SARS-CoV-2 was the cause of the global COVID-19 pandemic. Irrespective of disease severity, a growing number of patients report a chronic fatigue syndrome (CFS), dyspnea, anemia and other symptoms. At least 10% of all COVID-19 patients experience various persistent or newly occuring health complaints after SARS-CoV-2 infection, lasting longer than three months. Recently, we demonstrated that SARS-CoV-2-induced dysregulation in hemoglobin (Hb)- and iron-metabolism contributes to the severe systemic course of COVID-19. Since, changes in the hemoglobin structure may also contribute to the development of Long-COVID symptoms, we analyzed the Hb- and iron-metabolism in Long-COVID-Patients in comparison to healthy individuals.

We performed blood gas analyses in more than 40 Long-Covid-19 samples and controls. Furthermore, an automated differential blood count was performed from peripheral blood of Long-COVID patients and compared those with healthy donors. Metabolites of the porphyrin metabolism were analyzed in plasma-reduced whole blood samples using mass spectrometry.

Whereas, no differences in the RBC count, Hb content and hematocrit were observed in Long-COVID patients compared to healthy donors, we interestingly found significantly increased levels of COHb and also profound changes in the spin state of the iron in Hb. The spin state of the iron was partially comparable to packed RBCs stored for 42 days, suggesting an accelerated ageing of RBCs in Long-COVID patients. In addition, BE- and BI values but not pH were diminished in Long-COVID patients compared to healthy donors, albeit still within the normal range. Lactate levels were also significantly elevated in the blood of Long-COVID patients. Thus, O2Hb was reduced in Long-COVID patients. Mass spectrometry revealed a significant increase in toxic porphyrin intermediates (uroporphyrin III, coproporphyrin I/ III) in erythrocytes of Long-COVID patients.

Our data suggest the formation of a secondary coproporphyria as a result from SARS-CoV-2 infection leading to accelerated ageing of RBCs in Long-COVID patients possibly further impairing their physiological function. Together with the diminished Acid-base balance and the enhanced formation of COHb, we describe a drastically impaired erythrocyte functionality in Long-COVID patients, leading to an impaired oxygen supply which explains common symptoms of Long-COVID, such as CFS, dyspnea and anemia.

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