J Cyst Fibros. 2023 Oct 7:S1569-1993(23)00915-3. doi: 10.1016/j.jcf.2023.09.010. Online ahead of print.

ABSTRACT

BACKGROUND: Alterations in gastrointestinal health are prominent manifestations of cystic fibrosis (CF) and can independently impact pulmonary function. Ivacaftor has been associated with robust improvements in pulmonary function and weight gain, but less is known about the impact of ivacaftor on the fecal microbiome, lipidome, and bile acids.

METHODS: Stool samples from 18 patients with CF and gating mutations (ages 6-61 years, 13 pancreatic insufficient) were analyzed for fecal microbiome and lipidome composition as well as bile acid concentrations at baseline and after 3 months of treatment with ivacaftor. Microbiome composition was also assessed in a healthy reference cohort.

RESULTS: Alpha and beta diversity of the microbiome were different between CF and reference cohort at baseline, but no treatment effect was seen in the CF cohort between baseline and 3 months. Seven lipids increased with treatment. No differences were seen in bile acid concentrations after treatment in CF. At baseline, 403 lipids and unconjugated bile acids were different between pancreatic insufficient (PI-CF) and sufficient (PS-CF) groups and 107 lipids were different between PI-CF and PS-CF after 3 months of treatment.

CONCLUSIONS: The composition and diversity of the fecal microbiome were different in CF as compared to a healthy reference, and did not change after 3 months of ivacaftor. We detected modest differences in the fecal lipidome with treatment. Differences in lipid and bile acid profiles between PS-CF and PI-CF were attenuated after 3 months of treatment.

PMID:37813785 | DOI:10.1016/j.jcf.2023.09.010

BMJ Case Rep. 2023 Oct 9;16(10):e256788. doi: 10.1136/bcr-2023-256788.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus that occurs in patients with asthma or cystic fibrosis. Here, we report a case of a young female with bronchial asthma who presented to our hospital with worsening breathlessness on exertion. She was diagnosed to have ABPA and was initiated on oral itraconazole while continuing inhaled long acting beta-2 adrenergic agonist and medium dose inhaled corticosteroid (ICS) for her asthma. Three months after initiation of therapy, the patient had significant improvement in breathlessness. However, she had weight gain, facial puffiness, increased facial hair and development of striae on her inner thighs, calf and lower abdomen. Her serum cortisol levels were found to be suppressed and hence a diagnosis of iatrogenic Cushing's syndrome was made. Our case describes the potentially serious interaction between ICS and oral itraconazole, a treatment very commonly prescribed in patients with ABPA.

PMID:37813554 | DOI:10.1136/bcr-2023-256788

Heliyon. 2023 Sep 16;9(9):e20110. doi: 10.1016/j.heliyon.2023.e20110. eCollection 2023 Sep.

ABSTRACT

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator that has led to large benefits in lung function, pulmonary exacerbation rates, and respiratory symptoms. Less is known about the effect of ETI on non-pulmonary symptoms. The objective of this study was to examine the changes in patient reported outcomes after starting ETI in multiple non-pulmonary symptoms.

METHODS: This was a prospective cohort study of adults with CF. Participants completed questionnaires prior to starting ETI and then at weeks 2, 4, 6, 8, 10, 12, and 14 after starting ETI. They completed the following validated instruments: PROMIS Pain Intensity, PROMIS Pain Interference, FACIT Fatigue, SNOT22, PAC-SYM, PHQ8, GAD7 and Pittsburgh Sleep Quality Index. Longitudinal changes for outcomes were modelled using linear regression based on general estimating equations.

RESULTS: 22 participants enrolled who answered questionnaires before and after starting ETI. The median age was 35.3 years (IQR 11.1) and 13 (59.1%) were male. In models adjusted for age, sex, and baseline value there were significant improvements in pain interference (β = -2.57; 95% CI -4.92, -0.23), sinus symptoms (β = -4.50; 95% CI -7.59, -1.41), and sleep disturbance (β = -1.90; 95% CI -2.71, -1.09) over 14 weeks after starting ETI. No symptom areas worsened over the study period.

CONCLUSIONS: In this prospective study we found statistically significant improvements in three different non-pulmonary symptom areas in people with CF started on ETI. While this was a small, uncontrolled study it suggests that use of highly effective CFTR modulators can result in benefits for patients beyond pulmonary symptoms.

PMID:37810077 | PMC:PMC10559839 | DOI:10.1016/j.heliyon.2023.e20110

Heliyon. 2023 Sep 9;9(9):e19968. doi: 10.1016/j.heliyon.2023.e19968. eCollection 2023 Sep.

ABSTRACT

BACKGROUND: Patients with bronchiectasis often require hospitalisation for the administration of intravenous antibiotics for the management of acute exacerbations. Increasingly, Outpatient Parenteral Antibiotic Therapy (OPAT) services have become available as a potential alternative for domiciliary management.

AIMS: This study assessed outcomes in both cystic fibrosis (CF) and non-CF bronchiectasis patients who received OPAT for the management of an acute exacerbation of bronchiectasis.

METHODS: A retrospective study of consecutive subjects was done in both CF and non-CF groups in a large metropolitan Health Service in Australia from 2016 to 2022.

RESULTS: There were 51 episodes of care in the non-CF group (22 subjects) and 73 episodes in the CF group (13 subjects). The non-CF group were nearly all treated with once daily domiciliary intravenous (IV) ceftriaxone (49/51 episodes) for a duration of 9.1 ± 3.0 days (mean and standard deviation (SD)) via a peripherally inserted venous canula (84% of episodes). In contrast, the CF group generally received dual IV antibiotics (64% of episodes), with an average duration of 16.8 ± 6.3 days via central venous access (100%). In the non-CF group, the admission rate to hospital after 1 month was 9.6% and in the CF group was 0%. At 3 and 6 months the readmission rate for the non-CF group was 15.7% and 19.6% and CF group was 21.9% and 31.5%. There was a low rate of complications for the OPAT admissions (2% for the non-CF group and 7% for CF group).

CONCLUSIONS: OPAT is a viable alternative for the management of bronchiectasis exacerbations.

PMID:37809890 | PMC:PMC10559547 | DOI:10.1016/j.heliyon.2023.e19968

Front Immunol. 2023 Sep 21;14:1194253. doi: 10.3389/fimmu.2023.1194253. eCollection 2023.

ABSTRACT

BACKGROUND: In chronic cystic fibrosis (CF) lung disease, neutrophilic inflammation and T-cell inhibition occur concomitantly, partly due to neutrophil-mediated release of the T-cell inhibitory enzyme Arg1. However, the onset of this tonic inhibition of T cells, and the impact of pulmonary exacerbations (PEs) on this process, remain unknown.

METHODS: Children with CF aged 0-5 years were enrolled in a longitudinal, single-center cohort study. Blood (n = 35) and bronchoalveolar lavage (BAL) fluid (n = 18) were collected at stable outpatient clinic visits or inpatient PE hospitalizations and analyzed by flow cytometry (for immune cell presence and phenotype) and 20-plex chemiluminescence assay (for immune mediators). Patients were categorized by PE history into (i) no prior PE, (ii) past history of PE prior to stable visit, or (iii) current PE.

RESULTS: PEs were associated with increased concentration of both pro- and anti-inflammatory mediators in BAL, and increased neutrophil frequency and G-CSF in circulation. PE BAL samples showed a trend toward an increased frequency of hyperexocytic "GRIM" neutrophils, which we previously identified in chronic CF. Interestingly, expression levels of the T-cell receptor associated molecule CD3 and of the inhibitory programmed death-1 (PD-1) receptor were respectively decreased and increased on T cells from BAL compared to blood in all patients. When categorized by PE status, CD3 and PD-1 expression on blood T cells did not differ among patients, while CD3 expression was decreased, and PD-1 expression was increased on BAL T cells from patients with current PE.

CONCLUSIONS: Our findings suggest that airway T cells are engaged during early-life PEs, prior to the onset of chronic neutrophilic inflammation in CF. In addition, increased blood neutrophil frequency and a trend toward increased BAL frequency of hyperexocytic neutrophils suggest that childhood PEs may progressively shift the balance of CF airway immunity towards neutrophil dominance.

PMID:37809107 | PMC:PMC10551126 | DOI:10.3389/fimmu.2023.1194253

Front Pharmacol. 2023 Sep 21;14:1245885. doi: 10.3389/fphar.2023.1245885. eCollection 2023.

ABSTRACT

Introduction: The availability of highly effective triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination therapy with elexacaftor-tezacaftor-ivacaftor (ETI) has improved pulmonary outcomes and quality of life of people with cystic fibrosis (pwCF). The aim of this study was to assess computed tomography (CT) changes under ETI visually with the Brody score and quantitatively with dedicated software, and to correlate CT measures with parameters of clinical response. Methods: Twenty two adult pwCF with two consecutive CT scans before and after ETI treatment initiation were retrospectively included. CT was assessed visually employing the Brody score and quantitatively by YACTA, a well-evaluated scientific software computing airway dimensions and lung parenchyma with wall percentage (WP), wall thickness (WT), lumen area (LA), bronchiectasis index (BI), lung volume and mean lung density (MLD) as parameters. Changes in CT metrics were evaluated and the visual and quantitative parameters were correlated with each other and with clinical changes in sweat chloride concentration, spirometry [percent predicted of forced expiratory volume in one second (ppFEV1)] and body mass index (BMI). Results: The mean (SD) Brody score improved with ETI [55 (12) vs. 38 (15); p < 0.001], incl. sub-scores for mucus plugging, peribronchial thickening, and parenchymal changes (all p < 0.001), but not for bronchiectasis (p = 0.281). Quantitatve WP (p < 0.001) and WT (p = 0.004) were reduced, conversely LA increased (p = 0.003), and BI improved (p = 0.012). Lung volume increased (p < 0.001), and MLD decreased (p < 0.001) through a reduction of ground glass opacity areas (p < 0.001). Changes of the Brody score correlated with those of quantitative parameters, exemplarily WT with the sub-score for mucus plugging (r = 0.730, p < 0.001) and peribronchial thickening (r = 0.552, p = 0.008). Changes of CT parameters correlated with those of clinical response parameters, in particular ppFEV1 with the Brody score (r = -0.606, p = 0.003) and with WT (r = -0.538, p = 0.010). Discussion: Morphological treatment response to ETI can be assessed using the Brody score as well as quantitative CT parameters. Changes in CT correlated with clinical improvements. The quantitative analysis with YACTA proved to be an objective, reproducible and simple method for monitoring lung disease, particularly with regard to future interventional clinical trials.

PMID:37808186 | PMC:PMC10552920 | DOI:10.3389/fphar.2023.1245885

Ital J Pediatr. 2023 Oct 8;49(1):135. doi: 10.1186/s13052-023-01485-w.

ABSTRACT

BACKGROUND: Children tend to have milder forms of COVID-19 than adults, however post-acute complications have been observed also in the paediatric population. In this study, we compared COVID-19-related outcomes and long-term complications between paediatric and adult patients infected by SARS-CoV-2.

METHODS: The study is based on individuals enrolled from October 2020 to June 2021 in the DECO COVID-19 multicentre prospective study supported by the Italian Ministry of Health (COVID-2020-12371781). We included individuals with RT-PCR -confirmed SARS-CoV-2 infection, who were evaluated in the emergency department and/or admitted to COVID-dedicated wards. The severity of SARS-CoV-2 infection was compared across age groups (children/adolescents aged < 18 years, young/middle-aged adults aged 18-64 years and older individuals) through the relative risk (RR) of severe COVID-19. Severity was defined by: 1) hospitalization due to COVID-19 and/or 2) need or supplemental oxygen therapy. RR and corresponding 95% confidence intervals were estimated using log-binomial models.

RESULTS: The study included 154 individuals, 84 (54.5%) children/adolescents, 50 (32.5%) young/middle-aged adults and 20 (13%) older adults. Compared to young/middle-aged adults the risk of hospitalization was lower among paediatric patients (RR: 0.49, 95% CI: 0.32-0.75) and higher among older adults (RR: 1.52, 95% CI: 1.12-2.06). The RR of supplemental oxygen was 0.12 (95% CI: 0.05-0.30) among children/adolescents and 1.46 (95% CI: 0.97-2.19) among older adults. Three children developed multisystem inflammatory syndrome (MIS-C), none was admitted to intensive care unit or reported post-acute Covid-19 complications.

CONCLUSIONS: Our study confirms that COVID-19 is less severe in children. MIS-C is a rare yet severe complication of SARS-CoV-2 infection in children and its risk factors are presently unknown.

PMID:37807040 | DOI:10.1186/s13052-023-01485-w

Trends Immunol. 2023 Oct 6:S1471-4906(23)00204-1. doi: 10.1016/j.it.2023.09.008. Online ahead of print.

ABSTRACT

Dietary fibers, including chitin, have a major impact on gastrointestinal (GI) physiology and immunity. Two recent articles, by Parrish et al. and Kim et al., credit depletion of dietary fibers or supplementation with chitin, with negative and positive effects, respectively, on the immune system of the murine digestive tract. This has relevant implications for food allergies and systemic metabolism.

PMID:37806931 | DOI:10.1016/j.it.2023.09.008

J Cyst Fibros. 2023 Oct 5:S1569-1993(23)00917-7. doi: 10.1016/j.jcf.2023.09.013. Online ahead of print.

NO ABSTRACT

PMID:37805356 | DOI:10.1016/j.jcf.2023.09.013

J Cyst Fibros. 2023 Oct 5:S1569-1993(23)00926-8. doi: 10.1016/j.jcf.2023.10.004. Online ahead of print.

ABSTRACT

Previous studies indicate that hospital rather than home treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) can improve outcomes. We evaluated characteristics of adult participants from the Standardized Treatment of Pulmonary Exacerbations (STOP2) trial with two separate comparisons: (1) those who were treated initially in hospital (N = 768) to those treated initially at home (N = 214) and (2) those treated only in hospital (N = 328) to those who were treated only at home or both at home and in hospital (N = 654). Participants who had Medicaid insurance, were treated for shorter duration, and traveled longer to reach treatment centers were more likely to have been treated initially in the hospital. Having Medicaid insurance, being treated for a shorter duration, and being male were associated with being treated only in the hospital. This analysis suggests decisions about the location of treatment are based on pragmatic factors rather than on clinical characteristics.

PMID:37805355 | DOI:10.1016/j.jcf.2023.10.004

Lancet Respir Med. 2023 Oct;11(10):871. doi: 10.1016/S2213-2600(23)00335-1.

NO ABSTRACT

PMID:37802080 | DOI:10.1016/S2213-2600(23)00335-1

Pediatr Dev Pathol. 2023 Oct 6:10935266231201935. doi: 10.1177/10935266231201935. Online ahead of print.

ABSTRACT

Liver histology in infants with cystic fibrosis (CF) and persistent cholestasis is seldom reported in detail. We extend previous observation of a distinctive intrahepatic cholangiopathy (ICCF) to 3 additional infants homozygous for CFTR pathological variants and a fourth infant with a heterozygous CFTR variant, summarizing our experience in 10 infants with CFTR variants and persistent cholestasis. Cholangiograms demonstrate abnormal extrahepatic ducts in 2 infants with CF, 1 with uniform dilatation interpreted as a choledochal cyst and the other with narrow patent ducts. Liver histology in 3 CF homozygotes had prominent ductular reaction with a focally destructive cholangiolitis (inflammation of small bile ducts). The CFTR heterozygote had generalized portal edema with ductular reaction and paucity but no cholangitis. Cholestasis slowly subsided in all infants. ICCF is characterized by severe ductular reaction, prominent cholangiocyte injury, and multifocal necrotizing cholangiolitis. Local aggregates of portal ceroid might suggest previous bile leakage from damaged ducts. ICCF in liver biopsies from infants with cystic fibrosis and persistent cholestasis is unrelated to the specific CFTR genotype. Liver biopsy findings and intraoperative cholangiogram help rule out biliary atresia. ICCF is an early manifestation of CF, a likely prototype for pathogenesis of cystic fibrosis liver disease later in life.

PMID:37801635 | DOI:10.1177/10935266231201935

FASEB J. 2023 Nov;37(11):e23220. doi: 10.1096/fj.202300077R.

ABSTRACT

Patients with cystic fibrosis (CF) exhibit pronounced respiratory damage and were initially considered among those at highest risk for serious harm from SARS-CoV-2 infection. Numerous clinical studies have subsequently reported that individuals with CF in North America and Europe-while susceptible to severe COVID-19-are often spared from the highest levels of virus-associated mortality. To understand features that might influence COVID-19 among patients with cystic fibrosis, we studied relationships between SARS-CoV-2 and the gene responsible for CF (i.e., the cystic fibrosis transmembrane conductance regulator, CFTR). In contrast to previous reports, we found no association between CFTR carrier status (mutation heterozygosity) and more severe COVID-19 clinical outcomes. We did observe an unexpected trend toward higher mortality among control individuals compared with silent carriers of the common F508del CFTR variant-a finding that will require further study. We next performed experiments to test the influence of homozygous CFTR deficiency on viral propagation and showed that SARS-CoV-2 production in primary airway cells was not altered by the absence of functional CFTR using two independent protocols. On the contrary, experiments performed in vitro strongly indicated that virus proliferation depended on features of the mucosal fluid layer known to be disrupted by absent CFTR in patients with CF, including both low pH and increased viscosity. These results point to the acidic, viscous, and mucus-obstructed airways in patients with cystic fibrosis as unfavorable for the establishment of coronaviral infection. Our findings provide new and important information concerning relationships between the CF clinical phenotype and severity of COVID-19.

PMID:37801035 | DOI:10.1096/fj.202300077R

Microbiol Spectr. 2023 Oct 6:e0219823. doi: 10.1128/spectrum.02198-23. Online ahead of print.

ABSTRACT

Polymicrobial airway infections in persons with cystic fibrosis (pwCF) can positively or negatively impact the course of disease. A major CF pathogen, Pseudomonas aeruginosa, often establishes a chronic infection leading to lung deterioration. Interestingly, the presence of certain oral commensal streptococci is correlated with improved outcomes for pwCF. We previously reported that hydrogen peroxide production by these commensals combined with nitrite generates reactive nitrogen intermediates (RNI), which inhibit P. aeruginosa in vitro. In this study, we utilized a rat co-infection lung model to assess whether oral commensal-generated RNI can restrict the pathogenesis of a CF isolate of P. aeruginosa. We report that the oral commensal Streptococcus parasanguinis and nitrite reduce P. aeruginosa-induced host inflammation in wild-type rats. To better recapitulate CF-specific airway conditions, we used a bronchial epithelial cell culture model to gain a better understanding of how S. parasanguinis and nitrite may influence P. aeruginosa burden during a CF infection. Hence, we co-infected wild-type and cystic fibrosis transconductance regulator (CFTR) channel-deficient bronchial epithelial cells with P. aeruginosa and S. parasanguinis with or without nitrite. Strikingly, S. parasanguinis reduced the bacterial burden of P. aeruginosa without nitrite, promoted epithelial cell viability, and stimulated nitrite production in the wild-type and CFTR-deficient epithelial cells, where nitrite induction was more apparent in the CFTR mutant cells. Taken together, our study demonstrates that the commensal S. parasanguinis may provide protection against P. aeruginosa-induced inflammation and cell death, as well as modulate nitrite flux in airway epithelial cells. IMPORTANCE Respiratory infections are a leading cause of morbidity and mortality in people with cystic fibrosis (CF). These infections are polymicrobial in nature with overt pathogens and other colonizing microbes present. Microbiome data have indicated that the presence of oral commensal bacteria in the lungs is correlated with improved outcomes. We hypothesize that one oral commensal, Streptococcus parasanguinis, inhibits CF pathogens and modulates the host immune response. One major CF pathogen is Pseudomonas aeruginosa, a Gram-negative, opportunistic bacterium with intrinsic drug resistance and an arsenal of virulence factors. We have previously shown that S. parasanguinis inhibits P. aeruginosa in vitro in a nitrite-dependent manner through the production of reactive nitrogen intermediates. In this study, we demonstrate that while this mechanism is evident in a cell culture model of the CF airway, an alternative mechanism by which S. parasanguinis may improve outcomes for people with CF is through immunomodulation.

PMID:37800950 | DOI:10.1128/spectrum.02198-23

Front Nutr. 2023 Sep 20;10:1158452. doi: 10.3389/fnut.2023.1158452. eCollection 2023.

ABSTRACT

OBJECTIVE: Poor diet quality contributes to metabolic dysfunction. This study aimed to gain a greater understanding of the relationship between dietary macronutrient quality and glucose homeostasis in adults with cystic fibrosis (CF).

DESIGN: This was a cross-sectional study of N = 27 adults with CF with glucose tolerance ranging from normal (n = 9) to prediabetes (n = 6) to being classified as having cystic fibrosis-related diabetes (CFRD, n = 12). Fasted blood was collected for analysis of glucose, insulin, and C-peptide. Insulin resistance was assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA2-IR). Subjects without known CFRD also underwent a 2-h oral glucose tolerance test. Three-day food records were used to assess macronutrient sources. Dietary variables were adjusted for energy intake. Statistical analyses included ANOVA, Spearman correlations, and multiple linear regression.

RESULTS: Individuals with CFRD consumed less total fat and monounsaturated fatty acids (MUFA) compared to those with normal glucose tolerance (p < 0.05). In Spearman correlation analyses, dietary glycemic load was inversely associated with C-peptide (rho = -0.28, p = 0.05). Total dietary fat, MUFA, and polyunsaturated fatty acids (PUFA) were positively associated with C-peptide (rho = 0.39-0.41, all p < 0.05). Plant protein intake was inversely related to HOMA2-IR (rho = -0.28, p = 0.048). Associations remained significant after adjustment for age and sex.

DISCUSSION: Improvements in diet quality are needed in people with CF. This study suggests that higher unsaturated dietary fat, higher plant protein, and higher carbohydrate quality were associated with better glucose tolerance indicators in adults with CF. Larger, prospective studies in individuals with CF are needed to determine the impact of diet quality on the development of CFRD.

PMID:37799765 | PMC:PMC10548231 | DOI:10.3389/fnut.2023.1158452

Cureus. 2023 Sep 4;15(9):e44662. doi: 10.7759/cureus.44662. eCollection 2023 Sep.

ABSTRACT

Objective Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus antigen mostly Aspergillus fumigatus that occurs almost exclusively in patients with asthma and cystic fibrosis. ABPA is an underdiagnosed and undertreated disease because of its presentation with various grades of severity in asthma patients. Data available regarding the clinical, serological, and radiological profile of ABPA patients is limited due to lack of consensus on diagnostic criteria and treatment guidelines. Thus ABPA is a significant disease, especially in the Indian population where the incidence of allergic diseases like asthma is on the rise. Methods This prospective study was conducted in the Department of Pulmonary Medicine at one of the tertiary centers of north India. All consecutive patients diagnosed with allergic bronchopulmonary aspergillosis (ABPA) from 1st January 2017 to 30th September 2017 were included in the study. A total of 67 consecutive patients diagnosed with bronchial asthma were included in the study. The diagnosis of ABPA was based upon either criterion given by Rosenberg and Paterson or the International Society of Human and Animal Mycology (ISHAM) criteria. Patients diagnosed with ABPA were finally divided into mild, moderate, and severe. Results The majority of patients showed an obstructive pattern on spirometry and moderate to severe obstruction was the most common pattern observed among patients who had an obstructive pattern on spirometry. Also, all three patients with the mixed pattern on spirometry had severe disease. Serological analysis revealed that patients in the moderate category had a higher level of absolute eosinophil count (AEC), total IgE, and Aspergillus-specific IgE antibodies, especially in patients who had either high attenuation mucus (HAM) or centrilobular nodules on their high-resolution computed tomography (HRCT) scan. Conclusion ABPA is a disease of divergent presentation. We concluded to have alternate or add-on criteria for the classification of ABPA which was not based on the sequelae of chronic inflammatory changes in the lungs.

PMID:37799220 | PMC:PMC10550260 | DOI:10.7759/cureus.44662

Expert Opin Drug Metab Toxicol. 2023 Oct 6. doi: 10.1080/17425255.2023.2266361. Online ahead of print.

ABSTRACT

INTRODUCTION: SPL84 is an inhaled antisense oligonucleotide (ASO) in development for the treatment of cystic fibrosis (CF) patients carrying the 3849 + 10kb C->T (3849) mutation. To support initiation of the first proof of concept clinical study, a full battery of safety and toxicology studies were performed.

RESEARCH DESIGN AND METHODS: SPL84 was administered by inhalation to mice and monkeys, to determine the no observed adverse effect level (NOAEL) and establish sufficient safety margins for the starting clinical dose.

RESULTS: There were no preclinical safety findings with SPL84; no related clinical signs, nor any effect on body weight, food consumption, or clinical pathology. The microscopic changes in the lungs were regarded as non-adverse and reflected a normal clearance process for inhaled compounds. Systemic exposure in both species was low. The NOAEL for mice and monkeys was the highest administered dose in both species, resulting in safety margins ~ 40X the proposed starting clinical dose.

CONCLUSION: These successful results supported initiation of a Phase 1/2 clinical study of SPL84 (ongoing), assessing the safety, tolerability, and pharmacokinetics of a single ascending dose in healthy subjects to be followed by assessment of safety, tolerability, pharmacokinetics, and preliminary efficacy of multiple ascending doses in CF patients carrying the 3849 mutation.

PMID:37799089 | DOI:10.1080/17425255.2023.2266361

Lancet Respir Med. 2023 Oct;11(10):864-865. doi: 10.1016/S2213-2600(23)00333-8.

NO ABSTRACT

PMID:37798057 | DOI:10.1016/S2213-2600(23)00333-8

Clin Microbiol Infect. 2023 Oct 3:S1198-743X(23)00485-8. doi: 10.1016/j.cmi.2023.08.036. Online ahead of print.

ABSTRACT

BACKGROUND: Mycobacterium abscessus belongs to the largest group of mycobacteria, the rapid-growing saprophytic mycobacteria (RGM), and is one of the most difficult-to-treat opportunistic pathogen. Several features pertain to the high adaptability of M. abscessus to the host. These include the capacity to survive and persist within amoebae, to transition from a smooth to a rough morphotype that occurs during the course of the disease and to express of a wide array of virulence factors.

OBJECTIVES: The main objective of this narrative review consists to report major assets of M. abscessus that contribute to the virulence of this RGM. Strikingly, many of these determinants, whether they are from a mycobacterial origin or acquired by horizontal gene transfer, are known virulence factors found in slow-growing and strict pathogens for humans and animals.

SOURCES: In the light of recent published work in the field we attempted to highlight major features characterizing M. abscessus pathogenicity and to explain why this led to the emergence of this mycobacterial species in cystic fibrosis patients.

CONTENT: M. abscessus genome plasticity, the smooth-to-rough transition, and the expression of a panel of enzymes associated with virulence in other bacteria are key players in M. abscessus virulence. In addition, the very large repertoire of lipid transporters, known as MmpL and MmpS, deeply influences the pathogenicity of M. abscessus, as exemplified here for some of them.

IMPLICATIONS: All these traits largely contribute to make M. abscessus a unique mycobacterium regarding to its pathophysiological processes, ranging from the early colonization steps to the establishment of severe and chronic pulmonary diseases.

PMID:37797823 | DOI:10.1016/j.cmi.2023.08.036

Nat Commun. 2023 Oct 5;14(1):6214. doi: 10.1038/s41467-023-41999-9.

ABSTRACT

Claudin family tight junction proteins form charge- and size-selective paracellular channels that regulate epithelial barrier function. In the gastrointestinal tract, barrier heterogeneity is attributed to differential claudin expression. Here, we show that claudin-23 (CLDN23) is enriched in luminal intestinal epithelial cells where it strengthens the epithelial barrier. Complementary approaches reveal that CLDN23 regulates paracellular ion and macromolecule permeability by associating with CLDN3 and CLDN4 and regulating their distribution in tight junctions. Computational modeling suggests that CLDN23 forms heteromeric and heterotypic complexes with CLDN3 and CLDN4 that have unique pore architecture and overall net charge. These computational simulation analyses further suggest that pore properties are interaction-dependent, since differently organized complexes with the same claudin stoichiometry form pores with unique architecture. Our findings provide insight into tight junction organization and propose a model whereby different claudins combine to form multiple distinct complexes that modify epithelial barrier function by altering tight junction structure.

PMID:37798277 | DOI:10.1038/s41467-023-41999-9