Seminars in respiratory and critical care medicine最新文献

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.

Sarcoidosis is a disease with high morbidity that has variable epidemiology based on genetics and sociodemographic factors. The etiology of this variability remains incompletely understood. This narrative review describes how genetics, social determinants of health, and the interactions between them may contribute to the differences in epidemiology and health outcomes observed in different patient groups with sarcoidosis.

Sarcoidosis is a complex, immune-mediated disease characterized by a broad spectrum of clinical and molecular phenotypes-often referred to as endophenotypes-some of which progress to chronic outcomes such as pulmonary fibrosis. Despite decades of research, the pathogenesis of sarcoidosis remains incompletely understood, primarily due to its clinical heterogeneity and the absence of robust preclinical models. Established risk factors include age, sex, ethnicity, geographic origin, and environmental exposures, all of which contribute to granuloma formation and the activation of profibrotic pathways. These inflammatory cascades promote fibroblast proliferation and aberrant tissue remodeling, ultimately leading to interstitial lung pathology and fibrosis. A central feature of sarcoidosis is the dysregulation of immune regulatory mechanisms, likely driven by genetic susceptibility and immune dysfunction. Understanding the genetic architecture of sarcoidosis is crucial for identifying the molecular drivers of the disease, discovering biomarkers for early diagnosis and prognosis, and developing targeted therapies. This review synthesizes current knowledge on the genetic and genomic landscape of sarcoidosis, highlighting key loci and biological pathways implicated in disease susceptibility and progression.

Cardiac sarcoidosis (CS) is a potentially fatal but often underrecognized manifestation of systemic sarcoidosis. Its diagnosis remains a major clinical challenge due to nonspecific symptoms, overlapping features with other cardiac and genetic diseases, and the lack of a universal diagnostic gold standard. This review outlines seven key diagnostic dilemmas frequently encountered in clinical practice: (1) failure to consider CS, (2) premature attribution of findings to CS, (3) limitations and misinterpretation of echocardiogram and cardiac magnetic resonance imaging, (4) limitations of ¹⁸F-FDG positron emission tomography, (5) mistaking mutation for granuloma, (6) biopsy paradox, and (7) navigating diagnostic definitions. Each dilemma highlights the need for careful clinical reasoning, multimodal imaging interpretation, integration of data, and expert multidisciplinary collaboration. Ultimately, a nuanced, patient-centered, and evidence-informed approach is essential to improve diagnosis and outcomes in patients with suspected CS.

Sarcoidosis is an enigmatic, multisystem inflammatory disorder characterized by the formation of non-necrotizing granulomas in affected organs. Sarcoidosis may be self-limited or spontaneously resolve in up to two-thirds of individuals, but 10% to 30% develop a more chronic syndrome requiring long-term treatment. Most individuals will require treatment at some point during the course of the disease. Currently, guidelines recommend treatment in those at risk of future morbidity or organ dysfunction to preserve the quality of life. Careful identification of those likely to benefit from treatment is critical, as current agents are cumbersome to monitor and all have adverse effects. There is a lack of validated prognostic markers to identify those at risk for poor outcomes, but identifying characteristic manifestations of severe disease early can assist with treatment planning. While corticosteroids have been central to the treatment of sarcoidosis, newer data have challenged the current treatment paradigm of steroids as first-line agents. Recent and ongoing clinical trials may provide evidence for individualized approaches centered on shared decision-making with patients, as balancing the benefits of treatment must always be weighed with the potential for toxicity. This paper will provide an update on current treatment paradigms, new therapeutic strategies, and potential novel agents on the horizon while highlighting the existing challenges and barriers to progress.

In sarcoidosis, pulmonary manifestations are almost universal; however, their severity ranges from asymptomatic to respiratory failure and death. Approximately 20% of patients progress to advanced pulmonary sarcoidosis (APS), a disease phenotype that is driven mostly by pulmonary fibrosis and associated complications, including bronchiectasis, chronic pulmonary aspergillosis, and pulmonary hypertension, which may result from multiple mechanisms. APS may be burnt out but is often active as confirmed by ¹⁸F-fluorodeoxyglucose-PET. APS is a major cause of morbidity and mortality in patients with sarcoidosis, but its natural history is largely unknown and evidence-based treatment guidelines are lacking. Here, we review the major patterns of APS with emphasis on clinical manifestations, pathophysiology, and management, although this is based on expert opinion and may include, based on the predominant disease phenotype, anti-inflammatory/immunosuppressive treatment, antifibrotics, pulmonary rehabilitation, antibiotics, vasodilators, and, in highly selected patients, lung transplantation.

Sarcoidosis is a granulomatous disease of unknown cause, triggered by an unidentified antigen. Although classically considered a T cell-mediated disorder with an IFN-γ signature driven by Th1, Th17, and Th17.1 cells, its pathogenesis reflects dysregulated crosstalk between innate and adaptive immunity. Granulomas form through macrophage differentiation at the core, fueled by aberrantly programmed monocytes and sustained by persistent antigen presentation to T cells. Hyperactive macrophages drive excessive peripheral cell recruitment, while dysregulated T cell responses promote T cell expansion, impaired effector regulation, and eventual exhaustion. Deficient regulatory pathways fail to counterbalance this activation, creating a perpetuating inflammatory loop that underlies disease persistence and fibrotic progression. This review integrates up-to-date transcriptomic and biological data to define the cellular and molecular mechanisms that initiate, sustain, and dysregulate immune responses in sarcoidosis.

Sarcoidosis remains a diagnostic and therapeutic challenge due to its heterogeneous clinical presentation and lack of pathognomonic features. Despite five decades of biomarker research, no single marker has achieved sufficient accuracy for a standalone diagnosis. Traditional biomarkers retain clinical utility when used strategically: High-sensitivity markers (soluble interleukin-2 receptor [sIL-2R], serum amyloid A [SAA], chitotriosidase) excel at confirming disease, while high-specificity markers (lysozyme) better exclude sarcoidosis. Chitotriosidase has emerged as superior to angiotensin-converting enzyme (ACE) for disease monitoring, and sIL-2R remains invaluable for detecting extrapulmonary involvement. However, their limitations necessitate multibiomarker approaches tailored to specific clinical phenotypes. Recent advances address critical unmet needs. High-sensitivity troponin T provides crucial prognostic information in cardiac sarcoidosis, with levels >14 ng/L predicting adverse outcomes. Novel fibrosis markers, including alveolar nitric oxide, heat shock protein 90α (HSP90α), and advanced Krebs von den Lungen-6 (KL-6) measurement, enable better assessment of disease progression. Prediagnostic inflammatory proteins elevated years before clinical manifestation suggest opportunities for early intervention. Revolutionary omics technologies are transforming biomarker discovery. Extracellular vesicle proteomics identifies treatment-responsive signatures, retrotrans-genomics reveals viral element activation in pathogenesis, and Mendelian randomization distinguishes causal from associative proteins. Integration of multiomics data through machine learning algorithms promises personalized diagnostic and therapeutic strategies. The future of sarcoidosis management lies in intelligent biomarker integration rather than reliance on single tests. Success will be measured by improved patient outcomes through earlier diagnosis, accurate risk stratification, and personalized treatment selection. This paradigm shift from empirical to precision medicine requires continued collaboration between researchers, clinicians, and patients to translate biomarker discoveries into clinical practice.

Neurosarcoidosis is a rare but clinically significant manifestation of sarcoidosis, often presenting with diverse neurologic symptoms that can lead to permanent disability if left untreated. This review aims to provide internists, pulmonologists, nonneurologist clinicians, and critical care specialists with a structured, pragmatic approach to the evaluation, diagnosis, and management of neurosarcoidosis in two distinct patient groups: those with a known diagnosis of systemic sarcoidosis and those with no prior history of sarcoidosis. We emphasize the recognition of key acute clinical syndromes such as seizures, stroke, neuroendocrinopathy, hydrocephalus, meningeal disease, myelopathy, and infectious complications that may be encountered in emergency and critical care scenarios. The management approach, which includes first-line therapies such as glucocorticoids and immunomodulatory treatments such as TNF inhibitors and IL-6 inhibitors, is now accepted in the critical care setting to minimize the development of long-standing neurological complications associated with neurosarcoidosis. Furthermore, there is a critical need for a safe and effective transition to steroid-sparing medications for long-term disease control, while closely monitoring the risk for infections, such as tuberculosis and opportunistic infections, metabolic disturbances, and other complications. Given the significance of neurosarcoidosis as a severe manifestation of systemic sarcoidosis, a multidisciplinary approach is essential to effectively manage both neurological and systemic manifestations.