The COMPASS-COVID-19-ICU Study: Identification of Factors to Predict the Risk of Intubation and Mortality in Patients with Severe COVID-19

In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation is an urgent need. Objectives. To derive a prognostic score for the risk of intubation or death in patients with COVID-19 admitted in intensive care unit (ICU), by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes. Design, Setting and Participants. A prospective, observational study enrolled 118 patients with COVID-19 admitted in the ICU. On the first day of ICU admission, all patients were assessed for biomarkers (protein C, protein S, antithrombin, D-Dimer, fibrin monomers, FVIIa, FV, FXII, FXII, FVIII, FvW antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing TF, IL-6, complement C3a, C5a, thrombin generation, PT, aPTT, hemogram, platelet count) and clinical predictors. Main Outcomes and Measures. The clinical outcomes were intubation and mortality during hospitalization in ICU. Results: The intubation and mortality rates were 70% and 18%, respectively. The COMPASS-COVID-19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively). Conclusions and Relevance. COVID-19 is related to severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID-19-ICU risk assessment model is accurate for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The COMPASS-COVID-19-ICU score is feasible in tertiary hospitals and could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention.

Diffusion capacity abnormalities for carbon monoxide in patients with COVID-19 at 3-month follow-up.

OBJECTIVE: To evaluate pulmonary function and clinical symptoms in coronavirus disease 2019 (COVID-19) survivors within 3 months after hospital discharge, and to identify risk factors associated with impaired lung function. METHODS AND MATERIAL: COVID-19 patients were prospectively followed-up with pulmonary function tests and clinical characteristics for 3 months following discharge from a hospital in Wuhan, China between January and February 2020. RESULTS: 647 patients were included. 87 (13%) patients presented with weakness, 63 (10%) with palpitations and 56 (9%) with dyspnoea. The prevalence of each of the three symptoms were markedly higher in severe patients than nonsevere patients (19% versus 10% for weakness, p=0.003; 14% versus 7% for palpitations, p=0.007; 12% versus 7% for dyspnoea, p=0.014). Results of multivariable regression showed increased odds of ongoing symptoms among severe patients (OR 1.7, 95% CI 1.1-2.6; p=0.026) or patients with longer hospital stays (OR 1.03, 95% CI 1.00-1.05; p=0.041). Pulmonary function test results were available for 81 patients, including 41 nonsevere and 40 severe patients. In this subgroup, 44 (54%) patients manifested abnormal diffusing capacity of the lung for carbon monoxide (D LCO) (68% severe versus 42% nonsevere patients, p=0.019). Chest computed tomography (CT) total severity score >10.5 (OR 10.4, 95% CI 2.5-44.1; p=0.001) on admission and acute respiratory distress syndrome (ARDS) (OR 4.6, 95% CI 1.4-15.5; p=0.014) were significantly associated with impaired D LCO. Pulmonary interstitial damage may be associated with abnormal D LCO. CONCLUSION: Pulmonary function, particularly D LCO, declined in COVID-19 survivors. This decrease was associated with total severity score of chest CT >10.5 and ARDS occurrence. Pulmonary interstitial damage might contribute to the imparied D LCO.

The COVID-19 Pandemic and the Need for an Integrated and Equitable Approach: An International Expert Consensus Paper.

BACKGROUND: One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. MANAGEMENT: Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. CURRENT ISSUES: The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. PERSPECTIVES: There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). CONCLUSION: The "PDA strategy" integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.

SARS-CoV-2 Vaccine and Thrombosis: An Expert Consensus on Vaccine-Induced Immune Thrombotic Thrombocytopenia.

Historically, the vaccination strategies developed in the second half of the 20th century have facilitated the eradication of infectious diseases. From the onset of COVID-19 pandemic to the end of April 2021, more than 150 million cases and 3 million deaths were documented worldwide with disruption of the economic and social activity, and with devastating material, physical, and psychological consequences. Reports of unusual and severe thrombotic events, including cerebral and splanchnic venous thrombosis and other autoimmune adverse reactions, such as immune thrombocytopenia or thrombotic microangiopathies in connection with some of the SARS-CoV-2 vaccines, have caused a great deal of concern within the population and the medical community. This report is intended to provide practical answers following an overview of our knowledge on these thrombotic events that are extremely rare but have serious consequences. Vaccine hesitancy threatens to reverse the progress made in controlling vaccine-preventable diseases. These adverse events must be put into perspective with an objective analysis of the facts and the issues of the vaccination strategy during this SARS-CoV-2 pandemic. Health care professionals remain the most pertinent advisors and influencers regarding vaccination decisions; they have to be supported to provide reliable and credible information on vaccines. We need to inform, reassure, and support our patients when the prescription is made. Facing these challenges and observations, a panel of experts express their insights and propose a tracking algorithm for vaccinated patients based on a 10-point guideline for decision-making on what to do and not to do.

COVID-19, hemostasis disorders and risk of thrombotic complications

The spread of a new coronavirus infection worldwide since the end of 2019 has becomes a pandemic. Thrombotic complications are the leading cause of death in this disease. After entering the human body, the virus starts a cascade of reactions leading to the development of a cytokine storm, activation of all parts of the hemostasis and complement systems and other changes that result in disturbances in the circulation system with the development of multiple organ failures. Numerous studies have shown that a predictor of a severe course of COVID-19 is a sharp increase of D-dimer concentration in the blood and rise of some other markers of hemostasis activation. Based on the pathogenesis, the developed schemes for the prevention and treatment of COVID-19 severe complications include low molecular weight heparins (LMWH) which are also recommended for an outpatient COVID-19 patient. The prescription of low molecular weight heparin, the duration of their use and doses should be decided on the basis of a risk assessment of factors for each individual patient in combination with laboratory monitoring. Распространение новой коронавирусной инфекции по всему миру с конца 2019 г. превратилось в пандемию. Тромботические осложнения являются ведущей причиной смерти при этом заболевании. После попадания в организм человека вирус запускает каскад реакций, приводящих к развитию цитокинового «шторма», активации всех звеньев системы гемостаза и комплемента, другим изменениям, приводящим к нарушениям в системе кровообращения с развитием полиорганных нарушений. Многочисленные исследования показали, что предиктором тяжелого течения заболевания является резкое повышение концентрации D-димера в крови и некоторых других маркеров активации гемостаза. Исходя из патогенеза, разработанные схемы профилактики и лечения тяжелых осложнений COVID-19 включают низкомолекулярные гепарины, которые также рекомендуют для применения в амбулаторных условиях. Назначение низкомолекулярных гепаринов, длительность их применения и дозы должны определяться на основе оценки факторов риска для каждого отдельного пациента в сочетании с лабораторным мониторингом.

COVID-19, septic shock and syndrome of disseminated intravascular coagulation syndrome. Part 2

The article discusses the issues of hemostatic system disorders in patients with COVID-19. Strengthening the coagulopathy characteristic of DIC-syndrome, is a key sign of deterioration and an unfavorable prognosis in COVID-19 patients. Data obtained by Chinese colleagues demonstrates that a significantly increased level of D-dimer is one of the predictors of death. The article also highlights the preliminary recommendations of the International society of Thrombosis and Hemostasis (ISTH, 2020) to identify markers such as D-dimer, prothrombin time and platelet count as significant predictive markers in severe COVID-19 patients. The necessity of anticoagulant therapy in hospitalized patients is justified. The article discusses the features of sepsis in pregnant women. Data from a meta-analysis of 19 studies evaluating pregnancy complications and outcomes in patients with various coronavirus infections are presented. Despite the complicated course of pregnancy, there were no cases of vertical transmission of viral infection. In the pathogenesis of severe COVID-19 complications with the formation of severe acute respiratory distress syndrome, multi-organ dysfunction, super inflammation and cytokine storm play a leading role. In connection with viral sepsis, the article discusses the role of hemophagocytic lymphohistiocytosis as a hyperinflammatory syndrome characterized by fulminant and fatal hypercytokinemia with multiple organ failure, the role of hyperferritinemia in predicting the outcomes of severe sepsis. Groups of patients at high risk of death are discussed, as well as the need for anticoagulant and anti-cytokine therapy in patients with COVID-19. В статье рассматриваются вопросы нарушения системы гемостаза у пациентов с COVID-19. Нарастание коагулопатии, характерной для диссеминированного внутрисосудистого свертывания крови (ДВС-синдрома), - ключевой признак ухудшения состояния и неблагоприятного прогноза у пациентов с COVID-19. Приводятся данные, полученные китайскими коллегами, согласно которым значительно повышенный уровень D-димера является одним из предикторов смерти. Также освещены предварительные рекомендации Международного общества тромбоза и гемостаза (International Society on Thrombosis and Haemostasis, ISTH, 2020) по определению таких маркеров, как D-димер, протромбиновое время и количество тромбоцитов, в качестве значимых прогностических маркеров у тяжелых больных COVID-19. Обосновывается необходимость антикоагулянтной терапии у госпитализированных больных. В статье обсуждаются особенности сепсиса у беременных. Приводятся данные метаанализа 19 исследований, посвященных оценке осложнений и исходов беременности у пациенток с различными коронавирусными инфекциями. Несмотря на осложненное течение беременности, не отмечено ни одного случая вертикальной передачи вирусной инфекции. В патогенезе тяжелых осложнений COVID-19 с формированием тяжелого острого респираторного дистресс-синдрома, полиорганной дисфункции ведущую роль играют супервоспаление и цитокиновый шторм. В статье в связи с вирусным сепсисом обсуждается роль гемофагоцитарного лимфогистиоцитоза как гипервоспалительного синдрома, характеризуемого фульминантной и фатальной гиперцитокинемией с полиорганной недостаточностью, роль гиперферритинемии в прогнозировании исходов тяжелого сепсиса. Обсуждаются группы пациентов высокого риска развития летальных исходов, а также необходимость антикоагулянтной и антицитокиновой терапии у больных COVID-19.

Derivation and Validation of a Predictive Score for Disease Worsening in Patients with COVID-19.

The prospective observational cohort study COMPASS-COVID-19 aimed to develop a risk assessment model for early identification of hospitalized COVID-19 patients at risk for worsening disease. Patients with confirmed COVID-19 (n = 430) hospitalized between March 18 and April 21, 2020 were divided in derivation (n = 310) and validation (n = 120) cohorts. Two groups became evident: (1) good prognosis group (G-group) with patients hospitalized at the conventional COVID-19 ward and (2) Worsening disease group (W-group) with patients admitted to the intensive care unit (ICU) from the emergency departments. The study end point was disease worsening (acute respiratory failure, shock, myocardial dysfunction, bacterial or viral coinfections, and acute kidney injury) requiring ICU admission. All patients were routinely evaluated for full blood count, prothrombin time, fibrinogen, D-dimers, antithrombin (AT), and protein C activity. Data from the first hospitalization day at the conventional ward or the ICU were analyzed. Cardiovascular risk factors and comorbidities were routinely registered. Obesity, hypertension, diabetes and male gender, increased fibrinogen and D-dimers, thrombocytopenia, AT deficiency, lymphopenia, and an International Society on Thrombosis and Haemostasis (ISTH) score for compensated disseminated intravascular coagulation score (cDIC-ISTH) ≥5 were significant risk factors for worsening disease. The COMPASS-COVID-19 score was derived from multivariate analyses and includes obesity, gender, hemoglobin, lymphocyte, and the cDIC-ISTH score (including platelet count, prothrombin time, D-dimers, AT, and protein C levels). The score has a very good discriminating capacity to stratify patients at high and low risk for worsening disease, with an area under the receiver operating characteristic curve value of 0.77, a sensitivity of 81%, and a specificity of 60%. Application of the COMPASS-COVID-19 score at the validation cohort showed 96% sensitivity. The COMPASS-COVID-19 score is an accurate clinical decision-making tool for an easy identification of COVID-19 patients being at high risk for disease worsening.

COVID-19, septic shock and syndrome of disseminated intravascular coagulation syndrome. Part 1

The pandemic of a new coronavirus infection (Coronavirus Disease 2019, COVID-19) caused by SARS-CoV-2 became a real challenge to humanity and the medical community in 2020 and raised a number of medical, social and even philosophical questions. An almost avalanche-like increase in the number of infected people in a short time, due to the high contagiousness of viral infection, allowed us to identify groups of patients with mild, moderate and severe forms of the disease. Doctors around the world are faced with an acute problem of treating a large number of patients in critical conditions caused by COVID-19. From the currently available information on clinical cases of COVID-19, it follows that COVID-19 patients in critical condition have a clinical picture of disseminated intravascular coagulation (DIC), septic shock with the development of multiple organ failure. The first part of the article discusses the pathogenesis of non-specific universal biological responses of the body in critical condition - from the Sanarelli-Schwartzman phenomenon to the DIC, septic shock, systemic inflammatory response syndrome and the so-called neutrophil extracellular traps (NETs). The questions of cytokine storm in severe forms of systemic inflammatory response syndrome (SIRS), the role of inflammation in the activation of coagulation, and the relationship between inflammation and thrombosis are discussed. Modern ideas about the mechanisms of so-called NETosis, their role in the occurrence of immunothrombosis and inflammation-induced thrombosis in autoimmune diseases - vasculitis, antiphospholipid syndrome, and systemic lupus erythematosus is highlighted. The article discusses the possibility of participation of ADAMTS-13 metalloproteinase in the pathogenesis of multiple organ failure in severe endotheliopathy in patients with viral septic shock. Пандемия новой коронавирусной инфекции (COronaVIrus Disease 2019, СOVID-19), вызванная тяжелым острым респираторным синдромом, связанным с коронавирусом 2 (severe acute respiratory syndrome-related coronavirus 2, SARS-CoV-2) стала настоящим вызовом человечеству и медицинскому сообществу в 2020 году и поставила целый ряд медицинских, социальных и даже философских вопросов. Практически лавинообразно нарастающее число зараженных за короткое время, связанное с высокой контагиозностью вирусной инфекции, позволило выделить группы пациентов с легкой, средней тяжести и тяжелой формами заболевания. Перед врачами всего мира встала острая проблема лечения большого количества больных в критических состояниях, вызванных COVID-19. Из имеющейся в настоящее время информации о клинических случаях COVID-19 следует, что у больных в критическом состоянии наблюдается клиническая картина диссеминированного внутрисосудистого свертывания крови, септического шока с развитием полиорганной недостаточности. В первой части статьи изложены вопросы патогенеза неспецифических универсальных биологических ответов организма в критических состояниях - от феномена Санарелли-Шварцмана до учения о диссеминированном внутрисосудистом свертывании крови, септическом шоке, синдроме системного воспалительного ответа и так называемых внеклеточных ловушках нейтрофилов (neutrophil extracellular traps, NETs). Обсуждаются вопросы цитокинового шторма при тяжелых формах синдрома системного воспалительного ответа, роль воспаления в активации коагуляции и взаимосвязь между воспалением и тромбозом (inflathrombosis). Освещаются современные представления о механизмах так называемых NETозов (NETosis) и их роли в возникновении иммунообусловленных и «воспалительных» тромбозов при аутоиммунных состояниях - васкулитах, антифосфолипидном синдроме, системной красной волчанке. Обсуждаются вопросы возможности участия металлопротеиназы ADAMTS-13 в патогенезе полиорганной недостаточности в условиях тяжелой эндотелиопатии у пациентов с вирусобусловленным септическим шоком.

Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine.

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

COVID-19, neutrophil extracellular traps and vascular complications in obstetric practice.

An issue of the novel coronavirus infection spreading is currently in the first place among others in the list of the international medical community. Due to lack of information, conflicting research findings, multicomponent effect of the virus on the body host, as well as various consequences that the virus triggers in the body, now every medical specialty does study the viral attack pathogenesis. Recent months showed that vascular complications are the most severe in the Coronavirus Disease 2019 (COVID-19) and are the main cause of death in the patients. The mechanisms of vascular complications are complex and affect both the hemostatic system and immune responses, "inflammatory storm", disorders of the renin-angiotensin-aldosterone system, endotheliopathy, etc. Due to the leading role of vascular complications in the viral infection pathogenesis, several groups of patients are at extra risk, including pregnant women, patients with a burdened obstetric history, with hereditary thrombophilia and antiphospholipid syndrome, and patients after in vitro fertilization (IVF). In this category of pregnant women, use of low-molecular-weight heparins (LMWH) is particularly important for both prevention of vascular and obstetric complications, and for pathogenetic therapy of COVID-19.

Prevention and Treatment of Venous Thromboembolism Associated with Coronavirus Disease 2019 Infection: A Consensus Statement before Guidelines.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic in just a few months, causing millions infected. Nearly 20% of COVID-19 patients present severe coagulation abnormalities, which may occur in almost all of the severe and critical ill COVID-19 cases. Concomitant venous thromboembolism (VTE), a potential cause of unexplained deaths, has been frequently reported in COVID-19 cases, but its management is still challenging due to the complexity between antithrombotic therapy and coagulation disorders. Based on frontline practical experience and comprehensive literature review, here a panel of experts and physicians from China and Europe developed an evidence and opinion-based consensus on the prophylaxis and management of VTE associated with COVID-19. This statement aims for clinicians treating COVID-19 and provides practical recommendations in detailed situations, for example, how to choose thromboprophylactic measures for patients with diverse severity of disease and bleeding risk, or which kind of anticoagulant should be prescribed. With limited experience on COVID19-associated VTE, this expert consensus statement should be helpful for clinicians worldwide with specific suggestions.

Hematological findings and complications of COVID-19.

COVID-19 is a systemic infection with a significant impact on the hematopoietic system and hemostasis. Lymphopenia may be considered as a cardinal laboratory finding, with prognostic potential. Neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases. During the disease course, longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including LDH, CRP and IL-6 may help to identify cases with dismal prognosis and prompt intervention in order to improve outcomes. Biomarkers, such high serum procalcitonin and ferritin have also emerged as poor prognostic factors. Furthermore, blood hypercoagulability is common among hospitalized COVID-19 patients. Elevated D-Dimer levels are consistently reported, whereas their gradual increase during disease course is particularly associated with disease worsening. Other coagulation abnormalities such as PT and aPTT prolongation, fibrin degradation products increase, with severe thrombocytopenia lead to life-threatening disseminated intravascular coagulation (DIC), which necessitates continuous vigilance and prompt intervention. So, COVID-19 infected patients, whether hospitalized or ambulatory, are at high risk for venous thromboembolism, and an early and prolonged pharmacological thromboprophylaxis with low molecular weight heparin is highly recommended. Last but not least, the need for assuring blood donations during the pandemic is also highlighted.