About the author: Saurabh Mandal is a Ph.D. Student at Manipal Institute of Regenerative Medicine (MIRM), Manipal Academy of Higher Education (MAHE), Bangalore. He has completed his Master of Science (M.Sc.) in Biotechnology from VIT University, Vellore. After completing his M.Sc., he worked as a project assistant for some time at the Institute of Nano Science and Technology (INST), Department of Science and Technology (DST) institution, Mohali. Now, at MIRM, Saurabh is carrying out his doctoral research. He broadly works in the area of cardiovascular diseases and breast cancer stem cells (bCSCs).
His Ph.D. research focuses on the generation of functional cardiomyocytes; he investigates small molecules, and microRNAs role in the differentiation of Wharton’s Jelly derived mesenchymal stem cells (WJMSCs) into functional cardiomyocytes. In addition, he is evaluating various microRNAs as a molecular therapeutic agent against cancer drug-induced cardiotoxicity. In the area of bCSC research, he has reported the potential anti-cancer effect of Wharton’s Jelly derived mesenchymal stem cells (WJMSCs) against bCSCs. He has also published a report describing the anti-CSCs properties of ursolic acid and miR-499a-5p role in bCSCs.
India faces an aggressive second wave of Covid-19 and reporting the world’s highest number of new Coronavirus positive cases for the last few days. However, the second wave is grappling the country with asymptomatic cases. Thus, experts suggesting the world’s most extensive vaccination program need acceleration.
In India’s new Covid-19 cases, the most emerging symptom is dropping down of patient’s blood oxygen level, and they are gasping for breath. The sudden surge in Covid-19 cases has increased medical oxygen demand across the country. The pandemic has exposed the deteriorated country’s health infrastructure, and now the news of the non-availability or scarcity of oxygen cylinders in Indian hospitals has flooded the internet, which added to panic among citizens. The government and administration are trying hard to manage but experiencing various challenges to meet the increased demand on time.
In this scenario, a critical question arises that why India’s Covid-19 second wave showing low blood oxygen level as a severe complication?
It is well-known that Coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the human respiratory system. The Coronavirus affects the lungs and the alveoli, which transfer oxygen to the red blood cells through a blood vessel or capillaries. The virus damages the wall and lining of the alveolus, and the debris from the damaged part gets deposited around the wall and thickens it. Such vascular constriction hinders the oxygenated blood flow, leading to decreased oxygen supply to the different parts of the body. Further, such damage fills the air sac with pus or fluid, which causes inflammation and leads to severe pneumonia.
An Overlooked Clinical Entity
On seeing the sudden surge in cases with low blood oxygen, it can be anticipated that hypoxemia is influencing the virus infection. Hypoxemia is made with three words hypo means ‘low,’ ox means ‘oxygen,’ and emia means ‘blood.’ In general, hypoxemia is a condition when oxygen is deficient in the blood. In hypoxemia, the patients may not find difficulty breathing, but the pulse oximeter result finds that their oxygen level is low. The normal level of oxygen dissolved in blood ranges between 95-100%, and if the level decreases to 92% or below then, it becomes serious. At this stage, the doctor decides to provide supplemental oxygen.
After searching in the scholarly database Pubmed and Google scholar using the combination of keywords such as, ‘Hypoxia,’ ‘Hypoxemia,’ ‘Silent Hypoxemia,’ ‘Covid-19’, ‘India’; found few published reports, summarised in the table,
|Hospital||Date and Time||Patients Number||Hypoxia/ Hypoxemia complication||Drugs used during treatment||References|
|Lokmanya Tilak Municipal Medical College, Sion, Mumbai||31st March to 5th July 2020||269||Patients with Persistent hypoxia (saturation 94% or less)||Tocilizumab||DOI: 10.1186/s12879-021-05912-3|
|RG Kar Medical College and Hospital, Kolkata, West Bengal||23rd April 2020||1||Patient’s oxygen saturation was 78%||Hydroxychloroquine Azithromycin||DOI:10.1136/bcr-2020-|
|Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi||8th May to 3rd July 2020||35||Nearly half (51%) of patients with hypoxemia||NA||DOI:10.4081/monaldi.2020.1568|
|Deenanath Mangeshkar Hospital and Research Center, Pune, Maharashtra, India||22nd March to 31st May 2020||134||77.2% patients having shortness of breath||Different combination of hydroxychloroquine, methylprednisolone, colchicine, etoricoxib, and tocilizumab||DOI: 10.5005/jp-journals-10071-23599|
The clinical study clearly describes that low blood oxygen in patients was observed during the first wave also. Indian medical fraternity has possibly overlooked hypoxemia complication and seems failed to think that what if patients with low blood oxygen increases like a wildfire.
The vicious cycle of Infection
Scientific evidence has demonstrated that once the SARS-CoV-2 virus infects the body cells, it stimulates hypoxemia in the cellular microenvironment, which activates a key transcriptional factor, Hypoxia-inducible factor-1 (HIF-1). The activated HIF-1 upregulates the expression of the Angiotensin-Convertase enzyme 2 (ACE2) receptor. This ACE2 is the crucial receptor through which the virus enters into the human cells and infects.
The hypoxemia-regulated HIF-1 modulates the blood coagulation factors such as Tissue Factor and Plasminogen activator inhibitor-1 (PAI-1), Tissue factor pathway inhibitor (TPFI), thrombomodulin, and protein S, which ultimately leads to the coagulation while inhibiting anticoagulation. These results emphasized that hypoxemia drives microvascular thrombosis, i.e., forming a blood clot in the lungs and other vital organs in Covid-19 patients, resulting in inflammation and finally causing lung injury and respiratory damage.
Besides HIF-1 activation, hypoxemia was found to elicit immune cells, macrophages to overproduce pro-inflammatory cytokines such as tumor necrosis factor (TNF), Interleukin-6 (IL-6), Interferon-gamma (IFN-γ), and Interleukin-1b (IL-1b), which is also known as ‘Cytokine storm’. And these pro-inflammatory cytokines are further responsible for causing lung cell damage.
By this mechanism, hypoxemia causes lung damage and deteriorates the respiratory system, leading to low oxygen in the blood. Overall this is the main reason behind the breathing problem observed in patients, thereby indicating the crucial role of hypoxemia in the progression of Covid-19 infection.
It is essential to understand that the way hypoxemia influences Covid-19 progression is the same as it regulates many other diseases such as cancer, cardiovascular diseases, neurological disorders, etc. So, it can be estimated that even after recovery, hypoxemia in Covid-19 patients could unexpectedly complicate the body’s physiological processes.
The way to go further
Researchers and doctors immediately need to (a) begin hypoxemia profiling of the patients and (b) establish intermittent hypoxia/hyperoxia training (IHHT) to mitigate the hypoxic effect. The hypoxemia profiling will comprise the change in hypoxia/hypoxemia-associated gene expression due to low oxygen level during Covid-19 infection. This will help the researchers and doctors to figure out its impact on overall biological processes. Generally, the gene expression analysis can be carried out by the Real-time Polymerase Chain Reaction (RT-PCR) and RNA sequencing.
Next, IHHT is a treatment that uses controlled and dosed hypoxia exposure as the therapeutic method. The treatment consists of normoxic and hypoxic air exposure, and each exposure is carried out for 3-10min. The procedure can be repeated several times at different time points over a day. A device known as a ‘hypoxicator’ is being used to carry out the process. The treatment compensates for the disruption caused due to low oxygen intake, ameliorates the alveoli functioning, and tunes the oxygen transport system to primarily improve the breathing issue.
However, in this situation, oxygen level measurement using a pulse oximeter at least three times a day in a home setting is necessary. Regular self-proning is highly recommended, which improves oxygen level.
After all, it is both the state and the central government’s duty to ensure the availability of proper ventilation facilities with sufficient oxygen supply at all the hospitals throughout the country to deal with the Covid-19 patient’s complication. Moreover, hospital management also needs to analyze and prioritize their preparedness from the beginning rather than ramping up the needs in the hustle.
Primarily, India needs to speed up the vaccination process before hypoxemia jeopardizes the vaccine effectiveness. In addition, scientists need to keep tracking the virus mutation before mutation starts favoring hypoxemia, which then may cause further lung damage and ultimately results in a fatality.
Written by: Saurabh Mandal
Edited by: Vikramsingh Gujar