Respiration. 2021 Mar 30:1-7. doi: 10.1159/000513954. Online ahead of print.

ABSTRACT

BACKGROUND: The ventilation heterogeneity (VH) is reliably assessed by the multiple-breath nitrogen washout (MBNW), which provides indices of conductive (Scond) and acinar (Sacin) VH as well as the lung clearance index (LCI), an index of global VH. VH can be alternatively measured by the poorly communicating fraction (PCF), that is, the ratio of total lung capacity by body plethysmography to alveolar volume from the single-breath lung diffusing capacity measurement.

OBJECTIVES: Our objective was to assess VH by PCF and MBNW in patients with asthma and with COPD and to compare PCF and MBNW parameters in both patient groups.

METHOD: We studied 35 asthmatic patients and 45 patients with COPD. Each patient performed spirometry, body plethysmography, diffusing capacity, and MBNW test.

RESULTS: Compared to COPD patients, asthmatics showed a significantly lesser degree of airflow obstruction and lung hyperinflation. In asthmatic patients, both PCF and LCI and Sacin values were significantly lower than the corresponding ones of COPD patients. In addition, in both patient groups, PCF showed a positive correlation with LCI (p < 0.05) and Sacin (p < 0.05), but not with Scond. Lastly, COPD patients with PCF >30% were highly likely to have a value ≥2 of the mMRC dyspnea scale.

CONCLUSIONS: These results showed that PCF, a readily measure derived from routine pulmonary function testing, can provide a comprehensive measure of both global and acinar VH in asthma and in COPD patients and can be considered as a comparable tool to the well-established MBNW technique.

PMID:33784705 | DOI:10.1159/000513954

Immun Inflamm Dis. 2021 Mar 30. doi: 10.1002/iid3.426. Online ahead of print.

ABSTRACT

BACKGROUND AND METHODS: Hypergammaglobulinemia (hyper-IgG) and hypogammaglobulinemia (hypo-IgG) have been reported in patients with cystic fibrosis (CF). Although the clinical respiratory course is paradoxically different, depending on the IgG status, this association remains elusive. Therefore, we performed a longitudinal study to assess the annual evolution of IgG profiles in a cohort of pediatric patients with CF, from their diagnosis until 2016. We then compared clinical findings with the patients' IgG status to determine whether IgG status could reflect the respiratory clinical course of patients with CF.

RESULTS: Among the 66 patients with CF that were aged between 12 months and 18 years in 2016 (mean age: 9.3 years [SD: 5.2]), hypo-IgG was observed in 15.2% and no hyper-IgG was identified. Longitudinal assessment since diagnosis revealed no hyper-IgG but 33.3% of patients had at least one sample showing hypo-IgG, among which two patients displayed persistent hypo-IgG. The number of pulmonary exacerbations, duration of antibiotic therapy, and erythrocyte sedimentation rate were all lower in hypo-IgG patients. No difference was observed for the genotype, chronic Pseudomonas aeruginosa or Staphylococcus aureus infection, and in the parameters of lung function.

CONCLUSION: The IgG profile of pediatric patients with CF has changed over recent decades, particularly with regard to hyper-IgG. In a significant portion of the pediatric CF population, hypo-IgG is transient and only identifiable in longitudinal assessments. This study reinforces that hypo-IgG patients paradoxically present a more favorable course of clinical status. Therefore, IgG levels could be a useful outcome marker in the follow-up of patients with CF.

PMID:33783131 | DOI:10.1002/iid3.426

Sci Rep. 2021 Mar 29;11(1):7126. doi: 10.1038/s41598-021-86407-8.

ABSTRACT

There are limited data regarding whether mortality is higher in patients with non cystic fibrosis bronchiectasis (bronchiectasis) than in those without bronchiectasis. Using 2005-2015 data from the Korean National Health Insurance Service, we evaluated hazard ratio (HR) for all-cause mortality in the bronchiectasis cohort relative to the matched cohort. The effect of comorbidities over the study period on the relative mortality was also assessed. All-cause mortality was significantly higher in the bronchiectasis cohort than in the matched cohort (2505/100,000 vs 2142/100,000 person-years, respectively; P < 0.001). Mortality risk was 1.15-fold greater in the bronchiectasis cohort than in the matched cohort (95% confidence interval [CI] 1.09-1.22); mortality was greatest among elderly patients (HR = 1.17, 95% CI 1.10-1.25) and men (HR = 1.19, 95% CI 1.10-1.29). Comorbidities over the study period significantly increased the risk of death in the bronchiectasis cohort relative to the matched cohort: asthma (adjusted HR = 1.20, 95% CI 1.11-1.30), chronic obstructive pulmonary disease (adjusted HR = 1.24, 95% CI 1.15-1.34), pneumonia (adjusted HR = 1.50, 95% CI 1.39-1.63), lung cancer (adjusted HR = 1.85, 95% CI 1.61-2.12), and cardiovascular disease (adjusted HR = 1.34, 95% CI 1.23-1.45). In contrast, there were no significant differences in the risk of death in patients without bronchiectasis-related comorbidities and the matched cohort, except in the case of non-tuberculous mycobacterial infection. In conclusion, all-cause mortality was higher in patients with bronchiectasis cohort than those without bronchiectasis, especially in elderly patients and men. Comorbidities over the study period played a major role in increasing mortality in patients with bronchiectasis relative to those without bronchiectasis.

PMID:33782457 | DOI:10.1038/s41598-021-86407-8

J Allergy Clin Immunol Pract. 2021 Mar 26:S2213-2198(21)00296-8. doi: 10.1016/j.jaip.2021.02.053. Online ahead of print.

ABSTRACT

BACKGROUND: Although blood eosinophils are a frequently used marker of type 2 inflammation in children with asthma, their sensitivity is relatively poor. Additional markers of type 2 inflammation are needed.

OBJECTIVE: We hypothesized that plasma concentrations of eosinophil cationic protein (ECP), a marker of eosinophil activation, would be useful for detection of type 2 inflammation and would predict poorer asthma outcomes over 1 year.

METHODS: Children and adolescents 6 through 17 years (N = 256) with confirmed asthma completed a baseline visit and a follow-up visit at 12 months. A subset also underwent systemic corticosteroid responsiveness testing with intramuscular triamcinolone. Outcome measures at 12 months included uncontrolled asthma, lung function, and asthma exacerbations treated with systemic corticosteroids.

RESULTS: Plasma ECP concentrations ranged from 0.03 to 413.61 ng/mL (median, 6.95 ng/mL) and were consistently associated with other markers of type 2 inflammation. At baseline, children in the highest ECP tertile had poorer asthma control, more airflow limitation, and more exacerbations, but also had greater symptom improvement with intramuscular triamcinolone. At 12 months, associations between the highest ECP tertile and exacerbations, but not lung function or asthma control, persisted after covariate adjustment. However, the sensitivity of ECP was modest and was not markedly different from that of blood eosinophil counts.

CONCLUSION: Plasma ECP concentrations may be a useful marker of type 2 inflammation in children and may help identify those children at highest risk for recurrent exacerbations who could benefit from corticosteroid treatment. However, additional markers may be needed to improve sensitivity for outcome detection.

PMID:33781764 | DOI:10.1016/j.jaip.2021.02.053

J Biol Chem. 2021 Mar 26:100598. doi: 10.1016/j.jbc.2021.100598. Online ahead of print.

ABSTRACT

Patients with cystic fibrosis (CF) harboring the P67L variant in the CF transmembrane conductance regulator (CFTR) often exhibit a typical CF phenotype, including severe respiratory compromise. This rare mutation (reported in <300 patients worldwide) responds robustly to CFTR correctors such as lumacaftor and tezacaftor, with rescue in model systems that far exceeds what can be achieved for the archetypical CFTR mutant F508del. However, the specific molecular consequences of the P67L mutation are poorly characterized. In this study, we conducted biochemical measurements following low temperature growth and/or intragenic suppression which suggest a mechanism underlying P67L that: 1) shares key pathogenic features with F508del, including off-pathway (non-native) folding intermediates, 2) is linked to folding stability of nucleotide binding domains (NBDs) 1 and 2, and 3) demonstrates pharmacologic rescue that requires domains in the carboxyl half of the protein. We also investigated the "lasso" helices 1 (Lh1) and 2 (Lh2), which occur immediately upstream of P67. Based on limited proteolysis, pulse chase, and molecular dynamics analysis of full-length CFTR and a series of deletion constructs, we argue that P67L and other maturational processing (class 2) defects impair the integrity of the lasso motif and confer misfolding of downstream domains. Thus, amino terminal missense variants elicit a conformational change throughout CFTR that abrogates maturation while providing a robust substrate for pharmacologic repair.

PMID:33781744 | DOI:10.1016/j.jbc.2021.100598

J Cyst Fibros. 2021 Mar 26:S1569-1993(21)00053-9. doi: 10.1016/j.jcf.2021.03.004. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about the effect of dysglycemia during cystic fibrosis pulmonary exacerbation (PEx) on recovery of FEV1 percentage predicted (ppFEV1) METHODS: Continuous glucose monitoring (CGM) was commenced at the time of admission to hospital for PEx and continued for 6 weeks. The CGM indices, percentage of time glucose greater than 7.8 mmol/L (%T>7.8) and mean glucose were evaluated as predictors of absolute ppFEV1 change following treatment of PEx.

RESULTS: Of the 20 participants who completed the study 13 (65%) had cystic fibrosis related diabetes (CFRD). The mean of both CGM indices were highest during the first week of pulmonary exacerbation and continued to decline over the first 4 weeks at which point they plateaued. Using multivariate regression models, factors which were predictive of maximum attained ppFEV1 change over 6 weeks were %T>7.8, mean glucose, HbA1c and preadmission ppFEV1 change from baseline. These relationships were independent of a diagnosis of CFRD, which was not associated with ppFEV1 recovery. In a longitudinal model of ppFEV1 change at weeks 1,2 and 6, the CGM index %T>7.8 approached significance as a predictive variable.

CONCLUSIONS: Hyperglycemia during PEx in adult CF patients is associated with poorer ppFEV1 recovery. Conversely, there was no association observed between CFRD diagnosis and ppFEV1 improvement, suggesting that optimization of glycemic control in CFRD patients may positively influence recovery of lung function. Further clinical trials are required to evaluate the merits of intensive glycemic control in CFRD during PEx.

PMID:33781701 | DOI:10.1016/j.jcf.2021.03.004

J Cyst Fibros. 2021 Mar 26:S1569-1993(21)00089-8. doi: 10.1016/j.jcf.2021.03.013. Online ahead of print.

ABSTRACT

Avoidance of cross infection is important between CF siblings living in the same household. In this study, we examined the ability of domestic steam disinfection to eradicate 16 species of CF bacterial and foodborne pathogens from the surface of contaminated crockery and cutlery. Domestic steam disinfection employing baby bottle disinfector devices, when performed properly under manufacturer's instructions, eradicated all organisms tested and offers a relatively inexpensive, simple, versatile and widely available technology for the elimination of common CF bacterial and foodborne pathogens from contaminated crockery and cutlery utensils. Most CF households may already have a baby bottle disinfector device, in order to disinfect nebulizers, respiratory equipment and toothbrushes and therefore employment of this device to disinfect crockery and cutlery would be easily achieved. We therefore advocate the employment of such devices to disinfect such common household utensils, as a critical control in the elimination of these organisms from these sources, thereby enhancing CF sibling safety.

PMID:33781700 | DOI:10.1016/j.jcf.2021.03.013

J Manag Care Spec Pharm. 2021 Mar 29:1-13. Online ahead of print.

ABSTRACT

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report for the management of chronic obstructive pulmonary disease (COPD) focuses on reducing existing symptoms, decreasing the risk of future exacerbations, and improving health status by recommending specific drug therapy based on exacerbation risk and symptoms. However, disparities exist between evidence-based recommendations and clinical practice. Research that quantifies the real-world effect of COPD regimen alignment with the GOLD recommendations on clinical and economic outcomes is needed. OBJECTIVE: To compare COPD-related health care resource utilization (HRU) and costs, as well as exacerbation rates, among patients with COPD on maintenance therapy based on 2017 GOLD treatment recommendation compliance status per GOLD ABCD risk group classification in a U.S. commercially insured/Medicare Advantage population. METHODS: This retrospective cohort study utilized administrative claims data in the HealthCore Integrated Research Database. The COPD population was identified using a previously validated claims-based predictive model. Among this population, patients with ≥ 1 claim for a COPD maintenance medication (earliest maintenance fill-date = index date) between January 1, 2014, and March 31, 2017, were identified. Patients were required to be aged ≥ 40 years, have ≥ 12 months of pre-index and ≥ 30 days of post-index health plan enrollment, with no diagnosis for asthma, cystic fibrosis, and/or lung cancer at any time from January 1, 2013, to March 31, 2018. Patients were categorized into exacerbation risk/symptomatology groups according to the 2017 GOLD ABCD assessment recommendations and were then classified into treatment-compliance status based on their maintenance therapy. Multivariable analyses were conducted to examine post-index COPD-related HRU, costs, and exacerbations by compliance status. RESULTS: The primary analytical study sample included 38,382 patients in the GOLD A/B group and 6,525 in the GOLD C/D group. Patients were further categorized into GOLD A (n = 19,345), B (n = 19,037), C (n = 1,865), and D (n = 4,670). GOLD-compliant regimens were observed in 32.9% of patients in the GOLD A/B group and in 58.9% of patients in the GOLD C/D group. Inhaled corticosteroid-containing regimens were the most commonly observed noncompliant regimen. Patients on compliant regimens had significantly fewer COPD-related inpatient and emergency department visits and therefore had significantly lower COPD-related medical costs in both the GOLD A/B and C/D cohorts. Similar results were observed for individual GOLD cohorts B, C, and D. These savings were offset by increased pharmacy expenditures. Being on GOLD guideline-compliant regimens significantly reduced the risk of exacerbation by 8% (hazard ratio [HR] = 0.92; P < 0.0001) in the GOLD A/B cohort and by 12% (HR = 0.88; P = 0.0005) in the GOLD C/D cohort, and was also associated with a significantly reduced exacerbation rate in the GOLD A/B (rate ratio [RR] = 0.93; P < 0.0001) and GOLD C/D (RR = 0.93; P = 0.0129) groups. CONCLUSIONS: This study suggests a continuing trend of high prevalence of suboptimal prescriber compliance to GOLD treatment recommendations. Treatment regimens compliant with GOLD recommendations were associated with improvement in exacerbations, reduced COPD-related HRU, and COPD-related medical cost offsets. DISCLOSURES: This study was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Palli and Shaikh are employees of BIPI. Willey is an employee of HealthCore, which was contracted by BIPI to conduct this study. Zhou was an employee of HealthCore at the time of study execution. Data were presented in part during an AMCP webinar (recording not made public) held in lieu of the Spring 2020 AMCP conference, which was canceled due to the COVID-19 pandemic.

PMID:33779246

Radiol Cardiothorac Imaging. 2020 Dec 17;2(6):e200022. doi: 10.1148/ryct.2020200022. eCollection 2020 Dec.

ABSTRACT

PURPOSE: To develop radiomics-based CT scores for assessing lung disease severity and exacerbation risk in adult patients with cystic fibrosis (CF).

MATERIALS AND METHODS: This two-center retrospective observational study was approved by an institutional ethics committee, and the need for patient consent was waived. A total of 215 outpatients with CF referred for unenhanced follow-up chest CT were evaluated in two different centers between January 2013 and December 2016. After lung segmentation, chest CT scans from center 1 (training cohort, 162 patients [median age, 29 years; interquartile range {IQR}, 24-36 years; 84 men]) were used to build CT scores from 38 extracted CT features, using five different machine learning techniques trained to predict a clinical prognostic score, the Nkam score. The correlations between the developed CT scores, two different clinical prognostic scores (Liou and CF-ABLE), forced expiratory volume in 1 second (FEV1), and risk of respiratory exacerbations were evaluated in the test cohort (center 2, 53 patients [median age, 27 years; IQR, 22-35 years; 34 men]) using the Spearman rank coefficient.

RESULTS: In the test cohort, all radiomics-based CT scores showed moderate to strong correlation with the Nkam score (R = 0.57 to 0.63, P < .001) and Liou scores (R = -0.55 to -0.65, P < .001), whereas the correlation with CF-ABLE score was weaker (R = 0.28 to 0.38, P = .005 to .048). The developed CT scores showed strong correlation with predicted FEV1 (R = -0.62 to -0.66, P < .001) and weak to moderate correlation with the number of pulmonary exacerbations to occur in the 12 months after the CT examination (R = 0.38 to 0.55, P < .001 to P = .006).

CONCLUSION: Radiomics can be used to build automated CT scores that correlate to clinical severity and exacerbation risk in adult patients with CF.Supplemental material is available for this article.See also the commentary by Elicker and Sohn in this issue.© RSNA, 2020.

PMID:33778637 | PMC:PMC7977785 | DOI:10.1148/ryct.2020200022

Am J Ophthalmol Case Rep. 2021 Mar 11;22:101056. doi: 10.1016/j.ajoc.2021.101056. eCollection 2021 Jun.

ABSTRACT

PURPOSE: Tacrolimus is a commonly used immunosuppressant medication after lung transplantation. In rare cases, tacrolimus causes a medication-induced optic neuropathy (TON) that can lead to significant vision loss.

OBSERVATIONS: In this series, we describe three cases of TON, 1-10 years after medication use. Two patients were young (22yr and 33yr) females with cystic fibrosis. The last case was a 65yr male with idiopathic pulmonary fibrosis. In 2/3 cases tacrolimus serum levels were normal. Visual acuity ranged from 20/20 to 20/300, and vision loss occurred acutely to sub-acutely, over a span of 2-3 months.

CONCLUSIONS AND IMPORTANCE: As presented here, TON can be highly variable. MRI findings are often non-specific, from normal brain findings to extensive white matter changes. There remains an unclear association with graft-versus-host disease and reduced kidney function. Visual findings are often subtle, including color vision aberration and peripheral visual field deficits, both of which usually require an ophthalmologic evaluation. When diagnosed in a timely fashion, TON is at least partially reversible in up to half of all cases. While rare, the cases described here support post-lung transplant ophthalmologic evaluation in those taking high-risk medications.

PMID:33778180 | PMC:PMC7985716 | DOI:10.1016/j.ajoc.2021.101056

ERJ Open Res. 2021 Mar 22;7(1):00614-2020. doi: 10.1183/23120541.00614-2020. eCollection 2021 Jan.

ABSTRACT

Nontypeable Haemophilus influenzae (NTHi) is commonly isolated from airways of patients suffering from chronic respiratory diseases, such as COPD or cystic fibrosis (CF). However, to what extent NTHi long-term infection contributes to the lung inflammatory burden during chronic airway disease is still controversial. Here, we exploited human respiratory samples from a small cohort of CF patients and found that patients chronically infected with NTHi had significantly higher levels of interleukin (IL)-8 and CXCL1 than those who were not infected. To better define the impact of chronic NTHi infection in fuelling inflammatory response in chronic lung diseases, we developed a new mouse model using both laboratory and clinical strains. Chronic NTHi infection was associated with chronic inflammation of the lung, characterised by recruitment of neutrophils and cytokine release keratinocyte-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2), granulocyte colony-stimulating factor (G-CFS), IL-6, IL-17A and IL-17F) at 2 and 14 days post-infection. An increased burden of T-cell-mediated response (CD4+ and γδ cells) and higher levels of pro-matrix metalloproteinase 9 (pro-MMP9), known to be associated with tissue remodelling, were observed at 14 days post-infection. Of note we found that both CD4+IL-17+ cells and levels of IL-17 cytokines were enriched in mice at advanced stages of NTHi chronic infection. Moreover, by immunohistochemistry we found CD3+, B220+ and CXCL-13+ cells localised in bronchus-associated lymphoid tissue-like structures at day 14. Our results demonstrate that chronic NTHi infection exerts a pro-inflammatory activity in the human and murine lung and could therefore contribute to the exaggerated burden of lung inflammation in patients at risk.

PMID:33778054 | PMC:PMC7983230 | DOI:10.1183/23120541.00614-2020

ERJ Open Res. 2021 Mar 22;7(1):00893-2020. doi: 10.1183/23120541.00893-2020. eCollection 2021 Jan.

ABSTRACT

In this review, the Paediatric Assembly of the European Respiratory Society (ERS) presents a summary of the highlights and most relevant findings in the field of paediatric respiratory medicine presented at the virtual ERS International Congress 2020. Early Career Members of the ERS and Chairs of the different Groups comprising the Paediatric Assembly discuss a selection of the presented research. These cover a wide range of research areas, including respiratory physiology and sleep, asthma and allergy, cystic fibrosis, respiratory infection and immunology, neonatology and intensive care, epidemiology, bronchology and lung and airway development. Specifically, we describe the long-term effect in lung function of premature birth, mode of delivery and chronic respiratory conditions such as cystic fibrosis. In paediatric asthma, we present risk factors, phenotypes and their progression with age, and the challenges in diagnosis. We confirm the value of the lung clearance index to detect early lung changes in cystic fibrosis. For bronchiectasis treatment, we highlight the importance of identifying treatable traits. The use of biomarkers and genotypes to identify infants at risk of long-term respiratory morbidity is also discussed. We present the long-term impact on respiratory health of early life and fetal exposures to maternal obesity and intrauterine hypoxia, mechanical ventilation hyperoxia, aeroallergens, air pollution, vitamin A deficient intake and bronchitis. Moreover, we report on the use of metabolomics and genetic analysis to understand the effect of these exposures on lung growth and alveolar development. Finally, we stress the need to establish multidisciplinary teams to treat complex airway pathologies.

PMID:33778048 | PMC:PMC7983204 | DOI:10.1183/23120541.00893-2020

Front Cell Infect Microbiol. 2021 Mar 12;11:621081. doi: 10.3389/fcimb.2021.621081. eCollection 2021.

ABSTRACT

The very common condition of sinusitis is characterized by persistent inflammation of the nasal cavity, which contributes to chronic rhinosinusitis and morbidity of cystic fibrosis patients. Colonization by opportunistic pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa triggers inflammation that is exacerbated by defects in the innate immune response. Pathophysiological mechanisms underlying initial colonization of the sinuses are not well established. Despite their extensive use, current murine models of acute bacterial rhinosinusitis have not improved the understanding of early disease stages due to analytical limitations. In this study, a model is described that is technically simple, allows non-invasive tracking of bacterial infection, and screening of host-responses to infection and therapies. The model was modified to investigate longer-term infection and disease progression by using a less virulent, epidemic P. aeruginosa cystic fibrosis clinical isolate LESB65. Tracking of luminescent bacteria was possible after intranasal infections, which were sustained for up to 120 h post-infection, without compromising the overall welfare of the host. Production of reactive oxidative species was associated with neutrophil localization to the site of infection in this model. Further, host-defense peptides administered by Respimat® inhaler or intranasal instillation reduced bacterial burden and impacted disease progression as well as cytokine responses associated with rhinosinusitis. Thus, future studies using this model will improve our understanding of rhinosinusitis etiology and early stage pathogenesis, and can be used to screen for the efficacy of emerging therapies pre-clinically.

PMID:33777834 | PMC:PMC7994591 | DOI:10.3389/fcimb.2021.621081

Front Pharmacol. 2021 Mar 10;12:643254. doi: 10.3389/fphar.2021.643254. eCollection 2021.

ABSTRACT

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.

PMID:33776778 | PMC:PMC7987926 | DOI:10.3389/fphar.2021.643254

Front Pharmacol. 2021 Mar 11;12:581645. doi: 10.3389/fphar.2021.581645. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator gene, which causes multifunctional defects that preferentially affect the airways. Abnormal viscosity of mucus secretions, persistent pathogen infections, hyperinflammation, and lung tissue damage compose the classical pathological manifestation referred to as CF lung disease. Among the multifunctional defects associated with defective CFTR, increasing evidence supports the relevant role of perturbed calcium (Ca2+) signaling in the pathophysiology of CF lung disease. The Ca2+ ion is a critical player in cell functioning and survival. Its intracellular homeostasis is maintained by a fine balance between channels, transporters, and exchangers, mediating the influx and efflux of the ion across the plasma membrane and the intracellular organelles. An abnormal Ca2+ profile has been observed in CF cells, including airway epithelial and immune cells, with heavy repercussions on cell function, viability, and susceptibility to pathogens, contributing to proinflammatory overstimulation, organelle dysfunction, oxidative stress, and excessive cytokines release in CF lung. This review discusses the role of Ca2+ signaling in CF and how its dysregulation in airway epithelial and immune cells contributes to hyperinflammation in the CF lung. Finally, we provide an outlook on the therapeutic options that target the Ca2+ signaling to treat the CF lung disease.

PMID:33776759 | PMC:PMC7990772 | DOI:10.3389/fphar.2021.581645

J Hosp Infect. 2021 Mar 25:S0195-6701(21)00139-0. doi: 10.1016/j.jhin.2021.03.018. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about Clostridioides difficile infection (CDI) in cystic fibrosis (CF) patients. Our aim was to investigate the prevalence, molecular epidemiology and risk factors for CDI in asymptomatic and symptomatic adults with CF in Western Australia (WA).

METHODS: Faecal samples from symptomatic and asymptomatic patients were prospectively collected and tested for the presence of C. difficile by toxigenic culture. Ribotyping was performed by established protocols. Logistic regression analysis was performed to analyse the risk factors for C. difficile colonisation and infection. Extensive environmental sampling was performed within the CF clinic in Perth, WA.

RESULTS: The prevalence of asymptomatic toxigenic and non-toxigenic C. difficile colonisation was 30% (14/46 patients) and 24% (11/46 patients), respectively. Fifteen ribotypes (RTs) of C. difficile were identified, of which non-toxigenic RT 039 was the most common. Amongst symptomatic patients, the prevalence of toxigenic CDI was 33% (11/33 patients). Impaired glucose tolerance/diabetes mellitus and length of time of intravenous antibiotic use in the past 12 months were significantly associated with an increased risk for asymptomatic toxigenic C. difficile carriage and CDI. A trend towards higher CF transmembrane conductance regulator modulator treatment was observed in the CDI group. Extensive environmental sampling showed no evidence of toxigenic C. difficile contamination within the CF clinic.

CONCLUSIONS: A high prevalence of asymptomatic carriage of toxigenic C. difficile was observed in adults with CF, comparable to that observed in the symptomatic CF population. There was no evidence of direct person-to-person transmission.

PMID:33775742 | DOI:10.1016/j.jhin.2021.03.018

J Cyst Fibros. 2021 Mar 25:S1569-1993(21)00058-8. doi: 10.1016/j.jcf.2021.03.009. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic Fibrosis (CF) is a chronic multi-system disease best cared for at Care centers with routine monitoring by interdisciplinary teams. Previously, remote home monitoring technology has been explored to augment in-person care. During the COVID-19 pandemic, traditional in-person care was limited and CF centers rapidly adapted to a telehealth delivery model. The purpose of this study was to understand how people with CF (PwCF) and families of PwCF experienced the shift to telehealthcare delivery.

METHODS: This was a cross-sectional survey-based study conducted in 11 CF Centers. Two surveys were designed (one for adult PwCF and one for parents/guardians of PwCF) by participating CF center members with patient and family partner input. Surveys were disseminated electronically via email/text to all patients who completed a telehealth visit, and data were collected on secure Google Forms.

RESULTS: Respondents rated their telehealth experiences as positive. Most were highly satisfied with their telehealth visit (77% adult, 72% pediatric) and found the visits to be highly convenient (85% for all surveyed). A majority of patients reported they had adequate time during the visit and had all questions and concerns addressed. Importantly, we also identified concerns regarding lack of in-person assessments including pulmonary function testing (PFT) and throat/sputum culture.

CONCLUSION: Telehealth was a feasible and well-accepted mechanism for delivering care in a chronic CF care model during the COVID-19 pandemic and may be useful in the post-pandemic era. Further work is needed to understand the impact of telehealth on patient outcomes, healthcare utilization and associated cost.

PMID:33775604 | DOI:10.1016/j.jcf.2021.03.009

J Cyst Fibros. 2021 Mar 25:S1569-1993(21)00087-4. doi: 10.1016/j.jcf.2021.03.011. Online ahead of print.

ABSTRACT

Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants.

PMID:33775603 | DOI:10.1016/j.jcf.2021.03.011

J Cyst Fibros. 2021 Mar 25:S1569-1993(21)00056-4. doi: 10.1016/j.jcf.2021.03.007. Online ahead of print.

ABSTRACT

BACKGROUND: Antimicrobial resistance in cystic fibrosis (CF) Pseudomonas aeruginosa airway infection is complex and often attributed to chromosomal mutations. How these mutations emerge in specific strains or whether particular gene mutations are clinically informative is unclear. This study focused on oprD, which encodes an outer membrane porin associated with carbapenem resistance when it is downregulated or inactivated.

AIM: Determine how mutations in oprD emerge in two prevalent Australian shared CF strains of P. aeruginosa and their clinical relevance.

METHODS: The two most common shared CF strains in Queensland were investigated using whole genome sequencing and their oprD sequences and antimicrobial resistance phenotypes were established. P. aeruginosa mutants with the most common oprD variants were constructed and characterised. Clinical variables were compared between people with or without evidence of infection with strains harbouring these variants.

RESULTS: Frequently found nonsense mutations arising from a 1-base pair substitution in oprD evolved independently in three sub-lineages, and are likely major contributors to the reduced carbapenem susceptibility observed in the clinical isolates. Lower baseline FEV1 %predicted was identified as a risk factor for infection with a sub-lineage (odds ratio=0.97; 95% confidence interval 0.96-0.99; p<0.001). However, acquiring these sub-lineage strains did not confer an accelerated decline in FEV1 nor increase the risk of death/lung transplantation.

CONCLUSIONS: Sub-lineages harbouring specific mutations in oprD have emerged and persisted in the shared strain populations. Infection with the sub-lineages was more likely in people with lower lung function, but this was not predictive of a worse clinical trajectory.

PMID:33775602 | DOI:10.1016/j.jcf.2021.03.007

J Cyst Fibros. 2021 Mar 25:S1569-1993(21)00088-6. doi: 10.1016/j.jcf.2021.03.012. Online ahead of print.

ABSTRACT

INTRODUCTION: Isolation of Exophiala species from sputum samples has become increasingly reported in Cystic Fibrosis (CF). However, the clinical significance of Exophiala spp. with regards to the paediatric CF population is unknown.

METHODS: A case control study was undertaken to compare CF children with and without chronic Exophiala spp. in their sputum samples. Demographic and clinical data were collected retrospectively for each case from the date of Exophiala isolation and for 12 months preceding isolation. Each case was compared to three age and year-matched controls. To determine the effect of Exophiala on clinical course, patients were then followed for 12 months post isolation.

RESULTS: In total, 27 of 244 eligible paediatric CF patients (11%) isolated Exophiala spp. on more than one occasion. There were no significant differences in the key clinical parameters: spirometry, mean number of intravenous (IV) antibiotic days and body mass index (BMI), between cases and controls (p = 0.91, p = 0.56 and p = 0.63 respectively). A higher proportion of cases isolated Candida spp. (67% vs 21%, p < 0.0001) and Aspergillus fumigatus (37% vs 26%, p = 0.37). There was no clinically significant difference in spirometry, mean number of IV antibiotic days and BMI in cases pre and post Exophiala spp. isolation. Posaconazole was the only drug used that successfully eradicated Exophiala.

CONCLUSION: Despite the frequent isolation of Exophiala spp. in this cohort, in most patients it is not associated with significant clinical deterioration. It does however seem to be associated with isolation of other fungi.

PMID:33775601 | DOI:10.1016/j.jcf.2021.03.012