Covid-19 Pandemic: Cardiovascular and Neurologic Impact, Early Signs and Symptoms

Background: Early neuro-sensorial like anosmia and dysgeusia are useful for diagnostic, patient’s isolation, and treatment. Angio-hematologic acro-ischemia syndrome and dermatological signs are mostly related with immune dysregulation, neoangiogenesis, vasculitis, and vessel thrombosis resulting from “cytokine storm syndrome”. Acro-ischemia syndrome allows diagnosis and early treatment of disseminated intravascular coagulation, with mortality risks for children and adults. a prothrombotic disease with a unique global lethality. Strong inflammatory response to viral infection affects cardiovascular, and neurologic systems, as well as respiratory, immune and hematologic systems. Fast identification of acro-ischemia syndrome permits the care of disseminated intravascular coagulation complications. Early symptoms like gustatory and olfactory loss are useful for Covid diagnostic. Mathematical models play a significant role in the understanding of COVID-19 transmission mechanisms, structures, and features. It should be of interest for policymakers and for explaining recurrent epidemic outbreaks.

Covid-19 patients can remain subjectively comfortable even when their oxygen saturation levels fall far below borderline ranges, becoming a "silent hypoxemia", low oxygen saturation associated with hypocapnia can be observed in pulmonary artery embolism [13]. Thoracic CT angiography scan and lung ultrasound imaging provide information for COVID diagnose and follow-up [14,15].

Cardiovascular and Hematological Impact
Covid-19 can have fatal consequences for people with underlying cardiovascular disease [7,16,17]. Over 65 years-old, patients with coronary artery disease, arterial hypertension and cardiac arrythmias are at more severe risk. More worrisome is the fact that COVID could cause heart damage in patients who did not have any previous problems [7]. It is reasonable to expect that significant cardiovascular complications from Covid-19 will occur in patients with severe symptoms due to the strong inflammatory response associated with this disease that affects the myocardium. The critical cases of Covid-19 are those which have reported respiratory failure, septic shock with evolution towards multiorgan failure.
In a new study including 100 patients recently recovered from COVID-19 infection [18], cardiovascular magnetic resonance imaging (CMR) revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of pre-existing conditions, severity and overall course of the acute illness, and time from the original diagnosis. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.

Viral Myocarditis
1% to 5% of all patients with acute viral infections may involve the myocardium [19]. The incidence of myocarditis is between 10 to 22 cases per 100,000 persons, it was observed in many viruses including enterovirus coxsackie B, parvovirus B-19, herpesvirus, influenza virus, and Covid-19 [20]. Viral myocarditis symptoms can range from nonspecific fatigue and shortness of breath to more aggressive symptoms that mimic acute coronary syndrome. After the initial acute phase, remission of symptoms can be observed or the viral infection may persist, leading to a persistent autoimmune-mediated inflammatory process with continuing symptoms of heart failure. Fulminant myocarditis associated with influenza A (H1N1) virus were observed in previously healthy patients [21].

Hematology
Clinical patient's outcome allows to consider COVID-19 as a new hematologic disease, thrombosis would be favored by the vascular attacks related to the Covid-19 infection. Curative anticoagulation in these patients prevents endothelial lesions. Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for in-tensive care unit (ICU) admission [25][26][27][28]. Pulmonary artery and vein thrombo-embolism doubled among ICU patients. Endotheliopathy, the activation of coagulation and the inflammatory syndrome contribute to increasing the risk of thrombosis, causes seem to be multifactorial. In obese patients, there is also impaired ventilation which can affect inflammation and organs perfusion. Elevated levels of D-dimers and clotting factors are known risk factors for pulmonary embolism in these cases [10]. COVID-19 seems to be an additional risk factor for Deep Vein Thrombosis (DVT). The prevalence of DVT in hospitalized patients with SRAS-CoV-2 infection is high and is associated with adverse outcomes [29].

Pathological Findings
Autopsies around the world show that the lungs of the COVID-19 had hundreds of micro clots inside the pulmonary vasculature, not observed in classic pneumonia. In some cases, migrate causing myocardial ischemia or brain stroke. In 38 autopsies analyzed in North Italy [30], the predominant pattern of lung lesions in COVID-19 patients was diffuse alveolar damage, as previously Extensive histopathological analysis [31] showed that SARS-CoV-2 infection can result in diverse, multi-organ pathology, the most significant being in the lungs (diffuse alveolar damage in its different phases, microthrombi, bronchopneumonia, necrotizing bronchiolitis, viral pneumonia), heart (lymphocytic myocarditis), kidney (acute tubular injury), central nervous system (microthrombi, ischemic necrosis, acute hemorrhagic infarction, congestion, and vascular edema), lymph nodes (hemophagocytosis and histiocytosis), bone marrow (hemophagocytosis) and vasculature (deep vein thrombosis).

Role of ECMO in Covid-19 infection
Extracorporeal Membrane Oxygenation has been proposed in the treatment of severe pulmonary and cardiac compromise in COVID-19 [32]. ECMO is an extracorporeal respiratory assistance system, its indications concern patients with severe acute respiratory distress syndrome (ARDS) for which all other approaches have failed. There are 2 indications for ECMO: A) can serve as pure respiratory assistance, the blood is then taken from the right side at heart-lung, with additional cardiac support. The blood is reinjected this time, not into the jugular vein, but into the aorta [33,34].
The care under ECMO can last several weeks. For influenza ARDS patients who are managed every winter, the ECMO is used over an average of 2-3 weeks. For Covid-19 patients, some of them need 1 month of care ( Figure 2). . ECMO machine is connected to patients through cannula, placed in large veins in the legs, neck or chest, and pumps blood from the patient's body to an artificial lung (oxygenator) that adds oxygen to it and removes carbon dioxide. The ECMO machine then sends the blood back to the patient via a pump with the same force as the heart, to arteries (A) or veins (B).

Acro Ischemia Syndrome
The basement membrane of the skin is equal to the renal membrane, the ocular structures, etc., and it receives the same type of aggression by immunoglobulins, immunocomplexes and all inflammatory cascades [35]. Acro-ischemia syndrome can be observed in Covid-19 children and adults requiring ICU hospitalization. This syndrome includes toe and/or finger cyanosis, skin bulla and dry gangrene. D-dimer, fibrinogen, and fibrinogen degradation product (FDP) are frequently elevated, increasing progressively when Covid exacerbated ( Figure 3). Most of these patients are diagnosed with disseminated intravascular coagulation (DIC), receiving anticoagulation therapy (low molecular weight heparin). The association of respiratory and cardiovascular complications leads to a fatal prognosis [36]. Therefore, the existence of hypercoagulation status in critical Covid patients should be closely monitored. Dermatological lesions are observed in the face, hands and feet, like "frostbite", including redness at the level of the fingers, nose and ears, swelling, temporary pain which corresponds to what it is observed in winter sports. In addition to this pseudo-frostbite, other skin manifestations have been identified, such as the sud-den onset of persistent, sometimes painful redness, and urticarial eruptions ( Figure 4A-4D). The pathophysiology of these lesions is unclear but may include immune dysregulation, vasculitis, vessel thrombosis and neoangiogenesis [37,38].

Loss of Sense of Smell and Taste as Viral Infection Markers
Early single reports and surveys have suggested that gustatory and olfactory loss may be early symptoms associated with COVID-19 infection also in the absence of other known symptoms of the disease. The first large Multicenter European Study [46] reported that in a population of 417 mild-to-moderate COVID-19 patients 85% and 88% had smell and taste dysfunctions respectively with a significant positive association between the two symptoms.
Interesting the symptoms were persistent in 56% of patients over while still seeing a beautiful, "simple", mathematical structure tell-ing us analytically where the weaknesses of the virus could be [51][52][53].

Non-Invasive Ventilation (NIV) in SARS
High Flow Nasal Cannula (HFNC) and Facemask are in development for severe acute hypoxemic respiratory failure of COVID-19 patients [54]. Instead of mechanical ventilation, a recent clinical study [55] showed that HFNC, which targeted a flow ≥ 50 L/min,

Therapeutic Plasma Exchange (TPE)
It is clinically estimated that 13% of Covid-19 cases are severe, and 6% are critical; the evolution can be acute respiratory distress In patients with COVID-19 pneumonia, high risk of thrombosis became a current issue, and D-dimer levels indicating fibrin degradation products (FDPs) in the plasma were found as a predictor for mortality [60,61]. Although unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) decrease the production of FDPs by inhibiting factors Xa and II, they cannot contribute metabolization of existing FDPs. Furthermore, FDPs cannot be filtered by known cytokine filters because of their molecular weight (minimum 240 kDa). FDPs can be removed by therapeutic plasma exchange. TPE might be proposed as supportive/adjunct therapy for the management of COVID-19 with severe pneumonia, cytokine storm, and multiorgan failure [62,63].

Structures of Coronaviral Proteins by Synchrotron Radiation Diffraction (Polytechnic University of Ancona, Italy)
Some determinations of 3D structures at atomic level of proteins and complexes, useful for discovery of drugs and vaccines, were performed by using the diffraction of X-Ray Synchrotron Radiation (64). Synchrotron light is created when centripetal acceleration is applied to an electron beam ( Figure 6A). The electrons inside a heated metal are excited enough to escape from the surface in a process known as thermionic emission, then they are directed by the linear accelerator or LINAC. This fits into the Booster ring, which adopts magnetic fields to force the electrons to travel in a circle. Microwaves are used to add even more energy to the electrons.
The radiation is produced in the Booster ring, having a multi-sided shape (similar an octagon). A charged particle in motion submitted to a magnetic field perpendicular to its trajectory experiences a force. If the field is constant, the particle describes a circular motion ( Figure 6B). was also investigated, identifying residues in the SARS-CoV-2 RBD that are essential for ACE2 binding and helping the future identification of cross-reactive antibodies [70]. are also initial symptoms useful for covid diagnosis and patients' isolation [46][47][48]. The goal is avoiding epidemic spreading.
Clinical evolution of patients allows to consider COVID-19 as a new hematologic disease [72]. Curative anticoagulation in these patients prevents endothelial lesions. Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients [25][26][27]. Coronavirus antibodies can disappear after 2-3 months of disease. Assessment of antibodies levels after recovery showed that patients cured of SARS-CoV-2 are only immunized for several weeks, thus antibodies remain in patient's serum for at least 40 days after the onset of signs. These antibodies persist active and dynamic to prevent reinfection for at least three months in 90% of cases [73]. This rate begins to decline after twenty to thirty days, most subjects tested lose 50% of active antibodies after six months. Afterwards lymphocytes develop and take in charge immunity, the so-called "memory" cells in turn would be ready to produce antibodies in the event of recontamination. Further research should clarify this subject. Exosomes could be a therapeutic option in coronavirus disease [74,71].