Hypoxia is a condition where the tissue is not oxygenated adequately to maintain an adequate homeostatic state. Hypoxia results from inadequate oxygen delivery to tissues. This inadequate due to low blood supply or low blood oxygen content (hypoxemia). Happy hypoxia or silent hypoxia syndrome is a condition when oxygen levels in the tissues are low without shortness of breath or dyspnea.

Hypoxia is a hazardous condition. Without adequate oxygen, the brain, kidneys, and various organs can be damaged within minutes after symptoms begin. If the blood's oxygen level continues to decrease, these organs can die, which is life-threatening.

In COVID-19 patients, the hypoxemia severity is independent of hospitalization mortality, but it remains an essential predictor that patients are at risk of requiring intensive care.

Pathophysiology of Happy Hypoxia Syndrome in COVID-19 Cases
Using Pulse Oximeter to Detect Happy Hypoxia 
Image source: https://www.npr.org

Pathophysiology of Happy Hypoxia in COVID-19

The cause of silent hypoxemia in COVID-19 is still not fully understood. There are currently several explanations regarding the pathophysiology of this condition: 
  • intrapulmonary shunting, 
  • loss of normal lung perfusion regulation, 
  • intravascular microthrombus, 
  • impaired pulmonary diffusion capacity, 
  • and the effect of viruses on hypoxia-sensing neurons.

a. Intrapulmonary Shunting

Arterial hypoxemia in SARS-CoV-2 infection is mainly due to V / Q (ventilation/perfusion) mismatch, reflected in the P (A-a) O2 gradient increase. Viral infection causes localized interstitial edema of the lung tissue structures (ground-glass opacities and consolidation on CT scan of the lungs), resulting in loss of surfactant and increased pressure. Then, the alveolar will collapse but still get blood flow from the cardiac output. This is what underlies the V / Q mismatch.

Over time, increased edema adds weight to the lungs and results in alveolar collapse and dependent atelectasis. This combination will further increase the shunt fraction and decrease oxygenation, which cannot be entirely corrected by increasing FiO2.

b. Loss of Pulmonary Perfusion Regulation

Using dual-energy CT, Lang et al. assessed the characteristics of lung perfusion in COVID-19 patients. They found that the relative failure of the hypoxic pulmonary vasoconstriction mechanism (constriction of small intrapulmonary arteries in response to alveolar hypoxia) causes the persistence of large blood flow to the non-ventilated / aerated alveolar pulmonary.  

It is unclear whether this is triggered solely by releasing endogenous vasodilators such as prostaglandins, bradykinins, and inflammatory cytokines. In the pathophysiology of COVID-19, there is a disruption in the renin-angiotensin system (RAS) with decreased levels of angiotensin-converting enzyme 2 (ACE2). This disruption plays a role in the regulation of pulmonary vasoconstriction.
Intravascular microthrombus

One of the primary pathogenesis of COVID-19 is endothelial damage due to cytopathic virus infection in capillary endothelial cells that express ACE2. Intravascular microthrombus results from procoagulant imbalance and fibrinolytic activity. 

Procoagulant activity occurs due to blood clots activation or inhibition of plasminogen activation and fibrinolysis. The activation of blood clots mediated by the complement system. Inhibition of plasminogen activation and fibrinolysis due to increased plasminogen activator inhibitors (PAI-1 and PAI-2). The increase in plasminogen activity is induced as an acute-phase protein under the influence of IL-6.

Additionally, in severe COVID-19 patients, disseminated intravascular coagulation (DIC) is mediated by the endothelial release of tissue factors and activation of clotting factors VII and XI.
Lung autopsy results of severe COVID-19 patients show fibrin deposition, diffuse alveolar damage, and thickening of the vascular walls. A complement-rich microthrombus can also occlude pulmonary capillaries and a larger thrombus that can cause pulmonary artery thrombosis and pulmonary embolism.

c. Impaired diffusion capacity

SARS-CoV-2 infection in alveolar type II cells will be followed by cell destruction mediated by an immune response (virus-linked pyroptosis). Alveolar epithelial cell damage and procoagulant conditions will cause debris consisting of fibrin, dead cells, and complement activation products (known as hyaline membranes) cover the basement membrane. And then that causes the diffusing capacity for carbon monoxide (DLCO). 

In the absence of hypoxic vasoconstriction and hyperdynamic pulmonary circulation, there is not enough time for erythrocytes to equilibrate oxygen uptake, thereby increasing the P (A-a) O2 gradient and exercise-induced arterial hypoxemia (EIAH).

A report by Xiaoneng Mo et al. confirms a decrease in DLCO in COVID-19 patients upon discharge from the hospital. DLCO disorders' prevalence was related to the degree of disease severity (30.4% for mild disease, 42.4% for pneumonia, and 84.2% for severe pneumonia).

d. Effects of Viruses on Hypoxia-Sensing Neurons

There is a hypothesis that damage to afferent hypoxia-sensing neurons in COVID-19 patients occurs as a direct effect of SARS-CoV-2 on the mitochondria or neuron fibers. However, damage to hypoxia-sensing neurons can also occur as part of a cytokine storm triggered by SARS-CoV-2 infection.
It should also be noted that the receptor cell responsible for SARS-CoV-2 infection, namely ACE2, is also expressed on the carotid body, which is one of the sense oxygen chemoreceptors that can be damaged in the infection process.

Although it still needs to be further proven, this hypothesis's physiological basis can play a role in disrupting afferent chemosensors' input to the brain stem's respiratory center area.

The findings of silent hypoxemia in COVID-19 suggest that perfusion optimization and V / Q mismatch improvement, including avoidance of microthrombus formation and fibrin deposition, should be part of the current therapeutic strategy COVID-19.

The administration of thromboprophylaxis in COVID-19 patients, especially those with high D-dimer levels at admission to hospitalization, needs to be considered. The use of monoclonal antibodies could potentially be used to treat systemic prothrombotic complications and correct the cytokine storm caused by SARS-CoV-2.

Monoclonal antibodies that can be used, namely IL-6R anti-receptor antibodies (such as tocilizumab or sarilumab) or IL-6 anti-receptor antibodies (such as siltuximab), 

Oxygen supplementation is still the first step in oxygenation. However, in patients with possible refractory hypoxemic respiratory failure, an appropriate time for intubation support must improve oxygenation, transpulmonary pressure, and open collapsed alveoli.

With reports that silent hypoxemia cases can lead to the use of a ventilator and even death.  It is worth considering changing the management strategy for asymptomatic COVID-19 patients, such as: 
  • pulse oximeter examination, 
  • blood gas analysis, 
  • and D-dimer examination during the initial screening and monitoring in isolation.

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