Long COVID debilitating symptoms are related to microscopic abnormalities that affect how oxygen is exchanged from the lungs to the red blood cells

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Many who experience what is now called “long COVID” report feeling brain fog, breathless, fatigued and limited in doing everyday things, often lasting weeks and months post-infection.

Using functional MRI with inhaled xenon gas, researchers have now identified for the first time that these debilitating symptoms are related to microscopic abnormalities that affect how oxygen is exchanged from the lungs to the red blood cells.

The LIVECOVIDFREE study, based at five centers across Ontario, and led by Western University professor Grace Parraga, is the largest MRI study of patients with long COVID. The research, published in Radiology, is the first to show a potential cause of these long COVID symptoms. By understanding the cause, team members responsible for patient care have been able to target treatment for these patients.

“I think it is always a conundrum when someone has symptoms, but you can’t identify the problem. Because if you can’t identify the problem, you can’t identify solutions,” said Parraga, Tier 1 Canada Research Chair in Lung Imaging to Transform Outcomes at Western’s Schulich School of Medicine & Dentistry.

By having study participants inhale polarized xenon gas while inside the MRI, the researchers see in real-time the function of the 300-500 million tiny alveolar sacs, which are about 1/5 of a mm in diameter and responsible for delivering oxygen to the blood.

“With our MRI technique, we can watch in real time the air moving through the alveolar membrane and through to the blood cells; and we can actually see the function of the tiny alveolar sacs in the lungs,” said Parraga. “What we saw on the MRI was that the transition of the oxygen into the red blood cells was depressed in these symptomatic patients who had had COVID-19, compared to healthy volunteers.”

Further CT scans pointed to “abnormal trimming” of the vascular tree, indicating an impact on the tiny blood vessels that deliver red blood cells to the alveoli to be oxygenated.

There also doesn’t appear to be any difference in severity of this abnormality between patients who had been hospitalized with COVID-19, and those who recovered without hospitalization, the study said. This is an important finding as the latest wave of COVID-19 infection has affected large numbers of people who did not need hospital-based care.

“For those who are symptomatic post-COVID, even if they hadn’t had a severe enough infection to be hospitalized, we are seeing this abnormality in the exchange of oxygen across the alveolar membrane into the red blood cells,” said Parraga.

The researchers recruited patients with suspected long COVID from two hospitals in London, Ontario: London Health Sciences Centre’s (LHSC) Urgent COVID-19 Care Clinic (LUC3), and St. Joseph’s Health Care London’s post-acute COVID-19 program. Participants were those with persistent shortness of breath more than six-weeks post-infection. Some study participants were still symptomatic after 35 weeks.

Study co-author Dr. Michael Nicholson is a respirologist with St. Joseph’s post-acute COVID-19 program, former member of the LUC3 clinical team at LHSC, and an associate scientist at Lawson Health Research Institute. He said patients who were describing these symptoms were also showing normal results on clinical breathing tests.

Innovative lung-imaging technique shows cause of long-COVID symptoms
These scans show what a healthy lung looks like (left) and lungs of patients after having COVID-19 (last three). The images also show where air flows in the lungs. Credit: Alexander Matheson

“We were looking for further modalities to look at their lung function that were not found through traditional clinical testing,” said Nicholson. “The findings allowed us to show that there was a physiological impact on their lungs that correlated with their symptoms.”

Study participant Alex Kopacz described his experience with COVID-19 as “harrowing.” He was admitted to LHSC’s University Hospital with the virus in 2021. A young, fit Canadian bobsledder and Olympic gold medalist, he never imagined that he would still be struggling to breathe months after infection.

“I was on oxygen for almost two months after COVID, and it took me almost three months to get to a place where I could go for a walk without gasping for air,” said Kopacz.

“The take-home message for me is that we have to remember that this virus can have very serious long-term consequences, which are not trivial. In my case, prior to getting sick, I didn’t think it would really affect me.”

A one-year follow-up is now underway to better understand these results longitudinally. The study was done in collaboration with researchers at LHSC, St. Joseph’s, Lakehead University, McMaster University, Toronto Metropolitan University and Sick Kids Hospital in Toronto.


COVID-19 and RBCs Metabolism

Many Coronavirus patients have acute lung involvement, accompanied by hypoxia and dyspnea as alarming symptoms. Others experience a seemingly well state, in which the lungs do not appear severely damaged despite insufficient blood oxygenation (silent hypoxia) [19]. These conditions have led several research groups to suppose a direct involvement of erythrocytes in Coronavirus infections [20,21,22].

Cosic et al., in 2020, through studies performed with the Resonant Recognition Model (RRM), proposed RBCs as an alternative point of access to the SARS-CoV-2 virus, which, by entering through the alveoli membrane in the lung, reaches the bloodstream [21]. In the blood, SARS-CoV-2 infects RBCs through the binding between S1 Spike protein and Band-3 protein on the erythrocyte membrane [20]. Moreover, Band-3 has already been indicated as a binding receptor for protozoan parasites, such as Plasmodium falciparum [23].

The link between Band-3 and the virus does not support viral replication but can affect different characteristics of the RBC, also linked to its functionality (as well as the release of oxygen). In this context, studies on RBCs from COVID-19 patients have highlighted significant metabolic alterations related to an increase in the glycolytic pathway to the detriment of the pentose phosphate pathway, highlighted by a characteristic increase in glucose consumption accompanied by an accumulation of intermediates of the glycolysis and higher levels of phosphofructokinase (PFK), the rate-limiting enzyme of glycolysis [24].

The metabolic shift towards ATP production in the glycolytic pathway clearly, also influences other metabolic pathways, such as the pentose phosphate pathway (PPP). In these conditions, the non-oxidative phase of PPP is increased, in which glycolysis intermediates are converted into the ribose-5-phosphate required for the synthesis of the nucleic acids, which is necessary for the virus replication [25,26].

In addition, high levels of oxidized glutathione and a significant decrease in enzymes forming part of the cellular defense line against oxidative stress were found, including superoxide dismutase 1 (SOD1), glucose-6-phosphate dehydrogenase, and peroxiredoxin [27,28,29]. RBCs from COVID-19 could, therefore, be more exposed to the attack of reactive oxygen species (ROS), resulting in induced cellular lysis and inability to carry oxygen.

Recalling the important role played by the cytoplasmic domain of Band-3 as a regulator of erythrocyte metabolism in response to the different states of Hb oxygenation, it could be thought that the SARS-Band-3 bond alters the binding capacity of the cytoplasmic domain of Band-3 to glycolytic enzymes and deoxygenated Hb, causing the recorded metabolic irregularities [30,31].

Last but not least, it has been shown that Band-3 protein is associated with RBC membrane in a macro-complex that coordinates the shape of the cell (by the cytoskeletal proteins bound), carbon dioxide uptake (by the action of Carbonic anhydrase II bound to the C-terminal domain of Band-3), and the oxygen release from Hb (by the Bhor effect and by the direct binding between the cytoplasmic domain of Band-3 and deoxygenated Hb) [32]. In this context the attack of S1 Spike protein to Band-3 protein on the erythrocyte membrane [20] may affect the release of oxygen to metabolically active tissues.

Hemoglobin and SARS-CoV-2

Coronavirus, similar to other viruses, is able to interact with protoporphyrin IX through the spike protein. The interaction takes place between the beta chains of Hb, ORF 8, and the surface glycoproteins of the virus [33,34]. Liu et al. highlighted a number of viral proteins (orf1ab, ORF3a, ORF7a, ORF8a, and ORF10) as potential ligands to the 1-beta chains of hemoglobin [33].

This binding causes the Hb denaturation and the inhibition of viral replication by blocking (as also seen for other viruses) the SARS-CoV-2-cell fusion mediated by the spike protein [33,35]. Hb alteration caused by the viral proteins, decreasing the percentage of fully functional Hb in oxygen transport, could contribute to the development of hypoxia and multi-faceted syndrome, one of the main signs of COVID-19.

The involvement of Hb beta chains in the evolution of COVID-19 finds an objective confirmation in some studies on the potential use of umbilical fetal blood transfusion on COVID-19 patients [36]. Increasing HbF in critically ill patients could help control disease progression, minimize morbidity, and increase survival rates [37]. Furthermore, the effect of SARS-CoV-2 on Hb has led to an assessment of COVID-19 as a potentially acquired acute porphyria [38].

Juan et al. reported an abnormal accumulation in the serum porphyrin profile of COVID-19 patients of the by-products uroporphyrin I, coproporphyrin I, and the metabolite coproporphyrin III, determined by high-performance liquid chromatography [39]. The interaction between SARS-CoV-2 and Hb would take place on two fronts: at the erythrocyte level, where the virus is introduced at the intracellular level through the link between spike and Band-3 protein, and at the level of the bone marrow, where the virus interacts with nascent erythroblasts through CD147 and CD26 [40,41].

The difference is that, at the erythrocyte level, the virus enters the red blood cell and interacts with the Hb molecule, but its replication is prevented by the absence of a nucleus while, in erythroblasts, the presence of nuclear material would facilitate viral replication and, in this case, the normal recycling of red blood cells from the spleen to the bloodstream would be inhibited, causing anemia [42].

It is important to note that high levels of glycosylated Hb increase CD147 expression, with an increased risk of further complications [43]. Lower Hb levels have been reported in several studies conducted in patients with severe COVID-19 disease, although there is no experimental evidence to date to support an alteration of the oxygen dissociation curve [44,44,45,46,47,48,49,50,51]. The decrease in Hb level might be a predictor of worsening pneumonia in COVID-19 patients, associated with the need for treatment with mechanical ventilation.

As the disease worsens, other hematological markers associated with hemoglobin become altered, such as bilirubin and ferritin, which progressively increase [52,53]. Several researchers show elevated methemoglobin (MetHb) and carboxyhemoglobin (COHb) concentrations in severely ill patients’ blood and suggest these former as potential markers of disease severity [54,55,56].

In addition to the obvious effect of oxidizing drugs, the increase in MetHb formation may derive from a physiological reaction due to the increase in nitric oxide (NO) caused by acute anemia as part of the physiological reaction to the disease [44,57,58,59,60]. In particular, in hospitalized COVID-19 cases, there has been an increase in cases of anemia equal to about 60–70%.

The release of NO is important for vasodilation and to prevent tissue hypoxia, but, at the same time, the NO release causes the oxidation of Hb in MetHb [55,56,57,61,62]. The increased level of CO-Hb could instead be related to the normal accumulation in the serum of porphyrin recorded in COVID-19 patients and to the progressive increase in bilirubin potentially linked to hemolytic anemia [38,39,52,53,56]. To this picture is added the breathing difficulty typical of COVID-19 that leads to a deficient CO elimination and potential formation of COHb.

Anemia and Iron Dysmetabolism in COVID-19

Anemia could be linked to iron homeostasis dysmetabolism found in subjects who suffered from severe or critical COVID-19 [63]. In detail, Sonnweber et al. highlighted persistent hyperferritinemia and alterations of iron homeostasis in non-resolving lung pathologies and poor patients’ performance [64]. Lanser et al. found the decline in Hb levels was more pronounced when accompanied by hyperferritinemia in hospitalized patients; transferrin levels decreased within the first week in all patients [63]. Many researches highlight low levels of Hb and high levels of ferritin in non-surviving patients [52,65,66].

Viruses generally increase iron deposits to promote their spread to host cells, and the immune system tends to control the overload of iron through transferrin saturation [67]. In COVID-19 patients, the virus invasion causes immune activation and the release of inflammatory cytokines such as interleukin 6, interleukin 1 beta, and tumor necrosis factor alpha [64]. Cytokines directly affect iron metabolism, triggering the production of hepcidin, the main hormone responsible for iron homeostasis, whose synthesis is increased by inflammatory cytokines and in cases of iron overload [68]. The release of hepcidin should instead be physiologically decreased in cases of anemia and hypoxia [69]. Ehsani also found a similarity (a conservative motif rich in cysteine) between the cytosolic subunit of the viral spike protein and hepcidin; SARS-CoV-2 would seem to mimic the hepcidin action [70]. Hepcidin binding to ferroportin limits the iron availability, blocking its export from cells; during COVID-19, there is, in fact, an iron overload in cells and tissues and a concomitantly reduced level of serum iron [65,69]. The reduced availability of serum iron results in a low transferrin saturation ratio that affects the Hb synthesis and erythropoiesis (RBCs production), leading to anemia of inflammation [69,71]. This decreased circulation of RBCs perpetuates hypoxemia and prevents tissue oxygenation, which is already difficult in patients with acute COVID-19 respiratory syndrome [72]. In fact, alterations in iron metabolism are associated with hypoxemia in COVID-19 patients [45,73].

referenc elink : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8878454/


More information: Alexander M. Matheson et al, Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-Acute COVID-19 Syndrome, Radiology (2022). DOI: 10.1148/radiol.220492

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