Search

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Infections due to Mycobacterium abscessus are a major cause of mortality and morbidity in cystic fibrosis (CF) patients. Furthermore, M. abscessus has been suspected to be involved in person-to-person transmissions. In 2016, dominant global clonal complexes (DCCs) that occur worldwide among CF patients have been described. To elucidate the epidemiological situation of M. abscessus among CF patients in Germany and to put these data into a global context, we performed whole-genome sequencing of a set of 154 M. abscessus isolates from 123 German patients treated in 14 CF centers. We used MTBseq pipeline to identify clusters of closely related isolates and correlate those with global findings. Genotypic drug susceptibility for macrolides and aminoglycosides was assessed by characterization of the erm (41), rrl, and rrs genes. By this approach, we could identify representatives of all major DCCs (Absc 1, Absc 2, and Mass 1) in our cohort. Intrapersonal isolates showed higher genetic relatedness than interpersonal isolates (median 3 SNPs versus 16 SNPs; P  < 0.001). We further identified four clusters with German patients from same centers clustering with less than 25 SNPs distance (range 3 to 18 SNPs) but did not find any hint for in-hospital person-to-person transmission. This is the largest study investigating phylogenetic relations of M. abscessus isolates in Germany. We identified representatives of all reported DCCs but evidence for nosocomial transmission remained inconclusive. Thus, the occurrence of genetically closely related isolates of M. abscessus has to be interpreted with care, as a direct interhuman transmission cannot be directly deduced. IMPORTANCE Mycobacterium abscessus is a major respiratory pathogen in cystic fibrosis (CF) patients. Recently it has been shown that dominant global clonal complexes (DCCs) have spread worldwide among CF patients. This study investigated the epidemiological situation of M. abscessus among CF patients in Germany by performing whole-genome sequencing (WGS) of a set of 154 M. abscessus from 123 German patients treated in 14 CF centers. This is the largest study investigating the phylogenetic relationship of M. abscessus CF isolates in Germany.

Cystic fibrosis (CF) lung disease is aggravated by recurrent and ultimately chronic bacterial infections. One of the key pathogens in adult CF lung disease is P. aeruginosa (PA). In addition to bacteria, respiratory viral infections are suggested to trigger pulmonary exacerbations in CF. To date, little is known on how chronic infections with PA influence susceptibility and response to viral infection. We investigated the interactions between PA, human rhinovirus (HRV) and the airway epithelium in a model of chronic PA infection using differentiated primary bronchial epithelial cells (pBECs) and clinical PA isolates obtained from the respiratory sample of a CF patient. Cells were repeatedly infected with either a mucoid or a non-mucoid PA isolate for 16 days to simulate chronic infection, and subsequently co-infected with HRV. Key cytokines and viral RNA were quantified by cytometric bead array, ELISA and qPCR. Proteolytic degradation of IL-6 was analyzed by Western Blots. Barrier function was assessed by permeability tests and transepithelial electric resistance measurements. Virus infection stimulated the production of inflammatory and antiviral mediators, including interleukin (IL)-6, CXCL-8, tumor necrosis factor (TNF)-α, and type I/III interferons. Co-infection with a non-mucoid PA isolate increased IL-1β protein concentrations (28.88 pg/ml vs. 6.10 pg/ml), but in contrast drastically diminished levels of IL-6 protein (53.17 pg/ml vs. 2301.33 pg/ml) compared to virus infection alone. Conditioned medium obtained from co-infections with a non-mucoid PA isolate and HRV was able to rapidly degrade recombinant IL-6 in a serine protease-dependent manner, whereas medium from individual infections or co-infections with a mucoid isolate had no such effect. After co-infection with HRV and the non-mucoid PA isolate, we detected lower mRNA levels of Forkhead box J1 (FOXJ1) and Cilia Apical Structure Protein (SNTN), markers of epithelial cell differentiation to ciliated cells. Moreover, epithelial permeability was increased and barrier function compromised compared to single infections. These data show that PA infection can influence the response of bronchial epithelial cells to viral infection. Altered innate immune responses and compromised epithelial barrier function may contribute to an aggravated course of viral infection in PA-infected airways., Competing Interests: The work presented in this manuscript was partially funded by Gilead Sciences, Grant Program Infectious Diseases, Germany. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript., (Copyright © 2022 Endres, Hügel, Boland, Hogardt, Schubert, Jonigk, Braubach, Rohde and Bellinghausen.)

Mycobacterium abscessus is a highly antibiotic-resistant opportunistic pathogen causing clinically challenging infections in patients with preexisting lung diseases or under immunosuppression. Hence, reliable antibiotic susceptibility data are required for effective treatment. Aims of this study were to investigate (i) the congruence of genotypic and phenotypic antimicrobial susceptibility testing, (ii) the relationship between resistance profile and clinical course, and (iii) the phylogenetic relations of M. abscessus in a German patient cohort. A total of 39 isolates from 29 patients infected or colonized with M. abscessus underwent genotypic and phenotypic drug susceptibility testing. Clinical data were correlated with susceptibility data. Phylogenetic analysis was performed by means of whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) analysis. Macrolide resistance was mainly mediated by functional Erm(41) methyltransferases (T28 sequevars) in M. abscessus subsp. abscessus ( n  = 25) and M. abscessus subsp. bolletii ( n  = 2). It was significantly associated with impaired culture conversion ( P  = 0.02). According to the core SNP phylogeny, we identified three clusters of closely related isolates with SNP distances below 25. Representatives of all circulating global clones (Absc. 1, Absc. 2, and Mass. 1) were identified in our cohort. However, we could not determine evidence for in-hospital interhuman transmission from clinical data. In our patient cohort, we identified three M. abscessus clusters with closely related isolates and representatives of the previously described international clusters but no human-to-human in-hospital transmission. Macrolide and aminoglycoside susceptibility data are critical for therapeutic decision-making in M. abscessus infections., (Copyright © 2020 American Society for Microbiology.)

Once overlooked, awareness of nontuberculous mycobacterial pulmonary disease (NTM-PD) is rapidly rising, in line with increasing prevalence worldwide. The European Respiratory Society (ERS) International Congress 2019, held in Madrid, Spain, provided a platform for invigorating discussions and exciting new research in the field. This article explores approaches being taken to combat NTM-PD with a focus not only on novel prevalence and risk factor data, but also on emerging antimicrobials and their routes of delivery, and other potential treatment options in early clinical development., Competing Interests: Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca and Boehringer Ingelheim, grants from Gilead Sciences, grants and personal fees from GlaxoSmithKline, grants from Grifols, grants and personal fees from Insmed, and personal fees from Chiesi, Novartis and Zambon, outside the submitted work. Conflict of interest: C. Balavoine has nothing to disclose. Conflict of interest: P.F. Castellotti has nothing to disclose. Conflict of interest: C. Hügel reports personal fees from Boehringer Ingelheim and PulmonX, and nonfinancial support from Mukoviszidose e.V., Gilead, Insmed and Novartis, outside the submitted work. Conflict of interest: A. Payet has nothing to disclose. Conflict of interest: D. Wat reports grants and personal fees from Chiesi and Insmed, and personal fees from GlaxoSmithKline, outside the submitted work. Conflict of interest: G. Rohde reports personal fees from Boehringer Ingelheim, Chiesi, Essex Pharma, GlaxoSmithKline, Grifols, Insmed, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Solvay and Vertex, outside the submitted work., (Copyright ©ERS 2020.)

Background: Approaches to pediatric induction of anesthesia vary widely. While oral sedative premedication and inhalational induction are common, total intravenous anesthesia is becoming increasingly popular. Total intravenous anesthesia without anxiolytic premedication, which is the most commonly used technique in our hospital, requires intravenous (IV) cannula placement in an awake child., Aims: To quantify the success rate of IV cannula placement in 1 or 2 attempts and to identify success factors and barriers., Methods: With ethical approval and written informed consent from participating anesthesiologists, a prospective audit of IV cannulation was undertaken over a 1-month period. The attending anesthesiologist captured basic demographics, IV insertion characteristics, setting, distraction techniques, the behavior of the child, number of attempts, and success/failure. A logistic regression model for successful IV cannulation was created. Anesthesiologists and procedural suite nurses participated in semi-structured interviews to identify success factors, barriers, and teaching approaches., Results: Data from 984 cases were analyzed. IV induction was planned in 562 cases, and IV cannulation was successful in 90% of these patients. Anxiolytic premedication was given in 6% of cases. Observations indicated that 64% of children were pain- and reaction-free, and 90% experienced minimal or no reaction. Predictors for success included older child's age and child behavior at first encounter. Qualitative interview data from 13 participants suggested success factors included effective distraction, preparing the family for IV induction, parental presence, support of the operating room team, effective use of local analgesic cream, adapting the approach to the individual child, and the anesthesiologist's efficiency. Barriers included needle phobia, uncooperative child, anxious parents, ineffective use of analgesic cream, and unfavorable anatomy. Distraction techniques varied by age and developmental stage of the child., Conclusions: Cannulation for planned IV induction is feasible for most children, enabling increased use of total intravenous anesthesia as an institutional anesthetic strategy., (© 2020 John Wiley & Sons Ltd.)

Objective: Phenotypic (Sensititre Myco, pDST) and genotypic drug susceptibility testing (GenoType NTM DR, gDST) in M. avium complex (MAC) have become available as standardized assays, but comparable data is needed. This study aimed to investigate the phenotypic and genotypic drug susceptibility patterns in MAC clinical isolates., Methods: Overall, 98 isolates from 85 patients were included. pDST and gDST were performed on all isolates and results compared regarding specificity and sensitivity using pDST as a reference method. The impact of drug instability on pDST results was studied using a biological assay over 14 days. In addition, the evolution of antimicrobial resistance was investigated in sequential isolates of 13 patients., Results: Macrolide resistance was rare, 1.2% (95% CI 0.7-7.3) of isolates in the base cohort. No aminoglycoside resistances were found, but 14.1% of the studied isolates (95% CI 7.8-23.8) showed intermediate susceptibility. The GenoType NTM DR identified two out of four macrolide-resistant isolates. Antibiotic stability was demonstrated to be poor in rifampicin, rifabutin, and doxycycylin., Conclusions: pDST results in NTM for unstable antibiotics must be interpreted with care. A combination of pDST and gDST will be useful for the guidance of antimicrobial therapy in MAC-disease., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human rhinoviruses (RV) belong to the Picornaviridae and are divided into three species: rhinovirus A, B and C. As causative viruses of upper airway infections (common cold), they possess enormous epidemiological and clinical importance. Furthermore, rhinoviruses are significant pathogens of acute exacerbations of chronic airway diseases such as asthma and chronic obstructive pulmonary disease. Their role as a cofactor in the development of pneumonia and their relevance in critically ill patients is still unclear and the focus of current research. Due to the unspecific clinical symptoms, diagnosis is difficult. Laboratory detection is sophisticated and a distinction between clinically relevant infection and contamination not always possible. Specific therapeutic antiviral strategies against rhinovirus infection do not exist as yet and, due to the large variety of subtypes, the development of vaccines remains a considerable challenge.

Purpose: NTM are ubiquitous bacteria that can cause colonisation and infection in immunocompetent and compromised hosts. The aim of this study was to elucidate the epidemiology of infection or colonisation with NTM for the metropolitan region of Frankfurt, Germany., Methods: All patients from whom NTM were isolated within the period from 2006 to 2016 were included in this retrospective analysis. Patient data were retrieved using the local patient data management system. Different groups were formed according to clinical manifestations, underlying diseases and mycobacterial species. They were compared in regard to mortality, duration of infection/colonisation and their geographical origins., Results: A total of 297 patients with a median of 28 new patients each year were included. Most patients suffered from lung infection or colonisation (72.7%, n = 216), followed by disseminated mycobacteriosis (12.5%, n = 37). The majority were HIV-positive, suffering from malignoma or cystic fibrosis (29.3%, n = 87, 16.2%, n = 48, and 13.8%, n = 41, respectively). 17.2% of patients showed no predisposing condition (n = 51). Mycobacterium avium complex (MAC) species were most frequently isolated (40.7%, n = 121). Infection/colonisation was longest in CF patients (median of 1094 days). The mortality was highest in malignoma patients (52.4%), while CF patients had the lowest overall mortality rate (5.3%). But mortality analysis showed non-significant results within different mycobacterial species and clinical manifestations., Conclusion: NTM remain rare but underestimated pathogens in lung and disseminated disease. MAC were the species most frequently isolated. Depending on species and underlying predispositions, the duration of infection/colonisation can be unexpectedly long.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa ( Pa ) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa -infection. This is a S3-clinical guideline which implements a definition for chronic Pa -infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa -infection in order to give guidance for individual treatment options., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-018., (© Georg Thieme Verlag KG Stuttgart · New York.)

Bronchoalveolar lavage [BAL] is an important procedure in the diagnosis of a variety of lung diseases. While it has enormous value in the diagnostics of inflammatory parenchymal diseases, its significance in lung cancer is unclear. Keeping in mind that immune therapy (e. g. application of checkpoint inhibitors) is gaining importance in the management of lung carcinoma, it is important to know if there are typical cellular patterns in BAL of lung cancer patients. Methods  In a retrospective proof of principle-study, we analyzed 38 patients who underwent BAL at the initial diagnosis of lung cancer. Results  We observed an elevated level of CD25 lymphocytes as well as an increased expression of DR antigen, both signaling lymphocyte activation. We could not find a typical cytologic pattern of inflammatory cells in lung carcinoma patients. Sensitivity of BAL to malignant cells was rare, thus confirming earlier analysis. Conclusion  We could not demonstrate typical cellular patterns in BAL of lung cancer patients. Evaluation of specific microRNA patterns might play a supporting role in the initial diagnosis as well as follow-up of lung cancer patients., (© Georg Thieme Verlag KG Stuttgart · New York.)