Nat Microbiol. 2022 Apr 25. doi: 10.1038/s41564-022-01091-2. Online ahead of print.

ABSTRACT

Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

PMID:35469019 | DOI:10.1038/s41564-022-01091-2

Iran Biomed J. 2022 Apr 26:A-10-4914-1. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis is the most common heredity disease among the Caucasian population. More than 350 known pathogenic variations in the CFTR gene (NM_000492.4) cause cystic fibrosis. Herein, we report the outcome of our investigation of two unrelated Iranian families with cystic fibrosis patients.

METHODS: We conducted phenotypic examination, segregation, and linkage analysis, and CFTR gene sequencing to define causative mutations.

RESULTS: Two novel mutations were found. One was a deletion causing frameshift, c.299delT p.(Leu100Profs*7) and the second one was a missense mutation, c.1857G>T at nucleotide binding domain 1 of the CFTR protein. Haplotype segregation data supported our new mutation findings.

CONCLUSION: These findings expand the spectrum of CFTR pathogenic variations and can improve prenatal diagnosis and genetic counseling for cystic fibrosis.

PMID:35468710

mBio. 2022 Apr 25:e0080322. doi: 10.1128/mbio.00803-22. Online ahead of print.

NO ABSTRACT

PMID:35467419 | DOI:10.1128/mbio.00803-22

Microbiol Resour Announc. 2022 Apr 25:e0015822. doi: 10.1128/mra.00158-22. Online ahead of print.

ABSTRACT

Stenotrophomonas maltophilia is an opportunistic bacterium that is commonly associated with respiratory infections in immunocompromised patients, including cystic fibrosis patients. In this report, we introduce the complete genome sequence of S. maltophilia podophage Pepon, which is a T7-like phage closely related to the previously reported phage Ponderosa.

PMID:35467385 | DOI:10.1128/mra.00158-22

Antimicrob Agents Chemother. 2022 Apr 25:e0020422. doi: 10.1128/aac.00204-22. Online ahead of print.

ABSTRACT

The rise of antimicrobial-resistant (AMR) bacteria is a global health emergency. One critical facet of tackling this epidemic is more rapid AMR diagnosis in serious multidrug-resistant pathogens like Pseudomonas aeruginosa. Here, we designed and then validated two multiplex quantitative real-time PCR (qPCR) assays to simultaneously detect differential expression of the resistance-nodulation-division efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM, the AmpC β-lactamase, and the porin OprD, which are commonly associated with chromosomally encoded AMR. Next, qPCRs were tested on 15 sputa from 11 participants with P. aeruginosa respiratory infections to determine AMR profiles in vivo. We confirmed multiplex qPCR testing feasibility directly on sputa, representing a key advancement in in vivo AMR diagnosis. Notably, comparison of sputa with their derived isolates grown in Luria-Bertani broth (±2.5% NaCl) or a 5-antibiotic cocktail showed marked expression differences, illustrating the difficulty in replicating in vivo expression profiles in vitro. Cystic fibrosis sputa showed significantly reduced mexE and mexY expression compared with chronic obstructive pulmonary disease sputa, despite harboring fluoroquinolone- and aminoglycoside-resistant strains, indicating that these loci do not contribute to AMR in vivo. oprD was also significantly downregulated in cystic fibrosis sputa, even in the absence of contemporaneous carbapenem use, suggesting a common adaptive trait in chronic infections that may affect carbapenem efficacy. Sputum ampC expression was highest in participants receiving carbapenems (6.7 to 15×), some of whom were simultaneously receiving cephalosporins, the latter of which would be rendered ineffective by the upregulated ampC. Our qPCR assays provide valuable insights into the P. aeruginosa resistome, and their use on clinical specimens will permit timely treatment alterations that will improve patient outcomes and antimicrobial stewardship measures.

PMID:35467369 | DOI:10.1128/aac.00204-22

Diabet Med. 2022 Apr 25:e14859. doi: 10.1111/dme.14859. Online ahead of print.

NO ABSTRACT

PMID:35466445 | DOI:10.1111/dme.14859

J Cyst Fibros. 2022 Apr 21:S1569-1993(22)00096-0. doi: 10.1016/j.jcf.2022.04.006. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents.

METHODS: We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted.

RESULTS: Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses.

CONCLUSIONS: We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa.

PMID:35466039 | DOI:10.1016/j.jcf.2022.04.006

Front Genome Ed. 2022 Apr 6;4:843885. doi: 10.3389/fgeed.2022.843885. eCollection 2022.

ABSTRACT

Background: Gene correction via homology directed repair (HDR) in patient-derived induced pluripotent stem (iPS) cells for regenerative medicine are becoming a more realistic approach to develop personalized and mutation-specific therapeutic strategies due to current developments in gene editing and iPSC technology. Cystic fibrosis (CF) is the most common inherited disease in the Caucasian population, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Since CF causes significant multi-organ damage and with over 2,000 reported CFTR mutations, CF patients could be one prominent population benefiting from gene and cell therapies. When considering gene-editing techniques for clinical applications, seamless gene corrections of the responsible mutations, restoring native "wildtype" DNA sequence without remnants of drug selectable markers or unwanted DNA sequence changes, would be the most desirable approach. Result: The studies reported here describe the seamless correction of the W1282X CFTR mutation using CRISPR/Cas9 nickases (Cas9n) in iPS cells derived from a CF patient homozygous for the W1282X Class I CFTR mutation. In addition to the expected HDR vector replacement product, we discovered another class of HDR products resulting from vector insertion events that created partial duplications of the CFTR exon 23 region. These vector insertion events were removed via intrachromosomal homologous recombination (IHR) enhanced by double nicking with CRISPR/Cas9n which resulted in the seamless correction of CFTR exon 23 in CF-iPS cells. Conclusion: We show here the removal of the drug resistance cassette and generation of seamless gene corrected cell lines by two independent processes: by treatment with the PiggyBac (PB) transposase in vector replacements or by IHR between the tandemly duplicated CFTR gene sequences.

PMID:35465025 | PMC:PMC9019469 | DOI:10.3389/fgeed.2022.843885

Cell Mol Life Sci. 2022 Apr 25;79(5):257. doi: 10.1007/s00018-022-04190-9.

ABSTRACT

The pathogenic mechanism of cystic fibrosis (CF) includes the functional interaction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with the epithelial sodium channel (ENaC). The reduction of ENaC activity may constitute a therapeutic option for CF. This hypothesis was evaluated using drugs that target the protease-dependent activation of the ENaC channel and the transcriptional activity of its coding genes. To this aim we used: camostat, a protease inhibitor; S-adenosyl methionine (SAM), showed to induce DNA hypermethylation; curcumin, known to produce chromatin condensation. SAM and camostat are drugs already clinically used in other pathologies, while curcumin is a common dietary compound. The experimental systems used were CF and non-CF immortalized human bronchial epithelial cell lines as well as human bronchial primary epithelial cells. ENaC activity and SCNN1A, SCNN1B and SCNN1G gene expression were analyzed, in addition to SCNN1B promoter methylation. In both immortalized and primary cells, the inhibition of extracellular peptidases and the epigenetic manipulations reduced ENaC activity. Notably, the reduction in primary cells was much more effective. The SCNN1B appeared to be the best target to reduce ENaC activity, in respect to SCNN1A and SCNN1G. Indeed, SAM treatment resulted to be effective in inducing hypermethylation of SCNN1B gene promoter and in lowering its expression. Importantly, CFTR expression was unaffected, or even upregulated, after treatments. These results open the possibility of CF patients' treatment by epigenetic targeting.

PMID:35462606 | DOI:10.1007/s00018-022-04190-9

Cell Physiol Biochem. 2022 Apr 25;56(2):180-208. doi: 10.33594/000000512.

ABSTRACT

Cancer is a chaos of uncontrolled cell proliferation that has consistently invented new circuitry programs to operate inside the cell machinery. Globally, cancer statistics account for 65% of mortality worldwide, mainly due to the adoption of lifestyle behaviours. In 2020, FDA approved 40 new drugs, out of which 16 (40%) were approved as cancer drugs. Overall, the risk of dying from cancer decreased, but further reductions in cancer death rates can be accelerated by applying existing cancer control knowledge across all the population segments, emphasising those in the lowest socio-economic and other disadvantaged population. Various therapeutic regimes, including low-molecular-weight inhibitors, targeting oncogenic signaling pathways are under development. However, the pitfall of targeted therapies is the quick emergence of acquired drug resistance encumbered with toxic side effects. Several FDA acclaimed therapeutic legacies or biosimilars earmarked signaling pathways of rare diseases (cystic fibrosis, erythropoietic protoporphyria, neuromyelitis optica spectrum disorder, tenosynovial giant cell tumor, sickle cell disease, systemic sclerosis-associated interstitial lung disease, muscular dystrophy), neurological and psychiatric disorders, infectious diseases, heart, lung, circulatory, endocrine diseases, autoimmune conditions, cancers and blood disorders. When cancer progresses, these signals develop specific characteristics that can be targeted for anti-cancer therapy. The designer inhibitors have emerged as novel pharmaceutical interventions that aim to block the pathways in an effort to reverse the abnormal phenotype of the cancer cells. Numerous cell-signaling channels have evolved and invigorated to make off three-dimensional feedback networks. The magnitude of accessible information by pathways occupies curated information as a consortium. To fully appreciate the pivotal roles that signaling cascades play in tumor development, it is necessary to understand the involved signaling cascades in the interaction between cancer cells. The prime endeavour is to canonically curate all signaling pathways involving cell cycle, EGFR, MAPK, GPCR, PI3K/ AKT/mTOR, immune checkpoints, nuclear receptors, janus kinase, transcription activators etc., involving the manipulation of genetic and nuclear receptors. Here, we will summarize the vast amount of information describing the signals that mediate crosstalk between cancer cells and the targets related to this crosstalk.

PMID:35462471 | DOI:10.33594/000000512

Curr Opin Pharmacol. 2022 Apr 21;64:102210. doi: 10.1016/j.coph.2022.102210. Online ahead of print.

ABSTRACT

To find a cure for cystic fibrosis, there has been tremendous progress in the development of treatments that target the basic defect in the protein channel, CFTR. However, 10% of cystic fibrosis patients have rare CFTR mutations that are still without an approved CFTR-targeting drug. To identify relevant therapies for these patients, culture models using nasal, bronchial, and rectal tissue from individual patients allow functional, biochemical, and cellular detection of drug-rescued CFTR. Additionally, novel systems such as induced pluripotent stem cell-derived models are utilized to characterize CFTR mutations and identify treatments. State-of-the-art translational models were instrumental for CFTR modulator development and may become important for gene-based drug discovery and other novel therapeutic strategies.

PMID:35462105 | DOI:10.1016/j.coph.2022.102210

J Cyst Fibros. 2022 Apr 20:S1569-1993(22)00100-X. doi: 10.1016/j.jcf.2022.04.011. Online ahead of print.

ABSTRACT

BACKGROUND: The relationship between ways of coping and health outcomes has been a focus of interest for decades. There is increasing recognition that positive psychological functioning can influence health outcomes beneficially. This work investigated the role of coping in predicting survival in CF.

METHODS: A longitudinal observational cohort study with a 20-year follow-up period was undertaken. At entry to the study, demographic and clinical variables were recorded, and ways of coping were assessed using the Cystic Fibrosis Coping Scale which measures four distinct ways of coping: optimism, hopefulness, distraction and avoidance. Survival outcome was measured as time in days from the date of recruitment to exit from the study, where exit was either death, loss to follow-up or the end of the follow-up period.

RESULTS: Survival time was modelled using Cox's proportional hazards model. At baseline, 116 people with CF were recruited. By the census date, 54 people had died (14 men had died during 248,565 person-days of observation and 40 women had died during 358,372 person-days of observation). Optimism was the only way of coping that showed any beneficial effect on survival (RR=0.984, p=0.040) after adjustments for age, gender, ppFEV1 and the three other coping variables measured at baseline.

CONCLUSION: This work suggests that optimistic coping serves as a prognostic measure of survival in CF beyond key clinical and demographic variables. Ways of coping are modifiable, providing a target for clinical intervention; to improve quality of life and clinical outcomes and potentially increase longevity.

PMID:35461783 | DOI:10.1016/j.jcf.2022.04.011

J Cyst Fibros. 2022 Apr 14:S1569-1993(22)00094-7. doi: 10.1016/j.jcf.2022.04.004. Online ahead of print.

ABSTRACT

Data regarding immunogenicity of SARS-CoV-2 BNT162b2 vaccine in cystic fibrosis (CF) patients are limited. We prospectively measured total (TAbs-RBD; U/ml) and neutralizing (NAbs-RBD; %) antibodies of SARS-CoV-2 spike-receptor binding domain (RBD) protein in 33 CF patients and 66 healthy controls with median age (IQR): 19.6 (17.6-24.3) years and 31 (29-36) years, respectively and investigated possible associations with epidemiological and clinical parameters. Compared to healthy controls, CF patients had higher levels of TAbs-RBD and NAbs-RBD after both doses (P-value < 0.001). One month after the second dose, CF patients and controls had TAbs-RBD: median (IQR): 3396 (2443) and 1452 (1231) U/ml, respectively. Similarly, the NAbs-RBD (%) were: 97.30 (1.00) and 95.70 (3.71) %, respectively. CF patients also had fewer local and systemic adverse events (AEs) (P-value < 0.001). Among CF patients, no significant differences in immunogenicity were detected regarding the phenotype, genotype, medications, or severity of the disease. BNT162b2 vaccine was immunogenic with limited reactogenicity in CF patients regardless of the phenotype or severity of disease.

PMID:35461782 | DOI:10.1016/j.jcf.2022.04.004

Transplant Proc. 2022 Apr 20:S0041-1345(22)00217-2. doi: 10.1016/j.transproceed.2022.02.059. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with end-stage lung disease owing to cystic fibrosis may require lung transplant, provided other therapeutic options were exhausted. During the posttransplant period, bronchial anastomoses' healing may sometimes be complicated and require bronchoscopic intervention (BI). The main aim of this study was to assess BI and its effect on long-term lung function among cystic fibrosis lung transplant recipients who have reached 2-year survival.

METHODS: This retrospective study includes 22 patients with cystic fibrosis who underwent primary double lung transplant in a single center between 2018 and 2020 and have checked in for their 2-year follow-up visit. BI is defined as performing endoscopic bronchoplasty through balloon dilatation, cryoprobe, argon plasma, and/or laser treatment.

RESULTS: All patients, who did not require BI during the first year, did not need bronchoplasty during the second posttransplant year as well. Results of forced expiratory volume in 1 second as percentage of predicted value and the 6-minute walk distance were similar at 2-year follow-up to those obtained at the end of 1 year for all patients. Significant time effects were observed for forced vital capacity (FVC) (weak effect), FVC as percentage of predicted value (weak effect), and forced expiratory volume in 1 second/FVC (moderate effect).

CONCLUSIONS: Patients who had never had bronchoscopic intervention owing to airway stenosis, as well as those who did in the first posttransplant year, maintained forced expiratory volume in 1 second as percentage of predicted value at a comparable level at the second posttransplant year follow-up visit. The number of BIs significantly decreased among patients, who were undergoing such procedures during the first posttransplant year.

PMID:35461714 | DOI:10.1016/j.transproceed.2022.02.059

Transplant Proc. 2022 Apr 20:S0041-1345(22)00204-4. doi: 10.1016/j.transproceed.2022.02.028. Online ahead of print.

ABSTRACT

The most important risk factor for the development of posttransplant lymphoproliferative disorders (PTLD) is Epstein-Barr virus (EBV) infection after transplant. It increases in seronegative EBV recipients from 23% to 50%. The aim of the study was to assess the serologic status of EBV infections (before lung transplant) and the expression of the virus itself after lung transplant in a 25-year-old patient with cystic fibrosis. In a 25-year-old patient with cystic fibrosis, immediately before lung transplant, all diagnostically significant antibodies related to EBV infection were determined in blood serum using enzyme-linked immunosorbent assay methods, using tests by Euroimmun and PerkinElmer Company. Additionally, the organ donor's serologic profile was assessed with the same tests. After lung transplant, the risk of EBV infection was monitored in whole blood and virus expression was determined by reverse transcriptase-polymerase chain reaction with Biomerieux Argene tests. Before lung transplant, the patient was shown to have no antibodies against EBV in both IgM and IgG classes. The constellation of organ donor antibodies clearly indicated a past infection. The presence of EBV virus copies in whole blood was demonstrated in the patient 9 months after transplant. Constant monitoring of the patient and modification of the treatment did not, unfortunately, protect him from the development of PTLD. The obtained results clearly confirm the purposefulness of both serologic and molecular determinations in lung recipients related to EBV. The likelihood of developing PTLD increases both in people who have not had EBV infection and patients with reactivation of the infection.

PMID:35461713 | DOI:10.1016/j.transproceed.2022.02.028

Transplant Proc. 2022 Apr 19:S0041-1345(22)00173-7. doi: 10.1016/j.transproceed.2022.02.041. Online ahead of print.

ABSTRACT

BACKGROUND: Healing of bronchial anastomoses may sometimes be complicated and require bronchoscopic intervention (BI). The main aim of the study was to assess whether patients who require BI present comparable lung function after reaching 1-year posttransplant survival to those who did not require any BI by means of spirometry and 6-minute walk test (6MWT).

METHODS: This retrospective study included an analysis of 44 primary double lung transplant recipients who underwent transplant for end-stage respiratory failure in the course of cystic fibrosis transplanted in a single center between 2018 and 2021. Bronchoscopic intervention is defined as performing endoscopic bronchoplasty through balloon dilatation, cryoprobe, argon plasma, and/or laser treatment. Group 1 (25 patients who required at least 1 BI) presented similar spirometry parameters at qualification as group 2 (no BI).

RESULTS: Statistically significant differences between the groups for the following parameters were reported: forced expiratory volume in 1 second (FEV1), FEV1 (%), Tiffeneau-Pinelli index (FEV1/forced vital capacity percentage of predicted value), oxygen saturation after conclusion of 6MWT (%) and oxygen saturation before 6MWT (%). In each case, the mean for the BI group in the first year was lower. All patients in this group received an average amount of 6.8 ± 4.9 bronchoscopic procedures during the first year (minimum = 1; maximum = 18). Strong negative correlations were observed between the number of balloons in the first year and the FEV1 (%) and FEV1/forced vital capacity percentage of predicted value indicators after the first year.

CONCLUSIONS: Lung transplant recipients who underwent transplant because of cystic fibrosis and required at least 1 BI during the first posttransplant year presented inferior spirometry and 6MWT results in comparison with those who did not require any.

PMID:35459464 | DOI:10.1016/j.transproceed.2022.02.041

Int J Mol Sci. 2022 Apr 14;23(8):4328. doi: 10.3390/ijms23084328.

ABSTRACT

Renal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5' AMP-activated protein kinase (AMPK) inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride secretion, leading to reduced progression of PKD. Here we investigated the pharmacological effects of panduratin A, a bioactive compound known as an AMPK activator, on CFTR-mediated chloride secretion and renal cyst development using in vitro and animal models of PKD. We demonstrated that AMPK was activated in immortalized normal renal cells and autosomal dominant polycystic kidney disease (ADPKD) cells following treatment with panduratin A. Treatment with panduratin A reduced the number of renal cyst colonies corresponding with a decrease in cell proliferation and phosphorylated p70/S6K, a downstream target of mTOR signaling. Additionally, panduratin A slowed cyst expansion via inhibition of the protein expression and transport function of CFTR. In heterozygous Han:Sprague-Dawley (Cy/+) rats, an animal model of PKD, intraperitoneal administration of panduratin A (25 mg/kg BW) for 5 weeks significantly decreased the kidney weight per body weight ratios and the cystic index. Panduratin A also reduced collagen deposition in renal tissue. Intraperitoneal administration of panduratin A caused abdominal bleeding and reduced body weight. However, 25 mg/kg BW of panduratin A via oral administration in the PCK rats, another non-orthologous PKD model, showed a significant decrease in the cystic index without severe adverse effects, indicating that the route of administration is critical in preventing adverse effects while still slowing disease progression. These findings reveal that panduratin A might hold therapeutic properties for the treatment of PKD.

PMID:35457146 | DOI:10.3390/ijms23084328

Microorganisms. 2022 Apr 13;10(4):810. doi: 10.3390/microorganisms10040810.

ABSTRACT

Microbes play an important role in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, cystic fibrosis, non-cystic fibrosis bronchiectasis, and asthma. While the role of bacterial pathogens has been extensively studied, the contribution of fungal species to the pathogenesis of chronic lung diseases is much less understood. The recent introduction of next-generation sequencing techniques has revealed the existence of complex microbial lung communities in healthy individuals and patients with chronic respiratory disorders, with fungi being an important part of these communities' structure (mycobiome). There is growing evidence that the components of the lung mycobiome influence the clinical course of chronic respiratory diseases, not only by direct pathogenesis but also by interacting with bacterial species and with the host's physiology. In this article, we review the current knowledge on the role of fungi in chronic respiratory diseases, which was obtained by conventional culture and next-generation sequencing, highlighting the limitations of both techniques and exploring future research areas.

PMID:35456861 | DOI:10.3390/microorganisms10040810

Microorganisms. 2022 Mar 29;10(4):739. doi: 10.3390/microorganisms10040739.

ABSTRACT

BACKGROUND: The clinical relevance of Aspergillus fumigatus (Af) in cystic fibrosis (CF) is controversial. The aims of the study were to assess the prevalence of Af disease in our cohort of CF patients and evaluate whether allergic bronchopulmonary aspergillosis (ABPA) and sensitization to Af affected lung function, body mass index (BMI) and exacerbations.

METHODS: Clinical data and lung function of CF patients aged 6-18 years followed at the CF Centre of Parma (Italy) were recorded. Patients were classified as: patients with no signs of Af, patients sensitized or colonized by Af, patients with ABPA or patients with Aspergillus bronchitis (Ab).

RESULTS: Of 38 CF patients (14.2 years (6.2-18.8) M 23), 8 (21%) showed Af sensitization, 7 (18.4%) showed ABPA, 1 (2.6%) showed Af colonization and 1 (2.6%) showed Ab. Compared to non-ABPA, patients with ABPA had lower BMI (15.9 ± 1.6 vs. 19.7 ± 3.4, p &lt; 0.005), lower lung function (FEV1 61.5 ± 25.9% vs. 92.3 ± 19.3%, p &lt; 0.001) and more exacerbations/year (4.43 ± 2.44 vs. 1.74 ± 2.33, p &lt; 0.005). Patients with Af sensitization showed more exacerbations/year than non-Af patients (3.5 ± 3.2 vs. 0.9 ± 1.2, p &lt; 0.005). ABPA and sensitized patients had more abnormalities on chest CT scans.

CONCLUSION: This study showed the relevant clinical impact of ABPA and Af sensitization in terms of exacerbations and lung structural damage.

PMID:35456789 | DOI:10.3390/microorganisms10040739

Microorganisms. 2022 Mar 26;10(4):716. doi: 10.3390/microorganisms10040716.

ABSTRACT

Cystic fibrosis (CF) is a life-threatening, inherited, multi-organ disease that renders patients susceptible throughout their lives to chronic and ultimately deteriorating protracted pulmonary infections. Those infections are dominated in adulthood by the opportunistic pathogen, Pseudomonas aeruginosa (Pa). As with other advancing respiratory illnesses, people with CF (pwCF) also frequently suffer from gastroesophageal reflux disease (GERD), including bile aspiration into the lung. GERD is a major co-morbidity factor in pwCF, with a reported prevalence of 35-81% in affected individuals. Bile is associated with the early acquisition of Pa in CF patients and in vitro studies show that it causes Pa to adopt a chronic lifestyle. We hypothesized that Pa is chemoattracted to bile in the lung environment. To evaluate, we developed a novel chemotaxis experimental system mimicking the lung environment using CF-derived bronchial epithelial (CFBE) cells which allowed for the evaluation of Pa (strain PAO1) chemotaxis in a physiological scenario superior to the standard in vitro systems. We performed qualitative and quantitative chemotaxis tests using this new experimental system, and microcapillary assays to demonstrate that bovine bile is a chemoattractant for Pa and is positively correlated with bile concentration. These results further buttress the hypothesis that bile likely contributes to the colonization and pathogenesis of Pa in the lung, particularly in pwCF.

PMID:35456767 | DOI:10.3390/microorganisms10040716