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.

Relationship between kalemia and intensive care unit admission or death in hospitalized COVID-19 patients: A cohort study.

BACKGROUND: SARS-CoV-2 uses Angiotensin-Converting Enzyme 2 as a viral gateway to the cell and could interact with the renin-angiotensin-aldosterone system. Other studies have shown kalemia abnormalities in patients with severe forms of coronavirus disease 2019. Our goal was to assess the prognosis value of kalemia within ten days of symptom offset in the COVID-19 hospitalized population. METHODS: We analyzed data from a prospective cohort that included 65 patients with COVID-19, admitted between March 15, 2020, and March 21, 2020. The study aimed at determining the relationship between baseline kalemia and the admission to an intensive care unit (ICU) or death. RESULTS: The median age of the patients was 65 [54-79] years old, and 66.2% of the patients were men. Baseline kalemia under 3.8mmol/l occurred in 31 patients (48%), including 11 patients (35.5%) who were admitted to an ICU and one patient (3.2%) who died before ICU admission. In the primary end-point analysis, the adjusted hazard ratios for admission to an ICU or death were 3.52 [95% confidence interval (CI), 1.12 to 11.04] among patients with low baseline kalemia. CONCLUSION: Our study suggests that low kalemia levels within ten days of the first symptom onset might be associated with an increased risk of intensive care unit admission or death. The future perspective should be to better understand this relationship.

Adjusting D-dimer to lung disease extent to exclude pulmonary embolism in COVID-19 patients (Co-LEAD)

Background : D-dimer is a safe tool to exclude pulmonary embolism (PE) but its specificity is decreased in COVID-19. Aims : Our aim was to derive a new algorithm with D-dimer threshold adjusted to CT extent of lung damage. Methods : We conducted a multicenter, retrospective cohort study among 774 COVID-19 patients with suspected PE. D-dimer threshold adjusted to CT extent of lung damage was derived in a patient set ( n = 337), and its safety assessed in an independent validation set ( n = 337). Results : According to ROC curves, D-dimer safely excluded PE, with one false negative when using a 900 ng/mL threshold when lung damage extent was <50% and 1700 ng/mL when lung damage extent was ≥50%. In the derivation set, the algorithm's sensitivity was 98.2% (95% CI: 94.7-100.0), and its specificity 28.4% (95% CI: 24.1-32.3). The negative likelihood ratio (NLR) was 0.06 (95% CI: 0.01-0.44) and the AUC was 0.63 (95% CI: 0.60-0.67). In the validation set, sensitivity and specificity were 96.7% (95% CI: 88.7-99.6) and 39.2% (95% CI: 32.2-46.1), respectively. The NLR was 0.08 (95% CI: 0.02-0.33), and the AUC did not differ from that of the derivation set (0.68 (95% CI: 0.64-0.72), P = 0.097). Using the Co-LEAD algorithm, 76/250 (30.4%) COVID-19 patients with suspected PE could have been managed without CT pulmonary angiography (CTPA). Conclusions : The Co-LEAD algorithm safely excludes PE, and allows reducing the use of CTPA in COVID-19 patients. Prospective management studies are necessary to validate this strategy.

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.

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.

BACKGROUND: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. OBJECTIVES: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus. METHODS: This observational study was conducted during 9-16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included. RESULTS: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic-natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL. CONCLUSIONS: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.

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.