long-haul covid: a pain physician’s perspective p

By Joseph V. Pergolizzi, Jr. MD

The COVID-19 pandemic continues to challenge both patients and the healthcare system in the form of “long-haul COVID-19,” sometimes just called “Long COVID,” a viral persistence phenomenon that first garnered international attention when an online community started to describe and document extended symptoms after recovery from acute infection.1 One of these websites, WeAreBodyPolitic, used multiple patient self-reports to help describe upward of 50 symptoms that individuals believed had an association with a prior case of COVID-19.2 While the scientific community must exercise caution when weighing patient self-reports from often anonymous online sources, it soon became clear that Long COVID may represent a real and serious challenge to public health.

Viral Persistence

Viral persistence has been observed with other infections, such as the relapsing/remitting phases of chikungunya3 or the prolonged symptoms endured by some infected with the Ebola virus.4 Viral persistence can be explained by one or more of the following5:

● The virus’s ability to sequester and hide itself in immune-privileged sites ● Aberrant immune responses of the patient ● Autoimmunity issues

Experts talk about acute COVID-19 and chronic COVID-19 with a proposed cutoff of about 3 weeks separating the acute infection from more persistent symptoms.6 A consensus definition of Long COVID has yet to been formulated, with some saying that Long COVID occurs 12 or more weeks after the acute infection.6,7 It is not known how long Long COVID typically lasts, but some reports maintain that symptoms may persist for months.8

Symptoms May Differ from Acute Phase

Long COVID has been associated with a wide range of symptoms that do not necessarily mirror the symptoms experienced during the acute infection.1 The most frequently reported of these effects appear to be fatigue, cough, and dyspnea.9-11 Pain has been reported with Long COVID in the form of chest pain, myalgia, joint pain,9 neuropathy, and myelopathy.5 Many Long COVID symptoms are symptoms that can typically occur in chronic pain patients; that is, fatigue, malaise, disordered sleep, depression, cognitive problems (“brain fog”), and anxiety. Thus, it is not always clear if a chronic pain patient experiencing pronounced fatigue or depression after overcoming acute COVID infection is suffering from Long COVID, typical secondary symptoms of chronic pain, or possibly a combination. Furthermore, chronic pain patients may have pre-existing painful symptoms, such as joint pain, that can be challenging to differentiate as part of Long COVID or the original painful syndrome. Pain is one of the primary symptoms of infection, and pathogens are known to act on the sensory nervous system.12 A good example of viral effects on nociceptors is the painful condition known as postherpetic neuralgia. It is not known if the SarS-COV-2 affects the dorsal root ganglia or the trigeminal ganglia, but this is certainly a possibility. Headache pain is a common neurological symptom of both acute COVID infection and Long COVID. Since certain forms of headache pain are caused by nociceptors in the meninges,13,14 this implies that the headaches characteristic of Long COVID might be caused by a viral infection of these nociceptors.12 It has also been speculated that the inflammatory response driven by cytokine storm in severe cases of acute infection adversely affects nociception. Despite the fact that COVID is a pandemic, there has been very little study on the potential impact Long COVID might have on pain syndromes, both in chronic pain patients and in those without chronic pain. Cytokine storm, which can drive extreme inflammatory response in severe cases of COVID-19, raises interesting considerations in light of pain syndromes associated with Long COVID. 12 The results of cytokine storm in COVID-19 resemble sepsis.12 In patients who experience sepsis after critical illness, 44% developed chronic pain with sepsis the predominant risk factor.15 Further study is needed to better understand how cytokine-mediated inflammatory processes might promote or create chronic painful conditions. If cytokine storm can trigger a form of chronic pain, an after-effect of the COVID pandemic may be a new subpopulation of chronic pain patients.

Hypotheses Include Brainstem Dysfunction

An intriguing hypothesis about Long COVID maintains that it may involve persistent brainstem dysfunction.16 Long COVID may turn out to be more than one syndrome, such as the long-term effects of tissue damage, viral persistence, symptoms of chronic inflammation brought on by the acute infection, or some kind of a postviral syndrome.17 The notion that Long COVID is a brainstem dysfunction is predicated on the notion that the brainstem has a greater expression of aCe2 receptors than other areas of the brain, such that SarS-COV-2 viral tropism is thus likely to occur in the brainstem, which is already vulnerable to pathological immune activation.16 Indeed, certain autopsy findings support the fact that the brainstem may be vulnerable to viral damage from SarSCOV-2.16 The symptoms of Long COVID have a degree of overlap with brainstem functions: respiratory regulation, cognitive problems, headache, fatigue, myalgia, and gastrointestinal symptoms.16 Thus, the hypothesis presented maintains that low-grade dysfunction of the brainstem caused by acute COVID may be what is now known as Long COVID, or at least one type of Long COVID. 16 Brainstem dysfunction has been implicated in chronic migraine and other forms of cephalgia.18,19 For chronic pain patients, it may be challenging to differentiate symptoms of Long COVID from chronic pain and its secondary symptoms, such as poor quality sleep, fatigue, and mental fogginess. Clinicians may be prudent to ask their chronic pain patients if they had acute

…it is not always clear if a chronic pain patient experiencing pronounced fatigue or depression after overcoming acute COVID infection is suffering from Long COVID...

COVID infection and the timeline of its course. Pain patients who have recovered from acute COVID may be asked if new symptoms emerged in the post-acute period or if pre-existing symptoms were exacerbated. Regardless of the etiology, pain in chronic pain patients must be recognized, assessed, and treated with professional compassion. Clinicians should take the lead in informing patients about Long COVID and its painful symptoms rather than allowing patients to find information online, some of which is of dubious quality. Patients need not be alarmed by Long COVID but should be informed, so that they can regard their pain care team as allies in helping them to manage this novel condition.

Conclusion

It may be possible that certain people with no history of chronic pain are troubled by persistent painful symptoms associated with Long COVID. Guidelines for the overall clinical treatment of Long COVID do not exist, although the National Institute for Health and Care Excellence (nICe) in Britain has offered a “living guideline” for Long COVID, but it does not specifically deal with the topic of pain.20 More guidance and public awareness is important to help patients obtain accurate diagnoses and appropriate care. In particular, pain specialists must be cognizant of this novel syndrome and its potential to cause or worsen painful conditions.

References

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