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Sami Hraiech,1,2 Fabienne Brégeon,1,3 Jean-Marc Rolain1 1Institut Hospitalo-Universitaire Méditerranée Infection, URMITE CNRS IRD INSERM UMR 7278, 2Réanimation Médicale – Détresses Respiratoires et Infections Sévères, APHM, CHU Nord, 3Service d’Explorations Fonctionnelles Respiratoires, APHM, CHU Nord, Marseille, France Abstract: Pulmonary infections involving Pseudomonas aeruginosa are among the leading causes of the deterioration of the respiratory status of cystic fibrosis (CF) patients. The emergence of multidrug-resistant strains in such populations, favored by iterative antibiotic cures, has led to the urgent need for new therapies. Among them, bacteriophage-based therapies deserve a focus. One century of empiric use in the ex-USSR countries suggests that bacteriophages may have beneficial effects against a large range of bacterial infections. Interest in bacteriophages has recently renewed in Western countries, and the in vitro data available suggest that bacteriophage-based therapy may be of significant interest for the treatment of pulmonary infections in CF patients. Although the clinical data concerning this specific population are relatively scarce, the beginning of the first large randomized study evaluating bacteriophage-based therapy in burn infections suggests that the time has come to assess the effectiveness of this new therapy in CF P. aeruginosa pneumonia. Consequently, the aim of this review is, after a brief history, to summarize the evidence concerning bacteriophage efficacy against P. aeruginosa and, more specifically, the in vitro studies, animal models, and clinical trials targeting CF. Keywords: pneumonia, pulmonary infection, bacterial infection, multidrug resistance

OBJECTIVE: Although aspiration pneumonitis is a severe complication in patients hospitalized in intensive care units, its pathogenesis is poorly understood. The aim of this study was to determine whether the intensity of lung injury and inflammation developing after aspiration during mechanical ventilation differed depending on the inflammatory activity of intensive care unit patients' gastric fluid. DESIGN: In vitro study on human gastric juice and randomized controlled animal study. SETTING: Research laboratories of academic institutions. SUBJECTS: Male New-Zealand white rabbits. INTERVENTIONS: Proinflammatory activity of gastric juice from 17 intensive care unit patients and 12 controls undergoing elective surgery was measured based on a target cell activation assay. Two gastric juices from intensive care unit patients with similar pH but differing for their in vitro proinflammatory activity (high and low) were further instilled into the trachea of ventilated rabbits. Lung function, mechanics, pathology, leukocyte infiltration, and local cytokine levels were measured after 6 hrs. MEASUREMENTS AND MAIN RESULTS: Gastric juice from intensive care unit patients, even buffered at pH 7.4, stimulated human type II-like A549 epithelial cells to up-regulate intercellular adhesion molecule-1 and interleukin-8, significantly more than juice obtained in controls. Gastric juice from an intensive care unit patient supporting high proinflammatory activity in vitro also induced a more severe and persistent drop in PaO2/FIO2 and respiratory system compliance in ventilated rabbits, a worse histologic score, higher lung lavage concentrations of inflammatory cells, interleukin-8 (p < 0.01), and growth-related oncogene-alpha (p < 0.01) than one fluid with low proinflammatory activity. CONCLUSION: Gastric juice from critically ill patients is proinflammatory and stimulates human pulmonary cells in vitro. A human gastric juice with high proinflammatory activity is more 'toxic' to the lung than one with low proinflammatory activity in a ventilated rabbit model, an effect that is independent of pH and particulate matter content. [ABSTRACT FROM AUTHOR]

BACKGROUND: Currently, there are limited data available describing the long-term outcomes of chest trauma survivors. Here, the authors sought to describe chest trauma survivor outcomes 6 months and 1 yr after discharge from the intensive care unit, paying special attention to pulmonary outcomes. METHODS: A cohort of 105 multiple trauma patients with blunt chest trauma admitted to the intensive care unit was longitudinally evaluated. After 6 months, a chest computed tomography scan, pulmonary function testing (PFT), and quality of life were collected in 55 of these patients. A subgroup of 38 patients was followed up for 1 yr. RESULTS: At least one abnormal PFT result was found in 39 patients (71%). Compared with normalized data of the age- and sex-matched population, physical function was decreased in 38 patients (70%). The 6-min walk distance was reduced for 29 patients (72%). Although pathologic images were observed on the chest computed tomography scan from 33 patients (60%), no relation was found between PFT and computed tomography. A ratio of arterial oxygen pressure to inspired oxygen fraction less than 200 at admission to the intensive care unit predicted an abnormal PFT result at 6 months. One year after discharge from the intensive care unit, paired comparisons showed a significant increase in forced vital capacity (P = 0.02) and Karnofsky Performance Status (P < 0.001). CONCLUSIONS: Survivors of multiple traumas including chest trauma demonstrate a persistent decrease in the 6-min walk distance, impairment on PFT, and reduced pulmonary-specific quality of life. [ABSTRACT FROM AUTHOR]

Sami Hraiech,1,2 Laurent Papazian,1,2 Jean-Marc Rolain,1 Fabienne Bregeon1,3IHU Méditerranée Infection, URMITE CNRS IRD INSERM UMR 7278, Marseille, France; 2Réanimation – Détresses respiratoires et Infections Sévères, APHM, CHU Nord, Marseille, France; 3Service d’Explorations Fonctionnelles Respiratoires, APHM, CHU Nord, Marseille, FranceAbstract: Pneumonia is one of the leading causes of severe and occasionally life-threatening infections. The physiopathology of pneumonia has been extensively studied, providing information for the development of new treatments for this condition. In addition to in vitro research, animal models have been largely used in the field of pneumonia. Several models have been described and have provided a better understanding of pneumonia under different settings and with various pathogens. However, the concept of one pathogen leading to one infection has been challenged, and recent flu epidemics suggest that some pathogens exhibit highly virulent potential. Although “two hits” animal models have been used to study infectious diseases, few of these models have been described in pneumonia. Therefore the aims of this review were to provide an overview of the available literature in this field, to describe well-studied and uncommon pathogen associations, and to summarize the major insights obtained from this information.Keywords: pneumonia, animal model, co-infections, polymicrobial, route of infection

Background: Ultrasound has demonstrated its interest in the analysis of diaphragm function in patients with respiratory failure. The criteria used to diagnose hemidiaphragm paralysis are not well defined., Methods: The aim of this observational retrospective study was to describe the ultrasound findings in 103 patients with diaphragm paralysis, previously diagnosed by conventional methods after various circumstances such as trauma or surgery. The ultrasound study included the recording of excursions of both diaphragmatic domes and the measurement of inspiratory thickening., Results: On paralyzed hemidiaphragm, thickening was less than 20% in all patients during deep inspiration. Thinning was recorded in 53% of cases. In some cases, the recording of the thickening could be difficult. The study of motion during voluntary sniffing reported a paradoxical excursion in all but one patient. During quiet breathing, an absence of movement or a paradoxical displacement was observed. During deep inspiration, a paradoxical motion at the beginning of inspiration followed by a reestablishment of movement in the cranio-caudal direction was seen in 82% of cases. In some patients, there was a lack of movement followed, after an average delay of 0.4 s, by a cranio-caudal excursion. Finally, in 4 patients no displacement was recorded. Evidence of hyperactivity (increased inspiratory thickening and excursion) of contralateral non-paralyzed hemidiaphragm was observed., Conclusion: To accurately detect hemidiaphragm paralysis, it would be interesting to combine the ultrasound study of diaphragm excursion and thickening. The different profiles reported by our study must be known to avoid misinterpretation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boussuges, Fourdrain, Leone, Brioude, Menard, Zieleskiewicz, Delliaux, Gouitaa, Dutau and Brégeon.)

We aimed to develop a systemic sclerosis (SSc) subtypes classifier tool to be used at the patient's bedside. We compared the heart rate variability (HRV) at rest (5-min) and in response to orthostatism (5-min) of patients (n = 58) having diffuse (n = 16, dcSSc) and limited (n = 38, lcSSc) cutaneous forms. The HRV was evaluated from the beat-to-beat RR intervals in time-, frequency-, and nonlinear-domains. The dcSSc group differed from the lcSSc group mainly by a higher heart rate (HR) and a lower HRV, in decubitus and orthostatism conditions. Stand-up maneuver lowered HR standard deviation (sd&#95;HR), the major axis length of the fitted ellipse of Poincaré plot of RR intervals (SD2), and the correlation dimension (CorDim) in the dcSSc group while increased these HRV indexes in the lcSSc group (p = 0.004, p = 0.002, and p = 0.004, respectively). We identified the 5 most informative and discriminant HRV variables. We then compared 341 classifying models (1 to 5 variables combinations × 11 classifier algorithms) according to mean squared error, logloss, sensitivity, specificity, precision, accuracy, area under curve of the ROC-curves and F1-score. F1-score ranged from 0.823 for the best 1-variable model to a maximum of 0.947 for the 4-variables best model. Most specific and precise models included sd&#95;HR, SD2, and CorDim. In conclusion, we provided high performance classifying models able to distinguish diffuse from limited cutaneous SSc subtypes easy to perform at the bedside from ECG recording. Models were based on 1 to 5 HRV indexes used as nonlinear markers of autonomic integrated influences on cardiac activity., (© 2024. The Author(s).)

Background: Although previous studies have determined limit values of normality for diaphragm excursion and thickening, it would be beneficial to determine the normal diaphragm motion-to-inspired volume ratio that integrates the activity of the diaphragm and the quality of the respiratory system., Methods: To determine the normal values of selected ultrasound diaphragm motion-volume indices, subjects with normal pulmonary function testing were recruited. Ultrasound examination recorded diaphragm excursion on both sides during quiet breathing and deep inspiration. Diaphragm thickness was also measured. The inspired volumes of the corresponding cycles were systematically recorded using a spirometer. The indices were calculated using the ratio excursion, or percentage of thickening, divided by the corresponding breathing volume. From this corhort, normal values and limit values for normality were determined. These measurements were compared to those performed on the healthy side in patients with hemidiaphragm paralysis because an increase in hemidiaphragm activity has been previously demonstated in such circumstances., Results: A total of 122 subjects (51 women, 71 men) with normal pulmonary function were included in the study. Statistical analysis revealed that the ratio of excursion, or percentage of thickening, to inspired volume ratio significantly differed between males and females. When the above-mentioned indices using excursion were normalized by body weight, no gender differences were found. The indices differed between normal respiratory function subjects and patients with hemidiaphragm paralysis (27 women, 41 men). On the paralyzed side, the average ratio of the excursion divided by the inspired volume was zero. On the healthy side, the indices using the excursion and the percentage of thickening during quiet breathing or deep inspiration were significantly increased comparedto patients with normal lung function. According to the logistic regression analysis, the most relevant indice appeared to be the ratio of the excursion measured during quiet breathing to the inspired volume., Conclusion: The normal values of the diaphragm motion-volume indices could be useful to estimate the performance of the respiratory system. Proposed indices appear suitable in a context of hyperactivity., Competing Interests: GC was employed by AltraBio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boussuges, Chaumet, Boussuges, Menard, Delliaux and Brégeon.)

Background: SARS-CoV-2 infection can impair diaphragm function at the acute phase but the frequency of diaphragm dysfunction after recovery from COVID-19 remains unknown., Materials and Methods: This study was carried out on patients reporting persistent respiratory symptoms 3-4 months after severe COVID-19 pneumonia. The included patients were selected from a medical consultation designed to screen for recovery after acute infection. Respiratory function was assessed by a pulmonary function test, and diaphragm function was studied by ultrasonography., Results: In total, 132 patients (85M, 47W) were recruited from the medical consultation. During the acute phase of the infection, the severity of the clinical status led to ICU admission for 58 patients (44%). Diaphragm dysfunction (DD) was detected by ultrasonography in 13 patients, two of whom suffered from hemidiaphragm paralysis. Patients with DD had more frequently muscle pain complaints and had a higher frequency of prior cardiothoracic or upper abdominal surgery than patients with normal diaphragm function. Pulmonary function testing revealed a significant decrease in lung volumes and DLCO and the dyspnea scores (mMRC and Borg10 scores) were significantly increased in patients with DD. Improvement in respiratory function was recorded in seven out of nine patients assessed 6 months after the first ultrasound examination., Conclusion: Assessment of diaphragm function by ultrasonography after severe COVID-19 pneumonia revealed signs of dysfunction in 10% of our population. In some cases, ultrasound examination probably discovered an un-recognized pre-existing DD. COVID-19 nonetheless contributed to impairment of diaphragm function. Prolonged respiratory physiotherapy led to improvement in respiratory function in most patients., Clinical Trial Registration: [www.cnil.fr], identifier [#PADS20-207]., Competing Interests: GC was employed by ALTRA BIO. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2022 Boussuges, Habert, Chaumet, Rouibah, Delorme, Menard, Million, Bartoli, Guedj, Gouitaa, Zieleskiewicz, Finance, Coiffard, Delliaux and Brégeon.)

Background: Inspiratory loading is experienced by military divers when they use rebreather device. Our objective was to assess the changes in diaphragm function induced by an increase in inspiratory load at values similar to those experienced by divers in real life. Methods : We recorded the excursion and the thickness of the right hemidiaphragm in 22 healthy male volunteers under inspiratory load conditions, using ultrasound in B- and M-mode. The measurements were performed at tidal volume and during breathing at 50% of inspiratory capacity. The breathing rate was regulated and similar in the various sessions with and without load. Results: The rebreather device used by French military divers leads to an increase in inspiratory load of close to 30 cmH 2 O. Consequently, the session under load was performed using a device set to this threshold. Significant increases in the excursion and the thickening fraction of the diaphragm were observed between the sessions at tidal volume and at high volume. With addition of the inspiratory load, the excursion of the right hemidiaphragm increased significantly from 2.3 to 3.4cm at tidal volume and from 3.9 to 4.7cm at high volume. The thickening fraction increased significantly from 30.4 to 76.6% at tidal volume and from 70 to 123% at high volume. The statistical analysis demonstrated that assessment of the changes of the thickening fraction during breathing at tidal volume was the most relevant marker to assess the impact of the inspiratory load on the diaphragm. Conclusion: Diaphragm ultrasound can be used to assess the changes in the diaphragm contraction pattern secondary to an increase in the respiratory load that can be generated by use a diving apparatus. The recording of the changes of the motion, and more importantly of the thickness of the diaphragm, during the breathing cycle is able to provide relevant information regarding the inspiratory load., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rives, Schmid, Chaumet, Brégeon and Boussuges.)

Background: Diagnosing diaphragm dysfunction in the absence of complete paralysis remains difficult. The aim of the present study was to assess the normal values of the thickness and the inspiratory thickening of both hemidiaphragms as measured by ultrasonography in healthy volunteers while in a seated position. Methods: Healthy volunteers with a normal pulmonary function test were recruited. The diaphragmatic thickness was measured on both sides at the zone of apposition of the diaphragm to the rib cage during quiet breathing at end-expiration, end-inspiration, and after maximal inspiration. The thickening ratio, the thickening fraction, and the thickness at end-inspiration divided by the thickness at deep breathing were determined. The mean values and the lower and upper limits of normal were determined for men and women. Results: 200 healthy volunteers (100 men and 100 women) were included in the study. The statistical analysis revealed that women had a thinner hemidiaphragm than men on both sides and at the various breathing times studied. The lower limit of normality of the diaphragm thickness measured at end-expiration was estimated to be 1.3 mm in men and 1.1 mm in women, on both sides. The thickening fraction did not differ significantly between men and women. In men, it ranged from 60 to 260% on the left side and from 57 to 200% on the right side. In women, it ranged from 58 to 264% on the left side and from 60 to 229% on the right side. The lower limits of normality of the thickening fraction were determined to be 40 and 39% in men and 39 and 48% in women for the right and left hemidiaphragms, respectively. The upper limit for normal of the mean of both sides of the ratio thickness at end-inspiration divided by the thickness at deep breathing was determined to be 0.78 in women and 0.79 in men. Conclusion: The normal values of thickness and the indexes of diaphragmatic function should help clinicians with detecting diaphragm atrophy and dysfunction., Competing Interests: GC was employed by ALTRA BIO SA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boussuges, Rives, Finance, Chaumet, Vallée, Risso and Brégeon.)

Chest ultrasonography has proven to be useful in the diagnosis of diaphragm dysfunction. The aim of the present study was to determine the normal values of the motion of both hemidiaphragms recorded by M-mode ultrasonography. Healthy volunteers were studied while in a seated position. Diaphragmatic excursions and diaphragm profiles were measured during quiet breathing, voluntary sniffing and deep breathing. Diaphragmatic excursions were assessed by M-mode ultrasonography, using an approach perpendicular to the posterior part of the diaphragm. Anatomical M-mode was used for the recording of the complete excursion during deep breathing. The study included 270 men and 140 women. The diaphragmatic motions during quiet breathing and voluntary sniffing were successfully recorded in all of the participants. The use of anatomical M-mode was particularly suitable for measurement of the entire diaphragmatic excursion during deep breathing. The statistical analysis showed that the diaphragmatic excursions were larger in men compared to women, supporting the determination of normal values based on sex. The lower and upper limits of normal excursion were determined for men and women for both hemidiaphragms during the three manoeuvres that were investigated. The lower limits of normal diaphragmatic excursions during deep breathing should be used to detect diaphragmatic hypokinesia, i.e. 3.3 and 3.2 cm in women and 4.1 and 4.2 cm in men for the right and the left sides, respectively. The normal values of the diaphragmatic motion and the lower and upper limits of normal excursion can be used by clinicians to detect diaphragmatic dysfunction., Competing Interests: Conflict of interest: A. Boussuges has nothing to disclose. Conflict of interest: J. Finance has nothing to disclose. Conflict of interest: G. Chaumet has nothing to disclose. Conflict of interest: F. Bregeon has nothing to disclose., (Copyright ©The authors 2021.)

Methanogens, the sole microbes producing methane, are archaea commonly found in human anaerobic microbiota. Methanogens are emerging as opportunistic pathogens associated with dysbiosis and are also detected and cultured in anaerobic abscesses. Their presence in the respiratory tract is yet unknown. As a preliminary answer, prospective investigation of 908 respiratory tract samples using polyphasic approach combining PCR-sequencing, real-time PCR, fluorescent in situ hybridization (FISH), and methanogens culture was carried out. Methanobrevibacter smithii and Methanobrevibacter oralis DNA sequences, were detected in 21/527 (3.9%) sputum samples, 2/188 (1.06%) bronchoalveolar lavages, and none of 193 tracheo-bronchial aspirations. Further, fluorescence in situ hybridization detected methanogens in three sputum investigated specimens with stick morphology suggesting M. oralis and in another one bronchoalveolar lavage sample investigated, diplococal morphology suggesting M. smithii . These observations extend the known territory of methanogens to the respiratory tract and lay the foundations for further interpretation of their detection as pathogens in any future cases of isolation from bronchoalveolar lavages and the lungs.

This article reports the various methods used to assess diaphragmatic function by ultrasonography. The excursions of the two hemidiaphragms can be measured using two-dimensional or M-mode ultrasonography, during respiratory maneuvers such as quiet breathing, voluntary sniffing and deep inspiration. On the zone of apposition to the rib cage for both hemidiaphragms, it is possible to measure the thickness on expiration and during deep breathing to assess the percentage of thickening during inspiration. These two approaches make it possible to assess the quality of the diaphragmatic function and the diagnosis of diaphragmatic paralysis or dysfunction. These methods are particularly useful in circumstances where there is a high risk of phrenic nerve injury or in diseases affecting the contractility or the motion of the diaphragm such as neuro-muscular diseases. Recent methods such as speckle tracking imaging and ultrasound shear wave elastography should provide more detailed information for better assessment of diaphragmatic function., Competing Interests: Conflict-of-interest statement: No conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Human tuberculosis is a life-threatening infection following the inhalation of Mycobacterium tuberculosis, while the closely related bacteria Mycobacterium bovis and Mycobacterium canettii are thought to be transmitted by ingestion. To explore whether M. tuberculosis could also infect individuals by ingestion, male BALBc mice were fed 2 x 106 CFUs of M. tuberculosis Beijing or phosphate-buffered saline as a negative control, over a 28-day experiment. While eight negative control mice remained disease-free, M. tuberculosis was identified in the lymph nodes and lungs of 8/14 mice and in the spleens of 4/14 mice by microscopy, PCR-based detection and culture. Whole-genome sequencing confirmed the identity of the inoculum and the tissue isolates. In these genetically identical mice, the dissemination of M. tuberculosis correlated with the results of the culture detection of four intestinal bacteria. These observations indicate that ingested M. tuberculosis mycobacteria can translocate, notably provoking lymphatic tuberculosis., Competing Interests: The authors have declared that no competing interests exist.

Many bacteria use quorum sensing (QS), a bacterial communication system based on the diffusion and perception of small signaling molecules, to synchronize their behavior in a cell-density dependent manner. QS regulates the expression of many genes associated with virulence factor production and biofilm formation. This latter is known to be involved in antibiotic and phage resistance mechanisms. Therefore, disrupting QS, a strategy known as quorum quenching (QQ), appears to be an interesting way to reduce bacterial virulence and increase antibiotic and phage treatment efficiency. In this study, the ability of the QQ enzyme Sso Pox-W263I, a lactonase able to degrade acyl-homoserine lactones, was investigated for quenching both virulence and biofilm formation in clinical isolates of Pseudomonas aeruginosa from diabetic foot ulcers, as well as in the PA14 model strain. These strains were further evolved to resist to bacteriophage cocktails. Overall, 10 antibiotics or bacteriophage resistant strains were evaluated and Sso Pox-W263I was shown to decrease pyocyanin, protease and elastase production in all strains. Furthermore, a reduction of more than 70% of biofilm formation was achieved in six out of ten strains. This anti-virulence potential was confirmed in vivo using an amoeba infection model, showing enhanced susceptibility toward amoeba of nine out of ten P. aeruginosa isolates upon QQ. This amoeba model was further used to demonstrate the ability of Sso Pox-W263I to enhance the susceptibility of sensitive and phage resistant bacteria to bacteriophage and antibiotic.