COVID-19: An acute onset of viral-induced HMR/D
Phase-I: Hypoxia
SARS-CoV-2 binding to host cell surface receptors (i.e., ACE2, NRP1) is an initial step in the pathogenesis of COVID-19. Viral binding to ACE2 receptors on alveolar epithelia affects renin-angiotensin-aldosterone system (RAAS), subsequently lowers the blood pressure and lung function of an infected host. The reduced O 2 transport (hypoxia) triggers a mitochondrial metabolic reprogramming/ dysregulation by alteration of OXPHOS/TCA cycle and activation of anaerobic glycolysis, known as the ‘Warburg Effect’. This shift in mitochondrial energy metabolism (or ATP synthesis) is regulated by different cellular systems, of which the hypoxia-inducible factor (HIF)-1α plays a critical role. HIF-1α induced HMR/D affects the available host energy reserves for immune function. Ultimately, HIF-1α could impair host immune response, exacerbate inflammation, and inflict tissue damage. SARS-CoV-2 could evade host innate immunity and sustain intracellular viral replication cycle by altering the mitochondrial dynamics through targeting the mitochondria-associated antiviral signaling (MAVS) pathways. HIF-1α could up-regulate vascular endothelial growth factor (VEGF) to cause vascular leakage, damage epithelial barriers of alveoli and vascular endothelia. Therefore, phase-I of COVID-19 is considered a hypoxia-induced blood disorder, associated with FeRD and HMR/D.
Phase-II: Hyperferritinemia
Severe COVID-19 is characterized by hyper-inflammation with elevated proinflammatory cytokines that stimulate synthesis of both ferritin and hepcidin, which ultimately mediate FeRD. The iron homeostatic imbalance is reflected by high iron content in reticuloendothelial cells and elevated serum ferritin levels. When the iron-binding capacity of transferrin (TF) in the blood exceeds, free iron is released into plasma in a redox-active state known as the labile plasma iron (LPI), which forms tissue damaging free radicals and cause fibrosis. A ferritin/TF ratio >10 predicts a five-fold higher risk of ICU admission and an eight-fold higher risk for need of mechanical ventilation in COVID-19 patients. A dysfunctional hyperimmune response in tandem with macrophage activation could trigger hyperferritinemia, and ‘cytokine storm’ or cytokine release syndrome (CRS). CRS is characterized by fulminant activation of large number of lymphocytes that release inflammatory cytokines and result in severe tissue damage with multi-organ dysfunction syndrome (MODS). Hyperferritinemia, and FeRD collectively play a detrimental role in disease progression of COVID-19. The phase-II of COVID-19 is considered a wide spectrum hyperinflammatory disease, amplified by CRS from HMR/D.
Phase-III: Thromboembolism
Acute COVID-19 due to severe iron toxicity from oxidized iron could modulate several systemic pathways of coagulation cascade and cause thrombocytopenia. SARS-CoV-2 could invade blood vessels, induce vascular damage, and activate systemic thrombotic events with severe to fatal coagulopathies in COVID-19 patients. Such coagulopathies (or blood clots) are characterized by elevated procoagulant factors such as fibrinogen, along with high levels of D-dimers linked to increased case fatality rate (CFR). Hematological parameters such as anemia of inflammation (AI), reduced numbers of peripheral blood lymphocytes and eosinophils with increased neutrophil-to-lymphocyte ratios are recognized as major risk factors. This clinical phase along with hypoxia, could exhibit signs of hemolysis with release of heme proteins and accumulation of free heme. The hemolysis-derived heme could initiate inflammatory OxS that may cause microvascular thrombosis, organ ischemia and MODS in severe COVID-19 cases.
COVID-19: Clinical Spectrum
Viral load usually reaches its peak at symptomatic onset during the initial weeks of infection and is detectable by reverse transcription polymerase chain reaction (RT-PCR) within the first week of infection. An infected person is estimated to carry about 10⁹ to 10¹¹ virions at the peak of infection. The incubation period, defined as the time from infection to the onset of signs and symptoms, is a crucial index of epidemiology in understanding the pathobiological spectrum of acute SARS-CoV-2 infection, and PASC. The median incubation period for COVID-19 was estimated to be 5.1 days, and 99% (101 out of every 10 000 cases) will develop symptoms after 14 days. The median viral clearance time (VCT, RT-PCR negative) is 24 days. The VCT was 30 days among severe COVID-19 patients and 39 days among ICU-admitted patients.
About 80% of SARS-CoV-2 infections are asymptomatic to mild, and many COVID-19 patients recover within 2 to 4 weeks. However, the onset of severe pneumonia and critical MODS may occur in 15% and 5% of patients, respectively, which could last for 3 to 6 weeks. COVID‐19 patients may develop a wide range of clinical manifestations, including severe acute pulmonary disease, hepatic dysfunction, kidney injury, heart damage, gastro-intestinal, skeleto-muscular, pancreatic, and sensory (smell and taste) dysfunctions. SARS-CoV-2 inflicts severe respiratory symptoms with a substantial pulmonary dysfunction, which may include severe arterial hypoxemia (low blood oxygenation) resulting in acute respiratory distress syndrome (ARDS). SARS-CoV-2 could also impair cardiovascular metabolism in COVID-19 patients. The viral S-protein and the ORF9b subunits could alter human cardiomyocyte metabolism and significantly impair contractile function of the heart. COVID-19 has a major impact on heart health and may lead to myocarditis or cardiac failure. In COVID patients, the SARS CoV-2 infection could also reach the brainstem and induce cerebral lesions due to HMR/D. Several neurological manifestations including cognitive dysfunction are often described in these cases. Thus, SARS-CoV-2 infections impact not only the respiratory organ but also inflict various bodily damage leading to shock and MODS.