Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Isolation and characterisation of human pulmonary microvascular endothelial cells from patients with severe emphysema.

BACKGROUND: Loss of the pulmonary microvasculature in the pathogenesis of emphysema has been put forward as a credible alternative to the classical inflammatory cell driven proteolysis hypothesis. Mechanistic studies in this area have to date employed animal models, immortalised cell lines, primary endothelial cells isolated from large pulmonary arteries and non-pulmonary tissues and normal human pulmonary microvascular endothelial cells. Although these studies have increased our understanding of endothelial cell function, their relevance to mechanisms in emphysema is questionable. Here we report a successful technique to isolate and characterise primary cultures of pulmonary microvascular endothelial cells from individuals with severe emphysema. METHODS: A lobe of emphysematous lung tissue removed at the time of lung transplantation surgery was obtained from 14 patients with severe end-stage disease. The pleura, large airways and large blood vessels were excised and contaminating macrophages and neutrophils flushed from the peripheral lung tissue before digestion with collagenase. Endothelial cells were purified from the cell mixture via selection with CD31 and UEA-1 magnetic beads and characterised by confocal microscopy and flow cytometry. RESULTS: Successful isolation was achieved from 10 (71%) of 14 emphysematous lungs. Endothelial cells exhibited a classical cobblestone morphology with high expression of endothelial cell markers (CD31) and low expression of mesenchymal markers (CD90, αSMA and fibronectin). E-selectin (CD62E) was inducible in a proportion of the endothelial cells following stimulation with TNFα, confirming that these cells were of microvascular origin. CONCLUSIONS: Emphysematous lungs removed at the time of transplantation can yield large numbers of pulmonary microvasculature endothelial cells of high purity. These cells provide a valuable research tool to investigate cellular mechanisms in the pulmonary microvasculature relevant to the pathogenesis of emphysema.

Pulmonary fibrosis: rate of disease progression as a trigger for referral for lung transplantation.

BACKGROUND: Lung transplantation is the only treatment modality that provides a survival advantage in pulmonary fibrosis, but many patients deemed suitable will die awaiting lung transplantation. While donor organ shortage undoubtedly contributes to this, late referral to the transplant centre may also play a role. This study investigates factors influencing the chance of patients with pulmonary fibrosis reaching lung transplantation. METHODS: A single-centre retrospective review of patient demographic data, assessment investigations and subsequent clinical outcomes was performed for patients with pulmonary fibrosis assessed for lung transplantation over a 5-year period. RESULTS: Between March 1999 and March 2004, 129 patients with pulmonary fibrosis underwent formal transplant assessment. Sixty-nine were accepted and listed for lung transplantation. Of these, 17 were transplanted, 37 died while waiting, 4 were removed from the list and 11 were still waiting at the conclusion of the study. The median waiting time on the list for those transplanted was 103 days (range 6-904) compared with 125 days (range 2-547) for those who died while on the list (p = 0.65). There was no significant difference in age, spirometry, total lung capacity, gas transfer measures or 6 min walk distance between those who died waiting and those transplanted. However, time from onset of symptoms to transplant assessment was significantly shorter in those who died on the waiting list (median 29 months (range 2-120)) than in those transplanted (median 46 months (range 6-204), p = 0.037). CONCLUSION: Patients with pulmonary fibrosis who died awaiting transplantation had similar disease severity at assessment as those who achieved transplantation. However, the interval between symptom onset and transplant referral was significantly shorter in those who died while on the waiting list, suggesting they had more rapidly progressive disease. The rate of disease progression appears to be a more sensitive indicator for transplantation referral than any single physiological measure of disease severity and should act as an important trigger for early transplant referral.

Pulse-wave analysis: clinical evaluation of a noninvasive, widely applicable method for assessing endothelial function.

Current methods for assessing vasomotor endothelial function are impractical for use in large studies. We tested the hypothesis that pulse-wave analysis (PWA) combined with provocative pharmacological testing might provide an alternative method. Radial artery waveforms were recorded and augmentation index (AIx) was calculated from derived aortic waveforms. Thirteen subjects received sublingual nitroglycerin (NTG), inhaled albuterol, or placebo. Twelve subjects received NTG, albuterol, and placebo separately during an infusion of N(G)-monomethyl-L-arginine (LNMMA) or norepinephrine. Twenty-seven hypercholesterolemic subjects and 27 controls received NTG followed by albuterol. Endothelial function was assessed by PWA and forearm blood flow in 27 subjects. Albuterol and NTG both significantly and repeatably reduced AIx (P<0.001). Only the response to albuterol was inhibited by LNMMA (-9.8+/-5.5% vs -4.7+/-2.7%; P=0.02). Baseline AIx was higher in the hypercholesterolemic subjects, who exhibited a reduced response to albuterol (P=0.02) but not to NTG when compared with matched controls. The responses to albuterol and acetylcholine were correlated (r=0.5, P=0.02). Consistent with an endothelium-dependent effect, the response to albuterol was substantially inhibited by LNMMA. Importantly, the response to albuterol was reduced in subjects with hypercholesterolemia and was correlated to that of intra-arterial acetylcholine. This methodology provides a simple, repeatable, noninvasive means of assessing endothelial function in vivo.