Enhancer deregulation inTET2-mutant clonal hematopoiesis is associated with increased COVID-19 severity and mortality

Background: COVID-19 causes significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. It remains unclear which host factors determine disease severity and survival. Given the propensity of clonal hematopoiesis (CH) to promote inflammation in healthy individuals, we investigated its effect on COVID-19 outcomes. Method(s): We performed a multi-omics interrogation of the genome, epigenome, transcriptome, and proteome of peripheral blood mononuclear cells from COVID-19 patients (n=227). We obtained clinical data, laboratory studies, and survival outcomes. We determined CH status and TET2-related DNA methylation. We performed single-cell proteogenomics to understand clonal composition in relation to cell phenotype. We interrogated single-cell gene expression in isolation and in conjunction with DNA accessibility. We integrated these multi-omics data to understand the effect of CH on clonal composition, gene expression, methylation of cis-regulatory elements, and lineage commitment in COVID-19 patients. We performed shRNA knockdowns to validate the effect of one candidate transcription factor in myeloid cell lines. Result(s): The presence of CH was strongly associated with COVID-19 severity and all-cause mortality, independent of age (HR 3.48, 95% CI 1.45-8.36, p=0.005). Differential methylation of promoters and enhancers was prevalent in TET2-mutant, but not DNMT3A-mutant CH. TET2- mutant CH was associated with enhanced classical/intermediate monocytosis and single-cell proteogenomics confirmed an enrichment of TET2 mutations in these cell types. We identified celltype specific gene expression changes associated with TET2 mutations in 102,072 single cells (n=34). Single-cell RNA-seq confirmed the skewing of hematopoiesis towards classical and intermediate monocytes and demonstrated the downregulation of EGR1 (a transcription factor important for monocyte differentiation) along with up-regulation of the lncRNA MALAT1 in monocytes. Combined scRNA-/scATAC-seq in 43,160 single cells (n=18) confirmed the skewing of hematopoiesis and up-regulation of MALAT1 in monocytes along with decreased accessibility of EGR1 motifs in known cis-regulatory elements. Using myeloid cell lines for functional validation, shRNA knockdowns of EGR1 confirmed the up-regulation of MALAT1 (in comparison to wildtype controls). Conclusion(s): CH is an independent prognostic factor in COVID-19 and skews hematopoiesis towards monocytosis. TET2-mutant CH is characterized by differential methylation and accessibility of enhancers binding myeloid transcriptions factors including EGR1. The ensuing loss of EGR1 expression in monocytes causes MALAT1 overexpression, a factor known to promote monocyte differentiation and inflammation. These data provide a mechanistic insight to the adverse prognostic impact of CH in COVID-19.

Between nation and empire: how the state matters in global health

The role of the state has been underplayed in scholarship on global health. Taking a historical view, this paper argues that state institutions, practices and ideologies have in fact been crucial to the realisation of contemporary global health governance and to its predecessor regimes. Drawing on state theory, work on governmentality, and Third World approaches to international law, it traces the origins of the 'health state' in late colonial developmentalism, which held out the prospect of conditional independence for the subjects of European empires. Progress in health was also a key goal for nationalist governments in the Global South, one which they sought to realise autonomously as part of a New International Economic Order. The defeat of that challenge to the dominance of the Global North in the 1980s led to the rise of 'global governance' in health. Far from rendering the state redundant, the latter was realised through the co-option and disciplining of institutions at national level. To that extent, the current order has an unmistakably imperial character, one which undercuts its declared cosmopolitan aspirations, as evidenced in the approach to vaccine distribution and travel bans during the Covid-19 pandemic.

'Choking the national demos': Research partnerships and the material constitution of global health

By foregrounding a widened view of the rule of law in transnational legal processes, the works under discussion in this symposium can support innovative critical perspectives on global health law-a field that has gained wide attention due to the spread of COVID-19 around the world (Lander, 2020;Bhatt, 2020). Legal and socio-legal scholars in the decade and a half before the pandemic worked on locating global health law and articulating its underlying principles. Lawrence Gostin's 2014 monograph offers a synoptic view centred on international institutions (e.g. the World Health Organization, World Trade Organization, UN Human Rights Council) and problems (e.g. infectious-disease response, tobacco control), along with an elaboration of its normative basis in universal moral principle and international human rights law (Gostin, 2014). Struggles over access to essential medicines and intellectual property in the early 2000s are, for example, represented in terms of the right to health constraining international trade law. Andreas Fischer-Lescano and Guenther Teubner's 2004 reading is oriented more by social theory than by doctrinal or ethical frames (Fischer-Lescano and Teubner, 2004, pp. 1006, 1008). A functional health regime has 'differentiated out', they observe, and operates as a discrete communication system across borders, albeit one that is threatened by the preponderant economic system. On this model, the battle for access to medicines amounts to ensuring, via human rights guarantees, that the rationality of the health system is not replaced by that of its economic rival in legal and policy communications (Fischer-Lescano and Teubner, 2004, pp. 1030, 1046). ©2021 The Author(s). Published by Cambridge University Press. © 2021 Cambridge University Press. All rights reserved.

Sevoflurane to the rescue: A convoluted case of respiratory failure in an asthmatic teenager

INTRODUCTION: We present a case of a medically nonadherent 16 years-old female with a history of moderate persistent asthma and vaping of nicotine and marijuana products who presented in severe respiratory distress during the COVID-19 pandemic. She had poor response to continuous inhaled albuterol, scheduled intermittent ipratropium, systemic steroids, intravenous magnesium, and non-invasive ventilator support which led to intubation and mechanical ventilation. Because of ongoing bronchospasm, heliox, terbutaline, and ketamine infusions were initiated, but she continued to exhibit worsening respiratory failure, poor lung compliance, and severe bronchospasm. She then developed hypotension requiring an epinephrine infusion. Given this picture, sevoflurane (SEVO) was initiated resulting in an immediate clinical response with normalization of blood gases and lung compliance without any adverse effects. METHODS: SEVO was titrated to effect between 1-3% over the next 24 hours. Multiple attempts to wean off SEVO were unsuccessful despite the addition of an aminophylline infusion. She received SEVO for a total of 96 hours and mechanical ventilation for 11 days. Extensive evaluation revealed chest x-ray with mild left lower lobe infiltrates, an otherwise negative CT chest, and negative workups for COVID-19, respiratory and blood cultures, allergic bronchopulmonary aspergillosis, sarcoidosis, and leptospirosis. An echocardiogram was obtained and she was found to have a trabeculated myocardium, with an ejection fraction (EF) <30% and LV non-compaction. She later developed critical illness myopathy, which improved with rehabilitation, and upon repeat echo she did not meet the criteria for non-compaction with 71% EF and her BNP had normalized. She was discharged home after 27 days and her clinical picture was most consistent with a severe asthma exacerbation likely due to noncompliance and vaping. RESULTS: SEVO is commonly used for anesthesia in children, and is known for its bronchodilation properties, but its use in pediatric critical care settings is rarely described. Our patient tolerated SEVO well and it was indeed a life saving measure that was used successfully in the PICU, avoiding the need for ECMO. This case supports using SEVO in patients with severe asthma who have failed conventional therapy.