THE CASE FOR IMMEDIATE G6PD AWARENESS, RESEARCH AND TESTING DURING THIS PANDEMIC Below we outline why it is our position that G6PD research and testing in the wake of COVID-19 is crucial – not only for people with G6PD deficiency – but also for the public as a whole and for a more complete understanding of the various effects, etiology, mechanism of action, and implications for treatment of SARS-Cov 2 and COVID-19. G6PD IMPORTANCE --- IN GENERAL, FOR CORONAVIRUS, AND IN EVALUATING TREATMENT OPTIONS Glucose-6-phosphate-dehydrogenase (G6PD) is an enzyme of utmost importance produced by the human body. It is needed by every cell in our bodies to overcome oxidative stress to prevent cell breakdown – but particularly for the red blood cells (RBC) and muscle cells. Without G6PD, there is no Pentose-Phosphate- Pathway (PPP), no NADPH, no reduced glutathione (GSH) – though at times articles and research papers are written that neglect to mention the critical role and necessity of G6PD. ”G6PD catalyzes nicotinamide adenine dinucleotide phosphate (NADP) to its reduced form, NADPH, in the pentose phosphate pathway. NADPH protects cells from oxidative damage. Because erythrocytes do not generate NADPH in any other way,3 they are more susceptible than other cells to destruction from oxidative stress. The level of G6PD activity in affected erythrocytes generally is lower than in other cells.5 Normal red blood cells that are not under oxidative stress generally exhibit G6PD activity at approximately 2 percent of total capacity.1 Even with enzyme activity that is substantially reduced, there may be few or no clinical symptoms. A total deficiency of G6PD is incompatible with life.” https://www.aafp.org/afp/2005/1001/p1277.html https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361223/ https://ashpublications.org/blood/article/120/21/5165/87123/Significance-of-Low-Levels-of-Glucose-6- Phosphate https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency/ Most people who have the genetic trait G6PD deficiency (G6PDd) are unaware they have it. Though it is present at birth, some cases have been first discovered in octogenarians. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176296/ This is because under normal circumstances there is enough G6PD activity to overcome the normal oxidative stress that comes constantly from metabolism and respiration. However, certain infections, drugs, and chemicals that cause extreme oxidative stress can trigger extra- and/or intra-vascular hemolysis and Rhabdomyolysis in people with G6PDd – due to their inability to produce enough G6PD to protect their red blood cells and muscle cells from oxidative damage. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987291/ G6PDd was first discovered and studied in the 1950’s when the US military noticed that some soldiers (especially African American) were having life-threatening reactions after being administered the anti-malarial primaquine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059509/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762880/ Since then, other drugs that cause oxidative stress have been identified as potentially harmful for people with G6PDd. Drugs that cause weakened cell membranes can also be dangerous for people with G6PD deficiency. Therefore -- at the very least – G6PDd should be included in tests during this pandemic so that treatments that might be contraindicated for such people can be identified. https://www.medpagetoday.com/infectiousdisease/covid19/85929 Current research indicates that SARS-Cov 2 creates extreme oxidative stress. https://www.sciencedirect.com/science/article/abs/pii/S0188440920305403 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133895/ https://www.smartpatients.com/trials/NCT04375137 https://www.cebm.net/covid-19/n-acetylcysteine- a-rapid-review-of-the-evidence-for-effectiveness-in-treating-covid-19/ https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.13432 In 2008, ex-vivo research showed that cells deficient in G6PD are more susceptible to coronavirus 229E (a virus similar to Sars-cov-2) than cells with normal G6PD. The virus was more able to infect & reproduce MUCH more in cells with low G6PD – as well as to kill the G6PD deficient cells more than G6PD ‘normal’ cells. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199897/ PREVALENCE OF G6PDD IN THE WORLD G6PD deficiency is often classified as a “rare disease” --- though it is not really a disease and is the most common enzyme deficiency in the world, affecting over 400 million people. This genetic variant offers some protection against malaria – as well as some forms of cancer https://pubmed.ncbi.nlm.nih.gov/27858887/ https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-13- 251https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770671/ – and is more common in peoples of African, Asian/Middle Eastern, and Mediterranean descent. There are five main classifications of G6PD activity and many variant alleles. The G6PD gene is on the Xq28 block – so is more often (and more severely) presented by males than females (The overall ratio of the G6PDd population is about 60% male to 40% female.) Due to the process of random X-inactivation (lyonization), females who are heterozygous will express varying quantities of G6PDd at various times --- with certain factors such as age and pregnancy causing an expression of the G6PDd cells more often. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762880/ https://academic.oup.com/biomedgerontology/article/61/10/1086/600477 https://ashpublications.org/blood/article/120/21/5165/87123/Significance-of-Low-Levels-of- Glucose-6-Phosphate In addition, recent research has shown that G6PD deficiency can be acquired by people who have what is considered “normal” G6PD. Inflammation-induced Tumor Necrosis Factor alpha causes depressed G6PD expression. https://figshare.com/articles/Highlights_from_Respiratory_Burst_of_COVID-19/12121575 PREVALENCE OF G6PDD IN THE US The only widespread regular testing for G6PDd in the US is that done by the US military. It would stand to reason that the trait would be slightly more common in the general population than in the military. Anyone who had suffered health effects as a young person from a triggering substance (whether aware of the role of G6PDd or not) would likely not have applied to serve in the armed forces. Active military members are one of the most physically fit cohorts. (State Department and Peace Corps volunteers posted to areas where malaria is prevalent are also tested for G6PDd.) Keeping the above in mind, what does the US Military report published in December 2019 tell us about the prevalence of G6PDd among the armed forces? https://health.mil/News/Articles/2019/12/01/Prevalence-of- Glucose The study was conducted of over 2 million active duty service members between 2004 and 2018. It found G6PD deficiency in about 2.3% of all men tested and 1.5% of women tested. If this is extrapolated to the 2019 US population of 330.8 million and 49.2% male, the result over 6.26 million people in the US would be expected to have G6PD deficiency. The starkest statistics were that --- while only 0.4% of white men had G6PDd --- 9.5% of African American active duty service members had G6PDd (11.2% of the men and 4.7% of the women.) Extrapolated to the whole population, the result is over 3.5 million African American people in the United States would be expected to have G6PDd. CORRELATION OF DEMOGRAPHICS (IN THE US & ABROAD) In the US, the demographic most likely to have inherited G6PDd corresponds to those who are having the most severe reactions to and deaths from COVID-19. While some studies have shown 60-88% of people totally asymptomatic and most of the rest with mild symptoms, we have already had well over 100,000 deaths and many with severe symptoms and lasting health consequences. Much has been rightly made of racial disparities in care and treatment being factors – as well as underlying health conditions. In addition, the increased inoculate load that would arise from cramped working and/or living conditions is likely a contributing factor. However, the fact that the racial and sex differences in severe COVID-19 reactions basically mirrors the demographics of those most likely to have G6PDd warrants immediate investigation. If genetic factors are being researched at all, this should be at the top of the list. There has also been much correlational evidence from around the world for a connection between G6PDd and severe COVID-19 reactions. For instance, there has been an uproar in Great Britain over the disproportionate representation among the deaths and severely ill of the BAME (Black, Asian, Minor Ethnic) communities. https://www.theguardian.com/world/2020/may/01/british-bame-covid-19-death-rate-more-than-twice-that-of- whites A Swiss study showed minimal ICU admissions in the German area, a moderate number in the French area, and the highest in the Italian area. India reports no ICU admissions from its territory with the lowest G6PDd prevalence. In addition to the correlation between G6PDd and severe reactions to COVID-19, there are likely other genetic factors that also need to be considered. For instance, though it is estimated that 42% of Saudi men have G6PDd, many also have protective alleles (D -ACE1) that serve to mitigate hemolytic reactions. This also deserves more attention. CORRELATION OF COVID-19 SYMPTOMS WITH REACTIONS FROM RHABDOMYOLYSIS & ACUTE EXTRA & INTRAVASCULAR HEMOLYSIS Even more than the demographic correlation, we note and are concerned that all the various current COVID-19 symptoms have been presented by patients with G6PDd in the past after being triggered into Rhabdomyolysis and hemolysis. The virus is new – but the myriad of symptoms is NOT. In addition, convincing evidence has shown that severe COVID-19 reactions are due to low endogenous reduced glutathione. https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00288?fbclid=IwAR0WXu7uta58eG07fhZgzj7QA8DdDZ 3B0Fnq1u4GJqewbp17HMezMZcyrIs#.XvKMshRY5_g.facebook However, the above article fails to mention that a primary reason someone would have low endogenous reduced glutathione would be G6PD deficiency. Oxidative stress with insufficient G6PD triggers Rhabdomyolysis and intravascular hemolysis, dumping the contents of the RBC’s into the plasma. Lowered Hemoglobin levels reduces oxygen transfer, bringing on hypoxia. Plasma free hemoglobin scavenges nitric oxide creating endothelial cell dysfunction, causing microvascular pulmonary thrombosis through platelet aggregation. Pulmonary pressure is increased from these blockages, creating hypertension. Thrombosis is noted in other organs such as kidneys and brains. Renal dysfunction from hemoglobinuria can lead to acute tublular necrosis. Immune response – chiefly through IL-6 is stimulating high fibrinogen levels for the noted angiogenesis to bypass blocked pulmonary capillaries. These high levels increase the viscosity of the blood, further increasing heart pressure. The high levels of IL-1 and IL-6 are in response for the need to stimulate increased production of Haptoglobin. Hemoglobin is being transformed to Methemoglobin and Carboxyglobin – further reducing Oxygen transfer. (Also – G6PD levels are higher in new blood cells being produced during early stages of hemolysis (why serum tests for G6PD are inaccurately high during a hemolytic crisis.) G6PD contributes to angiogenesis, & G6PD inhibitors stop angiogenesis, but cause extreme inflammation throughout the body. Rhabdomyolysis dumps Myoglobin into the plasma stream. This further depletes Haptoglobin and Nitric Oxide, contributing to the above effects, especially Acute Kidney Injury. https://jamanetwork.com/journals/jama/fullarticle/200611 https://meridian.allenpress.com/aph/article/6/1/23/432022/Hemolysis-Associated-Endothelial- Dysfunction-and Immune Response to SARS-CoV-2 + G6PD Def/RBCs Rhabdomyolysis + Acute Intravascular Hemolysis Scavenging of Endothelial derived Nitric Oxide Endothelial Dysfunction Microvascular Pulmonary Thrombosis Other Microvascular Thrombosis (Kidney, Brain, etc) Further Distorted Immune System Response (Kawasaki Syndrome?) https://academic.oup.com/rheumatology/article/56/1/6/2631538 https://pubmed.ncbi.nlm.nih.gov/17205013/ https://journal-inflammation.biomedcentral.com/articles/10.1186/s12950-015-0078-z https://casereports.bmj.com/content/bmjcr/13/6/e236719.full.pdf G6PD inhibition causes severe autoinflammatory reaction https://www.hindawi.com/journals/crivem/2017/4275305/ We theorize that Rhabdomyolysis and hemolysis are being triggered by the extreme oxidative stress caused by the virus– with the immune response impaired due to the inability to overcome the oxidative stress on the muscle cells and RBCs that are G6PD deficient -- and possibly worsened by some of the treatments that might add to oxidative stress. High Myoglobin and Troponin levels and related bio-markers are being noted. While it is recognized they are not from Myocardial Infarction, they are NOT being accounted for in accounts we have seen. We further suggest that hemolytic anemia is being overlooked in many cases due to common testing practices for hemoglobin that can give a higher level reading than it actually is. http://eclinpath.com/hematology/tests/hemoglobin/ Any method that uses a lysing agent to disrupt the RBCs and releases hemoglobin into the plasma fluid to then be measured by a spectrophotometer would also include any free hemoglobin that would be in the plasma due to intravascular hemolysis. Blood clots all over the body, hypoxia, heart arrythmia, and many other current COVID19 severe reactions have all been experienced in the past by G6PD deficient people after being triggered by a drug, chemical, or virus producing extreme oxidative stress. Medications that weaken cell walls also make muscle cells more vulnerable. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275177/ https://medlineplus.gov/ency/article/000571.htm https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770956/ https://www.karger.com/Article/PDF/451030 https://www.ahajournals.org/doi/full/10.1161/atvbaha.109.184812 MORE & MORE DCOTORS ARE SEEING A POSSIBLE G6PDD-COVID19 SEVERE REACTION LINK https://www.hematologyadvisor.com/home/topics/general-hematology/case-study-reveals-glucose-6- phosphate-dehydrogenase-deficiency-linked-to-worse-sars-cov-2-infection/ https://www.sciencedirect.com/science/article/pii/S0188440920309486 https://bit.ly/g6pd-covid https://www.medpagetoday.com/infectiousdisease/covid19/85929 https://www.mayoclinicproceedings.org/article/S0025-6196(20)30598-X/pdf We recommend that all physicians treating COVID-19 patients be aware of all aspects of rhabdomyolysis and both extra and intravascular hemolysis, including the most accurate testing, the presentations at various stages, the likelihood of a virus such as COVID-19 to cause it, and the most appropriate treatments – taking care not to heighten the oxidative stress if possible. G6PDd history and testing should also be indicated for COVID-19 patients. It should be noted that during a hemolytic crisis, the G6PD level will read inaccurately high with a serum test (due to the body desperately producing new RBCs and free hemoglobin being dumped into the plasma.) Therefore, the genetic test is needed --- and it must be understood that all heterozygous women should be noted. For current or past military members, the G6PDd status in their military records should be considered accurate – as they would have been done when the service person was not in a hemolytic crisis. In addition, for women the military used the cytochemical assay test which more accurately detects G6PD activity in women than the typical fluorescent spot test used for men. IMPLICATIONS FOR TREATMENT If the extreme oxidative stress of COVID19 is a main reason for severe reactions, then treatment implications would start with suspending or limiting any treatments that increase oxidative stress or weaken cell membranes. Fluids help with Rhabdomyolysis – to the extent that lungs are not negatively affected. Treatments that help overcome oxidative stress and increase GSH and NADPH (n-acetyl-cysteine, IV glutathione, IV Vitamin C at the low level recommended for people with G6PD deficiency) and increase G6PD activity (Vitamin D) should be beneficial. https://www.cebm.net/covid-19/n-acetylcysteine-a-rapid-review-of-the-evidence-for- effectiveness-in-treating-covid-19/ https://www.researchgate.net/post/Potential_Cheap_and_effective_Drug_for_COVID-19 https://medicalxpress.com/news/2020-05-vitamin-d-severity-covid-advice.html https://www.sciencedaily.com/releases/2008/05/080513112351.htm THE QUICKEST, SIMPLEST PRELIMINARY RESEARCH If researchers had access to records regarding the G6PDd status of military members diagnosed with COVID-19 – along with severity of symptoms from asymptomatic to fatal – a quick comparison could be made to see if a greater percentage of those with severe symptoms have G6PDd than the 2.2% for the military overall. Comparisons of G6PDd of armed forces on military bases who have contracted COVI-19 would be valuable information. Some of the larger VA Medical Centers could also help in this regard --- as well as other hospitals that have had large numbers of cases. In addition, similar information from the USS Theodore Roosevelt could prove beneficial. Of nearly 1200 infected, 60% were asymptomatic, only eight were admitted to the hospital. There was one death, 41-year-old Chief Petty Officer Charles Robert Thacker. https://www.businessinsider.com/doctors-warned-dozens-of-uss-theodore-roosevelt-sailors-might-die-2020-5 Though the number of severe reactions is a small sample, the release of the G6PDd status to civilian researchers for a comparative analysis could benefit the people of the United States as a whole – as well as the rest of the world as we struggle to understand and effectively manage this pandemic. Comparing just ONE VA Hospital ICU admissions for COVID19 with G6PD status would be so simple, quick, and inexpensive and could yield such valuable information during this pandemic. But so far, NO study during this pandemic that we are aware of – whether correlational or drug trial – has taken G6PD status into account at all – despite persistent pleas from the head of the G6PD Deficiency Foundation. It is way past time to stop ignoring over 6.25 million people in the US and over 400 million world-wide! WHAT WE ARE ASKING OF ANY AGENCIES, ORGANIZATIONS, OR INDIVIDUALS CONCERNED ABOUT COVID-19 1. Help in educating about G6PDd regarding the important implications for treatment and understanding of COVID-19 (& sign this petition) https://www.change.org/p/world-health-organization-need-more- awareness-and-research-g6pd-deficiency-and-its-role-in-the-corona-virus-pandemic 2. Advising of the importance of any known G6PDd records of patients, as well as genetic TESTING for all COVID patients who do not have G6PDd records. 3. If in the US: Help in gaining access to military data that already exists to do a quick correlational analysis or – convincing ONE Hospital to do a study. If in a country that regularly tests for G6PD – a quick comparative study of COVID19 ICU admissions of ONE Hospital to start. 4. Help in educating about the recognition of Rhabdomyolysis and hemolysis -- most accurate testing, bio- markers, etc. 5. More biological research into the G6PDd-COVID-19 connection, including oxidative stress caused by COVID-19 (as well as any proposed treatments), the necessity of G6PD to balance the oxidative stress – including its necessity for GSH production, NADPH, & the P-P-P, and Rhabdomyolysis and hemolysis resulting from inability to overcome oxidative stress on RBCs and muscle cells. To comment on this paper, please email: terri.falbo@gmail.com
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