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Scedosporium spp. and Lomentospora prolificans are emerging non-Aspergillus filamentous fungi. The Scedosporiosis/lomentosporiosis Observational Study we previously conducted reported frequent fungal vascular involvement, including aortitis and peripheral arteritis. For this article, we reviewed 7 cases of Scedosporium spp. and L. prolificans arteritis from the Scedosporiosis/lomentosporiosis Observational Study and 13 cases from published literature. Underlying immunosuppression was reported in 70% (14/20) of case-patients, mainly those who had solid organ transplants (10/14). Osteoarticular localization of infection was observed in 50% (10/20) of cases; infections were frequently (7/10) contiguous with vascular infection sites. Scedosporium spp./Lomentospora prolificans infections were diagnosed in 9 of 20 patients ≈3 months after completing treatment for nonvascular scedosporiosis/lomentosporiosis. Aneurysms were found in 8/11 aortitis and 6/10 peripheral arteritis cases. Invasive fungal disease­–related deaths were high (12/18 [67%]). The vascular tropism of Scedosporium spp. and L. prolificans indicates vascular imaging, such as computed tomography angiography, is needed to manage infections, especially for osteoarticular locations.

Abstract Background The worldwide dissemination of extended spectrum beta-lactamase producing Enterobacteriales (ESBL-E) is of major concern. Microbiota may play a role in the host resistance to colonization with ESBL-E, but the underlying mechanisms remain unknown. We aimed to compare the gut microbiota composition between ESBL-producing E. coli or K. pneumoniae carriers and ESBL-E non-carriers according to the bacterial species. Results Among 255 patients included, 11 (4,3%) were colonized with ESBL-producing E. coli and 6 (2,4%) with ESBL-producing K. pneumoniae, which were compared with age- and sex-matched ESBL-E non carriers. While no significant differences were found between ESBL-producing E. coli carriers and non-carriers, gut bacteriobiota α-diversity was decreased in ESBL-K. pneumoniae faecal carriers compared both with non-carriers (p = 0.05), and with ESBL-producing E. coli carriers. The presence of Sellimonas intestinalis was associated with the absence of ESBL-producing E. coli fecal carriage. Campylobacter ureolyticus, Campylobacter hominis, bacteria belonging to Clostridium cluster XI and Saccharomyces sp. were associated with the absence of ESBL-producing K. pneumoniae faecal carriage. Conclusions The composition of the gut microbiota differs between ESBL-producing E. coli and K. pneumoniae faecal carriers suggesting that microbial species should be taken into account when investigating the role of gut microbiota in resistance to gut colonization with ESBL-E. Trial registration number: NCT04131569, date of registration: October 18, 2019.

ABSTRACT Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection in critically ill-ventilated patients. Oropharyngeal and lung microbiota have been demonstrated to be associated with VAP occurrence, but the involvement of gut microbiota has not been investigated so far. Therefore, the aim of this study is to compare the composition of the gut microbiota between patients who subsequently develop VAP and those who do not. A rectal swab was performed at admission of every consecutive patient into the intensive care unit (ICU) from October 2019 to March 2020. After DNA extraction, V3-V4 and internal transcribed spacer 2 regions deep-sequencing was performed on MiSeq sequencer (Illumina) and data were analyzed using Divisive Amplicon Denoising Algorithm 2 (DADA2) pipeline. Among 255 patients screened, 42 (16%) patients with invasive mechanical ventilation for more than 48 h were included, 18 (43%) with definite VAP and 24 without (57%). Patients who later developed VAP had similar gut bacteriobiota and mycobiota α-diversities compared to those who did not develop VAP. However, gut mycobiota was dissimilar (β-diversity) between these two groups. The presence of Megasphaera massiliensis was associated with the absence of VAP occurrence, whereas the presence of the fungal genus Alternaria sp. was associated with the occurrence of VAP. The composition of the gut microbiota, but not α-diversity, differs between critically ill patients who subsequently develop VAP and those who do not. This study encourages large multicenter cohort studies investigating the role of gut-lung axis and oropharyngeal colonization in the development of VAP in ICU patients. Trial registration number: NCT04131569, date of registration: 18 October 2019. IMPORTANCE The composition of the gut microbiota, but not α-diversity, differs between critically ill patients who subsequently develop ventilator-associated pneumonia (VAP) and those who do not. Investigating gut microbiota composition could help to tailor probiotics to provide protection against VAP.

The advent of CFTR modulators represents a turning point in the history of cystic fibrosis (CF) management, changing profoundly the disease’s clinical course by improving mucosal hydration. Assessing changes in airway and digestive tract microbiomes is of great interest to better understand the mechanisms and to predict disease evolution. Bacterial and fungal dysbiosis have been well documented in patients with CF; yet the impact of CFTR modulators on microbial communities has only been partially deciphered to date. In this review, we aim to summarize the current state of knowledge regarding the impact of CFTR modulators on both pulmonary and digestive microbiomes. Our analysis also covers the inter-organ connections between lung and gut communities, in order to highlight the gut-lung axis involvement in CF pathophysiology and its evolution in the era of novel modulators therapies.

Abstract Background While there seems to be a consensus that a decrease in gut microbiome diversity is related to a decline in health status, the associations between respiratory microbiome diversity and chronic lung disease remain a matter of debate. We provide a systematic review and meta-analysis of studies examining lung microbiota alpha-diversity in patients with asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or bronchiectasis (NCFB), in which a control group based on disease status or healthy subjects is provided for comparison. Results We reviewed 351 articles on title and abstract, of which 27 met our inclusion criteria for systematic review. Data from 24 of these studies were used in the meta-analysis. We observed a trend that CF patients have a less diverse respiratory microbiota than healthy individuals. However, substantial heterogeneity was present and detailed using random-effects models, which limits the comparison between studies. Conclusions Knowledge on respiratory microbiota is under construction, and for the moment, it seems that alpha-diversity measurements are not enough documented to fully understand the link between microbiota and health, excepted in CF context which represents the most studied chronic respiratory disease with consistent published data to link alpha-diversity and lung function. Whether differences in respiratory microbiota profiles have an impact on chronic respiratory disease symptoms and/or evolution deserves further exploration.

BackgroundMalnutrition is both a feature and major cause of morbidity in cystic fibrosis (CF). Therefore, nutritional management is an essential element of patient care. In 2016, an international guideline for nutritional management in patients with CF was published. In light of these recommendations, the aim of this study was to investigate the dietary intake of children with CF at the University Hospital of Bordeaux.MethodsWe conducted a retrospective study at the Paediatric CF Centre of the University Hospital of Bordeaux. Patients aged 2–18 years with CF who completed a 3-day food diary at home between January 2015 and December 2020 were included.ResultsA total of 130 patients, with a median age of 11.8 [interquartile range (IQR): 8.3; 13.4] years, were included. The median Z-score for BMI was −0.35 (IQR: −0.9; 0.2) and 20% of the patients had a Z-score for BMI

BackgroundNutritional status is a major prognostic factor for breathing and the survival of patients with cystic fibrosis (CF). Since 2012, the development of CFTR modulators has considerably transformed the outcome of this disease. Indeed, both lung function and body mass index are improved by CFTR modulators, such as Lumacaftor/Ivacaftor. However, few data exist regarding the outcome of nutritional intakes under Lumacaftor/Ivacaftor.MethodsWe conducted a prospective single-center study in children with CF treated with Lumacaftor/Ivacaftor to evaluate their nutritional intake before and after treatmentResultsThirty-four children were included in this study, with a median age of 12.4 years [11.9; 14.7]. There was no significant improvement in weight, height or BMI. Patients' total energy intake was not significantly changed with Lumacaftor/Ivacaftor, while carbohydrate intakes decreased significantly. We found that blood levels of vitamin E and Selenium were significantly increased under Lumacaftor/Ivacaftor, without a significant increase in supplementation. In patients with a BMI Z-score

Abstract Introduction Gut microbiota is associated with host characteristics such as age, sex, immune condition or frailty and is thought to be a key player in numerous human diseases. Nevertheless, its association with outcome in critically ill patients has been poorly investigated. The aim of this study is to assess the association between gut microbiota composition and Day-28 mortality in critically ill patients. Methods Rectal swab at admission of every patient admitted to intensive care unit (ICU) between October and November 2019 was frozen at − 80 °C. DNA extraction was performed thanks to QIAamp® PowerFecal® Pro DNA kit (QIAgen®). V3–V4 regions of 16SRNA and ITS2 coding genes were amplified by PCR. Sequencing (2x250 bp paired-end) was performed on MiSeq sequencer (Illumina®). DADA2 pipeline on R software was used for bioinformatics analyses. Risk factors for Day-28 mortality were investigated by logistic regression. Results Fifty-seven patients were consecutively admitted to ICU of whom 13/57 (23%) deceased and 44/57 (77%) survived. Bacteriobiota α-diversity was lower among non-survivors than survivors (Shannon and Simpson index respectively, p

(1) Background: Aspergillus flavus is a cosmopolitan mold with medical, veterinary, and agronomic concerns. Its morphological similarity to other cryptic species of the Flavi section requires molecular identification techniques that are not routinely performed. For clinical isolates of Aspergillus section Flavi, we present the molecular identification, susceptibility to six antifungal agents, and clinical context of source patients. (2) Methods: One hundred forty fungal clinical isolates were included in the study. These isolates, recovered over a 15-year period (2001–2015), were identified based on their morphological characteristics as belonging to section Flavi. After the subculture, sequencing of a part of the β-tubulin and calmodulin genes was performed, and resistance to azole antifungals was screened on agar plates containing itraconazole and voriconazole. Minimum inhibitory concentrations were determined for 120 isolates by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. (3) Results: Partial β-tubulin and calmodulin sequences analysis showed that 138/140 isolates were A. flavus sensu stricto, 1 isolate was A. parasiticus/sojae, and 1 was A. nomiae. Many of the isolates came from samples collected in the context of respiratory tract colonization. Among probable or proven aspergillosis, respiratory infections were the most frequent, followed by ENT infections. Antifungal susceptibility testing was available for isolates (n = 120, all A. flavus ss) from one hospital. The MIC range (geometric mean MIC) in mg/L was 0.5–8 (0.77), 0.5–8 (1.03), 0.125–2 (0.25), 0.03–2 (0.22), 0.25–8 (1.91), and 0.03–0.125 (0.061) for voriconazole, isavuconazole, itraconazole, posaconazole, amphotericin B, and caspofungin, respectively. Two (1.67%) isolates showed resistance to isavuconazole according to current EUCAST breakpoints with MICs at 8 mg/L for isavuconazole and voriconazole. One of these two isolates was also resistant to itraconazole with MIC at 2 mg/L. (4) Conclusions: The present characterization of a large collection of Aspergillus belonging to the Flavi section confirmed that A. flavus ss is the predominant species. It is mainly implicated in respiratory and ENT infections. The emergence of resistance highlights the need to perform susceptibility tests on section Flavi isolates.

ABSTRACT The objective of this study was to characterize the effect of Bacillus Calmette-Guérin (BCG) vaccination and M. tuberculosis infection on gut and lung microbiota of C57BL/6 mice, a well-characterized mouse model of tuberculosis. BCG vaccination and infection with M. tuberculosis altered the relative abundance of Firmicutes and Bacteroidetes phyla in the lung compared with control group. Vaccination and infection changed the alpha- and beta-diversity in both the gut and the lung. However, lung diversity was the most affected organ after BCG vaccination and M. tuberculosis infection. Focusing on the gut–lung axis, a multivariate regression approach was used to compare profile evolution of gut and lung microbiota. More genera have modified relative abundances associated with BCG vaccination status at gut level compared with lung. Conversely, genera with modified relative abundances associated with M. tuberculosis infection were numerous at lung level. These results indicated that the host local response against infection impacted the whole microbial flora, while the immune response after vaccination modified mainly the gut microbiota. This study showed that a subcutaneous vaccination with a live attenuated microorganism induced both gut and lung dysbiosis that may play a key role in the immunopathogenesis of tuberculosis. IMPORTANCE The microbial communities in gut and lung are important players that may modulate the immunity against tuberculosis or other infections as well as impact the vaccine efficacy. We discovered that vaccination through the subcutaneous route affect the composition of gut and lung bacteria, and this might influence susceptibility and defense mechanisms against tuberculosis. Through these studies, we can identify microbial communities that can be manipulated to improve vaccine response and develop treatment adjuvants.

IntroductionCryptococcus spp. infection of the central nervous system (CINS) is a devastating opportunistic infection that was historically described in patients with acquired immunodeficiency syndrome (AIDS). Cryptococcus spp. infections are also associated with sarcoidosis; the impairment of cell-mediated immunity and long-term corticosteroid therapy being evoked to explain this association. Nevertheless, this assertion is debated and the underlying pathophysiological mechanisms are still unknown. The aims of this study were (i) to describe the clinical and biological presentation, treatments, and outcomes of CINS patients with and without sarcoidosis and (ii) to review the pathophysiological evidence underlying this clinical association.Patients and MethodsEvery patient with positive cerebrospinal fluid (CSF) cryptococcal antigen testing, India ink preparation, and/or culture from January 2015 to December 2020 at a tertiary university hospital were included, and patients with sarcoidosis were compared with non-sarcoidosis patients. Quantitative variables are presented as mean ± SD and are compared using the Mann-Whitney Wilcoxon rank-sum test. Categorical variables are expressed as the number of patients (percentage) and compared using the χ2 or Fisher's tests.ResultsDuring the study period, 16 patients experienced CINS, of whom 5 (31%) were associated with sarcoidosis. CINS symptoms, biological, and CSF features were similar between CINS patients with and without sarcoidosis except regarding CD4 cells percentages and CD4/CD8 ratio that was higher in those with sarcoidosis (47 ± 12 vs. 22 ± 18, p = 0.02 and 2.24 ± 1.42 vs. 0.83 ± 1.10, p = 0.03, respectively). CINS patients with sarcoidosis had less often positive blood antigen testing than those without sarcoidosis (2/5 vs. 11/11, p = 0.02). CINS patients with and without sarcoidosis were treated with similar drugs, but patients with sarcoidosis had a shorter length of treatment. CD4 cell levels do not seem to explain the association between sarcoidosis and cryptococcosis.ConclusionSarcoidosis was the most frequently associated condition with CINS in this study. CINS patients associated with sarcoidosis had overall similar clinical and biological presentation than CINS patients associated with other conditions but exhibited a lower rate of positive blood cryptococcal antigen testing and higher CD4/CD8 T cells ratio. Pathophysiological mechanisms underlying this association remain poorly understood but B-1 cell deficiency or lack of IgM could be a part of the explanation. Another plausible mechanism is the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in a subset of patients with sarcoidosis, which could impair macrophage phagocytic function. Further studies are strongly needed to better understand those mechanisms and to identify at-risk patients.

Pneumocystis pneumonia (PCP) remains the most frequent AIDS-defining illness in developed countries. This infection also occurs in non-AIDS immunosuppressed patients, e.g., those who have undergone an organ transplantation. Moreover, mild Pneumocystis jirovecii infections related to low pulmonary fungal burden, frequently designated as pulmonary colonization, occurs in patients with chronic pulmonary diseases, e.g., cystic fibrosis (CF). Indeed, this autosomal recessive disorder alters mucociliary clearance leading to bacterial and fungal colonization of the airways. This mini-review compiles and discusses available information on P. jirovecii and CF. It highlights significant differences in the prevalence of P. jirovecii pulmonary colonization in European and Brazilian CF patients. It also describes the microbiota associated with P. jirovecii in CF patients colonized by P. jirovecii. Furthermore, we have described P. jirovecii genomic diversity in colonized CF patients. In addition of pulmonary colonization, it appears that PCP can occur in CF patients specifically after lung transplantation, thus requiring preventive strategies. In other respects, Pneumocystis primary infection is a worldwide phenomenon occurring in non-immunosuppressed infants within their first months. The primary infection is mostly asymptomatic but it can also present as a benign self-limiting infection. It probably occurs in the same manner in CF infants. Nonetheless, two cases of severe Pneumocystis primary infection mimicking PCP in CF infants have been reported, the genetic disease appearing in these circumstances as a risk factor of PCP while the host-pathogen interaction in older children and adults with pulmonary colonization remains to be clarified.

The gut and lungs are anatomically distinct, but potential anatomic communications and complex pathways involving their respective microbiota have reinforced the existence of a gut–lung axis (GLA). Compared to the better-studied gut microbiota, the lung microbiota, only considered in recent years, represents a more discreet part of the whole microbiota associated to human hosts. While the vast majority of studies focused on the bacterial component of the microbiota in healthy and pathological conditions, recent works have highlighted the contribution of fungal and viral kingdoms at both digestive and respiratory levels. Moreover, growing evidence indicates the key role of inter-kingdom crosstalks in maintaining host homeostasis and in disease evolution. In fact, the recently emerged GLA concept involves host–microbe as well as microbe–microbe interactions, based both on localized and long-reaching effects. GLA can shape immune responses and interfere with the course of respiratory diseases. In this review, we aim to analyze how the lung and gut microbiota influence each other and may impact on respiratory diseases. Due to the limited knowledge on the human virobiota, we focused on gut and lung bacteriobiota and mycobiota, with a specific attention on inter-kingdom microbial crosstalks which are able to shape local or long-reached host responses within the GLA.

Patients with obesity are known to exhibit gut microbiota dysbiosis and memory deficits. Bariatric surgery (BS) is currently the most efficient anti-obesity treatment and may improve both gut dysbiosis and cognition. However, no study has investigated association between changes of gut microbiota and cognitive function after BS. We prospectively evaluated 13 obese patients on anthropometric data, memory functions, and gut microbiota-mycobiota before and six months after BS. The Rey Auditory Verbal Learning Test (AVLT) and the symbol span (SS) of the Weschler Memory Scale were used to assess verbal and working memory, respectively. Fecal microbiota and mycobiota were longitudinally analyzed by 16S and ITS2 rRNA sequencing respectively. AVLT and SS scores were significantly improved after BS (AVLT scores: 9.7 ± 1.7 vs. 11.2 ± 1.9, p = 0.02, and SS scores: 9.7 ± 23.0 vs. 11.6 ± 2.9, p = 0.05). An increase in bacterial alpha-diversity, and Ruminococcaceae, Prevotella, Agaricus, Rhodotorula, Dipodascus, Malassezia, and Mucor were significantly associated with AVLT score improvement after BS, while an increase in Prevotella and a decrease in Clostridium, Akkermansia, Dipodascus and Candida were linked to SS scores improvement. We identified several changes in the microbial communities that differ according to the improvement of either the verbal or working memories, suggesting a complex gut-brain-axis that evolves after BS.

Fusarium spp. are widespread environmental fungi as well as pathogens that can affect plants, animals and humans. Yet the epidemiology of human fusariosis is still cloudy due to the rapidly evolving taxonomy. The Mass Spectrometry Identification database (MSI) has been developed since 2017 in order to allow a fast, accurate and free-access identification of fungi by matrix-assisted laser desorption ionization—time of flight (MALDI-TOF) mass spectrometry. Taking advantage of the MSI database user network, we aim to study the species distribution of Fusarium spp. isolates in an international multicenter prospective study. This study also allowed the assessment of the abilities of miscellaneous techniques to identify Fusarium isolates at the species level. The identification was performed by PCR-sequencing and phylogenic-tree approach. Both methods are used as gold standard for the evaluation of mass spectrometry. Identification at the species complex was satisfactory for all the tested methods. However, identification at the species level was more challenging and only 32% of the isolates were correctly identified with the National Center for Biotechnology Information (NCBI) DNA database, 20% with the Bruker MS database and 43% with the two MSI databases. Improvement of the mass spectrometry database is still needed to enable precise identification at the species level of any Fusarium isolates encountered either in human pathology or in the environment.

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., “disease tolerance”) and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a “co-immunity,” where an organism is protected by both its own immune system and components of its microbiota.

Propidium monoazide (PMA)-pretreatment has increasingly been applied to remove the bias from dead or damaged cell artefacts, which could impact the microbiota analysis by high-throughput sequencing. Our study aimed to determine whether a PMA-pretreatment coupled with high-throughput sequencing analysis provides a different picture of the airway mycobiome and bacteriome.We compared deep-sequencing data of mycobiota and microbiota of 15 sputum samples from 5 cystic fibrosis (CF) patients with and without prior PMA-treatment of the DNA-extracts. PMA-pretreatment had no significant effect on the entire and abundant bacterial community (genera expressed as operational taxonomic units (OTUs) with a relative abundance greater than or equal to 1%), but caused a significant difference in the intermediate community (less than 1%) when analyzing the alpha biodiversity Simpson index (p = 0.03). Regarding PMA impact on the airway mycobiota evaluated for the first time here; no significant differences in alpha diversity indexes between PMA-treated and untreated samples were observed. Regarding beta diversity analysis, the intermediate communities also differed more dramatically than the total and abundant ones when studying both mycobiome and bacteriome. Our results showed that only the intermediate (or low abundance) population diversity is impacted by PMA-treatment, and therefore that abundant taxa are mostly viable during acute exacerbation in CF. Given such a cumbersome protocol (PMA-pretreatment coupled with high-throughput sequencing), we discuss its potential interest within the follow-up of CF patients. Further studies using PMA-pretreatment are warranted to improve our "omic" knowledge of the CF airways.