Progressive Lung Damage Research Articles

Mesenchymal Stem Cell Therapy Mitigates Acute and Chronic Lung Damages of Sulfur Mustard Analog Exposure

Sulfur mustard (SM) is an established chemical weapon that can result in severe damage to parts of the body. Currently, there are no effective treatments available for SM-caused damage. We aimed to investigate the therapeutic potential of adipose-derived mesenchymal stromal cells (AD-MSCs) and conditioned medium (CM-MSCs) in acute and chronic pulmonary mouse models caused by 2-chloroethyl ethyl sulfide (CEES), an SM analog. The mice were divided into 4 experimental groups:(1) CEES+AD-MSCs, (2) CEES+CM-MSCs, (3) CEES, and (4) control. The model observation time was divided into 7 days for the short and 6 months for the long term. AD-MSCs were injected into mice via intraperitoneal injection 24 hours after CEES exposure. The therapeutic effects of AD-MSCs on pulmonary tissue damage were assessed using a histopathologic assay, measuring the neutrophil count, and bronchial alveolar lavage fluid (BALF) protein level. The levels of inflammatory and anti-inflammatory cytokines were evaluated using the enzyme-linked immunosorbent assay as the outcomes of interest. Lung damage progression was reduced by AD-MSC treatment in mice after CEES injection into the peritoneum. The proportion of CD11b+F4/80+ macrophages in the peritoneum was significantly lowered by AD-MSC treatment following CEES exposure. AD-MSC administration also reduced the level of pro-inflammatory cytokines, BALF protein, and nitric oxide levels in the peritoneal cavity. By reducing inflammation and enhancing tissue healing, AD-MSCs and CM-MSC help prevent acute lung damage caused by CEES. The current study supports the use of a mouse model as a solid experimental foundation and indicates potential use for future cell treatment.

Noninvasive biomarkers for the detection of GERD-induced pulmonary injury.

The role of gastroesophageal reflux in progressive lung damage is increasingly recognized. We have proposed, based on our work with lung transplant recipients, a novel immune mechanism of pulmonary injury after aspiration of gastric contents, during which higher levels of normally sequestered lung self-antigens (SAgs) collagen V (Col-V) and K-alpha-1 tubulin (Kα1T) in circulating small extracellular vesicles (EVs) induce the production of self-antibodies (SAbs) anti-Col-V and anti-Kα1T. Thus, we aimed to determine whether levels of SAbs or SAgs increased in an animal model of aspiration-induced lung damage in a nontransplant setting. We created a murine model of repetitive lung aspiration using C57BL/6J mice. Mice were aspirated weekly with 1mL/kg of hydrochloric acid (n = 9), human gastric contents (n = 9), or combined (1:1) fluid (n = 9) once, three, or six times (n = 3 in each subgroup; control group, n = 9). Blood samples were periodically obtained, and all animals were sacrificed at day 90 for pathological assessment. SAbs were measured using an enzyme-linked immunosorbent assay; SAgs and NF-κB contained in small EVs were assessed by western blot. Aspirated mice weighed significantly less than controls throughout the study and had histological evidence of pulmonary injury at day 90. Overall, aspirated mice developed higher concentrations of anti-Col-V at day 28 (53.9 ± 28.7 vs. 29.9 ± 4.5ng/mL, p < 0.01), day 35 (42.6 ± 19.8 vs. 28.6 ± 7.2ng/mL, p = 0.038), and day 90 (59.7 ± 27.7 vs. 34.1 ± 3.2ng/mL, p = 0.014) than the control group. Circulating small EVs isolated from aspirated mice on day 90 contained higher levels of Col-V (0.7 ± 0.56 vs. 0.18 ± 0.6m.o.d., p = 0.009) and NF-κB (0.42 ± 0.27 vs. 0.27 ± 0.09m.o.d., p = 0.095) than those from controls. This experimental study supports the theory that gastroesophageal reflux leads to the development of lung damage and an increase of humoral markers that may serve as noninvasive biomarkers to detect asymptomatic lung injury among patients with gastroesophageal reflux disease.

Design of N-acetylcysteine vesicles as a potential chemopreventive tool in lung cancer: Characterization, Tc-99 m radiolabeling and in vivo evaluation

Lung cancer is a type of cancer which is characterized by high incidence and elevated mortality rate. In an attempt to counteract the carcinogens’ load and prevent the development of lung cancer especially in heavy smokers, chemoprevention has emerged as a promising strategy in this regard. Among the popular chemopreventive agents is N-acetyl cysteine (NAC), which prevents the progression of lung damage by virtue of its antioxidant and anti-inflammatory properties. In order to increase the amount of NAC reaching the lung following intravenous administration, the current work explored its formulation in transcutol-containing liposomes. The vesicles prepared using the ethanol injection method were characterized in vitro for their particle size, zeta potential, polydispersity, entrapment efficiency, storage stability, drug release, antioxidant and anti-inflammatory properties, safety and morphology. Their in vivo biodistribution was assessed in body organs after radiolabeling with technetium-99 m. Results showed that the transcutol-containing liposomes exhibited a particle size of 250 ± 17 nm, a zeta potential of −18.90 ± 2.30, entrapment efficiency 41 % ± 3.4, sustained release, and they preserved the antioxidant and anti-inflammatory properties of the encapsulated NAC. The biodistribution study delineated that NAC was deposited about three-fold higher in the lung when administered in transcutol-containing liposomes compared to the solution form. Therefore, it can be concluded that transcutol-containing liposomes is a promising lung-targeting modality for delivering NAC, which is worthy of further exploration with other drugs targeting pulmonary diseases.

Bronquiectasias: enfoque diagnóstico y terapéutico

Bronchiectasis is a chronic inflammatory disease of the airways that is manifested by chronic cough, mucosal o mucopurulent bronchorrhea, and recurrent exacerbations. Its etiology is varied, but it is essential within its study to try to identify the cause to avoid progressive lung damage, a product of the so-called “vicious circle” with recurrent infections, inflammation and permanent structural damage. The diagnosis is clinical and must be confirmed by performing a high-resolution chest computed tomography. Therapeutic management should be aimed at controlling infection and bronchial inflammation, as well as managing associated complications and comorbidities.

Pathomorphology of the heart in COVID-19

Cardiovascular system is a significant target for SARS-CoV-2.The objective was to study morphological changes in the heart in patients who died from COVID-19.Materials and methods. Autopsy material of the heart of those who died from COVID-19 (700 autopsies) was analyzed. The analysis of autopsy protocols was carried out, macroscopic changes were assessed, histological preparations stained with hematoxylin and eosin, van Gieson stain, Schiff’s reagent, the results of immunohistochemistry with antibodies to CD68, CD3, CD4, CD8, CD45 were analyzed.Results. The leading pathomorphological changes in the heart in COVID-19 are acute discirculatory changes with predominant disorders in small intramyocardial vessels. Lymphocytic myocarditis was confirmed in 1 % of cases.Conclusion. Damage to cardiomyocytes in COVID-19 is multifactorial and associated with manifestations of the underlying cardiovascular pathology, changes in intramyocardial vessels due to the action of SARS-CoV-2, and hypoxia due to progressive lung damage.

Cyclosporine A therapy in patients with COVID-19 and failure of immunosuppression therapy: a retrospective cohort propensity-score matched analysis

INTRODUCTION: Therapy of COVID-19 patients with progressive lung damage after the use of glucocorticosteroids (GCS) and interleukin-6 inhibitors (IIL-6) has not yet been developed. OBJECTIVE: Assessment of the effectiveness of cyclosporine A in patients with COVID-19 with progression of lung damage and hypoxemic acute respiratory failure, who received therapy with GCS and IIL-6. MATERIALS AND METHODS: A retrospective cohort propensity-score matched analysis (n = 98). Cyclosporine A was prescribed in the first 72–96 hours after IIL-6 administration when the patient's condition worsened. The patients of comparison group corresponded to the study group, but did not receive cyclosporine A therapy. The primary end point was in-hospital mortality. Secondary endpoints — duration of hospitalization, number of patients admitted to the intensive care unit (ICU), need for respiratory support. RESULTS: Mortality was 12 (22) % in the cyclosporine group and 27 (61) % in the comparison group, р = 0.001 (hazard ratio [HR] 2.00 (1.12–3.48), р = 0.018), ICU admission rate 14 (26) % vs 29 (66) %, р = 0.001, respectively. In the cyclosporine group on day 7 CT-4, there were 26 % of patients vs 52 % in the control group, р = 0.014, the need for respiratory support (37 % vs 63.6 %, р = 0.011); saturation 88 % (82–93) vs 80 % (70–86), р = 0.001, respectively. The need for respiratory support at day 11 after IIL-6 increased the likelihood of death (HR 7.10 (2.5–20), р = 0.001). Risk factors for death: age over 57.5 years, body mass index over 30 kg/m2, hemoglobin oxygen saturation below 85.5 % on the day of IIL-6 application. Duration of hospitalization was 18.5 (14–24) days vs 18 (12–24) days, р = 0.778. CONCLUSIONS: Cyclosporine A in addition to GCS and IIL-6 for COVID-19 therapy may reduce mortality, ICU admissions, and respiratory support requirements.

Type 1 diabetes contributes to combined pulmonary fibrosis and emphysema in male alpha 1 antitrypsin deficient mice.

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia and can affect multiple organs, leading to life-threatening complications. Increased prevalence of pulmonary disease is observed in T1D patients, and diabetes is a leading cause of comorbidity in several lung pathologies. A deficiency of alpha-1 antitrypsin (AAT) can lead to the development of emphysema. Decreased AAT plasma concentrations and anti-protease activity are documented in T1D patients. The objective of this study was to determine whether T1D exacerbates the progression of lung damage in AAT deficiency. First, pulmonary function testing (PFT) and histopathological changes in the lungs of C57BL/6J streptozotocin (STZ)-induced T1D mice were investigated 3 and 6 months after the onset of hyperglycemia. PFT demonstrated a restrictive pulmonary pattern in the lungs of STZ-injected mice, along with upregulation of mRNA expression of pro-fibrotic markers Acta2, Ccn2, and Fn1. Increased collagen deposition was observed 6 months after the onset of hyperglycemia. To study the effect of T1D on the progression of lung damage in AAT deficiency background, C57BL/6J AAT knockout (KO) mice were used. Control and STZ-challenged AAT KO mice did not show significant changes in lung function 3 months after the onset of hyperglycemia. However, histological examination of the lung demonstrated increased collagen accumulation and alveolar space enlargement in STZ-induced AAT KO mice. AAT pretreatment on TGF-β-stimulated primary lung fibroblasts reduced mRNA expression of pro-fibrotic markers ACTA2, CCN2, and FN1. Induction of T1D in AAT deficiency leads to a combined pulmonary fibrosis and emphysema (CPFE) phenotype in male mice.

Extracellular Acetylated Histone 3.3 Induces Inflammation and Lung Tissue Damage.

Extracellular histones, part of the protein group known as damage-associated molecular patterns (DAMPs), are released from damaged or dying cells and can instigate cellular toxicity. Within the context of chronic obstructive pulmonary disease (COPD), there is an observed abundance of extracellular histone H3.3, indicating potential pathogenic implications. Notably, histone H3.3 is often found hyperacetylated (AcH3.3) in the lungs of COPD patients. Despite these observations, the specific role of these acetylated histones in inducing pulmonary tissue damage in COPD remains unclear. To investigate AcH3.3's impact on lung tissue, we administered recombinant histones (rH2A, rH3.3, and rAcH3.3) or vehicle solution to mice via intratracheal instillation. After 48 h, we evaluated the lung toxicity damage and found that the rAcH3.3 treated animals exhibited more severe lung tissue damage compared to those treated with non-acetylated H3.3 and controls. The rAcH3.3 instillation resulted in significant histological changes, including alveolar wall rupture, epithelial cell damage, and immune cell infiltration. Micro-CT analysis confirmed macroscopic structural changes. The rAcH3.3 instillation also increased apoptotic activity (cleavage of caspase 3 and 9) and triggered acute systemic inflammatory marker activation (TNF-α, IL-6, MCP-3, or CXCL-1) in plasma, accompanied by leukocytosis and lymphocytosis. Confocal imaging analysis confirmed lymphocytic and monocytic/macrophage lung infiltration in response to H3.3 and AcH3.3 administration. Taken together, our findings implicate extracellular AcH3.3 in inducing cytotoxicity and acute inflammatory responses, suggesting its potential role in promoting COPD-related lung damage progression.

Higher levels of Pseudomonas aeruginosa LasB elastase expression are associated with early-stage infection in cystic fibrosis patients

Pseudomonas aeruginosa is a common pathogen in cystic fibrosis (CF) patients and a major contributor to progressive lung damage. P. aeruginosa elastase (LasB), a key virulence factor, has been identified as a potential target for anti-virulence therapy. Here, we sought to differentiate the P. aeruginosa isolates from early versus established stages of infection in CF patients and to determine if LasB was associated with either stage. The lasB gene was amplified from 255 P. aeruginosa clinical isolates from 70 CF patients from the Toulouse region (France). Nine LasB variants were identified and 69% of the isolates produced detectable levels of LasB activity. Hierarchical clustering using experimental and clinical data distinguished two classes of isolates, designated as ‘Early’ and ‘Established’ infection. Multivariate analysis revealed that the isolates from the Early infection class show higher LasB activity, fast growth, tobramycin susceptibility, non-mucoid, pigmented colonies and wild-type lasR genotype. These traits were associated with younger patients with polymicrobial infections and high pFEV1. Our findings show a correlation between elevated LasB activity in P. aeruginosa isolates and early-stage infection in CF patients. Hence, it is this patient group, prior to the onset of chronic disease, that may benefit most from novel therapies targeting LasB.

Pharmacological approaches to pulmonary fibrosis following COVID-19.

Background: In the past few years, COVID-19 became the leading cause of morbidity and mortality worldwide. Although the World Health Organization has declared an end to COVID-19 as a public health emergency, it can be expected, that the emerging new cases at the top of previous ones will result in an increasing number of patients with post-COVID-19 sequelae. Despite the fact that the majority of patients recover, severe acute lung tissue injury can in susceptible individuals progress to interstitial pulmonary involvement. Our goal is to provide an overview of various aspects associated with the Post-COVID-19 pulmonary fibrosis with a focus on its potential pharmacological treatment options. Areas covered: We discuss epidemiology, underlying pathobiological mechanisms, and possible risk and predictive factors that were found to be associated with the development of fibrotic lung tissue remodelling. Several pharmacotherapeutic approaches are currently being applied and include anti-fibrotic drugs, prolonged use or pulses of systemic corticosteroids and non-steroidal anti-inflammatory and immunosuppressive drugs. In addition, several repurposed or novel compounds are being investigated. Fortunately, clinical trials focused on pharmacological treatment regimens for post-COVID-19 pulmonary fibrosis have been either designed, completed or are already in progress. However, the results are contrasting so far. High quality randomised clinical trials are urgently needed with respect to the heterogeneity of disease behaviour, patient characteristics and treatable traits. Conclusion: The Post-COVID-19 pulmonary fibrosis contributes to the burden of chronic respiratory consequences among survivors. Currently available pharmacotherapeutic approaches mostly comprise repurposed drugs with a proven efficacy and safety profile, namely, corticosteroids, immunosuppressants and antifibrotics. The role of nintedanib and pirfenidone is promising in this area. However, we still need to verify conditions under which the potential to prevent, slow or stop progression of lung damage will be fulfilled.

IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.

Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice.

WS14.03 Combined therapeutic strategies for the restoration of airway epithelial integrity and function in cystic fibrosis

Background: In CF airways, dysfunctional Cl– secretion and mucociliary clearance favor bacterial infections contributing to progressive lung damage and respiratory failure, the first cause of morbidity and mortality. We thus devote our efforts to identify novel therapeutic strategies to promote CF lung repair. We previously discovered that the capability of CF airway epithelia to repair is less efficient, than in healthy controls, due to the CFTR defect and bacterial infections, in particular with P. aeruginosa (PA) and S. aureus (SA). Our work also unveiled that CFTR modulators enhance airway repair, but both CFTR rescue and repair improvement are dampened by infection.

Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.

Primary ciliary dyskinesia (PCD) is a rare heterogenic genetic disorder associated with perturbed biogenesis or function of motile cilia. Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive lung damage. Current approaches to treat PCD are symptomatic, only, indicating an urgent need for curative therapeutic options. Here, we developed an in vitro model for PCD based on human induced pluripotent stem cell (hiPSC)-derived airway epithelium in Air-Liquid-Interface cultures. Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.

Development of musculoskeletal deficits in children with cystic fibrosis in later childhood.

Cystic fibrosis (CF) is a genetic condition primarily affecting the respiratory system, with the associated progressive lung damage and loss of function resulting in reduced lifespan. Bone health is also impaired in individuals with CF, leading to much higher fracture risk even in adolescence. However, the development of these deficits during growth and the relative contributions of puberty, body size and muscular loading remain somewhat unexplored. We therefore recruited 25 children with CF (10 girls, mean age 11.3±2.9y) and 147 children without CF (75 girls, mean age 12.4±2.6y). Bone characteristics were assessed using peripheral quantitative computed tomography (pQCT) at 4% and 66% distal-proximal tibia. Muscle cross-sectional area (CSA) and density (an indicator of muscle quality) were also assessed at the latter site. Tibial bone microstructure was assessed using high-resolution pQCT (HR-pQCT) at 8% distal-proximal tibial length. In addition, peak jump power and hop force were measured using jumping mechanography. Group-by-age interactions and group differences in bone and muscle characteristics were examined using multiple linear regression, adjusted for age, sex and pubertal status and in additional models, height and muscle force. In initial models group-by-age interactions were evident for distal tibial total bone mineral content (BMC) and trabecular volumetric bone mineral density (vBMD), with a lower rate of age-related accrual evident in children with CF. In assessments of distal tibial microstructure, similar patterns were observed for trabecular number and thickness, and cortical CSA. In the tibial shaft, group-by-age interactions indicating slower growth in CF were evident for total BMC and cortical CSA, whilst age-independent deficits in CF were observed for several other variables. Peak jump power and hop force also exhibited similar interactions. Group-by-age interactions for bone were partially attenuated at the distal tibia and fully attenuated at the tibial shaft by adjustment for muscle force. These results suggest that bone and muscle deficits in children with CF develop throughout later childhood, independent of differences in pubertal stage and body size. These diverging growth patterns appear to be mediated by differences in muscle function, particularly for bone characteristics in the tibial shaft. Given the high fracture risk in this population from childhood onwards, development of interventions to improve bone health would be of substantial clinical value.

ОСОБЕННОСТИ ТЕЧЕНИЯ КОРОНАВИРУСНОЙ ИНФЕКЦИИ У РЕЦИПИЕНТА ПОЧЕЧНОГО ТРАНСПЛАНТАТА

The new coronavirus infection poses a particular threat to patients receiving immunosuppressive therapy, including those with a history of organ transplantation. The article provides a clinical observation of coronavirus infection in a kidney transplant recipient. Patient M., 61 years old, was admitted to the infectious diseases department of the Kursk City Clinical Hospital No. 4 with complaints of high fever, cough, shortness of breath, severe weakness, loss of appetite. When examining a swab from the nose and throat by PCR for SARS-Cov-2 RNA, a positive result was obtained. Based on the clinical picture, computed tomography of the lungs, positive PCR result for SARS-Cov-2 RNA, the diagnosis was made: Coronavirus infection Covid-19 confirmed, moderate form. Bilateral polysegmental pneumonia of moderate severity. RF - 0-I degree (CT-1). Bilateral nephrosclerosis. Condition after kidney transplant (2006). On the fifth day, the patient's condition worsened, which was combined with the progression of lung damage according to CT of the chest to 45% (CT-2), the appearance of signs of acute respiratory distress syndrome. Taking into account the severity of the patient's condition, a consultation was held with a transplantologist and a decision was made to correct immunosuppressive therapy with temporary withdrawal of cyclosporine. Over the next two days, the patient's condition remained stably grave. Subsequently, against the background of complex therapy, including glucocorticosteroids, antibacterial drugs, monoclonal antibodies to the interleukin-6 receptor, positive dynamics was noted in the form of a decrease in shortness of breath, cough, normalization of body temperature, and an increase in SpO2 up to 95%. This was combined with the restoration of disturbed laboratory parameters and the positive dynamics of the inflammatory process in the lungs according to CT scans. The treatment of kidney transplant recipients with Covid-19 has a number of features due to a pronounced suppression of the immune system against the background of immunosuppressive therapy and, as a result, the development of a severe infection, often with impaired graft function. At the same time, despite the severity of the course of the infectious process, the complete abolition of immunosuppressive therapy is not carried out, but its correction is carried out in the form of the exclusion of one of the drugs and a decrease in the dose of other immunosuppressants. Coronavirus infection in patients with a history of organ transplantation justifies the need for timely hospitalization and correction of immunosuppressive therapy to prevent a severe course of the disease and adverse outcomes.

BEAT CF pulmonary exacerbations core protocol for evaluating the management of pulmonary exacerbations in people with cystic fibrosis

BackgroundCystic fibrosis (CF) is a rare, inherited, life-limiting condition predominantly affecting the lungs, for which there is no cure. The disease is characterized by recurrent pulmonary exacerbations (PEx), which are thought to drive progressive lung damage. Management of these episodes is complex and generally involves multiple interventions targeting different aspects of disease. The emergence of innovative trials and use of Bayesian statistical methods has created renewed opportunities for studying heterogeneous populations in rare diseases. Here, we present the protocol for the BEAT CF PEx cohort, a prospective, multi-site, perpetual, platform enrolling adults and children with CF. The BEAT CF PEx cohort will be used to evaluate the comparative effectiveness of interventions for the treatment of PEx requiring intensive therapy (PERITs), with a primary focus on short-term improvements in lung function. This will be achieved through the conduct of cohort-nested studies, including adaptive clinical trials, within the BEAT CF PEx cohort. This protocol will outline key features of the BEAT CF PEx cohort, including the design, implementation, data collection and management, governance and analysis, and dissemination of results.MethodsThis platform will be conducted across multiple sites, commencing with CF treatment centers in Australia. People of all ages with a clinical diagnosis of CF will be eligible to participate, except those who have previously received a lung transplant. Data including demographic and clinical information, treatment details, and outcomes (including safety, microbiology, and patient-reported outcome measures including quality of life scores) will be systematically collected and securely stored via a digital centralized trial management system (CTMS). The primary endpoint is the absolute change in the percentage predicted forced expiratory volume in 1 s (ppFEV1) from the commencement of intensive therapy to 7 to 10 days afterwards.DiscussionThe BEAT CF PEx cohort will report clinical, treatment, and outcome data for PEx among people with CF and is intended to serve as a core (master) protocol for future nested, interventional trials evaluating treatment(s) for these episodes. The protocols for nested sub-studies are beyond the scope of this document and will be reported separately.Trial registrationANZCTR BEAT CF Platform – ACTRN12621000638831. Registration date: Sept. 26, 2022.

Cervical spinal cord injury leads to injury and altered metabolism in the lungs.

High-cervical spinal cord injury often disrupts respiratory motor pathways and disables breathing in the affected population. Moreover, cervically injured individuals are at risk for developing acute lung injury, which predicts substantial mortality rates. While the correlation between acute lung injury and spinal cord injury has been found in the clinical setting, the field lacks an animal model to interrogate the fundamental biology of this relationship. To begin to address this gap in knowledge, we performed an experimental cervical spinal cord injury (N = 18) alongside sham injury (N = 3) and naïve animals (N = 15) to assess lung injury in adult rats. We demonstrate that animals display some early signs of lung injury two weeks post-spinal cord injury. While no obvious histological signs of injury were observed, the spinal cord injured cohort displayed significant signs of metabolic dysregulation in multiple pathways that include amino acid metabolism, lipid metabolism, and N-linked glycosylation. Collectively, we establish for the first time a model of lung injury after spinal cord injury at an acute time point that can be used to monitor the progression of lung damage, as well as identify potential targets to ameliorate acute lung injury.

Management of respiratory tract exacerbations in people with cystic fibrosis: Focus on imaging.

Respiratory tract exacerbations play a crucial role in progressive lung damage of people with cystic fibrosis, representing a major determinant in the loss of functional lung tissue, quality of life and patient survival. Detection and monitoring of respiratory tract exacerbations are challenging for clinicians, since under- and over-treatment convey several risks for the patient. Although various diagnostic and monitoring tools are available, their implementation is hampered by the current definition of respiratory tract exacerbation, which lacks objective "cut-offs" for clinical and lung function parameters. In particular, the latter shows a large variability, making the current 10% change in spirometry outcomes an unreliable threshold to detect exacerbation. Moreover, spirometry cannot be reliably performed in preschool children and new emerging tools, such as the forced oscillation technique, are still complementary and need more validation. Therefore, lung imaging is a key in providing respiratory tract exacerbation-related structural and functional information. However, imaging encompasses several diagnostic options, each with different advantages and limitations; for instance, conventional chest radiography, the most used radiological technique, may lack sensitivity and specificity in respiratory tract exacerbations diagnosis. Other methods, including computed tomography, positron emission tomography and magnetic resonance imaging, are limited by either radiation safety issues or the need for anesthesia in uncooperative patients. Finally, lung ultrasound has been proposed as a safe bedside option but it is highly operator-dependent and there is no strong evidence of its possible use during respiratory tract exacerbation. This review summarizes the clinical challenges of respiratory tract exacerbations in patients with cystic fibrosis with a special focus on imaging. Firstly, the definition of respiratory tract exacerbation is examined, while diagnostic and monitoring tools are briefly described to set the scene. This is followed by advantages and disadvantages of each imaging technique, concluding with a diagnostic imaging algorithm for disease monitoring during respiratory tract exacerbation in the cystic fibrosis patient.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Neuromuscular Blockade in the Pre- and COVID-19 ARDS Patients

Acute respiratory distress syndrome (ARDS) accounts for a quarter of mechanically ventilated patients, while during the pandemic, it overwhelmed the capacity of intensive care units (ICUs). Lung protective ventilation (low tidal volume, positive-end expiratory pressure titrated to lung mechanics and oxygenation, permissive hypercapnia) is a non-pharmacological approach that is the gold standard of management. Among the pharmacological treatments, the use of neuromuscular blocking agents (NMBAs), although extensively studied, has not yet been well clarified. The rationale is to minimize the risk for lung damage progression, in the already-injured pulmonary parenchyma. By abolishing rigorous spontaneous efforts, NMBAs may decrease the generation of high transpulmonary pressures that could aggravate patients’ self-inflicted lung injury. Moreover, NMBAs can harmonize the patient–ventilator interaction. Recent randomized controlled trials reported contradictory results and changed the clinical practice in a bidirectional way. NMBAs have not been documented to improve long-term survival; thus, the current guidance suggests their use only in patients in whom a lung protective ventilation protocol cannot be applied, due to asynchrony or increased respiratory efforts. In the present review, we discuss the published data and additionally the clinical practice in the “war” conditions of the COVID-19 pandemic, concerning NMBA use in the management of patients with ARDS.