Seminars in respiratory and critical care medicine最新文献

Chronic lung disease is a sequela of unresolving pathogenesis in the lung. Current estimates report approximately 7.4% of the world's population live with chronic respiratory diseases. The architectural differences in the airways and individual alveoli provide unique microenvironments for mechanisms of disease and thus necessitate specialized modes of regulation. A key immune cell type that has the ability to adapt and provide copius regulatory mechanisms are T regulatory cells (Tregs). In the last two decades, studies have revealed that Tregs respond to their microenvironment and phenotypically change to conduct versatile functions; however, during chronic inflammatory diseases, Tregs are potentially skewed toward pathogenic mechanisms. In this review, we will focus on the differential mechanisms of Treg responses in the lung airways versus interstitium as unique microenvironments by focusing on asthma, acute lung injury/airway respiratory disease syndrome, and interstitial lung disease.

Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm characterized by infiltration of abnormal smooth muscle-like and epithelioid cells into the lung parenchyma, leading to cystic changes and progressive respiratory failure. In recent years, LAM has been an exemplar of meaningful progress in a rare lung disease, driven by close collaboration between patients, scientists, and clinicians, leading to the development of the U.S. Food and Drug Administration (FDA)-approved therapy, a diagnostic biomarker, a worldwide clinic network, and clinical practice guidelines. Integrating state-of-the-art bioinformatics and experimental approaches is helping accelerate the scientific progress in LAM and promises the development of novel biomarkers and therapies in the coming few years.

Pulmonary fibrosis is characterized by scarring and thickening of the lung parenchyma due to excessive deposition of collagen and other extracellular matrix (ECM) proteins. This leads to disruption of gas exchange areas and ultimately respiratory failure, a pathology shared across multiple interstitial lung diseases (ILDs). Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive ILD characterized by exertional dyspnea, dry cough, and restrictive lung defects. Clinical progression is marked by worsening lung function, declining exercise tolerance, and hypoxemia. High-resolution computed tomography in IPF typically shows reticular opacities and honeycombing, predominantly distributed in the subpleural regions and lower lobes of the lungs. The disease course is variable, with episodes of acute exacerbation associated with high mortality. Myofibroblasts and fibroblasts are central drivers of fibrogenesis through uncontrolled proliferation, migration, survival, senescence, myofibroblast differentiation, and ECM production. Myofibroblasts represent a heterogeneous population in both origin and function, arising from diverse precursor cells, including lung resident fibroblasts, endothelial cells, and mesothelial cells, and are shaped by tissue-specific niches. Persistent activation of (myo)fibroblasts is sustained by a complex network of profibrotic growth factors and their downstream transcriptional regulators. In this review, we comprehensively examine the cellular origins and molecular pathways underlying fibroblast activation, with an emphasis on mechanistic insights that may inform the development of targeted antifibrotic therapies to attenuate disease progression and improve patient outcomes.

Poor repair following lung injury is a significant cause of morbidity and mortality. Clearance of apoptotic cells, termed efferocytosis, has emerged as a key process that can influence repair outcomes and facilitate successful repair. Although prior literature has focused on efferocytosis by macrophages, evidence is emerging that nonprofessional phagocytes, including fibroblasts and epithelial cells, may play critical roles in efferocytosis during tissue repair. This review summarizes existing knowledge of different lung phagocytes that can participate in efferocytosis, evidence linking efferocytosis to lung health and tissue repair, and discusses factors that may inhibit or redirect efferocytosis to promote mis-repair. A deeper understanding of how the integrated landscape of lung phagocytes participates in efferocytosis will likely provide significant insight into repair and mis-repair processes.

Patients with neuromuscular disease are living longer with advancements in respiratory assistive devices for airway clearance and ventilatory support. This technology has been successfully applied to the perioperative and peripartum periods, making these previously prohibitively high-risk procedures now a risk-controlled intervention. This review will cover preoperative planning and assessment, key intraoperative management interventions, postoperative management, and peripartum management for patients with neuromuscular disorders.

Neuromuscular disorders in adults can present with a wide array of clinical features and vary from acute life-threatening complications such as respiratory failure to slow progressive weakness and comorbidity. Common to most of these disorders are symptoms of weakness and dyspnea. Many patients with occult neuromuscular disorders will be evaluated for underlying cardiac and pulmonary disease by primary care and subspecialty providers and can experience delays in diagnosis due to challenges in attaining early neurological testing and recognizing vague symptoms as potentially arising from the neuromuscular apparatus. Additionally, many adults who develop neuromuscular disorders have concomitant cardiac or pulmonary disease and the presence of dyspnea or limitations in mobility are often attributed to these without pursuing further workup. We outline a review of neuromuscular diseases in adults and an approach to evaluation.

Neuromuscular diseases encompass a wide array of clinical manifestations, age at presentation, and severity of morbidity and mortality. Central to most patients with these disorders are symptoms of dyspnea and increased work of breathing related to varying degrees of impairment of the neuromuscular apparatus. The degree of dyspnea is often compounded by impaired clearance from the tracheobronchial tree, leading to patients who are weak, dyspneic, and impacted by pulmonary secretions. Approaches to determining contributing causes and management of dyspnea in these patients vary among adult and pediatric patients and are also distinct depending on the natural progression of the specific neuromuscular disorder. We describe an approach to the management of dyspnea in patients with neuromuscular diseases and review the roles of pharmacologic and respiratory support devices in alleviating symptoms and supporting respiration.

Lung involvement in Sjögren's disease (SjD) is common and significantly impacts patients' quality of life, with the most frequent manifestation being interstitial lung disease (ILD). This study explored the clinical course and prognostic factors in patients with SjD-associated ILD. We conducted a retrospective analysis of patients diagnosed with SjD-ILD across two tertiary care academic referral centers. We assessed key clinical, radiological, and histopathological features of patients with SjD-ILD to investigate the long-term outcomes and determine the factors that can help better prognosticate patients in the clinic. A total of 81 patients with SjD-ILD were included in our analysis. ILD was the presenting manifestation in 21% (n = 17) of the SjD patients. The median survival following diagnosis of SjD-ILD was 11 years. Among ILD subtypes, the UIP pattern was associated with more rapid lung function decline and higher mortality. In contrast, higher baseline forced vital capacity (FVC) and anti-SSA antibody positivity were linked to reduced mortality risk. ILD is a common manifestation that can lead to the diagnosis of SjD. The presence of ILD has an adverse effect on the overall survival of patients with SjD. Baseline lung function and serologies can further assist in prognostication. A critical review of imaging patterns to determine the underlying ILD pattern can aid individualized counseling and therapeutic decision-making in patients with SjD-ILD.

Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.

Patients with neuromuscular disease are living longer lives but continue to have significant and often unpredictable morbidity and mortality. End-of-life planning for these patients is thus an essential part of their medical care. This planning should include the following topics: health care surrogates, swallowing and nutrition, daytime respiratory support, and all aspects of when end of life is near. Adult-onset and early-onset diseases may require different approaches to these topics. All patients with neuromuscular disease will benefit from these discussions to best reach patient-centered goals. We present health care providers these five questions and explanations as a guide.