Nutrients. 2022 Feb 16;14(4):834. doi: 10.3390/nu14040834.

ABSTRACT

(1) Background: Malnutrition has been a hallmark of cystic fibrosis (CF) for some time, and improved nutritional status is associated with improved outcomes. While individuals with CF historically required higher caloric intake than the general population, new CF therapies and improved health in this population suggest decreased metabolic demand and prevalence of overweight and obesity have increased. This study aimed to (a) examine diet quality in a population of young adults with CF using the Healthy Eating Index, a measure of diet quality in accordance with the U.S. Dietary Guidelines for Americans and (b) evaluate and describe how subcomponents of the HEI might apply to individuals with CF (2) Methods: 3-day dietary recalls from healthy adolescents and young adults with CF were obtained and scored based on the Healthy Eating Index (3) Results: Dietary recalls from 26 (14M/12F) adolescents and young adults with CF (ages 16-23), were obtained. Individuals with CF had significantly lower HEI scores than the general population and lower individual component scores for total vegetables, greens and beans, total fruits, whole fruits, total protein, seafood and plant protein and sodium (p values < 0.01 for all). (4) Conclusion: Dietary quality was poor in these healthy adolescents and young adults with CF. Given the increased prevalence of overweight and obesity in CF, updated dietary guidance is urgently needed for this population. The Healthy Eating Index may be a valuable tool for evaluating dietary quality in CF.

PMID:35215485 | DOI:10.3390/nu14040834

Pharmaceuticals (Basel). 2022 Feb 21;15(2):260. doi: 10.3390/ph15020260.

ABSTRACT

Therapeutic solutions to counter Burkholderia cepacia complex (Bcc) bacteria are challenging due to their intrinsically high level of antibiotic resistance. Bcc organisms display a variety of potential virulence factors, have a distinct lipopolysaccharide naturally implicated in antimicrobial resistance. and are able to form biofilms, which may further protect them from both host defence peptides (HDPs) and antibiotics. Here, we report the promising anti-biofilm and immunomodulatory activities of human HDP GVF27 on two of the most clinically relevant Bcc members, Burkholderia multivorans and Burkholderia cenocepacia. The effects of synthetic and labelled GVF27 were tested on B. cenocepacia and B. multivorans biofilms, at three different stages of formation, by confocal laser scanning microscopy (CLSM). Assays on bacterial cultures and on human monocytes challenged with B. cenocepacia LPS were also performed. GVF27 exerts, at different stages of formation, anti-biofilm effects towards both Bcc strains, a significant propensity to function in combination with ciprofloxacin, a relevant affinity for LPSs isolated from B. cenocepacia as well as a good propensity to mitigate the release of pro-inflammatory cytokines in human cells pre-treated with the same endotoxin. Overall, all these findings contribute to the elucidation of the main features that a good therapeutic agent directed against these extremely leathery biofilm-forming bacteria should possess.

PMID:35215373 | DOI:10.3390/ph15020260

Pharmaceuticals (Basel). 2022 Feb 11;15(2):217. doi: 10.3390/ph15020217.

ABSTRACT

N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have been discovered over the years, making it a promising drug for diseases such as cystic fibrosis (CF). Its antioxidant activity plays a key role in CF airway inflammation and redox imbalance. Furthermore, this molecule appears to play an important role in the prevention and eradication of biofilms resulting from CF airway infections, in particular that of Pseudomonas aeruginosa. The aim of this review is to provide an overview of CF and the role that NAC could play in preventing and eliminating biofilms, as a modulator of inflammation and as an antioxidant, restoring the redox balance within the airways in CF patients. To do this, NAC can act alone, but it can also be used as an adjuvant molecule to known drugs (antibiotics/anti-inflammatories) to increase their activity.

PMID:35215328 | DOI:10.3390/ph15020217

Pathogens. 2022 Jan 28;11(2):181. doi: 10.3390/pathogens11020181.

ABSTRACT

Achromobacter is an opportunistic pathogen that mainly causes chronic lung infections in cystic fibrosis (CF) patients and is associated with increased mortality. Little is known about Achromobacter spp. in the lung transplant recipient (LTXr) population. We aimed at describing rates of Achromobacter spp. infection in LTXr prior to, in relation to, and after transplantation, as well as all-cause mortality proportion in infected and uninfected LTXr. We included 288 adult LTXr who underwent lung transplantation (LTX) between 1 January 2010 and 31 December 2019 in Denmark. Bronchoalveolar lavage was performed at regular intervals starting two weeks after transplantation. Positive cultures of Achromobacter spp. were identified in nationwide microbiology registries, and infections were categorized as persistent or transient, according to the proportion of positive cultures. A total of 11 of the 288 LTXr had transient (n = 7) or persistent (n = 4) Achromobacter spp. infection after LTX; CF was the underlying disease in 9 out of 11 LTXr. Three out of the four patients, with persistent infection after LTX, also had persistent infection before LTX. The cumulative incidence of the first episode of infection one year after LTX was 3.8% (95% CI: 1.6-6.0). The incidence rates of transient and persistent infection in the first year after LTX were 27 (12-53) and 15 (5-37) per 1000 person-years of follow-up, respectively. The all-cause mortality proportion one year after LTX was 27% in the Achromobacter spp. infected patients and 12% in the uninfected patients (p = 0.114). Achromobacter spp. mainly affected LTXr with CF as the underlying disease and was rare in non-CF LTXr. Larger studies are needed to assess long-term outcomes of Achromobacter spp. in LTXr.

PMID:35215124 | DOI:10.3390/pathogens11020181

Pathogens. 2022 Jan 19;11(2):116. doi: 10.3390/pathogens11020116.

ABSTRACT

The innate immune response to P. aeruginosa pulmonary infections relies on a network of pattern recognition receptors, including intracellular inflammasome complexes, which can recognize both pathogen- and host-derived signals and subsequently promote downstream inflammatory signaling. Current evidence suggests that the inflammasome does not contribute to bacterial clearance and, in fact, that dysregulated inflammasome activation is harmful in acute and chronic P. aeruginosa lung infection. Given the role of mitochondrial damage signals in recruiting inflammasome signaling, we investigated whether mitochondrial-targeted therapies could attenuate inflammasome signaling in response to P. aeruginosa and decrease pathogenicity of infection. In particular, we investigated the small molecule, ZLN005, which transcriptionally activates peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration. We demonstrate that P. aeruginosa infection promotes the expression of inflammasome components and attenuates several components of mitochondrial repair pathways in vitro in lung epithelial cells and in vivo in an acute pneumonia model. ZLN005 activates PGC-1α and its downstream effector, Sirtuin 3 (SIRT3), a mitochondrial-localized deacetylase important for cellular metabolic processes and for reactive oxygen species homeostasis. ZLN005 also attenuates inflammasome signaling induced by P. aeruginosa in bronchial epithelial cells and this action is dependent on ZLN005 activation of SIRT3. ZLN005 treatment reduces epithelial-barrier dysfunction caused by P. aeruginosa and decreases pathogenicity in an in vivo pneumonia model. Therapies that activate the PGC-1α-SIRT3 axis may provide a complementary approach in the treatment of P. aeruginosa infection.

PMID:35215060 | DOI:10.3390/pathogens11020116

Pharmaceutics. 2022 Feb 13;14(2):408. doi: 10.3390/pharmaceutics14020408.

ABSTRACT

The aim of this prospective study was to evaluate the pharmacokinetics of ganciclovir in lung transplant recipients, to explore its covariates, and to propose an individualized dosing regimen. Ganciclovir was administered according to the protocol in a standardized intravenous dose of 5 mg/kg twice daily. Serum ganciclovir concentrations were monitored as a trough and at 3 and 5 h after dosing. Individual ganciclovir pharmacokinetic parameters were calculated in a two-compartmental pharmacokinetic model, while regression models were used to explore the covariates. Optimal loading and maintenance doses were calculated for each patient. In lung transplant recipients (n = 40), the median (IQR) ganciclovir total volume of distribution and clearance values were 0.65 (0.52-0.73) L/kg and 0.088 (0.059-0.118) L/h/kg, respectively. We observed medium-to-high inter-individual but negligible intra-individual variability in ganciclovir pharmacokinetics. The volume of distribution of ganciclovir was best predicted by height, while clearance was predicted by glomerular filtration rate. Bodyweight-normalized clearance was significantly higher in patients with cystic fibrosis, while distribution half-life was reduced in this subgroup. On the basis of the observed relationships, practical nomograms for individualized ganciclovir dosing were proposed. The dosing of ganciclovir in patients with cystic fibrosis requires special caution, as their daily maintenance dose should be increased by approximately 50%.

PMID:35214140 | DOI:10.3390/pharmaceutics14020408

Ann Am Thorac Soc. 2022 Feb 25. doi: 10.1513/AnnalsATS.202108-965OC. Online ahead of print.

ABSTRACT

Rationale The pathobiology of Staphylococcus aureus in non-cystic fibrosis bronchiectasis (nCFB) is poorly defined. When present at high density or "inoculum", some methicillin-sensitive S. aureus (MSSA) can inefficiently degrade anti-Staphylococcal beta-lactam antibiotics via BlaZ penicillinases (termed, the inoculum effect). Given the high burden of organisms in bronchiectatic airways, this is particularly relevant. Objectives Drawing from a prospectively-collected biobank, we sought to understand the prevalence, natural history, potential for transmission, and antibiotic resistance profiles amongst nCFB-derived MSSA isolates. Methods All individuals attending a regional consultancy nCFB clinic with sputum collected between 1981-2017 were considered, and those with ≥1 S. aureus-positive culture comprised the cohort. Each individual's most recent biobank isolate was subjected to whole genome sequencing (including the blaZ gene), antibacterial susceptibility testing, and comparative beta-lactam testing at standard (5 x 105CFU/mL) and high (5 x 107CFU/mL) inoculum to assess for the inoculum, and pronounced inoculum effect (IE and pIE, respectively). Results Seventy-four of 209 (35.4%) individuals had ≥1 sputum sample(s) with S. aureus (68 MSSA, 6 MRSA). Those with S. aureus infection were more likely to be female. Amongst 60/74 MSSA isolates subjected to WGS, no evidence of transmission was identified, although specific MLST types were prevalent including ST-1, ST-15, ST-30, and ST-45. Antibiotic resistance was uncommon except for macrolides (~20%). Amongst the 60 MSSA, prevalence of IE and pIE, respectively, were observed to be drug specific; meropenem (0%, 0%), cefepime (3%, 5%), ceftazidime (8%, 0%), cloxacillin (12%, 0%), cefazolin (23%, 0%) and piperacillin-tazobactam (37%, 17%). The cefazolin IE associated with blaZ type A (p<0.01) and ST-30 (p<0.01), whereas the piperacillin-tazobactam IE associated with type C blaZ (p<0.001) and ST-15 (p<0.05). Conclusions S. aureus infection was common, although no evidence of transmission was apparent in our nCFB cohort. While routine susceptibility testing did not identify significant resistance, inoculum-related resistance was found to be relevant for commonly used nCFB antibiotics including cefazolin and piperacillin-tazobactam. Given previous associations between IEs and negative patient outcomes, further work is warranted to understand how this phenotype impacts nCFB disease progression.

PMID:35213810 | DOI:10.1513/AnnalsATS.202108-965OC

Blood. 2022 Feb 25:blood.2021014699. doi: 10.1182/blood.2021014699. Online ahead of print.

ABSTRACT

Polymorphonuclear neutrophils (PMN) figure prominently in host defense against infection and in non-infectious inflammation. Mobilized early in an inflammatory response, PMN mediate immediate cellular defense against microbes and orchestrate events that culminate in cessation of inflammation and restoration of homeostasis. Failure to terminate inflammation, due either to persistent stimulation or faulty downregulation, can fuel exuberant inflammation characteristic of many human diseases, including cystic fibrosis (CF). An autosomal recessive genetic disease caused by mutations in the cystic fibrosis conductance regulator (CFTR), CF affects multiple end-organs, with chronic neutrophilic inflammation in airways predominating the clinical picture. To match the diverse microbial challenges that they may encounter, PMN possess a variety of antimicrobial systems to slow or kill invading microorganisms confined in their phagosomes. Prominent among PMN defense systems is their ability to generate hypochlorous acid (HOCl), a potent microbicide, by reacting oxidants generated by the NADPH oxidase with myeloperoxidase (MPO) released from azurophilic granules in the presence of chloride (Cl-). Products of the MPO-H2O2-Cl system oxidize susceptible biomolecules and support a robust antimicrobial action against many, but not all, potential human pathogens. Underscoring that the MPO-H2O2-Cl system is integral to optimal host defense and proper regulation of inflammation, individuals with defects in any component of this system, as seen in chronic granulomatous disease or MPO deficiency, incur increased rates or severity of infection and signs of dysregulated inflammatory responses.

PMID:35213685 | DOI:10.1182/blood.2021014699

Microbiologyopen. 2022 Feb;11(1):e1264. doi: 10.1002/mbo3.1264.

ABSTRACT

Adaptation of opportunistic pathogens to their host environment requires reprogramming of a vast array of genes to facilitate survival in the host. Burkholderia cenocepacia, a Gram-negative bacterium with a large genome of ∼8 Mb that colonizes environmental niches, is exquisitely adaptable to the hypoxic environment of the cystic fibrosis lung and survives in macrophages. We previously identified an immunoreactive acidic protein encoded on replicon 3, BCAS0292. Deletion of the BCAS0292 gene significantly altered the abundance of 979 proteins by 1.5-fold or more; 19 proteins became undetectable while 545 proteins showed ≥1.5-fold reduced abundance, suggesting the BCAS0292 protein is a global regulator. Moreover, the ∆BCAS0292 mutant showed a range of pleiotropic effects: virulence and host-cell attachment were reduced, antibiotic susceptibility was altered, and biofilm formation enhanced. Its growth and survival were impaired in 6% oxygen. In silico prediction of its three-dimensional structure revealed BCAS0292 presents a dimeric β-structure with a negative surface charge. The ΔBCAS0292 mutant displayed altered DNA supercoiling, implicated in global regulation of gene expression. Three proteins were identified in pull-downs with FLAG-tagged BCAS0292, including the Histone H1-like protein, HctB, which is recognized as a global transcriptional regulator. We propose that BCAS0292 protein, which we have named Burkholderia negatively surface-charged regulatory protein 1 (Bnr1), acts as a DNA-mimic and binds to DNA-binding proteins, altering DNA topology and regulating the expression of multiple genes, thereby enabling the adaptation of B. cenocepacia to highly diverse environments.

PMID:35212475 | DOI:10.1002/mbo3.1264

Medicine (Baltimore). 2022 Feb 25;101(8):e28904. doi: 10.1097/MD.0000000000028904.

ABSTRACT

BACKGROUND: Pathogenesis of chronic pancreatitis (CP) is still not entirely understood with many patients probably having more than 1 underlying etiology. Besides toxic-metabolic factors, genetics contribute to disease development. Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) are shown to increase risk for CP. Activity of CFTR can easily be accessed in vivo by measurement of nasal potential difference (PD).

METHODS: We compared in this monocentric study 17 CP patients from the outpatient unit of our university hospital with 30 healthy controls regarding nasal PDs by using a superfusion protocol. Additionally, demographic and lifestyle data of all persons were recorded.

RESULTS: Seventeen patients (12% female, median age 48 years) with CP and 30 healthy volunteers (47% female, 25 years) were included in the study. Patients with CP had a significant higher proportion of CFTR dysfunction (P = .04). Furthermore, demographics differed between the 2 groups with CP patients being older (P < .001). There were differences in daily alcohol consumption (P = .001) and smoking habits (smokers vs nonsmokers: P = .01, pack years: P = .002).

CONCLUSIONS: PD measurement is an easily accessible way to show CFTR dysfunction as an etiological factor of CP. Cigarette smoking might impair CFTR function and therefore be 1 preventable cause of CP evolution.

PMID:35212296 | DOI:10.1097/MD.0000000000028904

Front Med (Lausanne). 2022 Feb 8;8:804892. doi: 10.3389/fmed.2021.804892. eCollection 2021.

ABSTRACT

BACKGROUND: With the improvement of cystic fibrosis (CF) patient survival, the prevalence of long-term complications increased, among them rheumatologic disorders.

METHODS: The aim of this prospective study was to evaluate the prevalence of spinal and joint pain, and their impact on disability, anxiety, depression, and quality of life in CF adult patients.

RESULTS: Forty-seven patients were analyzed, 72% of men, mean aged 28 years, with a mean body mass index of 22 kg/m2 and a mean FEV1% of 63%. Twenty-two patients (47%) described rheumatologic pain either spinal (n = 15, 32%) and/or joint pain (n = 14, 30%). Patients with spinal and/or joint pain were shorter (p = 0.023), more frequently colonized with Staphylococcus aureus (p < 0.008), had more frequent ΔF508 homozygous mutations (p = 0.014), and a trend for more impairment of the 6-min walking distance (p = 0.050). The presence of rheumatologic pain tended to be associated with disability according to the Health Assessment Questionnaire (HAQ) and anxiety. Compared with patients with no pain patients with both spinal and joint pain exhibited a more pronounced impact on the St George's Respiratory Questionnaire (SGRQ).

CONCLUSION: Rheumatologic pain is frequent in CF adult patients, and may affect daily living, anxiety and quality of life. Systematic assessment of rheumatologic pain should be included in the management of CF patients.

PMID:35211488 | PMC:PMC8861186 | DOI:10.3389/fmed.2021.804892

Biochem Med (Zagreb). 2022 Feb 15;32(1):010501. doi: 10.11613/BM.2022.010501.

ABSTRACT

The sweat test (ST) is a cornerstone in the diagnosis of cystic fibrosis (CF), together with newborn screening and genetic testing. However, the performance of the ST can depend on the operator's skill, so several international guidelines have been published to standardise the ST, but inconsistencies remain. The joint Working Group for ST Standardisation (WG STS) of the Croatian Society of Medical Biochemistry and Laboratory Medicine, in association with cistic fybrosis health professional and the Cistic Fibrosis Centre for Paediatrics and Adults, have issued National Guidelines for the Performance of the Sweat Test in order to ensure consistency in ST performance and accuracy of reported results. Many of the standards were taken from the 2nd Edition of the UK Guidelines for Performance of the ST for the Diagnosis of CF, while others were taken from independent consensus statements from the WG STS based on local ST equipment and practices. The standards cover every step of the ST, from the indications for testing to reporting of results and their interpretation, including the analytical phase and quality control. In addition, National Guidelines include appendices with practical examples in order to aid implementation of the recommendations in routine practice.

PMID:35210925 | PMC:PMC8833251 | DOI:10.11613/BM.2022.010501

Nat Chem Biol. 2022 Feb 24. doi: 10.1038/s41589-022-00971-2. Online ahead of print.

ABSTRACT

Many diseases are driven by proteins that are aberrantly ubiquitinated and degraded. These diseases would be therapeutically benefited by targeted protein stabilization (TPS). Here we present deubiquitinase-targeting chimeras (DUBTACs), heterobifunctional small molecules consisting of a deubiquitinase recruiter linked to a protein-targeting ligand, to stabilize the levels of specific proteins degraded in a ubiquitin-dependent manner. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48-ubiquitin-specific deubiquitinase OTUB1. We showed that a DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR), robustly stabilized ΔF508-CFTR protein levels, leading to improved chloride channel conductance in human cystic fibrosis bronchial epithelial cells. We also demonstrated stabilization of the tumor suppressor kinase WEE1 in hepatoma cells. Our study showcases covalent chemoproteomic approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS.

PMID:35210618 | DOI:10.1038/s41589-022-00971-2

Eur Respir J. 2022 Feb 24;59(2):2102380. doi: 10.1183/13993003.02380-2021. Print 2022 Feb.

NO ABSTRACT

PMID:35210304 | DOI:10.1183/13993003.02380-2021

Arch Dis Child. 2022 Feb 24:archdischild-2022-323836. doi: 10.1136/archdischild-2022-323836. Online ahead of print.

NO ABSTRACT

PMID:35210219 | DOI:10.1136/archdischild-2022-323836

Microorganisms. 2022 Feb 11;10(2):420. doi: 10.3390/microorganisms10020420.

ABSTRACT

Achromobacter species are emerging pathogens in cystic fibrosis with inherent resistance to several classes of antimicrobial agents. We exposed strains with wild-type antimicrobial susceptibility to ticarcillin and generated mutants with broad β-lactam resistance. Within the detection limit of the assay, the capability to develop mutational resistance was strain-specific and reproducible. Mutational resistance was observed for all three tested strains of Achromobacter ruhlandii, for one of seven strains of Achromobacter xylosoxidans, and for none of five strains of Achromobacter insuavis. All mutants were resistant to piperacillin-tazobactam, while minimal inhibitory concentration of several other β-lactams increased 4-32-fold. Whole genome sequencing identified 1-4 non-synonymous mutations in known genes per mutant. All mutants encoded amino acid substitutions in cell wall recycling proteins, primarily Mpl, and the observed resistance is probably caused by hyperproduction of OXA-114-like β-lactamases. Related, but not identical substitutions were detected in clinical strains expressing acquired antimicrobial resistance.

PMID:35208874 | DOI:10.3390/microorganisms10020420

Microorganisms. 2022 Jan 24;10(2):264. doi: 10.3390/microorganisms10020264.

ABSTRACT

Pseudomonas aeruginosa is a common, opportunistic bacterial pathogen among patients with cystic fibrosis, asthma, and chronic obstructive pulmonary disease. During the course of these diseases, l-ornithine, a non-proteinogenic amino acid, becomes more abundant. P. aeruginosa is chemotactic towards other proteinogenic amino acids. Here, we evaluated the chemotaxis response of P. aeruginosa towards l-ornithine. Our results show that l-ornithine serves as a chemoattractant for several strains of P. aeruginosa, including clinical isolates, and that the chemoreceptors involved in P. aeruginosa PAO1 are PctA and PctB. It seems likely that P. aeruginosa's chemotactic response to l-ornithine might be a common feature and thus could potentially contribute to pathogenesis processes during colonization and infection scenarios.

PMID:35208720 | DOI:10.3390/microorganisms10020264

Microorganisms. 2022 Jan 19;10(2):210. doi: 10.3390/microorganisms10020210.

ABSTRACT

Multi-drug resistant (MDR) clinical strains of Pseudomonas aeruginosa are the most prevalent bacteria in the lungs of patients with cystic fibrosis (CF) and burn wounds and among the most common in immunocompromised hospital patients in Australia. There are currently no promising antibiotics in the pipeline being developed against these strains. Phage therapy, which uses viruses known as bacteriophages to infect and kill pathogenic bacteria, could be a possible alternative treatment. To this end, we isolated and characterised four novel phages against Australian clinical strains of P. aeruginosa isolated from patients with cystic fibrosis, from infected blood and joint aspirate in Southeast Queensland, Australia. Activated sludge was enriched for phages using the clinical strains, and four bacteriophages were isolated. The phages were able to cause lysis in a further three identified clinical isolates. Morphology showed that they were all tailed phages (of the order Caudovirales), two belonging to the family Myoviridae and the others assigned to the Podoviridae and Siphoviridae. Their genomes were sequenced to reveal a doubled stranded DNA topology with genome sizes ranging from 42 kb to 65 kb. In isolating and characterising these novel phages, we directed our efforts toward the development and use of these phages as candidates for phage therapy as an alternative strategy for the management or elimination of these pathogenic strains. Here we describe novel phage candidates for potential therapeutic treatment of MDR Australian clinical isolates of P. aeruginosa.

PMID:35208664 | DOI:10.3390/microorganisms10020210

J Pers Med. 2022 Feb 10;12(2):252. doi: 10.3390/jpm12020252.

ABSTRACT

Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy. A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years. We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA.

PMID:35207740 | DOI:10.3390/jpm12020252

J Clin Med. 2022 Feb 16;11(4):1021. doi: 10.3390/jcm11041021.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype.

METHODS: Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety.

RESULTS: ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed.

CONCLUSIONS: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.

PMID:35207295 | DOI:10.3390/jcm11041021