A Randomized Controlled Trial for Cervicothoracic Sympathetic Chain Block Against Sham Injection Evaluation for Post COVID Condition: the CeASE RCT

Post COVID Condition (PCC): In the wake of the COVID-19 pandemic, while many individuals recover fully from an acute COVID-19 infection, a substantial proportion experience ongoing or evolving symptoms well beyond the initial illness. These prolonged effects are broadly referred to as long COVID, also commonly referred to as the post-COVID conditions (PCC). The WHO defines long COVID as a condition following confirmed or probable SARS-CoV-2 infection, with symptoms lasting at least 2 months, typically beginning 3 months postinfection, and not explained by an alternative diagnosis. In Canada, at least 15 million people were infected with COVID-19 and 1 in 5 adults who had COVID-19 developed long-lasting symptoms after their initial infection. Of those, more than half (58.2% or about 2.1 million people) still have ongoing symptoms, defined as PCC. The annual economic burden of PCC in Canada is significant, with estimates from a Public Health Agency of Canada report suggesting a total healthcare cost between CAD 7.8 and CAD 50.6 billion. Costs per case can range from CAD 1,675 to CAD 7,340 in the first year after infection, with unvaccinated individuals experiencing higher costs and quality-adjusted life-year decrements.

Manifestations of and autonomic dysfunction in PCC: PCC presents in diverse ways and can affect multiple organ systems, including the cardiovascular, respiratory, neurological, and gastrointestinal systems. There is a range of symptoms that are encompassed within the syndrome of PCC, including fatigue, shortness of breath, chest pain, palpitations, headache, cognitive impairment ('brain fog'), rashes, anxiety, depression, gastrointestinal upset, persistent anosmia, and more with chronic fatigue and dyspnea as the most common. When cardiovascular or autonomic symptoms are present, clinicians are advised to evaluate for conditions associated with long-term sequelae of COVID-19 infection including myalgic encephalomyelitis or chronic fatigue syndrome; post-exertional malaise and post-exertional symptom exacerbation, dysautonomia with cardiac manifestations (e.g. inappropriate sinus tachycardia and postural orthostatic tachycardia syndrome (POTS: sustained and symptomatic increase in heart rate of ≥30 bpm within 10 minutes of standing without a drop in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg)), and mast cell activation syndrome (MCAS).

While some symptoms result from tissue damage of COVID-19, persistent symptoms despite tissue repair suggest additional mechanisms in PCC. A key hypothesis implicates pathological inflammation, potentially driven by persistent viral presence, T-cell dysfunction, and B-cell hyperactivity,sustaining a hyperinflammatory state. This process contributes to cytokine storms, immune dysregulation, multiorgan inflammation, reactivation of latent pathogens, autoimmunity, and microclot formation. The sympathetic nervous system plays a critical role in immune regulation. Sympathetic fibers innervate primary and secondary lymphoid organs, and immune cells express adrenergic receptors and neuropeptides, enabling modulation by neurotransmitters released from sympathetic nerve terminals. Through these mechanisms, the SNS regulates both immune homeostasis and pathological activation. This neuroimmune cross-talk provides context for understanding the role of SNS in chronic inflammation, including PCC. Symptoms resembling autonomic dysfunction have also been observed following various viral infections such as HIV and herpes viruses, and a similar pattern is evident in PCC. Symptoms such as brain fog, fatigue, chest pain, palpitations, and severe orthostatic intolerance syndromes suggest an interaction between inflammation and autonomic hyperactivity. These findings implicate the sympathetic nervous system as a potential therapeutic target for PCC.

Many PCC symptoms that are resistant to conventional treatments have been associated with dysautonomia an abnormal functioning of the autonomic nervous system, which regulates involuntary bodily functions such as heart rate and blood pressure, respiration, and digestion. While the underlying pathophysiology of PCC remains incompletely understood, emerging evidence suggests that the autonomic dysfunction in these patients reflect immune-mediated dysregulation of the autonomic nervous system. The sympathetic branch of the autonomic nervous system plays a key role in neuroimmune communication; however, this delicate balance can be disturbed by elevated levels of pro-inflammatory cytokines, which drive sympathetic overactivity and contribute to systemic inflammation. In SARS-CoV-2 infection, this process has been well described in the literature and attributed to the cytokine storm, in which sympathetic activation is a central component of the immune response. Heightened sympathetic signaling further engages the brainstem to initiate "sickness behaviors" a cluster of physiological and behavioral responses that closely resemble the symptomatology of PCC. When this state of sympathetic hyperactivity persists over time, it may contribute to, or exacerbate, the chronic and debilitating symptoms experienced by individuals with PCC.

Treatment approaches for PCC: Medications such as ivabradine, beta blockers, midodrine, and fludrocortisone are recommended by the Canadian POTS guidelines and may improve orthostatic tolerance and cerebral perfusion in POTS patients, including those with PCC. However, responses are highly variable, access remains a barrier, and side effects can be limiting. Rehabilitation is further complicated by post-exertional symptom exacerbation (PESE), which makes structured exercise risky for many PCC patients. Preliminary studies outside of PCC suggest possible benefit from transcutaneous vagus nerve stimulation and jugular vein compression collars, but do not achieve symptom remission and benefits may wane once the user stops wearing the device.