The Paradox of Happy Hypoxia in COVID 19

Ever since the human race has been exposed to the novel COVID 19 illness, newer and newer intriguing features of the COVID viral plethora are seen with each passing day. Many manifestations of the COVID 19 illness have been baffling and unexplainable to researchers currently. One such unusual presentation seen is ‘happy hypoxia’ or silent hypoxemia in a third of patients' total number. This review article is intending to put some light on the puzzling condition of happy hypoxia. We authors refer you through various theories postulated for happy hypoxia. It has definite clinical implications in the sense that it can be lifesaving if detected early and promptly in a COVID patient. We conclude that happy hypoxia or silent hypoxemia is a new entity and should be diagnosed with a high index of suspicion in COVID suspect patients in both young patients with no co morbidities and the elderly and diabetics. Diagnostic modalities like pulse oximeter should be widely used at hospitals and clinics and for self-monitoring by the patients at homes. Also, chest Xrays or HRCT imaging of the lungs is essential in the early stages to identify the early infective changes with compromised lung function and rule out this happy hypoxia. Also, further research is essential to find the exact ethologic of this subclinical though ominous prognostic entity.


INTRODUCTION
COVID-19, the disease caused by SARS CoV19 virus, has infected millions globally. It is a novel coronavirus with not much knowledge to clinicians and researchers. The disease varies from a short asymptomatic illness to a rapidly deteriorating fatal course or lingering symptoms of myalgia and weakness over many days. Many atypical patterns and findings are seen with this novel, notorious and potentially fatal COVID illness [1].
One such unusual presentation seen is 'happy hypoxia', or silent hypoxemia. In happy hypoxia, oxygen levels of the patient, become low. Still, the paradox is that the patient is unaware of it and may not complain of shortness of breath or any other complaint. The exact cause of such a condition is not yet proven, but many experts have put up their theories in this regard. The degree of hypoxemia and the patients' symptoms are mismatched in COVID 19, but very little is known about the lung hemodynamic and its path physiology. The normal saturation [2] of oxygen in the blood is 95 to 99%. Any level is lower than 94% can compromise lung oxygenation and hemodynamic. This is seen with any acute lung pathologies like pneumonia and can cause the patient to be breathless, called hypoxic (tissues) due to hypoxemia (blood).

Objective
The role of happy hypoxia in COVID-19 infected patients.

LITERATURE SURVEY
The various theories postulated are:  Shortness of breath is subjective and complained by the patient, so a clinician may not diagnose it unless the patient complains, which he may not, due to various reasons like a good lung reserve.  Fever or inflammation may alter the body's response to hypoxia: The chemo receptors in carotid bodies respond only to PaO2 alone and not to the SaO2. But there can be variation with temperatures [3].  There is an increased brain sensitivity to low carbon dioxide CO2 levels, but it is absent for oxygen levels in the blood in a hypoxic state. There can be mild changes in ventilation only when PaO2 begins to drop to less than 60 mmHg; this is only half of the patients. But if the PaO2 levels fall with an increase in carbon dioxide, the changes are not as dramatic as PacO2 [4] changes alone.  The ox haemoglobin dissociation curve may shift to the left because of the result of respiratory alkalosis (drop-in PaCO2), which is due to tachypnoea and hyperpnoea as a result of hypoxemia. During low PaCO2 periods, there is an increased affinity of the haemoglobin [5] for oxygen, and so there is increase inO2 saturation for PaO2. Hence SpO2 is very stable during very low levels of PaO2.But if the PaO2 levels fall with an increase in carbon dioxide, the changes are not as dramatic as with PaCO2 changes alone [6].  During the early phase of COVID-19, low saturation levels are not always accompanied by obvious respiratory difficulties. As there is a fall in oxygen levels in COVID-19 patients, there is no brain response till the oxygen falls to a minimum. The patient becomes breathless [7] at this time. Also, as seen in most patients, if there is very less carbon dioxide, it reduces the effect of lowering the oxygen level. So it is suspected to be COVID infection in sensing like the case of the sense of smell.  Deep breathing may be comfortable even when carbon dioxide levels are in the normal range. Normally as in lung infection and consolidation, the fall in SPO2 levels is seen along with pulmonary edema and effusion [8] and highCO2 levels in the lungs. This can cause breathlessness and not the low levels of oxygen in the blood.  According to recent research, the COVID virus acts by using the ACE2 receptor for entry in cells. The receptors are expressed in multiple organs like the heart, lungs, brain, and intestines. The brain cells, with the carotid bodies involved in sensing breathlessness, possess the ACE2 [9] receptors; hence, they may fail in sensing the hypoxia, which can lead to the phenomenon of happiness hypoxia.  Another reason could be clotting mechanisms and micro emboli like in cases of pulmonary embolism. It causes an increase in alveolar dead space and alveolar hypoventilation [10] if the minute volume remains unchanged. Impaired alveolar diffusion of oxygen will lead to 'silent hypoxia' and a consistent drop in oxygen saturation. Unlike other diseases, the body tries to compensate by increasing tidal volume and, to a lesser extent, the respiratory rate in COVID-19 disease. The rise in tidal volume may be achieved by increasing the aspiratory flow and consequently the work of breathing. The patient may be completely unaware of the increased respiratory load, and this is a state called 'happy hypoxia [11].  Two conditions can attenuate the feedback of the respiratory system to hypoxia. These are type 2 diabetes mellitus and old age, wherein the response is reduced to half, thus making them candidates for silent hypoxia.  Also, there is a vast difference in the lungs' respiratory drive and capacities in various patients, which could explain why a limited number of patients have this condition of happy hypoxia.

Happy Hypoxemia
In COVID-19 patients, the hypoxemia and mild respiratory discomfort has difference in opinion among the physicians who treats the patients in respiratory failure. Guan reported dyspnea in only 18.7% of 1099 hospitalized COVID-19 patients, despite low PaO2/FiO2 ratios, abnormal CT scans (86%) and common requirement for supplemental oxygen (41%). Happy or silent hypoxemia is not exclusively seen in COVID-19, but may also occur in patients with atelectasis, intrapulmonary shunt (i.e. arterio-venous malformations) or right-to-left intracardiac shunt. The adequacy of gas exchange is primarily determined by the balance between pulmonary ventilation and capillary blood flow, referred as ventilation/perfusion (V/Q) matching. In the initial phase of COVID-19, several mechanisms contribute to the development of arterial hypoxemia, without a concomitant increase in work of breathing. Rapid clinical deterioration may occur.

PROPOSED METHODOLOGIES
In a study of COVID 19 disease, only 19% had breathlessness; 62% of severe COVID disease and 46% of intubated, ventilated, and dead patients are present.
A study suggested direct interaction by COVID with the heme moiety of haemoglobin. It was postulated the theme levels in serum increase in COVID illness and act with dangerous iron ions (Fe3+), leading to inflammatory reactions and death of the cell [12] (ferroptosis). Hence serum ferritin is produced in large amounts, which bind these free ions to minimize tissue damage.
A study suggests that minimal thrombotic episodes may start forming in the lungs in the early stages of the disease due to inflammatory [13] reactions in their blood vasculature, starting the blood's clotting mechanism, thus restrict lungs from getting the required oxygen.
This scenario may be like the setting of COVID pneumonia [14] of Type L, with low elasticity but normal lung compliance. The other presentation is seen as Acute Respiratory Distress Syndrome (ARDS), a Type H phenotype. As opposed to this, [15] have presented a group of patients' with early intubation in the COVID course. This group had reduced compliance and a standard presentation in concordance with the Berlin criteria for ARDS [9].
Breathing has a central control by the medullar and centres of respiration of the midbrain (Fig.  1), which monitors the 'respiratory drive' to coordinate breathing with the other systems' varying demands. Also, breathing is affected by multiple sensory, pain, and mental affective stimuli via the cerebrum and hypothalamus's cortex.

RESULTS AND DISCUSSION
The key role of the respiratory drive is played by the chemo receptors, both central and peripheral. The difference in the carbon dioxide pressure is dissolved in the blood as PaCO2 is the most important determinant, which can act by shifts in pH at both the peripheral and central chemo receptors [1].
A report by Guan showed only 18.7% of 1099 hospitalized COVID-19 patients had dyspnoea despite low PaO2/Fi Orations, common requirements for supplemental oxygen (41%), and abnormal CT scans (86%), the Happy/silent hypoxemia is not only seen in COVID-19 infected diseases but also seen in patients with the intra pulmonary's hunt (i.e., arteriovenous malformations), a telecast is or right-to-left intra cardiac shunt. The difference primarily decides the requisite gas exchange between the lung ventilation and capillary blood perfusion, commonly known as the ventilation-perfusion (V/Q) matching. Intrapulmonary shunting, loss of lung perfusion regulation, intravascular micro thrombi can lead to COVID-19 with hypoxemia.

Clinical Implications
 Happy hypoxia is a harbinger of a morbid and downhill course of illness with oxygen therapy using mechanical ventilation, as shown in Fig. 2, so increased awareness and early identification of cases to avoid serious complications of COVID.  The symptoms include lung perfusion loss, anticoagulation, and anti-inflammatory process in the body.
 The loss of the immune system, loss of dead space with lung compliance, CO2 retention anxiety, and fatigue.  The sense of smell loss, anxiety, loss of hope, loss of sleep leading to hypoxia, and suppression of oxygen level are the common symptoms that the patients of COVID-19 infections face.  As shown in Fig. 2, it relies on diagnostic methods like pulse oximeter and imaging to screen patients than clinically diagnosing the hypoxia.

CONCLUSIONS
Happy hypoxia or silent hypoxemia is a new entity. It should be diagnosed with a high index of suspicion in COVID-19 suspects the patients, especially the young patients with no co morbidities. There are elderly and diabetic patients who also suffer from hypoxemia. It leads to many health diseases that affect cardiac and breathing problems. Diagnostic modalities like pulse oximeter should be used widely at hospitals and clinics, but self-monitoring of the hypoxemia patients should be done at home. So the increased awareness and early identification of cases are necessary to avoid the serious complications of COVID.
The symptoms include lung perfusion loss, anticoagulation, and anti-inflammatory process in the body. The effects of fatal COVID disease infection lead to a lower immune system, the loss of dead space with lung compliance, CO2 retention in the lung is reduced, anxiety and fatigue. The sense of smell loss, anxiety, loss of hope, loss of sleep leading to hypoxia, and suppression of oxygen level are the common symptoms that the patients of COVID-19 infections face. Chest Xray or HRCT imaging of the lungs is required in the early stages to identify the lung function complications with any novel disease of COVID 19. Much of the research is needed to find the exact ethologic of this subclinical though ominous prognostic entity.

CONSENT
It is not applicable.

ETHICAL APPROVAL
Ethical approval has been taken from Symbiosis International (Deemed University), Pune, Maharashtra, India.