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Chronic Obstructive Pulmonary Disease (COPD) represents the 3rd leading cause of death in the world. The underlying pathophysiological mechanisms have been the focus of extensive research in the past. The lung has a complex architecture, where structural cells interact continuously with immune cells that infiltrate into the pulmonary tissue. Both types of cells express chemokines and chemokine receptors, making them sensitive to modifications of concentration gradients. Cigarette smoke exposure and recurrent exacerbations, directly and indirectly, impact the expression of chemokines and chemokine receptors. Here, we provide an overview of the evidence regarding chemokines involvement in COPD, and we hypothesize that a dysregulation of this tightly regulated system is critical in COPD evolution, both at a stable state and during exacerbations. Targeting chemokines and chemokine receptors could be highly attractive as a mean to control both chronic inflammation and bronchial remodeling. We present a special focus on the CXCL8-CXCR1/2, CXCL9/10/11-CXCR3, CCL2-CCR2, and CXCL12-CXCR4 axes that seem particularly involved in the disease pathophysiology.

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.

Although the memory capacity of innate immune cells, termed trained immunity (TI), is a conserved evolutionary trait, the cellular and molecular mechanisms involved are incompletely understood. One fundamental question is whether the induction of TI generates a homogeneous or heterogeneous population of trained cells. In this issue of the JCI, Zhang, Moorlag, and colleagues tackle this question by combining an in vitro model system of TI with single-cell RNA sequencing. The induction of TI in human monocytes resulted in three populations with distinct transcriptomic profiles. Interestingly, the presence of lymphocytes in the microenvironment of monocytes substantially impacted TI. The authors also identified a similar population of monocytes in various human diseases or in individuals vaccinated with bacillus Calmette-Guérin. These insights warrant in-depth analysis of TI in responsive versus nonresponsive immune cells and suggest that modulating TI may provide a strategy for treating infections and inflammatory diseases.

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  < 0.001 and p  = 0.001) as was mycobiota α -diversity (respectively p  = 0.03 and p  = 0.03). Both gut bacteriobiota and mycobiota Shannon index were independently associated with Day-28 mortality in multivariate analysis (respectively OR: 0.19, 97.5 CI [0.04–0.60], p  < 0.01 and OR: 0.29, 97.5 CI [0.09–0.75], p  = 0.02). Bacteriobiota β -diversity was significantly different between survivors and non-survivors ( p  = 0.05) but not mycobiota β -diversity ( p  = 0.57). Non-survivors had a higher abundance of Staphylococcus haemolyticus , Clostridiales sp., Campylobacter ureolyticus , Akkermansia sp., Malassezia sympodialis , Malassezia dermatis and Saccharomyces cerevisiae , whereas survivors had a higher abundance of Collinsella aerofaciens , Blautia sp., Streptococcus sp., Faecalibacterium prausnitzii and Bifidobacterium sp. Conclusion The gut bacteriobiota and mycobiota α diversities are independently associated with Day-28 mortality in critically ill patients. The causal nature of this interference and, if so, the underlying mechanisms should be further investigated to assess if gut microbiota modulation could be a future therapeutic approach.

Alveolar macrophages (AMs) reside in the lower airways and play a crucial role in lung health and response to sterile inflammation and infections. AMs possess remarkable adaptability to different environmental challenges that can persist through their memory capacity (trained immunity). β-Glucan has been characterized as a potent inducer of central trained immunity by reprogramming haematopoietic stem cells in the bone marrow. In the present study, we show that systemic administration of β-glucan in mice induces peripheral trained immunity by reprogramming AMs in the lungs, in a Dectin1-independent manner. We furthermore demonstrate that AM reprogramming at both the transcriptional and metabolic levels exacerbate lung injury following bacterial (lipopolysaccharide) or viral (polyI:C) challenges via a neutrophil/IFN-γ-dependent manner. These findings identify an additional facet of β-glucan in trained immunity involving AM reprogramming and shed light on the potential detrimental effects of trained immunity.

To the editor Since the first wave of COVID-19, the management of patients with severe COVID-19 in intensive care unit (ICU) has changed with the widespread use of dexamethasone (DXM) in severe patients [1]. [...]in another report, we recently described a 15% incidence of chronic kidney disease (CKD) at 3 months after COVID-19-induced AKI [6], all of these patients developing acute kidney disease (AKD) before CKD. SEE PDF] Risk factors for AKD In univariate analysis, prior CKD (OR = 13.8 [3.14–97.44]), chronic respiratory disease (OR = 5.16 [1.54–19.19]), immunosuppression (OR = 7.67 [1.60–55.75]) were significantly associated with AKD.

Background Animal models and, in particular, mice models, are important tools to investigate the pathogenesis of respiratory diseases and to test potential new therapeutic drugs. Lung function measurement is a key step in such investigation. In mice, it is usually performed using forced oscillation technique (FOT), negative pressure-driven forced expiratory (NPFE) and pressure-volume (PV) curve maneuvers. However, these techniques require a tracheostomy, which therefore only allows end-point measurements. Orotracheal intubation has been reported to be feasible and to give reproducible lung function measurements, but the agreement between intubation and tracheostomy generated-data remains to be tested. Methods Using the Flexivent system, we measured lung function parameters (in particular, forced vital capacity (FVC), forced expiratory volume in the first 0.1 s (FEV0.1), compliance (Crs) of the respiratory system, compliance (C) measured using PV loop and an estimate of inspiratory capacity (A)) in healthy intubated BALB/cJ mice and C57BL/6 J mice and compared the results with similar measurements performed in the same mice subsequently tracheostomized after intubation, by means of paired comparison method, correlation and Bland-Altman analysis. The feasibility of repetitive lung function measurements by intubation was also tested. Results We identified parameters that are accurately evaluated in intubated animals (i.e., FVC, FEV0.1, Crs, C and A in BALB/cJ and FVC, FEV0.1, and A in C57BL/6 J). Repetitive lung function measurements were obtained in C57BL/6 J mice. Conclusion This subset of lung function parameters in orotracheally intubated mice is reliable, thereby allowing relevant longitudinal studies.

Background Acute respiratory distress syndrome (ARDS) is responsible for 400,000 deaths annually worldwide. Few improvements have been made despite five decades of research, partially because ARDS is a highly heterogeneous syndrome including various types of aetiologies. Lower airway microbiota is involved in chronic inflammatory diseases and recent data suggest that it could also play a role in ARDS. Nevertheless, whether the lower airway microbiota composition varies between the aetiologies of ARDS remain unknown. The aim of this study is to compare lower airway microbiota composition between ARDS aetiologies, i.e. pulmonary ARDS due to influenza, SARS-CoV-2 or bacterial infection. Methods Consecutive ARDS patients according to Berlin’s classification requiring invasive ventilation with PCR-confirmed influenza or SARS-CoV-2 infections and bacterial infections (> 105 CFU/mL on endotracheal aspirate) were included. Endotracheal aspirate was collected at admission, V3-V4 and ITS2 regions amplified by PCR, deep-sequencing performed on MiSeq sequencer (Illumina®) and data analysed using DADA2 pipeline. Results Fifty-three patients were included, 24 COVID-19, 18 influenza, and 11 bacterial CAP-related ARDS. The lower airway bacteriobiota and mycobiota compositions (β-diversity) were dissimilar between the three groups ( p  = 0.05 and p  = 0.01, respectively). The bacterial α-diversity was significantly lower in the bacterial CAP-related ARDS group compared to the COVID-19 ARDS group ( p  = 0.04). In contrast, influenza-related ARDS patients had higher lung mycobiota α-diversity than the COVID-19-related ARDS ( p  = 0 < 01). Conclusion Composition of lower airway microbiota (both microbiota and mycobiota) differs between influenza, COVID-19 and bacterial CAP-related ARDS. Future studies investigating the role of lung microbiota in ARDS pathophysiology should take aetiology into account.

Background Thrombo-inflammation and neutrophil extracellular traps (NETs) are exacerbated in severe cases of COVID-19, potentially contributing to disease exacerbation. However, the mechanisms underpinning this dysregulation remain elusive. We hypothesised that lower DNase activity may be associated with higher NETosis and clinical worsening in patients with COVID-19. Methods Biological samples were obtained from hospitalized patients (15 severe, 37 critical at sampling) and 93 non-severe ambulatory cases. Our aims were to compare NET biomarkers, functional DNase levels, and explore mechanisms driving any imbalance concerning disease severity. Results Functional DNase levels were diminished in the most severe patients, paralleling an imbalance between NET markers and DNase activity. DNase1 antigen levels were higher in ambulatory cases but lower in severe patients. DNase1L3 antigen levels remained consistent across subgroups, not rising alongside NET markers. DNASE1 polymorphisms correlated with reduced DNase1 antigen levels. Moreover, a quantitative deficiency in plasmacytoid dendritic cells (pDCs), which primarily express DNase1L3 , was observed in critical patients. Analysis of public single-cell RNAseq data revealed reduced DNase1L3 expression in pDCs from severe COVID-19 patient. Conclusion Severe and critical COVID-19 cases exhibited an imbalance between NET and DNase functional activity and quantity. Early identification of NETosis imbalance could guide targeted therapies against thrombo-inflammation in COVID-19-related sepsis, such as DNase administration, to avert clinical deterioration. Trial registration : COVERAGE trial (NCT04356495) and COLCOV19-BX study (NCT04332016). Graphical Abstract

Background Group A Streptococcus is responsible for severe and potentially lethal invasive conditions requiring intensive care unit (ICU) admission, such as streptococcal toxic shock-like syndrome (STSS). A rebound of invasive group A streptococcal (iGAS) infection after COVID-19-associated barrier measures has been observed in children. Several intensivists of French adult ICUs have reported similar bedside impressions without objective data. We aimed to compare the incidence of iGAS infection before and after the COVID-19 pandemic, describe iGAS patients’ characteristics, and determine ICU mortality associated factors. Methods We performed a retrospective multicenter cohort study in 37 French ICUs, including all patients admitted for iGAS infections for two periods: two years before period (October 2018 to March 2019 and October 2019 to March 2020) and a one-year after period (October 2022 to March 2023) COVID-19 pandemic. iGAS infection was defined by Group A Streptococcus isolation from a normally sterile site. iGAS infections were identified using the International Classification of Diseases and confirmed with each center's microbiology laboratory databases. The incidence of iGAS infections was expressed in case rate. Results Two hundred and twenty-two patients were admitted to ICU for iGAS infections: 73 before and 149 after COVID-19 pandemic. Their case rate during the period before and after COVID-19 pandemic was 205 and 949/100,000 ICU admissions, respectively ( p  < 0.001), with more frequent STSS after the COVID-19 pandemic (61% vs. 45%, p  = 0.015). iGAS patients ( n  = 222) had a median SOFA score of 8 (5–13), invasive mechanical ventilation and norepinephrine in 61% and 74% of patients. ICU mortality in iGAS patients was 19% (14% before and 22% after COVID-19 pandemic; p  = 0.135). In multivariate analysis, invasive mechanical ventilation (OR = 6.08 (1.71–21.60), p  = 0.005), STSS (OR = 5.75 (1.71–19.22), p  = 0.005), acute kidney injury (OR = 4.85 (1.05–22.42), p  = 0.043), immunosuppression (OR = 4.02 (1.03–15.59), p  = 0.044), and diabetes (OR = 3.92 (1.42–10.79), p  = 0.008) were significantly associated with ICU mortality. Conclusion The incidence of iGAS infections requiring ICU admission increased by 4 to 5 after the COVID-19 pandemic. After the COVID-19 pandemic, the rate of STSS was higher, with no significant increase in ICU mortality rate.