Cystic Fibrosis
Monovalent: Divalent Anion Selectivity in the CFTR Channel Pore
Cell Biochem Biophys. 2021 May 24. doi: 10.1007/s12013-021-00998-7. Online ahead of print.
ABSTRACT
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel shows only weak selectivity between different small monovalent anions, however, little is known about its ability to discriminate between monovalent and divalent anions. The present study uses patch clamp recording to investigate the interaction between the small divalent anions S2O32- and SO42- and wild-type and pore-mutant forms of human CFTR. Binding of these anions to wild-type CFTR appears weak; at 10 mM, intracellular S2O32- and SO42- blocked <20 and <5% of macroscopic Cl- current respectively, while these same concentrations had no discernible blocking effect when present in the extracellular solution. However, introduction of additional positive charge into the inner vestibule of the pore (in I344K and S1141K mutant channels) drastically strengthened block by intracellular (but not extracellular) S2O32- and SO42-. Block of these mutant channels was highly voltage-dependent; at very negative membrane potentials, apparent binding affinities were ~100 µM for S2O32- and <1 mM for SO42-. Permeability of S2O32- and SO42- was too small to be quantified in wild-type CFTR, but was <1% of Cl- permeability. Mutants that strengthened divalent binding (I344K, S1141K), as well as the selectivity-altering mutant F337A, also showed immeasurably low S2O32- and SO42- permeabilities. Overall CFTR selects well for monovalent over divalent anions, both in terms of binding and permeability. The number or density of fixed positive charges in the pore appears well optimized to disfavour binding of divalent anions, which may be an important facet of the monovalent Cl- permeation mechanism.
PMID:34031860 | DOI:10.1007/s12013-021-00998-7
Effects of indacaterol on the LPS-evoked changes in fluid secretion rate and pH in swine tracheal membrane
Pflugers Arch. 2021 May 24. doi: 10.1007/s00424-021-02560-z. Online ahead of print.
ABSTRACT
An acquired dysregulation of airway secretion is likely involved in the pathophysiology of chronic bronchitis and chronic obstructive pulmonary disease (COPD). Nowadays, it is widely known that several kinds of long-acting bronchodilators reduce the frequency of COPD exacerbations. However, limited data are available concerning the complementary additive effects on airflow obstruction. Using an optical method and a selective pH indicator, we succeeded in evaluating the gland secretion rate and the pH in swine tracheal membrane. A physiologically relevant concentration of acetylcholine (ACh) 100 nM induced a gradual increase in the amount of gland secretion. Lipopolysaccharides (LPS) accelerated the ACh-induced secretory responses up to around threefold and lowered the pH level significantly. Long-acting β2-agonists (LABAs) including indacaterol (IND), formoterol, and salmeterol restored the LPS-induced changes in both the hypersecretion and acidification. The subsequent addition of the long-acting muscarine antagonist, glycopyrronium, further increased the pH values. Two different inhibitors for cystic fibrosis transmembrane conductance regulator (CFTR), NPPB and CFTRinh172, abolished the IND-mediated pH normalization in the presence of both ACh and ACh + LPS. Both immunofluorescence staining and western blotting analysis revealed that LPS downregulated the abundant expression of CFTR protein. However, IND did not restore the LPS-induced decrease in CFTR expression on Calu-3 cells. These findings suggest that the activation of cAMP-dependent HCO3- secretion through CFTR would be partly involved in the IND-mediated pH normalization in gland secretion and may be suitable for the maintenance of airway defense against exacerbating factors including LPS.
PMID:34031755 | DOI:10.1007/s00424-021-02560-z
Phosphorus stress induces the synthesis of novel glycolipids in Pseudomonas aeruginosa that confer protection against a last-resort antibiotic
ISME J. 2021 May 24. doi: 10.1038/s41396-021-01008-7. Online ahead of print.
ABSTRACT
Pseudomonas aeruginosa is a nosocomial pathogen with a prevalence in immunocompromised individuals and is particularly abundant in the lung microbiome of cystic fibrosis patients. A clinically important adaptation for bacterial pathogens during infection is their ability to survive and proliferate under phosphorus-limited growth conditions. Here, we demonstrate that P. aeruginosa adapts to P-limitation by substituting membrane glycerophospholipids with sugar-containing glycolipids through a lipid renovation pathway involving a phospholipase and two glycosyltransferases. Combining bacterial genetics and multi-omics (proteomics, lipidomics and metatranscriptomic analyses), we show that the surrogate glycolipids monoglucosyldiacylglycerol and glucuronic acid-diacylglycerol are synthesised through the action of a new phospholipase (PA3219) and two glycosyltransferases (PA3218 and PA0842). Comparative genomic analyses revealed that this pathway is strictly conserved in all P. aeruginosa strains isolated from a range of clinical and environmental settings and actively expressed in the metatranscriptome of cystic fibrosis patients. Importantly, this phospholipid-to-glycolipid transition comes with significant ecophysiological consequence in terms of antibiotic sensitivity. Mutants defective in glycolipid synthesis survive poorly when challenged with polymyxin B, a last-resort antibiotic for treating multi-drug resistant P. aeruginosa. Thus, we demonstrate an intriguing link between adaptation to environmental stress (nutrient availability) and antibiotic resistance, mediated through membrane lipid renovation that is an important new facet in our understanding of the ecophysiology of this bacterium in the lung microbiome of cystic fibrosis patients.
PMID:34031546 | DOI:10.1038/s41396-021-01008-7
The role of suboptimal concentrations of nebulized tobramycin in driving antimicrobial resistance in Pseudomonas aeruginosa isolates in cystic fibrosis - an in vitro study
Respir Care. 2021 May 24:respcare.08671. doi: 10.4187/respcare.08671. Online ahead of print.
ABSTRACT
BACKGROUND: Antimicrobial resistance in Pseudomonas aeruginosa (PA) may be driven by exposure to suboptimal concentrations of tobramycin antibiotic delivered by less efficient nebulizers.METHODS: PA isolates (N=114; 32 first+82 chronic) were challenged in vitro employing extrapolated peak and trough concentrations of tobramycin inhalation solution (TIS), corresponding to three nebulizers, PARI LC PLUS, Sidestream12NEB400 and MistyNeb2035G . Bacterial persistence and antibiotic susceptibility to tobramycin was determined following four TIS cycles:- (i) 28d ON, (ii) 28d ON+28d OFF (iii) 2x28d ON and (iv) 28d ON+28d ON+28d OFF.RESULTS: All first isolates were eradicated at peak and trough concentrations except for the trough concentration for Sidestream 12NEB400 (bactericidal activity 87%). For chronic isolates, peak concentrations eradicated 88%, 90% & 92% and trough concentrations eradicated 43%, 62% & 85%, with Sidestream 12NEB400, MistyNeb2035G and PARI LC PLUS, respectively. A statistically significant increase in antibiotic resistance (MIC) with sensitive, intermediate and resistant PA was noted following cycles (i)-(iv), at trough concentrations with Sidestream 12NEB400 and MistyNeb2035G. There was a significant reduction in tobramycin resistance following a 28d OFF cycle and no difference, following 1x28d ON versus 2x28d ON cycles.CONCLUSION: This in vitro study showed that suboptimal tobramycin concentrations drove antibiotic resistance, emulating standard ON/OFF cycles. This was evident at extrapolated tobramycin concentrations at trough levels with less efficient nebulizers, by (i). initially allowing for the survival of intermediate and resistant organisms, because nebuliser performance did not achieve critical MIC concentrations sufficient to eradicate the organism, (ii). allowing the development of resistance in those cells that were able to survive the initial tobramycin challenge. Transferred to clinical practice, this means for CF individuals on TIS treatment, it is important that clinicians employ an efficient nebulizer that helps mitigate an upward drift in antibiotic resistance, thereby protecting the continued clinical value of TIS within CF care.
PMID:34031222 | DOI:10.4187/respcare.08671
Survival models to support shared decision-making about advance care planning for people with advanced stage cystic fibrosis
BMJ Open Respir Res. 2021 May;8(1):e000794. doi: 10.1136/bmjresp-2020-000794.
ABSTRACT
BACKGROUND: For people with advanced stage cystic fibrosis (CF), tailored survival estimates could facilitate preparation for decision-making in the event of acutely deteriorating respiratory function.
METHODS: We used the US CF Foundation national database (2008-2013) to identify adult people with incident advanced stage CF (forced expiratory volume in 1 s (FEV1) ≤45% predicted). Using the lasso method for variable selection, we divided the dataset into training and validation samples (2:1), and developed two multivariable Cox proportional hazards models to calculate probabilities of survival from baseline (T0 model), and from 1 year after (T12 model). We also performed Kaplan-Meier survival analyses.
RESULTS: 4752 people were included. For the T0 model, FEV1; insurance; non-invasive ventilation; supplemental oxygen; Burkholderia colonisation; cirrhosis; depression; dialysis; current smoking; unclassifiable mutation class and cumulative CF exacerbations predicted increased mortality. Baseline transplant evaluation status of 'accepted, on waiting list' predicted decreased mortality. For the T12 model, interim decrease in FEV1 >10%, and pulmonary exacerbations additionally increased predicted mortality. Lung transplantation was associated with lower mortality. Of the 4752, 93.5%, 86.4%, 79.7% and 73.9% survived to 1, 2, 3 and 4 years, respectively, without considering any confounding variables. The models had moderate predictive ability indicated by the area under the time-dependent receiver operating characteristic curve (0.787, 95% CI 0.769 to 0.794 for T0 model; and 0.779, 95% CI 0.767 to 0.797 for T12 model).
CONCLUSION: We have developed models predicting survival in people with incident advanced stage CF, which can be reapplied over time to support shared decision-making about end-of-life treatment choices and lung transplantation. These estimates must be updated as data become available regarding long-term outcomes for people treated with CF transmembrane conductance regulator modulators.
PMID:34031106 | DOI:10.1136/bmjresp-2020-000794
Cerebral paradoxical embolisation in a patient with cystic fibrosis with patent foramen ovale: a comparative review of literature
BMJ Case Rep. 2021 May 24;14(5):e242302. doi: 10.1136/bcr-2021-242302.
ABSTRACT
A 52-year-old woman with cystic fibrosis presented to the emergency department with expressive aphasia and right-sided hemiparesis. CT scan of the brain revealed a left middle cerebral artery territory infarct. A diagnosis of cerebral paradoxical embolisation associated with patent foramen ovale and a history of deep venous thrombosis was made. The patient underwent endovascular thrombectomy and percutaneous closure of patent foramen ovale. Current literature, including five published case reports, pertaining to the subject is discussed. The unique aspects of the case are highlighted, including the particular risk of cerebral paradoxical embolisation in patients with cystic fibrosis. The result of this case report, in context to previously reported literature, suggests that clinicians should be aware of paradoxical embolisation in patients with cystic fibrosis via an intracardiac shunt, particularly with implanted vascular access devices and a history of deep venous thrombosis.
PMID:34031090 | DOI:10.1136/bcr-2021-242302
Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis
J Cyst Fibros. 2021 May 21:S1569-1993(21)00121-1. doi: 10.1016/j.jcf.2021.04.011. Online ahead of print.
ABSTRACT
BACKGROUND: Treatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations.
METHODS: Prospective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites.
RESULTS: Azithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC.
CONCLUSION: PK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52-53, 2017.
PMID:34030986 | DOI:10.1016/j.jcf.2021.04.011
Pseudomonas aeruginosa infection, but not mono or dual-combination CFTR modulator therapy affects circulating regulatory T cells in an adult population with cystic fibrosis
J Cyst Fibros. 2021 May 21:S1569-1993(21)00128-4. doi: 10.1016/j.jcf.2021.05.001. Online ahead of print.
ABSTRACT
BACKGROUND: Chronic infection and an exaggerated inflammatory response are key drivers of the pathogenesis of cystic fibrosis (CF), especially CF lung disease. An imbalance of pro- and anti-inflammatory mediators, including dysregulated Th2/Th17 cells and impairment of regulatory T cells (Tregs), maintain CF inflammation. CF transmembrane conductance regulator (CFTR) modulator therapy might influence these immune cell abnormalities.
METHODS: Peripheral blood mononuclear cells and serum samples were collected from 108 patients with CF (PWCF) and 40 patients with non-CF bronchiectasis. Samples were analysed for peripheral blood lymphocytes subsets (Tregs; Th1-, Th1/17-, Th17- and Th2-effector cells) and systemic T helper cell-associated cytokines (interleukin [IL]-5, IL-13, IL-2, IL-6, IL-9, IL-10, IL-17A, IL-17F, IL-4, IL-22, interferon-γ, tumour necrosis factor-α) using flow cytometry.
RESULTS: 51% of PWCF received CFTR modulators (ivacaftor, ivacaftor/ lumacaftor or tezacaftor/ ivacaftor). There were no differences in proportions of analysed T cell subsets or cytokines between PWCF who were versus were not receiving CFTR modulators. Additional analysis revealed lower percentages of Tregs in PWCF and chronic pulmonary Pseudomonas aeruginosa infection; this difference was also present in PWCF treated with CFTR modulators. Patients with non-CF bronchiectasis tended to have higher percentages of Th2- and Th17-cells and higher levels of peripheral cytokines versus PWCF.
CONCLUSIONS: Chronic P. aeruginosa lung infection appears to impair Tregs in PWCF (independent of CFTR modulator therapy) but not those with non-CF bronchiectasis. Moreover, our data showed no statistically significant differences in major subsets of peripheral lymphocytes and cytokines among PWCF who were versus were not receiving CFTR modulators.
PMID:34030985 | DOI:10.1016/j.jcf.2021.05.001
The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart
Expert Opin Drug Saf. 2021 May 25. doi: 10.1080/14740338.2021.1932814. Online ahead of print.
ABSTRACT
Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.
PMID:34030570 | DOI:10.1080/14740338.2021.1932814
The Impact of Resistant Bacterial Pathogens including Pseudomonas aeruginosa and Burkholderia on Lung Transplant Outcomes
Semin Respir Crit Care Med. 2021 Jun;42(3):436-448. doi: 10.1055/s-0041-1728797. Epub 2021 May 24.
ABSTRACT
Pseudomonas and Burkholderia are gram-negative organisms that achieve colonization within the lungs of patients with cystic fibrosis, and are associated with accelerated pulmonary function decline. Multidrug resistance is a hallmark of these organisms, which makes eradication efforts difficult. Furthermore, the literature has outlined increased morbidity and mortality for lung transplant (LTx) recipients infected with these bacterial genera. Indeed, many treatment centers have considered Burkholderia cepacia infection an absolute contraindication to LTx. Ongoing research has delineated different species within the B. cepacia complex (BCC), with significantly varied morbidity and survival profiles. This review considers the current evidence for LTx outcomes between the different subspecies encompassed within these genera as well as prophylactic and management options. The availability of meta-genomic tools will make differentiation between species within these groups easier in the future, and will allow more evidence-based decisions to be made regarding suitability of candidates colonized with these resistant bacteria for LTx. This review suggests that based on the current evidence, not all species of BCC should be considered contraindications to LTx, going forward.
PMID:34030205 | DOI:10.1055/s-0041-1728797
The Lung Allocation Score and Its Relevance
Semin Respir Crit Care Med. 2021 Jun;42(3):346-356. doi: 10.1055/s-0041-1729541. Epub 2021 May 24.
ABSTRACT
Lung transplantation in the United States, under oversight by the Organ Procurement Transplantation Network (OPTN) in the 1990s, operated under a system of allocation based on location within geographic donor service areas, wait time of potential recipients, and ABO compatibility. On May 4, 2005, the lung allocation score (LAS) was implemented by the OPTN Thoracic Organ Transplantation Committee to prioritize patients on the wait list based on a balance of wait list mortality and posttransplant survival, thus eliminating time on the wait list as a factor of prioritization. Patients were categorized into four main disease categories labeled group A (obstructive lung disease), B (pulmonary hypertension), C (cystic fibrosis), and D (restrictive lung disease/interstitial lung disease) with variables within each group impacting the calculation of the LAS. Implementation of the LAS led to a decrease in the number of wait list deaths without an increase in 1-year posttransplant survival. LAS adjustments through the addition, modification or elimination of covariates to improve the estimates of patient severity of illness, have since been made in addition to establishing criteria for LAS value exceptions for pulmonary hypertension patients. Despite the success of the LAS, concerns about the prioritization, and transplantation of older, sicker individuals have made some aspects of the LAS controversial. Future changes in US lung allocation are anticipated with the current development of a continuous distribution model that incorporates the LAS, geographic distribution, and unaccounted aspects of organ allocation into an integrated score.
PMID:34030198 | DOI:10.1055/s-0041-1729541
Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease
J Med Chem. 2021 May 24. doi: 10.1021/acs.jmedchem.1c00343. Online ahead of print.
ABSTRACT
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.
PMID:34028270 | DOI:10.1021/acs.jmedchem.1c00343
Perinatal outcomes in women with cystic fibrosis: data from the Italian Cystic Fibrosis Registry
Acta Obstet Gynecol Scand. 2021 May 24. doi: 10.1111/aogs.14190. Online ahead of print.
ABSTRACT
INTRODUCTION: Data from the Italian Cystic Fibrosis Registry concerning pregnancies in the period 2010-2015 were used to investigate the association between the pre-conception clinical status and perinatal outcomes of women with CF.
MATERIAL AND METHODS: The assessed clinical variables were genotype, age at the time of conception, body mass index (BMI), and the percentage of predicted forced expiratory volume in the first second (ppFEV1 ); the analysed outcomes were gestational age, birthweight, and the frequency of cesarean deliveries. Generalized Linear Mixed model (GLIMMIX) was used to evaluate the association between type of delivery and age at the time of becoming pregnant, BMI, ppFEV1 and gestational age. Robust multivariable regression was used to evaluate the relationship between gestational age and age at the time of becoming pregnant, BMI and ppFEV1 . Multivariable linear regression was performed to verify association between birth weight and BMI, ppFEV1 .
RESULTS: Complete information concerning mother and child was available for 56 completed pregnancies. Median age at the time of conception was 30.8 years (range: 18.7-42.3); median BMI was 21.5 kg/m2 (range: 16.5-26.8); and median ppFEV1 was 73.9 (range: 30-128). Thirty-one women (55.36%) had a genotype consisting of two CF-causing variants. Eight were homozygous for the F508del mutation (14.28% of the total). The median duration of pregnancy was 37 weeks (range: 31-41), and the frequency of prematurity (<37 weeks of gestational age) was 28.30%. Median birthweight was 2,910 g (range: 1,300-3,650). The overall frequency of cesarean sections was 63.64%. A low pre-conception ppFEV1 was associated with prematurity (p=0.014), and birthweight was positively related to ppFEV1 (p=0.04). There was no association between the clinical variables or gestational age and the type of delivery.
CONCLUSIONS: Maternal pre-conceptional respiratory function correlates with the duration of pregnancy and the birthweight of newborns. Cesarean deliveries are also frequent among young women with CF with normal respiratory function.
PMID:34028004 | DOI:10.1111/aogs.14190
What role for cysteamine in the defence against infection?
Emerg Top Life Sci. 2021 May 24:ETLS20200351. doi: 10.1042/ETLS20200351. Online ahead of print.
ABSTRACT
The aminothiol cysteamine has many potential therapeutic applications and is also an endogenous molecule, produced in the body via the activity of pantetheinase enzymes such as vanin-1. This simple small molecule is highly reactive in biological settings and much is yet unknown about its endogenous role in innate immunity to infection, including the impact of cysteamine on bacterial pathogens. We discuss the literature surrounding its biochemistry and challenges to its development as well as the multiple beneficial properties which have been uncovered that support research into its development as novel antimicrobial therapy.
PMID:34027984 | DOI:10.1042/ETLS20200351
Cystic fibrosis in the kidney: new lessons from impaired renal HCO3- excretion
Curr Opin Nephrol Hypertens. 2021 Jul 1;30(4):437-443. doi: 10.1097/MNH.0000000000000725.
ABSTRACT
PURPOSE OF REVIEW: A key role of cystic fibrosis transmembrane conductance regulator (CFTR) in the kidney has recently been uncovered. This needs to be integrated into the understanding of the developed phenotypes in cystic fibrosis (CF) patients.
RECENT FINDINGS: In the beta-intercalated cells of the collecting duct , CFTR functions in very similar terms as established in the exocrine pancreatic duct and both CFTR and SLC26A4 (pendrin) orchestrate regulated HCO3- secretion. Like in the pancreas, the hormone secretin is a key agonist to activate renal HCO3- secretion. In mice lacking CFTR or pendrin, acute and chronic base challenges trigger marked metabolic alkalosis because collecting duct base secretion is defective. Also in CF patients, the ability to acutely increase renal HCO3- excretion is markedly reduced.
SUMMARY: The now much enlarged understanding of CFTR in the kidney may permit the measurement of challenged urine HCO3- excretion as a new biomarker for CF. We suggest a new explanation for the electrolyte disorder in CF termed Pseudo-Bartter Syndrome. The hallmark electrolyte disturbance features of this can be well explained by a reduced function of collecting duct Cl-/HCO3- exchange. Eventually, we suggest the diagnostic term distal renal tubular alkalosis to cover those disturbances that causes metabolic alkalosis by a reduced collecting duct base secretion.
PMID:34027905 | DOI:10.1097/MNH.0000000000000725
The Human Microbiome, an Emerging Key-Player in the Sex Gap in Respiratory Diseases
Front Med (Lausanne). 2021 May 7;8:600879. doi: 10.3389/fmed.2021.600879. eCollection 2021.
ABSTRACT
The sex gap is well-documented in respiratory diseases such as cystic fibrosis and chronic obstructive pulmonary disease. While the differences between males and females in prevalence, severity and prognosis are well-established, the pathophysiology of the sex difference has been poorly characterized to date. Over the past 10 years, metagenomics-based studies have revealed the presence of a resident microbiome in the respiratory tract and its central role in respiratory disease. The lung microbiome is associated with host immune response and health outcomes in both animal models and patient cohorts. The study of the lung microbiome is therefore an interesting new avenue to explore in order to understand the sex gap observed in respiratory diseases. Another important parameter to consider is the gut-lung axis, since the gut microbiome plays a crucial role in distant immune modulation in respiratory diseases, and an intestinal "microgenderome" has been reported: i.e., sexual dimorphism in the gut microbiome. The microgenderome provides new pathophysiological clues, as it defines the interactions between microbiome, sex hormones, immunity and disease susceptibility. As research on the microbiome is increasing in volume and scope, the objective of this review was to describe the state-of-the-art on the sex gap in respiratory medicine (acute pulmonary infection and chronic lung disease) in the light of the microbiome, including evidence of local (lung) or distant (gut) contributions to the pathophysiology of these diseases.
PMID:34026772 | PMC:PMC8137850 | DOI:10.3389/fmed.2021.600879
Bone Cells Differentiation: How CFTR Mutations May Rule the Game of Stem Cells Commitment?
Front Cell Dev Biol. 2021 May 7;9:611921. doi: 10.3389/fcell.2021.611921. eCollection 2021.
ABSTRACT
Cystic fibrosis (CF)-related bone disease has emerged as a significant comorbidity of CF and is characterized by decreased bone formation and increased bone resorption. Both osteoblast and osteoclast differentiations are impacted by cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The defect of CFTR chloride channel or the loss of CFTRs ability to interact with other proteins affect several signaling pathways involved in stem cell differentiation and the commitment of these cells toward bone lineages. Specifically, TGF-, nuclear factor-kappa B (NF-B), PI3K/AKT, and MAPK/ERK signaling are disturbed by CFTR mutations, thus perturbing stem cell differentiation. High inflammation in patients changes myeloid lineage secretion, affecting both myeloid and mesenchymal differentiation. In osteoblast, Wnt signaling is impacted, resulting in consequences for both bone formation and resorption. Finally, CFTR could also have a direct role in osteoclasts resorptive function. In this review, we summarize the existing literature on the role of CFTR mutations on the commitment of induced pluripotent stem cells to bone cells.
PMID:34026749 | PMC:PMC8139249 | DOI:10.3389/fcell.2021.611921
Internet and smartphone-based ecological momentary assessment and personalized advice (PROfeel) in adolescents with chronic conditions: A feasibility study
Internet Interv. 2021 Apr 20;25:100395. doi: 10.1016/j.invent.2021.100395. eCollection 2021 Sep.
ABSTRACT
OBJECTIVE: Growing up with a chronic disease comes with challenges, such as coping with fatigue. Many adolescents are severely fatigued, though its associated factors exhibit considerable interpersonal and longitudinal variation. We assessed whether PROfeel, a combination of a smartphone-based ecological momentary assessment (EMA) method using the internet, followed by a face-to-face dialogue and personalized advice for improvement of symptoms or tailor treatment based on a dynamic network analysis report, was feasible and useful.
STUDY DESIGN: Feasibility study in fatigued outpatient adolescents 12-18 years of age with cystic fibrosis, autoimmune disease, post-cancer treatment, or with medically unexplained fatigue. Participants were assessed at baseline to personalize EMA questions. EMA was conducted via smartphone notifications five times per day for approximately six weeks. Hereby, data was collected via the internet. The EMA results were translated into a personalized report, discussed with the participant, and subsequently translated into a personalized advice. Afterwards, semi-structured interviews on feasibility and usefulness were held.
RESULTS: Fifty-seven adolescents were assessed (mean age 16.2 y ± 1.6, 16% male). Adolescents deemed the smartphone-based EMA feasible, with the app being used for an average of 49 days. Forty-two percent of the notifications were answered and 85% of the participants would recommend the app to other adolescents. The personalized report was deemed useful and comprehensible and 95% recognized themselves in the personalized report, with 64% rating improved insight in their symptoms and subsequent steps towards an approach to reduce one's fatigue as good or very good.
CONCLUSIONS: PROfeel was found to be highly feasible and useful for fatigued adolescents with a chronic condition. This innovative method has clinical relevance through bringing a patient's daily life into the clinical conversation.
PMID:34026566 | PMC:PMC8131314 | DOI:10.1016/j.invent.2021.100395
Novel reaction to new cystic fibrosis medication Trikafta
Clin Case Rep. 2021 May 4;9(5):e04116. doi: 10.1002/ccr3.4116. eCollection 2021 May.
ABSTRACT
We present a novel case of an urticaria multiforme-type drug reaction to the new cystic fibrosis medication Trikafta (elexacaftor + tezacaftor + ivacaftor). Equipped with this information, clinicians may be more prepared to counsel and treat patients if they experience similar symptoms after beginning Trikafta.
PMID:34026156 | PMC:PMC8122137 | DOI:10.1002/ccr3.4116
Ivacaftor Reduces Inflammatory Mediators in Upper Airway Lining Fluid From Cystic Fibrosis Patients With a G551D Mutation: Serial Non-Invasive Home-Based Collection of Upper Airway Lining Fluid
Front Immunol. 2021 May 5;12:642180. doi: 10.3389/fimmu.2021.642180. eCollection 2021.
ABSTRACT
In cystic fibrosis (CF) therapy, the recent approval of CF-transmembrane conductance regulator (CFTR) channel modulators is considered to be the major breakthrough. However, the current first-line approach based mainly on pulmonary function to measure effects of the novel therapy, tested by forced expiratory volumes in one second (FEV1), provides restricted sensitivity to detect early structural damages. Accordingly, there is a need for new sensitive surrogate parameters. Most interestingly, these should quantify inflammation that precedes a decline of pulmonary function. We present a novel method assessing inflammatory markers in the upper airways' epithelial lining fluid (ELF) obtained by nasal lavage (NL). In contrast to broncho-alveolar lavage, ELF sampling by NL is an attractive method due to its limited invasiveness which allows repeated analyses, even performed in a home-based setting. In a longitudinal cohort study (ClinicalTrials.gov, Identifier: NCT02311140), we assessed changes of inflammatory mediators in 259 serially obtained nasal lavages taken up to every second day before and during therapy with ivacaftor from ten CF patients carrying a G551D mutation. Patients were trained to sample NL-fluid at home, to immediately freeze and transfer chilled secretions to centers. Neutrophil Elastase, Interleukins IL-1β, IL-6 and IL-8 in NL were quantified. During 8-12 weeks of ivacaftor-treatment, median values of IL-1β and IL-6 significantly declined 2.29-fold (2.97→1.30 pg/mL), and 1.13-fold (6.48→5.72 pg/mL), respectively. In parallel, sweat tests and pulmonary function improved considerably. This is the first study assessing changes of airway inflammation on a day-to-day basis in CF patients receiving a newly administered CFTR-modulator therapy. It proves a decline of airway inflammation during ivacaftor-therapy.
PMID:34025651 | PMC:PMC8131546 | DOI:10.3389/fimmu.2021.642180