Should lung biopsies be performed in patients with severe asthma?

Asthma, and severe asthma, in particular, is increasingly recognised as a heterogeneous disease. Identifying these different phenotypes of asthma and assigning patients to phenotype-specific treatments is one of the current conundrums in respiratory medicine. Any diagnostic procedure in severe asthma (or any disease) should have two aims: 1) better understanding or identifying the diagnosis, and 2) providing information on the heterogeneity of asthma phenotypes to guide therapy with the objective of improving outcomes. Lung biopsies can target the large and small airways as well as the lung parenchyma. All compartments are affected in severe asthma; however, knowledge on the distal lung is limited. At this point, it remains uncertain whether lung specimens routinely add diagnostic information that is unable to be obtained otherwise. Indeed, whether a lung biopsy is indicated in the workup of a patient with severe asthma remains an individual decision. It is hoped this review will support rational decision-making and provide a detailed synopsis of the varied histopathological features seen in biopsies of patients with a diagnosis of severe asthma. Due to limited data on this topic this review is primarily based on opinion with recommendations arising primarily from the personal experience of the authors

Granulomatosis with Polyangiitis Presenting with Coronary Artery and Pericardial Involvement

Granulomatosis with polyangiitis is a systemic disease resulting in necrotizing vasculitis of small- and medium-sized vessels. Cardiac involvement is rare and when present usually manifests with pericarditis and coronary artery vasculitis. We report here a case of granulomatosis with polyangiitis involving the native coronary arteries, bypass graft, and pericardium with interesting imaging findings on contrast-enhanced CT and MRI. A 57-year-old man with a history of chronic headaches presented to the emergency room with syncope. Contrast-enhanced CT demonstrated extensive soft tissue attenuation around the native coronary arteries and bypass graft. Contrast-enhanced MRI demonstrated enhancing nodular soft tissue surrounding the coronary arteries, bypass graft, and pericardium. Pericardial biopsy revealed a necrotizing granulomatous pericarditis with vasculitis concerning for granulomatosis with polyangiitis. The patient demonstrated MPO-positive and PR-3 negative serologies. After being discharged on rituximab and prednisone, follow-up CT 3 years later showed significant improvement of the soft tissue thickening surrounding the coronary arteries, bypass graft, and pericardium

Co-existence of vocal cord dysfunction with pulmonary conditions other than asthma: A case series

Background: Vocal cord dysfunction (VCD) is defined as inappropriate movement of the vocal cords resulting in functional airway obstruction and symptoms including cough, wheezing, and dyspnea. VCD is often misdiagnosed with asthma but can also co-exist with asthma. The association of VCD with other serious pulmonary conditions has not been described to date. Case reports: We describe the first case series of two adult patients evaluated at a university asthma clinic who in addition to having VCD also had significant pulmonary pathology other than asthma. Patient 1 had VCD and pulmonary veno-occulsive disease which necessitated a lung transplant. Patient 2 had VCD and a patent ductus arteriosis who necessitated surgical closure. Conclusion: It is important to recognize that VCD can exist with pulmonary conditions other than asthma. Lack of improvement in respiratory symptoms after appropriate treatment for VCD should alert the clinician to evaluate for additional conditions. Keywords: Vocal cord dysfunction, Pulmonary veno-occlusive disease, Patent ducus arteriosu

High CO 2

The c-Jun amino-terminal kinase (JNK) plays a role in inflammation, proliferation, apoptosis, and cell adhesion and cell migration by phosphorylating paxillin and β-catenin. JNK phosphorylation downstream of AMP-activated protein kinase (AMPK) activation is required for high CO(2) (hypercapnia)-induced Na,K-ATPase endocytosis in alveolar epithelial cells. Here, we provide evidence that during hypercapnia, JNK promotes the phosphorylation of LMO7b, a scaffolding protein, in vitro and in intact cells. LMO7b phosphorylation was blocked by exposing the cells to the JNK inhibitor SP600125 and by infecting cells with dominant-negative JNK or AMPK adenovirus. The knockdown of the endogenous LMO7b or overexpression of mutated LMO7b with alanine substitutions of five potential JNK phosphorylation sites (LMO7b-5SA) or only Ser-1295 rescued both LMO7b phosphorylation and the hypercapnia-induced Na,K-ATPase endocytosis. Moreover, high CO(2) promoted the colocalization and interaction of LMO7b and the Na,K-ATPase α(1) subunit at the plasma membrane, which were prevented by SP600125 or by transfecting cells with LMO7b-5SA. Collectively, our data suggest that hypercapnia leads to JNK-induced LMO7b phosphorylation at Ser-1295, which facilitates the interaction of LMO7b with Na,K-ATPase at the plasma membrane promoting the endocytosis of Na,K-ATPase in alveolar epithelial cells

High CO2 Leads to Na,K-ATPase Endocytosis via c-Jun Amino-Terminal Kinase-Induced LMO7b Phosphorylation

The c-Jun amino-terminal kinase (JNK) plays a role in inflammation, proliferation, apoptosis, and cell adhesion and cell migration by phosphorylating paxillin and β-catenin. JNK phosphorylation downstream of AMP-activated protein kinase (AMPK) activation is required for high CO2 (hypercapnia)-induced Na,K-ATPase endocytosis in alveolar epithelial cells. Here, we provide evidence that during hypercapnia, JNK promotes the phosphorylation of LMO7b, a scaffolding protein, in vitro and in intact cells. LMO7b phosphorylation was blocked by exposing the cells to the JNK inhibitor SP600125 and by infecting cells with dominant-negative JNK or AMPK adenovirus. The knockdown of the endogenous LMO7b or overexpression of mutated LMO7b with alanine substitutions of five potential JNK phosphorylation sites (LMO7b-5SA) or only Ser-1295 rescued both LMO7b phosphorylation and the hypercapnia-induced Na,K-ATPase endocytosis. Moreover, high CO2 promoted the colocalization and interaction of LMO7b and the Na,K-ATPase α1 subunit at the plasma membrane, which were prevented by SP600125 or by transfecting cells with LMO7b-5SA. Collectively, our data suggest that hypercapnia leads to JNK-induced LMO7b phosphorylation at Ser-1295, which facilitates the interaction of LMO7b with Na,K-ATPase at the plasma membrane promoting the endocytosis of Na,K-ATPase in alveolar epithelial cells

Single cell RNA sequencing identifies IGFBP5 and QKI as ciliated epithelial cell genes associated with severe COPD

Background: Whole lung tissue transcriptomic profling studies in chronic obstructive pulmonary disease (COPD) have led to the identifcation of several genes associated with the severity of airfow limitation and/or the presence of emphysema, however, the cell types driving these gene expression signatures remain unidentifed. Methods: To determine cell specifc transcriptomic changes in severe COPD, we conducted single-cell RNA sequencing (scRNA seq) on n=29,961 cells from the peripheral lung parenchymal tissue of nonsmoking subjects without underlying lung disease (n=3) and patients with severe COPD (n=3). The cell type composition and cell specifc gene expression signature was assessed. Gene set enrichment analysis (GSEA) was used to identify the specifc cell types contributing to the previously reported transcriptomic signatures. Results: T-distributed stochastic neighbor embedding and clustering of scRNA seq data revealed a total of 17 distinct populations. Among them, the populations with more diferentially expressed genes in cases vs. controls (log fold change>|0.4| and FDR=0.05) were: monocytes (n=1499); macrophages (n=868) and ciliated epithelial cells (n=590), respectively. Using GSEA, we found that only ciliated and cytotoxic T cells manifested a trend towards enrichment of the previously reported 127 regional emphysema gene signatures (normalized enrichment score [NES]=1.28 and=1.33, FDR=0.085 and=0.092 respectively). Among the signifcantly altered genes present in ciliated epithelial cells of the COPD lungs, QKI and IGFBP5 protein levels were also found to be altered in the COPD lungs. Conclusions: scRNA seq is useful for identifying transcriptional changes and possibly individual protein levels that may contribute to the development of emphysema in a cell-type specifc manner. Keywords: Single cell RNA-seq, COPD, Cigarette smok