More important than the actual symptoms may be the causes of those symptoms. The causes of Long COVID are vast, but they at least help elucidate many of the body’s processes and pathways that are linked to the symptoms that are presented. It also helps provide avenues for possible therapeutics. So here we’ll outline some of the possible causative agents in Long COVID.
Persistent COVID Infection
One of the first proposals for Long COVID questioned whether people who continued to experience symptoms may actually still be infected with COVID. This idea would be validated to an extent when patients who believed they were fully recovered still tested positive with rt-PCR tests. However, many of these researchers and clinicians overlooked the nature of rt-PCR, which only measures the presence of specific genes (i.e. genes for the nucleocapsid and spike protein). Thus, rt-PCR only validates the presence of genes both intact and fragmented, and provides no actual relationship into the nature of the viral genome. As Dr. Yo put it in his interview with Jimmy Dore, further testing through genomic sequencing of the SARS-COV2 viral genome came back negative. Viral replication is only possible if the whole genome of SARS-COV2 was intact as this is the only way a virus’ information can propagate. Such a finding would eventually discredit the idea that Long COVID is associated with persistent COVID infection for many patients. However, if concerns over unresolved viral infection are an issue it may be more proper for clinicians to look into the possibilities of genomic sequencing for their patients.
Extensive, Unresolved Tissue/Organ Damage
A more plausible explanation for Long COVID relates to the extensive tissue and organ damage experienced by many. Reports of ground glass opacity findings in many pulmonary CT scans weeks after COVID indicate extensive, unresolved lung damage that is likely to contribute to the symptoms of dyspnea and recurrent coughs that persist for weeks and months after the virus has been cleared from the body. Take into account the extent of microclot formation and neuroinvasion, and there is really no organ system that is left spared. As more evidence emerges with respect to COVID’s damaging effects on the vascular system, widespread vascular damage from COVID may be responsible for a host of Long COVID symptoms due to the impaired effects of blood and nutrient circulation. This likely explains why more severe cases of COVID are related to higher rates of Long COVID. Utilization of various imaging techniques such as MRIs and CT scans are likely to uncover underlying damage that should be addressed by medical professionals.
Prolonged Inflammation and Autoimmunity
Cytokine storms, a state of progressive hyperinflammation, occurs in many hospitalized and ICU COVID patients. Prolonged, unchecked cytokine storms can eventually lead to pervasive multiorgan failure and death of a patient. Therefore, for many infected with COVID inflammation plays a major role in disease pathology. However, inflammation many not end after a viral infection. Post-COVID inflammation may indicate systemic inflammation that is likely to continue to target many organs. In children this scenario is referred to as multisystem inflammatory syndrome in children, or MIS-C, and was reported extensively as a concerning result of COVID infection in children. However, there have been cases of this occurring in adults as well (named MIS-A). Overall, inflammation is a major concern with COVID and evidence suggests it plays a major role in Long COVID as well.
Elevated inflammatory markers have been seen in those with Long COVID, although the results are not always consistent (taken from Yong, S.):
Elevated blood urea nitrogen (BUN) and D-dimer levels were found to be risk factors for pulmonary dysfunction among survivors of COVID-19 at three-month post-hospital discharge . Other studies have shown that COVID-19 pulmonary lesions at two-month post-admission were associated with elevated systemic inflammatory biomarkers, such as D-dimer, interleukin-6 (IL-6), and CRP [62,148]. Systemic inflammatory biomarkers (e.g. CRP, procalcitonin, and neutrophil count) also correlated with radiological abnormalities of the heart, liver, and kidney in a 2- to 3-month follow-up study of discharged COVID-19 patients . In another study, increased D-dimer and CRP levels and decreased lymphocytes were more common in COVID-19 survivors who developed persistent symptoms than their fully recovered counterparts . Another report also found that lymphopenia correlated with chest tightness and heart palpitations, whereas elevated troponin-1 correlated with fatigue, among sufferers of long COVID . Therefore, changes in levels of D-dimer, CRP, and lymphocyte appeared consistent in a few studies, and may serve as potential biomarkers of long COVID.
However, other studies have found no changes in pro-inflammatory biomarkers (e.g. CRP, D-dimer, IL-6, CD25, and neutrophil and lymphocyte counts) between COVID-19 cases with and without persistent symptoms [39,41,150,151,46]. Such discrepancies may be due to different study methods as studies differ in their sample characteristics, measured endpoints, and data collection and analyses. Another reason may be the heterogeneous and relapsing-remitting nature of long COVID with multifaceted symptomatic presentations  (Table 2). This hints at the possible involvement of multiple pathophysiology, with each type possessing a unique set of biomarkers that may even fluctuate. Indeed, inflammatory biomarkers in autoimmune and other chronic inflammatory diseases are known to fluctuate depending on the disease activity and patient’s characteristics [152,153].
Persistent inflammation goes hand-in-hand with the immune response. As Dr. Yo and Dr. Patterson found with their predictive study many activated immune cells, including monocytes, still persist long after SARS-COV2 is cleared. The emergence of cytokine storms can mostly be traced back to the immune system’s response to SARS-COV2 and the release of inflammatory biomarkers. More pertinent to Dr. Yo and Dr. Patterson’s study is examining which inflammatory markers are predictive of Long COVID. Therefore, it would make sense that the level of chronic inflammation and Long COVID would be associated with variations in immune response (taken from Patterson et. al.):
The scientific evidence generated during the last months strongly supports that the different outcomes on COVID-19 patients are determined by the immune mechanisms activated in response to the viral infection (20).
The immune response to SARS-CoV-2 induces a release of different molecules with inflammatory properties such as cytokines including interleukins and chemokines. This event, known as cytokine storm (20), is an immunopathological feature of COVID-19 and it has been associated with the severity of the disease. The increase in blood concentrations of different cytokines such as interleukins and chemokines such as IL-6, IL-8, IL-10, TNF-α, IL-1β, IL-2, IP-10, MCP-1, CCL3, CCL4, and CCL5 has been described for COVID-19 patients (4). Some of these molecules have been proposed as biomarkers to monitor the clinical evolution and to determine treatment selection for COVID-19 patients (21–23). Nevertheless, it is important to consider that some of these molecules function in a context dependent manner, therefore the clinical relevance of analyzing single cytokine changes is limited.
Paradoxically, some researchers have suggested that persistent immunosuppression, possibly through COVID treatments or the body’s own responses that are meant to quell the cytokine storm, may end up causing harm by preventing the immune system from properly targeting other pathogens. This scenario is referred to as compensatory anti-inflammatory response syndrome (CARS; following excerpt and figure taken from Oronsky et. al.):
Following trauma or a severe primary infectious disease like COVID-19, in which a systemic inflammatory response syndrome or SIRS is predominant, an overwhelming and long-lasting counterbalancing compensatory anti-inflammatory response syndrome (CARS) occurs that leads to postinfectious/posttraumatic immunosuppression . The purpose of the CARS response, a mirror-imaged counter-regulation to SIRS or systemic inflammatory response syndrome, is to dampen the proinflammatory state, prevent maladaptive multiple-organ dysfunction , and govern the return to immunologic homeostasis or normalcy …
If, on the other hand, the inflammatory response is repressed too far in the direction of CARS, then the patient, having managed to “weather” the initial hyperinflammatory cytokine storm and the progression to ARDS, may enter a stage of protracted immunosuppression [14, 15] known as PICS for persistent inflammation, immunosuppression, and catabolism syndrome that is seen post-sepsis and which is one of the hypothesized causes of persistent post-COVID syndrome (PPCS), as shown in Fig. 2.
Even as blurry of a scenario as Long COVID is, the role of inflammation itself has contradictory viewpoints, but that is likely to depend upon the timing of the inflammation, the severity of the inflammation, and the timing of immunosuppressant treatments. Persistent inflammation has been associated with many diseases such as diabetes, obesity, and cardiovascular disease so it makes sense that inflammation after a bout with COVID may cause some of the persistent symptoms seen. However, evidence of post-COVID secondary infection, and even concurrent infection with the flu (colloquially referred to as “flurona”) suggest that immunosuppression and extensive suppression of inflammation may be at play as well. Multiple factors contribute to the elaborate nature of assessing which role inflammation plays in Long COVID and the proper way to treat it.
Reactivation/Secondary Viral Infection
Adding onto the idea of a prolonged, compromised immune system, some evidence suggests that several of the symptoms of Long COVID may actually be due to the reactivation of dormant viruses or possibly even a secondary infection. This is nothing new to COVID as prior viral infections may also lead to the emergence of dormant viruses. With respect to COVID, Dr. Yo spoke more specifically in regards to reactivation of Epstein-Barr virus and herpes zoster (the virus responsible for shingles), two viruses that many of us have come into contact with and may lie dormant in a large majority of us. Both of these herpes viruses are responsible for rash formation, which may be related to the presence of rashes seen in many Long COVID patients.
Looking at some of the symptoms of Epstein-Barr infections we can see that many of these overlap with Long COVID (taken from the CDC website):
As strange as this may seem, this is not all too uncommon. Remember that “flurona” is a common enough search term that it has created its own portmanteau. But even looking through the literature one can find evidence of herpes zoster and COVID coinfections. A review by Algaadi, S.A. found several articles associating coinfections of herpes zoster and COVID. Interestingly, many of these patients who had both HZ and COVID tended to be older and had comorbidities such as immunosupression, diabetes, and high blood pressure. Essentially, demographics that were already more susceptible to COVID. Even though the sample size was very small it raises important questions as to whether many of the symptoms of COVID may actually be related to reactivation of dormant viruses.
Unlike other causative agents, viral infections would be easy to eliminate through laboratory testing and would likely be the first approach to take in evaluating Long COVID. The most important thing to consider is whether many of the symptoms during an active COVID infection may be associated with other viruses, and the same questions should be raised with respect to Long COVID as well. Possibly more important than that is understanding how COVID may lead to compromised immune function that provides opportunistic reactivation of viruses.
Neuropathy and Neuroinflammation
Neurological and psychiatric issues are more of a niche topic and has been covered under prior categories, but considering how common these symptoms are in Long COVID it may be appropriate to cover it separately. Neuroinvasion of SARS-COV2 has been well documented and likely accounts for the high number of neurological changes during and after infection. How SARS-COV2 targets the brain is up for debate, although some have suggested passage through the olfactory bulb or through targeting of the blood-brain barrier by the spike protein. Causative factors in neurological symptoms include possible hypoxia (reduced oxygen), but more than likely is related to neuroinflammation from viral invasion into the nervous system.. Aside from headaches and brain fogs anosmia and ageusia are very common Long COVID symptoms and indicates possible damage of cells responsible for neuronal signaling.
A very small study from Oaklander et. al. found that, even in mild COVID patients, small fiber peripheral neuropathy (damage to the body’s nerve extremities, in particular the hands and feet) was seen among many of the participants. The authors suggest that lack of myelination and other protective features make these nerves more susceptible to stressors. However, the researchers presented a case study of an elderly patient with signs of multifocal demyelination as well.
These results identify small-fiber neuropathy as most prevalent in this small group of patients with long COVID, also known as post-acute sequelae of SARS CoV-2 infection.2 In SFN, the small-diameter unmyelinated and/or thinly myelinated sensory and autonomic fibers are predominantly affected, although most patients with severe or advanced polyneuropathy, e.g., case 9, develop large- and small-fiber damage. The small fibers are disproportionately vulnerable, with their lack of myelin exposing them to environmental stressors including immunity, while inability to use saltatory conduction increases metabolic demand, and cytoplasmic paucity limits axonal regeneration. However, small-fiber axons grow throughout life to reinnervate continuously dividing tissues such as the skin and to help repair injuries. If toxic conditions improve, axon elongation and sprouting accelerate to increase the probability of reinnervating enough target cells to resolve symptoms.
When it comes to post-COVID coughs, there are some suspicions that persistent or recurring coughs may be related to sensory nerve infection. Prior viral infections can target sensory neurons that may stimulate the cough reflex. Therefore, inflammation and hypersensitive of the nervous system may cause peripheral hypersensitivity and the recurring urge to cough (taken from Song et. al.):
Urge to cough, frequently seen in subjects with common cold and possibly also in those with acute COVID-19-associated cough, has been linked to altered central processing of sensory input and cough reflex (termed central sensitisation).66 Substance P, which might be upregulated in the nodose ganglionic neurons by viral infection,64 can drive central sensitisation in virus-associated cough. Murine pneumovirus infection induced inflammatory glial cell activation and altered neuronal responsiveness in the brainstem nucleus tractus solitarius of mice, the primary site of vagal sensory inputs.67 Therefore, increased inflammatory activation of sensory neurons could induce altered reflex processing in the brain.
Overall, the possible damage to the CNS should be examined extensively and not be underminded for their cognitive presentations. As we have discussed before, chronic fatigue and depression, which are more likely to manifest in women and are common for many other diseases, may be missed or discredited as a sign of Long COVID. Medical professionals should take care to not stigmatize patients and try to understand the relationship between Long COVID and cognitive dysfunction.
Although this newsletter is not exhaustive, I believe it is very important to address the role that social media, legacy media, social pressure plays in causing many of the symptoms of Long COVID. It may seem strange, but keep in mind the high levels of anxiety and stress that have been implanted into the public over the past two years. Fears of succumbing to COVID and dying have prevented us from living regular lives or interacting with others the way we used to. For people who happened to get sick, hysteria is likely to follow with fears of death and being shamed by others for being “unclean” and recklessly spreading COVID. Remember, the media has told us that if we did everything they told us to we should not get sick. Someone who gets sick clearly did not do what they were supposed to and have brought disarray to the new social order. Stress for those who would miss out on a full paycheck due to isolation may weigh heavy for many people who live paycheck to paycheck.
This excerpt from Sher, L. perfectly encapsulates this perspective:
For many people to learn that they are infected with COVID-19 evokes significant emotional stress.6 The experience of the potentially lethal and untreatable disease is the cause of a severe distress, which may induce a mental illness or aggravate a pre-existing psychiatric disorder.2,6,14 Symptoms of COVID-19, especially serious symptoms, worry about infecting other people, social isolation and concerns about loss of income and the ability to work in the future may result in a severe emotional distress which may persist for a long time.
I have written about how much shame people have felt over becoming ill and telling others of their status. With Omicron, catching COVID became nearly inevitable, and therefore there is no reason for people to feel shamed for getting sick.
Keep in mind that studies examining comorbidities in COVID include stress and depression as some of the most frequent comorbidities. Although likely to be caused by the virus, the messaging and stress of needing hospitalization or finding out you were positive in no doubt played a role as well. Even more concerning are the increased levels of antidepressants being prescribed and suicidal ideations seen in younger generations.
Ironically, many of the psychological factors of Long COVID may not be associated with the virus itself, but with the idea of how long social isolation and lockdowns have been occurring. I’ve occasionally joked that I have Long COVID because this COVID stuff has been going on for too long, and I am sure many feel the same. Even to this day the psychological trauma caused by lockdown measures are still not being properly addressed. Although places are beginning to lift mask and vaccine mandates the psychological damage caused over the past two years will remain for many and must be treated. Otherwise, irreparable harm will persist for many years to come. Clinicians who are concerned about the high levels of depression and suicidal ideation would be wise to evaluate whether these are valid symptoms of Long COVID or if these are the results of two years of fear mongering and learned helplessness.
Causes as varied as the symptoms
This list does not encapsulate all of the possible causes of Long COVID, but it represents all of the avenues that should be properly be examined if Long COVID is to be seriously addressed. The variations in presentations means that patients should be assessed on an individual basis with symptoms paired with plausible causative agents. Only then can proper management and treatment be achieved.
The next installment will examine possible treatment options for Long COVID based on what is available within the literature.
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