Seminars in respiratory and critical care medicine最新文献

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.

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.

Severe asthma affects approximately 3% to 10% of the asthmatic population and is characterized by persistent symptoms and frequent exacerbations despite high-intensity therapy. Historically, glucocorticoids (GCs) have been the mainstay of treatment due to their broad anti-inflammatory effects. However, long-term systemic GC use is associated with substantial toxicity and heterogeneous clinical response, largely influenced by underlying inflammatory endotypes. Type 2 (T2) asthma, marked by eosinophilia and cytokines such as IL-4, IL-5, and IL-13, generally responds well to GCs. In contrast, non-T2 phenotypes, often associated with neutrophilic inflammation, obesity, or smoking, exhibit GC resistance. Molecular mechanisms underlying GC resistance include GRβ overexpression, impaired GRα nuclear translocation via mitogen-activated protein kinase (MAPK) activation, and histone deacetylase-2 (HDAC2) inactivation by oxidative stress. Therapeutic strategies for severe asthma involve maximizing inhaled corticosteroids (ICSs) and adding long-acting bronchodilators or biologics before considering maintenance oral corticosteroids (OCSs). Despite these guidelines, OCS overuse remains common, with many patients exposed to cumulative doses associated with severe adverse effects. These include osteoporosis, diabetes, infections, neuropsychiatric symptoms, and adrenal suppression. Therefore, reducing systemic GC exposure is a key objective in modern asthma management. Biologic therapies targeting IgE (omalizumab), IL-5 (mepolizumab, reslizumab), IL-5Rα (benralizumab), IL-4Rα (dupilumab), and thymic stromal lymphopoietin (tezepelumab) have shown substantial OCS-sparing effects in clinical trials, enabling dose reduction or discontinuation in many patients with steroid-dependent asthma. These agents, aligned with precision medicine principles, allow for phenotype-specific treatment and improved safety profiles. Future efforts should focus on improving biomarker-driven treatment selection, expanding non-T2 therapeutic options, and implementing steroid stewardship protocols. In conclusion, while GCs remain essential for acute exacerbations and as bridging therapy, their chronic use should be minimized. Biologic therapies offer a transformative opportunity to reduce GC burden, improving long-term outcomes and quality of life in patients with severe asthma.

The prevalence of immunosuppression in the general population has been increasing over time due to a combination of factors, including advances in health care and the emergence of new therapies. Population-based studies show that approximately 3% of the population are prescribed systemic corticosteroid therapy at least once a year. Additionally, the number of immunomodulatory agents, such as biologics and small molecules, continues to grow. The chronic use of systemic corticosteroid and immunomodulating agents has an impact not only on the incidence of patients with pneumonia, but also on their microbiology, clinical presentation, and outcomes. Recent cohort studies show that chronic corticosteroid therapy is one of the leading causes of immunosuppression in patients with nosocomial pneumonia and community-acquired pneumonia requiring hospitalization. Different immunomodulating agents can have varying effects on the immune system; hence, each agent should be individually analyzed when assessing their impact on the immune system. Important factors to consider are the dose and duration of immunosuppressive medications, as well as their indication. Many of the conditions for which corticosteroids and immunomodulators are prescribed also lead to immunosuppression. In the study, we aim to assess the literature on the risk of pneumonia associated with the use of chronic systemic corticosteroid therapy and immunomodulating agents, particularly biologics and small molecules. We also discuss clinical manifestations and management of patients who develop pneumonia while on these therapies.