Vagus nerve inflammation contributes to dysautonomia in COVID-19, 2023, Woo et al.

[SNT Gatchaman]

Vagus nerve inflammation contributes to dysautonomia in COVID-19
Woo, Marcel S.; Shafiq, Mohsin; Fitzek, Antonia; Dottermusch, Matthias; Altmeppen, Hermann; Mohammadi, Behnam; Mayer, Christina; Bal, Lukas C.; Raich, Lukas; Matschke, Jakob; Krasemann, Susanne; Pfefferle, Susanne; Brehm, Thomas Theo; Lütgehetmann, Marc; Schädler, Julia; Addo, Marylyn M.; Schulze zur Wiesch, Julian; Ondruschka, Benjamin; Friese, Manuel A.; Glatzel, Markus

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction.

We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19.

Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID.

Link | PDF (Acta Neuropathologica)

 

[Hutan]

and found a decreased respiratory rate in non-survivors of critical COVID-19.

Apologies for my black humour this evening and no disrespect meant. But a strongly decreased respiratory rate rather reliably goes with the territory of being a non-survivor.

 

[Hutan]

Okay, looking at the paper.

I've criticised a lot of the vagus nerve related stuff - the clip on the ear that is supposed to send a current to the vagus nerve when there was little evidence of a neural connection; the singing in the shower to tone the vagus nerve; the lack of clarity over whether the problem is supposed to be an under or over active vagus nerve... I think there's been more.

But, this idea of the vagus nerve being infected with a pathogen, and that causing dysautonomia, and perhaps a sickness response? I think it's plausible.

Next, we aimed to determine whether SARS-CoV-2 is directly detectable in vagus nerves. We performed quantitative PCR in 23 samples of deceased COVID-19 patients and detected SARS-CoV-2 RNA in all specimens which was not the case for control samples (Fig. 1f).

This comment and chart don't help us a whole lot. The chart shows the presence of SARS-CoV-2 RNA in the vagus nerve for only 23 people who died of Covid-19. (The study consisted of 5 controls and 27 Covid-19 patients, post-mortem.) So, we don't know what the researchers found in the control samples - that is not charted. All we know is that they found the virus in the vagus nerve of all the Covid-19 patients, and that they didn't find the virus in all of the people who died of other causes. Maybe they didn't find the virus in the vagus nerves of any of the people who died of other causes, but we can't tell.

No evidence of degeneration of the neurons:

Of note, we did not find differences in axonal damage assessed by quantifying neurofilament, indicating that SARS-CoV-2-induced inflammation and neuronal stress responses do not lead to overt degeneration of the vagal neurons (Fig. 2i).

For the analysis of respiratory rate, they used the records of over 300 patients admitted to the ER with Covid-19. They found that respiratory rate increased with severity, but, for the people who later died, the respiratory rate was not what would have been expected - it was lower (orange box on the right of the chart below).

The spontaneous respiratory rate at admission was used as a biomarker for vagus nerve dysfunction due to the well-documented observations that stimulating the vagus nerve leads to an increased respiratory rate [22]. As expected, the respiratory rate steadily increased with disease severity. However, when looking at patients with critical COVID-19, we found that the respiratory rate had increased in survivors but not in non-survivors (Fig. 3d). Additionally, reduced respiratory rate was the strongest predictor for mortality in critical COVID-19 (Fig. 3e, summary statistics is provided in Table S3), supporting our hypothesis of vagus nerve dysfunction in COVID-19.

 

[Jonathan Edwards]

but, for the people who later died, the respiratory rate was not what would have been expected - it was lower.

That seems to fit with the story that people with severe Covid who do badly could be very hypoxic without shortness of breath. This was supposed to be due to the nature of the interstitial pneumonitis I think. Hypoxia is not necessarily a drive to breathing on its own but usually goes with high CO2. I think the suggestion was that microvascular changes skewed this.

I was not impressed by the macrophages in the vagus nerve being significant on the pictures. All nerves have a few macrophages and there did not seem to be much sign of inflammation as such - oedema or fibrin deposition etc.

 

[SNT Gatchaman]

From Happy or Silent Hypoxia in COVID-19–A Misnomer Born in the Pandemic Era (2021, Frontiers in Physiology) —

In conclusion, patients with COVID-19 pneumonia may present without dyspnea, despite severe hypoxemia. The absence of dyspnea is not specifically related to COVID-19 but may occur in any patient with acute hypoxemic respiratory failure exhibiting normal respiratory muscle function and relatively normal respiratory system mechanics.

Why COVID-19 Silent Hypoxemia Is Baffling to Physicians (2020, American Journal of Respiratory and Critical Care Medicine)
The pathophysiology of ‘happy’ hypoxemia in COVID-19 (2020, Respiratory Research)
Hypoxaemia related to COVID-19: vascular and perfusion abnormalities on dual-energy CT (2020, The Lancet Infectious Diseases)

 

[Hutan]

I think we can say that they have shown that the virus can and does infect the vagus nerve in severe acute cases - and that's something. It's a shame they weren't clearer about what they found in the five controls who died of other causes, and that they didn't tell us whether those cases had had Covid-19.

With respect to the idea that infection of the vagus nerve is the cause of dysautonomia and perhaps ME/CFS-like symptoms in general, I think we next need to see some post-mortem results about the infection of the vagus nerve from people who have died of other causes and a. had post-Covid-19 symptoms and b. had had covid-19 but no post-Covid-19 symptoms. It probably would also be useful to know if there any sort of latent viruses in the vagal nerves of people with Long Covid and healthy controls, not just SARS-CoV-2.

I don't think we would necessarily need to see evidence of much inflammation for the hypothesis to possibly be true.

I'm wondering about an animal model. If this hypothesis was correct, I think it's likely that other mammals would show evidence of dysautonomia with infected vagus nerves.