Children (Basel). 2022 Feb 14;9(2):252. doi: 10.3390/children9020252.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is an immune-mediated inflammatory airway disease that predominantly affects patients with cystic fibrosis (CF) and, less commonly, patients with asthma. ABPA can lead to irreversible lung injury and bronchiectasis if not treated early and aggressively. Long-term oral steroids are the standard therapy of ABPA. However, it is associated with an increased risk of steroids side effects and possible medication noncompliance. Monthly intravenous pulse methylprednisolone (IV-PS) has been used as an alternative to oral steroids to treat CF-related ABPA with a reportedly similar clinical response and less steroid-related side effects. To our knowledge, the use of IV-PS in asthma-related ABPA has not been previously reported. We report the successful management of asthma-related ABPA in an adolescent using intravenous pulse methylprednisolone in addition to oral itraconazole with no significant steroid-related side effects.

PMID:35204972 | DOI:10.3390/children9020252

Children (Basel). 2022 Jan 26;9(2):157. doi: 10.3390/children9020157.

ABSTRACT

(1) Background: Cystic fibrosis (CF) is a multisystemic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lung disease, the leading cause of morbimortality, is marked by acute worsening of symptoms-such as pulmonary exacerbations (PEx). The objectives of this study were: Identifying the frequency of PEx in pediatric CF patients; Characterizing each PEx; Finding association between the frequency and characteristics of the PEx and patients' features. (2) Methods: Retrospective analysis of all PEx from a period of January 2015 to December 2019 in a group of pediatric patients from a single CF center. Data were collected from medical records. Descriptive statistics and chi-square/Fisher's test were used. (3) Results: Thirty-four pediatric patients contributed to the total sample used in this study and 198 PEx were identified, median of 1.0 PEx/patient/year. Most frequent PEx symptoms were increased cough (93.9%) and change in secretions (88.4%), most common pathogens were Staphylococcus aureus (54.9%) and Pseudomonas aeruginosa (24.9%). The majority were treated as outpatient (85.9%). Most common antibiotics included amoxicillin/clavulanate (35.9%) and ciprofloxacin (22.7%). Outcome was favorable in all PEx. (4) Conclusion: Results were consistent with what has been described in literature. More studies are necessary for a better characterization of CF PEx, in order to develop standardized protocols for their management.

PMID:35204878 | DOI:10.3390/children9020157

Biomolecules. 2022 Jan 25;12(2):202. doi: 10.3390/biom12020202.

ABSTRACT

SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype and treatment response, SLC26A9 has emerged as one of the most interesting alternative targets for the treatment of cystic fibrosis (CF). However, despite relevant clues, some open issues and controversies remain. The lack of specific pharmacological modulators, the elusive expression reported in the airways, and its complex relationships with CFTR and the CF phenotype prevent us from conclusively understanding the contribution of SLC26A9 in human lung physiology and its real potential as a therapeutic target in CF. In this review, we summarized the various studies dealing with SLC26A9 expression, molecular structure, and function as an anion channel or transporter; its interaction and functional relationships with CFTR; and its role as a gene modifier and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment.

PMID:35204703 | DOI:10.3390/biom12020202

Diagnostics (Basel). 2022 Feb 1;12(2):376. doi: 10.3390/diagnostics12020376.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) lung disease determines the outcome of this condition. For lung evaluation processes, computed tomography (CT) is the gold standard, but also causes irradiation. Lately, lung ultrasound (LUS) has proven to be reliable for the diagnosis of consolidations, atelectasis, and/or bronchiectasis. The aim of our study was to evaluate the value of a newly conceived LUS score by comparing it to the modified Bhalla CT score. A further aim was to evaluate the correlation between the score and the lung clearance index (LCI).

METHODS: Patients with CF were screened by LUS, followed by a CT scan. Spearman's test was used for correlations.

RESULTS: A total of 98 patients with CF were screened, and 57 were included in the study; their mean age was 11.8 ± 5.5 (mean ± SD) years. The mean LUS score was 5.88 ± 5.4 SD. The LUS CF score had a very strong correlation with the CT score of rs = 0.87 (p = 0.000). LUS showed a good sensibility for detecting atelectasis (Se = 83.7%) and consolidations (Se = 94.4%). A lower Se (77.7%) and Sp (9%) were found for cylindrical bronchiectasis.

CONCLUSION: Our study shows that LUS and the lung CF score are parameters that can be used with a complementary role in the diagnosis and monitoring of CF lung disease in children.

PMID:35204467 | DOI:10.3390/diagnostics12020376

Antibiotics (Basel). 2022 Feb 19;11(2):275. doi: 10.3390/antibiotics11020275.

ABSTRACT

It remains unknown whether the type of aerosol generating device is affecting efficacy and safety among non-cystic fibrosis bronchiectasis (NCFB) adults. The proposal of this network meta-analysis (NMA) is to evaluate effectiveness and safety of inhaled antibiotics administered via dry powder inhaler (DPI) and via nebulizers (SVN) among adult patients with NCFB. Inclusion criteria were randomized-controlled trials, adults (≥18 years) with NCFB, and inhaled antibiotics administered via DPI as intervention. Search strategy was performed in PubMed, Web of Science, and Cochrane Library from 2000 to 2019. Sixteen trials (2870 patients) were included. Three trials (all ciprofloxacin) used DPIs and thirteen used SVN (three ciprofloxacin). Both DPI and SVN devices achieved similar safety outcomes (adverse events, antibiotic discontinuation, severe adverse events, and bronchospasm). Administration of ciprofloxacin via DPI significantly improved time to first exacerbation (87 days, 95% CI 34.3-139.7) and quality of life (MD -7.52; 95% CI -13.06 to -1.98) when compared with via SVN. No other significant differences were documented in clinical efficacy (at least one exacerbation, FEV1% predicted) and microbiologic response (bacterial eradication, emergence of new potential pathogens, and emergence of antimicrobial resistance) when comparing devices. Our NMA documented that time to first exacerbation and quality of life, were more favorable for DPIs. Decisions on the choice of devices should incorporate these findings plus other criteria, such as simplicity, costs or maintenance requirements.

PMID:35203878 | DOI:10.3390/antibiotics11020275

Antibiotics (Basel). 2022 Feb 1;11(2):192. doi: 10.3390/antibiotics11020192.

ABSTRACT

Stenotrophomonas maltophilia is increasingly recognized as a nosocomial bacterial pathogen with a multi-drug resistance profile. In this study, the novel drug gepotidacin, the first compound of the novel triazaacenaphthylene topoisomerase inhibitor antibiotics class, was evaluated on its activity against clinical S. maltophilia isolates. Ninety-nine S. maltophilia isolates plus reference strain K279a (N = 100) were tested on their susceptibility towards gepotidacin in a broth microdilution. Additional susceptibility testing was performed towards the commonly applied combination trimethoprim/sulfamethoxazole (TMP/SXT), moxifloxacin, and levofloxacin. The time-kill kinetic of gepotidacin was observed in a time-kill assay. The greater wax moth Galleria mellonella was used to determine the activity of gepotidacin against S. maltophilia in vivo. Gepotidacin showed minimum inhibitory concentrations (MICs) between 0.25 and 16 mg/L (MIC50: 2 mg/L; MIC90: 8 mg/L), independently of its susceptibility towards TMP/SXT. The five TMP/SXT resistant strains exhibited gepotidacin MICs from 1 to 4 mg/L. The S. maltophilia strains resistant to the assessed fluoroquinolones showed in parts high MICs of gepotidacin. The time-kill assay revealed a time- and strain-dependent killing effect of gepotidacin. In vivo, injection of gepotidacin increased the survival rate of the larvae from 61 % to 90 % after 2 days. This study showed antimicrobial effects of gepotidacin towards S. maltophilia.

PMID:35203795 | DOI:10.3390/antibiotics11020192

Biomedicines. 2022 Jan 31;10(2):334. doi: 10.3390/biomedicines10020334.

ABSTRACT

As demonstrated in COPD, bronchiectasis patients may experience respiratory and peripheral muscle dysfunction. We hypothesized that respiratory and peripheral (upper and lower limbs) muscle function and nutritional status may be more significantly altered in female than in males for identical age and disease severity. In mild-to-moderate bronchiectasis patients (n = 150, 114 females) and 37 controls (n = 37, 21 females), radiological extension, maximal inspiratory and expiratory pressures (MIP and MEP), sniff nasal inspiratory pressure (SNIP), hand grip and quadriceps muscle strengths, body composition, and blood analytical biomarkers were explored. Compared to the controls, in all bronchiectasis patients (males and females), BMI, fat-free mass index (FFMI), fat tissue, upper and lower limb muscle strength, and respiratory muscle strength significantly declined, and FFMI, fat tissue, and quadriceps muscle function were significantly lower in female than male patients. In patients with mild-to-moderate bronchiectasis, respiratory and peripheral muscle function is significantly impaired and only partly related to lung disease status. Quadriceps muscle strength was particularly weakened in the female patients and was negatively associated with their exercise tolerance. Muscle weakness should be therapeutically targeted in bronchiectasis patients. Body composition and peripheral muscle function determination should be part of the comprehensive clinical assessment of these patients.

PMID:35203543 | DOI:10.3390/biomedicines10020334

Biomedicines. 2022 Jan 28;10(2):314. doi: 10.3390/biomedicines10020314.

ABSTRACT

Integrin-dependent adhesion of neutrophils to tissue, accompanied by the development of neutrophil-induced inflammation, occurs both in the focus of infection and in the absence of infection in metabolic disorders such as reperfusion after ischemia, diabetes mellitus, or the development of pneumonia in patients with cystic fibrosis or viral diseases. Hyaluronic acid (HA) plays an important role in the recruitment of neutrophils to tissues. 4-methylumbilliferon (4-MU), an inhibitor of HA synthesis, is used to treat inflammation, but its mechanism of action is unknown. We studied the effect of 4-MU on neutrophil adhesion and concomitant secretion using adhesion to fibronectin as a model for integrin-dependent adhesion. 4-MU reduced the spreading of neutrophils on the substrate and the concomitant secretion of granule proteins, including pro-inflammatory components. 4-MU also selectively blocked adhesion-induced release of the free amino acid hydroxylysine, a product of lysyl hydroxylase, which can influence cell invasion by modifying the extracellular matrix. Finally, 4-MU inhibited the formation of cytonemes, the extracellular membrane secretory structures containing the pro-inflammatory bactericides of the primary granules. The anti-inflammatory effect of 4-MU may be associated with the suppression of secretory processes that ensure the neutrophil invasion and initiate inflammation. We suggest that HA, due to the peculiarities of its synthesis, can promote the release of secretory carriers from the cell and 4-MU can block this process.

PMID:35203523 | DOI:10.3390/biomedicines10020314

Biomedicines. 2022 Jan 21;10(2):225. doi: 10.3390/biomedicines10020225.

ABSTRACT

Differential phenotypic characteristics using data mining approaches were defined in a large cohort of patients from the Spanish Online Bronchiectasis Registry (RIBRON). Three differential phenotypic clusters (hierarchical clustering, scikit-learn library for Python, and agglomerative methods) according to systemic biomarkers: neutrophil, eosinophil, and lymphocyte counts, C reactive protein, and hemoglobin were obtained in a patient large-cohort (n = 1092). Clusters #1-3 were named as mild, moderate, and severe on the basis of disease severity scores. Patients in cluster #3 were significantly more severe (FEV1, age, colonization, extension, dyspnea (FACED), exacerbation (EFACED), and bronchiectasis severity index (BSI) scores) than patients in clusters #1 and #2. Exacerbation and hospitalization numbers, Charlson index, and blood inflammatory markers were significantly greater in cluster #3 than in clusters #1 and #2. Chronic colonization by Pseudomonas aeruginosa and COPD prevalence were higher in cluster # 3 than in cluster #1. Airflow limitation and diffusion capacity were reduced in cluster #3 compared to clusters #1 and #2. Multivariate ordinal logistic regression analysis further confirmed these results. Similar results were obtained after excluding COPD patients. Clustering analysis offers a powerful tool to better characterize patients with bronchiectasis. These results have clinical implications in the management of the complexity and heterogeneity of bronchiectasis patients.

PMID:35203435 | DOI:10.3390/biomedicines10020225

Biomedicines. 2022 Jan 21;10(2):222. doi: 10.3390/biomedicines10020222.

ABSTRACT

Drug-resistant Pseudomonas aeruginosa is rapidly developing resulting in a serious global threat. Immunocompromised patients are specifically at risk, especially those with cystic fibrosis (CF). Novel metal complexes incorporating 1,10-phenanthroline (phen) ligands have previously demonstrated antibacterial and anti-biofilm effects against resistant P. aeruginosa from CF patients in vitro. Herein, we present the in vivo efficacy of {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4]·EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid). Individual treatments of these metal-tdda-phen complexes and in combination with the established antibiotic gentamicin were evaluated in vivo in larvae of Galleria mellonella infected with clinical isolates and laboratory strains of P. aeruginosa. G. mellonella were able to tolerate all test complexes up to 10 µg/larva. In addition, the immune response was affected by stimulation of immune cells (hemocytes) and genes that encode for immune-related peptides, specifically transferrin and inducible metallo-proteinase inhibitor. The amalgamation of metal-tdda-phen complexes and gentamicin further intensified this response at lower concentrations, clearing a P. aeruginosa infection that were previously resistant to gentamicin alone. Therefore this work highlights the anti-pseudomonal capabilities of metal-tdda-phen complexes alone and combined with gentamicin in an in vivo model.

PMID:35203432 | DOI:10.3390/biomedicines10020222

Biomedicines. 2022 Jan 18;10(2):200. doi: 10.3390/biomedicines10020200.

ABSTRACT

INTRODUCTION: Biologic drugs have dramatically improved severe eosinophilic asthma (SEA) outcomes. Our aim was to evaluate the long-term efficacy of biological therapy in SEA in a real-life setting and to identify the predictors for switching to another biological drug in patients with poor asthma control. The outcomes for efficacy were decreased annual exacerbations (AE) and improved asthma control test (ACT).

METHODS: In 90 SEA patients being treated with a biological drug, clinical examination, ACT, blood eosinophils count and spirometry were assessed before (T0) and after 6 (T1), 12 (T2), 24 (T3) and 36 (T4) months from the start of biological therapy. Patients were considered responders (R) or non-responders (NR) to biologics depending on whether or not they had less than two AE and a 20% increase in the ACT after 12 months of treatment.

RESULTS: 75% of the patients were R, 25% NR. In R patients, biological therapy add-on was followed by significant improvement in AE and ACT throughout the whole follow-up period. The percentage of patients on oral corticosteroids (OCS) dropped from 40% to 12%. By contrast, the NR patients were shifted to another biological drug after 12 months of therapy, as they still had high AE and nearly unchanged ACT; 40% of them still needed OCS treatment. The predictors of switching to another biological drug were three or more AE, ACT below 17, nasal polyposis and former smoking (p < 0.05). In NR, the shift to another biological drug was followed by a significant decrease in AE and an increase in the ACT.

DISCUSSION: This real-life study confirms the long-term efficacy of biologics in most SEA patients and indicates that even in non-responders to a first biological drug, it is worth trying a second one. It is hoped that the availability of additional biologics with different targets will help improve the personalization of SEA therapy.

PMID:35203409 | DOI:10.3390/biomedicines10020200

Cells. 2022 Feb 16;11(4):699. doi: 10.3390/cells11040699.

ABSTRACT

Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has been demonstrated as an objective readout of BOS and RAS and bears prognostic importance, but has yet to be correlated to biological measures. Using a topological technique, we evaluate the distribution and arrangement of PRM-derived classifications of pulmonary abnormalities from lung transplant recipients undergoing redo-transplantation for end-stage BOS (N = 6) or RAS (N = 6). Topological metrics were determined from each PRM classification and compared to structural and biological markers determined from microCT and histopathology of lung core samples. Whole-lung measurements of PRM-defined functional small airways disease (fSAD), which serves as a readout of BOS, were significantly elevated in BOS versus RAS patients (p = 0.01). At the core-level, PRM-defined parenchymal disease, a potential readout of RAS, was found to correlate to neutrophil and collagen I levels (p < 0.05). We demonstrate the relationship of structural and biological markers to the CT-based distribution and arrangement of PRM-derived readouts of BOS and RAS.

PMID:35203345 | DOI:10.3390/cells11040699

Respir Med. 2022 Feb 15;194:106773. doi: 10.1016/j.rmed.2022.106773. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the association between time to active sitting position and clinical features in people with COVID-19 admitted to intensive care unit (ICU) and referred to physiotherapists.

METHOD: Prospective study conducted in the largest temporary ICU in Lombardy (Italy) between April 2020 and June 2021. All individuals with COVID-19 who received physiotherapy were included. Multivariable Cox proportional hazard model was fitted to explore the statistical association between active sitting position and characteristics of patients referred to physiotherapists, also accounting for the different multidisciplinary teams responsible for patients.

RESULTS: 284 individuals over 478 (59.4%) had access to physiotherapy, which was performed for a median of 8 days, without difference between multidisciplinary teams (P = 0.446). The active sitting position was reached after a median of 18 (IQR: 10.0-32.0) days. Sex was the only characteristic associated with the time to active sitting position, with males showing a reduced hazard by a factor of 0.65 (95% CI: 0.48-0.87; P = 0.0042) compared to females. At ICU discharge, nearly 50% individuals increased Manchester Mobility Score by 3 points. During physiotherapy no major adverse event was recorded.

CONCLUSION: Individuals with COVID-19 take long time to reach active sitting position in ICU, with males requiring longer rehabilitation than females.

PMID:35203010 | DOI:10.1016/j.rmed.2022.106773

Cell Chem Biol. 2022 Feb 22:S2451-9456(22)00052-6. doi: 10.1016/j.chembiol.2022.02.001. Online ahead of print.

ABSTRACT

In cystic fibrosis (CF), excessive furin activity plays a critical role in the activation of the epithelial sodium channel (ENaC), dysregulation of which contributes to airway dehydration, ineffective mucociliary clearance (MCC), and mucus obstruction. Here, we report a highly selective, cell-permeable furin inhibitor, BOS-318, that derives selectivity by eliciting the formation of a new, unexpected binding pocket independent of the active site catalytic triad. Using human ex vivo models, BOS-318 showed significant suppression of ENaC, which led to enhanced airway hydration and an ∼30-fold increase in MCC rate. Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Additional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aeruginosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value.

PMID:35202587 | DOI:10.1016/j.chembiol.2022.02.001

PLoS Pathog. 2022 Feb 24;18(2):e1010325. doi: 10.1371/journal.ppat.1010325. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that often infects individuals with the genetic disease cystic fibrosis, and contributes to airway blockage and loss of lung function. Natural killer (NK) cells are cytotoxic, granular lymphocytes that are part of the innate immune system. NK cell secretory granules contain the cytolytic proteins granulysin, perforin and granzymes. In addition to their cytotoxic effects on cancer and virally infected cells, NK cells have been shown to play a role in an innate defense against microbes, including bacteria. However, it is not known if NK cells kill extracellular P. aeruginosa or how bacterial killing might occur at the molecular level. Here we show that NK cells directly kill extracellular P. aeruginosa using NK effector molecules. Live cell imaging of a co-culture of YT cells, a human NK cell line, and GFP-expressing P. aeruginosa in the presence of the viability dye propidium iodide demonstrated that YT cell killing of P. aeruginosa is contact-dependent. CRISPR knockout of granulysin or perforin in YT cells had no significant effect on YT cell killing of P. aeruginosa. Pre-treatment of YT and NK cells with the serine protease inhibitor 3,4-dichloroisocoumarin (DCI) to inhibit all granzymes, resulted in an inhibition of killing. Although singular CRISPR knockout of granzyme B or H had no effect, knockout of both in YT cells completely abrogated killing of P. aeruginosa in comparison to wild type YT cell controls. Nitrocefin assays suggest that the bacterial membrane is damaged. Inhibition of killing by antioxidants suggest that ROS are required for the bactericidal mode-of-action. Taken together, these results identify that NK cells kill P. aeruginosa through a membrane damaging, contact-dependent process that requires granzyme induced ROS production, and moreover, that granzyme B and H are redundant in this killing process.

PMID:35202434 | DOI:10.1371/journal.ppat.1010325

Opt Express. 2022 Jan 3;30(1):414-426. doi: 10.1364/OE.444701.

ABSTRACT

We present a low-cost, 3D-printed, and biocompatible fluidic device, engineered to produce laminar and homogeneous flow over a large field-of-view. Such a fluidic device allows us to perform multiplexed temporal monitoring of cell cultures compatible with the use of various pharmacological protocols. Therefore, specific properties of each of the observed cell cultures can be discriminated simultaneously during the same experiment. This was illustrated by monitoring the agonists-mediated cellular responses, with digital holographic microscopy, of four different cell culture models of cystic fibrosis. Quantitatively speaking, this multiplexed approach provides a time saving factor of around four to reveal specific cellular features.

PMID:35201218 | DOI:10.1364/OE.444701

Nutr Clin Pract. 2022 Feb 24. doi: 10.1002/ncp.10831. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with cystic fibrosis (CF) and pancreatic insufficiency are at risk for suboptimal fat absorption, inability to maintain weight, poor growth, and increased gastrointestinal (GI) symptoms due to malabsorption. Enteral nutrition (EN) is used to supplement caloric intake and requires pancreatic enzyme replacement for effective digestion. We evaluated the relationship between long-term use of an in-line digestive enzyme cartridge with EN and changes in anthropometric measures and GI symptoms in patients with CF.

METHODS: This is a single-center, retrospective case review of patients with CF using a digestive enzyme cartridge with EN. Data were collected from the patient medical records and included weight, height, body mass index, EN regimen, and reported GI symptoms.

RESULTS: Thirteen pediatric and five adult patients with a mean age of 12.6 years used a digestive enzyme cartridge with EN for a period of 3-27 months. Most patients (n = 14) had been using oral digestive enzymes with EN before using the digestive enzyme cartridge, whereas four started from the onset of EN. The indications to convert from oral enzymes to the digestive enzyme cartridge included poor growth (72.2%) and poor tolerance of EN (69.2%). There was a reduction in reported GI symptoms after initiating use of the digestive enzyme cartridge. After 12 months of digestive cartridge use, there were improvements in anthropometrics.

CONCLUSIONS: This real-world experience with prolonged use of a digestive enzyme cartridge with EN demonstrated improved clinical outcomes and a reduction in GI symptoms in patients with CF.

PMID:35199869 | DOI:10.1002/ncp.10831

Autoimmunity. 2022 Mar;55(2):109-117. doi: 10.1080/08916934.2021.2021193. Epub 2022 Jan 4.

ABSTRACT

Cystic fibrosis (CF) lung disease begins early in childhood and is characterized by neutrophilic inflammation of the airways. Neutrophil extracellular traps (NETs) represent one mechanism by which neutrophils contribute to lung damage. The enzyme peptidylarginine deiminase 4 (PAD4) is required for NET formation. Our overall concept is that NET formation delivers PAD4 outside the neutrophil resulting in autoantibody generation, and this autoimmunity may be a novel mechanism contributing to CF lung disease progression. The aim of this study was to investigate clinical predictors of serum anti-PAD4 autoantibody (PAD4 Ab) levels in CF subjects with a wide range of ages from early childhood through middle age. We measured PAD4 Ab levels in sera from 104 CF subjects. PAD4 Abs were detectable among CF children as young as one year of age and elevated compared to paediatric healthy controls. PAD4 Ab levels increased significantly with age (r = 0.584, p <.001) and correlated with lower lung function (r = -0.481, n = 99, p <.001). PAD4 Abs were elevated in subjects with chronic Pseudomonas aeruginosa airways infection (p <.001), but not with other key clinical CF co-variates including sex, CFTR genotype, sweat chloride, pancreatic enzyme use, nutritional status, recent pulmonary exacerbations, Staphylococcus aureus, or CF-related diabetes. PAD4 Ab levels were also correlated with serum anti-double-stranded DNA IgA autoantibodies, which have similarly been shown to be elevated in CF subjects and associated with lung damage. In multivariable analysis, age and lung function remained correlated with PAD4 Ab levels. In summary, we describe novel findings of anti-PAD4 autoantibodies in CF that are present early in childhood, increase over time with age, and correlate with lung disease severity. Autoimmunity to antigens extruded by NETs appears to be an early event in CF lung disease, and airway autoimmunity related to NET formation is a potential mechanism of lung disease progression in CF.HighlightsSerum anti-PAD4 autoantibodies are detected in paediatric CF serum and are elevated compared to healthy paediatric controlsAnti-PAD4 autoantibodies increase with ageAnti-PAD4 autoantibodies correlate with lower lung function, Pseudomonas aeruginosa airway infection and anti-dsDNA IgA autoantibodies, but not with other key clinical CF co-variatesAge and lung function remain correlated with anti-PAD4 autoantibodies in multivariable analysis.

PMID:35199621 | DOI:10.1080/08916934.2021.2021193

Infect Prev Pract. 2022 Jan 21;4(1):100202. doi: 10.1016/j.infpip.2022.100202. eCollection 2022 Mar.

ABSTRACT

BACKGROUND: This report describes recurrent A. xylosoxidans bloodstream and PICC (peripherally-inserted central catheter) line infection in an immunocompromised patient.

PRESENTATION OF CASE: A 64-year-old female with acute promyelocytic leukaemia presented during a non-neutropenic febrile episode, and A. xylosoxidans was isolated from multiple PICC and peripheral blood cultures, and from the tip of the line on removal. The patient was treated with meropenem and a new PICC line was inserted after sterile blood cultures. Six weeks later, she represented with A. xylosoxidans from multiple cultures from the line. She was treated with piperacillin-tazobactam and the line was removed. There was no evidence of deep-seated infection. Further discussion revealed that the patient was using a sponge to clean, and a sleeve to cover her PICC-line while bathing. A. xylosoxidans was cultured from both the sponge and the swab. Whole Genome Sequencing performed on two blood culture isolated and both environmental isolates confirmed all four isolates were indistinguishable. The patient was advised not to use the sponge/sleeve in future and we have incorporated specific advice in this regard into our patient information.

DISCUSSION: Achromobacter xylosoxidans is an aerobic, non-lactose fermenting gram-negative bacillus usually considered an opportunistic pathogen. It is associated with infection in immunocompromised patients, and is an emerging pathogen in catheter-related infections, sometimes associated with contaminated water.

CONCLUSION: This case of recurrent A. xylosoxidans line infection highlights diagnostic and management challenges associated with catheter-related infections. Treatment is challenging because of intrinsic and acquired resistance mechanisms. Empiric treatment with anti-pseudomonal penicillins or carbapenems with line removal is typically required.

PMID:35198965 | PMC:PMC8844297 | DOI:10.1016/j.infpip.2022.100202

Eur Respir Rev. 2022 Feb 22;31(163):210241. doi: 10.1183/16000617.0241-2021. Print 2022 Mar 31.

ABSTRACT

Neutrophilic inflammation has a key role in the pathophysiology of multiple chronic lung diseases. The formation of neutrophil extracellular traps (NETs) has emerged as a key mechanism of disease in neutrophilic lung diseases including asthma, COPD, cystic fibrosis and, most recently, bronchiectasis. NETs are large, web-like structures composed of DNA and anti-microbial proteins that are able to bind pathogens, prevent microbial dissemination and degrade bacterial virulence factors. The release of excess concentrations of proteases, antimicrobial proteins, DNA and histones, however, also leads to tissue damage, impaired mucociliary clearance, impaired bacterial killing and increased inflammation. A number of studies have linked airway NET formation with greater disease severity, increased exacerbations and overall worse disease outcomes across the spectrum of airway diseases. Treating neutrophilic inflammation has been challenging in chronic lung disease because of the delicate balance between reducing inflammation and increasing the risk of infections through immunosuppression. Novel approaches to suppressing NET formation or the associated inflammation are in development and represent an important therapeutic target. This review will discuss the relationship between NETs and the pathophysiology of cystic fibrosis, asthma, COPD and bronchiectasis, and explore the current and future development of NET-targeting therapies.

PMID:35197267 | DOI:10.1183/16000617.0241-2021