONS: Overall, MITT use among patients with asthma is low. Patients initiating MITT have substantial disease burden and significant unmet needs.

PMID:34626859 | DOI:10.1016/j.jaip.2021.09.033

Acta Paediatr. 2021 Oct 8. doi: 10.1111/apa.16143. Online ahead of print.

ABSTRACT

AIM: Gastrointestinal (GI) symptoms are often reported by CF-patients. Despite a proven relation to exocrine pancreatic insufficiency (PI), it remains unclear whether GI symptoms are related to the timing of pancreatic enzyme replacement therapy (PERT). Whereas most international recommendations suggest administration of PERT at the beginning of meals, it has not been studied whether such a proceeding is associated with lower burden of symptoms.

METHODS: Thirty CF patients aged 0-17 years of age with PI were randomized to four weeks of PERT prior to meals followed by four weeks of PERT after meals or vice versa. Using the CF-specific validated CFAbd-Score, abdominal pain, dysfunctional bowel habits and Quality of Life (QoL) related to GI symptoms were assessed in relation to the timing of PERT. Data was analyzed using a linear mixed model.

RESULTS: There was no significant difference regarding abdominal pain, bowel habits or QoL related to GI symptoms when timing of PERT was changed from prior to after meals.

CONCLUSION: No significant difference was found when administration mode of PERT changed from prior to after meals or vice versa. However, after an individual assessment, some patients may profit from changing administration mode of PERT from prior to after meals.

PMID:34626004 | DOI:10.1111/apa.16143

Respir Med. 2021 Sep 25;189:106623. doi: 10.1016/j.rmed.2021.106623. Online ahead of print.

ABSTRACT

BACKGROUND: As most cystic fibrosis (CF) patients progress to respiratory failure, lung functionality assessment is pivotal. We previously developed a test that indirectly monitors airways (inflammation/functional test) by measuring the spin-spin relaxation time (T2m) of the water hydrogens present in CF sputum. Here the T2m significance in the monitoring of CF lung disease was further investigated by studying the correlation of T2m with: 1) sputum viscoelasticity, 2) mucociliary clearability index (MCI)/cough clearability index (CCI) and 3) sputum average mesh-size.

METHODS: Sputum samples from 25 consenting CF subjects were analyzed by rheology tests (elastic modulus G and zero shear viscosity η0) and Low Field Nuclear Magnetic (LF-NMR) resonance (T2m). MCI/CCI were calculated from the rheological parameters. The average mesh-size (ξ) of the sputum structure was then evaluated by rheology/LF-NMR, together with FEV1 for each patient.

RESULTS: There was an inverse correlation between G and η0 versus T2m, indicating that a worsening of the lung condition (T2m-FEV1 drop) is paralleled by an increase in sputum viscoelasticity (G and η0) favoring mucus stasis/inflammation. A direct correlation was also observed between T2m and MCI/CCI, showing that T2m provides information as to airway mucus clearing. Moreover, there was a direct correlation between T2m and the average sputum mesh size (ξ).

CONCLUSIONS: We demonstrated a correlation between T2m (measured in CF patient's sputum) and the sputum viscoelasticity/average mesh-size and with MCI/CCI, parameters related to airway mucus clearing. Thus, the present data strengthen the potential of our test to provide indirect monitoring of airway disease course in CF patients as T2m depends on mucus solid concentration and nanostructure.

PMID:34624628 | DOI:10.1016/j.rmed.2021.106623

Int J Pharm. 2021 Oct 5:121160. doi: 10.1016/j.ijpharm.2021.121160. Online ahead of print.

ABSTRACT

The multi-drug resistance of Pseudomonas aeruginosa is an overwhelming cause of terminal and persistent lung infections in cystic fibrosis (CF) patients. Antimicrobial synergy has been shown for colistin and ivacaftor, and our study designed a relatively high drug-loading dry powder inhaler formulation containing nanoparticles of ivacaftor and colistin. The ivacaftor-colistin nanosuspensions (Iva-Col-NPs) were prepared by the anti-solvent method with different stabilizers. Based on the aggregation data, the formulation 7 (F7) with DSPG-PEG-OMe as the stabilizer was selected for further studies. The F7 consisted of ivacaftor, colistin and DSPG-PEG-OMe with a mass ratio of 1:1:1. The F7 powder formulation was developed using the ultrasonic spray-freeze-drying method and exhibited a rough surface with relatively high fine particle fraction values of 61.4 ± 3.4 % for ivacaftor and 63.3 ± 3.3 % for colistin, as well as superior emitted dose of 97.8 ± 0.3 % for ivacaftor and 97.6 ± 0.5 % for colistin. The F7 showed very significant dissolution improvement for poorly water soluble ivacaftor than the physical mixture. Incorporating two drugs in a single microparticle with synchronized dissolution and superior aerosol performance will maximize the synergy and bioactivity of those two drugs. Minimal cytotoxicity in Calu-3 human lung epithelial cells and enhanced antimicrobial activity against colistin-resistant P. aeruginosa suggested that our formulation has potential to improve the treatment of CF patients with lung infections.

PMID:34624446 | DOI:10.1016/j.ijpharm.2021.121160

Health Sci Rep. 2021 Oct 1;4(4):e381. doi: 10.1002/hsr2.381. eCollection 2021 Dec.

ABSTRACT

RATIONALE AND AIMS: Lung health of people with cystic fibrosis (PwCF) can be preserved by daily use of inhaled therapy. Adherence to inhaled therapy, therefore, provides an important process measure to understand the success of care and can be used as a quality indicator. Defining adherence is problematic, however, since the number of prescribed treatments varies considerably between PwCF. The problem is less pronounced among those with Pseudomonas aeruginosa (PA), for whom at least three daily doses of nebulized therapy should be prescribed and who thus constitute a more homogeneous group. The UK CF Registry provides routine data on PA status, but data are only available 12 months after collection. In this study, we aim to prospectively identify contemporary PA status from historic registry data.

METHOD: UK CF Registry data from 2011 to 2015 for PwCF aged ≥16 was used to determine a pragmatic prediction rule for identifying contemporary PA status using historic registry data. Accuracy of three different prediction rules was assessed using the positive predictive value (PPV). The number and proportion of adults predicted to have PA infection were determined overall and per center for the selected prediction rule. Known characteristics linked to PA status were explored to ensure the robustness of the prediction rule.

RESULTS: Having CF Registry defined chronic PA status in the two previous years is the selected definition to predict a patient will have PA infection within the current year (population-level PPV = 96%-97%, centre level PPV = 85%-100%). This approach provides a subset of data between 1852 and 1872 patients overall and a range of 8 to 279 patients per center.

CONCLUSION: Historic registry data can be used to contemporaneously identify a subgroup of patients with chronic PA. Since this patient group has a narrower treatment schedule, this can facilitate a better benchmarking of adherence across centers.

PMID:34622017 | PMC:PMC8485591 | DOI:10.1002/hsr2.381

Surg Neurol Int. 2021 Sep 6;12:447. doi: 10.25259/SNI_472_2021. eCollection 2021.

ABSTRACT

BACKGROUND: Pandoraea apista is predominantly recovered from the respiratory tract of patients with cystic fibrosis (CF). Authors report first case of central nervous system infection by P. apista in the form of skull base osteomyelitis.

CASE DESCRIPTION: A 67-year-old male presented with complaints of earache and hearing deficit for few months. The radiology was suggestive of skull base osteomyelitis and polypoidal soft tissue extending from the middle cranial fossa to the infratemporal fossa. The sample from the targeted area revealed P. apista on matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. With adequate antibiotic therapy, there was clinicoradiologic improvement. P. apista is an infection exclusively seen in pulmonary infection in patients with CF. We identified its intracranial involvement in a patient for the 1st time in the literature. The serendipitous diagnosis needs evaluation on specific PCR and matrix-assisted laser desorption spectrometry. The treatment with antibiotics provides a definite cure.

CONCLUSION: We report a rare opportunistic infection with central nervous system involvement which can be cured by accurate diagnosis and appropriate antibiotic treatment.

PMID:34621562 | PMC:PMC8492433 | DOI:10.25259/SNI_472_2021

Front Immunol. 2021 Sep 21;12:745326. doi: 10.3389/fimmu.2021.745326. eCollection 2021.

ABSTRACT

Cystic Fibrosis (CF) is a genetic disease that causes chronic and severe lung inflammation and infection associated with high rates of mortality. In CF, disrupted ion exchange in the epithelium results in excessive mucus production and reduced mucociliary clearance, leading to immune system exacerbation and chronic infections with pathogens such as P. aeruginosa and S. aureus. Constant immune stimulation leads to altered immune responses including T cell impairment and neutrophil dysfunction. Specifically, CF is considered a Th17-mediated disease, and it has been proposed that both P. aeruginosa and a subset of neutrophils known as granulocytic myeloid suppressor cells (gMDSCs) play a role in T cell suppression. The exact mechanisms behind these interactions are yet to be determined, but recent works demonstrate a role for arginase-1. It is also believed that P. aeruginosa drives gMDSC function as a means of immune evasion, leading to chronic infection. Herein, we review the current literature regarding immune suppression in CF by gMDSCs with an emphasis on T cell impairment and the role of P. aeruginosa in this dynamic interaction.

PMID:34621276 | PMC:PMC8490623 | DOI:10.3389/fimmu.2021.745326

Curr Opin Pulm Med. 2021 Nov 1;27(6):538-543. doi: 10.1097/MCP.0000000000000823.

ABSTRACT

PURPOSE OF REVIEW: The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a dramatic impact that is still ongoing around the world. Cystic fibrosis (CF) has been identified as a possible risk factor of poor outcome.

RECENT FINDINGS: Data collected by multiple National CF registries around the world have indicated that persons with CF (PwCF) are not more likely to be affected by SARS-CoV-2 than the general population. The course of SARS-CoV-2 is usually mild in PwCF who are relatively young. Severe outcomes have been described in patients with low lung function and in those with immune suppression (i.e. solid organ transplantation). Indirect impact of the pandemic on the CF community has also been observed, including difficulties in the organization of CF care, leading to a dramatic increase in telehealth for PwCF. The pandemic has further affected clinical research by complicating ongoing clinical trials. Vaccination appears important to all PwCF, with special priority on developing adequate vaccination scheme for transplant recipients. Long-term effects of COVID-19 on the CF population remains unknown.

SUMMARY: The COVID-19 pandemic has caused significant impacts on PwCF and on healthcare professionals who provide specialized CF care and clinical research.

PMID:34620788 | DOI:10.1097/MCP.0000000000000823

BMJ Open Respir Res. 2021 Oct;8(1):e000877. doi: 10.1136/bmjresp-2021-000877.

ABSTRACT

BACKGROUND: A standardised framework for selecting outcomes for evaluation in trials has been proposed by the Core Outcome Measures in Effectiveness Trials working group. However, this method does not specify how to ensure that the outcomes that are selected are causally related to the disease and the health intervention being studied. Causal network diagrams may help researchers identify outcomes that are both clinically meaningful and likely to be causally dependent on the intervention, and endpoints that are, in turn, causally dependent on those outcomes. We aimed to (1) develop a generalisable method for selecting outcomes and endpoints in trials and (2) apply this method to select outcomes for evaluation in a trial investigating treatment strategies for pulmonary exacerbations of cystic fibrosis (CF).

METHODS: We conducted a series of online surveys and workshops among people affected by CF. We used a modified Delphi approach to develop a consensus list of important outcomes. A workshop involving domain experts elicited how these outcomes were causally related to the underlying pathophysiological processes. Meaningful outcomes were prioritised based on the extent to which each outcome captured separate rather than common aspects of the underlying pathophysiological process.

RESULTS: The 10 prioritised outcomes were: breathing difficulty/pain, sputum production/clearance, fatigue, appetite, pain (not related to breathing), motivation/demoralisation, fevers/night sweats, treatment burden, inability to meet personal goals and avoidance of gastrointestinal symptoms.

CONCLUSIONS: This proposed method for selecting meaningful outcomes for evaluation in clinical trials may improve the value of research as a basis for clinical decisions.

PMID:34620699 | DOI:10.1136/bmjresp-2021-000877