What Is Long COVID?


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Research suggests that 31-69% of COVID-19 patients suffer from post COVID symptoms

The US Centers for Disease Control and Prevention (CDC) describes “post-COVID conditions” as those that develop during the acute COVID-19 infection and persist for at least 4 weeks. In the scientific literature, these conditions are described as “post-acute sequalae of SARS-COV-2 infection” (PASC). In October 2021, the World Health Organization released a working definition of PASC summarized as follows: at least four weeks to many months after onset of infection, with waxing and waning severity and a constellation of symptoms, most commonly fatigue, shortness of breath, anxiety, depression, and impaired attention, concentration, memory and sleep. The Research Action Plan on Long COVID, created April 2022, is the first US government wide national research initiative “focused on advancing prevention, diagnosis, treatment, and provision of services and supports for individuals and families experiencing Long COVID.” Given the general interest in better understanding PASC, the National Center for Health Statistics’ Household Pulse Survey now includes questions assessing long COVID. Since the survey’s release in June 2022, there has been a steady climb in percentage of responders who have experienced persistent COVID symptoms. Other research suggests that 31%–69% of COVID-19 patients suffer with PASC at some point.

“…multiple studies suggest abnormal or excessive immune responses play a key role.”

Although the exact mechanism of PASC is not yet fully understood, multiple studies suggest abnormal or excessive immune responses play a key role. There also may be a link with the gut-microbiome, as COVID-19 can lead to symptoms of certain disorders of brain gut interactions, including post-infectious irritable bowel syndrome (Ghoshal et al. 2022; Settani et al. 2021). Specific inflammatory biomarkers, or cytokines, found to be involved in the PASC process are tumor necrosis factor alpha (TNF- α) and interferon gamma (IFN-y). In one study, during early COVID-19 recovery, patients who ultimately developed PASC had significantly higher levels of TNF- α and IFN-y- induced protein 10, as well as higher interleukin 6 levels, which continued to rise in late recovery. Another important finding is that re-activation of latent viruses during COVID infection (ie: Epstein Barr Virus or EBV) and pre-existing conditions – particularly autoimmune diseases – may pre-dispose to development of PASC.

“Both post-acute sequalae of SARS-COV-2 infection and Chronic Fatigue Syndrome are multisystem disorders of unknown pathophysiology and with debilitating symptoms.”

Many of the debilitating symptoms seen in PASC, specifically profound fatigue, post-exertional malaise, trouble with concentration and attention, and poor sleep are also key features of Chronic Fatigue Syndrome (CFS) alternatively named Myalgic Encephalomyelitis (ME). Both PASC and CFS/ME are multisystem disorders of unknown pathophysiology and with debilitating symptoms. One widespread systematic review found that out of 29 ME/CFS symptoms, 25 were also reported by at least one long COVID study. One proposed mechanism for both conditions is that naturally occurring oxidative and nitrosative stress outweighs the body’s defense mechanisms. Increased levels of so-called pro-oxidants (i.e. free iron, homocysteine, superoxides, nitrous oxide) combined with psychosocial and physiologic stress can lead to cell damage and perpetuate chronic inflammation. Decreased levels of antioxidants have also been reported in PASC and CFS/ME, specifically glutathione (which modulates immune activation), cysteine, selenium, vitamin C/ascorbate, and vitamin E. Both conditions may also result in impaired production of adenosine triphosphate (ATP), a key molecule for energy metabolism, which predisposes to a subsequent hypometabolic state. Similarly thought to be a trigger in PASC as described above, EBV seems to be a common precipitate for CFS/ME, with evidence of EBV-induced gene 2 upregulation in this population. This gene is critical for immune and central nervous system function and its increased expression may cause neurologic and immune related symptoms.

“Currently, there are no curative treatments for post-acute sequalae of SARS-COV-2 infection and Chronic Fatigue”

Currently, there are no curative treatments for PASC or CFS/ME; however, therapies with potential benefit include antivirals, anti-inflammatories, and immune modulators. Possible medications being studied to target oxidative stress include glutathione (and glutathione donors), N-acetyl cysteine, cysteamine, ubiquinol, nicotinamide, melatonin, selenium, vitamins C, D, E, disulfiram, and corticosteroids. However, unfortunately to date, no clinically significant improvements with any of these therapies have been found for either CFS/ME or PASC. The RECOVER Initiative established by the NIH is one nationwide project dedicated to understanding the long-term effects of COVID, mechanisms by which these effects occur, and developing effective therapies . Given the evidence of similar biochemical processes for CFS/ME and PASC, better understanding one may inform the other.

Until research discovers effective therapies, symptomatic management of fatigue and inflammation is the mainstay for both of the above conditions. Ensuring adequate hydration, optimizing sleep habits (duration and quality), and making dietary changes such as limiting added sugars and artificial sweeteners and cooking with olive, coconut, or avocado oils may provide anti-inflammatory benefits. Eating plenty of leafy greens, foods rich in omega 3 fatty acids (such as wild salmon, sardines, walnuts, flax seeds, and avocado) can also decrease inflammation and support mental health. Incorporating fermented foods like sauerkraut, kimchee, and yogurt may be beneficial, along with adding spices such as turmeric, ginger, cardamom, cumin, fennel, mustard seed and berberine which have long been used in complementary medicine to treat inflammatory conditions. Not only may these lifestyle and dietary changes benefit symptoms of CFS/ME and PASC, but they are also excellent ways for anyone to optimize their mental and physical wellbeing.

Other Useful Resources:

  • COVID.gov has a dedicated site to provide information and resources for PASC
  • Long COVID Patient Fact Sheet can be downloaded and printed.
  • The American Academy of Physical Medicine and Rehab regularly updates their PASC Dashboard to reflect current estimates of cases nationally and by state.

MariaLisa Itzoe, DO, MPH is an Internal Medicine resident at Pennsylvania Hospital of the University of Pennsylvania, with a passion for helping patients who experience disorders of brain-gut interaction (DBGI). She specializes in neuro-gastroenterology and health communication. MariaLisa is also a certified yoga instructor who loves cooking and sharing nutritious meals with family and friends