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Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 pa...

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Background: It is understood that chronic allograft failure occurs as a result of alloimmune and nonalloimmune injury. Dendritic cells (DC) are thought to be crucial in regulating (allo)immune airway damage and interactions with epithelial cells are likely. Studies in human lung transplantation are limited, however, and the available literature on DC is inconsistent. This study focused on the ex vivo influence of primary bronchial epithelial cells derived from lung allografts on DC differentiation. Methods: Epithelial cell conditioned media (ECCM) were added to monocytes differentiating into DC under the influence of interleukin-4 and granulocyte macrophagecolony stimulating factor. The resultant cells were compared with DC cultured without ECCM and with monocyte-derived macrophages. Expression of typical DC (eg, CD1a) and macrophage (eg, CD14) markers was assessed by flow cytometry. Phenotypical assessments were complemented by functional studies of mannose receptor-mediated phagocytosis (FITC-dextran uptake) and antigen-presenting capability (mixed lymphocyte reactions). Results: Cells exposed to ECCM expressed significantly lower levels of CD1a than unexposed DC. CD14 expression and phagocytic function were increased. ECCM cultured cells also expressed lower levels of T cell co-stimulatory molecules, secreted an anti-inflammatory cytokine profile and had significantly reduced antigenpresenting capability. Conclusion: Using phenotypic and functional approaches, this study has shown that ECCM from lung allografts drives the production of macrophage-like cells from monocytes rather than DC. The data suggest that epithelial cells may restrain airway DC and potential alloimmunity. It is unclear whether the observed effect is specifically seen in lung transplant recipients or is a general property of bronchial epithelial cells. This may reflect a homeostatic inter-relationship between airway epithelial and DC populations relevant both to lung allografts and the lung more generally.

IntroductionSevere asthma is a complex, multi-dimensional disease. Optimal treatment adherence and outcomes require shared decision-making, rooted in mutual understanding between patient and clinician. This study used a novel, patient-centred approach to examine the most bothersome aspects of severe asthma to patients, as seen from both perspectives in asthma registries.MethodsAcross seven countries, 126 patients with severe asthma completed an open-ended survey regarding most bothersome aspect(s) of their asthma. Patients’ responses were linked with their treating clinician who also completed free-text survey about each patient's most bothersome aspect(s). Responses were coded using content analysis, and patient and clinician responses were compared. Finally, asthma registries that are part of the SHARP Clinical Research Collaboration were examined to see the extent to which they reflected the most bothersome aspects reported by patients.ResultsEighty-eight codes and 10 themes were identified. Clinicians were more focused on direct physical symptoms and were less focused on ‘holistic’ aspects such as the effort required to self-manage their disease. Clinicians accurately identified a most bothersome symptom for 29% of patients. Agreement was particularly low in younger patients and those infrequently using oral corticosteroids. In asthma registries, patient aspects were predominantly represented in questionnaires.ConclusionsResults demonstrated different perspectives and priorities between patients and clinicians, with clinicians more focused on physical aspects. These differences must be considered when treating individual patients, and within multi-disciplinary treatment teams. The use of questionnaires that include multi-faceted aspects of disease may result in improved asthma research.