J Cyst Fibros. 2024 Aug 24:S1569-1993(24)00829-4. doi: 10.1016/j.jcf.2024.08.003. Online ahead of print.

ABSTRACT

INTRODUCTION: The effects of cystic fibrosis (CF) on females' sexuality have not been described. The aims of the present study were to describe and characterize sexual issues in females with CF.

METHODS: We included adult (≥18 years) females with CF currently or previously in a sexual relationship from 11 adult CF centres in France. We collected quantitative data using a modified version of the self-administered Pelvic Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR). We performed one-to-one interviews using a semi-directive framework in volunteer females to further characterize the effects of CF on sexual life. We summarized answers to questionnaire as percentages and analysed interviews by theme according to discourse analysis method.

RESULTS: Between November 2019 and July 2021, 212 females completed the PISQR-IR, of whom 15 were interviewed. Of the females who completed the questionnaire, 93.4% were concerned about the discomfort, pain, or unpleasantness they experienced during sexual intercourse. The most frequent cause of sexual difficulties was a lack of vaginal lubrication (78.8%), followed by pain (74.1%) and discomfort. Interviews revealed sexual lives that were uncomfortable or painful, unsatisfying or avoided for most females, with a strong impression of being sexually different, incompetent, and betrayed by their bodies in terms of sexual desire.

CONCLUSION: Sexual difficulties faced by females with CF are highly prevalent. Increasing awareness regarding sex life issues in females with CF appears necessary to improve their management by CF multidisciplinary teams.

PMID:39183126 | DOI:10.1016/j.jcf.2024.08.003

Ann Transplant. 2024 Aug 13;29:e944049. doi: 10.12659/AOT.944049.

ABSTRACT

BACKGROUND End-stage renal disease is a major issue in the management of patients undergoing lung transplantation. Combined kidney-lung transplantation (CKLT) and kidney after lung transplantation (KALT) are the 2 preferred solutions to manage this situation. To evaluate these strategies, we describe kidney and lung graft outcomes and patient survival in patients managed with CKLT and KALT. MATERIAL AND METHODS We conducted a retrospective single-center cohort study. Patients who underwent a CKLT or a KALT were included in this study. Retrospective extraction of data from medical records was performed. RESULTS Seventeen patients underwent CKLT and 9 underwent KALT. Most of the patients had cystic fibrosis and presented renal failure related to anti-calcineurin toxicity. The 30-day and 1-year survival of CKLT recipients were both 75.6%. No patients with KALT died during the follow-up. Kidney graft prognosis was almost exclusively influenced by patient survival in relation to postoperative lung transplant complications. The rate of severe surgical complications was close to 60% for CKLT compared with 30% for KALT. The kidney graft function (estimated kidney graft function) did not differ according to the transplantation strategy. CONCLUSIONS KALT is a safe option, with postoperative morbidity and renal graft function identical to those of kidney transplantation in non-lung-transplanted patients. The results of CKLT depend mainly on the morbidity associated with lung transplantation but remain an attractive option for patients with respiratory failure associated with end-stage renal disease. The choice of transplant strategy must also take into account the most ethical and efficient allocation of kidney grafts.

PMID:39182171 | DOI:10.12659/AOT.944049

Respir Care. 2024 Aug 24;69(9):1218-1219. doi: 10.4187/respcare.12382.

NO ABSTRACT

PMID:39181717 | DOI:10.4187/respcare.12382

J Control Release. 2024 Aug 22:S0168-3659(24)00577-7. doi: 10.1016/j.jconrel.2024.08.029. Online ahead of print.

ABSTRACT

Antimicrobial resistance is considered one of the biggest threats to public health worldwide. Methicillin-resistant S. aureus is the causative agent of a number of infections and lung colonization in people suffering from cystic fibrosis. Moreover, a growing body of evidence links the microbiome to the development of cancer, as well as to the success of the treatment. In this view, the development of novel antibiotics is of critical importance, and SV7, a novel antibiotic active against MRSA at low concentrations, represents a promising candidate. However, the low aqueous solubility of SV7 hampers its therapeutic translation. In this study, SV7 was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to improve the solubility profile, to ensure sustained release and eventually support deposition in the airways. Furthermore, PLGA NPs were formulated as dry powder to extend their shelf-life and were shown to efficiently target intracellular infections. After identifying a formulation with suitable physico-chemical characteristics, SV7-loaded NPs were investigated in vitro in terms of inhibitory activity against MRSA, and their safety profile in lung epithelial cells. Subsequently, the activity against MRSA intracellular infections was investigated in a co-culture model of MRSA and macrophages. To test the translatability of our findings, SV7-loaded NPs were tested in vivo in a Galleria mellonella infection model. In conclusion, SV7-loaded NPs showed a safe profile and efficient inhibitory activity against MRSA at low concentrations. Furthermore, their activity against intracellular infections was confirmed, and was retained in vivo, rendering them a promising candidate for treatment of MRSA lung infections.

PMID:39181163 | DOI:10.1016/j.jconrel.2024.08.029

Andrology. 2024 Aug 24. doi: 10.1111/andr.13742. Online ahead of print.

ABSTRACT

BACKGROUND: Current guidelines indicate that patients with extreme oligozoospermia or azoospermia should be tested for chromosomal imbalances, azoospermia factor (AZF) deletions and/or CFTR variants. For other sperm abnormalities, no genetic diagnostics are recommended.

OBJECTIVES: To determine whether exome sequencing (ES) with combined copy number variant (CNV) and single nucleotide variant (SNV) analysis is a reliable first-tier method to replace current methods (validation study), and to evaluate the diagnostic yield after 10 months of implementation (evaluation study).

MATERIALS AND METHODS: In the validation study, ES was performed on DNA of patients already diagnosed with AZF deletions (n = 17), (non-)mosaic sex chromosomal aneuploidies or structural chromosomal anomalies (n = 37), CFTR variants (n = 26), or variants in known infertility genes (n = 4), and 90 controls. The data were analyzed using our standard diagnostic pipeline, with a bioinformatic filter for 130 male infertility genes. In the evaluation study, results of 292 clinical exomes were included.

RESULTS: All previously reported variants in the validation cohort, including clinically relevant Y-chromosomal microdeletions, were correctly identified and reliably detected. In the evaluation study, we identified one or more clinically relevant genetic anomalies in 67 of 292 of all cases (22.9%): these included aberrations that could have been detected with current methods in 30 of 67 patients (10.2% of total), (possible) (mono)genetic causes in the male infertility gene panel in 28 of 67 patients (9.6%), and carriership of cystic fibrosis in nine of 67 patients (3.1%).

CONCLUSION: ES is a reliable first-tier method to detect the most common genetic causes of male infertility and, as additional genetic causes can be detected, in our evaluation cohort the diagnostic yield almost doubled (10.2%-19.8%, excluding CF carriers). A genetic diagnosis provides answers on the cause of infertility and helps the professionals in the counseling for treatment, possible co-morbidities and risk for offspring and/or family members. Karyotyping will still remain necessary for detecting balanced translocations or low-grade chromosomal mosaicism.

PMID:39180390 | DOI:10.1111/andr.13742

J Psychosom Res. 2024 Aug 8;186:111877. doi: 10.1016/j.jpsychores.2024.111877. Online ahead of print.

ABSTRACT

OBJECTIVE: People living with cystic fibrosis (PwCF) are at increased risk of mental health conditions. There is little evidence addressing psychotropic medication use in PwCF. This study aimed to estimate the dispensing prevalence of antidepressant, anxiolytic, antipsychotic, psychostimulant, and hypnotic/sedative medication in PwCF in Australia between 2013 and 2022.

METHOD: A 10% random sample of Australian Pharmaceutical Benefits Scheme data was used to identify PwCF and their medications between 2013 and 2022. Annual prevalence of psychotropic medication dispensing was estimated using a 3-year rolling average, stratified by sex, age, and medication class.

RESULTS: Psychotropic medications were dispensed to 206/478 (41.3%) PwCF. Antidepressant and anxiolytic dispensing prevalence was highest in adult females, increasing from 201 5 by 50% to their peak in 2021 (antidepressants 36.8%; anxiolytics 12.3%). Psychostimulant prevalence was highest in adolescent males and increased over three-fold during the study period from 3.6% to 13.2%. The prevalence of antipsychotic medication was lower than other classes with adult females having the highest prevalence (3.1% and 5.8% in 201 5 and 2022 respectively). Hypnotic/sedative medications remained consistently low or decreased in all groups except male children, where it increased from 0.6% to 2.8% from 201 5 to 2022.

CONCLUSION: Psychotropic medication use is higher among Australian PwCF compared to the general population, with varying prevalence across age and sex groups. This is of interest due to complexities with CF comorbidities and potential medication influences and interactions. Future studies should investigate the reasons for psychotropic use disparities within PwCF with the aim to establish targeted guidelines and optimize outcomes.

PMID:39178579 | DOI:10.1016/j.jpsychores.2024.111877

PLoS Biol. 2024 Aug 23;22(8):e3002781. doi: 10.1371/journal.pbio.3002781. Online ahead of print.

ABSTRACT

Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria metabolism functions radically differently compared with more naïve strains. Whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear. Here, we characterize a convergent shift in metabolic function(s) linked with the persistence phenotype during Pseudomonas aeruginosa colonization in the airways of people with cystic fibrosis. We show that clinically relevant mutations in the key metabolic enzyme, pyruvate dehydrogenase, lead to a host-specialized metabolism together with a lower virulence and immune response recruitment. These changes in infection phenotype are mediated by impaired type III secretion system activity and by secretion of the antioxidant metabolite, pyruvate, respectively. Our results show how metabolic adaptations directly impinge on persistence and pathogenicity in this organism.

PMID:39178315 | DOI:10.1371/journal.pbio.3002781

Expert Rev Respir Med. 2024 Aug 23. doi: 10.1080/17476348.2024.2394694. Online ahead of print.

ABSTRACT

INTRODUCTION: The availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulators opens the possibility of discontinuing some chronic pulmonary therapies to decrease cystic fibrosis (CF) treatment burden. However, CFTR modulators may not adequately address neutrophilic inflammation, which contributes to a self-perpetual cycle of viscous CF sputum, airway obstruction, inflammation, and lung function decline.

AREAS COVERED: This review discusses the emerging role of neutrophil extracellular traps in CF and its role in CF sputum viscosity, airway obstruction, and inflammation, based on a literature search of PubMed (1990-present). We summarize clinical trials and real-world studies that support the efficacy of dornase alfa (Pulmozyme) in improving lung function and reducing pulmonary exacerbation in people with CF (PwCF), and we discuss the potential role of dornase alfa in reducing airway inflammation. We also examine the findings of short-term trials evaluating the discontinuation of mucoactive therapy in PwCF receiving CFTR modulators.

EXPERT OPINION: Long-term studies are needed to assess the impact of discontinuing mucoactive therapy in PwCF who are clinically stable while receiving CFTR modulatory therapy. Treatment decisions should take into account the severity of underlying lung disease. People with advanced CF will likely require ongoing mucoactive therapy.

PMID:39176450 | DOI:10.1080/17476348.2024.2394694

World Allergy Organ J. 2024 Jul 29;17(8):100941. doi: 10.1016/j.waojou.2024.100941. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Aging implies changes in terms of lung function, immune system, and respiratory and extra-respiratory comorbidities. Few studies have specifically addressed the relevance of age on severe asthma burden and control. We aimed to evaluate whether age acts as an independent determinant of asthma severity, in terms of clinical, functional, and inflammatory profile, and to explore potential cofactors that contribute to a more difficult disease control in different age groups.

METHODS: Patients from Severe Asthma Network Italy (SANI) registry were retrospectively divided in subgroups according to their age. Cutoffs for age were established according to quartiles in order to obtain a comparable number of patients for each group, and then rounded for the sake of simplicity.

RESULTS: Overall, 1805 severe asthma patients were analyzed. Lung function represented the most important age-related variable. On the opposite the level of asthma control was not differently distributed among age ranges. In young people the presence of atopy-related comorbidities (allergic rhinitis, atopic dermatitis) predominated, whilst systemic-metabolic and degenerative comorbidities such as diabetes, cardiovascular diseases, anxious-depressive syndrome, and osteoporosis prevailed in elderly. Bronchiectasis and sleep disturbances were significantly associated with age.

CONCLUSIONS: Despite that it cannot be considered a treatable trait, our study suggests that age should be evaluated within a personalized approach to severe asthma patients, in order to provide a better clinical profiling and a more tailored treatment strategy.

PMID:39176287 | PMC:PMC11338937 | DOI:10.1016/j.waojou.2024.100941

Eur Respir J. 2024 Aug 22:2301683. doi: 10.1183/13993003.01683-2023. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVE: Cystic fibrosis (CF) is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators offer significant improvements, but approximately 10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimized for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial.

METHODS: Air-liquid interface cultures of primary human bronchial epithelial cells (HBEC) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalized human lung epithelial cell line mimicking Class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay (PLA) for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies.

RESULTS: rSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a Class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalization assay.

CONCLUSIONS: The results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.

PMID:39174284 | DOI:10.1183/13993003.01683-2023

Sci Rep. 2024 Aug 22;14(1):19487. doi: 10.1038/s41598-024-70514-3.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pneumonia with extremely heterogeneous clinical presentation, ranging from asymptomatic to severely ill patients. Previous studies have reported links between the presence of host genetic variants and the outcome of the COVID-19 infection. In our study, we used whole exome sequencing in a cohort of 444 SARS-CoV-2 patients, admitted to hospital in the period October-2020-April-2022, to search for associations between rare pathogenic/potentially pathogenic variants and COVID-19 progression. We used gene prioritization-based analysis in genes that have been reported by host genetic studies. Although we did not identify correlation between the presence of rare pathogenic variants and COVID-19 outcome, in critically ill patients we detected known mutations in a number of genes associated with severe disease related to cardiovascular disease, primary ciliary dyskinesia, cystic fibrosis, DNA damage repair response, coagulation, primary immune disorder, hemoglobin subunit β, and others. Additionally, we report 93 novel pathogenic variants found in severely infected patients who required intubation or died. A network analysis showed main component, consisting of 13 highly interconnected genes related to epithelial cilium. In conclusion, we have detected rare pathogenic host variants that may have influenced the COVID-19 outcome in Bulgarian patients.

PMID:39174791 | DOI:10.1038/s41598-024-70514-3

Therapie. 2024 Jul 14:S0040-5957(24)00073-8. doi: 10.1016/j.therap.2024.06.005. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis transmembrane regulator (CFTR) channel modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) represent a major advance in the management of cystic fibrosis. However, few data are available on the real-life safety profile of these medications, in particular on adverse events that may lead to their discontinuation. The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France).

MATERIALS AND METHODS: A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France.

RESULTS: Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case.

CONCLUSION: This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of "caftors", their possible risk factors, and the impact of adjusting dosing modalities.

PMID:39174453 | DOI:10.1016/j.therap.2024.06.005

Ann Am Thorac Soc. 2024 Aug 22. doi: 10.1513/AnnalsATS.202402-201OC. Online ahead of print.

ABSTRACT

RATIONALE: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age.

OBJECTIVE: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2 through 5 years.

METHODS: This phase 2 trial had two parts: Part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2 through 5 years (previously reported) was followed by a 48-week open-label treatment period where all children received LUM/IVA (Part 2; reported here). Endpoints assessed in Part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at week 96; lung clearance index (LCI2.5) through week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at week 96; sweat chloride, serum levels of immunoreactive trypsinogen, fecal elastase-1 levels, and fecal calprotectin through week 96; and number of pulmonary exacerbations (PEx), time-to-first PEx, and number of CF-related hospitalizations.

RESULTS: Forty-nine children received ≥1 dose of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group); mean exposure 47.1 (SD, 5.2) weeks. The mean absolute change in MRI global score (negative value = improvement) from baseline at Week 96 was -2.7 (SD 7.0; 95% CI, -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events (AEs) considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment due to AEs (distal intestinal obstruction syndrome [n=1] and alanine aminotransferase increase [n=1]).

CONCLUSION: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT03625466.

PMID:39173175 | DOI:10.1513/AnnalsATS.202402-201OC

J Clin Psychopharmacol. 2024 Aug 22. doi: 10.1097/JCP.0000000000001906. Online ahead of print.

NO ABSTRACT

PMID:39173037 | DOI:10.1097/JCP.0000000000001906

Radiographics. 2024 Sep;44(9):e240008. doi: 10.1148/rg.240008.

ABSTRACT

Cystic fibrosis is a genetic disease with multisystem involvement and associated morbidity and mortality that are most directly related to progressive lung disease. The hallmark findings of cystic fibrosis in the lungs are chronic inflammation and infection, leading to progressive loss of pulmonary function and often requiring lung transplant. Predominant lung findings include mucous plugging, bronchiectasis, and air trapping, often with associated atelectasis, consolidation, and emphysema; these findings form the basis of several clinical scoring systems that are used for imaging assessment. Recently, there have been major breakthroughs in the pharmacologic management of cystic fibrosis, including highly effective modulator therapies that directly target the underlying cystic fibrosis transmembrane conductance regulator molecular defect, often leading to remarkable improvements in lung function and quality of life with corresponding significant improvements in imaging markers. The authors review current guidelines regarding cystic fibrosis with respect to disease monitoring, identifying complications, and managing advanced lung disease. In addition, they discuss the evolving role of imaging, including current trends, emerging technologies, and proposed updates to imaging guidelines endorsed by international expert committees on cystic fibrosis, which favor increased use of cross-sectional imaging to enable earlier detection of structural changes in early disease and more sensitive detection of acute changes in advanced disease. It is important for radiologists to be familiar with these trends and updates so that they can most effectively assist clinicians in guiding the management of patients with cystic fibrosis in all stages of disease. ©RSNA, 2024.

PMID:39172707 | DOI:10.1148/rg.240008

J Aerosol Med Pulm Drug Deliv. 2024 Aug;37(4):202-218. doi: 10.1089/jamp.2024.29117.mk.

ABSTRACT

An increasing growth in nanotechnology is evident from the growing number of products approved in the past decade. Nanotechnology can be used in the effective treatment of several pulmonary diseases by developing therapies that are delivered in a targeted manner to select lung regions based on the disease state. Acute or chronic pulmonary disorders can benefit from this type of therapy, including respiratory distress syndrome (RDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary infections (e.g. tuberculosis, Yersinia pestis infection, fungal infections, bacterial infections, and viral infections), lung cancer, cystic fibrosis (CF), pulmonary fibrosis, and pulmonary arterial hypertension. Modification of size and surface property renders nanoparticles to be targeted to specific sites, which can serve a vital role in innovative pulmonary drug delivery. The nanocarrier type chosen depends on the intended purpose of the formulation and intended physiological target. Liquid nanocarriers and solid-state nanocarriers can carry hydrophilic and hydrophobic drugs (e.g. small molecular weight drug molecules, large molecular weight drugs, peptide drugs, and macromolecular biological drugs), while surface modification with polymer can provide cellular targeting, controlled drug release, and/or evasion of phagocytosis by immune cells, depending on the polymer type. Polymeric nanocarriers have versatile architectures, such as linear, branched, and dendritic forms. In addition to the colloidal dispersion liquid state, the various types of nanoparticles can be formulated into the solid state, offering important unique advantages in formulation versatility and enhanced stability of the final product. This chapter describes the different types of nanocarriers, types of inhalation aerosol device platforms, liquid aerosols, respirable powders, and particle engineering design technologies for inhalation aerosols.

PMID:39172256 | DOI:10.1089/jamp.2024.29117.mk

J Leukoc Biol. 2024 Aug 22:qiae185. doi: 10.1093/jleuko/qiae185. Online ahead of print.

NO ABSTRACT

PMID:39171927 | DOI:10.1093/jleuko/qiae185

Curr Opin Pulm Med. 2024 Aug 23. doi: 10.1097/MCP.0000000000001115. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Advanced cystic fibrosis lung disease remains the main cause of death in people with cystic fibrosis (pwCF). Cystic fibrosis transmembrane regulator (CFTR) modulators have changed the disease burden for eligible pwCF with access to this therapy.

RECENT FINDINGS: Real-world data show that there are no safety concerns for patients with advanced cystic fibrosis lung disease treated with highly effective triple CFTR modulator therapy. The improvements are comparable to those in other people with cystic fibrosis and in part even better. Mortality and rates of lung transplantation have decreased since the approval of CFTR modulator therapy and, especially, highly effective triple CFTR modulator therapy. Nevertheless, at least 10% of people with cystic fibrosis are not eligible for highly effective CFTR modulator therapy, and the development of alternative treatments remains important.

SUMMARY: The approval of highly effective CFTR modulator therapies has been a breakthrough in treatment for most people with cystic fibrosis, especially those with advanced lung disease, improving survival and reducing the burden of the disease.

PMID:39171565 | DOI:10.1097/MCP.0000000000001115

J Allergy Clin Immunol Glob. 2024 Jul 3;3(4):100298. doi: 10.1016/j.jacig.2024.100298. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a rare airway disorder primarily affecting patients with asthma and cystic fibrosis. Persistent airway inflammation brought on by Aspergillus fumigatus exacerbates the underlying condition and can cause significant respiratory damage. Treatments center on reducing inflammation with the use of corticosteroids and antifungals. PANoptosis is a new concept in the field of cell death and inflammation that posits the existence of cross talk and a master control system for the 3 programmed cell death (PCD) pathways, namely, apoptosis, pyroptosis, and necroptosis. This concept has revolutionized the understanding of PCD and opened new avenues for its exploration. Studies show that Aspergillus is one of the pathogens that is capable of activating PANoptosis via the Z-DNA binding protein 1 (ZBP1) pathway and plays an active role in the inflammation caused by this organism.

OBJECTIVE: This article explores the nature of inflammation in ABPA and ways in which PCD could lead to novel treatment options.

METHOD: PubMed was used to review the literature surrounding Aspergillus infection-related inflammation and PANoptosis.

RESULTS: There is evidence that apoptosis and pyroptosis protect against Aspergillus-induced inflammation, whereas necroptosis promotes inflammation.

CONCLUSION: Experimental medications, in particular, necroptosis inhibitors such as necrosulfonamide and necrostatin-1, should be studied for use in the treatment of ABPA.

PMID:39170913 | PMC:PMC11338086 | DOI:10.1016/j.jacig.2024.100298

Transpl Int. 2024 Aug 7;37:12973. doi: 10.3389/ti.2024.12973. eCollection 2024.

ABSTRACT

Humoral immunity is a major waypoint towards chronic allograft dysfunction in lung transplantation (LT) recipients. Though allo-immunization and antibody-mediated rejection (AMR) are well-known entities, some diagnostic gaps need to be addressed. Morphological analysis could be enhanced by digital pathology and artificial intelligence-based companion tools. Graft transcriptomics can help to identify graft failure phenotypes or endotypes. Donor-derived cell free DNA is being evaluated for graft-loss risk stratification and tailored surveillance. Preventative therapies should be tailored according to risk. The donor pool can be enlarged for candidates with HLA sensitization, with strategies combining plasma exchange, intravenous immunoglobulin and immune cell depletion, or with emerging or innovative therapies such as imlifidase or immunoadsorption. In cases of insufficient pre-transplant desensitization, the effects of antibodies on the allograft can be prevented by targeting the complement cascade, although evidence for this strategy in LT is limited. In LT recipients with a humoral response, strategies are combined, including depletion of immune cells (plasmapheresis or immunoadsorption), inhibition of immune pathways, or modulation of the inflammatory cascade, which can be achieved with photopheresis. Altogether, these innovative techniques offer promising perspectives for LT recipients and shape the 21st century's armamentarium against AMR.

PMID:39170865 | PMC:PMC11336419 | DOI:10.3389/ti.2024.12973