mSphere. 2021 Jun 23:e0035821. doi: 10.1128/mSphere.00358-21. Online ahead of print.

ABSTRACT

Staphylococcus aureus is one of the most common pathogens isolated from the airways of cystic fibrosis (CF) patients and often persists for extended periods. There is limited knowledge about the diversity of S. aureus in CF. We hypothesized that increased diversity of S. aureus would impact CF lung disease. Therefore, we conducted a 1-year observational prospective study with 14 patients with long-term S. aureus infection. From every sputum, 40 S. aureus isolates were chosen and characterized in terms of phenotypic appearance (size, hemolysis, mucoidy, and pigmentation), important virulence traits such as nuclease activity, biofilm formation, and molecular typing by spa sequence typing. Data about coinfection with Pseudomonas aeruginosa and clinical parameters such as lung function, exacerbation, and inflammatory markers in blood (C-reactive protein [CRP], interleukin 6 [IL-6], and S100A8/9 [calprotectin]) were collected. From 58 visits of 14 patients, 2,319 S. aureus isolates were distinguished into 32 phenotypes (PTs) and 50 spa types. The Simpson diversity index (SDI) was used to calculate the phenotypic and genotypic diversity, revealing a high diversity of PTs ranging from 0.19 to 0.87 among patients, while the diversity of spa types of isolates was less pronounced. The SDI of PTs was positively associated with P. aeruginosa coinfection and inflammatory parameters, with IL-6 being the most sensitive parameter. Also, coinfection with P. aeruginosa was associated with mucoid S. aureus and S. aureus with high nuclease activity. Our analyses showed that in CF patients with long-term S. aureus airway infection, a highly diverse and dynamic S. aureus population was present and associated with P. aeruginosa coinfection and inflammation. IMPORTANCE Staphylococcus aureus can persist for extended periods in the airways of people with cystic fibrosis (CF) in spite of antibiotic therapy and high numbers of neutrophils, which fail to eradicate this pathogen. Therefore, S. aureus needs to adapt to this hostile niche. There is only limited knowledge about the diversity of S. aureus in respiratory specimens. We conducted a 1-year prospective study with 14 patients with long-term S. aureus infection and investigated 40 S. aureus isolates from every sputum in terms of phenotypic appearance, nuclease activity, biofilm formation, and molecular typing. Data about coinfection with Pseudomonas aeruginosa and clinical parameters such as lung function, exacerbation, and inflammatory markers in blood were collected. Thirty-two phenotypes (PTs) and 50 spa types were distinguished. Our analyses revealed that in CF patients with long-term S. aureus airway infection, a highly diverse and dynamic S. aureus population was associated with P. aeruginosa coinfection and inflammation.

PMID:34160233 | DOI:10.1128/mSphere.00358-21

Cochrane Database Syst Rev. 2021 Jun 23;6:CD002007. doi: 10.1002/14651858.CD002007.pub5.

ABSTRACT

BACKGROUND: The choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. This is an update of a previously published review.

OBJECTIVES: To assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with CF.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Group's Trials Register: 07 October 2020. We also searched online trials registries on 16 November 2020.

SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF.

DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We assessed the certainty of the data using GRADE.

MAIN RESULTS: We identified 59 trials, of which we included eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination. There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor and the certainty of the evidence ranged from low to moderate. The review did not find any differences between monotherapy and combination therapy in either the short term or in the long term for the outcomes of different lung function measures, bacteriological outcome measures, need for additional treatment, adverse effects, quality of life or symptom scores.

AUTHORS' CONCLUSIONS: The results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow-up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials.

PMID:34159577 | DOI:10.1002/14651858.CD002007.pub5

Eur J Pediatr. 2021 Jun 23. doi: 10.1007/s00431-021-04161-5. Online ahead of print.

ABSTRACT

Plastic bronchitis (PB) is a rare and life-threatening complication encountered in several disease states that leads to airway obstruction by branching casts. PB is most often reported in children with cyanotic congenital heart disease where recurrence is common, and mortality is high. There is limited data on optimal management strategies or recurrence of non-structural heart disease-related PB in children. We describe the clinical features, management, and outcomes in our cohort of children with non-structural heart disease-related PB. Among the 12 identified patients, asthma was the most common (67%) diagnosis. Ventilatory requirements ranged from room air to one patient who required extracorporeal membrane oxygenation (ECMO). Most patients (92%) required bronchoscopy, and cryotherapy was successfully utilized in two patients to relieve refractory obstructive airway casts. All patients received chest physiotherapy, and 11 patients were treated with two or more medications. There was one mortality despite ECMO, and one-third had recurrent PB, all of whom had asthma.Conclusion: Asthma is a risk factor for recurrent PB. Bronchoscopic interventions including cryotherapy are safe and effective treatment options in patients with refractory PB. What is Known: • Plastic bronchitis is a rare but life-threatening cause of airway obstruction caused by branching casts that are generally reported in patients with congenital heart disease. What is New: • In children without structural heart disease, asthma is a risk factor for recurrent plastic bronchitis. Cryotherapy via bronchoscopy is a safe and effective intervention in patients with refractory plastic bronchitis.

PMID:34159443 | DOI:10.1007/s00431-021-04161-5

Sci Rep. 2021 Jun 22;11(1):13037. doi: 10.1038/s41598-021-91932-7.

ABSTRACT

Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous metaplasia (MM). Many molecular pathways triggering MM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagy pathway is required for resolution of MM by eliminating excess non-secreted intracellular mucin granules. We found increased intracellular levels of mucins Muc5ac and Muc5b in mice deficient in autophagy regulatory protein, Atg16L1, and that this difference was not due to defects in the known baseline or stimulated mucin secretion pathways. Instead, we found that, in mucous secretory cells, Lc3/Lamp1 vesicles colocalized with mucin granules particularly adjacent to the nucleus, suggesting that some granules were being eliminated in the autophagy pathway rather than secreted. Using a mouse model of MM resolution, we found increased lysosomal proteolytic activity that peaked in the days after mucin production began to decline. In purified lysosomal fractions, Atg16L1-deficient mice had reduced proteolytic degradation of Lc3 and Sqstm1 and persistent accumulation of mucin granules associated with impaired resolution of mucous metaplasia. In normal and COPD derived human airway epithelial cells (AECs), activation of autophagy by mTOR inhibition led to a reduction of intracellular mucin granules in AECs. Our findings indicate that during peak and resolution phases of MM, autophagy activity rather than secretion is required for elimination of some remaining mucin granules. Manipulation of autophagy activation offers a therapeutic target to speed resolution of MM in airway disease exacerbations.

PMID:34158522 | DOI:10.1038/s41598-021-91932-7

Int J Antimicrob Agents. 2021 Jun 19:106381. doi: 10.1016/j.ijantimicag.2021.106381. Online ahead of print.

ABSTRACT

Cystic fibrosis affects several organs, predisposing patients to severe bacterial respiratory infections, including those caused by methicillin-resistant Staphylococcus aureus. Cystic fibrosis is also associated with a wide spectrum of pathological changes that can significantly affect the absorption, distribution, metabolism and/or elimination of several drugs, including antibacterial agents. Awareness of the pharmacokinetic derangements in patients with cystic fibrosis is, therefore, mandatory for the optimization of antibiotic therapy. This review discusses the basic principles of pharmacokinetics and the pathophysiology of the pharmacokinetics-changes associated with cystic fibrosis, providing also an update of available data for the most widely used antibiotics. Indeed, evidence accumulated in the last few years has clearly shown that a significant amount of cystic fibrosis patients treated with conventional dosing schemes have sub-therapeutic antibiotic concentrations, increasing their risk of therapeutic failure and/or the emergence of resistant pathogens. Some proposals to optimize antibiotic therapies in this clinical setting based on therapeutic drug monitoring are also discussed.

PMID:34157401 | DOI:10.1016/j.ijantimicag.2021.106381

Respir Physiol Neurobiol. 2021 Jun 19:103722. doi: 10.1016/j.resp.2021.103722. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is characterized by small airway disease; but central airways may also be affected. We hypothesized that airway resistance estimated from computational fluid dynamic (CFD) methodology in infants with CF was higher than controls and that early airway inflammation in infants with CF is associated with airway resistance. Central airway models with a median of 51 bronchial outlets per model (interquartile range 46,56) were created from chest computed tomography scans of 18 infants with CF and 7 controls. Steady state airflow into the trachea was simulated to estimate central airway resistance in each model. Airway resistance was increased in the full airway models of infants with CF versus controls and in models trimmed to 33 bronchi. Airway resistance was associated with markers of inflammation in bronchoalveolar lavage fluid obtained approximately 8 months earlier but not with markers obtained at the same time. In conclusion, airway resistance estimated by CFD modeling is increased in infants with CF compared to controls and may be related to early airway inflammation.

PMID:34157384 | DOI:10.1016/j.resp.2021.103722

Radiology. 2021 Jun 22:204052. doi: 10.1148/radiol.2021204052. Online ahead of print.

ABSTRACT

Background Chronic obstructive pulmonary disease (COPD) and bronchiectasis can overlap and share pathologic features, such as small airway disease (SAD). Whether the presence of SAD and emphysema in smokers with CT-derived bronchiectasis is associated with exacerbations is unknown. Purpose To assess whether SAD and emphysema in smokers with CT-derived bronchiectasis are associated with future exacerbations. Materials and Methods SAD and emphysema were quantified using the parametric response map method in former and current heavy smokers with and without bronchiectasis at CT from the COPDGene Study (from July 2009 to July 2018). Exacerbations were prospectively assessed through biannual follow-up. An exacerbation was defined as an increase in or new onset of respiratory symptoms treated with antibiotics and/or corticosteroids. Severe exacerbations were defined as those that required hospitalization. The association of a high burden of SAD (≥15.6%) and high burden of emphysema (≥5%) at CT with exacerbations was assessed with generalized linear mixed models. Results Of 737 participants, 387 (median age, 64 years [interquartile range, 58-71 years]; 223 women) had CT-derived bronchiectasis. During a 9-year follow-up, after adjustment for age, sex, race, body mass index, current smoking status, pack-years, exacerbations before study entry, forced expiratory volume in 1 second, or FEV1, and bronchiectasis severity CT score, high burden of SAD and high burden of emphysema were associated with a higher number of exacerbations per year (relative risk [RR], 1.89 [95% CI: 1.54, 2.33] and 1.37 [95% CI: 1.13, 1.66], respectively; P ≤ .001 for both). Results were comparable among participants with bronchiectasis meeting criteria for COPD (n = 197) (RR, 1.67 [95% CI: 1.23, 2.27] for high burden of SAD and 1.51 [95% CI: 1.20, 1.91] for high burden of emphysema; P ≤ .001 for both). Conclusion In smokers with CT-derived bronchiectasis and chronic obstructive pulmonary disease, structural damage to lung parenchyma and small airways was associated with a higher number of exacerbations per year. Clinical trial registration no. NCT00608764 © RSNA, 2021.

PMID:34156303 | DOI:10.1148/radiol.2021204052

mSystems. 2021 Jun 22:e0019321. doi: 10.1128/mSystems.00193-21. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (Pa) is a major bacterial pathogen responsible for chronic lung infections in cystic fibrosis patients. Recent work has implicated Pf bacteriophages, nonlytic filamentous viruses produced by Pa, in the chronicity and severity of Pa infections. Pf phages act as structural elements in Pa biofilms and sequester aerosolized antibiotics, thereby contributing to antibiotic tolerance. Consistent with a selective advantage in this setting, the prevalence of Pf-positive (Pf+) bacteria increases over time in these patients. However, the production of Pf phages comes at a metabolic cost to bacteria, such that Pf+ strains grow more slowly than Pf-negative (Pf-) strains in vitro. Here, we use a mathematical model to investigate how these competing pressures might influence the relative abundance of Pf+ versus Pf- strains in different settings. Our model suggests that Pf+ strains of Pa cannot outcompete Pf- strains if the benefits of phage production falls onto both Pf+ and Pf- strains for a majority of parameter combinations. Further, phage production leads to a net positive gain in fitness only at antibiotic concentrations slightly above the MIC (i.e., concentrations for which the benefits of antibiotic sequestration outweigh the metabolic cost of phage production) but which are not lethal for Pf+ strains. As a result, our model suggests that frequent administration of intermediate doses of antibiotics with low decay rates and high killing rates favors Pf+ over Pf- strains. These models inform our understanding of the ecology of Pf phages and suggest potential treatment strategies for Pf+ Pa infections. IMPORTANCE Filamentous phages are a frontier in bacterial pathogenesis, but the impact of these phages on bacterial fitness is unclear. In particular, Pf phages produced by Pa promote antibiotic tolerance but are metabolically expensive to produce, suggesting that competing pressures may influence the prevalence of Pf+ versus Pf- strains of Pa in different settings. Our results identify conditions likely to favor Pf+ strains and thus antibiotic tolerance. This study contributes to a better understanding of the unique ecology of filamentous phages in both environmental and clinical settings and may facilitate improved treatment strategies for combating antibiotic tolerance.

PMID:34156288 | DOI:10.1128/mSystems.00193-21

mSystems. 2021 Jun 22:e0048021. doi: 10.1128/mSystems.00480-21. Online ahead of print.

ABSTRACT

While bacterial metabolism is known to impact antibiotic efficacy and virulence, the metabolic capacities of individual microbes in cystic fibrosis lung infections are difficult to disentangle from sputum samples. Here, we show that untargeted metabolomic profiling of supernatants of multiple strains of Pseudomonas aeruginosa and Staphylococcus aureus grown in monoculture in synthetic cystic fibrosis media (SCFM) reveals distinct species-specific metabolic signatures despite intraspecies metabolic variability. We identify a set of 15 metabolites that were significantly consumed by both P. aeruginosa and S. aureus, suggesting that nutrient competition has the potential to impact community dynamics even in the absence of other pathogen-pathogen interactions. Finally, metabolites that were uniquely produced by one species or the other were identified. Specifically, the virulence factor precursor anthranilic acid, as well as the quinoline 2,4-quinolinediol (DHQ), were robustly produced across all tested strains of P. aeruginosa. Through the direct comparison of the extracellular metabolism of P. aeruginosa and S. aureus in a physiologically relevant environment, this work provides insight toward the potential for metabolic interactions in vivo and supports the development of species-specific diagnostic markers of infection. IMPORTANCE Interactions between P. aeruginosa and S. aureus can impact pathogenicity and antimicrobial efficacy. In this study, we aim to better understand the potential for metabolic interactions between P. aeruginosa and S. aureus in an environment resembling the cystic fibrosis lung. We find that S. aureus and P. aeruginosa consume many of the same nutrients, suggesting that metabolic competition may play an important role in community dynamics during coinfection. We further identify metabolites uniquely produced by either organism with the potential to be developed into species-specific biomarkers of infection in the cystic fibrosis lung.

PMID:34156287 | DOI:10.1128/mSystems.00480-21

Pediatr Pulmonol. 2021 Jun 22. doi: 10.1002/ppul.25547. Online ahead of print.

ABSTRACT

RATIONALE: Post-infectious bronchiolitis obliterans (PIBO) is a rare, chronic respiratory condition, which follows an acute insult due to a severe infection of the lower airways.

OBJECTIVES: The objective of this study was to investigate the long-term course of bronchial inflammation and pulmonary function testing in children with PIBO.

METHODS: Medical charts of 21 children with PIBO were analyzed retrospectively at the Children's University Hospital Frankfurt/Main Germany. Pulmonary function tests (PFTs) with an interval of at least one month were studied between 2002 - 2019. A total of 382 PFTs were analyzed retrospectively and per year, the two best PFTs, in total 217, were evaluated. Additionally, 56 sputum analysis were assessed and the sputum neutrophils were evaluated.

RESULTS: The evaluation of the 217 PFTs showed a decrease in FEV1 with a loss of 1.07% and a loss in z-score of -0.075 per year. FEV1/FVC decreased by 1.44 per year. FVC remained stable, showing a non-significant increase by 0.006 in z-score per year. However, FEV1 and FVC in L increased significantly with FEV1 0.032 L per cm and FVC 0.048 L per cm in height. Sputum neutrophils showed a significant increase of 2.12% per year.

CONCLUSION: Our results demonstrated that in patients with PIBO pulmonary function decreased significantly showing persistent obstruction over an average follow-up period of 8 years. However, persistent lung growth was revealed. In addition, pulmonary inflammation persisted clearly showing an increasing amount of neutrophils in induced sputum. Patients did not present with a general susceptibility to respiratory infections. This article is protected by copyright. All rights reserved.

PMID:34156164 | DOI:10.1002/ppul.25547

Child Care Health Dev. 2021 Jun 22. doi: 10.1111/cch.12890. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a chronic, life-threatening condition that results in life-long morbidity and premature mortality. CF has a significant impact on healthy siblings' adaptation and well-being. Siblings of patients with a chronic disease may experience psychological difficulties, such as anxiety, depression symptoms, and troubles in adaptation. This study aimed to explore the participants' experiences of growing up with a CF patient diagnosed at a paediatric age and their adaptation strategies.

METHOD: We enrolled eight CF siblings (adolescents and young adults) in a six-month focus group sessions program. Each session had two phases (psychoeducational and experiential). Transcripts were analysed and grouped through grounded theory analysis to elaborate on data-driven theory.

RESULTS: We identified 14 subthemes by which the raw data could be organised. All the subthemes were gathered together according to the axial coding process into six themes (illness, changes, communication, avoidance, normalisation, and protection and care). We then grouped the six themes into two main themes ('Growing up with a CF brother or sister' and 'Finding the right distance') and conceptualised the grounded theory 'Keeping the right distance'. The participants described the evolving process of maintaining a balance between the illness of their brother or sister, family organisation, and their own needs.

CONCLUSIONS: Knowing siblings' experiences and their common strategies to deal with the experience of having a brother or sister with a chronic health condition may be useful to ensure more tailored and specific interventions.

PMID:34156117 | DOI:10.1111/cch.12890

Biol Open. 2021 Jun 22:bio.058868. doi: 10.1242/bio.058868. Online ahead of print.

ABSTRACT

Claudin (Cldn) -10 tight junction (TJ) proteins are hypothesized to form the paracellular Na+ secretion pathway of hyposmoregulating mummichog (Fundulus heteroclitus) branchial epithelia. Organ-specific expression profiles showed that only branchial organs (the gill and opercular epithelium, OE) exhibited abundant cldn-10 paralog transcripts, which typically increased following sea water (SW) to hypersaline (2SW) challenge. Post-translational properties, protein abundance, and ionocyte localization of Cldn-10c, were then examined in gill and OE. Western blot analysis revealed two Cldn-10c immunoreactive bands in the mummichog gill and OE at ∼29 kDa and ∼40 kDa. The heavier protein could be eliminated by glycosidase treatment, demonstrating the novel presence of a glycosylated Cldn-10c. Protein abundance of Cldn-10c increased in gill and OE of 2SW-exposed fish. Cldn-10c localized to the sides of gill and OE ionocyte apical crypts and partially colocalized with cystic fibrosis transmembrane conductance regulator and F-actin, consistent with TJ complex localization. Cldn-10c immunofluorescent intensity increased but localization was unaltered by 2SW conditions. In support of our hypothesis, cldn-10/Cldn-10 TJ protein dynamics in gill and OE of mummichogs and TJ localization are functionally consistent with the creation and maintenance of salinity-responsive, cation-selective pores that facilitate Na+ secretion in hyperosmotic environments.

PMID:34156063 | DOI:10.1242/bio.058868

Biol Rev Camb Philos Soc. 2021 Jun 21. doi: 10.1111/brv.12764. Online ahead of print.

ABSTRACT

In this review, we summarize current knowledge of perhaps one of the most intriguing phenomena in cell biology: the mitochondrial permeability transition pore (mPTP). This phenomenon, which was initially observed as a sudden loss of inner mitochondrial membrane impermeability caused by excessive calcium, has been studied for almost 50 years, and still no definitive answer has been provided regarding its mechanisms. From its initial consideration as an in vitro artifact to the current notion that the mPTP is a phenomenon with physiological and pathological implications, a long road has been travelled. We here summarize the role of mitochondria in cytosolic calcium control and the evolving concepts regarding the mitochondrial permeability transition (mPT) and the mPTP. We show how the evolving mPTP models and mechanisms, which involve many proposed mitochondrial protein components, have arisen from methodological advances and more complex biological models. We describe how scientific progress and methodological advances have allowed milestone discoveries on mPTP regulation and composition and its recognition as a valid target for drug development and a critical component of mitochondrial biology.

PMID:34155777 | DOI:10.1111/brv.12764

Zentralbl Chir. 2021 Jun;146(3):346-358. doi: 10.1055/a-1361-2252. Epub 2021 Jun 21.

ABSTRACT

Bronchiectasis is a mostly irreversible bronchial dilatation induced by a destruction of elastic and muscular fibers of the bronchial wall. Radiological criteria of bronchiectasis are met, when the inner diameter of the bronchial wall surpasses the outer diameter of the accompanying pulmonary artery. Its incidence increases with age, even though it often lacks true clinical signs of disease. Only when it is accompanied by cough, expectorations and recurring bronchopulmonary infections, it can be considered a true bronchiectatic disease. Cystic fibrosis (CF) is one of its preeminent triggers, but certainly plays a particular role in this entity, which is why the terminus of "non-CF-bronchiectasis" was coined in the first place.Multidisciplinary management consists in extensive diagnostic work-up, treatment of potential triggers of bronchiectasis and supportive care in form of vaccination programs, secretolysis and pulmonary rehabilitation, as well as antibiotic treatment of pulmonary exacerbations.Surgical treatment has to be considered a last resort in case of hemoptysis, recurring severe pneumonia or secondary aspergilloma with complete resection of all pathological findings, ideally by minimally-invasive approach.

PMID:34154019 | DOI:10.1055/a-1361-2252

Am J Otolaryngol. 2021 Jun 16;42(6):103107. doi: 10.1016/j.amjoto.2021.103107. Online ahead of print.

ABSTRACT

PURPOSE: Paranasal mucocele (PM) is reported as a complication in children with cystic fibrosis (CF) in up to 4% of patients. The objective of this study was to identify PMs in the personal large series of children with CF and to assess their diagnosis and treatment.

MATERIAL AND METHODS: Medical records of children with CF and PM who were admitted and treated by means of endoscopic nasal surgery between 2004 and 2020 were retrospectively reviewed.

RESULTS: Thirty-four patients were included in the study (mean age 7.7 years). CT scan of sinuses showed a total of 53 PMs. Nasal endoscopic findings suggestive for PM were present in almost 80% of patients. PMs were located in the maxillary, ethmoid, and sphenoid sinuses in 29/34 (85.3%, bilateral in 17 cases), 4/34 (11.8%) and 1/34 (2.9%) patients, respectively. Marsupialization of PMs was performed in all patients using an endoscopic transnasal approach. No complications were observed. Resolution of symptoms and normalization of the endoscopic nasal picture was evident in all patients. After a mean follow-up of 85 months, no recurrences were observed.

CONCLUSIONS: To the best of our knowledge, this is the largest series of CF patients with PMs. Even if not frequently reported in the literature, PMs should not be considered an uncommon finding in patients affected by CF. Routine nasal endoscopy is mandatory to favor early diagnosis. Endoscopic transnasal marsupialization represents the gold standard of care for patients with CF and PM(s).

PMID:34153745 | DOI:10.1016/j.amjoto.2021.103107

J Allergy Clin Immunol Pract. 2021 Jun 18:S2213-2198(21)00671-1. doi: 10.1016/j.jaip.2021.06.006. Online ahead of print.

ABSTRACT

Concerns for anaphylaxis may hamper SARS-CoV-2 immunization efforts. We convened a multi-disciplinary group of international experts in anaphylaxis comprised of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the WHO global coronavirus database, and the grey literature (inception-March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the GRADE approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases/million (n=41,000,000 vaccinations, 95%CI 4.02-15.59; 26 studies, moderate certainty), the prevalence of PEG allergy is 103 cases/million (95%CI 88-120; 2 studies, very low certainty), and the sensitivity for PEG skin testing is poor though specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

PMID:34153517 | DOI:10.1016/j.jaip.2021.06.006

J Gastroenterol Hepatol. 2021 Jun 21. doi: 10.1111/jgh.15590. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: There are few clinical data on Adalimumab (ADA) biosimilars in inflammatory bowel disease. We aimed to perform a multicenter, observational, prospective study on safety and effectiveness of ADA biosimilar ABP 501 in patients with inflammatory bowel disease.

METHODS: All consecutive patients from the cohort of the Sicilian Network for Inflammatory Bowel Disease treated with ADA biosimilar ABP 501 from February 2019 to February 2020 were enrolled. Patients were divided into 3 groups: group A, naïve to ADA and naïve to anti-TNFs; group B, naïve to ADA and previously exposed to anti-TNFs; group C: switched from ADA originator to ABP 501.

RESULTS: 559 patients (median age 39 years; CD 88.0%, UC 12.0%) were included, with a follow-up time of 403.4 patient-years. Thirty-six SAEs occurred in 36 patients [(6.4% - incidence rate (IR): 8.9 per 100 person-years (PY)]. The IR of SAEs was higher among patients in group A compared with group C (17.4 vs. 4.8 per 100 PY; IR ratio=3.61; p<0.001) and among patients in group B compared with group C (16.4 vs. 4.8 per 100 PY; IR ratio=3.42; p=0.041). Among ADA-naïve patients (group A+B), 188 (85.8%) had a clinical response after 12 weeks, including 165 (75.3%) who achieved steroid-free remission. Higher treatment persistence estimates were reported for patients in group C compared with group A and B (log-rank p<0.001).

CONCLUSIONS: Safety and effectiveness of ABP 501 seem to be overall similar to those reported for ADA originator. Switching from originator to ABP 501 was safe and effective.

PMID:34152636 | DOI:10.1111/jgh.15590

JHEP Rep. 2021 Apr 24;3(4):100297. doi: 10.1016/j.jhepr.2021.100297. eCollection 2021 Aug.

ABSTRACT

BACKGROUND & AIMS: A single point mutation in the Z-variant of alpha 1-antitrypsin (Z-AAT) alone can lead to both a protein folding and trafficking defect, preventing its exit from the endoplasmic reticulum (ER), and the formation of aggregates that are retained as inclusions within the ER of hepatocytes. These defects result in a systemic AAT deficiency (AATD) that causes lung disease, whereas the ER-retained aggregates can induce severe liver injury in patients with ZZ-AATD. Unfortunately, therapeutic approaches are still limited and liver transplantation represents the only curative treatment option. To overcome this limitation, a better understanding of the molecular basis of ER aggregate formation could provide new strategies for therapeutic intervention.

METHODS: Our functional and omics approaches here based on human hepatocytes from patients with ZZ-AATD have enabled the identification and characterisation of the role of the protein disulfide isomerase (PDI) A4/ERP72 in features of AATD-mediated liver disease.

RESULTS: We report that 4 members of the PDI family (PDIA4, PDIA3, P4HB, and TXNDC5) are specifically upregulated in ZZ-AATD liver samples from adult patients. Furthermore, we show that only PDIA4 knockdown or alteration of its activity by cysteamine treatment can promote Z-AAT secretion and lead to a marked decrease in Z aggregates. Finally, detailed analysis of the Z-AAT interactome shows that PDIA4 silencing provides a more conducive environment for folding of the Z mutant, accompanied by reduction of Z-AAT-mediated oxidative stress, a feature of AATD-mediated liver disease.

CONCLUSIONS: PDIA4 is involved in AATD-mediated liver disease and thus represents a therapeutic target for inhibition by drugs such as cysteamine. PDI inhibition therefore represents a potential therapeutic approach for treatment of AATD.

LAY SUMMARY: Protein disulfide isomerase (PDI) family members, and particularly PDIA4, are upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. PDI inhibition upon cysteamine treatment leads to improvements in features of AATD and hence represents a therapeutic approach for treatment of AATD-mediated liver disease.

PMID:34151245 | PMC:PMC8192868 | DOI:10.1016/j.jhepr.2021.100297

Access Microbiol. 2021 Apr 15;3(4):000222. doi: 10.1099/acmi.0.000222. eCollection 2021.

ABSTRACT

INTRODUCTION: Burkholderia cepacia is an aerobic, Gram-negative bacillus, which exhibits innate resistance to multiple antibiotics and disinfectants. Although it is a chronic colonizer of the respiratory tract, it may rarely present with fatal necrotizing pneumonia-like features in immunosuppressed individuals, as those with chronic granulomatous disease, or patients with significant pulmonary compromise, like cystic fibrosis.

CASE PRESENTATION: A 76-year-old male presented with complaints of breathlessness, cough with mucoid expectoration and fever for 3 days. He had a history of coronary artery disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus and hypertension, under treatment. Pulmonary function tests were suggestive of very severe obstruction (FEV1/FVC was 55 %). So, clinical diagnosis of acute exacerbation of COPD was established. Sputum culture grew B. cepacia . The patient was treated with ceftazidime and meropenem along with inhalational bronchodilators and steroids, and showed symptomatic response to therapy.

CONCLUSION: There is paucity of the literature describing B. cepacia as a potential cause for acute exacerbations in relatively common clinical conditions, such as COPD. This case report highlights the speculation of this rare possibility, thereby alerting a clinician dealing with such cases.

PMID:34151173 | PMC:PMC8208758 | DOI:10.1099/acmi.0.000222

Biochim Biophys Acta Gen Subj. 2021 Jun 17:129951. doi: 10.1016/j.bbagen.2021.129951. Online ahead of print.

ABSTRACT

BACKGROUND: Antimicrobial peptides are considered potential alternatives for antibiotics. Here we describe the antibacterial properties of a family of novel cathelicidin-related (CR-) peptides, which we named PepBiotics, against bacteria typically present in cystic fibrosis (CF) patients.

METHODS: Broth dilution assays were used to determine antibacterial activity of PepBiotics under physiological conditions, as well as development of bacterial resistance against these peptides. Toxicity was tested in mice and cell cultures while molecular interactions of Pepbiotics with bacterial membrane components was determined using CD, ITC and LPS/LTA induced macrophage studies.

RESULTS: A relatively small number of PepBiotics remained highly antibacterial against CF-related respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus, at high ionic strength and low pH. Interestingly, these PepBiotics also prevented LPS/LTA induced activation of macrophages and was shown to be non-toxic to primary human nasal epithelial cells. Furthermore, both P. aeruginosa and S. aureus were unable to induce resistance against CR-163 and CR-172, two PepBiotics selected for their excellent antimicrobial and immunomodulatory properties. Toxicity studies in mice indicated that intratracheal administration of CR-163 was well tolerated in vivo. Finally, interaction of CR-163 with bacterial-type anionic membranes but not with mammalian-type (zwitterionic lipid) membranes was confirmed using isothermal titration calorimetry and 31P solid state NMR.

CONCLUSIONS: PepBiotics are a promising novel class of highly active antimicrobial peptides, of which CR-163 showed the most potential for treatment of clinically relevant (CF-) pathogens in physiological conditions.

GENERAL SIGNIFICANCE: These observations emphasize the therapeutic potential of PepBiotics against CF-related bacterial respiratory infections.

PMID:34147544 | DOI:10.1016/j.bbagen.2021.129951