Antibiotics (Basel). 2022 Nov 16;11(11):1637. doi: 10.3390/antibiotics11111637.

ABSTRACT

Cystic fibrosis (CF) is a genetic and multisystemic disease that requires a high therapeutic demand for its control. The aim of this study was to assess therapeutic adherence (TA) to different treatments to study possible clinical consequences and clinical factors influencing adherence. This is an ambispective observational study of 57 patients aged over 18 years with a diagnosis of CF. The assessment of TA was calculated using the Medication Possession Ratio (MPR) index. These data were related to exacerbations and the rate of decline in FEV1 percentage. Compliance was good for all CFTR modulators, azithromycin, aztreonam, and tobramycin in solution for inhalation. The patients with the best compliance were older; they had exacerbations and the greatest deterioration in lung function during this period. The three variables with the highest importance for the compliance of the generated Random Forest (RF) models were age, FEV1%, and use of Ivacaftor/Tezacaftor. This is one of the few studies to assess adherence to CFTR modulators and symptomatic treatment longitudinally. CF patient therapy is expensive, and the assessment of variables with the highest importance for a high MPR, helped by new Machine learning tools, can contribute to defining new efficient TA strategies with higher benefits.

PMID:36421281 | DOI:10.3390/antibiotics11111637

Open Forum Infect Dis. 2022 Oct 27;9(11):ofac550. doi: 10.1093/ofid/ofac550. eCollection 2022 Nov.

ABSTRACT

A 7-day course of glecaprevir/pibrentasvir started in the preoperative period prevented transmission of hepatitis C virus (HCV) from viremic donors to 10 HCV-negative recipients (2 heart, 1 lung, 6 kidney, 1 heart/kidney) with 100% sustained virological response at 12 weeks.

PMID:36420058 | PMC:PMC9679803 | DOI:10.1093/ofid/ofac550

J Cyst Fibros. 2022 Nov 20:S1569-1993(22)01410-2. doi: 10.1016/j.jcf.2022.11.001. Online ahead of print.

ABSTRACT

BACKGROUND: Achromobacter species are emerging pathogens isolated from respiratory samples of Patients with cystic fibrosis (pwCF) causing growing concerns in the CF community. The epidemiology and the clinical impact of Achromobacter in CF is unclear since data are restricted to small case control studies or selected populations.

AIM: To characterize the effect of Achromobacter respiratory infection on CF lung disease.

METHODS: European CF Society Patient Registry data was analysed for association between Achromobacter infection and demographic/clinical characteristics and outcomes of pwCF.

RESULTS: Of eligible 38,795 patients, Achromobacter infection was reported in 2,093 (prevalence (95% CI) of 5.40% (5.17 - 5.62). The prevalence varied significantly between the countries and increased with age peaking at the age 20-30. Achromobacter infection was more prevalent in pwCF carrying class minimal function mutations, having worse nutrition or lower pulmonary function, and more patients inhaled antibiotics against P. aeruginosa. Patient infected with Achromobacter had similar pulmonary function and BMI to patients infected with P. aeruginosa at all age groups. Being infected with both bacteria was associated with significantly lower pulmonary function and BMI at all age groups.

CONCLUSIONS: Achromobacter infection was associated with disease severity similar to infection with P. aeruginosa. Being infected with both bacteria is associated with even more severe disease. This suggests to study if eradication will improve the outcome of pwCF.

PMID:36418214 | DOI:10.1016/j.jcf.2022.11.001

Tuberculosis (Edinb). 2022 Nov 17;138:102276. doi: 10.1016/j.tube.2022.102276. Online ahead of print.

ABSTRACT

Nontuberculous mycobacteria (NTM) are opportunistic pathogens that affect a relatively small but significant portion of the people with cystic fibrosis (CF), and may cause increased morbidity and mortality in this population. Cultures from the airway are the only test currently in clinical use for detecting NTM. Culture techniques used in clinical laboratories are insensitive and poorly suited for population screening or to follow progression of disease or treatment response. The lack of sensitive and quantitative markers of NTM in the airway impedes patient care and clinical trial design, and has limited our understanding of patterns of acquisition, latency and pathogenesis of disease. Culture-independent markers of NTM infection have the potential to overcome many of the limitations of standard NTM cultures, especially the very slow growth, inability to quantitate bacterial burden, and low sensitivity due to required decontamination procedures. A range of markers have been identified in sputum, saliva, breath, blood, urine, as well as radiographic studies. Proposed markers to detect presence of NTM or transition to NTM disease include bacterial cell wall products and DNA, as well as markers of host immune response such as immunoglobulins and the gene expression of circulating leukocytes. In all cases the sensitivity of culture-independent markers is greater than standard cultures; however, most do not discriminate between various NTM species. Thus, each marker may be best suited for a specific clinical application, or combined with other markers and traditional cultures to improve diagnosis and monitoring of treatment response.

PMID:36417800 | DOI:10.1016/j.tube.2022.102276

Ir J Med Sci. 2022 Nov 23. doi: 10.1007/s11845-022-03225-1. Online ahead of print.

ABSTRACT

BACKGROUND: Oscillating positive expiratory pressure (OPEP) devices play a key role in airway clearance, particularly in patients with cystic fibrosis. These devices, however, have the potential to become reservoirs for pathogenic organisms and require daily, or even more frequent, cleaning. This places a large burden on patients and their carers.

AIMS: The objective of this work was to develop a disposable OPEP device, with comparable mechanical performance to commercial devices, that negates the need for cleaning after use thus reducing microbiological risks.

METHODS: 3D printing was used to iterate and develop a prototype disposable device (The University of Limerick OPEP, abbreviated to the UL-OPEP) that was compared with a selection of commercially available devices for mean pressure and oscillation amplitude (cmH2O), as well as oscillation frequency (Hz). All devices were tested using a healthy volunteer at a target expiratory flow of ~ 20 L/min. The target therapeutic range was 10-20 cmH2O at a flow rate of 10-20 L/min as is reported widely in the literature.

RESULTS: The prototype disposable device achieved a mean pressure of 14.82 cmH2O at a mean flow rate of 18.82 L/min, and generated an oscillation frequency of 26 Hz with an amplitude of 1.28 cmH2O. These characteristics compare favourably with existing, more complex, reusable OPEP devices.

CONCLUSIONS: The UL-OPEP device is a small, disposable OPEP device, that generates pressure and oscillation amplitudes for clinically effective airway clearance. The device negates the need for cleaning and disinfecting, removing the risk of devices acting as a potential reservoir for pathogenic organisms while maintaining mucus-clearing benefits.

PMID:36417107 | DOI:10.1007/s11845-022-03225-1

Prague Med Rep. 2022;123(4):279-286. doi: 10.14712/23362936.2022.26.

ABSTRACT

Spontaneous pneumothorax is a serious and life-threatening complication of SARS-CoV-2 pneumonia. It most commonly occurs during the acute phase of the disease in patients with pre-existing lung disease (e.g. emphysema, bronchiectasis, cystic fibrosis, etc.) and in patients who require oxygen supplementation in any form (low-flow oxygen therapy, high-flow non-invasive or mechanical invasive or mechanical invasion). A rare case of a 52-year-old patient with a spontaneous pneumothorax who developed four weeks after PCR SARS-CoV-2 positivity was described. Interestingly, the patient did not have any factors that the literature considered risky for the development of this complication. During the acute phase of the disease, his condition did not require hospitalization. Imaging examinations could not clarify the cause of pneumothorax. With this case report, we want to point out the fact that spontaneous pneumothorax, as a rare and life-threatening complication of COVID-19 infection, may develop during recovery, and it is necessary to think about this complication in the differential diagnosis of dyspnoea.

PMID:36416466 | DOI:10.14712/23362936.2022.26

Clin Sci (Lond). 2022 Nov 23:CS20220450. doi: 10.1042/CS20220450. Online ahead of print.

ABSTRACT

Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid and excess of Mead acid. Relative deficiency of docosahexaenoic acid is variably found. However, the initial development of these abnormalities is not understood. We examined fatty acid composition in young CF ferrets and pigs, finding abnormalities from the day of birth onward including relative deficiency of linoleic acid in both species. Fatty acid composition abnormalities were present in both liver and serum phospholipids of newborn CF piglets even prior to feeding, including reduced linoleic acid and increased Mead acid. Serum fatty acid composition evolved over the first weeks of life in both non-CF and CF ferrets, though differences between CF and non-CF persisted. Although red blood cell phospholipid fatty acid composition was normal in newborn animals, it became perturbed in juvenile CF ferrets including relative deficiencies of linoleic and docosahexaenoic acids and excess of Mead acid. In summary, fatty acid composition abnormalities in CF pigs and ferrets exist from a young age including at birth independent of feeding and overlap extensively with the abnormalities found in humans with CF. That the abnormalities exist prior to feeding implies that dietary measures alone will not address the mechanisms of imbalance.

PMID:36416119 | DOI:10.1042/CS20220450

Pediatr Pulmonol. 2022 Nov 23. doi: 10.1002/ppul.26253. Online ahead of print.

ABSTRACT

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) has been underway universally in the USA for more than a decade, as well in most European countries, and algorithms have been evolving throughout this period with quality improvement projects as immunoreactive trypsinogen determinations alone have been transformed to a 2-tier strategy with DNA analyses.

OBJECTIVE: To apply next generation sequencing (NGS) as a screening method to expand the DNA tier and identify substantially more variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene to enhance sensitivity and equity while minimizing incidental findings.

DESIGN: Sequential evaluation and improvement plan in three phases using algorithm modifications coupled to statewide follow up and analysis of screening outcomes.

RESULTS: After demonstrating feasibility in the first phase, we studied an IRT/NGS algorithm that included CFTR Variants with Varying Clinical Consequences (VVCCs). This revealed a high identification of CF patients with 2-variants detected through screening, but for every CF case there were 1.4 with cystic fibrosis metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). This led us to a third phase of improvement in which the VVCCs were eliminated except for R117H, resulting in 94% 2-variant detection of patients and 0.44:1 ratio of CRMS/CFSPID to CF.

CONCLUSION: NGS can be used with IRT as an effective method of identifying infants at risk for CF without an appreciable increase in detection of carriers. Its potential added value includes facilitating equity, enhancing sensitivity and detecting more CF patients with 2-variants during the screening process. This article is protected by copyright. All rights reserved.

PMID:36416003 | DOI:10.1002/ppul.26253

Acta Clin Belg. 2022 Nov 22:1-5. doi: 10.1080/17843286.2022.2145684. Online ahead of print.

ABSTRACT

BACKGROUND: To examine safety and efficacy of tezacaftor-ivacaftor (TEZ/IVA) in a real-life setting in adults living with cystic fibrosis.

METHODS: A multicentre retrospective observational study, including adults living with cystic fibrosis (pwCF) eligible for TEZ/IVA, with assessments at baseline, 3 months (visit3mo) and 6 months (visit6mo) after start of treatment. Outcomes included change in FEV1, LCI, FeNO, CFQ-R, estimated number of annual acute exacerbations, BMI, dosage of pancreatic enzyme replacement therapy (PERT) and airway microbiology. We also assessed safety.

RESULTS: Forty-eight adult pwCF (mean (±SD) age 33 (±12) years; mean FEV1 65 (±19) %P) were included. Three subgroups were identified: pwCF F/F CFTR modulator-naive (n = 28; 58%), pwCF F/F previously treated with lumacaftor-ivacaftor (n = 11; 23%) and pwCF F/RF (n = 9; 19%). Adverse events were described in 3 pwCF (6%) during the 6-month observation period (in one leading to treatment interruption). At visit3mo, FEV1 had improved in all subgroups. In the entire group, mean FEV1 had increased from 66 (±2.9) %P to 72 (±2.9) %P (p < 0.0001). Similarly, LCI improved by approximately one unit at visit3mo (p = 0.02). At visit6mo mean annual acute exacerbation rate decreased significantly (p = 0.02). Only in the CFQ-R social functioning domain score, a significant improvement was observed at visit6mo (p < 0.01).

CONCLUSIONS: We showed that TEZ/IVA is safe, well tolerated and effective in terms of improvement of lung function, ventilation inhomogeneity, health-related social functioning, and reduction of estimated annual acute exacerbation rate, in adult pwCF F/F and F/RF. Results in this real-life study reflect those observed in RCTs.

PMID:36415912 | DOI:10.1080/17843286.2022.2145684

Access Microbiol. 2022 Oct 7;4(10):acmi000413. doi: 10.1099/acmi.0.000413. eCollection 2022.

ABSTRACT

In cystic fibrosis (CF) patients, Gram-negative Burkholderia cepacia complex (Bcc) infections are associated with recurrent pulmonary exacerbations. Bcc organisms are innately resistant to many antibiotics, and infection with B. cenocepacia is a contraindication to lung transplantation. We report a CF patient with severe lung disease, colonized with Bcc, with a history of around nine exacerbations per year for over 10 years, for whom antibiotic regimens (including targeted and broad-spectrum antibiotics) had not cleared infection or extended the interval between exacerbations. After receiving a 2 week cefiderocol-containing regimen, the patient remained stable for more than 5 months without the need for additional antibiotics or hospital admissions for respiratory exacerbations.

PMID:36415733 | PMC:PMC9675169 | DOI:10.1099/acmi.0.000413

Colomb Med (Cali). 2022 May 30;53(2):e2014832. doi: 10.25100/cm.v53i2.4832. eCollection 2022 Apr-Jun.

ABSTRACT

BACKGROUND: Inborn errors of immunity, mainly Predominantly Antibody deficiencies with normal IgG levels are unrecognized in adults with lung diseases such as bronchiectasis or recurrent pneumonia.

OBJECTIVE: To determine IgM, IgA, IgG2 subclass deficiencies, and Specific antibody deficiency (anti-pneumococcal polysaccharide antibodies) in adults with non-cystic fibrosis bronchiectasis or recurrent pneumonia.

METHODS: Cross-sectional study. Consecutive patients with non-cystic fibrosis bronchiectasis or recurrent pneumonia were recruited in Cali, Colombia. IgG, IgA, IgM, and IgE, IgG2subclass and IgG anti-pneumococcal serum levels were measured.

RESULTS: Among the 110 participants enrolled, Antibody deficiencies with normal serum IgG levels were found in 11(10%) cases. IgA deficiency (3 cases), IgM deficiency (2 cases) and IgG2 deficiency (2 cases) were the most frequent primary immunodeficiencies. In addition, IgG2+IgA deficiency, Ataxia-telangiectasia, Hyper-IgE syndrome and Specific Antibody Deficiency(anti-polysaccharides) were found in one case each.

CONCLUSIONS: Predominantly antibody deficiencies with normal IgG levels are an important etiology of non-cystic fibrosis bronchiectasis and recurrent pneumonia in adults.

PMID:36415694 | PMC:PMC9651167 | DOI:10.25100/cm.v53i2.4832

J Ayub Med Coll Abbottabad. 2022 Jul-Sep;34(Suppl 1)(3):S686-S690. doi: 10.55519/JAMC-03-S1-9678.

ABSTRACT

BACKGROUND: Long term hypertonic saline use has been found to improve mucus transport, airway hydration, and mucociliary clearance in patients with cystic fibrosis. However, the effect of hypertonic saline on the outcomes of patients with cystic fibrosis is not well established. The aim of our study was to determine the long-term use of hypertonic saline in reducing pulmonary exacerbations, length of hospital stay and pseudomonas colonization in patients with cystic fibrosis admitted for treatment at a tertiary care referral center.

METHODS: Retrospective cohort study was conducted on 71 patients with cystic fibrosis. Patients ranged in age between 3-18 years. All patients with two to five pulmonary exacerbations in the preceding six months were included in the study. Those who received regular inhaled 3-7% hypertonic saline twice daily during their admission and till 6 months after discharge from hospital were categorized as hypertonic saline (HTS) group. Patients who did not receive regular hypertonic saline for 6 months were included in the non-hypertonic saline (NHTS) group. Data was analyzed at the end of one year.

RESULTS: The HTS group had 37 patients whereas, the NHTS group had 34 patients. Mean number of exacerbation episodes was significantly lower in HTS group (2.18±0.84) as compared to NHTS group (3.67±0.91) (p<0.01) whereas, length of hospital stays and frequency of pseudomonas colonization did not significantly differ between the two groups (p=0.78 and p=0.12 respectively). The mean number of pulmonary exacerbations also significantly reduced from 3.11±1.07 to 2.18±0.84 p-value <0.01 in the HTS group over the follow-up period of one year.

CONCLUSION: : Long term hypertonic saline therapy is beneficial in patients with cystic fibrosis in preventing pulmonary exacerbations and subsequently reducing morbidity.

PMID:36414591 | DOI:10.55519/JAMC-03-S1-9678

Int J Neonatal Screen. 2022 Oct 27;8(4):58. doi: 10.3390/ijns8040058.

ABSTRACT

Testing immunoreactive trypsinogen (IRT) is the first step in cystic fibrosis (CF) newborn screening. While high IRT is associated with CF, some cases are missed. This survey aimed to find factors associated with missed CF cases due to IRT levels below program cutoffs. Twenty-nine states responded to a U.S-wide survey and 13 supplied program-related data for low IRT false screen negative cases (CFFN) and CF true screen positive cases (CFTP) for analysis. Rates of missed CF cases and odds ratios were derived for each factor in CFFNs, and two CFFN subgroups, IRT above ("high") and below ("low") the CFFN median (39 ng/mL) compared to CFTPs for this entire sample set. Factors associated with "high" CFFN subgroup were Black race, higher IRT cutoff, fixed IRT cutoff, genotypes without two known CF-causing variants, and meconium ileus. Factors associated with "low" CFFN subgroup were older age at specimen collection, Saturday birth, hotter season of newborn dried blood spot collection, maximum ≥ 3 days laboratories could be closed, preterm birth, and formula feeding newborns. Lowering IRT cutoffs may reduce "high" IRT CFFNs. Addressing hospital and laboratory factors (like training staff in collection of blood spots, using insulated containers during transport and reducing consecutive days screening laboratories are closed) may reduce "low" IRT CFFNs.

PMID:36412584 | DOI:10.3390/ijns8040058

Hum Vaccin Immunother. 2022 Nov 22:2140533. doi: 10.1080/21645515.2022.2140533. Online ahead of print.

ABSTRACT

Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in children under one year and a leading cause of infant hospitalization. Palivizumab was approved by the FDA in 1998 as RSV immunoprophylaxis to prevent severe RSV disease in children with specific health conditions and those born at <35 weeks gestational age (wGA). This study compared RSV-related hospitalization (RSVH) and RSVH characteristics in very preterm (<29 wGA) and term (>37 wGA) infants. Using the MarketScan Commercial and Multi-State Medicaid administrative claims databases, infants born between 7/1/2003 and 6/30/2020 were identified and classified as very preterm or term. Infants with evidence of health conditions, such as congenital heart disease and cystic fibrosis, were excluded. During 2003-2020 RSV seasons (November to March), claims incurred by infants while they were <12 months old were evaluated for outpatient administration of palivizumab and RSVH. The study included 40,123 very preterm infants and 4,421,942 term infants. Rate of RSVH in very preterm infants ranged 1.5-3.8 per 100 infant-seasons in commercially insured infants and 3.5-8.4 in Medicaid insured infants and were inversely related to wGA at birth. Relative risk of RSVH in very preterm was 3-4 times higher, and ICU admissions and mechanical ventilation were more common during RSVH in very preterm infants relative to term infants. However, these outcomes were less common or less severe in very preterm infants who received outpatient palivizumab administration, despite evidence of higher baseline risk of RSVH in these infants.

PMID:36412253 | DOI:10.1080/21645515.2022.2140533

Monaldi Arch Chest Dis. 2022 Nov 18. doi: 10.4081/monaldi.2022.2399. Online ahead of print.

ABSTRACT

Oxygen is probably the most commonly prescribed drug in the emergency setting and is a life-saving modality as well. However, like any other drug, oxygen therapy may also lead to various adverse effects. Patients with chronic obstructive pulmonary disease (COPD) may develop hypercapnia during supplemental oxygen therapy, particularly if uncontrolled. The risk of hypercapnia is not restricted to COPD only; it has also been reported in patients with morbid obesity, asthma, cystic fibrosis, chest wall skeletal deformities, bronchiectasis, chest wall deformities, or neuromuscular disorders. However, the risk of hypercapnia should not be a deterrent to oxygen therapy in hypoxemic patients with chronic lung diseases, as hypoxemia may lead to life-threatening cardiovascular complications. Various mechanisms leading to the development of oxygen-induced hypercapnia are the abolition of 'hypoxic drive', loss of hypoxic vasoconstriction and absorption atelectasis leading to an increase in dead-space ventilation and Haldane effect. The international guideline recommends a target oxygen saturation of 88% to 92% in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and other chronic lung diseases at risk of hypercapnia. Oxygen should be administered only when oxygen saturation is below 88%. We searched PubMed, EMBASE, and the CINAHL from inception to June 2022. We used the following search terms: "Hypercapnia", "Oxygen therapy in COPD", "Oxygen-associated hypercapnia", "oxygen therapy", and "Hypoxic drive". All types of study are selected. This review will focus on the physiological mechanisms of oxygen-induced hypercapnia and its clinical implications.

PMID:36412131 | DOI:10.4081/monaldi.2022.2399

Respir Med Case Rep. 2022 Nov 12;40:101772. doi: 10.1016/j.rmcr.2022.101772. eCollection 2022.

ABSTRACT

We present a patient with cystic fibrosis who used nebulized levofloxacin off-label to suppress chronic Burkholderia cenocepacia pulmonary infection. The patient was initially using tobramycin inhalation powder (TIP) off-label continuously for suppression of chronic B. cenocepacia; this was changed to alternating months of nebulized levofloxacin and TIP. Following initiation of nebulized levofloxacin, the patient had significant improvement in respiratory symptom burden and lung function (as measured by forced expiratory volume in 1 second [FEV1]), and a decrease in the frequency of pulmonary exacerbations. Further research is necessary to determine whether the benefits observed with nebulized levofloxacin in our patient translate to a larger population of patients with chronic Burkholderia spp. pulmonary infection.

PMID:36411822 | PMC:PMC9674917 | DOI:10.1016/j.rmcr.2022.101772

Respir Med Case Rep. 2022 Nov 7;40:101775. doi: 10.1016/j.rmcr.2022.101775. eCollection 2022.

ABSTRACT

Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) is a triple combination drug therapy approved for individuals with cystic fibrosis (CF) who possess at least one copy of the F508del cystic fibrosis transmembrane conductance regulator (CFTR) variant. ELX/TEZ/IVA improves lung function and decreases the frequency of CF exacerbations in clinical studies, which has led to investigation of this therapy on rare CFTR variants. Rare mutations have limited research publications; therefore, reporting outcomes is critical to expanding knowledge and understanding of therapeutic efficacy. This case highlights a CF adolescent homozygous for the G85E CFTR variant who had resolution of chronic respiratory symptoms after initiating ELX/TEZ/IVA.

PMID:36411821 | PMC:PMC9674891 | DOI:10.1016/j.rmcr.2022.101775

Creat Nurs. 2022 Nov 10;28(4):279-282. doi: 10.1891/CN-2021-0082.

ABSTRACT

Hygge is a Nordic practice and mindset of creating warmth and comfort from within to improve one's wellness. Hygge has not been explored well in the scientific literature, especially in the context of a chronic illness. This article describes the experiences of an adult woman with cystic fibrosis, a progressive, incurable genetic disease primarily affecting the respiratory and gastrointestinal tracts, as she uses hygge to cope with the daily challenges of her illness. She also uses hygge as a framework for an online support group she founded to encourage other women with CF in their quest for optimal physical and emotional health. Hygge offers practical self-care behaviors that have the potential to make positive impacts on quality of life across healthy communities and those with chronic conditions, especially in the current setting of a global pandemic.

PMID:36411040 | DOI:10.1891/CN-2021-0082

Otolaryngol Clin North Am. 2023 Feb;56(1):169-179. doi: 10.1016/j.otc.2022.09.013.

ABSTRACT

Support for the unified airway hypothesis is embedded in similarities in upper and lower airway structure, function, and cellular/extracellular compositions. The impact of endoscopic sinus surgery (ESS) on the unified airway is influenced by multiple factors including the underlying upper and lower airway condition(s) present and severity of pathology. Beyond improvements in subjective and objective CRS outcomes, ESS also improves clinical asthma outcomes and measures of asthma control. Emerging evidence suggests that early ESS may mitigate the risk of developing asthma in CRS patients without asthma. Comprehensive management of upper and lower airways is paramount to optimize patient outcomes.

PMID:36410989 | DOI:10.1016/j.otc.2022.09.013

Eur J Pharmacol. 2022 Nov 18:175396. doi: 10.1016/j.ejphar.2022.175396. Online ahead of print.

ABSTRACT

The most prevalent cystic fibrosis (CF)-causing mutation - F508del - impairs the folding of CFTR protein, resulting in its defective trafficking and premature degradation. Small molecules termed correctors may rescue F508del-CFTR and therefore constitute promising pharmacotherapies acting on the fundamental cause of the disease. Here, we screened a collection of triazole compounds to identify novel F508del-CFTR correctors. The functional primary screen identified four hit compounds (LSO-18, LSO-24, LSO-28, and LSO-39), which were further validated and demonstrated to rescue F508del-CFTR processing, plasma membrane trafficking, and function. To interrogate their mechanism of action (MoA), we examined their additivity to the clinically approved drugs VX-661 and VX-445, low temperature, and genetic revertants of F508del-CFTR. Rescue of F508del-CFTR processing and function by LSO-18, LSO-24, and LSO-28, but not by LSO-39, was additive to VX-661, whereas LSO-28 and LSO-39, but not LSO-18 nor LSO-24, were additive to VX-445. All compounds under investigation demonstrated additive rescue of F508del-CFTR processing and function to low temperature as well as to rescue by genetic revertants G550E and 4RK. Nevertheless, none of these compounds was able to rescue processing nor function of DD/AA-CFTR, and LSO-39 (similarly to VX-661) exhibited no additivity to genetic revertant R1070W. From these findings, we suggest that LSO-39 (like VX-661) has a putative binding site at the NBD1:ICL4 interface, LSO-18 and LSO-24 seem to share the MoA with VX-445, and LSO-28 appears to act by a different MoA. Altogether, these findings represent an encouraging starting point to further exploit this chemical series for the development of novel CFTR correctors.

PMID:36410419 | DOI:10.1016/j.ejphar.2022.175396