Klaus Cort @Klaus-Cort

EPO levels were significantly lower in critical and deceased Covid-19 patients:

Article The relationship between serum erythropoietin, hepcidin, and...

Article Low Serum Erythropoietin Levels are Associated with Fatal CO...

Suggested treatment for both Covid-19 and LongCovid: rhEPO :

https://brieflands.com/articles/jkums-126623.html

https://pubmed.ncbi.nlm.nih.gov/?term=erythropoietin+covid

https://www.researchgate.net/post/Covid-19_Erythropoietin_EPO_deficiency_syndrome2

https://www.researchgate.net/post/EPO_treatment_of_Covid-194

Signs, symptoms and co-morbidities in PostCovid indicate continued EPO deficiency:

Inflammatory cytokines

TNF-alpha, IFN-gamma, IL1B, IL6, IL17A ... (etc.) all suppress EPO:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279918/

Article The Role of Interferons in Long Covid Infection

Article IFN-γ directly inhibits the activity of erythropoietin in hu...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805325/

https://journals.lww.com/jasn/Fulltext/2003/07000/Increased_Expression_of_Erythropoiesis_Inhibiting.8.aspx

https://drive.google.com/file/d/1oPSw3MSpMkjW74HLoT2gXV1oWUNecSuO/view?usp=sharing

arrow direction = "increase of") EPO treatment would move "Covid-19" to the right in the figure. It follows that too much EPO can be harmful (at the far right in the figure.

Obesity, diabetes and pain in the joints

https://nature.com/articles/ncomms1526

Article Erythropoietin (EPO) ameliorates obesity and glucose homeost...

https://pubmed.ncbi.nlm.nih.gov/?term=diabetes+covid

https://pubmed.ncbi.nlm.nih.gov/?term=diabetes+erythropoietin

Article Erythropoietin Reduces Insulin Resistance via Regulation of ...

https://www.jpeds.com/article/S0022-3476(96)70195-6/fulltext

Article Erythropoietin Non-hematopoietic Tissue Response and Regulat...

Article Erythropoietin and obesity-induced white adipose tissue infl...

Article Adipose tissue is a critical regulator of osteoarthritis

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(22)00227-2/fulltext

Article Blunted erythropoietin to anemia in rheumatoid arthritis

Article Hypoxia and its implications in rheumatoid arthritis

Article What is the role of erythropoietin prolotherapy on pain reli...

https://www.jrheum.org/content/jrheum/28/11/2430.full.pdf

Article The links of hepcidin and erythropoietin in the interplay of...

Article Decreased serum erythropoietin and its relation to anti-eryt...

Muscle pain and exercise intolerance

Article Clinical Characteristics and Mechanisms of Musculoskeletal P...

Article The erythropoietin receptor expressed in skeletal muscle is ...

https://pubmed.ncbi.nlm.nih.gov/?term=erythropoietin+Muscle

Article The erythropoietin receptor expressed in skeletal muscle is ...

Article Effect of Erythropoietin on Exercise Capacity in Patients Wi...

Article Skeletal muscle alterations and exercise performance decreas...

Article Effect of Erythropoietin on Exercise Capacity in Patients Wi...

Lack of energy

Article Erythropoietin, a Novel Versatile Player Regulating Energy M...

Article The erythropoietin receptor expressed in skeletal muscle is ...

Article Acute erythropoietin injection increases muscle mitochondria...

Lack of energy - red blood cells

EPO regulates the lives and deaths of red blood cells:

Article Hematological alterations associated with long COVID-19

Article Changes in Hematological and Hemorheological Parameters Foll...

https://pubmed.ncbi.nlm.nih.gov/32825629/

https://pubmed.ncbi.nlm.nih.gov/33171297/

Article Anemia of inflammation

Article IFN-γ directly inhibits the activity of erythropoietin in hu...

https://pubmed.ncbi.nlm.nih.gov/32983414/

http://researchgate.net/publication/357172246_Activation_of_Sphingomyelinase-Ceramide-Pathway_in_COVID-19_Purposes_Its_Inhibition_for_Therapeutic_Strategies/comments

EPO is the natural inhibitor of the Sphingomyelinase-Ceramide-Pathway :

Article Oxidative Stress and Suicidal Erythrocyte Death

Article Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role a...

Article Cholesterol Deficiency Causes Impaired Osmotic Stability of ...

Article Fine‐Tuning of Cholesterol Homeostasis Controls Erythroid Di...

Endothelial dysfunction and heart disease

Article Persistent Endothelial Dysfunction in Post-Acute COVID-19 Sy...

Article Diabetes, Heart Failure, and COVID-19: An Update

Article Evidence of Pulmonary Hypertension after SARS-CoV-2 Infectio...

https://www.kidney-international.org/article/S0085-2538(15)45998-8/fulltext

https://academic.oup.com/eurheartj/article/28/16/2018/492834?login=false

Article Erythropoietin therapy improves endothelial function in pati...

Article Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by...

Article Important Role of Endogenous Erythropoietin System in Recrui...

https://www.sciencedirect.com/science/article/abs/pii/S0196978119301597

Article Erythropoietin Activates Mitochondrial Biogenesis and Couple...

Article Erythropoietin Attenuates Cardiac Dysfunction in Rats by Inh...

Article Cardiomyocyte Specific Knock‐out of Erythropoietin Has Adapt...

Article Regulation of TLR4 expression mediates the attenuating effec...

Article Erythropoietin and Its Angiogenic Activity

HDL-Cholesterol deficiency, lipids and thrombosis

Article High-density lipoprotein cholesterol: A marker of COVID-19 i...

https://www.frontiersin.org/articles/10.3389/fpubh.2021.705916/full

https://www.ajkd.org/article/S0272-6386(06)00763-3/fulltext

https://www.hilarispublisher.com/open-access/effect-of-erythropoietin-therapy-on-the-lipid-profile-in-patients-with-chronic-kidney-disease-a-single-center-study-2161-0959.1000140.pdf

Article COVID-19 and lipids. The role of lipid disorders and statin ...

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00389-8/full

Article Kidney-secreted erythropoietin lowers lipidemia via activati...

Article High-density lipoprotein as a modulator of platelet and coag...

Article Post–COVID-19 Arterial Thrombosis: A Systematic Review

Article Thrombo-inflammation in Long COVID – the elusive key to post...

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1257988/full

EPO inhibits (/regulates) NF-kappaB:

Article Suppression of NLRP3 Inflammasome by Erythropoietin via the ...

(........to be continued)

https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0043-1775965.pdf

Unfortunately it is likely that LongCovid patients will need EPO treatment for a long time to fully recover - they have suffered from EPO deficiency for a long time. Too high a dose will provoke the production of TNF-alpha & Co., and therefore have no effect on the inflammation. (Similar to treatment with corticosteroids - see below under "Hypocortisolemia ..."). Decreasing the dose over time is suggested.

Co-aministration of thrombolytic therapy and rhEPO should be avoided:

Article Recombinant Human Erythropoietin in the Treatment of Acute I...

Micro-amyloid-fibrinogen-clots

All the effects of the EPO deficiency are more than likely to be statistically associated.

Therefore should even strong statistical association between any two of them be interpreted with caution.

Otherwise we could end up with male reproduction/sexual problems being cause of blindness :) (see below).

Known molecular mechanisms or proof of new ones should be provided before claiming that the "micro clots" have any effect.

Article Plasmapheresis to remove amyloid fibrin(ogen) particles for ...

The micro amyloid fibrinogen clots are yet another sign of erythropoietin deficiency in LongCovid :

Article Inflammation, serum C-reactive protein, and erythropoietin resistance

And EPO treatment is how to get rid of them :

https://karger.com/hrp/article-abstract/44/4/189/370642/Total-Fibrin-and-Fibrinogen-Degradation-Products?redirectedFrom=fulltext

Lowered sperm quantity, motility and vitality

Article Changes of sperm parameters in men recovered from coronaviru...

Article Erythropoitein Increases In Vitro Motility and Vitality of H...

Article Sphingomyelin Modulates Capacitation of Human Sperm In Vitro

Endothelial Dysfunction in Erectile Dysfunction:

https://onlinelibrary.wiley.com/doi/10.1002/j.1939-4640.2003.tb02743.x

Hypocortisolemia

... caused by EPO-deficiency, inflammatory stress and maybe corticosteroid treatment.

https://www.sciencedirect.com/science/article/abs/pii/S000689931500181X?via%3Dihub

"Prolonged or exaggerated stress response may perpetuate cortisol dysfunction, widespread inflammation, and pain." :

Article Chronic Stress, Cortisol Dysfunction, and Pain: A Psychoneur...

Article Cortisol Exerts Bi-Phasic Regulation of Inflammation in Humans

Article Protracted stress-induced hypocortisolemia may account for t...

Article Erythropoietin attenuates locomotor and cognitive impairment...

Article Erythropoietin prevents the effect of chronic restraint stre...

Loss of memory - brain fog

https://pubmed.ncbi.nlm.nih.gov/?term=amyloid+beta+erythropoietin

https://pubmed.ncbi.nlm.nih.gov/?term=Erythropoietin+myelin

Article Erythropoietin Increases Myelination in Oligodendrocytes: Ge...

https://www.eneuro.org/content/6/4/ENEURO.0421-18.2019

https://pubmed.ncbi.nlm.nih.gov/?term=Erythropoietin+dementia

Article The Impact of Low Hemoglobin Levels on Cognitive Brain Functions

Article Erythropoietin attenuates locomotor and cognitive impairment...

Article Erythropoietin improves memory function with reducing endoth...

Article Erythropoietin promotes hippocampal mitochondrial function a...

Article Erythropoietin Regulates the In Vitro and In Vivo Production...

Erythropoietin re-wires cognition-associated transcriptional networks:

https://www.nature.com/articles/s41467-023-40332-8

https://article.imrpress.com/bri/Landmark/articles/pdf/Landmark4408.pdf

Depression and anxiety

https://www.nature.com/articles/1301439

Article Antidepressant-Like Effects of Erythropoietin: A Focus on Be...

Article Erythropoietin Pathway: A Potential Target for the Treatment...

Article Effects of erythropoietin on emotional processing biases in ...

https://www.iomcworld.org/open-access/a-possible-mechanism-of-antidepressant-like-effect-of-recombinant-human-erythropoietin-46047.html

Cognitive impairment in children

Article Cognition and Mental Health in Pediatric Patients Following COVID-19

EPO is essential for brain development:

Article Erythropoietin Regulates the In Vitro and In Vivo Production...

Article Erythropoietin in Brain Development and Beyond

https://nature.com/articles/s41380-022-01551-5

https://sciencedirect.com/science/article/pii/S1878747923004452

https://www.hindawi.com/journals/ari/2012/953264/

https://nature.com/articles/s41598-023-46783-9

Article Erythropoietin in Human Milk: Physiology and Role in Infant Health

Loss of or distorted taste

EPO is vital for the maintenance of both myelin and sphingomyelin.

Article Taste Dysfunction in Multiple Sclerosis

Article Differential effects of membrane sphingomyelin and cholester...

Article Sphingolipid/cholesterol regulation of neurotransmitter rece...

Article No Smell, No Taste—Dealing With a “Senseless” Phase of the P...

Blindness

Article Abrupt bilateral blindness as a rare post-acute demyelinatin...

Article Vision Loss and COVID-19 Infection A Systematic Review and M...

https://pubmed.ncbi.nlm.nih.gov/?term=erythropoietin%20blindness&page=2

Article Erythropoietin in Optic Neuropathies: Current Future Strateg...

Article Erythropoietin in ophthalmology: A literature review

Article The effect of systemic erythropoietin and oral prednisolone ...

Hearing loss

Article One year on: an updated systematic review of SARS-CoV-2, COV...

https://www.everydayhealth.com/coronavirus/hearing-loss-and-tinnitus-are-lesser-known-symptoms-of-covid-19/

https://pubmed.ncbi.nlm.nih.gov/?term=hearing+eryhthropoietin

Article Sudden Sensorineural Hearing Loss Associated with Nutritiona...

EPO ↔ Melatonin ↔ Serotonin ↔ EPO --> dopamine

https://core.ac.uk/reader/82431570

https://pubmed.ncbi.nlm.nih.gov/19767630/

https://pubmed.ncbi.nlm.nih.gov/31132978/

https://www.researchgate.net/publication/365592639_Efficacy_and_safety_of_oral_melatonin_in_patients_with_severe_COVID-19_a_randomized_controlled_trial

https://www.researchgate.net/publication/359178853_Melatonin_increased_hypoxia-inducible_factor_HIF_by_inhibiting_prolyl_hydroxylase_A_hypothesis_for_treating_anemia_ischemia_and_covid-19

https://www.researchgate.net/publication/373771449_The_global_challenges_of_the_long_COVID-19_Journal_of_Clinical_Images_and_Medical_Case_Reports

https://www.pnas.org/doi/10.1073/pnas.2113852118

https://www.cell.com/cell/fulltext/S0092-8674(23)01034-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867423010346%3Fshowall%3Dtrue

https://www.nature.com/articles/1301439

https://www.pnas.org/doi/10.1073/pnas.1103964108

https://www.mdpi.com/1422-0067/23/15/8144

Article Erythropoietin improves neurobehavior by reducing dopaminerg...

Article Stimulating effect of erythropoietin on the release of dopam...

Article Erythropoietin Regulates the In Vitro and In Vivo Production...

Article International Journal of Molecular Sciences Dopamine Transmi...

Fatty liver

Article Metabolic-Associated Fatty Liver Disease Is Highly Prevalent...

https://besps.journals.ekb.eg/article_210608.html

Article Erythropoietin suppresses hepatic steatosis and obesity by i...

Article The Potential Role of Erythropoietin on Fatty Liver Induced ...

https://www.nature.com/articles/srep17878

Kidney damage

Article Long-term interplay between COVID-19 and chronic kidney disease

Article Kidney Damage in Long COVID: Studies in Experimental Mice

Article Erythropoietin ameliorates renal interstitial fibrosis via t...

https://journals.lww.com/jasn/fulltext/2021/11000/kidney_outcomes_in_long_covid.19.aspx

Article Erythropoietin Protects the Kidney by Regulating the Effect ...

Article Renal Cell Protection of Erythropoietin beyond Correcting Th...

Article Erythropoietin and renal protection

https://www.frontiersin.org/articles/10.3389/fmed.2020.00047/full

https://journals.lww.com/jasn/fulltext/2021/10000/erythropoietin_reduces_auto__and_alloantibodies_by.21.aspx

Inflammation and lung tissue damage

(Not meaning that inflammation is only in lungs)

Article Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A P...

Article Suppression of NLRP3 Inflammasome by Erythropoietin via the ...

Article Post-COVID-19 Pulmonary Fibrosis: Facts-Challenges and Futur...

https://erj.ersjournals.com/content/54/suppl_63/PA2425

Preprint Multimodal Molecular Imaging Reveals Tissue-Based T Cell Act...

https://www.nature.com/articles/nrneph.2014.73

Article Neutrophil Extracellular Traps and Long COVID

Article Erythropoietin inhibits neutrophil extracellular traps forma...

https://www.nature.com/articles/s41590-023-01724-6

Article Immunosuppressive Effects of Erythropoietin on Human Allorea...

Article Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity

Article Differential Roles of SOCS Family Members in EpoR Signal Transduction

Article SOCS Proteins: Negative Regulators of Cytokine Signaling

Article Covid-19 Hyperinflammation and Post-Covid-19 Illness May Be ...

Article Erythropoietin acts as an anti-inflammatory signal on murine...

https://researchgate.net/publication/51902180_The_Receptor_That_Tames_the_Innate_Immune_Response

https://www.nature.com/articles/s41419-020-2276-8

https://researchgate.net/publication/331975246_Erythropoietin_a_multifaceted_protein_with_innate_and_adaptive_immune_modulatory_activit

Article EPO ameliorates lung injury by accelerating pulmonary endoth...

Article Cytoprotective effects of erythropoietin: What about the lung?

Article Erythropoietin Attenuates Pulmonary Vascular Remodeling in E...

Article Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role a...

Article Erythropoietin: A Potent Inducer of Peripheral Immuno/Inflam...

Article Erythropoietin as a new therapeutic opportunity in brain inf...

Autoimmunity

Article Autoimmunity is a hallmark of post-COVID syndrome

https://www.frontiersin.org/articles/10.3389/fimmu.2021.639370/full

Article Erythropoietin and autoimmune neuroinflammation: lessons fro...

https://www.sciencedirect.com/science/article/abs/pii/S0896841121000378

https://journals.lww.com/jasn/fulltext/2021/10000/erythropoietin_reduces_auto__and_alloantibodies_by.21.aspx

Article Erythropoietin inhibits SGK1-dependent TH17 induction and TH...

Article Erythropoietin: A Potent Inducer of Peripheral Immuno/Inflam...

Article Erythropoietin Reduces Auto- and Allo-Antibodies By Inhibiti...

Gut microbiota dysbiosis

https://www.sepsis.org/news/the-connection-between-covid-19-sepsis-and-sepsis-survivors/

Article Detection of Intestinal Dysbiosis in Post-COVID-19 Patients ...

https://www.sciencedirect.com/science/article/pii/S0753332223008636

https://diabetesjournals.org/diabetes/article/72/Supplement_1/239-LB/149885/239-LB-Erythropoietin-Alters-Fat-Mass-and-Gut

Functional iron deficiency

Article Iron deficiency and postcovid syndrome: a clinical case

Chapter Iron Deficiency and Anemia Associated with Infectious and In...

Article Pantohematogen Efficacy Evaluation in Complex Sanatorium Reh...

Article The role of hypoxia and inflammation in the regulation of ir...

Article SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeo...

Article Anemia and iron metabolism in COVID-19: a systematic review ...

https://www.nature.com/articles/labinvest201711

Dysautonomia and POTS

The causes of these conditions are not fully known/understood/agreed upon. But many very likely explanatory factors have been mentioned in the above.

Why women more often suffer from LongCovid ?

Adult females mount stronger innate and adaptive immune responses than males: https://www.nature.com/articles/nri.2016.90

This means a stronger EPO-TNFalpha imbalance.

Estrogen suppresses and testosterone increases the production of EPO in the kidneys:

https://pubmed.ncbi.nlm.nih.gov/15784734/

Article Testosterone Induces Erythrocytosis via Increased Erythropoi...

This makes a threshold for younger to middle age female patients to recover their own EPO-production, while in particular younger men quickly recover from or don't get Covid-19 and rarely suffer from LongCovid.

This may thus in part also explain the age-distribution in Covid-19 and in LongCovid.

Racial/ethnic differences

Article Racial/Ethnic Disparities in Post-acute Sequelae of SARS-CoV...

Article The Association of Race With Erythropoietin Dose in Patients...

Article Ethnic differences in anemia among patients with diabetes me...

Conclusion

EPO deficiency is "the common denominator" in both LongCovid and in Covid-19.

Covid-19 and LongCovid are immunologic, hematologic, metabolic, neurologic and endocrinologic diseases.

That sounds complicated, but it is all due to deficiency of a single substance, that stands ready in our common medicine cabinet.