COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 beta [IL-1beta] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy. Copyright © 2021, The Author(s), under exclusive licence to Springer Nature B.V.

Les anomalies EEG précoces sont associées à l’évolution des patients Covid-19 hospitalisés en réanimation pour syndrome de détresse respiratoire aiguë: une étude prospective observationnelle bicentrique

Déclaration de liens d’intérêts: Les auteurs n’ont pas précisé leurs éventuels liens d’intérêts. Financements: Cette étude a été financée par le Département Médico-Universitaire Urgences-Réanimation APHP. Centre-Université de Paris.

Déterminants et impact pronostique de la dépense énergétique de repos des patients Covid-19 sous ventilation mécanique invasive en réanimation

Déclaration de liens d’intérêts: Les auteurs déclarent ne pas avoir de liens d’intérêts.

Suspicion of heparin-induced thrombocytopenia in COVID-19: Results from a multi-centric retrospective study

Background : High rates of venous thromboembolic events associated to LMWH/heparin therapy lead to numerous heparin-induced thrombocytopenia (HIT) suspicion during COVID-19 outbreak. Aims : We aim to describe HIT-suspected patient's characteristics and prevalence between March 15 and April 15 of 2020. Methods : This is a multi-centric retrospective cohort study of HITsuspected patients referred to our center. 4T score has been realized by experienced hematologist and/or pharmacologist and allowed us to trigger specific HIT assays if score was >3 (IgG anti-PF4/H and 14C-serotonine release assay, SRA). We included all consecutive HIT-suspected patients during COVID-19 outbreak compared to the same period in 2019. Results : During 2019 and 2020-study periods we identified, respectively, 17 and 41 consecutive HIT-suspected patients. Among the 2020-group, 23 were COVID-19 and 18 were non-COVID-19 patients. Clinical and biological characteristics were not significantly different between the 2019, 2020 non-COVID-19 and COVID-19 HIT-suspected patients. During 2019-period study, 11 (64.7%) patients had a 4T score >3, 4 (36.3%) of them had positive anti-PF4/H antibodies and only one had a positive SRA assay. During 2020-period study, 8 (44.4%) non-COVID-19 and 10 (43.5%) COVID-19 patients had a 4T score >3. Among them, respectively, 3 (37.5%) and 3 (30.%) had positive anti-PF4/H antibodies. SRA assay was positive in 3 non-COVID-19 patients tested and in the only one COVID-19 tested patient. The 4T score was able to exclude HIT in 67% of COVID-19 patients suspected. In 2020-study period, when comparing COVID-19 and non-COVID-19 patients, the only significantly difference in term of HIT suspicion criteria was the mean duration of heparin exposition before suspicion: 9.9 days ±6.3 for non-COVID-19 patients versus 15.2 days ±8.8 for COVID-19 patients, P = 0.043). Conclusions : HIT suspicion in COVID-19 occurs after longer anticoagulation time than non-COVID-19. We did not observe more confirmed HIT in COVID-19 in contrast our two non-COVID-19 control groups.

Lupus anticoagulant positivity is not associated with venous thromboembolism or in-hospital mortality in COVID-19

Background : Antiphospholipid antibodies (APA) clinical relevance in COVID-19 is controversial. Aims : We aimed to investigate the prevalence and prognostic value of conventional and non-conventional APA in COVID-19 patients. Methods : This study was a multi-centric, prospective observational French cohort of patients hospitalized for COVID-19 suspicion. Results : 249 patients were hospitalized for suspected COVID-19, including 154 (61.8%) with confirmed COVID-19 and 95 (38.2%) not confirmed. We found a significant increase in lupus anticoagulant (LA) positivity among COVID-19 positive patients (60.9% versus 23.7% in non-COVID19 patients, P < 0.001), while prevalence of conventional (LA, IgG, IgM and IgA isotypes) and non-conventional APA (anti-phosphatidylserine/prothrombin IgG and IgM) were low in both groups. COVID-19 patients with LA positivity had higher levels of fibrinogen (6.0 g/L, IQR 5.0-7.0 versus 5.3 IQR 4.3-6.4, P = 0.028) and C-reactive protein (CRP, 115.5 IQR 66.0-204.8 versus 91.8 mg/L, IQR 27.0-155.1, P = 0.019). Univariate analysis did not show any association between LA positivity and higher risk of venous thromboembolism (VTE, OR 1.02, 95% CI 0.44-2.43, P = 0.95) or inhospital mortality (OR 1.80, 95% CI 0.70-5.05, P = 0.24). Unadjusted and adjusted (to CRP, age and sex) Kaplan-Meier survival curves according to LA positivity confirmed the absence of association with VTE or in-hospital mortality (unadjusted: P = 0.64 and P = 0.26, respectively;adjusted: hazard ratio = 1.13 95% CI 0.48-2.60 and 1.80 95% CI 0.67-5.01). Conclusions : COVID-19 patients have an increased prevalence of LA positivity associated with biological inflammation markers. However, positive LA at admission is not associated with VTE risk and/or inhospital mortality.

Testosterone level and severity of COVID-19 infection in ambispective cohorts: The TESTOVID study

Background: Lower risk of COVID-19 was reported in men with prostate cancer receiving androgen deprivation therapy while low levels of testosterone (T) were associated with a more severe disease and poor clinical outcomes in COVID-19 male patients (pts). In the latter case, it is unclear whether low levels of T and dihydrotestoserone (DHT) are risk factors or consequences of COVID-19. Here, we investigated T and DHT levels impact on COVID-19 severity in ambispective cohorts of symptomatic SARS-CoV-2 infected males. Methods: Both prospective (European Hospital Georges Pompidou patients, P-cohort) and retrospective (French COVID-19 cohort, REacting project, R-cohort) cohorts included male pts admitted for severe COVID-19. The P-cohort included pts admitted in a medical unit (non-ICU) or in ICU immediately (ICU-I). The R-cohort included pts admitted to a medical unit, ICU-I or to ICU secondarily (ICU-S). The size of ICU-S pts group in P-cohort was insufficient to include their data in the analysis. We collected information on pts demographics and COVID-19-related outcomes. T, DHT levels and inflammation markers were measured. Wilcoxon-Mann-Whitney test and chi2-test (or Fisher’s exact test, if appropriate) were performed. All tests were two-sided at 0.05 significance level. Results: The P-cohort included 71 pts (median age: 64 years) and the R-cohort 89 pts (median age: 62 years). The median duration between admission and measurement of hormone levels was 2 days (range: 0-16) and 0.5 days (range: 0-11) respectively. T and DHT levels were low in all pts as compared to standards and even lower in ICU pts (Table). In the R-cohort, T and DHT lowest values were observed for ICU-I pts and median values for ICU-S pts. [Formula presented] Conclusions: Low T and DHT levels were associated with the severity of the disease and the poorest clinical outcomes in males with severe COVID-19. This suggests that COVID-19 may cause a rapid and profound decrease in androgens levels and that T and DHT serum levels may be used as prognostic markers. Legal entity responsible for the study: Pr. Stéphane Oudard. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Evolution of the nutritional status of COVID-19 critically-ill patients: A prospective observational study from ICU admission to three months after ICU discharge.

BACKGROUND & AIMS: Malnutrition following intensive care unit (ICU) stay is frequent and could be especially prominent in critically ill Coronavirus Disease 2019 (COVID-19) patients as they present prolonged inflammatory state and long length stay. We aimed to determine the prevalence of malnutrition in critically ill COVID-19 patients both at the acute and recovery phases of infection. METHODS: We conducted a prospective observational study including critically ill COVID-19 patients requiring invasive mechanical ventilation discharged alive from a medical ICU of a university hospital. We collected demographic, anthropometric and ICU stay data (SAPS2, recourse to organ support and daily energy intake). Nutritional status and nutritional support were collected at one month after ICU discharge (M1) by phone interview and at 3 months after ICU discharge (M3) during a specialized and dedicated consultation conducted by a dietitian. Malnutrition diagnosis was based on weight loss and body mass index (BMI) criteria following the Global Leadership Initiative on Malnutrition. Primary outcome was the prevalence of malnutrition at M3 and secondary outcomes were the evolution of nutritional status from ICU admission to M3 and factors associated with malnutrition at M3. RESULTS: From march 13th to may 15th, 2020, 38 patients were discharged alive from the ICU, median [IQR] age 66 [59-72] years, BMI 27.8 [25.5-30.7] kg/m2 and SAPS2 47 [35-55]. Thirty-three (86%) patients were followed up to M3. Prevalence of malnutrition increased during the ICU stay, from 18% at ICU admission to 79% at ICU discharge and then decreased to 71% at M1 and 53% at M3. Severe malnutrition prevailed at ICU discharge with a prevalence of 55% decreasing 32% at M3. At M3, the only factors associated with malnutrition in univariate analysis were the length of invasive mechanical ventilation and length of ICU stay (28 [18-44] vs. 13 [11-24] days, P = 0.011 and 32 [22-48] vs. 17 [11-21] days, P = 0.006, respectively), while no ICU preadmission and admission factors, nor energy and protein intakes distinguished the two groups. Only 35% of undernourished patients at M3 had benefited from a nutritional support. CONCLUSION: Malnutrition is frequent, protracted and probably underrecognized among critically ill Covid-19 patients requiring invasive mechanical ventilation with more than half patients still being undernourished three months after ICU discharge. A particular attention should be paid to the nutritional status of these patients not only during their ICU stay but also following ICU discharge.

Respiratory mechanics and gas exchanges in the early course of COVID-19 ARDS: a hypothesis-generating study.

RATIONALE: COVID-19 ARDS could differ from typical forms of the syndrome. OBJECTIVE: Pulmonary microvascular injury and thrombosis are increasingly reported as constitutive features of COVID-19 respiratory failure. Our aim was to study pulmonary mechanics and gas exchanges in COVID-2019 ARDS patients studied early after initiating protective invasive mechanical ventilation, seeking after corresponding pathophysiological and biological characteristics. METHODS: Between March 22 and March 30, 2020 respiratory mechanics, gas exchanges, circulating endothelial cells (CEC) as markers of endothelial damage, and D-dimers were studied in 22 moderate-to-severe COVID-19 ARDS patients, 1 [1-4] day after intubation (median [IQR]). MEASUREMENTS AND MAIN RESULTS: Thirteen moderate and 9 severe COVID-19 ARDS patients were studied after initiation of high PEEP protective mechanical ventilation. We observed moderately decreased respiratory system compliance: 39.5 [33.1-44.7] mL/cmH2O and end-expiratory lung volume: 2100 [1721-2434] mL. Gas exchanges were characterized by hypercapnia 55 [44-62] mmHg, high physiological dead-space (VD/VT): 75 [69-85.5] % and ventilatory ratio (VR): 2.9 [2.2-3.4]. VD/VT and VR were significantly correlated: r2 = 0.24, p = 0.014. No pulmonary embolism was suspected at the time of measurements. CECs and D-dimers were elevated as compared to normal values: 24 [12-46] cells per mL and 1483 [999-2217] ng/mL, respectively. CONCLUSIONS: We observed early in the course of COVID-19 ARDS high VD/VT in association with biological markers of endothelial damage and thrombosis. High VD/VT can be explained by high PEEP settings and added instrumental dead space, with a possible associated role of COVID-19-triggered pulmonary microvascular endothelial damage and microthrombotic process.