COVID-19, ARDS & Cell-Free Hemoglobin – The Ascorbic Acid Connection

By Doris Loh 

At 1:00 am, GMT March 24, 2020, the entire world of 195 countries have reported confirmed cases of COVID-19.  379,000 people have been confirmed with the disease and 16,500 of the infected did not survive [54]. 

As the world lays hostage to the unexpected, exponential and disastrous spread of COVID-19 caused by the SARS-CoV-2 coronavirus, governments and central banks around the globe are making desperate, albeit almost futile attempts to stem the economic and financial hemorrhage in their countries. Economic stimulus plans reported to be as high as 16% of GDP (Germany) are being undertaken by countries stricken with COVID-19 to combat massive disruptions in the lives of people and businesses in all industries and sectors due to unprecedented containment measures [1, 2, 3]. 

As COVID-19 spreads, it is becoming apparent that the world was totally unprepared for the COVID-19 pandemic. Italy and other countries like France are struggling to meet exploding demands to treat the infected in the face of dwindling resources including protective gear, medical equipment, hospital space and manpower [55]. 

What makes COVID-19 uniquely damaging and different from other viruses such as influenza, is its ability to cause ARDS in up to 41.8% of infected patients in a relatively short amount of time, regardless of age and underlying comorbidity.  After onset of COVID-19, patients may start to experience dyspnea (shortness of breath) which could devolve rapidly into Acute Respiratory Distress Syndrome (ARDS) and end-organ failure [50, 56, 57]. 

Some of the responses from countries to contain COVID-19 range from blanket testing of the entire population in an area [4], to the severe limitation of testing [5].  The World Health Organization urges all countries to test ALL suspected cases as it believes COVID-19 is turning out to be the “GLOBAL HEALTH CRISIS of our time” [6].

Transmissibility & Containment

The reason why testing is emphasized by WHO, and also why countries like the United Kingdom have chosen to take an opposing course both stem from the fundamental understanding that COVID-19 has an extremely high transmissibility rate.  Countries that delayed containment measures experience exponential increases in confirmed cases.  Draconian measures implemented by the government of China that restricted the movements of close to half of its entire population effectively stemmed the spread of the virus in Hubei and other parts of China [9].  

{Source: Macintyre CR. On a knife’s edge of a COVID-19 pandemic: is containment still possible? Public Health Res Pract. 2020;30(1):3012000.]

The immediate crisis faced by healthcare systems all over the world, especially in countries who failed to implement timely containment measures is the total collapse of their ICU systems from the high demands in the treatment of ARDS during uncontrolled outbreaks.  

Lombardy, Italy has reported an unmanageable surge in patients who require ICU admissions. In Lombardy, 12% of total positive cases and 16% of all hospitalized patients needed ICU care [10]. The proportion reported is significantly higher than that reported from China where only 5% of total positive cases required ICU admission [11].  Countries like the USA are already projecting a tremendous shortfall in ICU care if the infection rate curve is not flattened.  

How Effective Are Containment Measures in Controlling Undocumented Transmissions?

In the USA, if 40% of the population become infected during a 6 month period, 98.8 million individuals in the USA will be infected and 20.5 million will require hospitalization. 4.4 million will need to be admitted to ICU. At current capacity, 1.3 million individuals will not have access to hospital beds and 295,000 individuals may not have access to ICU beds. If the infection rate is reduced by half to 20%, then the USA may be able to meet demands of patients during the crisis if concurrent measures of reduction of bed occupancy by 50% and the transmission curve can be extended from 6 months to 12 months [12, 13]. 

Beginning on March 21, 2020, lock down measures in the United States affected 70 million Americans in the cities of New York, Los Angeles, Chicago, San Diego and San Francisco [14].  Containment is probably the only effective measure to flatten the transmission curve at this moment because of the enormously high undocumented COVID-19 cases that have been responsible for the spread of disease. 

Ruiyun Li et al. reported on March 13th, 2020 that prior to the implementation of travel restrictions in China on 23 January 2020,  approximately 86% of all infections were undocumented.  Li et al. concluded that undocumented infections were the source for 79% of documented cases, thus providing a credible explanation for the rapid geographical expansion of SARS-CoV2 [15].  

The discovery of prolonged presence of SARS-CoV2 viral RNA in fecal samples for up to 47 days after first symptom onset in adults and children who tested negative for respiratory tract samples, raises the possibility of oral-fecal transmission, further complicating the task of controlling the infectious spread of COVID-19 [16, 17]. 

Asymptomatic transmissions have never been reported in past epidemics and pandemics.  This feature of COVID-19 is unique and unprecedented. 

The high transmissibility and the ability to cause ARDS in the infected is what makes COVID-19 the “GLOBAL HEALTH CRISIS of our time”  As of March 24, 2020 there is no officially recognized protocol for the prevention and/or treatment of COVID-19.  However, scientists around the world have reported success in the use of a pharmaceutical drug called chloroquine.

COVID-19, Chloroquine & Hydroxychloroquine – The Malaria Connection

The Federal Food and Drugs Administration (FDA) in the United States issued a statement on March 20, 2020 clarifying its position stating that there are at present, “no FDA-approved therapeutics or drugs to treat, cure or prevent COVID-19”, but the agency is actively collaborating with innovators in China, Japan, South Korea, Italy and USA to expedite solutions for the treatment of COVID-19 [18]. 

Even though several antivirals have been used successfully in countries like China, and Korea, chloroquine has shown the most promise.  Major hospitals in China are conducting clinical trials on the efficacies of chloroquine as treatment for COVID-19; while French and Korean physicians have also reported great success [25, 19, 20, 21, 22, 23]. 

Chloroquine and its less toxic derivative hydroxychloroquine have been used to treat malaria since the 1940’s [24].  The potential cytotoxic effects of this compound is a factor that requires due consideration before wide-scale implementation [20, 26, 27].  Why has an old antimalarial drug shown to be effective in the treatment of COVID-19?

COVID-19, Malaria & Haptoglobin – The Cell-Free Hemoglobin Connection

The Malaria parasite infects hosts by digesting hemoglobin and releasing an oxidized form of heme that is toxic for biological membranes. The malaria parasite can sequester these toxic free hemes to protect themselves.  The antimalarial drug chloroquine binds to the toxic free heme, enhancing its toxicity, while interfering with the ability of the parasite to sequester these toxic free heme. Thus the cytotoxic free heme accumulates to lethal levels in erythrocytes (red blood cells) that are infected by malaria parasites [28, 29]. 

In severe malaria, cell-free hemoglobin, being a POTENT QUENCHER OF NITRIC OXIDE, are often significantly elevated, causing hemolysis. The ability of cell-free hemoglobin to quench nitric oxide increases production of proinflammatory cytokines, endothelial activation of Nuclear factor-κB, cytoadherence and subsequent cellular damage. Cell-free hemoglobin increases in proportion to disease severity in malaria and its levels are often correlated to poor clinical outcome [30].  

Cell-Free Hemoglobin – The Cause of Acute Respiratory Distress Syndrome in COVID-19

Critically ill COVID-19 patients often develop acute respiratory distress syndrome (ARDS) where alveolar flooding (edema), interstitial inflammation and compression atelectasis, as well as increase in lung tissue and reduction in lung gas volume have been observed [33,34, 35].  ARDS patients have a 30-50% mortality rate due to an uncontrolled cascading event starting with pulmonary capillary endothelial cell permeability and leakage of fluid into the pulmonary parenchyma, only to be followed by cytokine storms marked by acute inflammatory responses [48]. 

COVID-19 patients who develop ARDS require intubation and invasive mechanical ventilation to assist difficulty in breathing because the increasing hypoxemic respiratory failure results in acute diffuse alveolar damage [36].   A paper released on March 18, 2020 reported that 41.8% of the 201 cohort patients with confirmed COVID-19 between Dec. 25, 2019, to Jan. 26, 2020 developed ARDS, and slightly more than half died [37, 56]. While another paper released on March 6, 2020 detailed the deranged coagulation functions in patients with SARS-CoV-2 compared to health controls [38]

It has been known for a long time that during critical illness, red blood cells undergo deleterious changes that cause hemolysis. 

It is only recently that the release of free heme is also associated with alveolar inflammation and coagulation in ARDS [39].  

Ever since 2015, the role of cell-free heme in nonhemolytic disorders such as acute lung injury and acute respiratory distress syndrome has been extensively documented. Free heme can scavenge nitric oxide (NO) up to 1,000 times faster than heme bound in red blood cells. The rapid loss of endothelial NO bioavailability leads to hypertension, coagulation and development of systemic inflammation [40]. 

The landmark study published by Shaver et. al in 2016 showed conclusively that elevated cell-free hemoglobin (CFH) in the air space is the essential driver of lung barrier permeability, inflammation and epithelial injury in human and experimental animal models of ARDS.  The most important revelation in that paper was the involvement of iron ions in the pathology of CFH in ARDS. Free heme with chloride centers only was able to increase alveolar permeability. Unlike heme with iron ions, chloride containing free heme were UNABLE to induce proinflammatory cytokine expression nor inflict epithelial cell injuries [41].  

The recent work of Habbeger et al. (2019) also demonstrated that cell-free hemoglobin in airspace of ARDS patients were definitely associated with lung epithelial injury, airspace inflammation and alveolar permeability [42].  

Why is Cell-Free Hemoglobin So Dangerous?

The term “Free Heme” may be somewhat of a misnomer because heme is extremely hydrophobic and cannot persist on its own under physiological pH conditions. Free heme actually describes heme that is NOT STABILIZED within heme proteins such as hemoglobin or myoglobin. Free heme is in the unstable FERRIC form that can be transferred to a wide range of heme acceptor membrane-based proteins and lipids, such as lipoproteins and albumin [31]. 

The problem is, when cell-free hemoglobin attaches to heme-acceptors, they initiate a cascade of free radical chain reactions, such as lipid-peroxidation in the case of attachment to lipoproteins. Oxidized lipoproteins are cytotoxic, and are one of the primary causes for free-heme cytotoxicity and inflammatory effects [31]. Cell-free hemoglobin in the vasculature leads to vasoconstriction and injury via nitric oxide scavenging and/or oxidative reactions of these free heme [32].

Just like the malaria parasite that can protect itself from the toxic effects of free heme, the human body also has an effective innate defense system that sequesters cytotoxic cell-free hemoglobin.  One of them is haptoglobin, an acute-phase protein that binds and removes free hemoglobin from the circulation [31]. By binding cell-free hemoglobin, haptoglobin prevents oxidative processes and inhibits the quenching of nitric oxide, thus significantly reducing toxicity of cell-free hemoglobin [43].

The Advantage of the Haptoglobin Hp2/Hp2 Polymorphism in COVID-19

There are two co-dominant alleles of the Haptoglobin (Hp) gene.  Hp1 and Hp2 have three genotypes: Hp1/Hp1, Hp1/Hp2 and Hp2/Hp2. Interestingly, a correlation with the severity of malaria has been observed where 74% of non-severe malaria patients have the Hp2/Hp2 genotype, while 31% of the carriers of this same Hp2/Hp2 allele exhibited severe malaria symptoms [44].  Malaria patients with Hp2/Hp2 alleles may have a distinct advantage where their haptoglobin binds cell-free hemoglobin more effectively.

But why do 31% of patients with the same genotype still develop severe malaria?  The question may be answered in another study that showed that the Hp2-2 genotype, when compared to the Hp-1 allele, had lower serum ascorbic levels if they did not supplement with adequate vitamin C [44].  What does ascorbic acid have to do with haptoglobin?

Even though haptoglobin can bind cell-free hemoglobin, to maintain these heme in a stable form, haptoglobin must depend on reductants (antioxidants) like ascorbic acid in plasma to maintain the free heme in a reduced, stable, unreactive ferrous  (Fe2+) redox state [31, 45].  

COVID-19 patients with the Hp2/Hp2 genotype may actually have a distinct advantage where their haptoglobin are more effective in binding cell-free hemoglobin than Hp1 carriers, as long as they have adequate antioxidants to supply reducing agents to haptoglobin.  These patients may also develop only mild symptoms and would not require hospitalization/intensive care during COVID-19 infections, providing they have adequate antioxidants in their bodies. 

However, not everyone is a Hp2-2 carrier, and by the time acute-phase haptoglobins are mobilized, the patient may already face extensive inflammation and lung damage from increased cell-free hemoglobin.  Therefore, the most attractive solution is the ability to prevent or reduce cell-free hemoglobin production as soon as the patient is aware of infection. 

As demonstrated by Shaver et al. in 2016, free heme without iron ion centers do not inflict as much damage [41].  Heme iron when maintained in the unreactive ferrous (Fe2+) redox state remains stable. Thus the key in controlling the deranged production of cell-free heme in the course of ARDS is to prevent the oxidation of heme to the ferric (Fe3+) redox states.  Even haptoglobin that sequesters free heme requires reducing agents to keep heme in the ferrous state. The most interesting aspect in this process is haptoglobin does not specifically require ascorbic acid as a reducing agent.  

The non-specificity of haptoglobin reductant requirement is possibly the main reason why the use of intravenous vitamin C in the treatment of COVID-19 has shown such remarkable success in speeding recovery and reducing mortality in critical COVID-10 patients. 

The Molecular Structures of Ascorbic Acid & Sodium Ascorbate – The REDOX Connection

The Shanghai Medical Association and the Shanghai city government now officially endorse the use of vitamin C for the treatment of COVID-19 infections.  Reports from the prestigious Ruijing Hospital in Shanghai, China documented the treatment of 50 cases of moderate to severe COVID-19 cases with high dose intravenous vitamin C (IVC).  Moderate cases were given IVC doses of 10 grams daily while severe cases as measured by pulmonary and coagulation status were given 20 grams daily for 7 to 10 days. None of the IVC patients died, and most IVC patients reduced hospital stay by 3-5 days [46].  

The undeniable success in the use of IV C to treat COVID-19 patients naturally begets the next logical question.  Can Vitamin C prevent or reduce the formation of cell-free hemoglobin that could mean significant reductions in systemic inflammation and extended lung damage in the infected?  

The answer depends on whether the vitamin C used is in the form of ascorbic acid or sodium ascorbate. 

The key to the stability of heme is the maintenance of iron ions in the ferrous (Fe2+) redox state.  In the ferric form, hemoglobin have been seen to lose heme to form free heme at substantially higher rates than ferrous forms [47].  

ARDS, Cell-Free Hemoglobin & Cytochrome b561 – The Ascorbic Acid Connection

Critically ill patients with ARDS are extremely difficult to oxygenate as their lungs are filled with fluid and cell-free hemoglobin (CFH) occupying most of the airspace.  The study by Shaver et al. indicated that the red color observed in the exudates from ARDS patients is not merely a benign sign of edema, but the presence of CFH and hemolysis [41]. Doctors in the USA are now reporting secretions from COVID-19 patients with ARDS that are pink in color [50]. 

Critically ill patients in sepsis, trauma, burns, or ischemia/reperfusion injury exhibit extremely low levels of plasma ascorbic acid [100, 101, 102].  The rapid depletion of ascorbic acid in plasma of critically ill patients has a direct impact on the highly conserved eukaryotic transmembrane enzyme known as Cytochrome b561 (Cytb561).  Cytb561 is ascorbate-dependent. That means this transmembrane enzyme uses ascorbate EXCLUSIVELY for its role in the recycling of ascorbate [73]. Cytb561 is also a ferrireductase enzyme responsible for the reduction of iron ions from the oxidized ferric state to the reduced ferrous state [74]. 

COVID-19 ARDS patients are difficult to oxygenate because of systematic destruction of red blood cells resulting in cell-free heme that have oxidized iron ions in the ferric state. Under normal conditions, the iron ions in heme can be reduced by Cytb561.  So why are COVID-19 patients unable to maintain stable heme?

The Ascorbic Acid REDOX Cascade in COVID-19

Upon infecting the host, SARS-CoV-2 employs unique viroporins proteins (E protein & ORF3a) that modify host cell membrane permeability in order to gain entry into host cells, promoting replication, release and proliferation.  These proteins are able to form ion channels to induce membrane permeability changes, and activate inflammasomes in order to facilitate viral dissemination [58, 59, 60, 61]. 

The requirement for ascorbic acid (AA) during this stage can be heightened as ascorbic acid may be used by plasma membrane redox enzymes to rescue mitochondria facing apoptotic events due to membrane depolarization from permeabilization initiated by viroporins [62].

While SARS-CoV-2 activates inflammasomes initiating cytokine storms which eventually result in severe lung damage [63], ascorbic acid is being commandeered systemically to support lymphocytes, neutrophils and other important regulators of the immune system [64, 65, 66, 67, 68, 69, 70, 71].  

At this stage, if the body does not have adequate melatonin to control inflammasomes [72], then the depletion rate of ascorbic acid will be exponential. Furthermore, if vitamin C cannot be recycled and regenerated by erythrocyte Cytb561 transmembrane enzymes,  iron centers in hemoglobin may start to oxidize into the unstable ferric redox state. In the ferric form, hemoglobin will start to lose heme to form cell-free hemoglobin at substantially higher rates than in the ferrous forms [47] This is also the point when the patient may start to experience dyspnea, or labored breathing. Why?  

Only iron ions in hemoglobin that are in the ferrous form can bind and transport oxygen. 

ARDS, Erythrocytes & Cytb561 – The Ascorbic Acid REDOX Connection

Erythrocytes (red blood cells) are able to deliver oxygen throughout the body because they contain hemoglobin [75, 76].  In vertebrates, hemoglobin contains four heme proteins. One iron ion is bound within each heme group, and each iron ion can bind one oxygen molecule. Therefore, a functional hemoglobin carries four iron ions and four oxygen molecules. Heme is the protein that carries BOTH iron AND oxygen [76].  

Hemoglobin in red blood cells are active only when the iron in the heme is in the ferrous reduced state.  In this state, the heme is able to bind oxygen reversibly. When the iron in heme is oxidized to the ferric state, the heme is inactivated, and the hemoglobin becomes cell-free hemoglobin that can cause hemolysis and ARDS in COVID-19 [32].  

In 2006, Dan Su et al. showed definitely that the previously unidentified plasma redox system used by human erythrocytes to reduce and recycle extracellular ascorbate in the one-electron oxidation form of monodehydroascorbate, was indeed cytochrome b561 (Cytb561).  Su et al. showed that Cytb561 could regenerate oxidized ascorbate outside the cell using BOTH NADH and/or ascorbate from inside the cell [77, 78]. 

Eight  years later, Peilong Lu et al. (2014) unveiled to the world high-resolution crystal structures of Cytochrome b561, demonstrating in precise details how Cytb561 attaches to the one-electron oxidation metabolite of ascorbate on one side of the plasma membrane, while using reducing agents like NADH and/or ascorbate from the other side of the membrane cytoplasm inside the cell to regenerate the ascorbate radical [73]. 

Cytochrome b561 Plasma Redox Enzyme Ascorbate-Dependent Ferric Reduction Electron Transfer Pathways

[Source: Lu P, Ma D, Yan C, Gong X, Du M, Shi Y. Structure and mechanism of a eukaryotic transmembrane ascorbate-dependent oxidoreductase. Proc Natl Acad Sci U S A. 2014;111(5):1813–1818. doi:10.1073/pnas.1323931111]

The work by Lu et al. supports the use of ascorbic acid as treatment for SARS-CoV2 infections to deter the formation of cell-free hemoglobin, the major cause of ARDS in COVID-19.  Erythrocytes must have access to ascorbate in order to maintain hemoglobin in the ferrous redox state. Without adequate ascorbic acid, heme will rapidly oxidize and become cell-free hemoglobin.  This is the reason why even young adults in good health and no underlying health conditions can develop ARDS quickly upon COVID-19 infection [50, 57].  

A critical question now remains regarding the use of Vitamin C for the prevention and treatment of COVID-19.  

Sodium ascorbate is the form used in all intravenous Vitamin C applications.  The extremely low pH of ascorbic acid (1.0 to 2.5 at 25 °C, 176 g/L in water) renders it unsuitable for intravenous injections [80].  All intravenous ascorbic acid has to be adjusted with buffers to raise pH between 5.5 to 7.0, using sodium bicarbonate [79, 81, 82]. When ascorbic acid is combined with sodium bicarbonate, sodium ascorbate is created.  

Hospitals in China and the rest of the world treat  COVID-19 patients with IV C in the molecular form of sodium ascorbate.  Clinical trials conducted on Vitamin C also use IV C in the form of sodium ascorbate [83].

Can sodium ascorbate be regenerated and recycled by the human body in the same manner as ascorbic acid?

Lu et al. in 2006 were able to demonstrate conclusively that the two highly conserved amino acids in Cytochrome b561, Lys81 on the cytoplasmic side (inside), and His106 on the other side of the plasma membrane were responsible for specifically recognizing L-ascorbate, as well as catalyzing the protonation and deprotonation of this exclusive substrate [73].   


[Source: Lu P, Ma D, Yan C, Gong X, Du M, Shi Y. Structure and mechanism of a eukaryotic transmembrane ascorbate-dependent oxidoreductase. Proc Natl Acad Sci U S A. 2014;111(5):1813–1818. doi:10.1073/pnas.1323931111]

SARS-CoV2 Furin Cleavage, Hypoxia & ARDS – The Ascorbic Acid Connection 

Most living organisms including plants, insects and animals produce ascorbic acid. Ascorbic acid exists naturally in the form of L-ascorbic acid [24]. In physiological pH, L-ascorbic acid exists predominantly in the ionic form of L-ascorbate [84]

The issue of specificity and the exclusivity in the use of L-ascorbate as electron donor and acceptor was also clearly demonstrated in a ground-breaking paper by  Osipyants et al. (2019). The team showed for the first time that ascorbic acid MUST BE IN THE SPECIFIC MOLECULAR STRUCTURE of L-ASCORBATE in order to suppress the hypoxia response protein HIF-1a [85, 86]. 

The SARS-CoV-2 coronavirus is activated by furin enzymes because it has a uniqe furin cleavage site in its S protein [89, 90]  The expression of furin enzymes are increased when the hypoxia pathways are activated [87, 88]

Hypoxia inducible factor 1α (HIF1α) is a transcription factor that can be activated under hypoxia. HIF-1a  levels are normally kept low in the presence of oxygen. When there is adequate oxygen, HIF-1a is bound by the von Hippel-Lindau (VHL) protein, which then prepares HIF-1a for degradation [91].  

What happens when a COVID-19 patient starts to lose the ability to bind and transport oxygen due to lack of adequate ascorbate to reduce ferric iron in heme?  Low oxygen levels will mobilize HIF1a, increasing furin enzyme expression. More furin enzymes will cleave and activate even more SARS-CoV-2 virus.

Only ascorbic acid in the anionic form of L-ascorbate can degrade the HIF1a protein, and stop its stabilization and ability to increase furin enzymes.  Without adequate ascorbate, the human body will be at a significant disadvantage in the fight against COVID-19. 

The true question remains whether we are properly utilizing the full capacity of ascorbic acid to treat SARS-CoV-2 if sodium ascorbate can only serve as an antioxidant, and not as a REDOX molecule preferred and used exclusively by the body. 

L-Ascorbate Attenuates Endothelial Permeability from Cell-Free Hemoglobin

Cell-free hemoglobin is the major cause of acute respiratory distress syndrome (ARDS), but the exact mechanism was never completely understood until Jamie L Kuck et al. (2018) conclusively demonstrated that cell-free hemoglobin decreased the integrity of epithelial monolayer causing increased permeability of macromolecules, while at the same time CFH significantly decreased intracellular ascorbate in human endothelial cells (HUVEC) [93]. 

Healthy endothelial cells maintain tight barriers with high resistance to current flow that limits permeability.  When this barrier is disrupted, current flow is facilitated and is concurrently marked by a drop in resistance. Kuck et al. showed that CFH caused a time-dependent and dose-dependent decrease in electrical resistance in endothelial monolayers resulting in a loss of barrier function, allowing the passage of large macromolecules due to increased permeability.  This disruption was observed with the concomitant decrease in intracellular L-ascorbate [93].

What is surprising, is that after treatment with L-ascorbate for 18 hours, human endothelial cells were able to prevent CFH from lowering monolayer resistance, preserving barrier integrity in HUVEC [93].  Kuck et al. achieved the results in their experiments by using L-ascorbic acid dissolved in sterile H2O [93].  Why did Kuck et al. not use sodium ascorbate since this is the molecule used almost exclusively in all intravenous Vitamin C applications?  Is it because L-ascorbate delivered better results? And if so, why?

It is possible that sodium ascorbate may not be utilized in the same manner as a result of its molecular structure.

Molecular Structures of Ascorbic Acid and Sodium Ascorbate

Ascorbic acid has 6 carbon, 8 hydrogen and 6 oxygen molecules.

Ascorbic Acid C6H8O6  

Sodium ascorbate has 6 carbon, 7 hydrogen, 6 oxygen, and one sodium ion that replaced the 8th hydrogen in its parent.

Sodium Ascorbate C6H7NaO6

It is entirely possible that the sodium ascorbate molecule may not be in the preferred form that is utilized by our REDOX systems.  There has actually been no evidence that compare side-by-side the difference in results of plasma concentration from oral ascorbic acid and sodium ascorbate (both IV C and oral), until the ground-breaking paper released by Owen Fonorow and Steve Hickey on March 13th, 2020 [94]. 

Sodium Ascorbate is NOT REGENERATED by The Human Body?

Humans do not produce ascorbic acid due to the pseudogenization of the GULO gene [96]. The production of ascorbate is dependent upon glucose in animals [95]. Therefore, the ascorbate molecule is very similar in structure to a glucose molecule.  Fonorow and Hickey exploited this feature and used glucose meters to measure minute-by-minute results of the two different forms of vitamin C – ascorbic acid and sodium ascorbate in different combinations of oral/oral and oral/IV C.  

Minute-by-minute tracking of plasma levels of vitamin C is completely novel to the literature, as it is almost impossible to collect, store and measure so many samples effectively.  The results from their study are truly remarkable and should be considered as a landmark moment in orthomolecular medicine due to the way their observations could be interpreted [94]. 

Fonorow and Hickey first demonstrated that results from glucose meters measuring glucose and ascorbic acid yielded completely distinct and different results, even though both have similar molecular structures. 

Single oral dose of 10.0 grams glucose compared with 10.0 grams of oral ascorbic acid

[Source: Owen Fonorow and Steve Hickey 2020 Unexpected Early Response in Oral Bioavailability of Ascorbic Acid – Townsend Letter  March 13, 2020, prior to print publication.]

When 10 grams of ascorbic acid was ingested orally, compared to 11.3 grams of sodium ascorbate (to account for additional weight of sodium in the compound) taken by mouth,  Fonorow and Hickey obtained a totally UNEXPECTED result showing that oral ascorbic acid is absorbed more efficiently and in higher quantities than sodium ascorbate. 

Single dose of 10 grams oral Ascorbic Acid compared with 11.3 grams oral Sodium Ascorbate

[Source: Owen Fonorow and Steve Hickey 2020 Unexpected Early Response in Oral Bioavailability of Ascorbic Acid – Townsend Letter  March 13, 2020, prior to print publication.]

The final real shocker is when Fonorow and Hickey measured the results of a single oral dose of 10 g ascorbic acid over the course of 50 minutes, and compared it to the results of IV C with sodium ascorbate.

Time series following a single oral dose of 10 g Ascorbic Acid versus IV C with Sodium Ascorbate

[Source: Owen Fonorow and Steve Hickey 2020 Unexpected Early Response in Oral Bioavailability of Ascorbic Acid – Townsend Letter  March 13, 2020, prior to print publication.]


A common misunderstanding about ascorbic acid absorption in the intestines is that there is an upper limit of about 200 milligrams, above which, the body would not be able to transport and utilize the molecule. This is the reason why intravenous delivery is the preferred method as it is believed to be able to provide a higher bioavailability.  

If you look at the oral/IV C chart above, what do you observe? There is a distinct spike within 2 to 8 minutes after a single ingestion of 10 g ascorbic acid.  The highest level is more than DOUBLE that achieved by IV C at the same minute mark. Why would the body absorb ascorbic acid better than sodium ascorbate? 

SVCT1 and SVCT2 – A Story About Capacity and Affinity

There are two major ascorbate transporters in our gut, called sodium-dependent vitamin C Transporter 1 & 2 (SVCT1 and SVCT2).  In the low pH environment of stomach acids, ascorbic acid can be absorbed rapidly by SVCT1, which is a LOW-AFFINITY, HIGH CAPACITY transporter. It will only transport in huge quantities when there is a high concentration of ascorbate.  If the pH is raised in the stomach, as in the case of sodium ascorbate, the transport becomes slower as the buffered stomach pH would inhibit and slow  absorption. It is entirely possible that sodium ascorbate is transported by the high-affinity but LOW CAPACITY SVCT2 [94, 97].  

This remarkable study by Fonorow and Hickey (March 2020) not only showed that oral ascorbic acid is fully absorbed and utilized in high quantities, it also revealed the true nature of ascorbic acid as a REDOX molecule. 

Continuous Recycling of Ascorbic Acid But Not Sodium Ascorbate

Look at the last chart again.  What do you see?  

There are three distinct successive peaks and valleys in diminishing intensities, while intravenous sodium ascorbate slowly accumulated to a peak and gradually subsided.  What this implies is that ascorbic acid, after it reaches plasma, quickly donates its electrons in redox reactions, becoming the oxidized monodehydroascorbate. This one-electron oxidation product is then captured and ‘docked’ by transmembrane redox enzymes like Cytb561.  That is when you see the valleys when the oxidized ascorbate is ‘hidden’ from detection by glucose meters while they are nested in Cytb561, waiting to be regenerated. The following peak is the release of successful regenerated ascorbate back into plasma for another round of active electron donation to quench free radicals and reactive oxygen species. 

If you compare the intensity of the peaks and valleys after oral dosage of 10 g ascorbic acid, to the relatively smooth curve of 11.3 g oral dosage of sodium ascorbate, you may start to wonder if sodium ascorbate can actually be regenerated and recycled by our body. 

Evidence From Literature Supporting The Findings of Fonorow and Hickey 

Most studies that document the results of IV C show a similar surge and then a ‘flatlining’ of the curve. The chart belows shows a distinct surge but no ensuing peaks and valleys in the IV C curve. The lower curve is obtained from oral vitamin C, However, the authors failed to identify whether the source of oral vitamin C was ascorbic acid or sodium ascorbate (or other forms), perhaps for obvious reasons. 

Plasma vitamin C concentrations after 1.25-g intravenous or oral dose in 12 persons 

[Source: Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533–537. doi:10.7326/0003-4819-140-7-200404060-00010]

Oral ascorbic acid when measured in plasma over an extended period would indeed produce peaks and valleys, if it is recycled and regenerated.  Has this unique feature ever been documented before the discovery by Fonorow and Hickey?

An exquisite study by Katsu Takenouchi and Kazuo Aso in 1964 showed the plasma levels of 1 g oral ascorbic acid administered three times during the daytime, measured over a period of 24 hours.  Arrows denote time of oral ingestions, and circles (open/closed) marked the times when measurements were taken.  

The most impressive part of their results was the distinct surge to the highest level at 3.5 hours after the last oral dosage of 1 g. 


The ability of the body to regenerate and recycle ascorbic acid, and the different REDOX capacities of individuals may explain the reason why a study on the correlation between ascorbic acid levels and all-cause mortality found plasma levels in individuals to differ by as much as ten-fold [99]. 

The recent unexpected findings by Fonorow and Hickey possibly marked the beginning of a new era in the understanding of ascorbic acid as the ultimate REDOX molecule preferred by all living organisms. 

A Call for Immediate Attention To The Use of Oral Ascorbic Acid in COVID-19 Patients

Until the position of sodium ascorbate as a REDOX molecule in the human body is further elucidated, it is my humble opinion that COVID-19 patients be afforded the most efficacious treatment using oral supplementation of ascorbic acid to reduce hypoxia and lower cell-free hemoglobin, the main cause for ARDS in COVID-19. 

The combined oral ascorbic acid AND intravenous sodium ascorbate treatment may confer COVID-19 patients the best of both worlds, in that sodium ascorbate IV C will deliver  a continuous supply of electrons to haptoglobin in the binding and stabilization of cell-free heme, while oral ascorbic acid is freed to support all cellular redox reactions, immune responsea and mitochondrial protection. 

The following supplementation guide for oral ascorbic acid is offered as informational purposes only, and should NOT be considered as MEDICAL ADVICE.

Initial onset of symptoms: 

3 to 5 g in one dose, followed by 1 g every 30 to 60 mins for the following 3 hours. Repeat this cycle until symptoms subside.

Milder cases:  

2 to 5 g in one dose, followed by 1 g every hour for the following 4 – 6 hours. Repeat this cycle until symptoms subside.

Severe/critical cases: 

10 g in one dose, followed by 2 g every 15  to 30 mins for the following 2 hours. Repeat this cycle until symptoms improve.  

Stomach Acidity

Patients exhibiting stomach discomforts can be given acidic beverages together with oral AA.  Lower pH will facilitate faster absorption through high capacity transporter SVCT1. High pH in stomach acids can slow or even prevent speedy absorption of ascorbic acid.  Examples of acidic beverages may include fresh squeezed lemon/lime in water, apple cider vinegar (1 tbs in 2-3 oz water).  Use acidic beverage only when necessary.

Importance of Sodium ions in Ascorbic Acid Transport

The transport of ascorbic acid is dependent upon the sodium electrochemical gradient generated across the plasma membrane by Na+/K+ ATPase.  It takes two sodium ions to move one ascorbate molecule across plasma membranes [92]. Attending physicians should closely monitor sodium adequacy together with increased hypertension from reduced nitric oxide.  Theoretically, ascorbate should significantly reduce quenching of NO, raising NO levels, thus stabilizing blood pressure. 

Inhibition of SVCT by Flavonoids

The flavonoid quercetin has been demonstrated to inhibit transport of ascorbate by SVCT1.  Ascorbate transport by the low-affinity, high capacity SVCT1 can be inhibited by as much as 80% in the presence of quercetin, and 100% when sodium was replaced by choline. Please be aware of this important conflict [98].   Quercetin occurring naturally in foods such as onions should not pose an issue as the amounts are not high enough in an average serving to exert true inhibitory effects.  Supplementation of quercetin may need to be reconsidered when using oral ascorbic acid during COVID-19 treatment. 

L-Ascorbic Acid and Commercially Available Ascorbic Acid

Ascorbic acid produced by plants and animals exist in the form of L-ascorbic acid.  In the living body, ascorbic acid exists mostly in the anionic form of L-ascorbate [95]. The D-ascorbic acid isomer must be produced artificially in laboratories [103].  Commercially available ascorbic acid, even if it is not specified as L-ascorbic acid, would be in the form of L-ascorbic acid.

Ascorbic Acid Recommendations for Children 

Children infected by COVID-19 should, under normal circumstances, recover quickly. However, they may be asymptomatic and have high transmissibility.  Upon infection children should be given oral ascorbic acid in the following dosages:

Ages Under 9

Initial dose – 200 mg per 10 lb. body weight

Subsequent doses – 100 mg per 10 lb. body weight

Follow the time schedule under mild cases for adults. If symptoms worsen, change to the time schedule for severe cases. 

Ages Between 10 – 15

Initial dose – 300 mg per 10 lb. body weight

Subsequent doses – 200 mg per 10 lb. body weight

Follow the time schedule under mild cases. If symptoms worsen, change to the time schedule for severe cases. 

Above 15 – treat as adult

Melatonin Recommendations for Children 

Children naturally have high melatonin when they are under the age of nine. However, in addition to ambient light exposure at night, the use of mobile phone, smart phone, tablets, computers and television at night can severely lower or inhibit production of melatonin.

I recommend the nighttime use of melatonin for children ONLY when they exhibit severe symptoms or have poor light-sleeping habits. 

Recommended Dosage: 

0.05 mg per 30-50 lb. of body weight. 

0.025 mg for 30 lb. and under body weight. 

(dilute 0.1 mg in liquid, then measure the liquid according to the proportion required. Half the liquid for 0.05 mg, then half again for 0.025 mg melatonin)

In conclusion, with proper attention to social distancing, adequate nutrition, sleep, exercise and supplementation with ascorbic acid and melatonin, in time, COVID-19 may actually become ‘just another flu’ after all.  Blessings and stay safe. 

This article is part of an ongoing in-depth series on COVID-19. Please read the previous article detailing the important roles of melatonin in COVID-19 prevention and treatment. 


[1] Fed announces massive stimulus to shield economy from coronavirus – POLITICO

[2] Europe sets up emergency lifeline worth billions – BBC News

[3] Here are the coronavirus bailouts being prepared around the world — Quartz 

[4] Coronavirus: Experiment in northern Italian town halts all new infections after trial | World News | Sky News

[5] Britain must change course – and resume Covid-19 testing to protect frontline NHS staff | Devi Sridhar | Opinion | The Guardian

[6] WHO: ‘Test every suspected case’ of COVID-19 – Live updates | News | Al Jazeera

[7] As Italy quarantines over coronavirus, swans appear in Venice canals, dolphins swim up playfully | TheHill

[8]  SCMP Lung Damage_Coronavirus: some recovered patients may have reduced lung function and are left gasping for air while walking briskly, Hong Kong doctors find | South China Morning Post 

[9] Macintyre CR. On a knife’s edge of a COVID-19 pandemic: is containment still possible? Public Health Res Pract. 2020;30(1):3012000.

[10] Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response | Critical Care Medicine | JAMA | JAMA Network 

[11] Clinical Characteristics of Coronavirus Disease 2019 in China – PubMed 

[12] American Hospital Capacity And Projected Need for COVID-19 Patient Care | Health Affairs

[13] Baseline capacity and projected need for inpatient and ICU care

[14] `Accept it’: 3 states lock down 70 million against the virus

[15] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2) 

[16] Prolonged presence of SARS-CoV-2 viral RNA in faecal samples – The Lancet Gastroenterology & Hepatology

[17] Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding | Nature Medicine

[18] Coronavirus (COVID-19) Update: FDA Continues to Facilitate Development of Treatments | FDA

[19] Coronavirus Covid-19: Chloroquine data; Japan to trial HIV drug

[20] Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro | Cell Discovery

[21] Breakthrough: Chloroquine Phosphate Has Shown Apparent Efficacy in Treatment of COVID-19 Associated Pneumonia in Clinical Studies – PubMed 

[22] French researcher posts successful Covid-19 drug trial

[23] COVID-19-Drug-Therapy_Mar-2020.pdf 

[24] Chloroquine: Mechanism of Drug Action and Resistance in Plasmodium Falciparum – PubMed

[25] Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study – ScienceDirect

[26] Chloroquine and Hydroxychloroquine: Side Effect Profile of Important Therapeutic Drugs] – PubMed

[27] Chloroquine Enhances Temozolomide Cytotoxicity in Malignant Gliomas by Blocking Autophagy – PubMed


[29] Quantification of Free Ferriprotoporphyrin IX Heme and Hemozoin for Artemisinin Sensitive Versus Delayed Clearance Phenotype Plasmodium Falciparum Malarial Parasites – PubMed

[30] Relationship of Cell-Free Hemoglobin to Impaired Endothelial Nitric Oxide Bioavailability and Perfusion in Severe Falciparum Malaria

[31] Haptoglobin, hemopexin, and related defense pathways—basic science, clinical perspectives, and drug development

[32] In vivo reduction of cell-free methemoglobin to oxyhemoglobin results in vasoconstriction in canines

[33] Regional Distribution of Gas and Tissue in Acute Respiratory Distress Syndrome. I. Consequences for Lung Morphology. CT Scan ARDS Study Group – PubMed

[34] Morphometric Differences in Pulmonary Lesions in Primary and Secondary ARDS. A Preliminary Study in Autopsies – PubMed

[35] Clinical review: Lung imaging in acute respiratory distress syndrome patients – an update

[36] Respiratory support for patients with COVID-19 infection – The Lancet Respiratory Medicine 

[37] Study identifies factors associated with ARDS in COVID-19

[38] Prominent Changes in Blood Coagulation of Patients With SARS-CoV-2 Infection – PubMed

[39] The role of red blood cells and cell-free hemoglobin in the pathogenesis of ARDS

[40] There is blood in the water: hemolysis, hemoglobin, and heme in acute lung injury 

[41] Cell-free hemoglobin: a novel mediator of acute lung injury [Shaver et al. 2016] 

[42] Cell-Free Hemoglobin Levels in the Distal Airspace of Patients with Acute Respiratory Distress Syndrome (ARDS) Are Associated with Markers of Lung Epithelial Injury, Airspace Inflammation, and Alveolar Permeability

[43]  Hemolysis and Cell-Free Hemoglobin Drive an Intrinsic Mechanism for Human Disease – PubMed

[44]  A Proteogenomic Analysis of Haptoglobin in Malaria – PubMed 

[45] Effects of Endogenous Ascorbate on Oxidation, Oxygenation, and Toxicokinetics of Cell-Free Modified Hemoglobin After Exchange Transfusion in Rat and Guinea Pig – PubMed 

[46] Hospital treatment of serious and critical COVID-19 infection with high-dose Vitamin C | Cheng Integrative Health Center Blog

[47] Differential heme release from various hemoglobin redox states and the upregulation of cellular heme oxygenase‐1

[48] The Acute Respiratory Distress Syndrome: Mechanisms and Perspective Therapeutic Approaches 

[50] A Medical Worker Describes Terrifying Lung Failure From COVID-19 — Even in His Young Patients — ProPublica–terrifying-lung-failure-from-covid19-even-in-his-young-patients

[51] Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens – PubMed 

[52] Vitamin C supplementation in the critically ill: A systematic review and meta-analysis

[53] Vitamin C in the critically ill – indications and controversies



[56] Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China | Critical Care Medicine | JAMA Internal Medicine | JAMA Network

[57] Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster

[58] Expression of SARS-coronavirus envelope protein in Escherichia coli cells alters membrane permeability. – PubMed – NCBI

[59] Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan: Emerging Microbes & Infections: Vol 9, No 1

[60]  Inflammasomes and viruses: cellular defence versus  viral offence

[61] Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis | mBio 

[62] Mitochondria & The Coronavirus – The Vitamin C Connection (Part 3) – 

[63] Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC | The FASEB Journal

Ascorbic acid: its role in immune system and chronic inflammation diseases. – PubMed – NCBI

[64] Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. – PubMed – NCBI

[65] Vitamin C and Immune Function 

[66] Effects of ascorbate on leucocytes: Part III. In vitro and in vivo stimulation of abnormal neutrophil motility by ascorbate. – PubMed – NCBI

[67] Lymphocytes 2018_Influence of Vitamin C on Lymphocytes: An Overview

[68] Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells. – PubMed – NCBI

[69] Promotion of IL-4- and IL-5-dependent differentiation of anti-mu-primed B cells by ascorbic acid 2-glucoside. – PubMed – NCBI

[70] Vitamin C and Infection | Nutrition Reviews | Oxford Academic

[71] Vitamin C and Infections. – PubMed – NCBI 

[72] COVID-19, Pneumonia & Inflammasomes – The Melatonin Connection – 

[73] Structure and Mechanism of a Eukaryotic Transmembrane Ascorbate-Dependent Oxidoreductase – PubMed 

[74] Ferrireductase_Three mammalian cytochromes b561 are ascorbate‐dependent ferrireductases – Su – 2006 – The FEBS Journal – Wiley Online Library

[75] hemoglobin | Definition, Structure, & Function | Britannica

[76] Biochemistry, Iron Absorption – StatPearls – NCBI Bookshelf

[77] Dan Su et al. Human Erythrocyte Membranes Contain a Cytochrome b561 That May Be Involved in Extracellular Ascorbate Recycling 

[78] Erythrocytes Reduce Extracellular Ascorbate Free Radicals Using Intracellular Ascorbate as an Electron Donor  

[79] Phase I clinical trial of i.v. ascorbic acid in advanced malignancy – Annals of Oncology


[81] Ascorbic Acid (Vitamin C): Uses, Dosage, Side Effects, Interactions, Warning

[82] Clinical and Experimental Experiences with Intravenous Vitamin C

[83] Vitamin C Infusion for the Treatment of Severe 2019-nCoV Infected Pneumonia – Full Text View – 

[84]  Ascorbic acid | HC6H7O6 – PubChem


[85]  L-ascorbic acid: A true substrate for HIF prolyl hydroxylase? 

[86] Vitamin C & Cancer – Health & Disease Masterkey (Part 3) –

[87] COVID-19, Furins & Hypoxia – The Vitamin C Connection –

[88] Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. – PubMed – NCBI\

[89] A furin cleavage site was discovered in the S protein of the 2019 novel coronavirus

[90] The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade – 

[91] Hypoxia-Inducible Factors in Physiology and Medicine

[92] The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C

[93] Ascorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin

[94] Unexpected Early Response in Oral Bioavailability of Ascorbic Acid – Townsend Letter

[95] Evolution of alternative biosynthetic pathways for vitamin C following plastid acquisition in photosynthetic eukaryotes | eLife

[96] Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates

[97] Expression, Purification and Low-Resolution Structure of Human Vitamin C Transporter SVCT1 (SLC23A1)

[98] Flavonoid Inhibition of Sodium-dependent Vitamin C Transporter 1 (SVCT1) and Glucose Transporter Isoform 2 (GLUT2), Intestinal Transporters for Vitamin C and Glucose 

[99] Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study – The Lancet

[100] Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes | Critical Care | Full Text 

[101] Dosing vitamin C in critically ill patients with special attention to renal replacement therapy: a narrative review | Annals of Intensive Care | Full Text 

[102]Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis | SpringerLink


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