The mechanism of action of damage to the nervous system in long COVID is likely multifactorial. COVID-19 can directly infect the central nervous system through a hematogenous route, which can result in direct cytolytic damage to neurons. Infection can also affect the blood–brain barrier.24 Additionally, COVID-19 can invade the central nervous system through peripheral nerves, including the olfactory and vagus nerves.25 Many human respiratory viruses, including SARS-CoV-2, result in an increase in pro-inflammatory and anti-inflammatory cytokines; this so-called cytokine storm is an exaggerated response to infection and can trigger neurodegenerative and psychiatric syndromes.26 It is unclear whether the cytokine storm is different for people with COVID-19, compared to other respiratory viruses.
Respiratory symptoms are very common after COVID-1915: In studies, as many as 87.1% of patients continued to have shortness of breath ≥ 140 days after initial symptom onset, including breathlessness (48% to 60%), wheezing (5.3%), cough (10.5% to 46%), and congestion (32%),14,18 any of which can persist for as long as 6 months.9 Among a sample of previously hospitalized COVID-19 patients in Wuhan, China, 22% to 56% displayed a pulmonary diffusion abnormality 6 months later, with those who required supplemental oxygen during initial COVID-19 having a greater risk for these abnormalities at follow-up, compared to those who did not require supplemental oxygen (odds ratio = 2.42; 95% CI, 1.15-5.08).11
Cardiovascular symptoms. New-onset autonomic dysfunction has been described in multiple case reports and in some larger cohort studies of patients post COVID-19.27 Many common long COVID symptoms, including fatigue and orthostatic intolerance, are commonly seen in postural orthostatic tachycardia syndrome. Emerging evidence indicates that there are likely similar underlying mechanisms and a significant amount of overlap between long COVID and postural orthostatic tachycardia syndrome.27
A study of patients within the US Department of Veterans Affairs population found that, regardless of disease severity, patients who had a positive COVID-19 test had a higher rate of cardiac disease 30 days after diagnosis,28 including stroke, transient ischemic attack, dysrhythmia, inflammatory heart disease, acute coronary disease, myocardial infarction, ischemic cardiopathy, angina, heart failure, nonischemic cardiomyopathy, and cardiac arrest. Patients with COVID-19 were at increased risk for major adverse cardiovascular events (myocardial infarction, stroke, and all-cause mortality).28 Demographics of the VA population (ie, most are White men) might limit the generalizability of these data, but similar findings have been found elsewhere.5,10,15Given that, in general, chest pain is common after the acute phase of an infection and the causes of chest pain are broad, the high rate of cardiac complications post COVID-19 nevertheless highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.
Other symptoms. Body aches and generalized joint pain are another common symptom group of long COVID.9 These include body aches (20%), joint pain (78%), and muscle aches (87.7%).14,18
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