Hypothesis: Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19, 2021, Kappelmann et al

[Andy]

Highlights

• Long COVID symptoms include fatigue, sleeping difficulties, depression and anxiety.
• These symptoms may arise from effects of interleukin 6 (IL-6) on the brain.
• Cytokine driven immuno-metabolic constraints on neuronal energy metabolism can cause fatigue.
• Anti-IL-6 treatment reduces severe complications and mortality in COVID-19 patients.
• IL-6/IL-6R pathway could be a target for treatment and prevention of long COVID.

Abstract

The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety. We propose that neuroimmune cross-talk via inflammatory cytokines such as interleukin-6 (IL-6) could underpin these long-term COVID-19 symptoms. This hypothesis is supported by several lines of research, including population-based cohort and genetic Mendelian Randomisation studies suggesting that inflammation is associated with fatigue and sleeping difficulties, and that IL-6 could represent a possible causal driver for these symptoms. Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic.

Open access, https://www.sciencedirect.com/science/article/pii/S0306453021001694

 

[Hutan]

Interesting to track who is getting involved in this type of hypothesising, I think.

NilsKappelmann a,b; RobertDantzer c; Golam M.Khandaker d,e,f,g
a Department of Research in Translational Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany
b International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
c Department of Symptom Research, University of Texas MD Anderson Cancer Centre, Houston, TX, USA
d MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
e Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
f Department of Psychiatry, University of Cambridge, Cambridge, UK
g Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK

The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety.

That seems a bold statement and unlikely to be true, if 'long-term' means anything like what I assume it to mean (i.e. more than 3 months) and 'depression' and 'anxiety' means substantially more than feeling a bit worried and sad about what the pandemic has done to one's family and community and financial well-being. The authors mention a Wuhan study that found that about 75% of patients still experienced at least one physical or mental health symptom six months after hospitalisation, with fatigue or muscle weakness (63%), sleeping difficulties (26%), and depression or anxiety (23%) being the most common - but these were hospital-discharged patients.

and specifically with somatic symptoms of depression such as fatigue, sleeping difficulties, and appetite alterations among others

Using data from the UK Biobank and the Netherlands Study of Depression and Anxiety (NESDA) cohorts, we have recently shown that fatigue and sleeping difficulties exhibit the most consistent links with inflammatory markers among all depressive and anxiety symptoms,

The authors seem to assume that fatigue and sleeping difficulties means depression. This inability to see fatigue as separate from depression means that their analysis lacks clarity.


Nevertheless, they do seem to be thinking about Long Covid in biological terms. This was interesting:

For greater insights into IL-6-related mechanisms of long COVID, future immunophenotyping studies would benefit from assays of soluble IL-6R (sIL-6R) and soluble glycoprotein 130 (sgp130). This would provide a more complete picture of IL-6 signalling, which occurs via two distinct pathways (Hunter and Jones, 2015, Scheller et al., 2014). IL-6 classic signalling occurs when IL-6 binds to membrane-bound IL-6Rs together with the ubiquitously expressed gp130. However, membrane-bound IL-6Rs are only present on hepatocytes and certain immune cells and this process is thought to be mainly responsible for central homoeostatic rather than inflammatory processes. In contrast, the pro-inflammatory effects of IL-6 are mainly mediated via IL-6 trans-signalling, whereby IL-6 binds sIL-6Rs and induces signalling on cells that naturally lack IL-6Rs.

IL-6 trans-signalling has been specifically associated with autoimmune conditions and with sleep-related processes (Dimitrov et al., 2006, Hunter and Jones, 2015), which provides a plausible link for the involvement of this form of signalling in long COVID. Blocking IL-6/IL-6R pathway is an established treatment strategy for various autoimmune and inflammatory diseases (Tanaka et al., 2012), which provides an opportunity for randomised controlled trials testing whether this could also be useful for treatment and prevention of long COVID. Such trials could include currently licensed anti-IL-6R monoclonal antibodies such as tocilizumab that inhibit both classic and trans-signalling, or novel IL-6 trans-signalling-specific drugs such as the soluble gp130 fused chimera (sgp130Fc) currently in development. These interventional trials would also be valuable for determining whether trans-signalling-specific drugs have a favourable risk-benefit profile compared to drugs that block both classic and trans signalling (Du et al., 2021).