Long-COVID
is a postviral illness that can affect survivors of
COVID-19, regardless of initial disease severity or age. Symptoms
of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac
problems, cognitive impairments, myalgia, and others. While the possible
causes of long-COVID include long-term tissue damage, viral persistence,
and chronic inflammation, the review proposes, perhaps for the first
time, that persistent brainstem dysfunction may also be involved.
This hypothesis can be split into two parts. The first is the brainstem
tropism and damage in COVID-19. As the brainstem has a relatively
high expression of ACE2 receptor compared with other brain regions,
SARS-CoV-2 may exhibit tropism therein. Evidence also exists that
neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the
brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins
in the brainstem. The brainstem is also highly prone to damage from
pathological immune or vascular activation, which has also been observed
in autopsy of COVID-19 cases. The second part concerns functions of
the brainstem that overlap with symptoms of long-COVID. The brainstem
contains numerous distinct nuclei and subparts that regulate the respiratory,
cardiovascular, gastrointestinal, and neurological processes, which
can be linked to long-COVID. As neurons do not readily regenerate,
brainstem dysfunction may be long-lasting and, thus, is long-COVID.
Indeed, brainstem dysfunction has been implicated in other similar
disorders, such as chronic pain and migraine and myalgic encephalomyelitis
or chronic fatigue syndrome.