Seminars in respiratory and critical care medicine
-
Semin Respir Crit Care Med · Apr 2020
ReviewNew Developments in the Pathogenesis of Pulmonary Cysts in Birt-Hogg-Dubé Syndrome.
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in Folliculin gene (FLCN). BHD is characterized by lower lobe-predominant pulmonary cysts with risk of pneumothorax, benign skin tumors (fibrofolliculomas), and renal cell carcinoma, often of an unusual chromophobe/oncocytic hybrid histology. The FLCN protein functions in multiple signaling and metabolic pathways including positive regulation of mechanistic target of rapamycin complex 1 (mTORC1) activity via FLCN's GTPase (GAP) activity for Rag C, positive regulation of Wnt signaling (in mesenchymal cells), and negative regulation of TFE3 nuclear localization. ⋯ Folliculin also has functions in autophagy, mitochondrial biogenesis, cell-cell adhesion, 5' AMP activated protein kinase activity, and other pathways. The specific contributions of these pathways to the lung manifestations of BHD are largely unknown. This review is focused on the pulmonary manifestations of BHD, highlighting selected recent advances in elucidating the cellular functions of FLCN and current hypotheses related to the pathogenesis of cystic lung disease in BHD, including the "stretch hypothesis." We also discuss important knowledge gaps in the field, including the genetic, cellular and physical mechanisms of cyst pathogenesis, and the timing of cyst initiation, which may occur during lung development.
-
Semin Respir Crit Care Med · Apr 2020
ReviewClinical Decision-Making in Hypersensitivity Pneumonitis: Diagnosis and Management.
This review provides an updated approach to the diagnosis and management of hypersensitivity pneumonitis (HP). The importance of using a multidisciplinary discussion to increase diagnostic and treatment confidence is emphasized. ⋯ Therapeutically, beyond antigen avoidance and newly available antifibrotic therapy for patients with a progressive fibrosing phenotype; the role, timing, and expected response to anti-inflammatory therapy in individual patients are unanswered questions. Since the evidence and validation of testing generally performed during the diagnostic work-up and longitudinal monitoring of HP is feeble at best, the viewpoints discussed are not intended to resolve current controversies but rather to provide a conceptual framework for evaluating discordant information when evaluating and caring for patients with HP.
-
Lymphangioleiomyomatosis (LAM) is a slow albeit progressive rare neoplastic disease featured with diffuse thin-walled cysts in lungs and angiomyolipomas in kidneys. LAM affects almost exclusively women and has one of the strongest gender predispositions of any extragenital human disease. Two forms of LAM present clinically, sporadic (S-LAM) and tuberous sclerosis complex-associated (TSC-LAM). ⋯ Sirolimus, an mTOR inhibitor, has been approved for LAM treatment in the United States and many other countries. Therapies targeting female sex hormones have shown preclinical efficacy in animal and cell culture-based experiments, but have not been properly investigated clinically. In this review, we summarize current recommendations in the diagnosis and treatment of LAM.
-
Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by progressive accumulation of pulmonary surfactant. This results in dyspnea, secondary pulmonary and systemic infection, and in some cases respiratory failure. PAP syndrome occurs in distinct diseases, classified according to pathogenetic mechanism; these include primary PAP (due to disruption of granulocyte-macrophage colony-stimulating factor [GM-CSF] signaling), secondary PAP (due to reduction in alveolar macrophage numbers/functions), and congenital PAP (due to disruption of surfactant production). ⋯ Autoimmune PAP can be accurately diagnosed by serum GM-CSF autoantibody levels and there now exist other diagnostic tests for rare causes of PAP syndrome. The current standard treatment is whole lung lavage; however, there is emerging evidence to support the use of novel therapeutic approaches, including inhaled GM-CSF, immune modulation, gene and cell therapy, and targeting macrophage cholesterol homeostasis. Furthermore, several innovative approaches to monitor disease severity and response to therapy have recently been developed.
-
Pulmonary alveolar microlithiasis (PAM) is a rare, autosomal recessive disorder that is caused by mutations in SCL34A2 that encodes for the type IIb sodium-dependent phosphate cotransporter (Npt2b). The loss of Npt2b transporter function from alveolar epithelial cells results in failure to export inorganic phosphate from the alveolar lining fluid, which then accumulates, binds to calcium, and forms hydroxyapatite microliths. ⋯ Pulmonary fibrosis, pulmonary hypertension, and respiratory failure can develop as the disease progresses, and treatment remains supportive. Lung transplantation is an option for those with end stage disease.