Pharmaceuticals (Basel). 2021 Sep 15;14(9):928. doi: 10.3390/ph14090928.

ABSTRACT

Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations, affecting approximately 80,000 people worldwide. CF is a complex multi-organ monogenic autosomal recessive disorder caused by a mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the discovery of the CFTR gene in 1989, more than 2000 mutations have been identified so far and about 240 can cause CF. Until recently, the treatment for CF was aimed to prevent and manage the manifestations of CFTR dysfunction, primarily recurrent pulmonary infections and pancreatic exocrine failure. Over the past few decades, the therapeutic approach to CF has been revolutionized by the development of a new class of small molecules called CFTR modulators that target specific defects caused by mutations in the CFTR gene. CFTR modulators have been shown to change profoundly the clinical course of the CF, leading to meaningful improvements in the lives of a large proportion of people of CF heterozygous for F508del, especially if started in young children. Further studies are needed to extend the use of triple CFTR modulation therapy also for young children in order to prevent the irreversible effects of the disease and for patients with very rare mutations with a personalized approach to treatment.

PMID:34577628 | DOI:10.3390/ph14090928

Microorganisms. 2021 Sep 21;9(9):2001. doi: 10.3390/microorganisms9092001.

ABSTRACT

A Pseudomonas aeruginosa (P. aeruginosa) airway infection is one of the predominant causes contributing to the high morbidity and mortality rates in cystic fibrosis (CF) patients. The emergence of antibiotic resistant P. aeruginosa strains has led to an urgent need for new therapeutic approaches. Bacteriophages (phages) are viruses that can infect and lyse specific bacteria, providing a potential alternative approach in targeting antibiotic-resistant strains. We aim to isolate and characterise novel P. aeruginosa phages for combination in a cocktail to kill P. aeruginosa. One particular phage, PA4, could lyse 14/20 clinical isolates as observed through spot assays. This phage could significantly reduce the growth of bacteria in vitro, as determined through planktonic adsorption and inhibition assays as well as crystal violet- and LIVE/DEAD-stained biofilm assays. A morphological and genomic analysis revealed that PA4 belongs to the Myoviridae family and contained 66,450 bp. The broad infectivity profile, good stability in various pH and temperature conditions, lytic ability and the absence of the absences of antibiotic resistance, toxic and lysogenic genes suggest that PA4 is a good candidate for clinical grade use. Overall, phage therapy represents a promising alternative treatment option to antibiotics when treating a P. aeruginosa infection.

PMID:34576896 | DOI:10.3390/microorganisms9092001

Microorganisms. 2021 Sep 3;9(9):1874. doi: 10.3390/microorganisms9091874.

ABSTRACT

The ultimate aim of any antimicrobial treatment is a better infection outcome for the patient. Here, we review the current state of treatment for bacterial infections in cystic fibrosis (CF) lung while also investigating potential new treatments being developed to see how they may change the dynamics of antimicrobial therapy. Treatment with antibiotics coupled with regular physical therapy has been shown to reduce exacerbations and may eradicate some strains. Therapies such as hypertonic saline and inhaled PulmozymeTM (DNase-I) improve mucus clearance, while modifier drugs, singly and more successfully in combination, re-open certain mutant forms of the cystic fibrosis transmembrane conductance regulator (CFTR) to enable ion passage. No current method, however, completely eradicates infection, mainly due to bacterial survival within biofilm aggregates. Lung transplants increase lifespan, but reinfection is a continuing problem. CFTR modifiers normalise ion transport for the affected mutations, but there is conflicting evidence on bacterial clearance. Emerging treatments combine antibiotics with novel compounds including quorum-sensing inhibitors, antioxidants, and enzymes, or with bacteriophages, aiming to disrupt the biofilm matrix and improve antibiotic access. Other treatments involve bacteriophages that target, infect and kill bacteria. These novel therapeutic approaches are showing good promise in vitro, and a few have made the leap to in vivo testing.

PMID:34576767 | DOI:10.3390/microorganisms9091874

Microorganisms. 2021 Aug 31;9(9):1846. doi: 10.3390/microorganisms9091846.

ABSTRACT

Despite the considerable progress made in recent years, our understanding of the human immune response to microbial biofilms is still poor. The aim of the present study was to compare the in vitro response of human peripheral blood mononuclear cells (PBMC) to biofilms and planktonic cells of Pseudomonas aeruginosa and Staphylococcus epidermidis, two bacterial species particularly relevant in patients with cystic fibrosis or undergoing endovascular catheterization, respectively. PBMC isolated from healthy donors were co-cultured with 24 h-old biofilms or with exponentially growing cells of both species. Following 24 h of co-culture, the expression of early activation markers and the levels of cytokines in the culture supernatants were assessed by flow cytometry, while biofilm biomass and architecture were evaluated by crystal violet staining, CFU count, and confocal microscopy. Around 20% of PBMC was activated in response to both biofilms and planktonic cells of P. aeruginosa. In contrast, planktonic cells of S. epidermidis induced a statistically higher degree of activation than their biofilm counterpart (25% versus 15%; p < 0.01). P. aeruginosa biofilms stimulated pro-inflammatory (TNF-α, IL-1β, IFN-γ, and IL-6) and anti-inflammatory (IL-10) cytokine production at statistically significant levels higher than its planktonic counterpart, while an opposite trend was observed with S. epidermidis. Differences in the architecture of the biofilms and in the number of PBMC infiltrating the biofilms between the two bacterial species may at least partially explain these findings. Collectively, the results obtained highlighted marked differences in the host-cell response depending on the species and the mode of growth (biofilms versus planktonic cultures), allowing speculations on the different strategies adopted by P. aeruginosa and S. epidermidis to persist in the host during the course of chronic infections.

PMID:34576742 | DOI:10.3390/microorganisms9091846

Microorganisms. 2021 Aug 25;9(9):1809. doi: 10.3390/microorganisms9091809.

ABSTRACT

Recalcitrant chronic infections of implanted medical devices are often linked to the presence of biofilms. The prevention and treatment of medical device-associated infections is a major source of antibiotic use and driver of antimicrobial resistance globally. Lowering the incidence of infection in patients that receive implanted medical devices could therefore significantly improve antibiotic stewardship and reduce patient morbidity. Here we determined if modifying the design of an implantable medical device to reduce bacterial attachment, impacted the incidence of device-associated infections in clinical practice. Since the 1980s cochlear implants have provided long-term treatment of sensorineural hearing deficiency in hundreds of thousands of patients world-wide. Nonetheless, a relatively small number of devices are surgically explanted each year due to unresolvable infections. Features associated with the accumulation of bacteria on the Cochlear™ Nucleus® CI24RE™ model of cochlear implant devices were identified using both in vitro bacterial attachment assays and examination of explanted devices. Macro-scale design modifications that reduced bacterial attachment in vitro were incorporated into the design of the CI500™ and Profile™ series of Nucleus implant. Analyses of mandatory post-market vigilance data of 198,757 CI24RE and 123,084 CI500/Profile series implantation surgeries revealed that these design modifications correlated with significantly reduced infection rates. This study demonstrates that a design-centric approach aimed at mitigating bacterial attachment was a simple, and effective means of reducing infections associated with Cochlear Nucleus devices. This approach is likely to be applicable to improving the designs of other implantable medical devices to reduce device-associated infections.

PMID:34576704 | DOI:10.3390/microorganisms9091809

Int J Mol Sci. 2021 Sep 11;22(18):9834. doi: 10.3390/ijms22189834.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.

PMID:34575997 | DOI:10.3390/ijms22189834

J Fungi (Basel). 2021 Aug 28;7(9):708. doi: 10.3390/jof7090708.

ABSTRACT

The occurrence of pulmonary fungal superinfection due to Aspergillus spp. in patients with COVID-19 is a well-described complication associated with significant morbidity and mortality. This can be related to a directed effect of the virus and to the immunosuppressive role of the therapies administered for the disease. Here, we describe the first case of pulmonary infection due to Mucorales occurring in a patient with a concomitant diagnosis of COVID-19-associated pulmonary aspergillosis.

PMID:34575746 | DOI:10.3390/jof7090708

J Pers Med. 2021 Aug 28;11(9):859. doi: 10.3390/jpm11090859.

ABSTRACT

OBJECTIVES: Immune regulation seems to be altered in cystic fibrosis (CF), thus potentially predisposing patients to developing autoimmune diseases (AID). In this meta-analysis, we aimed to evaluate the prevalence of celiac disease (CeD) among CF patients as by far the most commonly reported autoimmune disease in this population and, secondly, to review the observations on other, less frequently studied autoimmune diseases.

METHODS: We conducted a systematic literature search for studies that discussed AIDs among CF patients. Following standard selection and data collection, we calculated pooled raw prevalence with 95% confidence intervals (CI) for biopsy-verified CeD and seropositivity.

RESULTS: Out of the 21 eligible studies, 15 reported on CeD. Pooled prevalence of biopsy-verified CeD was 1.8% (CI 1.1-2.7%) according to a homogeneous dataset from six prospective, consecutive screening studies, while it proved to be 2.3% (CI 1.1-4.7%) according to a heterogeneous dataset from the other studies. Tissue transglutaminase IgA positivity was detected in 4.5% of CF cases (CI 2.8-6.9%), while tissue transglutaminase IgA-endomysial antibody IgA double positivity was found in 2.4% of them (CI 1.5-3.9%). Findings on other AIDs were strongly limited.

CONCLUSIONS: The pooled prevalence of CeD in CF seemed to be more than twice as high compared to the global prevalence; therefore, routine screening of CeD could be considered in CF.

PMID:34575636 | DOI:10.3390/jpm11090859

Diagnostics (Basel). 2021 Aug 25;11(9):1540. doi: 10.3390/diagnostics11091540.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare genetic disease characterized by dyskinetic cilia. Respiratory symptoms usually start at birth. The lack of diagnostic gold standard tests is challenging, as PCD diagnostics requires different methods with high expertise. We founded PCD-UNIBE as the first comprehensive PCD diagnostic center in Switzerland. Our diagnostic approach includes nasal brushing and cell culture with analysis of ciliary motility via high-speed-videomicroscopy (HSVM) and immunofluorescence labeling (IF) of structural proteins. Selected patients undergo electron microscopy (TEM) of ciliary ultrastructure and genetics. We report here on the first 100 patients assessed by PCD-UNIBE. All patients received HSVM fresh, IF, and cell culture (success rate of 90%). We repeated the HSVM with cell cultures and conducted TEM in 30 patients and genetics in 31 patients. Results from cell cultures were much clearer compared to fresh samples. For 80 patients, we found no evidence of PCD, 17 were diagnosed with PCD, two remained inconclusive, and one case is ongoing. HSVM was diagnostic in 12, IF in 14, TEM in five and genetics in 11 cases. None of the methods was able to diagnose all 17 PCD cases, highlighting that a comprehensive approach is essential for an accurate diagnosis of PCD.

PMID:34573882 | DOI:10.3390/diagnostics11091540

Genes (Basel). 2021 Aug 31;12(9):1372. doi: 10.3390/genes12091372.

ABSTRACT

Inflammatory bowel diseases (IBDs) are chronic relapsing inflammatory conditions of the gastrointestinal tract, encompassing Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBD-U). They are currently considered as systemic disorders determined by a set of genetic predispositions, individual susceptibility and environmental triggers, potentially able to involve other organs and systems than the gastrointestinal tract. A large number of patients experiences one or more extraintestinal manifestations (EIMs), whose sites affected are mostly represented by the joints, skin, bones, liver, eyes, and pancreas. Pancreatic abnormalities are not uncommon and are often underestimated, encompassing acute and chronic pancreatitis, autoimmune pancreatitis, exocrine pancreatic insufficiency and asymptomatic elevation of pancreatic enzymes. In most cases they are the result of environmental triggers. However, several genetic polymorphisms may play a role as precipitating factors or contributing to a more severe course. The aim of this paper is to provide an updated overview on the available evidence concerning the etiology, pathogenesis and clinical presentation of pancreatic diseases in IBD pediatric patients.

PMID:34573354 | DOI:10.3390/genes12091372

Antioxidants (Basel). 2021 Sep 3;10(9):1412. doi: 10.3390/antiox10091412.

ABSTRACT

Chronic rhinosinusitis (CRS) is a characteristic feature of cystic fibrosis (CF) multiorgan disease and develops early in the life of patients with CF. The study aimed to correlate the inflammatory markers and the presence of structural abnormalities detected by MRI in the paranasal sinuses of patients with CF. Methods: Nasal lavage and MRI of the paranasal sinuses was performed in a cohort of 30 CF patients (median age 14 y; range 7-20 y). Morphological abnormalities characteristic of CF were evaluated with a dedicated CRS MRI scoring system and correlated with different inflammation parameters measured in nasal lavage. Inflammation of the paranasal sinuses was positively associated with structural abnormalities in MRI. The concentration of the pro-inflammatory markers neutrophil elastase (NE) and the neutrophil elastase/alpha1-antitrypsin (NE/A1AT) complex correlated significantly with CRS-MRI sum score (p < 0.05, r = 0.416 and p < 0.05, r = 0.366, respectively). S. aureus infection was associated with the increased pro-inflammatory cytokine activity of IL-6 and IL-8, and increased levels of NE/A1AT complex in our patients (p < 0.05, respectively). CRS-MRI sum score and individual sinus MRI scores were positively associated with inflammatory activity as a sign of CRS pathology present in CF.

PMID:34573044 | DOI:10.3390/antiox10091412

Antibiotics (Basel). 2021 Aug 26;10(9):1043. doi: 10.3390/antibiotics10091043.

ABSTRACT

Vicious cycles of chronic airway obstruction, lung infections with Pseudomonas aeruginosa, and neutrophil-dominated inflammation contribute to morbidity and mortality in cystic fibrosis (CF) patients. Rhesus theta defensin-1 (RTD-1) is an antimicrobial macrocyclic peptide with immunomodulatory properties. Our objective was to investigate the anti-inflammatory effect of RTD-1 in a murine model of chronic P. aeruginosa lung infection. Mice received nebulized RTD-1 daily for 6 days. Bacterial burden, leukocyte counts, and cytokine concentrations were evaluated. Microarray analysis was performed on bronchoalveolar lavage fluid (BALF) cells and lung tissue homogenates. In vitro effects of RTD-1 in THP-1 cells were assessed using quantitative reverse transcription PCR, enzyme-linked immunosorbent assays, immunoblots, confocal microscopy, enzymatic activity assays, and NF-κB-reporter assays. RTD-1 significantly reduced lung white blood cell counts on days 3 (-54.95%; p = 0.0003) and 7 (-31.71%; p = 0.0097). Microarray analysis of lung tissue homogenates and BALF cells revealed that RTD-1 significantly reduced proinflammatory gene expression, particularly inflammasome-related genes (nod-like receptor protein 3, Mediterranean fever gene, interleukin (IL)-1α, and IL-1β) relative to the control. In vitro studies demonstrated NF-κB activation was reduced two-fold (p ≤ 0.0001) by RTD-1 treatment. Immunoblots revealed that RTD-1 treatment inhibited proIL-1β biosynthesis. Additionally, RTD-1 treatment was associated with a reduction in caspase-1 activation (FC = -1.79; p = 0.0052). RTD-1 exhibited potent anti-inflammatory activity in chronically infected mice. Importantly, RTD-1 inhibits inflammasome activity, which is possibly a downstream effect of NF-κB modulation. These findings support that this immunomodulatory peptide may be a promising therapeutic for CF-associated lung disease.

PMID:34572625 | DOI:10.3390/antibiotics10091043

Biomedicines. 2021 Aug 31;9(9):1121. doi: 10.3390/biomedicines9091121.

ABSTRACT

The role of S1P in Cystic Fibrosis (CF) has been investigated since 2001, when it was first described that the CFTR channel regulates the inward transport of S1P. From then on, various studies have associated F508del CFTR, the most frequent mutation in CF patients, with altered S1P expression in tissue and plasma. We found that human bronchial epithelial immortalized and primary cells from CF patients express more S1P than the control cells, as evidenced by mass spectrometry analysis. S1P accumulation relies on two- to four-fold transcriptional up-regulation of SphK1 and simultaneous halving of SGPL1 in CF vs. control cells. The reduction of SGPL1 transcription protects S1P from irreversible degradation, but the excessive accumulation is partially prevented by the action of the two phosphatases that are up-regulated compared to control cells. For the first time in CF, we describe that Spns2, a non-ATP dependent transporter that normally extrudes S1P out of the cells, shows deficient transcriptional and protein expression, thus impairing S1P accrual dissipation. The in vitro data on CF human bronchial epithelia correlates with the impaired expression of Spns2 observed in CF human lung biopsies compared to healthy control.

PMID:34572307 | DOI:10.3390/biomedicines9091121

Children (Basel). 2021 Sep 13;8(9):802. doi: 10.3390/children8090802.

ABSTRACT

Children with End Stage Lung Disease (ESLD) are part of the growing population of individuals with life-limiting conditions of childhood. These patients present with a diverse set of pulmonary, cardiovascular, neuromuscular, and developmental conditions. This paper first examines five cases of children with cystic fibrosis, bronchopulmonary dysplasia, neuromuscular disease, pulmonary hypertension, and lung transplantation from Texas Children's Hospital. We discuss the expected clinical course of each condition, then review the integration of primary and specialized palliative care into the management of each diagnosis. This paper then reviews the management of two children with end staged lung disease at Hospital Civil de Guadalajara, providing an additional perspective for approaching palliative care in low-income countries.

PMID:34572234 | DOI:10.3390/children8090802

Pharmacol Res. 2021 Sep 24:105915. doi: 10.1016/j.phrs.2021.105915. Online ahead of print.

ABSTRACT

If short acting β2-agonists and muscarinic antagonists (SABA/SAMA) may have proarrhythmic effects during acute COPD exacerbations (AECOPD) is still unknown. The primary objective of the study was to investigate the incidence of new onset arrhythmias in hospitalized patients shifted to SABA/SAMA during an AECOPD compared with continuing chronic inhaled therapy. Secondary objectives were to assess the clinical characteristics of patients shifted to SABA/SAMA and risk factors for arrhythmia. This was a retrospective, observational, study enrolling consecutive patients hospitalized with an AECOPD. Incidence of arrhythmias was obtained reviewing digital records. Patients with chronic arrhythmias or home-treated with SABA/SAMA were excluded. 235 patients (63.8% males) were included, and 10/182 patients shifted to SABA/SAMA experienced arrhythmias, while no events were observed in patients on chronic inhaled therapy (p=0.122). Shifted patients had a more severe AECOPD and history of paroxysmal atrial fibrillation was an independent risk factor for arrhythmia (OR 14.010,IC95%:2.983-65.800;p=0.001). In conclusion, shifting patients to SABA/SAMA appears not to increase the risk for arrhythmia during severe AECOPD. However, the pharmacological approach in patients with a history of paroxysmal arrhythmia should be carefully evaluated and monitored.

PMID:34571145 | DOI:10.1016/j.phrs.2021.105915

Pulm Pharmacol Ther. 2021 Sep 24:102078. doi: 10.1016/j.pupt.2021.102078. Online ahead of print.

ABSTRACT

Actinomycosis is a rare chronic infection triggered by species of Actinomyces. Although thoracic involvement represents about 15% of human actinomycosis, its true incidence may be underestimated, not only because of its challenging diagnosis, but also because it can be treated unintentionally with antibiotics for other diseases. In this sense, this work aims at providing an up-to-date literature review on thoracic actinomycoses, with particular emphasis on presentation, diagnostic and therapeutic approaches, also paving upcoming clinical interventions from findings obtained of a presentation of a case series. Data discussed here clearly denote the rarity, non-specificity and heterogeneity of clinical presentations of the disease, reinforcing the need for individualized therapeutic approaches.

PMID:34571094 | DOI:10.1016/j.pupt.2021.102078

Lancet Respir Med. 2021 Sep 24:S2213-2600(21)00277-0. doi: 10.1016/S2213-2600(21)00277-0. Online ahead of print.

ABSTRACT

Bronchiectasis refers to both a clinical disease and a radiological appearance that has multiple causes and can be associated with a range of conditions. Disease heterogeneity and the absence of standardised definitions have hampered clinical trials of treatments for bronchiectasis and are important challenges in clinical practice. In view of the need for new therapies for non-cystic fibrosis bronchiectasis to reduce the disease burden, we established an international taskforce of experts to develop recommendations and definitions for clinically significant bronchiectasis in adults to facilitate the standardisation of terminology for clinical trials. Systematic reviews were used to inform discussions, and Delphi processes were used to achieve expert consensus. We prioritised criteria for the radiological diagnosis of bronchiectasis and suggest recommendations on the use and central reading of chest CT scans to confirm the presence of bronchiectasis for clinical trials. Furthermore, we developed a set of consensus statements concerning the definitions of clinical bronchiectasis and its specific signs and symptoms, as well as definitions for chronic bacterial infection and sustained culture conversion. The diagnosis of clinically significant bronchiectasis requires both clinical and radiological criteria, and these expert recommendations and proposals should help to optimise patient recruitment into clinical trials and allow reliable comparisons of treatment effects among different interventions for bronchiectasis. Our consensus proposals should also provide a framework for future research to further refine definitions and establish definitive guidance on the diagnosis of bronchiectasis.

PMID:34570994 | DOI:10.1016/S2213-2600(21)00277-0

Pediatr Pulmonol. 2021 Sep 27. doi: 10.1002/ppul.25703. Online ahead of print.

ABSTRACT

With improved therapies, people with cystic fibrosis are living longer and healthier lives and increasingly have questions surrounding their sexual and reproductive health. This article will summarize the important issues of which providers should be aware during the lifespan of people with cystic fibrosis, including puberty, adulthood, and menopause. A wide range of sexual and reproductive health topics are addressed such as puberty, transgender and gender non-binary identities, contraception, sexually transmitted infections, hypogonadism, sexual functioning, cyclical hemoptysis, and urinary incontinence. We discuss gaps in knowledge and current evidence as well as management strategies to optimize care. Our goal is to support providers to enable them to give comprehensive care throughout the lifespan of people with cystic fibrosis. This article is protected by copyright. All rights reserved.

PMID:34570960 | DOI:10.1002/ppul.25703

Immun Inflamm Dis. 2021 Sep 27. doi: 10.1002/iid3.540. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well-recognised problem but other allergic conditions are less well documented in CF.

OBJECTIVE: To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA.

METHODS: A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features.

RESULTS: The cohort included 37 children with median age of 9 years (interquartile range: 6-12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross-sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection.

PMID:34570951 | DOI:10.1002/iid3.540

ANZ J Surg. 2021 Sep 27. doi: 10.1111/ans.17238. Online ahead of print.

NO ABSTRACT

PMID:34570398 | DOI:10.1111/ans.17238