In severe SARS-CoV-2 infections, emerging data including recent histopathological studies have emphasized the crucial role of endothelial cells (ECs) in vascular dysfunction, immunothrombosis, and inflammation.Histopathological studies have evidenced direct viral infection of ECs, endotheliitis with diffuse endothelial inflammation, and micro- and macrovascular thrombosis both in the venous and arterial circulations. Venous thrombotic events, particularly pulmonary embolism, with elevated D-dimer and coagulation activation are highly prevalent in COVID-19 patients. The pro-inflammatory cytokine storm, with elevated levels of interleukin-6 (IL-6), IL-2 receptor, and tumor necrosis factor-α, could also participate in endothelial dysfunction and leukocyte recruitment in the microvasculature. COVID-19-induced endotheliitis may explain the systemic impaired microcirculatory function in different organs in COVID-19 patients. Ongoing trials directly and indirectly target COVID-19-related endothelial dysfunctions: i.e., a virus-cell entry using recombinant angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS-2) blockade, coagulation activation, and immunomodulatory therapies, such as anti-IL-6 strategies. Studies focusing on endothelial dysfunction in COVID-19 patients are warranted as to decipher their precise role in severe SARS-CoV-2 infection and organ dysfunction and to identify targets for further interventions.

Background: Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. Main text: Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. Conclusions: Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.

Anti-synthetase (AS) and dermato-pulmonary associated with anti-MDA-5 antibodies (aMDA-5) syndromes are near one of the other autoimmune inflammatory myopathies potentially responsible for severe acute interstitial lung disease. We undertook a 13-year retrospective multicenter study in 35 French ICUs in order to describe the clinical presentation and the outcome of patients admitted to the ICU for acute respiratory failure (ARF) revealing AS or aMDA-5 syndromes. From 2005 to 2017, 47 patients (23 males; median age 60 [1st–3rd quartiles 52–69] years, no comorbidity 85%) were admitted to the ICU for ARF revealing AS (n = 28, 60%) or aMDA-5 (n = 19, 40%) syndromes. Muscular, articular and cutaneous manifestations occurred in 11 patients (23%), 14 (30%) and 20 (43%) patients, respectively. Seventeen of them (36%) had no extra-pulmonary manifestations. C-reactive protein was increased (139 [40–208] mg/L), whereas procalcitonine was not (0.30 [0.12–0.56] ng/mL). Proportion of patients with creatine kinase ≥ 2N was 20% (n = 9/47). Forty-two patients (89%) had ARDS, which was severe in 86%, with a rate of 17% (n = 8/47) of extra-corporeal membrane oxygenation requirement. Proportion of patients who received corticosteroids, cyclophosphamide, rituximab, intravenous immunoglobulins and plasma exchange were 100%, 72%, 15%, 21% and 17%, respectively. ICU and hospital mortality rates were 45% (n = 21/47) and 51% (n = 24/47), respectively. Patients with aMDA-5 dermato-pulmonary syndrome had a higher hospital mortality than those with AS syndrome (n = 16/19, 84% vs. n = 8/28, 29%; p = 0.001). Intensivists should consider inflammatory myopathies as a cause of ARF of unknown origin. Extra-pulmonary manifestations are commonly lacking. Mortality is high, especially in aMDA-5 dermato-pulmonary syndrome.

The vascular endothelium is crucial for the maintenance of vascular homeostasis. Moreover, in sepsis, endothelial cells can acquire new properties and actively participate in the host's response. If endothelial activation is mostly necessary and efficient in eliminating a pathogen, an exaggerated and maladaptive reaction leads to severe microcirculatory damage. The microcirculatory disorders in sepsis are well known to be associated with poor outcome. Better recognition of microcirculatory alteration is therefore essential to identify patients with the worse outcomes and to guide therapeutic interventions. In this review, we will discuss the main features of endothelial activation and dysfunction in sepsis, its assessment at the bedside, and the main advances in microcirculatory resuscitation.

Acute Kidney Injury (AKI) is a frequent complication of severe SARS-CoV-2 infection. Multiple mechanisms are involved in COVID-19-associated AKI, from direct viral infection and secondary inflammation to complement activation and microthrombosis. However, data are limited in critically-ill patients. In this study, we sought to describe the prevalence, risk factors and prognostic impact of AKI in this setting. Retrospective monocenter study including adult patients with laboratory confirmed SARS-CoV-2 infection admitted to the ICU of our university Hospital. AKI was defined according to both urinary output and creatinine KDIGO criteria. Overall, 100 COVID-19 patients were admitted. AKI occurred in 81 patients (81%), including 44, 10 and 27 patients with AKI stage 1, 2 and 3 respectively. The severity of AKI was associated with mortality at day 28 (p = 0.013). Before adjustment, the third fraction of complement (C3), interleukin-6 (IL-6) and ferritin levels were higher in AKI patients. After adjustment for confounders, both severity (modified SOFA score per point) and AKI were associated with outcome. When forced in the final model, C3 (OR per log 0.25; 95% CI 0.01–4.66), IL-6 (OR per log 0.83; 95% CI 0.51–1.34), or ferritin (OR per log 1.63; 95% CI 0.84–3.32) were not associated with AKI and did not change the model. In conclusion, we did not find any association between complement activation or inflammatory markers and AKI. Proportion of patients with AKI during severe SARS-CoV-2 infection is higher than previously reported and associated with outcome.