Circulating adipokine levels and COVID-19 severity in hospitalized patients.

BACKGROUND: Obesity is a risk factor for adverse outcomes in COVID-19, potentially driven by chronic inflammatory state due to dysregulated secretion of adipokines and cytokines. We investigated the association between plasma adipokines and COVID-19 severity, systemic inflammation, clinical parameters, and outcome of COVID-19 patients. METHODS: In this multi-centre prospective cross-sectional study, we collected blood samples and clinical data from COVID-19 patients. The severity of COVID-19 was classified as mild (no hospital admission), severe (ward admission), and critical (ICU admission). ICU non-COVID-19 patients were also included and plasma from healthy age, sex, and BMI-matched individuals obtained from Lifelines. Multi-analyte profiling of plasma adipokines (Leptin, Adiponectin, Resistin, Visfatin) and inflammatory markers (IL-6, TNFα, IL-10) were determined using Luminex multiplex assays. RESULTS: Between March and December 2020, 260 SARS-CoV-2 infected individuals (age: 65 [56-74] BMI 27.0 [24.4-30.6]) were included: 30 mild, 159 severe, and 71 critical patients. Circulating leptin levels were reduced in critically ill patients with a high BMI yet this decrease was absent in patients that were administered dexamethasone. Visfatin levels were higher in critical COVID-19 patients compared to non-COVID-ICU, mild and severe patients (4.7 vs 3.4, 3.0, and 3.72 ng/mL respectively, p < 0.05). Lower Adiponectin levels, but higher Resistin levels were found in severe and critical patients, compared to those that did not require hospitalization (3.65, 2.7 vs 7.9 µg/mL, p < 0.001, and 18.2, 22.0 vs 11.0 ng/mL p < 0.001). CONCLUSION: Circulating adipokine levels are associated with COVID-19 hospitalization, i.e., the need for oxygen support (general ward), or the need for mechanical ventilation and other organ support in the ICU, but not mortality.

Late histopathologic characteristics of critically ill COVID-19 patients: Different phenotypes without evidence of invasive aspergillosis, a case series.

PURPOSE: Pathological data of critical ill COVID-19 patients is essential in the search for optimal treatment options. MATERIAL AND METHODS: We performed postmortem needle core lung biopsies in seven patients with COVID-19 related ARDS. Clinical, radiological and microbiological characteristics are reported together with histopathological findings. MEASUREMENT AND MAIN RESULTS: Patients age ranged from 58 to 83 years, five males and two females were included. Time from hospital admission to death ranged from 12 to 36 days, with a mean of 20 ventilated days. ICU stay was complicated by pulmonary embolism in five patients and positive galactomannan on bronchoalveolar lavage fluid in six patients, suggesting COVID-19 associated pulmonary aspergillosis. Chest CT in all patients showed ground glass opacities, commonly progressing to nondependent consolidations. We observed four distinct histopathological patterns: acute fibrinous and organizing pneumonia, diffuse alveolar damage, fibrosis and, in four out of seven patients an organizing pneumonia. None of the biopsy specimens showed any signs of invasive aspergillosis. CONCLUSIONS: In this case series common late histopathology in critically ill COVID patients is not classic DAD but heterogeneous with predominant pattern of organizing pneumonia. Postmortem biopsy investigations in critically COVID-19 patients with probable COVID-19 associated pulmonary aspergillosis obtained no evidence for invasive aspergillosis.

Selective pulmonary artery perfusion followed by blood flow occlusion: new challenge for the treatment of pulmonary malignancies.

INTRODUCTION: Selective pulmonary artery perfusion (SPAP) is an experimental endovascular technique for the treatment of pulmonary malignancies. This study evaluated blood flow occlusion (BFO) after SPAP and dose-escalation in order to delay washout of gemcitabine from the lung tissue, to augment pulmonary drug exposure and to maintain plasma concentrations equivalent to intravenous administration. MATERIAL AND METHODS: Six groups of pigs underwent left-sided SPAP using gemcitabine in a clinically applied dose of 1-1.5g/m(2) after balloon catheterisation. BFO experiment: four groups (n=4, each) were treated with SPAP with 1g/m(2) of gemcitabine during 2 min followed by BFO for 0, 10, 20 and 30 min, respectively. Dose-escalation experiment: two more groups (n=3, each) received SPAP with 1.25 and 1.5 g/m(2) of gemcitabine during 2 min followed by 30 min BFO. All pigs underwent left thoracotomy with sampling of lung, liver and blood. The animals were sacrificed after 1h. The lung and plasma areas under the curve (AUC) were calculated for each group and ANOVA and t-test was used for comparison. RESULTS: Thirty minutes BFO resulted in the highest lung AUC compared to 0, 10 and 20 min BFO (p<0.001), while no significant differences in plasma AUC and liver levels were observed. Gemcitabine dose-escalation up to 1.25 g/m(2) resulted in significantly higher lung AUC (p=0.02) compared to 1g/m(2), while plasma AUC was equivalent with intravenous treatment. Further dose-escalation to 1.5g/m(2) did not result in significantly higher lung levels compared to 1.25 g/m(2). CONCLUSION: BFO after SPAP delays the washout of gemcitabine from lung tissue. Dose-escalation resulted in higher lung concentrations, while plasma levels were equivalent with intravenous administration. We advocate 2 min of SPAP with 1.25 g/m(2) of gemcitabine followed by 30 min of BFO to be investigated as a new treatment modality for pulmonary malignancies.

Isolated lung perfusion for pulmonary metastases, a review and work in progress.

Pulmonary metastasectomy is a widely accepted treatment for many patients with pulmonary metastases from various solid tumors. Nevertheless, 5-year survival is disappointing, with rates of 25-40%, and many patients develop recurrences. Isolated lung perfusion (ILuP) is a promising new technique to deliver high-dose chemotherapy to the lungs, while minimising systemic toxicities. This procedure is technically safe and feasible; however, clinical value and efficacy remain unclear. The aim of this paper is to give a review of literature on ILuP in humans, and to describe the development of the perfusion procedure in our institute.

Isolated lung perfusion with melphalan for resectable lung metastases: a phase I clinical trial.

BACKGROUND: Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose. METHODS: From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5. RESULTS: In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial. CONCLUSIONS: Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.