Most clinicians in our setting rely on laboratory confirmation of SARS-CoV-2 before any clinical decisions can be made. That would have been the case in the given case series especially that confirmatory diagnosis of COVID-19 is only made with RT-PCR. As indicated by the clinical scenarios above, most of our patients had severe hypoxia which was not consistent with the clinical presentation. What has been observed so far is that the physiological and pathological changes characterising COVID-19 involve an inflammatory response and a prothrombotic state (4,5,7). We, therefore, suggest the following proxies for COVID-19 diagnosis using available scientific evidence.
1. Chest x-ray and pulse oximetry
Some COVID-19 patients appear to have a disconnect between the extent of hypoxaemia and signs of respiratory distress which is termed “happy hypoxia” (8,9) as was the case with patient 3. Dhont et al reported that before the onset of dyspnoea; defined as laboured breathing as opposed to tachypnoea which is fast breathing, various mechanisms are involved which causes an imbalance between pulmonary ventilation and capillary blood flow. Proposed mechanisms include; intrapulmonary shunting, loss of perfusion regulation, impaired diffusion, and most importantly the emerging hallmark of COVID-19, intravascular microthrombi (9).
It has been noted that lung compliance is preserved in hypoxic COVID-19 on ventilation atypical of acute severe respiratory distress syndrome (ARDS) (10,11). Microthrombi occurring in the pulmonary vasculature in COVID-19 has been postulated to be responsible for hypoxia as it alters lung perfusion, impairs gas exchange and results in loss of oxygen transfer capacity of haemoglobin. It is further proposed that if these processes are not identified and managed early through anti-inflammatory medication, lung recruitment strategies such as awake prone ventilation and anticoagulation (9,12), they may lead to rapid clinical deterioration requiring more expensive interventions such as invasive ventilation and often lead to poor clinical outcomes as was noted in our first patient.
However, to identify these processes accurately, extensive tests are required. These tests, among many, include; assessing the pressure of arterial oxygen (PaO2) and carbon dioxide (PaCO2) dissolved in the blood, blood pH, lung diffusion capacity (DLCO), angiotensin II levels, coagulation profiles, high-resolution CT-imaging, Ventilation/Perfusion (V/Q) scans and multiple inert gas elimination technique (MIGET) (9,13). However, these tests are scarce in Zambia and likely mirrored in other resource-limited settings. We propose that using pulse oximetry which measures the SPO2 might be a significant intermediary in identifying COVID-19 presenting as “happy hypoxic”. Happy hypoxia and ARDS can accurately be identified by pulse oximetry and the Kigali criteria respectively (14). This was evidenced in our cases where management was instituted immediately without hanging tight for the long procedures of test results.
2. Thrombotic events and Procoagulation profiles
Studies have shown an increase in thrombotic events such as strokes, pulmonary embolism and myocardial infarction in COVID-19 patients (5,15–17). Additionally, a study by Ackermann et al showed that the lungs of patients who died from SARS-CoV-2 infection had 9 times more thrombi formation when compared to the lungs of patients with influenza (18).
SARS-Cov-2 infects the human cells using the angiotensin-converting enzyme 2 (ACE 2) receptors (19,20). The receptors are expressed in the lungs, heart, kidneys, intestines and endothelial cells. SARS-CoV-2 primary entry point is through the respiratory tract but may cause widespread infection in severe disease. The ACE 2 receptor acts as a catalytic site for the ACE 2, an enzyme that degrades angiotensin 2 (ATII) to angiotensin-1,7 (AT-1,7) (13,21). ATII cause vasoconstriction, increase cardiac contractility and stimulate the production of aldosterone among other neurohormonal functions. However, there is scientific evidence that ATII also promotes inflammatory response by stimulating NADPH-oxidase; an enzyme responsible for the generation of the reactive oxygen species (ROS) such as super oxides (22). Super oxides can induce endothelial cell damage and activate polymorphonuclear cells (PMNs) recruiting them to the site of injury (23,24). Chemical mediators produced by the polymorphonuclear leukocytes further cause cellular damage creating a vicious inflammatory cycle (24,25).
On the other hand, AT-1,7 causes vasodilatation, inhibits oxidative cellular damage by blocking NADPH-oxidase and stimulate the production of nitric oxide (NO) via nitric synthase pathways (7). All these cellular processes have a protective effect on the endothelium by counteracting effects of ATII. It has been theorised that in COVID-19, the SARS-CoV-2 binds to the ACE 2 receptor inhibiting its catalytic effect (20,21). This downgrades the function of AT-1,7 while there are unrestrained effects of ATII induced endothelial injury (26). Platelets tend to adhere faster to injured endothelium due to the excess release of von Willebrand factor (vWF); a glycoprotein which facilitates platelet adhesion and aggregation as a response to ECD occurring due to injury (27). ECD from different conditions, including COVID-19, causes high levels of circulating multimeric endothelial-associated vWF and factor VIII (17). The multimeric form of vWF performs its hemostatic functions in vivo by binding to factor VIII, to platelets surface glycoproteins and certain elements of connective tissue resulting in widespread thrombus formation(28,29). This may explain why thrombotic events are seen in COVID-19 patients including our patient 4. We, therefore, propose that thrombotic events such as stroke, pulmonary embolism, myocardial infarction, deep venous or arterial thrombosis should have samples collected for SARS-CoV-2 testing, while anticoagulation therapy or thrombolytic therapy, if possible, must be instituted immediately.
Also, most severe cases of COVID-19 patients with thromboembolic pulmonary complications have been shown to present with a pro-coagulant profile, elevated D-dimers and angiogenesis (18). Increased circulating D-dimer concentrations and high cardiac enzymes even with normal fibrinogen levels and platelets are key early features of severe pulmonary intravascular coagulopathy related to COVID-19 (30). This has been attributed to thrombosis with fibrinolysis and stress on the myocardium.
A study by Ranucci et al in critically ill COVID-19 with ARDS indicated procoagulant state with high clot strength predominantly from fibrinogen and platelet contribution (16). The study also noted a positive correlation between interleukin-6 levels and fibrinogen levels although this was ameliorated with anticoagulation therapy. IL-6 has been noted to induce synthesis of tissue factor, fibrinogen, and increased platelet production (31). Tissue factor also triggers thrombin formation. The interplay of these factors is generally responsible for a procoagulant state.
The procoagulant state indicated by elevated D-dimers ( ≥2.0 µg/mL) as was the case with patient 4, factor VIII and vWF have also been associated with poor outcomes in COVID-19 patients (32,33). We suggest that enhancing D-dimer testing in a hospital setting can be used to assess individuals at high risk of having COVID-19, and assist in the therapeutic interventions and prognosis of COVID-19.
From our case scenarios, the worst outcome was noted with patient 1 who had diabetes and hypertension. There is little epidemiological evidence to show that people with diabetes have a higher risk of getting COVID-19, although diabetic patients with hyperglycaemia have been shown to have worse outcomes (34). However, there has been a notable trend of new-onset diabetes, as well as complications such as diabetic ketoacidosis (DKA) in pre-existing diabetes in COVID-19 hence the credence that the relationship between COVID-19 and diabetes may be bidirectional (35–37).
An impaired immune response like the pre-existing proinflammatory state is postulated to reduce viral clearance and worsen macrophage activation syndrome (MAS), also known as a cytokine storm (38,39). Scientific evidence indicates a strong association between diabetes mellitus and abnormal secretion of proinflammatory mediators such as interleukin 6, tumour necrosis alpha (TNF-a) and interferons (34,40,41). The procoagulant state has also been noted to be significantly higher in COVID-19 pneumonia with diabetes compared to those without diabetes (34). Diabetes also tends to commonly occur with other conditions known to cause oxidative stress such as hypertension and obesity. The factors outlined above can increase the virulence of SARS-CoV-2 and thus may be responsible for worse outcomes and are also implicated in the development of hyperglycaemia, either worsening or new-onset.
Furthermore, studies have shown that some viruses, including the 2003 SARS-CoV are diabetogenic (42,43). More scientific evidence is needed as to whether this holds for SARS-CoV-2 and may explain new-onset hyperglycaemia seen in some COVID-19 pneumonia, especially that ACE-2 receptors are also widely expressed in endocrine tissues including pancreatic beta cells (44). Although we could not do blood glucose in other patients, the case of patient 1 as highlighted the need. We propose routine glucose check for hospital admissions and urgent test for SARS-CoV-2 in those with new-onset or worsening hyperglycaemia.