G6PD Deficiency and COVID-19 Medical Research Review

Revised 08/2020

The COVID-19 pandemic has impacted almost every part of the world. As scientists continue to research effective treatments and vaccines that can prevent future infections, some are wondering if there are genetic predispositions that make it more likely for someone to be more susceptible to contracting or exhibiting more severe symptoms of COVID-19. One such example is patients with Glucose-6-Phosphate Dehydrogenase Deficiency (G6PDd.)

G6PD Deficiency has a complex genetic inheritance pattern of expression as the G6PD enzyme is located on the X chromosome and there are numerous mutated variants of this enzyme that causes G6PD Deficiency. It is a relatively common condition that impacts over 400 million people worldwide.1 G6PDd is also one of the most common human enzyme defect in the world.2

Because of the unique clinical impacts of G6PD Deficiency (G6PDd), there are many who are wondering if patients with G6PD Deficiency are at a greater risk of developing severe complications. This is where the relationship between G6PD Deficiency and COVID-19 merits further investigation.

G6PD Deficiency: A Role in Viral Diseases

G6PD is an important enzyme in the pentose phosphate pathway.3 This is a shunt of glucose metabolism where G6PD catalyzes NADPH production. NADPH plays an important role in the body, as it takes part in free radical neutralizing. This will protect and preserve cells.

The role of G6PD Deficiency in viral diseases has been studied extensively.8, 9, 10, 11 NADPH plays a critical role in counteracting free radicals by balancing glutathione (GSH) with oxidized glutathione (GSSG). This takes place both in the cytoplasm of cells and in the mitochondria. When G6PD levels are decreased, NADPH levels decrease thus increasing of free radicals levels  because of inadequate neutralizing process by GSH. Clinically, oxidative stress manifests into hemolysis and complications of it.

Are Patients with G6PD Deficiency at Higher Risk for COVID-19?

A Study on Human Coronavirus

To date, studies that have explicitly examined G6PD Deficiency and COVID-19 are rare; however, an in vitro study published in 2008 takes a closer look at the impact of its sister virus, human coronavirus HCoV229Eon cells with G6PD Deficiency.5

In this laboratory investigation, the researchers studied infected HCoV229E virus cells that were deficient in the production of G6PD. There was a markedly increased amount of oxidant production, demonstrating cell stress. Furthermore, the researchers also found that the rate of viral replication was higher in infected cells that lacked G6PD.

When the researchers added an antioxidant, which was designed to reduce levels of oxidative stress in these cells, the cells were more likely to survive. In the study, the researchers attenuated the oxidation that is taking place in the cells by adding lipoic acid. This reduced the production ROS (Reactive Oxygen Species) and rendered the cells less susceptible to infection and death. This addition shows that issues related to oxidative stress played a direct in cell death caused by coronavirus HCoV229E.

Review:

G6PD Enzyme and its Relationship to Red Blood Cell Hemolysis
G6PD Deficiency is most closely linked to red blood cell hemolysis. This is because red blood cells lack mitochondria needed for its source of Glutathione for oxidative stability. Therefore, red blood cells rely on the Pentose Phosphate Pathway (PPP) to exist. The G6PD enzyme helps regulate this biochemical cycle PPP. This is why the most severe symptoms of G6PD Deficiency tend to show up as red blood cells breaking apart. Testing for hemolysis can be determined on blood smears when bites cells and Heinz bodies are present.

G6PD Enzyme and its Relationship to Immune System

G6PD Deficiency has also been found to impact the immune system. Infection is the most common cause of acute hemolysis in G6PD-deficient persons.2 The onset of hemolysis can cause insufficient oxygen delivery and an activation of the intrinsic coagulation cascade, which can lead to blood clot formation & tissue damage.17

COVID-19 Stimulates a Pro-Inflammatory Response

It is important to note that COVID-19 causes cellular death by initiating a pro-inflammatory, systemic response. Inflammation is known to lead to oxidative stress.6 This leads to an overproduction of free oxygen radicals. These radicals further stimulate a systemic inflammatory response syndrome.

Given that people with G6PD Deficiency are constantly dealing with oxidative stress,7 patients with G6PD Deficiency may suffer from even worse inflammation during a COVID-19 infection. Being G6PD Deficient are not able to neutralize free oxygen radicals as well as patients without this enzymatic defect. The combination of pro-inflammatory free oxygen radicals with a virus that stimulates a pro-inflammatory response may lead to more significant complications.

Patients with G6PD Deficiency May Be At An Increased Risk of Coagulopathy from COVID-19 Infection?

While COVID-19 has been shown to present as a mild to moderate disease in most patients, this may not be the case in patients with G6PD Deficiency. A cross-sectional analysis was conducted looking at various laboratory parameters in COVID-19 cases.15,16 The researchers found certain laboratory parameters that indicate more severe cases of COVID-19 that may shed light into possible worsening outcome in patients with G6PD Deficiency.  Patients with severe clinical manifestations from COVID-19 were found to have:

  • Increased CRP
  • Decreased Albumin
  • Increased ESR
  • Decreased Eosinophils
  • Increased IL-6
  • Increased LDH

Venous thromboembolism (VTE) has been a commonly reported finding in patients who die from the disease. In recent years, multiple cases/studies have indicated that G6Pd Deficiency patients are also at an increase probability of developing multiple types of coagulopathy including pulmonary obstructions17, rhabdomylolysis,20,21,22 and venous thrombosis18,19. Given that patients with G6PD Deficiency are at an increased risk of coagulopathy, patients with G6PD Deficiency and COVID-19 showing these lab values are at a markedly increased risk of VTE.

Because G6PD Deficiency may lead to a hemolytic crisis, the following professional COVID-19 viewpoints have been noted:4, 16

  • G6PD Deficiency, particularly cases that are unrecognized, can lead to hemolytic crises and worse outcomes in the presence of a viral infection such as COVID-19
  • G6PD Deficiency, particularly cases that are unrecognized, can lead to clotting problems such as VTEs which may also lead to CV complications

Therefore, it is critical for medical professionals to screen for G6PD Deficiency in patients who are being worked up for COVID-19. G6PD Deficiency may lead to worse outcomes. This diagnosis can also impact treatment parameters.

Can the Treatment of COVID-19 in G6PD Patients have an impact on outcome?

Medical providers must consider the Risks and Benefits of any kind of treatment that are questioned as a contraindication for the G6PD deficient population.

Antimalarial Drugs:

As COVID-19 has spread, the antimalarial drug chloroquine, and its sister drug hydroxychloroquine (HCQ) have been used by some medical providers as a treatment.

It is important to know the facts about chloroquine-based medications and G6PD Deficiency. Numerous studies have been released showing that chloroquine induces widespread hemolysis in patients with G6PD Deficiency.12, 13, 14 This leads to increased oxidative injury throughout the body’s tissues. This can lead to severe retinopathy, causing partial vision loss.

In contrast, hydroxychloroquine is not directly contraindicated in patients with G6PD Deficiency (G6PDd); however, it should be used with caution:

A well-known study of HCQ treatment for Lupus concluded that hydroxychloroquine was safe for patients with African G6PD deficient variant yet these 11 participants were not exposed to an infection (oxidative overload).23 This study requested for more research because the small G6PDd study sample size and other types of G6PD Deficiency variants were not in the study. Different variants may respond differently to HCQ due to their different reactivity class level. More research must be done to determine the safety of using antimalarial drug treatments for patients who are G6PD deficient. Therefore, it is important to weigh the risks and benefits of using chloroquine and hydroxychloroquine on a case-by-case approach for patients with G6PD Deficiency.

Consensus Information on G6PD Deficiency and COVID-19 from the Above Medical Research Review

COVID-19 is still a relatively new virus, which means that the current research information is still relatively limited; however, medical professionals and research experts have made a number of important, actionable points for medical professionals who are treating patients with COVID-19. These include:

  • COVID-19 causes a tremendous amount of oxidative stress on cells throughout the body, particularly the lungs, which leads to inflammation and respiratory failure
  • Patients with G6PD Deficiency are already predisposed to oxidative stress due to a lack of NADPH, which plays a key role in the pentose phosphate pathway (PPP) and glutathione pathway
  • A research study on a different human coronavirus showed that G6PD-deficient cells suffer from increased levels of oxidative stress, cell death, viral replication, and viral expression when infected by this coronavirus in vitro. It also concluded that adding an antioxidant reduces the rate of cell death, showing that oxidative stress in coronavirus-infected cells that lack G6PD is a direct cause of cell death
  • Patients with G6PD Deficiency who get COVID-19 possibly suffer worse oxidative stress and levels of inflammation. They are potentially at an increased risk of developing coagulopathies which could include hemolysis, VTEs, and CV complications
  • Patients who are being worked up for COVID-19 should be screened for G6PD Deficiency
  • Because chloroquine and hydroxychloroquine are antimalarial drugs which could lead to extreme oxidative stress in patients with G6PD Deficiency. They should only be used with caution in G6PD Deficiency patients treated for COVID-19.

What is the last straw that breaks the camel’s back?

These are important points to note when it comes to a possible relationship between G6PD Deficiency and COVID-19, and this information will certainly play a role in the healthcare decision-making process. To date, there are no direct studies that specifically analyze the relationship between G6PD Deficiency and COVID-19. Severe cases reported of COVID-19 patients who were tested for G6PD Deficiency because of hemolysis, were patients that also had other underlying health issues.24,25
As this global pandemic rages on, there are hundreds of millions of people who could be at a higher risk to COVID-19 than the average person. That is why the world needs scientific studies analyzing these relationships and not merely hypotheses.

Please see the WHO Letter established by the COVID-19 & G6PD Deficiency Task Force requesting more concerning attention for the G6PD Deficiency population during this Pandemic Crisis.

Cited References

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