Seminars In Respiratory And Critical Care Medicine[JOURNAL]
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200 papers
Complications Associated with Glucocorticoids Treatment in Critically Ill Patients.
Confalonieri P, Reccardini N, Kette S … +1 more , Salton F
Semin Respir Crit Care Med · 2026 Feb · PMID 41061762 · Publisher ↗
Glucocorticoids (GCs) are essential immunomodulatory agents in the management of critically ill patients with severe systemic inflammation, particularly in conditions such as sepsis, acute respiratory distress syndrome,...
Glucocorticoids (GCs) are essential immunomodulatory agents in the management of critically ill patients with severe systemic inflammation, particularly in conditions such as sepsis, acute respiratory distress syndrome, and severe community-acquired pneumonia. When administered in low-to-intermediate doses for short durations (typically ≤4 weeks, including tapering), GCs have demonstrated substantial benefits in improving patient-centered outcomes, including reduced time on mechanical ventilation, shorter ICU stays, and lower mortality rates. However, the risk-benefit profile of GC therapy in critical illness differs markedly from long-term use in chronic inflammatory diseases and must be carefully evaluated. This study provides an evidence-based synthesis of the most relevant complications associated with the use of GCs in critically ill adults. Hyperglycemia is the most frequent metabolic effect, but it is typically transient and manageable with insulin, and is not associated with worse clinical outcomes. The risk of nosocomial infections has not been shown to increase significantly with appropriate dosing; in fact, immunomodulation by GCs may improve bacterial clearance. Nevertheless, clinicians should remain vigilant for opportunistic infections, particularly invasive fungal infections, in high-risk populations such as those with COVID-19. Musculoskeletal effects, including ICU-acquired weakness, appear to result more from underlying disease and immobilization than from GCs themselves, especially at moderate doses. Neuropsychiatric and gastrointestinal complications are dose-dependent and generally reversible. The transient suppression of the hypothalamic-pituitary-adrenal axis underscores the importance of gradual tapering to prevent inflammatory rebound and adrenal insufficiency. Overall, contemporary data support the safety of GCs when used with precision, directed by patient severity and response to treatment, with careful tapering and monitoring. The incorporation of integrative strategies, such as micronutrient and probiotic supplementation, may enhance GC receptor function and reduce required doses, further improving outcomes. Recognizing and managing potential complications enables clinicians to harness the therapeutic potential of GCs in critical illness fully.
Malignancies Presenting with Alveolar Infiltrates: Diagnostic Pitfalls, Radiologic Clues, and Clinical Patterns.
Mathavan A, Mathavan A, Rojas ORG … +1 more , Ataya A
Semin Respir Crit Care Med · 2025 Oct · PMID 41052636 · Publisher ↗
Alveolar infiltrates are a common but nonspecific radiologic finding that can obscure the diagnosis of underlying malignancy. While infections and inflammatory processes are typical considerations, a subset of cancers, b...
Alveolar infiltrates are a common but nonspecific radiologic finding that can obscure the diagnosis of underlying malignancy. While infections and inflammatory processes are typical considerations, a subset of cancers, both primary and secondary, can present with alveolar opacities that mimic these benign conditions. This review synthesizes the spectrum of neoplastic diseases that manifest with an alveolar radiographic pattern, focusing on both primary pulmonary malignancies (such as lepidic-predominant adenocarcinoma, invasive mucinous adenocarcinoma, and pulmonary lymphoma) and select metastatic solid tumors (notably renal cell carcinoma, gastrointestinal cancers, melanoma, and breast cancer) that exhibit a nondestructive, airspace-filling growth. We also describe secondary and paraneoplastic processes, including immune-mediated pneumonitis, eosinophilic pneumonia, leukemic pulmonary hemorrhage, diffuse alveolar hemorrhage, and secondary alveolar proteinosis, that can similarly produce alveolar opacities in the setting of malignancy. Each entity is discussed with emphasis on its clinical presentation, diagnostic approach, imaging features, and distinguishing characteristics. Radiographic findings and other diagnostics are integrated to highlight the importance of early recognition and appropriate investigation. Distinguishing malignant from infectious or inflammatory causes of alveolar disease remains challenging but critical, as misdiagnosis can lead to inappropriate treatment or delays in therapy. Summary tables are provided to support practical clinical differentiation and management. By improving recognition of neoplastic causes of alveolar infiltrates, clinicians may better tailor diagnostic workups and initiate appropriate treatment strategies.
Advances in Multimodality Management of Localized Non-Small Cell Lung Cancer.
Jonna S, Nusair JA, Santos GFC … +1 more , Jalal S
Semin Respir Crit Care Med · 2025 Oct · PMID 41043474 · Publisher ↗
Lung cancer represents the most common cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) comprising the vast majority of cases. Outcomes for stage II-III NSCLC remain suboptimal due to l...
Lung cancer represents the most common cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) comprising the vast majority of cases. Outcomes for stage II-III NSCLC remain suboptimal due to late presentation, biological heterogeneity, and limited efficacy of traditional therapies. Recent advances have reshaped the therapeutic landscape, with immunotherapy and targeted treatments now integrated into the management of resectable NSCLC. Landmark trials such as CheckMate 816 demonstrated improved event-free and overall survival with neoadjuvant chemoimmunotherapy approaches. Similarly, adjuvant targeted therapies such as osimertinib and alectinib have shown benefit in patients with and alterations, respectively. This review provides an overview of evolving diagnostic strategies, highlights pivotal clinical trials, and explores multidisciplinary treatment approaches across stages I to III NSCLC. We also address key challenges including optimal treatment sequencing, patient selection, and duration of therapy. As clinical trial data continue to mature, personalized multimodal strategies guided by molecular and clinical features remain central to improving long-term outcomes in resectable NSCLC.
Lysosomal Storage Disorders.
Cefalo J, Crestani B, Guyard A … +4 more , Pettazzoni M, Mauhin W, Debray MP, Borie R
Semin Respir Crit Care Med · 2025 Oct · PMID 41043473 · Publisher ↗
Lysosomes are intracellular organelles that are responsible for degrading and recycling macromolecules. Lysosomal diseases (LDs) are a group of rare inherited diseases caused by deleterious variants affecting genes that...
Lysosomes are intracellular organelles that are responsible for degrading and recycling macromolecules. Lysosomal diseases (LDs) are a group of rare inherited diseases caused by deleterious variants affecting genes that encode the lysosomal enzymes, their transporter or their cofactor. Among LDs that are associated with lung involvement and/or interstitial lung disease (ILD) acid sphingomyelinase deficiency [ASMD formerly called Niemann-Pick A, AB, and B diseases]) is the most common. An history of lower respiratory tract infections and exertional dyspnea are the most frequent respiratory manifestations. In ASMD, ILD is frequent and is usually associated with spleen and/or liver enlargement, low platelet count, and low level of high-density lipoprotein cholesterol. A restrictive lung functional pattern and a reduction in DLCO value are usually observed. Analysis of bronchoalveolar lavage fluid and lung biopsy showing foamy cells can orientate the diagnosis, based on the demonstration of an enzymatic deficiency in sphingomyelinase in the blood, associated with biallelic pathogenic variants of the gene. An enzyme replacement therapy (ERT), based on intravenous recombinant enzyme infusions (olipudase alfa), is available from 2021 with very encouraging results both in pediatric and adult patients affected with type B or AB. Olipudase alfa administration decreased liver and spleen volume, increased DLCO value and improved radiological lung involvement. Available enzyme replacement therapy supports an early diagnosis to implement therapy before any irreversible organ damage.
Emerging Concepts in Pathogenesis, Multiomics Applications, and Clinical Research in Lymphangioleiomyomatosis.
Yu JJ, Gupta N, Guo M … +2 more , Olatoke T, Xu Y
Semin Respir Crit Care Med · 2025 Aug · PMID 41005369 · Publisher ↗
Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm characterized by infiltration of abnormal smooth muscle-like and epithelioid cells into the lung parenchyma, leading to cystic changes and...
Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm characterized by infiltration of abnormal smooth muscle-like and epithelioid cells into the lung parenchyma, leading to cystic changes and progressive respiratory failure. In recent years, LAM has been an exemplar of meaningful progress in a rare lung disease, driven by close collaboration between patients, scientists, and clinicians, leading to the development of the U.S. Food and Drug Administration (FDA)-approved therapy, a diagnostic biomarker, a worldwide clinic network, and clinical practice guidelines. Integrating state-of-the-art bioinformatics and experimental approaches is helping accelerate the scientific progress in LAM and promises the development of novel biomarkers and therapies in the coming few years.
General Approach to Immunocompromised Patients with Pneumonia: Insights from the Latest Consensus Documents.
Ramirez JA
Semin Respir Crit Care Med · 2026 Apr · PMID 40997866 · Publisher ↗
Immunocompromised adults with pneumonia represent a growing and heterogeneous patient population requiring a tailored diagnostic and therapeutic approach. This review synthesizes insights from the latest consensus docume...
Immunocompromised adults with pneumonia represent a growing and heterogeneous patient population requiring a tailored diagnostic and therapeutic approach. This review synthesizes insights from the latest consensus documents and guidelines to provide a structured framework for clinicians managing pneumonia in immunocompromised hosts. Patients are stratified into four categories of immune dysfunction: Severely immunocompromised, immunocompromised, abnormal immune system (not at risk for opportunistic pathogens), and no identifiable immune abnormality. This classification informs both the likelihood of infection with core respiratory pathogens and opportunistic pathogens. A comprehensive microbiological evaluation is critical, incorporating sputum, nasopharyngeal swabs, blood cultures, urinary antigens, and, when indicated, bronchoalveolar lavage and biopsy. For most immunocompromised patients presenting with community-acquired pneumonia, empiric therapy parallels that of non-immunocompromised hosts. Empiric coverage for opportunistic pathogens is warranted in unstable patients with compatible risk factors, when delayed therapy may increase mortality.
Pneumonia after Solid Organ Transplantation.
Narvaez-Ramirez PO, Bustos IG, Serrano-Mayorga CC … +1 more , Reyes LF
Semin Respir Crit Care Med · 2026 Apr · PMID 40992415 · Full text
Solid organ transplantation (SOT) has significantly increased over the past few decades, with more than 170,000 SOTs performed worldwide in 2023. Although immunosuppressive treatments have improved patient survival, they...
Solid organ transplantation (SOT) has significantly increased over the past few decades, with more than 170,000 SOTs performed worldwide in 2023. Although immunosuppressive treatments have improved patient survival, they have also increased the risk of infections among SOT recipients (SOTRs), especially pneumonia. Pneumonia remains one of the leading causes of morbidity and mortality, with respiratory infections contributing to 30 to 70% of deaths in SOTRs, depending on the organ transplanted and the timing of infection. This review summarizes current knowledge on the epidemiology, risk factors, microbial etiology, and clinical manifestations of pneumonia in SOTRs. Temporal patterns of infection are also explored, with early posttransplant infections frequently caused by nosocomial or donor-derived pathogens, and community-acquired infections predominating beyond 6 to 12 months posttransplantation. The lack of robust, SOT-specific guidelines for pneumonia complicates the management of this entity in SOTRs. Most recommendations are based on extrapolations from immunocompetent populations. Furthermore, the lack of large, prospective trials comparing empirical antibiotic strategies in SOTRs limits evidence-based decision-making. Despite these challenges, early initiation of empirical therapy remains crucial to improving outcomes. The review highlights the importance of timely microbiological diagnosis, individualized antimicrobial stewardship, and targeted therapeutic approaches in the context of increasing antimicrobial resistance. Incorporating local epidemiological data and patient-specific risk profiles may enhance the accuracy of diagnosis and support the de-escalation of therapy upon pathogen identification.
The Evaluation of the Oncologic Patient for Drug-Induced Pneumonitis.
Swanson TC, Kinder BW, Clark JM
Semin Respir Crit Care Med · 2025 Oct · PMID 40967605 · Publisher ↗
The National Cancer Institute (NCI) estimates that over 2 million Americans will be diagnosed with cancer in 2025. A significant proportion of these patients will receive chemotherapeutics, radiation, molecularly targete...
The National Cancer Institute (NCI) estimates that over 2 million Americans will be diagnosed with cancer in 2025. A significant proportion of these patients will receive chemotherapeutics, radiation, molecularly targeted therapies, or immunotherapies-many of which are associated with pulmonary toxicity. Drug-induced interstitial lung disease (D-ILD) is a growing and well-recognized complication of cancer-related therapies, carrying substantial morbidity and mortality. In addition to its direct health impact, D-ILD often necessitates modification or discontinuation of cancer treatment, further complicating oncologic care. As such, pulmonologists must be proficient in the evaluation and management of suspected D-ILD. In this review, we propose a structured approach to assessing patients with malignancy who present with diffuse parenchymal lung disease. We also summarize commonly implicated cancer therapies and their associated pulmonary toxicities.
Cryptogenic Organizing Pneumonia.
Root MZ, Lee JS
Semin Respir Crit Care Med · 2025 Oct · PMID 40967604 · Publisher ↗
Cryptogenic organizing pneumonia (COP), formerly called bronchiolitis obliterans organizing pneumonia (BOOP), was first described in the 1980s and is classified as a rare idiopathic interstitial pneumonia (IIP). COP clas...
Cryptogenic organizing pneumonia (COP), formerly called bronchiolitis obliterans organizing pneumonia (BOOP), was first described in the 1980s and is classified as a rare idiopathic interstitial pneumonia (IIP). COP classically presents in a subacute fashion following a flu-like illness with fever, non-productive cough, and fatigue. Imaging often reveals diffuse, bilateral, peribronchovascular and peripheral, consolidative and ground-glass opacities although various imaging subtypes also exist. Physical examination may be normal or reveal inspiratory crackles. Hypoxemia, when present, is commonly identified with exertion but can also occur at rest. Diagnostic evaluation relies on excluding secondary causes of organizing pneumonia and includes a thorough history including medications, exposures, and signs or symptoms of underlying rheumatologic disease. Invasive diagnostic testing including tissue sampling allows for histopathologic confirmation of COP while excluding secondary causes including infection and malignancy. Although video-assisted thoracoscopic surgery (VATS) lung biopsy is often the preferred method of obtaining sufficient tissue, less invasive means may be employed based on patient-specific factors. A defining feature of COP is steroid-responsiveness, and most experts recommend prolonged corticosteroid courses (6-12 months). Response to corticosteroids and prognosis are typically excellent. Relapse rates range from 25 to 50% and occur most often during steroid taper or complete withdrawal necessitating additional therapy. Steroid-sparing immunosuppression may be used in select circumstances. Further study is needed to define optimal corticosteroid dose and duration.
T Regulatory Mechanisms in Airway and Interstitial Lung Disease.
Pastore CF, Stadler BD, Sperling AI … +1 more , Velez TE
Semin Respir Crit Care Med · 2025 Aug · PMID 40967603 · Full text
Chronic lung disease is a sequela of unresolving pathogenesis in the lung. Current estimates report approximately 7.4% of the world's population live with chronic respiratory diseases. The architectural differences in th...
Chronic lung disease is a sequela of unresolving pathogenesis in the lung. Current estimates report approximately 7.4% of the world's population live with chronic respiratory diseases. The architectural differences in the airways and individual alveoli provide unique microenvironments for mechanisms of disease and thus necessitate specialized modes of regulation. A key immune cell type that has the ability to adapt and provide copius regulatory mechanisms are T regulatory cells (Tregs). In the last two decades, studies have revealed that Tregs respond to their microenvironment and phenotypically change to conduct versatile functions; however, during chronic inflammatory diseases, Tregs are potentially skewed toward pathogenic mechanisms. In this review, we will focus on the differential mechanisms of Treg responses in the lung airways versus interstitium as unique microenvironments by focusing on asthma, acute lung injury/airway respiratory disease syndrome, and interstitial lung disease.
Glucocorticoid Treatment in Community-Acquired Pneumonia.
Dequin PF, Confalonieri M
Semin Respir Crit Care Med · 2026 Feb · PMID 40967602 · Full text
Despite a fairly large number of comparative trials (which are, however, very heterogeneous), the role of corticosteroids in the adjuvant treatment of community-acquired pneumonia remains controversial. Nevertheless, rec...
Despite a fairly large number of comparative trials (which are, however, very heterogeneous), the role of corticosteroids in the adjuvant treatment of community-acquired pneumonia remains controversial. Nevertheless, recent randomized trials with adequate power in intensive care unit patients, albeit with conflicting results, have contributed to clarifying our understanding of this issue. More accurate phenotyping of patients likely to benefit from corticosteroid treatment must now be performed. In COVID-19 pneumonia, their benefit is not in question. For certain specific pathogens, including viral pathogens, their indications must be refined. They are still not recommended for influenza. They appear generally safe for short-term use in select populations.
The Glucocorticoid System: A Multifaceted Regulator of Mitochondrial Function, Endothelial Homeostasis, and Intestinal Barrier Integrity.
Meduri GU, Psarra AG
Semin Respir Crit Care Med · 2026 Feb · PMID 40962264 · Publisher ↗
Critical illness initiates a cascade of systemic disturbances-including energy deficits, oxidative stress, endothelial injury, and intestinal barrier dysfunction. Mitochondria, the vascular endothelium, and the intestina...
Critical illness initiates a cascade of systemic disturbances-including energy deficits, oxidative stress, endothelial injury, and intestinal barrier dysfunction. Mitochondria, the vascular endothelium, and the intestinal barrier are three critical interfaces that facilitate the restoration of homeostasis. These processes are regulated by the glucocorticoid (GC) signaling system, specifically through the glucocorticoid receptor α (GRα), which coordinates cellular metabolism, immune modulation, and vascular integrity. This integrated signaling network offers therapeutic targets to prevent or reduce organ dysfunction and damage. Mitochondria function as metabolic hubs, transforming substrates mobilized by GC-GRα into adenosine triphosphate (ATP) via oxidative phosphorylation (OXPHOS), while also regulating calcium homeostasis, reactive oxygen species (ROS) signaling, and apoptosis. However, excessive ROS generation during critical illness can disrupt cellular energetics, leading to systemic inflammation and critical illness-related corticosteroid insufficiency (CIRCI). GC-GRα signaling helps mitigate mitochondrial dysfunction by promoting mitochondrial biogenesis, enhancing antioxidant defenses, and maintaining redox balance, which is essential for metabolic recovery and survival. The vascular endothelium and the intestinal barrier are the two most extensive and vulnerable surfaces affected during critical illness, and their preservation or restoration is vital for recovery. These active interfaces are essential for maintaining vascular integrity, immune balance, and metabolic stability-functions that are often severely impaired in critical illness. The vascular endothelium, which lines the entire circulatory system, plays a crucial role in regulating vascular tone, permeability, and immune cell recruitment through mediators like nitric oxide and prostacyclin. In conditions such as sepsis and acute respiratory distress syndrome (ARDS), inflammatory injury damages the endothelial glycocalyx and tight junctions, leading to microvascular leakage and widespread inflammation. Activation of GC-GRα pathways helps restore endothelial integrity by inhibiting nuclear factor-κB (NF-κB), lowering proinflammatory cytokine production, increasing tight junction proteins, and boosting endothelial nitric oxide synthase (eNOS) activity-mechanisms that collectively prevent thrombosis and edema. The intestinal barrier, maintained by tight junctions and gut microbiota, is essential for nutrient absorption and mucosal immune defense. During critical illness, gut dysbiosis-marked by a depletion of beneficial commensals and overgrowth of pathogenic species-compromises barrier integrity, increases intestinal permeability, and promotes bacterial translocation. GC-GRα signaling plays a key role in preserving the intestinal barrier by regulating tight junctions, lowering permeability, and affecting microbiota composition. Combining GC therapy with microbiota-focused interventions offers hope for reducing inflammation, supporting recovery, and improving survival in critically ill patients.
Updates in Lung Cancer Screening: A Decade of Evidence.
Sakoda LC, Henderson LM
Semin Respir Crit Care Med · 2025 Oct · PMID 40957611 · Full text
In this review, we summarize recent evidence from approximately the last 5 years across the lung cancer screening (LCS) care continuum. First, we review the results from the NELSON trial, from the extended follow-up of o...
In this review, we summarize recent evidence from approximately the last 5 years across the lung cancer screening (LCS) care continuum. First, we review the results from the NELSON trial, from the extended follow-up of other LCS randomized controlled trials (RCTs), and from a meta-analysis of RCTs. Together, these RCTs reported a 16% relative reduction in lung cancer mortality for low-dose CT (LDCT) LCS versus non-LDCT controls. Next, we summarize updates to clinical guidelines and recommendations around LCS in the United States, noting the current debate around the use of time since quit as an eligibility criterion. We also discuss the implementation of LCS focusing on the following areas: (1) global landscape, (2) selection criteria and approach, (3) LCS program structure, (4) shared decision making, (5) smoking cessation, (6) LCS uptake, (7) American College of Radiology Lung Reporting and Data System, (8) annual LCS adherence, (9) screen-detected findings and management, (10) incidental findings and management, and (11) disparities. Lastly, we highlight emerging data and considerations for personalized LCS and new technologies, with an emphasis on risk prediction models, biomarkers, and artificial intelligence. This review highlights the latest changes to LCS and the ongoing need to monitor and evaluate LCS as it diffuses into clinical practice across various real-world settings.
Glucocorticoid Treatment in Severe COPD Exacerbations: Biological Rationale, Clinical Effects, and Practical Advice.
Sartori F, Sartori G, Di Chiara C … +2 more , Fantin A, Crisafulli E
Semin Respir Crit Care Med · 2026 Feb · PMID 40957597 · Publisher ↗
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD), particularly those requiring hospitalization or intensive care unit (ICU) admission, represent a significant clinical and prognostic burden. Systemic...
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD), particularly those requiring hospitalization or intensive care unit (ICU) admission, represent a significant clinical and prognostic burden. Systemic corticosteroids remain a cornerstone of AECOPD management, supporting their role in improving time to recovery, symptom relief, and hospital length of stay. These benefits are primarily attributed to corticosteroids' broad anti-inflammatory and immunomodulatory actions, including the downregulation of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and tumor necrosis factor α, as well as the restoration of glucocorticoid receptor function impaired in severe disease. Randomized controlled trials and meta-analyses confirm that short-course, low-to-moderate corticosteroid regimens are as effective as prolonged or higher-dose treatments, minimizing adverse effects such as hyperglycemia and infections. Oral administration is equally effective as intravenous therapy in most hospitalized patients, streamlining care without compromising efficacy. In ICU settings, systemic corticosteroids have been shown to reduce the need for invasive ventilation and shorten ICU stay, although mortality benefits remain inconsistent. Emerging precision medicine approaches highlight the relevance of blood eosinophil counts in predicting corticosteroid responsiveness. Eosinophilic patients experience shorter hospital stays, faster clinical improvement, and fewer treatment failures, suggesting the utility of eosinophil-guided corticosteroid therapy. Conversely, patients with neutrophil-predominant or infectious exacerbations may derive less benefit and face a greater risk of steroid-related complications. This narrative review synthesizes current evidence on the pharmacological, clinical, and biomarker-guided use of corticosteroids in severe AECOPD, emphasizing individualized treatment strategies to optimize therapeutic outcomes. With limitations represented by heterogeneity in study populations, lack of standardized eosinophil thresholds, and sparse data in critically ill or comorbid patients, future directions should include defining optimal corticosteroid regimens, refining eosinophil thresholds, exploring adjunctive therapies, and expanding biomarker-based protocols in ICU populations. Corticosteroid stewardship, guided by inflammatory profiles, represents a critical step toward personalized care in high-risk patients with COPD.
Glucocorticoids and GRα Signaling in Critical Illness: Phase-Specific Homeostatic Corrections Across Systems.
Meduri GU
Semin Respir Crit Care Med · 2026 Feb · PMID 40957596 · Publisher ↗
Glucocorticoid (GC)-activated glucocorticoid receptor α (GRα) signaling-underpins survival and recovery during severe physiological stress. Rooted in evolution, these adjustments are not mere damage control; they constit...
Glucocorticoid (GC)-activated glucocorticoid receptor α (GRα) signaling-underpins survival and recovery during severe physiological stress. Rooted in evolution, these adjustments are not mere damage control; they constitute a coordinated, dynamic, phase-specific program that integrates metabolic, immune (innate and adaptive), cardiovascular, neuroendocrine, and organ functions. By boosting mitochondrial energy production and regulating inflammatory and hemostatic pathways, the GC-GRα axis enables adaptation to the demands of critical illness. These mechanisms operate across tissues and time to sustain systemic stability. This program unfolds in three phases. In the priming phase, innate immunity is rapidly mobilized, bioenergetic reserves are secured, and cardiovascular function is enhanced to build resilience. With the immediate threat contained, the modulatory phase suppresses excessive inflammation and oxidative stress and restores and preserves vascular integrity. In the restorative phase, resolution of injury enables structural and functional repair, re-establishing tissue architecture and function for long-term recovery. Failure to enter or complete the modulatory phase prolongs dysregulated responses that impede recovery. GRα is central: beyond anti-inflammatory actions, it shapes pro-inflammatory and metabolic programs. Through context-dependent co-regulation with nuclear factor-κB and activator protein-1, GRα directs cell-specific responses, drives chromatin remodeling, and orchestrates phase-specific gene expression to maintain a dynamic balance essential for survival. When transition to the modulatory phase fails, persistent stress signaling depletes neuroendocrine reserves, impairs bioenergetics, and exhausts key micronutrients, increasing allostatic load and mortality risk. Clinical modifiers-including critical illness-related corticosteroid insufficiency (CIRCI), mitochondrial dysfunction, hypovitaminosis, and oxidative stress-accelerate metabolic strain and decline toward organ failure. Mechanism-aligned care targeting GRα and synchronizing therapy with recovery phases enables individualized CIRCI correction, tempering of dysregulated inflammation, and organ recovery. Recognizing GC-GRα as the coordinator of homeostatic corrections highlights its evolutionary importance and guides strategies that complement the body's capacity to restore homeostasis.
Corticosteroid Treatment in Septic Shock.
Liu J, Xing Q, Pan X … +3 more , Zhang S, Chen D, Annane D
Semin Respir Crit Care Med · 2026 Feb · PMID 40957595 · Publisher ↗
Septic shock, the most severe manifestation of sepsis, is characterized by profound circulatory failure and carries the highest mortality risk among sepsis-related conditions. Current therapeutic strategies remain primar...
Septic shock, the most severe manifestation of sepsis, is characterized by profound circulatory failure and carries the highest mortality risk among sepsis-related conditions. Current therapeutic strategies remain primarily supportive, emphasizing empirical antimicrobial therapy and advanced organ system support. The immunomodulatory properties of corticosteroids in sepsis pathophysiology have been extensively investigated since the 1970s, though current guidelines recommend corticosteroid therapy for sepsis patients, albeit with a weak evidence base. In this review, we explore the molecular underpinnings of corticosteroid activity in septic shock and clinical evidence from randomized controlled trials, with a special emphasis on the stabilization of hemodynamics and the impact on mortality outcomes. Furthermore, we analyze recent advances in pharmacodynamic understanding that may inform more targeted corticosteroid administration in septic shock.
Heterogeneity of Lung Phagocytes and Clearance of Apoptotic Cells in Lung Injury and Repair.
Bersie SM, McCubbrey AL
Semin Respir Crit Care Med · 2025 Aug · PMID 40907535 · Full text
Poor repair following lung injury is a significant cause of morbidity and mortality. Clearance of apoptotic cells, termed efferocytosis, has emerged as a key process that can influence repair outcomes and facilitate succ...
Poor repair following lung injury is a significant cause of morbidity and mortality. Clearance of apoptotic cells, termed efferocytosis, has emerged as a key process that can influence repair outcomes and facilitate successful repair. Although prior literature has focused on efferocytosis by macrophages, evidence is emerging that nonprofessional phagocytes, including fibroblasts and epithelial cells, may play critical roles in efferocytosis during tissue repair. This review summarizes existing knowledge of different lung phagocytes that can participate in efferocytosis, evidence linking efferocytosis to lung health and tissue repair, and discusses factors that may inhibit or redirect efferocytosis to promote mis-repair. A deeper understanding of how the integrated landscape of lung phagocytes participates in efferocytosis will likely provide significant insight into repair and mis-repair processes.
Glucocorticoid Treatment for Hospital-Acquired and Ventilator-Associated Pneumonia.
Poulain C, Bouras M, Roquilly A
Semin Respir Crit Care Med · 2026 Feb · PMID 40902632 · Publisher ↗
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain among the most frequent complications in critically ill patients. Despite the implementation of modern preventive strategies and the wide...
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain among the most frequent complications in critically ill patients. Despite the implementation of modern preventive strategies and the widespread use of broad-spectrum antibiotics, both the incidence and treatment failure rates remain high. However, no adjunctive therapy is currently recommended. Glucocorticoids have recently attracted renewed interest as potential immunomodulatory agents in this setting. By reducing excessive inflammation and promoting the resolution of the immune response, they may help limit lung injury and improve clinical outcomes. This hypothesis is supported by findings from related conditions such as community-acquired pneumonia, acute respiratory distress syndrome, and severe COVID-19, where corticosteroids have demonstrated benefits in selected populations. However, evidence specific to HAP and VAP remains limited. A few randomized trials have evaluated corticosteroids for prevention, particularly in trauma patients, where findings suggest a potential benefit and highlight the relevance of this strategy in select populations. More recently, individualized approaches based on inflammatory biomarkers have shown promise in identifying patients who are more likely to benefit from corticosteroid therapy. Two randomized controlled trials, currently ongoing to evaluate their role as adjunctive treatment in established HAP and VAP, will help define the efficacy and tolerance of steroids. Given the heterogeneity of immune responses in critically ill patients, a "one-size-fits-all" approach is unlikely to be effective. Identifying inflammatory sub-phenotypes using clinical and biological markers (such as C-reactive protein or interleukin-6) may help guide a more personalized use of immunomodulatory therapies. Alterations in the lung microbiome could also influence host response and treatment efficacy. Altogether, corticosteroids represent a promising but still understudied adjunctive strategy for HAP and VAP. Future research should aim to refine patient selection and optimize treatment strategies within a precision medicine framework.
Factors Influencing Glucocorticoid Treatment Response: Mechanism-Based Strategies to Overcome Glucocorticoid Resistance and Restore GRα Function.
Meduri GU
Semin Respir Crit Care Med · 2026 Feb · PMID 40876825 · Publisher ↗
Glucocorticoids (GCs) remain central to managing dysregulated systemic inflammation in critical illness, yet therapeutic response varies widely due to multifactorial glucocorticoid resistance (GCR). This chapter provides...
Glucocorticoids (GCs) remain central to managing dysregulated systemic inflammation in critical illness, yet therapeutic response varies widely due to multifactorial glucocorticoid resistance (GCR). This chapter provides a translational framework to guide clinicians in identifying and overcoming GCR, with a central emphasis on restoring glucocorticoid receptor α (GRα) function. Mechanisms of resistance include reduced GRα expression, GRβ dominance, impaired nuclear translocation, oxidative stress, mitochondrial dysfunction, micronutrient depletion, and epigenetic suppression. Pharmacokinetic and pharmacodynamic barriers-such as suboptimal dosing, impaired tissue penetration, accelerated clearance, erratic dosing schedules, and premature tapering-further compromise GRα engagement and treatment efficacy. In addition, interindividual variability in GR responsiveness is shaped by genetic polymorphisms, isoform balance, and local tissue conditions, compounded by up to 10-fold variability in circulating drug levels within the same patient. This chapter outlines evidence-based strategies to optimize GC therapy, including dose refinement, continuous infusion protocols, biomarker-guided escalation, and structured tapering. Adjunctive therapies-such as antioxidants, micronutrients, probiotics, and melatonin-are also highlighted for their role in enhancing mitochondrial resilience, redox stability, and GRα signaling across key regulatory phases. Importantly, many of these disruptions-whether arising from mitochondrial dysfunction, epigenetic changes, or intestinal dysbiosis-converge on shared molecular pathways such as nuclear factor kappa-B (NF-κB) activation, mitogen-activated protein kinase (MAPK) signaling, histone deacetylase 2 (HDAC2) inhibition, and oxidative stress, all of which compromise GRα function across systems. Recognizing this mechanistic convergence helps explain the multisystem nature of steroid resistance. It supports a unified therapeutic approach that targets oxidative stress, restores mitochondrial function, modulates the microbiome, and reinforces epigenetic regulation-working together to preserve GRα signaling across affected systems. While this framework is grounded in mechanistic and translational evidence, its application in clinical practice-including tapering strategies, biomarker thresholds, and adjunctive therapies-requires validation in randomized controlled trials.
Reimagining Fibrosis Research, Outcomes, and Therapeutics Through the Lens of Resolution.
Fortier SM, Redente EF, Peters-Golden M
Semin Respir Crit Care Med · 2025 Aug · PMID 40829653 · Full text
Tissue fibrosis contributes to progressive organ dysfunction in a multitude of chronic human diseases. Despite decades of ongoing research dedicated to determining the cellular and molecular origins of fibrosis across mu...
Tissue fibrosis contributes to progressive organ dysfunction in a multitude of chronic human diseases. Despite decades of ongoing research dedicated to determining the cellular and molecular origins of fibrosis across multiple organs, we continue to lack truly impactful therapies that halt or reverse scarring. This unmet need is especially evident among individuals with fibrotic lung disease, such as idiopathic pulmonary fibrosis (IPF), who frequently succumb to progressive respiratory failure a few years after diagnosis. Current therapies approved for IPF and progressive fibrotic lung diseases emerged from a longstanding drug development paradigm focused on the inhibition of pro-fibrotic drivers of fibrosis. Given that the vast majority of patients with fibrotic lung disease present with already established scarring, the relative paucity of research focused on fibrosis resolution pathways represents a glaring and critical gap in our knowledge. In contrast to the progressive pathologic fibrosis emblematic of IPF, fibrosis evolved as a self-limited wound-healing response to tissue injury, and spontaneous resolution of lung fibrosis is observed in various experimental animal models. These naturally resolving animal models of fibrosis provide an opportunity to define endogenous anti-fibrotic mediators that inhibit multiple drivers of fibrosis and can orchestrate the return of tissue homeostasis. Therapeutic restoration of these endogenous "resolvers"-which are ostensibly disabled in states of pathologic fibrosis-has immense therapeutic potential. In this perspective, we contend that a paradigm shift in our approach toward fibrosis research is needed. Specifically, we propose that pulmonary fibrosis research be reprioritized to collectively focus on mechanisms of fibrosis resolution using rigorous methods designed to unveil, validate, and explore the therapeutic implications of endogenous resolvers.
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