Seminars in respiratory and critical care medicine最新文献

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.

Sarcoidosis is a systemic inflammatory disorder of unknown cause, mainly affecting the lungs and lymph nodes. Symptoms are diverse and range from dyspnea and cough to fatigue, cognitive impairment, and pain. An important cause of pain in patients with sarcoidosis is small fiber neuropathy (SFN), with an estimated prevalence of 33 to 86%. The underlying pathogenesis of SFN in sarcoidosis is not known. In sarcoidosis, symptoms related to SFN can be grouped into general symptoms (e.g., fatigue), sensory symptoms (e.g., pain and numbness), and autonomic symptoms (e.g., gastrointestinal dysmotility, palpitations, or sexual dysfunction). Presentation of SFN in patients with sarcoidosis is heterogeneous and can either be length-dependent or nonlength-dependent. The small fiber neuropathy screening list assesses the frequency and severity of symptoms suggestive of SFN. As a diagnostic gold standard is lacking for SFN, the diagnosis is made on different levels of certainty based on the presence of clinical signs, normal nerve conduction studies, and either abnormal quantitative sensory testing or decreased intraepidermal nerve fiber density on skin biopsy. Autonomic dysfunction in sarcoidosis is even more difficult to diagnose, often under-recognized, and may also have a negative impact on quality of life. At present, only symptomatic relief can sometimes be achieved. While treatment of sarcoidosis usually includes corticosteroids and other immunosuppressants, these drugs are not proven effective in alleviating SFN symptoms related to sarcoidosis. This review provides an overview of symptoms, available diagnostic tools, and treatment options specific to sarcoidosis-associated SFN and autonomic dysfunction.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by abnormal accumulation of surfactant in alveoli. Pathogenetically, in aPAP, the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies hinders physiological binding of GM-CSF to its receptor, disrupting terminal differentiation of alveolar macrophages and the activation GM-CSF-PU.1-PPARG1-ABCG1 axis, resulting in a primary reduction in cholesterol efflux from alveolar macrophages and a secondary reduction in surfactant clearance through macrophages from the alveolar surface. APAP is the most common, accounting for more than 90 to 95% of all patients included under the PAP term, which encompasses and classifies all forms of PAP according to etiopathogenetic mechanisms, as primary, secondary, congenital, and unclassified. APAP is worldwide distributed with an estimated prevalence fluctuating between 7.0 and 9.7 cases/million and an annual incidence of 1.65, affecting middle-aged men and women. Clinical manifestation may be gradual and insidious, mainly manifesting with progressive dyspnea, but the natural history is variable, since some patients stabilize for a long period, while others progress to respiratory failure and death; in a minority, spontaneous resolution may be observed, while some develop lung and/or systemic infections, and rarely pulmonary fibrosis. Until recently, whole lung lavage (WLL) was universally accepted as the gold-standard therapeutic modality in aPAP. However, after considerable progress in the past 25 years and the publication of several positive studies, replacing the use of inhaled-GM-CSF as the standard of care for aPAP and conceding WLL a rescue option is becoming more and more concrete. In conclusion, aPAP is the classic paradigm of a scientific disease progressing from the "bench-to-bedside," since several discoveries made in the laboratory setting have become necessary to clarify its pathogenetic mechanisms, define diagnostic tools, and implement new therapeutic modalities, which established the disease as treatable and fully reversible, literally, moving patients from "hell to heaven."

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by progressive accumulation of surfactant in pulmonary alveoli, resulting in hypoxemic respiratory insufficiency and an increased risk of secondary infections and pulmonary fibrosis. Secondary PAP (sPAP) occurs because of an underlying disease that reduces the number and/or functions of alveolar macrophages, with hematological disorders being the commonest underlying cause. sPAP accounts for 4% of PAP cases, often occurs in the fourth decade of life, and has a slight male predominance. Patients with sPAP often present in the context of their underlying clinical condition. The prognosis of sPAP is considerably worse than aPAP, with an estimated median survival of less than 20 months. Given the nonspecific clinical presentation of PAP, its diagnosis requires appropriate serological, radiological, and bronchoscopic evaluation. The characteristic "crazy-paving" appearance described in aPAP might not always be present in sPAP. Ground glass opacifications in sPAP typically show a more diffuse pattern compared with a patchy geographic pattern seen in aPAP. The only proven therapy for sPAP is the treatment of the underlying disease, with whole lung lavage demonstrating efficacy in a small number of cases. In this review, we discuss the presentation, prognosis, and treatment of sPAP.

Diffuse alveolar hemorrhage (DAH) is a life-threatening clinical syndrome characterized by bleeding from the pulmonary microcirculation into alveolar spaces. It typically presents with acute respiratory failure, anemia, and diffuse radiological infiltrates. Importantly hemoptysis may be absent in up to half of cases. Etiologies are diverse, encompassing systemic vasculitides, connective tissue diseases, coagulopathies, drugs, infections, hemodynamic disturbances, and idiopathic processes. Histopathologically, DAH manifests as one of three overlapping patterns: pulmonary capillaritis, bland alveolar hemorrhage, or diffuse alveolar damage, which help guide diagnostic and therapeutic strategies. Capillaritis, commonly associated with immune-mediated vasculitis such as antineutrophil cytoplasmic antibody-associated vasculitis and anti-glomerular basement membrane disease, typically necessitating prompt and aggressive immunosuppression. In contrast, bland hemorrhage often reflects coagulopathy or hemodynamic factors, whereas diffuse alveolar damage is linked to toxins, infections, or acute respiratory distress syndrome. Prompt recognition and systematic evaluation are critical to optimizing outcomes, given DAH's high in-hospital mortality exceeding 20%. Diagnosis relies on a combination of imaging, bronchoalveolar lavage (demonstrating progressively bloodier returns and hemosiderin-laden macrophages), and targeted laboratory evaluation for vasculitis, infection, and coagulopathy. Management includes patient stabilization with supplementary oxygen or indeed ventilatory support, careful avoidance of ventilator-induced lung injury, and etiology-directed therapy. High-dose corticosteroids, cytotoxic agents, and rituximab remain central in immune-mediated cases, whereas plasma exchange is indicated in anti-glomerular basement membrane disease and severe refractory hemoptysis. Antimicrobial therapy, drug withdrawal, hemostatic interventions, and, in select cases, extracorporeal support may also be required. This review outlines the histopathological spectrum, etiologic categories, diagnostic algorithms, and evidence-based therapeutic approaches to DAH, emphasizing the importance of early multidisciplinary management to improve survival and functional recovery.

Pulmonary infection is an important cause of hospitalization, morbidity, and mortality in people living with human immunodeficiency virus (HIV; PWH) infection, especially in those with significant immunosuppression. Pneumonia, including Pneumocystis jirovecii and Mycobacterium tuberculosis etiologies, continues to be the most frequent pulmonary infection in PWH. However, identifying the etiology of pulmonary infection in PWH is challenging because of the overlap in clinical features and the frequency of co-infection. This review focuses on the current scientific evidence regarding pulmonary infection in PWH, including its epidemiology, clinical presentation, diagnosis, and management.

Pulmonary alveolar microlithiasis (PAM) has been well characterized in terms of its description, genetic background, and diagnostic process for decades; however, no effective prevention or treatment has yet been established. PAM is classified as an ultrarare lung disease linked to mutations in the autosomal recessive sodium-phosphate co-transporter gene SLC34A2, which may serve as a potential target for future therapies. As new variants of SLC34A2 mutations continue to be identified, a broader genetic understanding could help predict the variable clinical course among patients and guide the development of therapies beyond palliative care. The creation of a disease severity score would be valuable for assessing disease burden, stratifying patients, and designing research studies. Given the clinico-radiological dissociation and heterogeneity of PAM, such a score should be developed as a composite index. Coupled with objective severity measures and identification of factors underlying individual variability, this approach could enhance insight into preventive and therapeutic strategies. Clinical advances in PAM remain limited, underscoring the need for international registries and cohorts as an urgent priority. Systematic re-evaluation of diagnosed cases and structured follow-up, rather than arbitrary visits, would generate standardized data critical for future research. A standardized patient evaluation form may facilitate the collection of data in a shared database.

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 SMPD1 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.