Seminars in respiratory and critical care medicine最新文献

Acute exacerbations of chronic obstructive pulmonary disease (ECOPD) represent crucial events in the natural history of the disease. These are mainly characterized by abrupt worsening of respiratory symptoms, i.e. dyspnea, cough, sputum production. Defined by GOLD initiative as acute symptom deterioration requiring additional therapy, ECOPD markedly worsen lung function and strong clinical outcomes of any patient involved. Pathobiology is multidimensional, arising from inflammatory, mechanical, and cardiovascular perturbations that are linked each other and are likely to generate a self-reinforcing cycle of respiratory derangement and/or failure. Indeed, lung inflammation and injuries intensify airflow limitation, which in turn promotes air trapping and dynamic hyperinflation, increases elastic loads, and predisposes to respiratory muscle dysfunction. The resulting alterations of the blood gases may lead to even severe respiratory system failure and to a increased risk of dead.

Acute respiratory distress syndrome (ARDS) remains a heterogeneous and a major challenge disease process despite five decades of study. Emerging translational data delineate three overlapping phases: exudative, proliferative, and fibroproliferative, each driven by distinct immune-mechanical pathways and potentially modifiable by glucocorticosteroids (GC) modulation. Contemporary clinical randomized trials and meta-analyses indicate that early (≤72 hours) administration of systemic GCs at receptor-saturating doses (e.g., dexamethasone from 20 to 10 mg/day, or methylprednisolone 1-2 mg/kg/day) accelerates resolution of pulmonary edema, shortens mechanical ventilation duration, and improves intensive care survival, while prolonged tapering regimens are required once fibroproliferation is established. Conversely, delayed initiation (>14 days), viral pneumonitis with high viral load, recent surgical anastomosis, or uncontrolled fungal coinfection constitute "red flags" in which GCs might increase mortality. Latent-class analyses-a statistical modeling approach in which multivariable data are reduced to indirectly observed (latent) variables-identified two (hyper- and hypoinflammatory) ARDS phenotypes that likely might respond differentially to GC exposure, although we lack validation studies. Therefore, it seems that biomarker-guided precision therapy is poised to replace the historical one-size-fits-all approach. This narrative review integrates epidemiology, pathobiology, pharmacology, and clinical evidence to provide a phase-specific, phenotype-directed framework for GC use in ARDS and outlines future research priorities aimed at harmonizing molecular endotyping with dose, timing, and tapering strategies.

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.

Glucocorticoid (GC) therapy has been a cornerstone of critical care; however, its full potential has been constrained by fixed-dose regimens and trial designs that predate current insights into the dynamic, phase-specific functions of glucocorticoid receptor α (GRα). This study shifts focus from mechanistic pathways to the clinical implications of phase-adaptive care, emphasizing how GC therapy can be optimized through individualized, response-guided strategies tailored to illness trajectory and biological variability. Rather than reiterating GRα's mechanistic role, which is discussed in Chapter 3, this work highlights its practical relevance in therapeutic decision-making across the three sequential phases of critical illness: priming, modulatory, and restorative. In this clinically oriented framework, phase-specific treatment adjustments are informed by real-time changes in systemic stress markers, immune dynamics, and metabolic indicators. Earlier randomized controlled trials were instrumental in establishing safety but often failed to account for evolving physiological demands or receptor variability, contributing to inconsistent outcomes. To bridge this translational gap, this study proposes the integration of response-guided protocols utilizing accessible clinical biomarkers-such as C-reactive protein, interleukin-6, D-dimer, and lactate-allowing for adaptive dosing and tapering strategies aligned with patient-specific recovery patterns. Moving beyond pharmacologic dosing, the study outlines adjunctive clinical strategies-including targeted micronutrient supplementation and microbiome-supportive therapies-not as theoretical possibilities but as practical co-interventions that can be incorporated into intensive care unit protocols. Furthermore, it explores how artificial intelligence-enabled clinical decision systems and adaptive trial designs can operationalize precision care by dynamically stratifying patients and tailoring interventions to shifting biological profiles. Together, these applied strategies support a transition from static treatment paradigms to a precision medicine model in critical care-one that aligns GC therapy with individualized recovery trajectories, maximizes therapeutic responsiveness, and reduces treatment-related risks through multimodal, phase-responsive interventions.

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.

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.

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.

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.

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.