Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses

Abstract

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.

Figure 1

Follow-up studies reporting persistent cough in patients with post-COVID syndrome Studies sorted by follow-up duration in ascending order from left to right. Follow-up duration ranges from 6 weeks to 6 months. Data were retrieved from available publications, including peer-reviewed papers and preprints., , , , , , , , , , , , , , , , Detailed characteristics of each study are summarised in table 1. Some studies did not report acute cough data.

Figure 2

Prevalence of post-COVID cough in 14 studies of patients who required hospitalisation Follow-up duration ranges from 6 weeks to 4 months. Detailed characteristics of included studies are summarised in table 1., , , , , , , , , , , , , We conducted a random-effects meta-analysis to estimate the pooled prevalence and standard errors for post-COVID-cough in previously hospitalised patients, and quantified the degree of heterogeneity between studies using the I in the MetaXL 5.3 software (EpiGear International Pty, Sunrise Beach, QLD, Australia).

Figure 3

Proposed mechanisms of cough in SARS-CoV-2 infection SARS-CoV-2 might induce cough via neuroinflammatory and neuroimmune mechanisms. (Left) Direct infection or viral recognition by vagal sensory neurons or sensory neuron-associated glial cells could promote a neuroinflammatory state, characterised by neuronal or glial release of neuroactive inflammatory mediators. Neuroinflammation could occur at the level of the nerve terminal in the airways and lungs, within the vagus nerve containing the neuronal axons, at the level of the vagal sensory ganglia containing neuronal cell bodies, or at sites within the CNS responsible for integrating vagal sensory inputs. Neuroinflammatory mediators include neuronally released interferons and glial-derived ATP, which are important for antiviral responses within the nervous system. (Right) Traditional inflammatory cells, including dendritic cells, macrophages, neutrophils, and epithelial cells, involved in SARS-CoV-2 infection and viral recognition can also release a broad range of inflammatory mediators, including antiviral interferons, cytokines, prostanoids, lipid mediators, and ATP. Many of these mediators can activate or sensitise vagal sensory nerves via cognate receptors or gating ion channels, providing a neuroimmune axis for alterations in vagal sensory neuron activity. Sensory neuron activation could enhance inflammation via the release of neuropeptides, which facilitate inflammatory cell recruitment and activation in a process known as neurogenic inflammation. Collectively, these cascades could upregulate sensory neuron activation and input to brain circuits mediating cough. ACE2=angiotensin-converting enzyme 2 (or other viral entry factors). IFNAR=interferon receptor. P2X2/3=purinergic receptors. TLRs=toll-like receptors. TNFR=tumour necrosis factor receptor. TRPs=transient receptor potential channels.