Multicentre retrospective detection of nailfold videocapillaroscopy abnormalities in long covid patients, 2025, Ginaldi et al.

[SNT Gatchaman]

Multicentre retrospective detection of nailfold videocapillaroscopy abnormalities in long covid patients
Lia Ginaldi; Giovanna Cuomo; Study Group on Capillaroscopy and Microcirculation in Rheumatic Diseases of the Italian Society of Rheumatology (Capsir); Emanuele Gotelli; Rosanna Campitiello; Dilia Giuggioli; Maurizio Cutolo; Serena Guiducci; Valeria Riccieri; Carmen Pizzorni; Francesco Carubbi; Evy Di Ruscio; Rossella De Angelis; Emanuela Martinelli; Massimo De Martinis; Vanessa Smith; Alberto Sulli; Silvia Sammorì; Ernesto Aitella; Francesca Ingegnoli; Sabrina Marrone; Marco Sebastiani

BACKGROUND
SARS-CoV-2 induces acute non-specific endothelial/microvascular alterations that have been identified by nailfold videocapillaroscopy (NVC). Details on NVC abnormalities in long covid (LC) patients (pts) are unknown.

METHODS
LC pts without and with systemic sclerosis (non-SSc-LC and SSc-LC), recovered COVID-19 (RC) pts that did not develop LC and healthy matched control subjects (CNT) that underwent NVC examinations were evaluated in a multicentre national study from the Capillaroscopy and Microcirculation in Rheumatic Diseases Study Group of the Italian Society of Rheumatology. Retrospective collection was performed for demographic data, course of SARS-CoV-2 infection, comorbidities, concomitant drugs. NVC alterations were quantified by validated scores. Pre-COVID-19 and post-COVID-19 microvascular status was analysed by NVC.

RESULTS
62 non-SSc-LC pts (49 female/13 male, 51±16 years old), 24 SSc-LC pts (21 female/3 male, 59±17 years old), 23 RC pts (18 female/5 male, 51±18 years old) and 84 CNT (68 female/16 male, 52±12 years old) were analysed. Non-SSc-LC pts showed significantly more dilated capillaries (p<0.01, p multivariate<0.01), microhaemorrhages (p=0.01, p multivariate<0.05), abnormal shapes (p<0.05, p multivariate<0.05) than CNT and of note, lower mean capillary number per linear millimetre (p<0.01, p multivariate<0.01) than both RC pts and CTN (p<0.01, p multivariate<0.05).Of highest interest, 16 non-SSc-LC pts showed statistically significantly more dilated capillaries (p<0.05) and microhaemorrhages (p<0.05) in NVC examinations after COVID-19, compared with pre-COVID-19 status.Similarly, SSc-LC pts (24) showed significantly lower capillary density (p=0.01) and more dilated capillaries (p<0.01) in NVC examinations after COVID-19, compared with pre-COVID-19 status.

CONCLUSIONS
LC pts show more microvascular alterations at NVC as compared with RC patients and CNT, which may contribute to the pathogenesis of persistent organ/systems dysfunction.

Link (RMD Open) [Open Access]

Note the journal page is not yet active. The PubMed link is here.

 

[Murph]

This looks like a really easy test, they push a microscope against the bit of skin where it joins onto the fingernail and take photos of the capillaries

https://www.sciencedirect.com/science/article/pii/S1521694223000359

Would be great to have this test tacked onto any future metabolomic / CPET / etc investigation, and clinical trials too, could help define subgroups.

 

[SNT Gatchaman]

Now published —

WHAT IS ALREADY KNOWN ON THIS TOPIC
SARS-CoV-2 induces endothelial and capillary damage, that is detectable by nailfold videocapillaroscopy (NVC). NVC shows significant capillary dilations, microhaemorrhages and abnormal shapes in the acute phase of COVID-19 and significant reduction of nailfold capillary density in the short-term recovery phase (3 months).

WHAT THIS STUDY ADDS
NVC shows significant microvascular damage in long covid (LC) patients compared with matched healthy controls. Dilated capillaries, microhaemorrhages, abnormal shapes and reduced capillary density are still detectable in LC patients 12 months after acute SARS-CoV-2 infection. NVC demonstrates normalisation of nailfold capillary density in recovered COVID-19 patients without LC symptoms 12 months after acute SARS-CoV-2 infection.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
NVC reveals significant persistence of microvascular damage in LC patients. The involvement of microcirculation is a matter of further investigation in LC pathogenesis and related systemic symptoms.

Link | PDF (RMD Open) [Open Access]

 

[SNT Gatchaman]

Although they had ~80% females in the groups, they've shown three males and one female in this figure.

Reformatting the legend —

(A) healthy control patient, male, 60 years old: normal hairpin capillaries without dilations, no microhaemorrhages, normal capillary density (12 capillaries per linear mm) and no abnormal shapes are present.

(B) a recovered COVID-19 patient without long covid, male, 53 years old: dilated capillaries are highlighted by asterisks and capillary density is normal (9 capillaries per linear mm).

(C) long covid patient without systemic sclerosis, male, 42 years old: two abnormal shapes (neoangiogenesis) are highlighted by asterisks and capillary density is reduced (5 capillaries per linear mm).

(D) long covid patient without systemic sclerosis, female 39 years old: two dilations are highlighted by asterisks and capillary density is 8 capillaries per linear mm

In each image, the black horizontal line represents a linear millimetre. Magnification 200x.

 

[SNT Gatchaman]

The discussion included this comment —

An important mediator of endothelial damage is type I interferon produced by plasmacytoid dendritic cells. Although type I interferon plays a crucial antiviral role, its aberrant production promotes hyperinflammatory syndrome through the stimulation of the cGAS-STING (cyclic GMP-AMP synthase - Stimulator of Interferon Genes) pathway in macrophages adjacent to endothelial cells.

@Jonathan Edwards you previously commented on nailfold capillaroscopy in FM and I think you'll be interested in this paper.

 

[wigglethemouse]

When I took part in a capillaroscopy study my wife's images looked like picture A and mine were worse than B, C, D. I could see what looked like damage in mine and quite a bit of looping despite my nails being good. Never really found a resource to explain it and what causes it.

At the time the researchers were interested in viewing red blood cells. I could see my (pwme) red blood cells whizzing along but my wifes (control) were rather slow, opposite of what I expected.

 

[Utsikt]

Could this be an issue in e.g. diabetes? If so, how does the results here compare to those?

 

[Murph]

Could this be an issue in e.g. diabetes? If so, how does the results here compare to those?

Yes, diabetes has microvascular abnormalities visible on capillaroscopy.


Apparently diabetes includes a lot of "connected" vessels, which reminds me of the idea of "shunting" which David Systrom has raised.

So it is unlikely this test would reveal patterns unique to me/cfs. What it might do is help define a subgroup, possibly (speculation follows) the group more prone to POTS. And I really believe we need to define subgroups because there's so much noise in our data.

Now. The dermatoscope the scientists used in that study is worth only $2000. Which is cheap in the scheme of medical devices. But I recently bought a microscope for my 5 year old with 800x magnification for about $45. Optics and electronics have come a very long way.

So I suspect a person who knew what they were doing could find a dermatoscope cost-effectively. (EDIT: I just gave myself a nailbed capillaroscopy without even getting off the couch, using the kids microscope; seeing the vessels turns out to be pretty easy, I just needed to pull the skin taut and they were visible. Apparently doctors add clear oil, I will try that next.)

And then the obvious thing to do would be to track over time. I don't know if or how fast you could expect the patterns to change, but it would be an interesting n=1 if they did!

 

[Jonathan Edwards]

I got involved in nail fold microscopy around 1984 and published a brief paper with Frances Ledford and Michael Snaith. You can certainly see abnormalities in autoimmune connective tissue diseases but it is rarely used in clinical practice. It is not easy to quantify, but probably could benefit from an AI algorithm.

I think it would be reasonable to do a blinded study of nail fold capillaries in ME/CFS - maybe deliberately choose a severe+ cohort to have biggest chance of a result. Forty cases and forty controls would probably be a minimum. Sixty would probably be good - age and sex matched. You might want to 'train' an AI algorithm on twenty and check another forty.

I think it quite likely that a rigorously blinded and controlled prospective study would come up with nothing but that in itself would be very worth documenting. If there was a real difference then that would be a major finding. Nailfold capillaries may change with lack of hand use but I don't think that would be expected to produce shape changes in capillaries, certainly not dilatations.

Maybe someone in Edinburgh or at LSHTM might pick this up? Or Australia of course.

 

[Utsikt]

I got involved in nail fold microscopy around 1984 and published a brief paper with Frances Ledford and Michael Snaith. You can certainly see abnormalities in autoimmune connective tissue diseases but it is rarely used in clinical practice. It is not easy to quantify, but probably could benefit from an AI algorithm.

I think it would be reasonable to do a blinded study of nail fold capillaries in ME/CFS - maybe deliberately choose a severe+ cohort to have biggest chance of a result. Forty cases and forty controls would probably be a minimum. Sixty would probably be good - age and sex matched. You might want to 'train' an AI algorithm on twenty and check another forty.

I think it quite likely that a rigorously blinded and controlled prospective study would come up with nothing but that in itself would be very worth documenting. If there was a real difference then that would be a major finding. Nailfold capillaries may change with lack of hand use but I don't think that would be expected to produce shape changes in capillaries, certainly not dilatations.

Maybe someone in Edinburgh or at LSHTM might pick this up? Or Australia of course.

Could they bring the microscope to their bed at home?

 

[EndME]

Could they bring the microscope to their bed at home?

I think at some point in the LC community there were some discussions about whether this couldn't be done at home via smartphone+accessory. I guess it might be more useful to first have a standard test in a condition where there is no knowledge about whether there are differences in Nailfold capillaroscopy or not.

I think this talk was around the same time different studies on retinal measurements were coming out (Hohberger and some others). Can one expect group differences in Nailfold capillaroscopy if there are no differences in retinal measurements?

 

[Jonathan Edwards]

Could they bring the microscope to their bed at home?

We used to do it with a drop of oil and a magnifying glass. That is good enough for picking up abnormal shapes. A smartphone with s drop of oil would probably do, maybe with a small portable lens and frame to lie on the finger in a reproducible way.

Can one expect group differences in Nailfold capillaroscopy if there are no differences in retinal measurements?

The nail fold capillaries are very unusual in that the nail fold, or cuticle, is constantly re-growing and vessels are constantly being replaced. This is probably why it is such a good place to look at capillary changes in scleroderma, where eventually you run out of telomere and no new capillaries form so the tissue dies off. In dermatomyositis new vessels form but immediately become abnormal. That is the basis of a clinical sign called 'mechanics hands'. The cuticles become tatty and bleed.

This might not be relevant to ME/CFS but if vessels are susceptible to damaging factors I think you are quite likely to see it at the nail and not in the eye.

 

[Utsikt]

This might not be relevant to ME/CFS but if vessels are susceptible to damaging factors I think you are quite likely to see it at the nail and not in the eye.

How would this tie into the discussion about disappearing fingerprint that we had here?
https://www.s4me.info/threads/fingerprints-and-fingertips-any-problems.43171/

 

[Jonathan Edwards]

How would this tie into the discussion about disappearing fingerprint that we had here?

I doubt it would much. The cuticle is a very unusual and very limited zone of skin - a few millimetre wide.

 

[Midnattsol]

I get horizontal grooves on my thumbnails a while after a crash, they nearly almost disappeared while I was pregnant but have returned post-partum. Could be an issue with nutrient delivery to the nail bed.

 

[wigglethemouse]

Could they bring the microscope to their bed at home?

When I took part in a nailfold pilot study the researchers came to my home. The hardest part for me was keeping my hand very steady to capture a clear image and video. It was done in the sitting position.

 

[wigglethemouse]

I think it would be reasonable to do a blinded study of nail fold capillaries in ME/CFS - maybe deliberately choose a severe+ cohort to have biggest chance of a result. Forty cases and forty controls would probably be a minimum. Sixty would probably be good - age and sex matched. You might want to 'train' an AI algorithm on twenty and check another forty.

I think it quite likely that a rigorously blinded and controlled prospective study would come up with nothing but that in itself would be very worth documenting. If there was a real difference then that would be a major finding. Nailfold capillaries may change with lack of hand use but I don't think that would be expected to produce shape changes in capillaries, certainly not dilatations.

Maybe someone in Edinburgh or at LSHTM might pick this up? Or Australia of course.

That all sounds rather straight forward, and I hope it happens, but we come up with the same old issue again of :

1. Where will funding come from. Start-up costs + running costs. Who will carry out the training and pilot work to prove the to be developed procedures? e.g. Do we need image stabilisation for clearer pictures and video? Who is expert and willing enough to review and grade the images? Do we need the help of a computational Scientist? Does hand temperature affect image colours and contrast?

2. Where is the clinic we can get patients from? The only options seem to be CureME in the UK, or Physio's for ME. Would love to be proven wrong.

Reminder :
1. Even the Raman Spectroscopy study at Oxford which had completed the exploratory and sample analysis pipeline work had to be done slowly as funding for more samples and analysis came in, mainly from the ME Association. It seemed to me to take years and years to have enough samples to publish.

2. A larger follow up of the pilot red blood cell deformability study at Stanford cost $250,000 and ended up with the assigned researcher finding null result (I believe improper prep of samples, and a much later finding at UC Davis that controlling the oxygen content during micro-fluidic analysis was important). I bring that project up as that had to develop similar computational tools for unbiased rating of samples.

 

[Jonathan Edwards]

1. Where will funding come from. Start-up costs + running costs. Who will carry out the training and pilot work to prove the to be developed procedures? e.g. Do we need image stabilisation for clearer pictures? Who is expert and willing enough to review and grade the images? Do we need the help of a computational Scientist. Does hand temperature affect image colours and contrast?

1. This to me is actually quite a fundable project. The charities could take it on. Versus Arthritis could take it on. Even MRC or NIHR could. It would need a young intelligent investigator for maybe two years. The training you could do in a morning. I forget how we got the pictures forty years ago but it didn't cost anything. We used some old microscope lying around I think and maybe some salicylate to 'clear' the epidermis for optics. Trying it out just now I think a decent smartphone would do with some clearing gent and a simple lens. You certainly don't need image stabilisation. An image analysis expert would help but they are probably easy enough to find. You want a nice warm room but nothing fancy. We did our project with no funding. A salaried anatomist was interested in doing a clinical project on the side. A rheumatology registrar could set it up on the side without funds if necessary. This really is the sort of thing anyone could do in their kitchen with a bit of determination.

2. A clinic with patients is a real issue, I agree. But CureME might be able to provide the patients and even the GOS team might be able to doit for younger patients.

We need some data to get people interested, there is no doubt. I think rheumatology trainees would be interested if then. And of course we have Fluge and Mella who seem to be able to get patients to do anything. In the USA there is the Bateman Horne Centre. It doesn't matter where it is done.

We do need a shift in attitudes but this to me is something that could actually be put into action with a charity grant.

 

[Sasha]

I think it would be reasonable to do a blinded study of nail fold capillaries in ME/CFS - maybe deliberately choose a severe+ cohort to have biggest chance of a result.

Why is this worth looking at in PwME whose ME didn't follow Covid? Isn't all this microcirculation stuff likely to be quite Covid-specific?

 

[wigglethemouse]

(EDIT: I just gave myself a nailbed capillaroscopy without even getting off the couch, using the kids microscope; seeing the vessels turns out to be pretty easy, I just needed to pull the skin taut and they were visible. Apparently doctors add clear oil, I will try that next.)

And then the obvious thing to do would be to track over time. I don't know if or how fast you could expect the patterns to change, but it would be an interesting n=1 if they did!

This could be a good topic for a standalone thread, perhaps even an S4me "Citizen Science Project".