Abstract Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with its global prevalence projected to increase substantially by 2050, making its management one of the greatest challenges in respiratory medicine. Although pharmacological and nonpharmacological therapies remain the cornerstone of care, many patients continue to experience debilitating breathlessness, recurrent exacerbations, and impaired quality of life despite optimal medical treatment. Advances in interventional technology, imaging, patient selection, and anesthetic safety have transformed the therapeutic landscape, expanding the role of bronchoscopic and surgical interventions in the management of selected patients with COPD. These therapies aim to address the structural and pathophysiological consequences of disease that cannot be adequately treated with conventional medical therapy alone. Over the past three decades, lung volume reduction (LVR) has been extensively investigated and is now an established treatment option for appropriately selected patients with advanced emphysema. Both surgical and bronchoscopic LVR techniques have demonstrated improvements in lung function, exercise capacity, symptoms, and quality of life in carefully selected populations. Beyond LVR, a new generation of bronchoscopic therapies is emerging to target other COPD phenotypes and unmet clinical needs, including interventions designed to reduce exacerbation frequency, modify airway pathology, and improve symptom control. As the range of available treatment options continues to expand, multidisciplinary assessment and precision phenotyping are becoming increasingly important to identify the most appropriate intervention for each patient. This review provides an overview of the current evidence supporting established surgical and bronchoscopic LVR procedures and examines emerging bronchoscopic therapies for COPD. We discuss patient selection, procedural considerations, clinical outcomes, and future directions, highlighting the evolving role of interventional therapies within a personalized, multidisciplinary approach to COPD management.
Abstract:Diffuse cystic lung diseases (DCLDs) comprise a heterogeneous group of disorders characterized by multiple pulmonary cysts with overlapping clinical and radiologic manifestations. Accurate diagnosis relies on recognizing characteristic imaging patterns in conjunction with clinical and extrapulmonary findings. High-resolution computed tomography (HRCT) plays a central role in distinguishing true pulmonary cysts from common cyst mimickers, including emphysema, bullae, cavities, pneumatoceles, cystic bronchiectasis, and honeycombing, thereby narrowing the differential diagnosis. This review summarizes the imaging features of the major DCLDs encountered in adults, including lymphocytic interstitial pneumonia, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, and folliculin deficiency-associated disease (formerly Birt-Hogg-Dubé syndrome). Emphasis is placed on cyst morphology, craniocaudal distribution, associated parenchymal abnormalities, and characteristic extrapulmonary manifestations that facilitate diagnosis. The underlying pathophysiologic mechanisms responsible for cyst formation and their relationship to imaging appearances are also discussed. In addition, the review highlights important clinical features, including smoking history, autoimmune disease, genetic predisposition, and systemic involvement, which help refine the differential diagnosis. An integrated pattern-recognition approach combining HRCT findings with clinical context allows confident differentiation of the major DCLDs in most patients while reducing the need for invasive diagnostic procedures. Awareness of ancillary imaging findings and less common cystic lung disorders is essential when the imaging pattern is atypical or overlaps with other diffuse pulmonary diseases. A systematic understanding of characteristic imaging appearances and associated extrapulmonary manifestations enables radiologists and clinicians to establish an accurate diagnosis, guide appropriate genetic and clinical evaluation, and optimize patient management.
Abstract:Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection resulting in organ dysfunction. While traditional paradigms have emphasized proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β, interferons (IFNs) are increasingly recognized as critical yet underexplored mediators of sepsis pathobiology. IFNs are central regulators of innate and adaptive immunity and have emerged as key mediators of the immune alterations observed during sepsis. Type I IFNs (IFN-α/β), type II IFN (IFN-γ), and type III IFNs exert pleiotropic effects on immune activation, pathogen clearance, endothelial function, immunometabolism, and tissue injury. While early IFN responses support antimicrobial defense, sustained or dysregulated signaling contributes to hyperinflammation, endothelial dysfunction, immune exhaustion, coagulopathy, and multiorgan failure. Increasing evidence from experimental models and clinical studies suggests that IFN activity differs substantially among septic patients and may define biologically distinct immune endotypes. IFN-stimulated gene signatures and IFN-related biomarkers therefore represent promising tools for patient stratification and precision immunotherapy. This review summarizes the biology of IFNs relevant to sepsis, their role across different disease phases, their contribution to organ dysfunction, and emerging therapeutic strategies targeting IFN pathways. Current evidence supports a shift toward biomarker-guided and phase-specific immunomodulation aimed at restoring immune homeostasis while minimizing harmful inflammation.
Abstract:The COVID-19 disease, presenting with complex immune dysregulation and leading to life-threatening organ dysfunction, represents a paradigm of viral sepsis. As heterogeneity of clinical presentation is contained in COVID-19 (one pathogen, one source of infection) related to bacterial sepsis, and due to the urgency of the pandemic for immediate responsive research networks, many trials have been conducted providing beneficial patient outcomes and changing the natural course of disease. In this review, we summarize lessons learnt from the COVID-19 pandemic related to immunotherapy, management of acute respiratory failure (ARF) and postinfectious sequelae that could be implemented in sepsis care. Biomarker-guided immunotherapy in a tailored, precision medicine approach may alter sepsis outcomes. Measures used during the pandemic to handle ARF, such as high-flow nasal oxygen and awake prone position, have already been incorporated in standard-of-care sepsis management. Last, postinfectious sequelae present equally after sepsis (postsepsis syndrome [PSS]) and COVID-19 (post-COVID-19 syndrome [PCS]); management of PSS may share details from PCS management and vice versa. Teachings from the pandemic are not limited to the above. Overall, the COVID-19 pandemic has transformed global health to a top priority; focus should remain now active on the sepsis agenda.
Abstract:Micronodular lung disease may occur secondary to a large number of pulmonary disorders. A systematic approach when interpreting a chest CT scan showing multiple micronodules can significantly narrow the differential diagnosis. This article describes the imaging characteristics of micronodular lung disease, with a structure organized according to the prevalent distribution of micronodular opacities relative to the secondary pulmonary lobule. While the large number of disorders that can cause a micronodular pattern prevents a thorough discussion of all conditions, this article reviews the most relevant diseases associated with each pattern, with particular attention to imaging findings useful for differential diagnosis.
Abstract:Lipoid pneumonia is an uncommon disorder characterized by intra-alveolar lipid accumulation and classified as exogenous or endogenous. Exogenous forms most commonly result from aspiration of oil-based substances, whereas endogenous forms are associated with airway obstruction, malignancy, inflammatory disorders, and impaired macrophage function. Imaging manifestations are varied and frequently misleading, ranging from ground-glass opacities and consolidation to crazy-paving, nodules, and mass-like lesions that may closely mimic malignancy, infection, or other alveolar filling disorders. Although low-attenuation, fat-containing pulmonary opacities are characteristic, they are absent in many patients, making diagnosis challenging and often requiring clinicoradiologic-pathologic correlation. Bronchoalveolar lavage and histopathology may provide supportive evidence but lack complete specificity. Management focuses on eliminating the inciting exposure, reducing future aspiration risk, providing supportive care, and treating superimposed infection, while corticosteroids and therapeutic lavage have been used in selected severe cases.
Abstract Aspiration-related lung diseases comprise a broad spectrum of disorders resulting from the entry of oropharyngeal or gastric contents into the lower respiratory tract. Clinical manifestations range from acute aspiration pneumonitis and aspiration pneumonia to chronic airway and parenchymal injury, including bronchiolitis, bronchiectasis, fibrosis, and lipoid pneumonia. Aspiration pneumonitis is driven primarily by chemical injury, whereas aspiration pneumonia results from infection caused by aspirated microorganisms in susceptible hosts. Contemporary microbiologic data indicate that aspiration pneumonia more closely resembles community- or hospital-acquired pneumonia than the classic anaerobic infection paradigm. Imaging plays a central role in diagnosis, yet radiographic findings are highly variable and frequently contribute to diagnostic uncertainty. Chest radiography may be entirely normal or demonstrate only subtle gravity-dependent or perihilar opacities, while in other cases it reveals multifocal or diffuse air-space opacities that overlap substantially with other infectious and inflammatory lung diseases. Computed tomography is considerably more sensitive and depicts a broad spectrum of acute and chronic aspiration-related abnormalities, including ground-glass opacities, consolidation, tree-in-bud opacities, centrilobular nodules, aspiration bronchiolitis, bronchiectasis, fibrotic remodeling, and dendriform pulmonary ossification, while also demonstrating characteristic findings in select aspiration-related conditions. Recognition of these imaging patterns, together with clinical history and swallowing evaluation, is critical for establishing the diagnosis and identifying the underlying mechanism of aspiration. Management requires integration of clinical history, imaging, swallowing assessment, and selective adjunctive testing, with treatment directed toward supportive care, appropriate antimicrobial therapy when infection is present, prevention of recurrent aspiration through correction of the underlying cause, and multidisciplinary management when indicated. Early diagnosis and intervention are essential to prevent recurrent lung injury and progressive pulmonary damage.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) are acute events characterized by rapid worsening of dyspnea, cough, and sputum production, often leading to gas exchange impairment, ventilatory failure, and hospitalization. While pharmacological therapy remains central for managing the acute phase, non-pharmacological interventions play a crucial role in stabilizing patients, reducing complications, and promoting functional recovery. Respiratory strategies—including conventional oxygen therapy (COT), high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), and invasive mechanical ventilation (IMV)—is tailored to disease severity and underlying pathophysiology, aiming to unload respiratory muscles, improve ventilation, and optimize gas exchange. Pulmonary rehabilitation (PR) is essential to counteract skeletal and respiratory muscle dysfunction, sarcopenia, and exercise intolerance, thereby enhancing quality of life (QoL) and physical performance. Nutritional management addresses malnutrition, negative energy balance, and micronutrient deficiencies, supporting muscle preservation, immune function, and overall recovery. Home-based care models, including hospital-at-home programs and tele-rehabilitation, reduce hospital stays, facilitate early discharge, and improve access to structured PR programs. Structured self-management strategies and individualized exacerbation action plans empower patients, enhance symptom control, and reduce hospital readmissions, though their effectiveness may vary according to patient health literacy. Integrating these interventions into a comprehensive, multidisciplinary care pathway addresses both acute physiological derangements and long-term functional decline. Emerging digital health solutions—including telemonitoring, wearable sensors, and artificial intelligence-based predictive models—offer opportunities for early detection, personalized interventions, and enhanced patient engagement. This review synthesizes current evidence on non-pharmacological management of AECOPD, highlighting practical strategies to optimize respiratory support, rehabilitation, nutritional interventions, and self-management, ultimately aiming to accelerate recovery, prevent relapse, and improve QoL in this high-risk patient population.
Abstract:Acute deteriorations of respiratory symptoms in people with chronic obstructive pulmonary disease (COPD), known as exacerbations, worsen COPD severity (e.g., speed up lung function decline), and increase hospital admissions, healthcare costs, and mortality risk. The prevention, diagnosis, and treatment of exacerbations remain challenging due to the heterogeneous nature of these events. This complexity is further compounded by the high prevalence of multiple comorbidities and incompletely understood underlying mechanisms. Exacerbations of COPD and comorbidities are linked through bidirectional relationships, characterized by mutual adverse impacts, overlapping clinical manifestations, and increased susceptibility to the other condition. The identification and management of comorbidities are pivotal for effective disease management. Although current clinical frameworks, that is, models that integrate clinical features and biomarker-based identification of exacerbations to guide risk stratification and management, represent promising approaches to improve patient outcomes, multimorbidity is insufficiently incorporated. This narrative review provides an overview of the complex clinical associations of comorbidities in COPD, with a particular focus on exacerbations. It highlights differences in comorbidity prevalence among exacerbators, explores clinical interrelationships, and underscores the importance of multimorbidity-oriented management.
Abstract:Immunocompromised patients include those with innate T or B cell suppression, acquired immunodeficiency states such as those caused by human immunodeficiency virus infection, and those with medication-induced immunosuppression (chemotherapy or immunotherapy, solid organ transplant recipients). Any of these entities can place patients at increased risk of severe respiratory infection. We propose an algorithmic approach to the diagnosis of pulmonary complications that can arise in the immunocompromised patient. The first step is to gather all relevant clinical data to understand the history leading up to presentation, as well as the specific underlying immunosuppressive state. Following this, the clinician must identify the predominant imaging pattern of disease to help narrow the differential diagnosis and guide clinical management. Third, the time course of the clinical and imaging findings should be classified as acute, subacute, or chronic. We define the distinction between acute/subacute and chronic disorders as before or after 12 weeks. At the conclusion of these steps, it is hoped that a tailored differential diagnosis will allow for a rapid and precise management plan of these challenging patients.
Abstract Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and alveolar macrophage pneumonia (AMP) are two rare but closely related conditions within the spectrum of smoking-related interstitial pneumonias. Both share characteristic histopathologic features, including the accumulation of pigmented alveolar macrophages alongside varying degrees of interstitial inflammation and fibrosis. RB-ILD is typically a localized, bronchiolocentric process often found in smokers, whereas AMP represents a more diffuse and clinically significant disease that may arise not only from tobacco smoke but also from other causes such as occupational exposures, autoimmune diseases, and drug reactions. This review highlights the clinical presentation, imaging findings, histopathology, and treatment of both entities, emphasizing their overlapping features as well as key distinctions. We further discuss the pathogenic mechanisms driven by cigarette smoke—including oxidative stress, immune activation, and fibrosis—that underlie these diseases. A clear understanding of the similarities and differences between RB-ILD and AMP is essential for accurate diagnosis, effective management, and prognostication, particularly in patients with a history of smoking and diffuse parenchymal lung involvement.
Abstract:Exacerbations of chronic obstructive pulmonary disease (ECOPD) represent key events in the natural history of COPD and are associated with several adverse outcomes. Respiratory infections are major and potentially modifiable triggers of ECOPD, with viral pathogens such as the influenza virus, respiratory syncytial virus (RSV), and SARS-CoV-2, as well as bacterial infections caused by Streptococcus pneumoniae, playing a central role. This narrative review examines the current evidence supporting vaccination as a preventive strategy for ECOPD and discusses its translation into clinical practice. The biological rationale for vaccination in COPD is reviewed, including disease-related immune dysregulation, impaired mucociliary clearance, and increased susceptibility to respiratory pathogens. Evidence from randomized clinical trials, observational studies, meta-analyses, and real-world data is summarized for pneumococcal, influenza, SARS-CoV-2, and RSV vaccines. Pneumococcal vaccination has been shown to reduce the burden of community-acquired pneumonia and invasive pneumococcal disease, with conjugate and higher-valent vaccines providing enhanced immunogenicity in older and high-risk adults. Influenza vaccination consistently reduces severe exacerbations, hospitalizations, and mortality, with additional cardioprotective effects of relevance in COPD. SARS-CoV-2 vaccination markedly lowers the risk of severe COVID-19 and related respiratory deterioration in COPD, while recently licensed RSV vaccines offer a novel opportunity to prevent RSV-associated lower respiratory tract disease and potentially reduce exacerbation risk. Patient populations most likely to benefit from vaccination include frequent exacerbators, older adults, individuals with severe airflow limitation, multimorbidity, immune dysfunction, infection-prone phenotypes, and socially vulnerable groups. Future perspectives include precision vaccination strategies, novel vaccine platforms, coadministration approaches, and interventions to improve vaccine uptake. Vaccination emerges as a cornerstone of ECOPD prevention, with substantial potential to reduce exacerbation burden and improve long-term outcomes in COPD.
Abstract:Critically ill, immunocompromised individuals are vulnerable to both common and uncommon etiologies of respiratory infection. Identifying the etiology of infection has therapeutic, prognostic, and public health implications. In some circumstances, immunocompromised patients may be empirically treated with excessively broad antibiotics but ultimately be diagnosed with a common cause of pneumonia. In other circumstances, immunocompromised patients may have a non-specific clinical presentation for severe respiratory failure and be diagnosed with a rare etiology of infection. Because this patient population is at risk for a broad array of infections, it is important to understand the advantages and limitations of sampling and diagnostic techniques. Furthermore, the last decades of research have produced novel methods to enhance diagnostic accuracy. Many of these tests are molecular diagnostics that have high sensitivity, but their clinical impact is unknown, particularly in immunocompromised individuals. In this article we discuss various approaches to sampling and microbiologic diagnosis in immunocompromised individuals with severe respiratory failure.
Abstract:Acute exacerbations of chronic obstructive pulmonary disease (ECOPD) are pivotal events that accelerate lung function decline, impair quality of life, and increase the risk of hospitalization and mortality. Beyond episodic airway deterioration, ECOPD should be conceptualized as a systemic inflammatory syndrome driven by dysregulated responses to infectious or environmental triggers. Among inflammatory biomarkers, C-reactive protein (CRP) is the most extensively studied in ECOPD because of its rapid kinetics, wide availability, and clinical accessibility. This narrative review aims to summarize the diagnostic, therapeutic, and prognostic role of CRP in ECOPD. CRP levels rise sharply during exacerbations, particularly in pneumonic events, supporting diagnostic stratification and differentiation from non-bacterial or eosinophilic phenotypes. When integrated with clinical assessment, CRP improves diagnostic accuracy and informs antibiotic stewardship; CRP-guided strategies have been shown to reduce unnecessary antibiotic use without compromising clinical outcomes. Elevated CRP at presentation is associated with greater exacerbation severity, increased need for ventilatory support, and longer hospital stay. Persistently elevated CRP at discharge is linked to early relapse and readmission, while higher levels have also been associated with thromboembolic and cardiovascular risk, highlighting the systemic consequences of ECOPD. Despite these advantages, CRP is inherently nonspecific, influenced by comorbidities and timing of measurement, and optimal thresholds vary across clinical settings. CRP is a robust and accessible biomarker that provides valuable diagnostic, therapeutic, and prognostic information in ECOPD. Its incorporation into routine clinical practice can improve patient stratification, support antibiotic stewardship, and enhance monitoring of individuals at high risk of adverse outcomes. Future advances are likely to rely on longitudinal interpretation of CRP and its integration into multimarker panels and predictive models, combined with clinical variables and digital health data, to enable phenotype-driven management and precision medicine approaches in ECOPD.
Abstract:Chronic obstructive pulmonary disease (COPD) exacerbations represent the most common acute event and the one with the greatest medium- to long-term clinical and prognostic impact, acting as a key driver of functional decline, deterioration in quality of life, and constituting a substantial share of the morbidity, mortality, and healthcare costs attributable to the disease. This review synthesizes the most relevant epidemiological evidence on the frequency, distribution, and environmental determinants of exacerbations, with particular emphasis on longitudinal trends, seasonal patterns, and economic burden. Overall, the last decades have seen a decline in exacerbation rates within the context of clinical trials; however, analyses based on hospital registries are constrained by methodological limitations, notably reliance on International Classification of Diseases-coded case identification and a predominant focus on severe events. Temporal trajectories also vary by region: in Spain, decrease followed by subsequent rebounds have been described, with a more pronounced increase among women, while other European and non-European settings report divergent patterns. Seasonality emerges as a robust feature in temperate climates, with winter peaks and a consistent association between low temperatures (and thermal variability) and higher admission rates and exacerbation severity. Ambient air pollution (PM2.5/PM10, NO2, SO2, O3) is linked to an increased risk of exacerbation, potentially with lagged effects, through biologically plausible pathways mediated by oxidative stress and inflammation. Finally, we discuss the impact of exposures arising from environmental disasters (wildfires, volcanic eruptions, and oil spills), illustrated by recent events in Spain, and integrate the economic dimension, underscoring that exacerbations account for a large proportion of the total cost of COPD.
Abstract: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, that is, dyspnea, cough, and sputum production. Defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as acute symptom deterioration requiring additional therapy, ECOPD markedly worsens lung function and has strong clinical outcomes for any patient involved. Pathobiology is multidimensional, arising from inflammatory, mechanical, and cardiovascular perturbations that are linked to 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 an increased risk of death.
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.
Abstract: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.
