Figure 1. Natural history of COVID-19 infection, from incubation to critical disease.
Incubation phase is reported as variable between 0-14 days,
3,
5 then first clinical symptoms, upper respiratory tract infection (URTI) (rhinitis, anosmia and agueusia) and/or lower respiratory tract infection (LRTI)(cough, fever, thoracic pain and “happy hypoxia”) are observed. The second phase is
characterised by persistent LRTI (Lower respiratory tract infections) and leads to medical consultation and/or hospitalization. In the second phase of the disease,
abnormal blood parameters involved in the severity of the disease can be observed. Then,from day 9 to 12 after the onset of symptoms (phase III), sudden deterioration caused by the cytokine storm syndrome and pulmonary (macro and micro) embolism can lead to acute respiratory distress syndrome (phase IV) and death. Therapeutic strategies have been proposed for each stage of the disease.
6 At the time of incubation, prophylaxis with hydroxychloroquine has showed mitigated results depending on the dosing.
7 In the first and second phase of the disease, hydroxychloroquine plus azithromycin and zinc showed promising results
6,
8,
9 Anticoagulant prophylaxis should be used from phase II to IV, since it was shown to reduce both, the cytokine storm and the risk of thrombotic complications.
10Tocilizumab therapy may be useful in the third phase of the disease at the time of cytokine storm syndrome. Oxygen and intensive care therapy are used in the third and fourth phases of the disease.
Figure 2. Extrapulmonary manifestations of COVID-19 identified in severe and critically ill patients (percentage in hospitalized patients).
Extrapulmonary manifestations are observed in one quarter to one third of hospitalized patients. Four mechanisms are involved in the pathophysiology of multiorgan injury: i. the direct viral toxicity, ii. Dysregulation of the renin-angiotensin-aldosterone system (RAAS). iii. Endothelial cell damage and thrombo-inflammation and iv. Dysregulation of the immune system and cytokine release syndrome that causes disseminated organ injuries. Histopathological analyses identified the virus in the lung, the kidney, the myocardium, the brain, and the gastro-intestinal tissues.
12-
18 The ACE2 and TMPRSS2 expression were confirmed by single cell RNA seq in epithelial cells of these organs.16,19. The entry of SARS-CoV-2 via ACE2 receptor in endothelial cells of arterial and venous capillaries generates the recruitment of innate immunosuppressive cells with pro-thrombotic features (“viral sepsis” like syndrome), favoring micro- and macro- thromboembolic events (stroke, infarction, myocarditis and pericarditis).
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