Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19, 2024, Hanson et al

Mij

Mij

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Low ferritin levels for pwME has been a mystery. My levels were normal when I was tested by an Internist during the first year of illness, but rapidly started decreasing for no apparent reason for many years after. I took iron supplements regularly. No one could figure it out why.

I don't think it was from inflammation in my case b/c I had a c-reactive protein test and it was normal.

https://www.cam.ac.uk/research/news...enews&utm_medium=miragenews&utm_campaign=news
 
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Mij said:
Low ferritin levels for pwME has been a mystery. My levels were normal when I was tested by an Internist during the first year of illness, but rapidly started decreasing for no apparent reason for many years after. I took iron supplements regularly. No one could figure it out why.

I don't think it was from inflammation in my case b/c I had a c-reactive protein test and it was normal.

https://www.cam.ac.uk/research/news...enews&utm_medium=miragenews&utm_campaign=news
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If you had inflammation or infection in your body your ferritin (iron stores) would have ended up higher than normal, not lower, because ferritin is a positive Acute Phase Protein. The body has iron in the blood stream (referred to in testing as serum iron) and also stores it in ferritin. The iron in the blood stream is available to pathogens so the body keeps that iron to a minimum, lowers haemoglobin, and stores the "excess" iron in ferritin (which pathogens can't get iron from thus reducing their chances of reproducing), which is why ferritin goes up in the case of inflammation and infection.

Since your ferritin levels were decreasing it would suggest that something (I don't know what) was preventing you from absorbing iron from your diet, or perhaps you were losing blood somewhere, or you developed one of the more unusual forms of anaemia. Whether your serum iron was going up while your ferritin was going down without being noticed could happen because doctors rarely do iron studies testing (which includes a serum iron test) because they think ferritin tells them everything they need to know about iron.
 
I tried a gluten free diet for almost a year even though I tested negative for gluten sensitivities, I cooked with cast iron pots, ate plenty of liver and roasts with vitamin C, took digestive enzymes that might have helped a little, eradicated h pylori, ate fermented foods . . . I dunno. My functional/integrated doctor was perplexed.

I also did an iron metabolism test. The TIBC and UIBC were both on the lower end. It indicates the that the storage capacity of iron is almost insufficient. A further decrease of UIBC would have led to free iron in circulation according to my records. This produces oxidative stress itself. I also had high oxidative stress.
 
Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19
Hanson, Aimee L.; Mulè, Matthew P.; Ruffieux, Hélène; Mescia, Federica; Bergamaschi, Laura; Pelly, Victoria S.; Turner, Lorinda; Kotagiri, Prasanti; Göttgens, Berthold; Hess, Christoph; Gleadall, Nicholas; Bradley, John R.; Nathan, James A.; Lyons, Paul A.; Drakesmith, Hal; Smith, Kenneth G. C.

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC.

A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes.

Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

Link | PDF (Nature Immunology) [Open Access]
 
Timely thread. I am currently under investigation for seriously low iron, despite being on heavy duty supplements for a few months now. Iron levels barely moved over that time, and are still below the minimum required, which raised my doctor's eyebrows.

My diet on its own should be good enough to supply it, but even with the supplements it just isn't showing up in the blood test. Might start including some liver in the diet (probably best source of heme iron, and very cheap), see if that helps.
 
Sean said:
Timely thread. I am currently under investigation for seriously low iron, despite being on heavy duty supplements for a few months now. Iron levels barely moved over that time, and are still below the minimum required, which raised my doctor's eyebrows.
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Are they checking your ferritin?

My sister has low iron levels from Hashimoto. Did you get your thyroid levels tested?
 
Don't know. But will ask at next visit.

Already been booked in for return visit to the gastroenterologist to do a capsule endoscopy, make sure the small intestine is okay. (Recently had a colonoscopy, so we know that section is okay.)
 
Sean said:
Timely thread. I am currently under investigation for seriously low iron, despite being on heavy duty supplements for a few months now. Iron levels barely moved over that time, and are still below the minimum required, which raised my doctor's eyebrows.

My diet on its own should be good enough to supply it, but even with the supplements it just isn't showing up in the blood test. Might start including some liver in the diet (probably best source of heme iron, and very cheap), see if that helps.
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What kind of supplements are you taking? Are they iron salts? Heme supplements? If they don't work because you don't absorb iron very well, and food doesn't help either, then perhaps you might need an iron infusion.
 
Sean said:
Maltofer (100mg iron as 370mg iron polymaltose).
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I've seen occasional references to that but have never read any experiences of it. I hope any side effects are minor. :thumbup: :)

I'm assuming you've seen the Patient Information Leaflet :

https://www.nps.org.au/medicine-finder/maltofer-syrup#full-pi

If you are taking an iron syrup, remember to rinse your mouth with water after taking each dose. Liquid iron products can blacken the teeth.
 
Arnie Pye said:
I hope any side effects are minor.
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Main one seems to be a substantial increase in muscle aches and pains, which makes sleep in particular more difficult and disturbed, which is why I am thinking of trying other means of getting iron.

Just had a couple of weeks off it and then went back on it, and the muscle stuff came back within a couple of days.

Might not be the iron polymaltose itself, of course, but the pill they wrap it up in. Going to halve the dose see if that helps.
 
Here we present an extended longitudinal characterization of 214 SARS-CoV-2-infected individuals, from asymptomatic to requiring ventilation, who were followed for up to one year from the first SARS-CoV-2-positive swab or symptom onset. Combined analysis of longitudinal immunological, hematological, transcriptomic and clinical data indicated inflammation-driven iron dysregulation that persisted beyond 2 weeks in patients who were hospitalized with COVID-19 and which had apparent physiological repercussions for erythropoiesis and iron homeostasis months after infection. With integrated assessment of patient-reported PASC symptoms, we show that this signature of slow-resolving inflammation, iron dysregulation and ineffective compensatory stress erythropoiesis was a strong early correlate of PASC more than 3 months later.
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That paragraph makes it sound as though the iron problems are an outcome of serious Covid-19 i.e. in hospitalised patients. Maybe not relevant to ME/CFS-like LC?
 
Study is a prospective one, healthy controls and then five groups of Covid-19. A is asymptomatic; B is mild infection; C-E is increasing severity.

The iron-regulating hormone hepcidin (induced by IL-6)25 blocks the release of iron from cells, particularly from erythrophagocytic macrophages, through direct binding and degradation of the cellular iron exporter ferroportin26. Hepcidin was elevated in the serum of groups C–E at day 0–14 compared with the HCs (Fig. 2a), and elevated serum concentrations of the iron storage protein ferritin were seen up to days 30, 90 and 180 for groups C, D and E, respectively (Fig. 2a), suggesting ongoing inflammation and increased cellular iron retention. In contrast, the levels of iron, the iron transport protein transferrin and transferrin iron saturation (TSAT; the ratio of serum iron to the blood’s total iron binding capacity) were markedly reduced in the serum of groups C–E at day 0–14 compared with HCs, and serum iron and TSAT remained significantly lower in group E at day 181–270 post onset (Fig. 2a,b and Supplementary Fig. 3). There was little evidence of systemic inflammation or associated disruptions to the iron levels of groups A and B (Fig. 2a).
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Screen Shot 2024-03-09 at 7.24.37 pm.png

Maybe there's something going on in A there (asymptomatic group), the blip on the right hand side of the normal distribution of the fold changes in iron homeostasis genes relative to the healthy controls? Maybe there could be some iron issue accounting for the onset of ME/CFS-like LC? But then, we should be seeing those symptoms at much higher levels in people with severe disease. And I don't think we've seen that, although if people with severe disease are mostly old, all sorts of ME/CFS-like symptoms in those people could be being swept under the carpet.

Overexpression of iron-homeostasis genes relative to HCs was observed up to day 90–180 in group C, day 30–90 in group D and day 180–270 in group E (Fig. 3b and Extended Data Fig. 3d). The upregulated genes reflected cellular responses consistent with both iron overload and iron deprivation, probably capturing signatures from different blood-cell subsets.
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The study goes on to look at persisting symptoms in the various groups. I think it's a study worth looking more at, although I'm still not sure how relevant it is to ME/CFS. There's a lot of fatigue being reported by the people who had severe illnesses - but that might just be an illustration of the many causes of fatigue, rather than of the fact that they have something like ME/CFS. I have to stop now.
 
Sean said:
Maltofer (100mg iron as 370mg iron polymaltose).
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I just want to make a comment about iron supplements in general. I was told to take Palafer many years ago and it was too much (300 mg) to take at once since our body only absorbs 10% and the rest has to be filtered out through the liver which makes us feel sick.

This was the best iron supplement I took rec by my integrative/functional M.D. It was developed by a biochemist who specializes in iron and owns a compounding pharmacy in my area. I've seen him several times for other tests years ago.

 
Sean said:
Timely thread. I am currently under investigation for seriously low iron, despite being on heavy duty supplements for a few months now. Iron levels barely moved over that time, and are still below the minimum required, which raised my doctor's eyebrows.

My diet on its own should be good enough to supply it, but even with the supplements it just isn't showing up in the blood test. Might start including some liver in the diet (probably best source of heme iron, and very cheap), see if that helps.
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Good that you're being checked out for possible gastro bleeds.

In case it's relevant, a consultant haematologist told me that it is better to take iron supplements every second day rather than every day - you actually absorb more that way. This was a moot point for me as I can't tolerate any of them, but might be worth looking into for you.

I developed severe anaemia a couple of years ago and after outruling a gastric bleed, it was rectified with an iron infusion and vitamin C (which helps iron absorption) - both were recommended by the haematologist. (They recommended 2 infusions but long story short, I didn't get the second.) I also had a 1-unit blood transfusion which was recommended by a different doctor - my understanding is that this was not necessary and should probably not have been given. But I did have tachycardia (due to severe anaemia) so they weren't messing around. I have been able to maintain normal levels since with a vitamin C supplement once a day, and a medication to reduce menstruation.
 
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My daily dose of iron supplementation was 27mg w vitamin C. It took 9 months to bring my ferritin up to 55 from 5 and it would drop back down to 14 within 2 months after I stopped taking iron.

Alternate-day administration of 100 and 200 mg taken from the link posted above would make sense b/c it's quite a high amount.
 
Sean said:
Main one seems to be a substantial increase in muscle aches and pains, which makes sleep in particular more difficult and disturbed, which is why I am thinking of trying other means of getting iron.

Just had a couple of weeks off it and then went back on it, and the muscle stuff came back within a couple of days.

Might not be the iron polymaltose itself, of course, but the pill they wrap it up in. Going to halve the dose see if that helps.
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Not being able to tolerate oral iron is a good reason for an iron infusion. Maybe you could ask for referral to a haematologist if you aren't seeing one already?
 
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