Sepsis is an inflammatory response to severe infection, which can affect any organ system. This inflammatory response can lead to life-threatening end organ dysfunction. In this article, we review pulmonary complications of sepsis including hypoxemia and acute respiratory distress syndrome. We also discuss pulmonary sources of sepsis including the management of community- and hospital-acquired pneumonia and ventilator-associated pneumonia.

Mechanical ventilation is a critical intervention for patients with respiratory failure, providing essential support for oxygenation and ventilation while reducing the work of breathing. It operates through key breath-phase variables: triggering (breath initiation), targeting (flow or pressure delivery), and cycling (ending inspiration). Various ventilation modes, including invasive and non-invasive methods, are tailored to patient needs. Non-invasive ventilation and high-flow nasal cannula are first-line options in acute respiratory distress, whereas invasive mechanical ventilation is necessary for severe cases. Optimal ventilatory strategies aim to prevent complications such as barotrauma, volutrauma, and dynamic hyperinflation by carefully adjusting parameters like tidal volume, respiratory rate, and positive end-expiratory pressure. One major challenge in mechanical ventilation is patient-ventilator dyssynchrony, where the patient's respiratory efforts do not align with the ventilator's cycles, leading to increased work of breathing and discomfort. Dyssynchrony can occur during the trigger, target, or cycle phases, requiring waveform analysis and ventilator adjustments to optimize synchrony. Weaning from mechanical ventilation follows a structured process involving readiness assessment, spontaneous breathing trials, and extubation. Successful weaning depends on maintaining stable respiratory function, with close monitoring to prevent post-extubation failure. Identifying and managing ventilatory complications, optimizing patient comfort, and ensuring an individualized approach to ventilator management are key to improving patient outcomes. This review provides a comprehensive understanding of mechanical ventilation, its principles, common challenges, and weaning strategies to guide effective clinical decision-making.

The opportunistic pathogen Pseudomonas aeruginosa primarily causes infections in immunocompromised individuals. Luteolin, a natural flavonoid, is widely present in plants, which exerts various pharmacological activities, including anti-inflammatory and antimicrobial activities.

This study aimed to explore the therapeutic efficacy of luteolin and the underlying molecular mechanisms in treating the P. aeruginosa-induced acute pneumonia.

Network pharmacology was utilized to identify the core targets of luteolin for treating acute P. aeruginosa pneumonia. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to dissect the potential effects of luteolin and the involved signaling pathways. Surface plasmon resonance (SPR) assay and molecular docking were employed for studying the binding affinities of luteolin with the key targets. Furthermore, we applied a mouse model of bacterial pneumonia for assessing the therapeutic effects of luteolin in vivo, and an in vitro infection model for specifically investigating the effects of luteolin on macrophages as well as the underlying mechanisms upon P. aeruginosa infection.

Network pharmacology identified TNF, IL-6, EGFR and AKT1 as the key targets of luteolin for treating acute P. aeruginosa pneumonia. Moreover, as revealed by GO and KEGG enrichment analysis, EGFR, MAPK and PI3K/AKT pathways were the potential pathways regulated the P. aeruginosa-induced inflammatory response. According to the in vivo results, luteolin effectively mitigated the P. aeruginosa-induced acute lung injury through reducing the pulmonary permeability, neutrophil infiltration, proinflammatory cytokine production (IL-1β, IL-6, TNF and MIP-2) and bacterial burden in lung tissues, which led to increased survival rate of mice. Furthermore, the luteolin-treated mice had diminished EGFR, PI3K, AKT, IκBα, NF-κB p65, ERK, c-Jun and c-Fos phosphorylation, down-regulated M1 macrophage marker levels (iNOS, CD86 and IL-1β) but up-regulated M2 macrophage marker levels (Ym1, CD206 and Arg1) in lung tissues. Consistently, the luteolin-pretreated macrophages exhibited reduced phosphorylation of these regulatory proteins, diminished proinflammatory cytokine production, and down-regulated expression of M1 macrophage markers, but up-regulated expression of IL-10 and M2 macrophage markers.

luteolin effectively suppressed the inflammatory responses and M1 macrophage polarization through inhibiting EGFR/PI3K/AKT/NF-κB and EGFR/ERK/AP-1 signaling pathways in the treatment of acute P. aeruginosa pneumonia. This study suggests that luteolin could be a promising candidate for development as a therapeutic agent for acute bacterial pneumonia.

Corticosteroids decrease the duration of organ dysfunction in sepsis and a range of overlapping and complementary infectious critical illnesses, including septic shock, pneumonia and the acute respiratory distress syndrome (ARDS). The risk and benefit of corticosteroids are not fully defined using the construct of organ dysfunction duration. This retrospective multicenter, proof-of-concept study aimed to evaluate the association between usage of corticosteroids and mortality of patients with sepsis, pneumonia and ARDS by emulating a target trial framework stratified by predicted organ dysfunction trajectory. The study employed a two staged machine learning (ML) methodology to first subphenotype based on organ dysfunction trajectory then predict this defined trajectory. Once patients were classified by predicted trajectory we conducted a target trial emulation. Our analysis revealed that the association between corticosteroid use and 28-day mortality varied by predicted trajectory and between cohorts.Our findings suggest that matching treatment strategies to empirically observed pathobiology may offer a more nuanced understanding of corticosteroid utility.

Coronavirus entry into host cells enables the virus to initiate its replication cycle efficiently while evading host immune response. Cell entry is intricately associated with pH levels in the cytoplasm or endosomes. In this study, we observed that the sodium hydrogen exchanger 3 (Na+/H+ exchanger 3 or NHE3), which is strongly activated by dexamethasone (Dex) to promote cell membrane Na+/H+ exchange, was critical for cytoplasmic and endosomal acidification. Dex activates NHE3, which increases intracellular pH and blocks the initiation of coronavirus infectious bronchitis virus (IBV) negative-stranded genomic RNA synthesis. Also, Dex antiviral effects are relieved by the glucocorticoid receptor (GR) antagonist RU486 and the NHE3 selective inhibitor tenapanor. These results show that Dex antiviral effects depend on GR and NHE3 activities. Furthermore, Dex exhibits remarkable dose-dependent inhibition of IBV replication, although its antiviral effects are constrained by specific virus and cell types. To our knowledge, this is the first report to show that Dex helps suppress the entry of coronavirus IBV into cells by promoting proton leak pathways, as well as by precisely tuning luminal pH levels mediated by NHE3. Disrupted cytoplasmic pH homeostasis, triggered by Dex and NHE3, plays a crucial role in impeding coronavirus IBV replication. Therefore, cytoplasmic pH plays an essential role during IBV cell entry, probably assisting viruses at the fusion and/or uncoating stages. The strategic modulation of NHE3 activity to regulate intracellular pH could provide a compelling mechanism when developing potent anti-coronavirus drugs.IMPORTANCESince the outbreak of coronavirus disease 2019, dexamethasone (Dex) has been proven to be the first drug that can reduce the mortality rate of coronavirus patients to a certain extent, but its antiviral effect is limited and its underlying mechanism has not been fully clarified. Here, we comprehensively evaluated the effect of Dex on coronavirus infectious bronchitis virus (IBV) replication and found that the antiviral effect of Dex is achieved by regulating sodium hydrogen exchanger 3 (NHE3) activity through the influence of glucocorticoid receptor on cytoplasmic pH or endosome pH. Dex activates NHE3, leading to an increase in intracellular pH and blocking the initiation of negative-stranded genomic RNA synthesis of coronavirus IBV. In this study, we identified the mechanism by which glucocorticoids counteract coronaviruses in cell models, laying the foundation for the development of novel antiviral drugs.

Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and associated with significant morbidity and mortality, posing a critical challenge to global public health. Among its complications, sepsis frequently causes acute respiratory distress syndrome (ARDS), which has a high incidence and mortality rate, particularly in intensive care units (ICUs). Currently, the management of sepsis-induced ARDS is largely limited to supportive care, as no specific pharmacological treatments are available. The progression of sepsis to ARDS is driven by severe inflammation and cytokine storms, highlighting the importance of anti-inflammatory therapies as a primary treatment focus. We summarize conventional drugs and emerging treatments targeting excessive inflammatory responses in sepsis-associated ARDS, reviewing progress in basic research and clinical trials. Additionally, we discuss current research challenges to propose future directions for anti-inflammatory treatments, aiming to develop highly effective drugs with better clinical translation potential.

Acute respiratory distress syndrome (ARDS) continues to pose significant difficulties due to the scarcity of successful preventative and therapeutic measures. Recent clinical trials and experimental research have confirmed the lung-protective and anti-inflammatory properties of dexmedetomidine. The objective of this study was to examine the relationship between the use of dexmedetomidine and mortality outcomes in ICU patients with ARDS.

This study retrospectively examined data from the Medical Information Mart for Intensive Care (MIMIC) IV, focusing on individuals diagnosed with ARDS. The primary endpoint was the occurrence of death within 28 days after entering the ICU. To ensure a balanced cohort, we applied propensity score matching at a 1:1 ratio. Additionally, multivariable analysis was performed to mitigate the effects of confounding factors.

In this study, a cohort comprising 612 patients diagnosed with ARDS was investigated. Analysis using both univariate and multivariate Cox regression indicated significantly reduced 28-day and 90-day mortality rates in patients administered dexmedetomidine compared to those who were not given this treatment. Following adjustments for potential confounders using propensity score matching, these results were confirmed to be robust.

The results indicate an association between the administration of dexmedetomidine and lower mortality rates among severely ill ARDS patients. However, this result should be interpreted with cause because of a lot of missing data of potential risk factors for clinical outcomes. Nonetheless, it is imperative to perform further randomized controlled trials to corroborate this finding.

Discovering effective anti-inflammatory drugs and targets is a critical research priority. Herein, 28 novel phenylamide derivatives were designed and synthesized. Compound D9 showed favorable anti-inflammatory activities in acute lung injury (ALI) and sepsis mouse models. The target of D9 was predicted and studied, and c-Kit was identified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA), which demonstrated high selectivity in kinase activity profiling. It was further verified that c-Kit participated in the LPS-induced inflammatory response in J774A.1, RAW264.7, MPMs, and lung tissue. Additionally, c-Kit is proved to be essential for LPS-induced activation of the NF-κB pathway. Finally, c-Kit was confirmed as a therapeutic target in the LPS-induced ALI with c-Kit gene knockdown and was further verified as the target of D9. Notably, there has been no report of c-Kit's influence on the LPS-induced inflammatory response. Therefore, c-Kit was identified as a new therapeutic target for the LPS-induced ALI.

Sepsis remains a significant global health threat with a disproportionate burden in low-income countries including those in sub-Saharan Africa where case fatality rates are as high as 30% to 50%. Defined as a severe systemic response to infection, sepsis leads to widespread immune dysregulation and organ dysfunction, including adrenal insufficiency. Critical illness-related corticosteroid insufficiency (CIRCI) arises from dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids, all of which can occur during sepsis. Clinical trials of corticosteroids for the treatment of patients with sepsis and septic shock have shown improvements in shock reversal, and in some studies, patient survival; however, their role in the treatment of sepsis in sub-Saharan Africa is unknown. The incidence of sepsis in sub-Saharan Africa is compounded by high rates of human immunodeficiency virus (HIV) and co-infections, including tuberculosis (TB), which is the leading cause of sepsis. Both HIV and TB can cause immune dysregulation and adrenal insufficiency, which may exacerbate CIRCI and prolong shock. Existing sepsis research has been predominantly conducted in high-income countries and has largely excluded people living with HIV or TB. Therefore, there is a need to better understand sepsis and CIRCI pathophysiology in the context of specific regional host and pathogen characteristics. In this narrative review, we explored the pathophysiology of sepsis in sub-Saharan Africa including the existing literature on the immune response to sepsis and the prevalence of adrenal insufficiency in patients with HIV and TB, with a focus on the implications for corticosteroid management. We found a compelling need to further evaluate corticosteroids for the treatment of sepsis in Africa.

Background: During the COVID-19 pandemic, treatment strategies evolved rapidly. The RECOVERY trial established corticosteroids as the standard care for reducing mortality in COVID-19 patients. However, some critical care clinicians began using doses higher than those recommended in RECOVERY. Objective: To characterize the use of high-dose corticosteroids and IL-6 inhibitors in critically ill COVID-19 patients and examine their association with adverse drug events (ADEs). Methods: A retrospective cohort study of 320 electronic health records (January 1, 2020 - June 30, 2022) was conducted on COVID-19 patients requiring high-flow oxygen or mechanical ventilation. Patients were categorized based on corticosteroid dose: "high dose dexamethasone" (daily dose greater than 12 mg and/or for longer than 10 days), "low dose dexamethasone" (daily dose 12 mg or less for 10 days or less), and "no dexamethasone" (no corticosteroid therapy). Subgroups were created based on IL-6 inhibitor use. Results: High-dose dexamethasone was associated with increased odds of ADEs compared to low dose (OR 2.55, 95% CI 1.45 to 4.49) and no dexamethasone (OR 6.29, 95% CI 2.08 to 19.03). No additional efficacy benefit was observed in patients receiving high dose corticosteroids when compared to low dose corticosteroids. Patients receiving both an IL-6 inhibitor and high-dose dexamethasone had further increased odds of ADEs. High-dose dexamethasone was also associated with increased mortality compared to low dose (OR 3.78, 95% CI 1.97-7.25) and no dexamethasone (OR 15.22, 95% CI 3.27-70.74). Conclusions: Acknowledging the risk for residual confounding, higher doses of dexamethasone were associated with increased ADEs and mortality. These findings highlight the need for careful consideration of the use of high-dose dexamethasone.

This review reconsiders the classification of corticosteroids as immunosuppressants in the management of acute inflammatory conditions in critical care. Despite their widespread use in ARDS and septic shock, the association between corticosteroid therapy and increased infection risk remains contentious. By exploring alternative mechanisms and presenting new hypotheses, this review suggests that the traditional view of corticosteroids as immunosuppressants may be overly simplistic and context dependent.

Impaired alveolar fluid clearance (AFC) is an important cause of alveolar edema fluid accumulation in patients with acute respiratory distress syndrome (ARDS). Alveolar edema leads to insufficient gas exchange and worse clinical outcomes. Thus, it is important to understand the pathophysiology of impaired AFC in order to develop new therapies for ARDS. Over the last few decades, multiple experimental studies have been done to understand the molecular, cellular, and physiological mechanisms that regulate AFC in the normal and the injured lung. This review provides a review of AFC in the normal lung, focuses on the mechanisms of impaired AFC, and then outlines the regulation of AFC. Finally, we summarize ongoing challenges and possible future research that may offer promising therapies for ARDS.

Severe community-acquired pneumonia (sCAP) is associated with higher morbidity and mortality. The use of glucocorticoids to improve the prognosis of severe community-acquired pneumonia remains a topic of controversy.

Following the guidelines given in the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA), we conducted a systematic review and meta-analysis to evaluate the effects of glucocorticoids on mortality and duration of mechanical ventilation in patients with sCAP. Randomized controlled studies investigating the use of glucocorticoids in the treatment of sCAP were extracted from PubMed, Embase, Cochrane Library, and Web of Science. Statistical analysis was performed to compare the differences in in-hospital mortality, mechanical ventilation duration, gastrointestinal bleeding, secondary infection, and other outcome measures between the glucocorticoid group and the control group.

A total of 8 studies involving 1769 patients were included in the analysis. The hospital mortality in the glucocorticoid group was significantly lower than that in the control group [8 studies, relative risk (RR) 0.59; 95% CI 0.47-0.76, p < 0.01. I2 = 25%, low certainty]. The duration of mechanical ventilation in the glucocorticoid group was significantly shorter than that in the control group [Mean Difference (MD) -3.08; 95% CI -4.96 to -1.19, p < 0.01; I2 = 0%, low certainty]. There was no significant difference in the incidence of gastrointestinal bleeding (RR 0.94; 95% CI 0.55-1.63, p = 0.84, I2 = 0%, low certainty) or secondary infection (RR 0.85; 95% CI 0.58-1.25, p = 0.85, I2 = 2%, moderate certainty) between the glucocorticoid group and the control group. In subgroup analysis, mortality was significantly lower in the hydrocortisone group compared to the control group (6.3% vs. 14.6%, RR 0.43; 95% CI 0.29-0.62, p < 0.01, I2 = 0%, very low certainty). However, there was no significant difference in mortality between the methylprednisolone group and the control group (15.6% vs. 19.9%, RR 0.78; 95% CI 0.57-1.08, p = 0.14, I2 = 0%, moderate certainty).

Glucocorticoids can reduce mortality in patients with sCAP, and the effect may vary depending on the type and the dose of glucocorticoids used. Additionally, glucocorticoid treatment can lead to a shorter duration of mechanical ventilation, as well as the length of ICU stay, without increasing the risk of gastrointestinal bleeding or secondary infection in patients with sCAP. PROSPERO registration: CRD42023416525.

Purpose: We aimed to identify the impact of conversion surgery to survival in patients with stage IV esophageal cancer who have a stabilized disease and good treatment response before surgery. Patients and Methods: This retrospective study included patients with esophageal cancer M1 disease treated at a tertiary medical center from April 2002 to June 2021. For patients with a good clinical response to chemoradiation and well-controlled metastatic lesions, esophagectomy and lymphadenectomy were performed. A propensity score-matching (PSM) study with a 1:2 ratio and based on patient age, tumor stage, and metastasis status was conducted for verifying the results. Results: We enrolled 162 patients, including 124 treated with concurrent chemoradiation therapy (CCRT) alone and 38 treated with CCRT followed by esophagectomy. A total of 114 patients were analyzed using PSM, including 76 patients treated with CCRT alone and 38 patients treated with CCRT and surgery. The 3- and 5-year OS was 24.6% vs. 2.8% and 12.3% vs. 1.4% (p = 0.006), and PSM was 24.6% vs. 4.6% and 12.3% vs. 2.3% (p = 0.033) for those with or without esophagectomy, respectively. Multivariate analysis revealed surgery with esophagectomy as an independent prognostic factor for OS with odd ratios (95% confidence interval [CI]) of 1.91 (1.23-2.95) (p = 0.004). Conclusions: Surgical resection following CCRT holds a potential survival benefit for the patients with a favorable response to CCRT for patients with stage IV esophageal cancer.

Objectives: There is a scarcity of pharmacological treatments that efficiently address lung injury in individuals experiencing acute respiratory distress syndrome (ARDS). Early inhaled corticosteroids and ipratropium may reduce pulmonary inflammation and injury of the lungs, minimizing the risk of ARDS. Method: This is a double-blinded randomized control trial conducted on patients at risk of ARDS. Patients were randomly allocated into two groups; the intervention group (63 patients) were administered aerosolized budesonide and ipratropium bromide, and the control group (56) were administered a placebo every eight hours for five days. Alteration in oxygen saturation divided by inspired oxygen (Fio2) (S/F) after five days was the primary outcome. Secondary outcomes included ARDS occurrence, mechanical ventilation (MV) requirement, hospital stay duration, and mortality rates. Results: Of the 604 screened, only 119 patients were included. The intervention group (63 patients) S/F ratio recovered versus the fall of the control group. Both groups had similar organ dysfunction and 28-day mortality. The intervention group had significantly (p < 0.001) fewer cases developing ARDS (9.5%) and MV (9.5%) than the control group (46.4% and 35.7%, respectively). Conclusions: The administration of inhaled budesonide and ipratropium bromide improved oxygenation, as assessed by the S/F ratio, and significantly reduced the rate of ARDS development and the requirement of MV versus the control group. Larger multi-center trials including diverse patient populations are needed to validate these results.

In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.

Human metapneumovirus (hMPV), a ubiquitous RNA virus of the Pneumoviridae family, has been associated with respiratory tract infections for decades in various age groups and populations. Though most of the infections, especially in children, are mild and self-limited, severe infections ranging from bronchiolitis or asthma exacerbation to severe pneumonia and acute respiratory distress syndrome (ARDS) have occasionally been reported. Among patients who require hospitalization for severe infections, treatment is supportive as no current antivirals or vaccines are effective or recommended. The following is a 45-year-old Caucasian man who developed severe ARDS complicating hMPV infection, and despite maximal medical support, he developed refractory life-threatening hypoxemia that required rescue therapy with veno-venous extracorporeal membrane oxygenation (V-V ECMO). After several days of ECMO support, the patient eventually recovered and was discharged home. This case highlights the importance of recognizing hMPV as an occasional culprit for severe respiratory infections, discusses the new global definition of ARDS, and delineates the updated recommended management, including the early application of V-V ECMO as a rescue therapy in severe cases with refractory, life-threatening respiratory failure.

Background: Acute lung injury (ALI) is a common respiratory emergency with high incidence and mortality. Among its main pathologic mechanisms is the rapid and intense inflammatory response. Ozone is a naturally occurring compound and is known for its properties as an oxidizing agent. Ozone therapy is the clinical application of a mixture of ozone (O 3 ) and oxygen, used within nontoxic, safe concentrations. It could be used for the treatment of several diseases. Ozone rectal insufflation (O 3 -RI) is a treatment in which medical O 3 is introduced into the rectum to treat and prevent disease. Although O 3 therapy exerts anti-inflammatory effects, its function in ALI remains unclear. The aim of this study was to preliminarily investigate the role and function of O 3 -RI in ALI. Methods: A mouse model of ALI was established by intratracheal administration of LPS. O 3 -RI was administered 4 h following the modeling procedure. Lung histopathology, lung wet/dry ratio, protein content in bronchoalveolar lavage fluid (BALF), and myeloperoxidase activity in lung tissues, as well as the number of inflammatory cells and inflammatory cytokines in BALF, were assessed. The expression levels of NOD-like receptor thermal protein domain associated protein (NLRP3)/apoptosis-associated speck-like protein (ASC)/caspase-1 axis-related proteins in lung tissues were examined by real-time fluorescence quantitative polymerase chain reaction and Western blotting. Results: Ozone therapy reduced the wet/dry ratio of lung tissue and total protein content in BALF and attenuated lung edema and microvascular leakage in ALI mice. Ozone therapy reduced the myeloperoxidase content in the lung tissue, the number of inflammatory cells, and the content of inflammatory cytokines in BALF and attenuated lung tissue inflammation in mice with ALI. Ozone therapy ameliorated lung tissue morphological damage in ALI mice. Ozone therapy downregulated the expression of NLRP3/ASC/caspase-1 axis-related proteins. Conclusion: Ozone therapy attenuated LPS-induced ALI in mice, possibly by inhibiting NLRP3/ASC/caspase-1 axis. Ozone therapy is a valuable potential therapeutic modality for ALI.

Acute lung injury is a devastating complication when occurring in immunocompromised patients. The incidence appears to be increasing as more patients survive for longer in this susceptible state. Being aware of potential causes of acute lung injury may lead to earlier recognition and diagnosis. Infection is a common cause of acute lung injury and needs to be considered in the diagnostic algorithm. Management involves use of supportive ventilatory strategies and potentially pharmacologic therapies.

ObjectiveTo evaluate the efficacy and adverse events of immunomodulators in the treatment of severe coronavirus disease 2019 (COVID-19).MethodsA literature search for the meta-analysis was performed using PubMed, The Cochrane Library, Embase, Wanfang Data, CNKI, and Web of Science to identify randomized controlled trials assessing the outcomes of patients treated with corticosteroids alone and/or interleukin-6 receptor antagonists for COVID-19. The risk of bias was assessed using the Cochrane method. The protocol was registered with PROSPERO (registry number: CRD42022356904).ResultsCompared with patients receiving standard of care, patients treated with corticosteroids alone had an increased risk of 14-day in-hospital death, whereas those treated with interleukin-6 receptor antagonists alone or in combination with corticosteroids had a lower risk of 14-day in-hospital death. Corticosteroid therapy alone was associated with increased risk of several adverse events, including intensive care unit admission and non-invasive ventilation, whereas interleukin-6 receptor antagonists alone or in combination with corticosteroids were not linked to adverse effects.ConclusionsThe findings supported the safety and efficacy of interleukin-6 receptor antagonists, either alone or together with corticosteroids, in patients with severe COVID-19; evidence supporting the efficacy and safety of corticosteroids monotherapy is lacking.

Pneumonia remains a leading cause of morbidity and mortality, particularly in critically ill patients with acute respiratory failure (ARF). This review discusses prevention strategies for pneumonia-induced ARF, categorized into primary, secondary, and tertiary prevention.

A literature search was conducted through PubMed covering the years 2000-2024, using the keywords 'acute respiratory failure,' pneumonia prevention," 'risk stratification,' and 'preventive strategies.' Primary prevention focuses on reducing pneumonia risk through vaccination, smoking cessation, and comorbidity management. Secondary prevention involves early detection, risk assessment using clinical tools like the Pneumonia Severity Index (PSI) biomarkers, such as procalcitonin and C-reactive protein, appropriate antibiotic use, and emerging machine learning tools for real-time stratification. Tertiary prevention focuses on optimizing care with noninvasive respiratory support, lung-protective ventilation strategies, and ventilator bundles for intubated patients. Emerging therapies, including targeted use of corticosteroids and other immunomodulatory agents, are also discussed as promising adjuncts to current standards of care.

While these prevention strategies show potential, continued research is necessary to refine these interventions, explore newer therapies and evaluate long-term outcomes. Implementation of these strategies aims to reduce the impact of pneumonia-induced ARF on healthcare systems and improve patient survival and quality of care.

Objective: We aimed to evaluate the protective effects of sivelestat sodium on the basis of corticosteroid therapy in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Methods: We retrospectively investigated 127 patients with confirmed moderate-to-severe ARDS treated in the intensive care unit (ICU) at Dazhou Central Hospital. Patients were divided into the control group (corticosteroids alone) and the combination therapy of steroids and sivelestat sodium (CTSSS) group according to the therapeutic interventions. The primary outcome was in-hospital mortality. And the baseline characteristics and laboratory findings of patients were collected for analysis. Results: The overall mortality rate in 127 patients was 48.8%. There was no statistically significant difference in in-hospital mortality between the CTSSS group and the control group (45.3% vs. 56.1%). In the subgroup of patients aged < 80 years or with an Acute Physiology and Chronic Health Evaluation (APACHE) II score < 30, CTSSS could reduce the risk of mortality (odds ratio [OR] = 0.41, 95% confidence interval [CI], 0.17-0.96, p=0.041; OR = 0.31, 95% CI, 0.13-0.77, p=0.012; respectively). Among patients aged 80 years or older, those with CTSSS exhibited a significantly elevated risk of mortality (OR = 13; 95% CI, 1.20-140.73; p=0.035). Conclusion: Compared with corticosteroids alone, CTSSS could improve oxygenation index, increase lymphocyte count, protect extrapulmonary organs and reduce in-hospital mortality rate in patients with moderate-to-severe ARDS in specific subgroups (age < 80 years or APACHE II score < 30). It might be advisable to avoid CTSSS in moderate-to-severe ARDS patients aged 80 years or older. Prospective studies involving larger sample sizes are needed to verify these findings.

The emergence of the COVID-19 pandemic made it critical to understand the immune and inflammatory responses to the SARS-CoV-2 virus. It became increasingly recognized that the immune response was a key mediator of illness severity and that its mechanisms needed to be better understood. Early infection of both tissue and immune cells, such as macrophages, leading to pyroptosis-mediated inflammasome production in an organ system critical for systemic oxygenation likely plays a central role in the morbidity wrought by SARS-CoV-2. Delayed transcription of Type I and Type III interferons by SARS-CoV-2 may lead to early disinhibition of viral replication. Cytokines such as interleukin-1 (IL-1), IL-6, IL-12, and tumor necrosis factor α (TNFα), some of which may be produced through mechanisms involving nuclear factor kappa B (NF-κB), likely contribute to the hyperinflammatory state in patients with severe COVID-19. Lymphopenia, more apparent among natural killer (NK) cells, CD8+ T-cells, and B-cells, can contribute to disease severity and may reflect direct cytopathic effects of SARS-CoV-2 or end-organ sequestration. Direct infection and immune activation of endothelial cells by SARS-CoV-2 may be a critical mechanism through which end-organ systems are impacted. In this context, endovascular neutrophil extracellular trap (NET) formation and microthrombi development can be seen in the lungs and other critical organs throughout the body, such as the heart, gut, and brain. The kidney may be among the most impacted extrapulmonary organ by SARS-CoV-2 infection owing to a high concentration of ACE2 and exposure to systemic SARS-CoV-2. In the kidney, acute tubular injury, early myofibroblast activation, and collapsing glomerulopathy in select populations likely account for COVID-19-related AKI and CKD development. The development of COVID-19-associated nephropathy (COVAN), in particular, may be mediated through IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling, suggesting a direct connection between the COVID-19-related immune response and the development of chronic disease. Chronic manifestations of COVID-19 also include systemic conditions like Multisystem Inflammatory Syndrome in Children (MIS-C) and Adults (MIS-A) and post-acute sequelae of COVID-19 (PASC), which may reflect a spectrum of clinical presentations of persistent immune dysregulation. The lessons learned and those undergoing continued study likely have broad implications for understanding viral infections' immunologic and inflammatory consequences beyond coronaviruses.

Traditional medicine uses the roots and rhizomes of Polygonum bistorta L. (Polygonaceae) to treat cough, bronchitis, and other respiratory infections. Our goal was to gain insights into the lung protective effects of the roots of P. bistorta L. against lipopolysaccharide-induced acute lung injury in rats, along with the possible mechanism(s). The outcomes revealed deliberate quantities of the total phenolic and flavonoid contents of 156.2 ± 5.13 GAE/g and 179.45 ± 2.08 mg QE/g, respectively. Crude extract possesses a maximum inhibitory potential of 81.77% ± 0.62% for acetylcholinesterase against eserine. Acute oral toxicity study revealed LD50 beyond 7 g/kg. Plant extract markedly restored LPS-induced hypoxemia, pulmonary edema, histopathological alterations, and leukocyte infiltration in the lung. ELISA testing on BALF found that the plant extract efficiently reinstated superoxide dismutase, total anti-oxidant capacity, malondialdehyde, and total oxidative stress. qRT-PCR indicated a decline in the endotoxin-induced overproduction of pro-inflammatory markers, oxidative stress, transcription factor, and downregulated antioxidant potential in extract-treated groups. Furthermore, 24 metabolites were identified and quantified via GC-MS. A molecular docking procedure was implemented on the bioactive metabolites that were identified to evaluate their potential for inhibiting AChE. In conclusion, P. bistorta roots mitigate inflammation and oxidative stress by improving redox signaling and NF-ĸβ (p65) pathways and can thus play a role in strategies for overcoming therapeutic challenges.

During critical illness, patients experience significant and rapid onsets of muscle wasting and dysfunction with loss of strength, mass, and power. These deficits often persist long after the ICU, leading to impairments in physical function including reduced exercise capacity and increased frailty and disability. While there are numerous studies describing the epidemiology of impaired muscle and physical function in the ICU, there are significantly fewer data investigating mechanisms of prolonged and persistent impairments in ICU survivors. Additionally, while several potential clinical risk factors associated with poor physical recovery have been identified, there remains a dearth of interventions that have effectively improved outcomes long-term among survivors. In this article, we aim to provide a thorough, evidence-based review of the current state of knowledge regarding muscle dysfunction and physical function after critical illness with a focus on post-ICU and post-hospitalization phase of recovery.

Acute respiratory distress syndrome (ARDS) is associated with high rates of morbidity and mortality. However, the evidence regarding the effectiveness of commonly used treatments, including corticosteroids, neuromuscular blocking agents (NMBAs), and inhaled nitric oxide (iNO), remains uncertain. Therefore, this study aimed to compare and rank these three treatments to identify the most effective option.

We searched PubMed, Embase, Cochrane Library, and Web of Science for clinical trials from the earliest records to 1 May 2024.

Clinical trials evaluating three interventions compared with the control group for ARDS were included, with restrictions on any language. Data were extracted by two independent reviewers. Frequentist network meta-analysis (NMA) was performed to identify the most effective intervention, and treatments were ranked using the surface under the cumulative ranking (SUCRA) curve. The primary outcome was 28-day mortality, while secondary outcomes included ventilator-free days up to 28 days, ICU mortality, in-hospital mortality, and the incidence of new infection events.

Data from 26 clinical trials encompassing 5,071 patients were analyzed. Vecuronium bromide was the most effective strategy for reducing 28-day mortality compared to conventional treatment, iNO, methylprednisolone, and placebo (OR 0.38, 95% CI 0.15-1.00, and OR 0.30, 95% CI 0.10-0.85 and OR 0.25, 95% CI 0.08-0.74 and OR 0.23, 95% CI 0.08-0.65; SUCRA: 96.6%). Dexamethasone was identified as the most effective treatment option for increasing ventilator-free days at 28 days compared to conventional therapy and cisatracurium (MD 3.60, 95% CI 1.77-5.43, and MD 3.40, 95% CI 0.87-5.92; SUCRA: 93.2%). Methylprednisolone demonstrated the highest effectiveness for preventing ICU mortality (SUCRA: 88.5%). Although dexamethasone, cisatracurium, conventional therapy, methylprednisolone, and iNO treatment did not show significant superiority in reducing in-hospital mortality, dexamethasone showed the highest probability of being the most effective treatment option (SUCRA: 79.7%). Furthermore, dexamethasone treatment showed the highest safety in reducing the incidence of new infection events compared with placebo and iNO (OR 0.61, 95% CI 0.42-0.88, and OR 0.33, 95% CI 0.19-0.58; SUCRA: 91.8%).

This NMA suggests that corticosteroids may provide benefits to patients with ARDS. While the application of NMBAs may reduce 28-day mortality, iNO did not demonstrate a significant beneficial effect as a therapeutic measure.

PROSPERO, CRD42022333165 https://www.crd.york.ac.uk/PROSPERO/.

With increasing prevalence globally, obesity presents unique challenges to the clinical management of other diseases. In the case of acute respiratory distress syndrome (ARDS), glucocorticoid therapy (e.g., dexamethasone (DEX)) represents one of the few pharmacological treatment options, but it comes with severe adverse effects, especially when long-term usage (>1 week) is required. One important reason for the adverse effects of DEX is its nonspecific accumulation in healthy tissues upon systemic administration. Therefore, we hypothesize that refining its pharmacokinetics (PK) and in vivo biodistribution may improve its therapeutic index (higher efficacy, lower toxicity) and thus make it safer for obese populations. To achieve this goal, DEX was conjugated with polyethylene glycol (PEG) with three different molecular weights (Mw, 2K, 5K, and 10K) via a reactive oxygen species (ROS)-cleavable linker. Their anti-inflammatory efficacy and long-term adverse effects were evaluated in a murine obesity-ARDS model. Strikingly, DEX-PEG-2K (conjugates with 2K PEG Mw) provided the optimal therapeutic index compared to free DEX and to the other two conjugates with longer PEGs (Mw of 5K and 10K): While retaining the comparable therapeutic efficacy to DEX, DEX-PEG-2K significantly reduced the accumulation of free DEX in the liver and spleen, which led to a 51% reduction of fatty area in liver and a 32% reduction of blood triglycerides concentration. DEX-induced apoptosis of the thymus was also rescued by DEX-PEG-2K under normal conditions. The PK and biodistribution were also investigated to elicit the underlying mechanism. In summary, we provided here a chemical modification strategy to improve the therapeutic index of dexamethasone and possibly other glucocorticoid drugs for ARDS treatment with an obesity background.

Acute lung injury is a significant global health issue, and its treatment is becoming a hot topic of the researchers. To investigate the feasibility of miRNA-150-5p tail vein injection in the treatment of SiO2-induced acute lung injury through the regulation of gut microbiota and serum metabolites based on multiomics technology. Twenty-four mice were randomly divided into the control, SiO2 and miRNA-150-5p intervention groups. The SiO2 and miRNA-150-5p intervention groups received a single intranasal dose of 100 µL 4 % SiO2 suspension. Meanwhile, the miRNA-150-5p intervention group was administered with two tail vein injections of miRNA-150-5p (15 nmol each per mouse) on the day of successful modelling and on the third day post modelling. Metagenomics and metabolomics techniques were used to measure gut microbiota and serum metabolites, respectively. Tail vein injection of miRNA-150-5p improved SiO2-induced acute lung injury and reduced the secretion of inflammatory factors interleukin (IL)-6, tumour necrosis factor-α and IL-1β. These conditions altered the structure of gut microbiota, which resulted in the notable modulation of eight species at the species level. In addition, tail vein injection of miRNA-150-5p considerably reduced the levels of substances, such as phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositol, in the glycerophospholipid metabolism and glycosylphosphatidylinositol-anchor biosynthesis pathways. Tail vein injection of miRNA-150-5p can alleviate acute lung injury. Combined metagenomics and untargeted metabolomics revealed the miRNA-150-5p-mitigated SiO2-induced acute lung injury that occurred through the regulation of gut microbiota and serum metabolites.

Limited guidelines exist for treating immunocompromised patients hospitalized for acute viral respiratory infection. Little is known about clinical and economic benefits of intravenous immunoglobulin (IVIG) administration in patients with acute viral respiratory infections.

To compare clinical and economic outcomes among immunocompromised patients hospitalized with viral respiratory infections who received IVIG with those who did not.

We performed a retrospective cohort study on all patients hospitalized for a respiratory viral infection between 2011 and 2016 at 2 large academic centers including data on age, sex, virus species, immunosuppression type, and receipt of IVIG. Outcomes included death, hospital readmission, length of stay (LOS) in the hospital, and LOS in the intensive care unit (ICU).

A total of 270 patient admissions were reviewed, and 35.6% received IVIG. The average age was 40.6 years, 50% were female, and 74% were transplant patients. The most common virus was rhinovirus (50.7%). Use of IVIG was significantly associated with a shorter ICU LOS (β = -0.534, P = .012) and a longer hospital LOS (β = 0.887, P < .01). IVIG administered within 48 hours of hospitalization (n = 229) was associated with a shorter ICU LOS (β = -2.08, P = .001) and a shorter hospital LOS for patients hospitalized at least 2 days (β = -0.461, P = .007). There were no significant differences in readmission rates or death.

This double-center, retrospective cohort analysis is one of the first studies to evaluate the effect of IVIG on immunocompromised patients hospitalized with respiratory viral infections. IVIG was associated with a shorter hospital and ICU LOS, especially when administered within 48 hours of admission.

Rational use of steroids is essential in the long term for improving patient safety. Systemic steroids are important in clinical treatment, but if they are misused, they might have negative effects. This study assessed systemic steroid use and its determinants at Debre Berhan University Hakim Gizawu Teaching Hospital (DBUHGTH), Ethiopia. A cross-sectional study was conducted among 210 admitted patients at the Medical ward of DBUHGTH. A simple random sampling method was used to recruit study participants. The data was collected from patient medical records and patient interviews using a structured data abstraction and patient interview format. Binary logistic regression was employed to identify the potential predictors of systemic steroid use. Finally, the results were interpreted and presented by tables, charts, and graphs. Most study participants were 142 (67.62%) male. The mean age of the participants was 44.94 (SD, 19.2) years. Prednisolone was mostly utilized drug 130 (42.07%), followed by hydrocortisone 81 (26.21%), beclomethasone 58 (18.77%), and dexamethasone 40 (12.94%). Respiratory disorders 112 (53.34%), meningitis 25 (11.91%), and rheumatoid arthritis 19 (9.05%) were the top three disease conditions in which steroids were used with the highest frequency. Most systemic steroids were administered orally, 130 (42.07%). Short-acting (hydrocortisone, beclomethasone) 139 (44.98%) were mostly used, followed by intermediate-acting steroids (prednisolone) 130 (42.07%). Study participants in the 18-40 age range were approximately 2.5 times more likely than those in the 65 + age group to be using systemic steroids (AOR = 2.5, 95% CI 2.86-6.07). Prednisolone was mostly utilized, followed by hydrocortisone, beclometasone, and dexamethasone drugs in the medical ward of DBUHGTH.

Dexamethasone 6 mg in patients with severe COVID-19 has been shown to decrease mortality and morbidity. The effects of higher doses of corticosteroid, that would further increase anti-inflammatory effects, are uncertain. The objective of our study was to assess the effect of 20 mg dexamethasone vs. 6 mg dexamethasone intravenously in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) and COVID-19.

In a multicenter, open-label, randomized trial conducted in nine hospitals in the Czech Republic, we randomized adult patients with ARDS and COVID-19 requiring high-flow oxygen, noninvasive or invasive mechanical ventilation to receive either intravenous high-dose dexamethasone (20 mg/day on days 1-5, 10 mg/day on days 6-10) or standard-dose dexamethasone (6 mg/d, days 1-10). The primary outcome was 28-day ventilator-free days. The five secondary outcomes were 60-day mortality, C-reactive protein dynamics, 14-day WHO (World Health Organization) Clinical Progression Scale score, adverse events and 90-day Barthel index. The long-term outcomes were 180- and 360-day mortality and the Barthel index. The planned sample size was 300, with interim analysis after enrollment of 150 patients.

The trial was stopped due to a lack of recruitment, and the follow-up was completed in February 2023. Among 234 randomized patients of 300 planned patients, the primary outcome was available for 224 patients (110 high-dose and 114 standard-dose dexamethasone; median [interquartile range (IQR)] age, 59.0 [48.5-66.0] years; 130 [58.0%] were receiving noninvasive or invasive mechanical ventilation at baseline). The mean number of 28-day ventilator-free days was 8.9 (± 11.5) days for high-dose dexamethasone and 8.0 (± 10.7) days for standard-dose dexamethasone, with an absolute difference of + 0.81 days (95% CI - 2.12-3.73 days). None of the prespecified secondary outcomes, including adverse events, differed between the groups.

Despite not reaching its prespecified enrollment, there was no signal to either benefit or harm high-dose dexamethasone over standard-dose dexamethasone in patients with COVID-19 and moderate-to-severe ARDS. Trial registration Trial registration: ClinicalTrials.gov Identifier: NCT04663555. Registered 10 December 2020, https://clinicaltrials.gov/study/NCT04663555?term=NCT04663555&rank=1 and EudraCT: 2020-005887-70.

To evaluate the necessity of the application of glucocorticoid (GC) in moderate COVID-19 patients, and which is the optimal choice between methylprednisolone (MP) and dexamethasone (DEX) in the clinical use of GC in different types of COVID-19 patients.

The study included patients with COVID-19 in Shanxi, China, from December 18, 2022, to March 1, 2023. The main clinical outcomes were 30-day mortality, disease exacerbations, and hospitalization days. Secondary outcomes included the demand for non-invasive ventilator-assisted ventilation (NIPPV)/invasive mechanical ventilation (IMV), the need for GC regimen escalation in follow-up treatment, duration of GC treatment, and complications including hyperglycemia and fungal infection.

In moderate patients (N = 351), the rate of exacerbation and the need for GC regimen escalation in follow-up treatment was highest in the no-use GC group (P = 0.025, P = 0.01), the rate of fungal infections was highest in the DEX group (P = 0.038), and MP 40 mg/day or DEX 5 mg/day reduced exacerbations with consistent effects. In severe patients (N = 371), the two GC regimens do not affect their 30-day mortality and exacerbation rate, but the number of hospital days was significantly lower in the MP group compared with the DEX group (P < 0.001).

GC use is beneficial in mitigating exacerbations in moderate patients and in patients with moderate COVID-19. In severe patients, MP reduces the number of hospitalization days compared with DEX and may be a superior choice.

Acute respiratory distress syndrome (ARDS) is a complex and life-threatening disease characterized by severe respiratory failure. The lethality of ARDS remains alarmingly high, especially with the persistent ravages of coronavirus disease 2019 (COVID-19) in recent years. ARDS is one of the major complications of neocoronavirus pneumonia and the leading cause of death in infected patients. The large-scale outbreak of COVID-19 has greatly increased the incidence and mortality of ARDS. Despite advancements in our understanding of the causes and mechanisms of ARDS, the current clinical practice is still limited to the use of supportive medications to alleviate its progression. However, there remains a pressing need for effective therapeutic drugs to combat this devastating disease. In this comprehensive review, we discuss the commonly used therapeutic drugs for ARDS, including steroids, vitamin C, targeted inhibitors, and heparin. While these medications have shown some promise in managing ARDS, there is still a significant gap in the availability of definitive treatments. Moreover, we highlight the potential of nanocarrier delivery systems, such as liposomes, lipid nanoparticles, polymer nanoparticles, and inorganic nanoparticles, as promising therapeutic approaches for ARDS in the future. These innovative delivery systems have demonstrated encouraging results in early clinical trials and offer the potential for more targeted and effective treatment options. Despite the promising early results, further clinical trials are necessary to fully assess the efficacy and safety of nanotherapies for ARDS. Additionally, more in-depth research should be conducted to focus on the continuous development of precision therapies targeting different stages of ARDS development or different triggers. This will provide more ideas and rationale for the treatment of ARDS and ultimately lead to better patient outcomes.

In recent years, dexamethasone (Dex) has been used to treat acute respiratory distress syndrome (ARDS) in patients with COVID-19 and achieved promising outcomes. Venovenous extracorporeal membrane oxygenation (VV ECMO) support for patients with ARDS has increased significantly worldwide. However, it remains unknown whether Dex could improve the efficiency of VV ECMO to reduce lung injury. Here, we investigate the combined efficiency of VV ECMO and Dex in rats with acute lung injury (ALI).

We established VV ECMO in oleic acid (OA)-treated ALI rats and administered Dex. We conducted HE staining and evaluated lung and bronchoalveolar lavage (BAL) fluid cytokines to assess lung injury and inflammation. Furthermore, we investigated the activation of Hippo/YAP signalling in alveolar epithelial type II cell (AT2)-mediated alveolar epithelial repair using quantitative PCR, Western blotting and immunofluorescence. In vitro, the human alveolar epithelial cell line A549 was used to investigate the key role of YAP in alveolar epithelial cell differentiation.

VV ECMO combined with Dex alleviated OA-induced lung injury and pulmonary inflammation. Pulmonary oedema and exudation were significantly alleviated, and the lung and BAL levels of IL-6, IL-8 and TNF-α were significantly reduced compared with those observed with ECMO alone. In addition, VV ECMO combined with Dex treatment protected alveolar epithelial cells by activating Hippo/YAP signalling. In vitro, Dex promoted YAP expression and alveolar epithelial cell differentiation, whereas YAP knockdown inhibited YAP-mediated differentiation.

Our findings suggest that adjuvant Dex treatment during VV ECMO could alleviate ALI and pulmonary inflammation by activating the Hippo/YAP signalling pathway, which promoted alveolar regeneration and AT2 differentiation.

A proposed new global definition of ARDS seeks to update the Berlin definition and account for nonintubated ARDS and ARDS diagnoses in resource-variable settings.

How do ARDS epidemiologic characteristics change with operationalizing the new global definition of ARDS in a resource-limited setting?

We performed a real-use retrospective cohort study among adult patients meeting criteria for the Berlin definition of ARDS or the global definition of ARDS at ICU admission in two public hospitals in the KwaZulu-Natal Department of Health, South Africa, from January 2017 through June 2022.

Among 5,760 adults (aged ≥ 18 years) admitted to the ICU, 2,027 patients (35.2%) met at least one ARDS definition, including 1,218 patients meeting the Berlin definition of ARDS (60.1% of all ARDS diagnoses) and 809 new diagnoses of the global definition of ARDS that were not captured by the Berlin definition alone (39.9% of all ARDS diagnoses and 14.0% of all ICU admissions). After adjustment for hospital-level factors, patients who met only the global definition of ARDS criteria (ie, who would not have been captured by the Berlin definition) showed no statistically significant ICU mortality difference vs patients with ARDS according to the Berlin definition (21.7% [95% CI, 18.9%-24.4%] vs 23.8% [95% CI, 21.5%-26.2%]; OR, 0.88 [95% CI, 0.70-1.10]; P = .25). In prespecified exploratory subgroup analyses, patients without COVID-19 who met only the criteria for the global definition of ARDS showed reduced ICU mortality (14.2% [95% CI, 11.6%-16.9%] vs 22.2% [95% CI, 19.8%-24.6%]; OR, 0.58 [95% CI, 0.45-0.75]; P < .0005) compared with patients without COVID-19 who met the Berlin definition for ARDS.

The new global definition of ARDS captures a significant proportion of patients who would not have been included by the Berlin definition alone. These additional patients with ARDS may have heterogenous patterns of outcomes among diagnostic subgroups, including by COVID-19 status, compared with patients with ARDS according to the Berlin definition.

Therapeutic considerations for aspiration pneumonia prioritize the risk of multidrug-resistant organisms. This involves integrating microbiological insights with each patient's unique risk profile, including the location at the time of aspiration, and whether it occurred in or out of the hospital. Our understanding of the microbiology of aspiration pneumonia has also evolved, leading to a reassessment of anaerobic bacteria as the primary pathogens. Emerging research shows a predominance of aerobic pathogens, in both community and hospital-acquired cases. This shift challenges the routine use of broad-spectrum antibiotics targeting anaerobes, which can contribute to antibiotic resistance and complications such as Clostridium difficile infections-concerns that are especially relevant given the growing issue of antimicrobial resistance. Adopting a comprehensive, patient-specific approach that incorporates these insights can optimize antibiotic selection, improve treatment outcomes, and reduce the risk of resistance and adverse effects.

Acute respiratory distress syndrome (ARDS), are respiratory diseases with high morbidity and mortality. Clinical trials investigating the efficacy of corticosteroids in the treatment of ARDS often yield contradictory results. We hereby conducted a systematic review and meta-analysis to investigate the efficacy of corticosteroids in ARDS management.

We conducted a search for randomized clinical trials (RCT) and observational studies that utilized corticosteroids for patients with ARDS in Web of Science, PubMed, and Embase. The primary outcome was mortality. Risk of bias was assessed using Cochrane or NOS scales. Statistical effect size was analyzed using the Mantel-Haenszel method.

A total of 20 studies, comprising 11 observational studies and 9 RCTs, were eligible for analysis. In RCTs, corticosteroids were associated with a reduction of mortality in ARDS patients (relative risk [RR] = 0.80, 95%CI: 0.71-0.91, p = 0.001). Further subgroup analysis indicated that specific variables, such as low-dose (RR = 0.81; 95%CI: 0.67-0.98; p = 0.034), methylprednisolone (RR = 0.70; 95%CI: 0.49-0.98; p = 0.035), and dexamethasone (RR = 0.82; 95%CI: 0.69-0.98; p = 0.029) were associated with mortality among patients receiving corticosteroids. However, in observational studies, corticosteroids increased the risk of death (RR = 1.16, 95%CI: 1.04-1.29; p = 0.001). Subgroup analysis showed that the use of high-dose corticosteroids was associated with higher patient mortality (RR = 1.20; 95%CI: 1.04-1.38; p = 0.001).

The efficacy of corticosteroids on the mortality of ARDS differed by the type and dosage of corticosteroids used, as well as the etiologies. Current data do not support routine use of corticosteroids in ARDS since protective effects were observed in RCTs but increased mortality was found in observational studies. More well designed and large clinical trials are needed to specify the favorable subgroups for corticosteroid therapy.

Acute respiratory distress syndrome (ARDS) is a multifactorial, inflammatory lung disease with significant morbidity and mortality that predominantly requires supportive care in its management. Although initially described in adult patients, the diagnostic definitions for ARDS have evolved over time to accurately describe this disease process in pediatric and, more recently, neonatal patients. The management of ARDS in each age demographic has converged in the application of lung-protective ventilatory strategies to mitigate the primary disease process and prevent its exacerbation by limiting ventilator-induced lung injury. However, differences arise in the preferred ventilatory strategies or adjunctive pulmonary therapies used to mitigate each type of ARDS. In this review, we compare and contrast the epidemiology, common etiologies, pathophysiology, diagnostic criteria, and outcomes of ARDS across the lifespan. Additionally, we discuss in detail the different management strategies used for each subtype of ARDS and spotlight how these strategies were applied to mitigate poor outcomes during the COVID-19 pandemic. This review is geared toward both clinicians and clinician-scientists as it not only summarizes the latest information on disease pathogenesis and patient management in ARDS across the lifespan but also highlights knowledge gaps for further investigative efforts. We conclude by projecting how future studies can fill these gaps in research and what improvements may be envisioned in the management of NARDS and PARDS based on the current breadth of literature on adult ARDS treatment strategies.

Acute respiratory distress syndrome (ARDS) is characterized by a dysregulated immune response to infection or injury. This framework has driven long-standing interest in immunomodulatory therapies as treatments for ARDS. In this narrative review, we first define what constitutes a dysregulated immune response in ARDS. In this context, we describe the rationale and available evidence for immunomodulatory therapies studied in randomized controlled trials of ARDS patients to date. Finally, we address factors that have contributed to the failure to develop therapies in the past and highlight current and future developments designed to address them.

Several novel high-dimensional biologic measurements are increasingly being applied to biomedical sciences. Acute respiratory distress syndrome (ARDS) is a theoretically fertile ground for such approaches. Not only are these biologic and analytic tools available to better understand ARDS but also arguably, simpler approaches such as respiratory physiology has been vastly underutilized as a means of delivering precision-based care in the field. Here we review the progress made in ARDS toward discovering biologically homogeneous phenotypes, treatment responsive subgroups, the challenges to implement these discoveries at the bedside, and the road ahead that will enable precision medicine in ARDS.

The COVID-19 pandemic has prompted the exploration of effective treatment options, with dexamethasone emerging as a key corticosteroid for severe cases. This review evaluates the efficacy and safety of dexamethasone, highlighting its ability to reduce mortality rates, alleviate acute respiratory distress syndrome (ARDS), and mitigate hyperinflammation. While dexamethasone shows therapeutic promise, potential adverse effects-including cardiovascular issues, neuropsychiatric complications, lung infections, and liver damage-necessitate careful monitoring and individualized treatment strategies. The review also addresses the debate over using dexamethasone alone versus in combination with other therapies targeting SARS-CoV-2, examining potential synergistic effects and drug resistance. In summary, dexamethasone is a valuable treatment option for COVID-19 but its risks highlight the need for tailored surveillance approaches. Further research is essential to establish clear guidelines for optimizing treatment and improving patient outcomes.