Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.

Feasibility of diaphragm pacing in patients after bilateral lung transplantation.

Recent animal studies and intraoperative studies in humans suggested that phrenic nerve stimulation could attenuate ventilator-induced diaphragm dysfunction. The purpose of the present study is to examine the safety and feasibility of diaphragm pacing during the weaning process after bilateral lung transplantation. Four patients, suffering from chronic pulmonary disease, were included, and diaphragm pacing was evaluated after lung transplantation. Implantation of electrodes at the end of the lung transplant procedure was possible in three of the four patients. In all implanted patients, stimulation of the diaphragm could trigger the ventilator. Implanted electrodes were completely removed by percutaneous retraction after up to 7 days of pacing. Adverse events related to pacing included occurrence of pain. Diaphragm pacing with temporary electrodes, inserted during surgery, is feasible and is able to trigger the ventilator in patients after bilateral lung transplantation. The use of intradiaphragmatic electrodes creates the additional opportunity to monitor the evolution of diaphragm electromyography during the postoperative weaning process.

High-dose vitamin D after lung transplantation: A randomized trial.

BACKGROUND: Vitamin D may have innate immunomodulatory functions with potentially beneficial therapeutic effects in lung transplant recipients. METHODS: This was a single-center, double blind, randomized, placebo-controlled, prevention trial of once-monthly oral vitamin D (cholecalciferol; 100,000 IU, n = 44) vs placebo (n = 43) during 2 years in adult lung transplant recipients enrolled from October 2010 to August 2013. Primary outcome was prevalence of chronic lung allograft dysfunction (CLAD) 3 years after transplantation. Secondary outcomes included overall survival, prevalence of acute rejection, lymphocytic bronchiolitis and infection, lung function, pulmonary and systemic inflammation, and bone mineral density. RESULTS: All included patients underwent bilateral lung transplantation and were mostly middle-aged men with prior smoking-related emphysema. Levels of 25-hydroxy vitamin D after 1 year (p < .001) and 2 years (p < .001) were significantly higher in the vitamin D group compared with the placebo group. No difference was observed for CLAD prevalence (p = 0.7) or CLAD-free survival between both groups (p = 0.7). Secondary outcomes were overall comparable between both groups (all p > 0.05). CONCLUSIONS: Once-monthly oral vitamin D supplementation after lung transplantation fails to demonstrate a significant difference in CLAD prevalence, innate immunomodulatory, or a beneficial clinical effect compared with placebo.

Interleukin-1α induced release of interleukin-8 by human bronchial epithelial cells in vitro: assessing mechanisms and possible treatment options.

Survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Persistently elevated BAL-neutrophilia is observed in some patients despite treatment with azithromycin, which may be induced by IL-1α. Our aim is to establish an in vitro model, assess mechanistic pathways and test different therapeutic strategies of IL-1α-induced release of IL-8 by human bronchial epithelial cells. Bronchial epithelial cells (16HBE) were stimulated with IL-1α with or without azithromycin or dexamethasone. IL-8 protein was analyzed in cell supernatant. Different MAP kinases (p38, JNK, ERK1/2 , Iκß) and targets known to be involved in tumor formation (PI3K, Akt) were investigated. Finally, different treatment options were tested for their potential inhibitory effect. IL-1α induced IL-8 in bronchial epithelial cells, which was dose-dependently inhibited by dexamethasone but not by azithromycin. IL-1α induced p38 and Akt phosphorylation, but activation of these MAPK was not inhibited by dexamethasone. JNK, ERK1/2 , Iκß and PI3K were not activated. None of the tested drugs reduced the IL-1α induced IL-8 production. We established an in vitro model wherein steroids inhibit the IL-1α-induced IL-8 production, while azithromycin was ineffective. Despite using this simple in vitro model, we could not identify a new treatment option for azithromycin-resistant airway neutrophilia.

Vitamin D deficiency in lung transplant patients: is it important?

BACKGROUND: Vitamin D deficiency has been reported in different chronic pulmonary diseases like asthma and chronic obstructive pulmonary disease, but little is known in lung transplant recipients. METHODS: Serum 25-hydroxyvitamin D (25-OHD) levels and pulmonary function (forced expiratory volume in 1 sec [FEV(1)] %predicted) were measured in 131 lung transplant patients during their yearly posttransplant check-up hospital stay, and the total number of infections and perivascular/peribronchiolar rejections were assessed from transplantation on. RESULTS: Vitamin D deficiency (<30 ng/mL) occurred in 62 of 131 patients (47.3%), of whom 26 (19.8%) were severely deficient (<20 ng/mL). The FEV(1) was significantly lower in the deficient group compared with the group with normal levels (P=0.019). Moreover, we could find an association between FEV(1) and 25-OHD levels in univariate analysis (P=0.018), which remained significant in multivariate analysis (P=0.012). The same holds true for the association between 25-OHD levels and the peak postoperative FEV(1) (P=0.021 in multivariate analysis). We also identified significantly more patients with moderate to severe B-grade rejections in the deficient group (P=0.0038). CONCLUSION: Vitamin D deficiency is present in 47% of our lung transplant patients and seems independently associated with a lower FEV(1) and more severe B-grade rejections. This study raises the potential need for additional vitamin D treatment in lung transplantation and clearly indicates the role of a randomized placebo-controlled trial with vitamin D supplementation, which is ongoing in our center.