Background and objective: Endosonography with intrathoracic nodal sampling is proposed as the single test with the highest granuloma detection rate in suspected sarcoidosis stage I/II. However,... Show moreBackground and objective: Endosonography with intrathoracic nodal sampling is proposed as the single test with the highest granuloma detection rate in suspected sarcoidosis stage I/II. However, most studies have been performed in limited geographical regions. Studies suggest that oesophageal endosonographic nodal sampling has higher diagnostic yield than endobronchial endosonographic nodal sampling, but a head-to-head comparison of both routes has never been performed.Methods: Global (14 hospitals, nine countries, four continents) randomized clinical trial was conducted in consecutive patients with suspected sarcoidosis stage I/II presenting between May 2015 and August 2017. Using an endobronchial ultrasound (EBUS) scope, patients were randomized to EBUS or endoscopic ultrasound (EUS)-B-guided nodal sampling, and to 22- or 25-G ProCore needle aspiration (2 x 2 factorial design). Granuloma detection rate was the primary study endpoint. Final diagnosis was based on cytology/pathology outcomes and clinical/radiological follow-up at 6 months.Results: A total of 358 patients were randomized: 185 patients to EBUS-transbronchial needle aspiration (EBUS-TBNA) and 173 to EUS-B-fine-needle aspiration (FNA). Final diagnosis was sarcoidosis in 306 patients (86%). Granuloma detection rate was 70% (130/185; 95% CI, 63-76) for EBUS-TBNA and 68% (118/173; 95% CI, 61-75) for EUS-B-FNA (p = 0.67). Sensitivity for diagnosing sarcoidosis was 78% (129/165; 95% CI, 71-84) for EBUS-TBNA and 82% (115/141; 95% CI, 74-87) for EUS-B-FNA (p = 0.46). There was no significant difference between the two needle types in granuloma detection rate or sensitivity.Conclusion: Granuloma detection rate of mediastinal/hilar nodes by endosonography in patients with suspected sarcoidosis stage I/II is high and similar for EBUS and EUS-B. These findings imply that both diagnostic tests can be safely and universally used in suspected sarcoidosis patients. Show less
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... Show moreBackground 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 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Show less
Background: In lung cancer patients, accurate assessment of mediastinal and vascular tumor invasion (stage T4) is crucial for optimal treatment allocation and to prevent unnecessary thoracotomies.... Show moreBackground: In lung cancer patients, accurate assessment of mediastinal and vascular tumor invasion (stage T4) is crucial for optimal treatment allocation and to prevent unnecessary thoracotomies. We assessed the diagnostic accuracy of linear endobronchial ultrasound (EBUS) for T4-status in patients with centrally located lung cancer.Methods: This is a retrospective study among consecutive patients who underwent EBUS for diagnosis and staging of lung cancer in four hospitals in The Netherlands (Amsterdam, Leiden), Italy (Bologna) and Poland (Zakopane) between 04-2012 and 04-2019. Patients were included if the primary tumor was detected by EBUS and subsequent surgical-pathological staging was performed, which served as the reference standard. T4-status was extracted from EBUS and pathology reports. Chest CT's were re-reviewed for T4-status.Results: 104 patients with lung cancer in whom EBUS detected the primary tumour, and who underwent subsequent surgical-pathological staging were included. 36 patients (35 %) had T4-status, based on vascular (n = 17), mediastinal (n = 15), both vascular and mediastinal (n = 3), or oesophageal invasion (n = 1). For EBUS, sensitivity, specificity, PPV and NPV for T4-status were (n = 104): 63.9 % (95 %CI 46.2-79.2 %), 92.6 % (83.7-97.6 %), 82.1 % (65.6-91.7 %), and 82.9 % (75.7-88.2 %), respectively. For chest CT (n = 72): 61.5 % (95 %CI 40.6-79.8 %), 37.0 % (23.2-52.5 %), 35.6 % (27.5-44.6 %), and 63.0 % (47.9-75.9 %), respectively. When combining CT and EBUS with concordant T4 status (n = 33): 90.9 % (95 %CI 58.7-99.8 %), 77.3 % (54.6-92.20 %), 66.7 % (47.5-81.6 %), and 94.4 % (721-99.1%), respectively.Conclusion: Both EBUS and CT alone are inaccurate for assessing T4-status as standalone test. However, combining a negative EBUS with a negative CT may rule out T4-status with high certainty. Show less
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to... Show moreThe genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease. Show less
Hoepel, W.; Chen, H.J.; Geyer, C.E.; Allahverdiyeva, S.; Manz, X.D.; Taeye, S.W. de; ... ; Dunnen, J. den 2021
Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies... Show morePatients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fc gamma receptor (Fc gamma R) Ila and FeyRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase. Show less
Residual pulmonary hypertension is an important sequela after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Recurrent thrombosis or embolism could be a contributor to... Show moreResidual pulmonary hypertension is an important sequela after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Recurrent thrombosis or embolism could be a contributor to this residual pulmonary hypertension but the potential extent of its role is unknown in part because data on incidence are lacking. We aimed to analyze the incidence of new intravascular abnormalities after pulmonary endarterectomy and determine hemodynamic and functional implications. A total of 33 chronic thromboembolic pulmonary hypertension patients underwent routine CT pulmonary angiography before and six months after pulmonary endarterectomy, together with right heart catheterization and exercise testing. New vascular lesions were defined as (1) a normal pulmonary artery before pulmonary endarterectomy and containing a thrombus, web, or early tapering six months after pulmonary endarterectomy or (2) a pulmonary artery already containing thrombus, web, or early tapering at baseline, but increasing six months after pulmonary endarterectomy. Nine of 33 (27%) chronic thromboembolic pulmonary hypertension patients showed new vascular lesions on CT pulmonary angiography six months after pulmonary endarterectomy. In a subgroup of patients undergoing CT pulmonary angiography 18 months after pulmonary endarterectomy, no further changes in lesions were noted. Hemodynamic and functional outcomes were not different between patients with and without new vascular lesions. New vascular lesions are common after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension; currently their origin, dynamics, and long-term consequences remain unknown. Show less
Background Bronchial Thermoplasty (BT) is an endoscopic treatment for severe asthma using radiofrequency energy to target airway remodeling including smooth muscle. The correlation of pulmonary... Show moreBackground Bronchial Thermoplasty (BT) is an endoscopic treatment for severe asthma using radiofrequency energy to target airway remodeling including smooth muscle. The correlation of pulmonary function tests and BT response are largely unknown. Forced Oscillation Technique (FOT) is an effort-independent technique to assess respiratory resistance (Rrs) by using pressure oscillations including small airways. Aim To investigate the effect of BT on pulmonary function, assessed by spirometry, bodyplethysmography and FOT and explore associations between pulmonary function parameters and BT treatment response. Methods Severe asthma patients recruited to the TASMA trial were analyzed in this observational cohort study. Spirometry, bodyplethysmography and FOT measurements were performed before and 6 months after BT. Asthma questionnaires (AQLQ/ACQ-6) were used to assess treatment response. Results Twenty-four patients were analyzed. AQLQ and ACQ improved significantly 6 months after BT (AQLQ 4.15 (+/- 0.96) to 4.90 (+/- 1.14) and ACQ 2.64 (+/- 0.60) to 2.11 (+/- 1.04), p = 0.004 and p = 0.02 respectively). Pulmonary function parameters remained stable. Improvement in FEV1 correlated with AQLQ change (r = 0.45 p = 0.03). Lower respiratory resistance (Rrs) at baseline (both 5 Hz and 19 Hz) significantly correlated to AQLQ improvement (r = - 0.52 and r = - 0.53 respectively, p = 0.01 (both)). Borderline significant correlations with ACQ improvement were found (r = 0.30 p = 0.16 for 5 Hz and r = 0.41 p = 0.05 for 19 Hz). Conclusion Pulmonary function remained stable after BT. Improvement in FEV1 correlated with asthma questionnaires improvement including AQLQ. Lower FOT-measured respiratory resistance at baseline was associated with favorable BT response, which might reflect targeting of larger airways with BT. Show less
Guidelines recommend endosonography for mediastinal nodal staging in patients with resectable nonsmall cell lung cancer (NSCLC). We hypothesise that a systematic endobronchial ultrasound (EBUS)... Show moreGuidelines recommend endosonography for mediastinal nodal staging in patients with resectable nonsmall cell lung cancer (NSCLC). We hypothesise that a systematic endobronchial ultrasound (EBUS) evaluation combined with an oesophageal investigation using the same EBUS bronchoscope (EUS-B) improves mediastinal nodal staging versus the current practice of targeted positron emission tomography (PET)-computed tomography (CT)-guided EBUS staging alone.A prospective, multicentre, international study (NCT02014324) was conducted in consecutive patients with (suspected) resectable NSCLC. After PET-CT, patients underwent systematic EBUS and EUS-B. Node(s) suspicious on CT, PET, EBUS and/or EUS-B imaging and station 4R, 4L and 7 (short axis >= 8 mm) were sampled. For patients without N2/N3 disease determined on endosonography, surgical-pathological staging was the reference standard.229 patients were included in this study. The prevalence of N2/N3 disease was 103 out of 229 patients (45%). A PET-CT-guided targeted approach by EBUS identified 75 patients with N2/N3 disease (sensitivity 73%, 95% CI 63-81%; negative predictive value (NPV) 81%, 95% CI 74-87%). Four additional patients with N2/N3 disease were found by systematic EBUS (sensitivity 77%, 95% CI 67-84%; NPV 84%, 95% CI 76-89%) and five more by EUS-B (84 patients total; sensitivity 82%, 95% CI 72-88%; NPV 87%, 95% CI 80-91%). Additional clinical relevant staging information was obtained in 23 out of 229 patients (10%). Systematic EBUS followed by EUS-B increased sensitivity for the detection of N2/N3 disease by 9% compared to PET-CT-targeted EBUS alone. Show less
Kuijvenhoven, J.C.; Crombag, L.; Breen, D.P.; Berk, I. van den; Versteegh, M.I.M.; Braun, J.; ... ; Annema, J.T. 2017
Objective-6-Mercaptopurine (6-MP), the active metabolite of the immunosuppressive prodrug azathioprine, is commonly used in autoimmune diseases and transplant recipients, who are at high risk for... Show moreObjective-6-Mercaptopurine (6-MP), the active metabolite of the immunosuppressive prodrug azathioprine, is commonly used in autoimmune diseases and transplant recipients, who are at high risk for cardiovascular disease. Here, we aimed to gain knowledge on the action of 6-MP in atherosclerosis, with a focus on monocytes and macrophages. Methods and Results-We demonstrate that 6-MP induces apoptosis of THP-1 monocytes, involving decreased expression of the intrinsic antiapoptotic factors B-cell CLL/Lymphoma-2 (Bcl-2) and Bcl2-like 1 (Bcl-xL). In addition, we show that 6-MP decreases expression of the monocyte adhesion molecules platelet endothelial adhesion molecule-1 (PECAM-1) and very late antigen-4 (VLA-4) and inhibits monocyte adhesion. Screening of a panel of cytokines relevant to atherosclerosis revealed that 6-MP robustly inhibits monocyte chemoattractant chemokine-1 (MCP-1) expression in macrophages stimulated with lipopolysaccharide (LPS). Finally, local delivery of 6-MP to the vessel wall, using a drug-eluting cuff, attenuates atherosclerosis in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice (P<0.05). In line with our in vitro data, this inhibition of atherosclerosis by 6-MP was accompanied with decreased lesion monocyte chemoattractant chemokine-1 levels, enhanced vascular apoptosis, and reduced macrophage content. Conclusion-We report novel, previously unrecognized atheroprotective actions of 6-MP in cultured monocytes/macrophages and in a mouse model of atherosclerosis, providing further insight into the effect of the immunosuppressive drug azathioprine in atherosclerosis. (Arterioscler Thromb Vasc Biol. 2010;30:1591-1597.) Show less
