COVID-19 is characterized by respiratory symptoms of various severities, ranging from mild upper respiratory signs to acute respiratory failure/acute respiratory distress syndrome associated with a high mortality rate. However, the pathophysiology of the disease is largely unknown. Shotgun metagenomics from nasopharyngeal swabs were used to characterize the genomic, metagenomic and transcriptomic features of patients from the first pandemic wave with various forms of COVID-19, including outpatients, patients hospitalized not requiring intensive care, and patients in the intensive care unit, to identify viral and/or host factors associated with the most severe forms of the disease. Neither the genetic characteristics of SARS-CoV-2, nor the detection of bacteria, viruses, fungi or parasites were associated with the severity of pulmonary disease. Severe pneumonia was associated with overexpression of cytokine transcripts activating the CXCR2 pathway, whereas patients with benign disease presented with a T helper “Th1-Th17” profile. The latter profile was associated with female gender and a lower mortality rate. Our findings indicate that the most severe cases of COVID-19 are characterized by the presence of overactive immune cells resulting in neutrophil pulmonary infiltration which, in turn, could enhance the inflammatory response and prolong tissue damage. These findings make CXCR2 antagonists, in particular IL-8 antagonists, promising candidates for the treatment of patients with severe COVID-19.
Strict anaerobes are undeniably important residents of the cystic fibrosis (CF) lung but are still unknowns. The main objectives of this study were to describe anaerobic bacteria diversity in CF airway microbiota and to evaluate the association with lung function. An observational study was conducted during eight months. A hundred and one patients were enrolled in the study, and 150 sputum samples were collected using a sterile sample kit designed to preserve anaerobic conditions. An extended-culture approach on 112 sputa and a molecular approach (quantitative PCR targeting three of the main anaerobic genera in CF lung: Prevotella, Veillonella, and Fusobacterium) on 141 sputa were developed. On culture, 91.1% of sputa were positive for at least one anaerobic bacterial species, with an average of six anaerobic species detected per sputum. Thirty-one anaerobic genera and 69 species were found, which is the largest anaerobe diversity ever reported in CF lungs. Better lung function (defined as Forced Expiratory Volume in one second > 70%) was significantly associated with higher quantification of Veillonella. These results raise the question of the potential impact of anaerobes on lung function.
The sex gap is well-documented in respiratory diseases such as cystic fibrosis and chronic obstructive pulmonary disease. While the differences between males and females in prevalence, severity and prognosis are well-established, the pathophysiology of the sex difference has been poorly characterized to date. Over the past 10 years, metagenomics-based studies have revealed the presence of a resident microbiome in the respiratory tract and its central role in respiratory disease. The lung microbiome is associated with host immune response and health outcomes in both animal models and patient cohorts. The study of the lung microbiome is therefore an interesting new avenue to explore in order to understand the sex gap observed in respiratory diseases. Another important parameter to consider is the gut-lung axis, since the gut microbiome plays a crucial role in distant immune modulation in respiratory diseases, and an intestinal “microgenderome” has been reported: i.e., sexual dimorphism in the gut microbiome. The microgenderome provides new pathophysiological clues, as it defines the interactions between microbiome, sex hormones, immunity and disease susceptibility. As research on the microbiome is increasing in volume and scope, the objective of this review was to describe the state-of-the-art on the sex gap in respiratory medicine (acute pulmonary infection and chronic lung disease) in the light of the microbiome, including evidence of local (lung) or distant (gut) contributions to the pathophysiology of these diseases.
Bacteriological diagnosis is traditionally based on culture. However, this method may be limited by the difficulty of cultivating certain species or by prior exposure to antibiotics, which justifies the resort to molecular methods, such as Sanger sequencing of the 16S rRNA gene (Sanger 16S). Recently, shotgun metagenomics (SMg) has emerged as a powerful tool to identify a wide range of pathogenic microorganisms in numerous clinical contexts. In this study, we compared the performance of SMg to Sanger 16S for bacterial detection and identification. All patients’ samples for which Sanger 16S was requested between November 2019 and April 2020 in our institution were prospectively included. The corresponding samples were tested with a commercial 16S semi-automated method and a semi-quantitative pan-microorganism DNA- and RNA-based SMg method. Sixty-seven samples from 64 patients were analyzed. Overall, SMg was able to identify a bacterial etiology in 46.3% of cases (31/67) vs. 38.8% (26/67) with Sanger 16S. This difference reached significance when only the results obtained at the species level were compared (28/67 vs. 13/67). This study provides one of the first evidence of a significantly better performance of SMg than Sanger 16S for bacterial detection at the species level in patients with infectious diseases for whom culture-based methods have failed. This technology has the potential to replace Sanger 16S in routine practice for infectious disease diagnosis.
The importance and abundance of strict anaerobic bacteria in the respiratory microbiota of people with cystic fibrosis (PWCF) is now established through studies based on high-throughput sequencing or extended-culture methods. In CF respiratory niche, one of the most prevalent anaerobic genera is Prevotella, and particularly the species Prevotella melaninogenica. The objective of this study was to evaluate the antibiotic susceptibility of this anaerobic species. Fifty isolates of P. melaninogenica cultured from sputum of 50 PWCF have been included. Antibiotic susceptibility testing was performed using the agar diffusion method. All isolates were susceptible to the following antibiotics: amoxicillin/clavulanic acid, piperacillin/tazobactam, imipenem and metronidazole. A total of 96% of the isolates (48/50) were resistant to amoxicillin (indicating beta-lactamase production), 34% to clindamycin (17/50) and 24% to moxifloxacin (12/50). Moreover, 10% (5/50) were multidrug-resistant. A significant and positive correlation was found between clindamycin resistance and chronic azithromycin administration. This preliminary study on a predominant species of the lung “anaerobiome” shows high percentages of resistance, potentially exacerbated by the initiation of long-term antibiotic therapy in PWCF. The anaerobic resistome characterization, focusing on species rather than genera, is needed in the future to better prevent the emergence of resistance within lung microbiota.
The development of resistome analysis, i.e. the comprehensive analysis of antibiotic-resistance genes (ARGs), is enabling a better understanding of the mechanisms of antibiotic-resistance emergence. The respiratory microbiome is a dynamic and interactive network of bacteria, with a set of ARGs that could influence the response to antibiotics. Viruses such as bacteriophages, potential carriers of ARGs, may also form part of this respiratory resistome. Chronic respiratory diseases (CRDs) such as cystic fibrosis, severe asthma, chronic obstructive pulmonary disease and bronchiectasis, managed with long-term antibiotic therapies, lead to multidrug resistance. Antibiotic susceptibility testing provides a partial view of the bacterial response to antibiotics in the complex lung environment. Assessing the ARG network would allow personalised, targeted therapeutic strategies and suitable antibiotic stewardship in CRDs, depending on individual resistome and microbiome signatures. This review summarises the influence of pulmonary antibiotic protocols on the respiratory microbiome, detailing the variable consequences according to antibiotic class and duration of treatment. The different resistome-profiling methods are explained to clarify their respective place in antibiotic-resistance analysis in the lungs. Finally, this review details current knowledge on the respiratory resistome related to therapeutic strategies and provides insight into the application of resistome analysis to counter the emergence of multidrug-resistant respiratory pathogens.
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