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Although most individuals recover completely from COVID-19 within a few weeks, some continue to experience symptoms after their initial recovery — even those who had mild COVID-19. These people (also known as "long haulers") suffer from what is called the "long COVID" - a term assigned for COVID-19 symptoms that persist for more than four weeks in people diagnosed with the SARS-CoV-2 infection. This article by Dr. Amisha Parekh describes the possible causes, current concepts in its pathophysiology, and the role of vaccination in alleviating these symptoms.
Long COVID [1-7]: According to the US CDC (Centers for Disease Control and Prevention) – ‘Long COVID is a range of symptoms that can last weeks or months after first being infected with the virus that causes COVID-19 or can appear weeks after infection. Long COVID can happen to anyone who has had COVID-19, even if the illness was mild, or they had no symptoms.’
- Recent data suggests that more than one out of ten people who have contracted SARS-CoV-2 infection have gone on to get long COVID. The World Health Organization recommends access to all COVID-19 patients for follow-up care in case of long COVID.
- Studies have found that long COVID symptoms can persist up to several months after recovering from the initial phase of the disease in adults and children. These symptoms involve multiple systems and are not limited to the respiratory system. Multi-system Inflammatory Syndrome (MIS) has been covered in Dental Tribune South Asia previously https://bit.ly/3xeltcC.
- A study showed that patients who have had COVID-19 had altered cytokine levels and protein markers in the blood, suggesting an imbalanced immune system and neuronal dysfunction. Evidence suggests that post COVID-19 infection, patients suffer from heart, liver, and kidney problems along with neurologic symptoms. Recently, an article in Dental Tribune South Asia has highlighted how COVID-19 can also lead to diabetes mellitus https://bit.ly/3wsHqoa.
- The systematic assessment of currently available data identifies female sex, middle age, white ethnicity, and specific underlying comorbidities as the potential risk for long COVID. Researchers from the UK have recently proposed a model that successfully predicts whether a person would get long COVID based on their age, sex, and the number of symptoms reported in the first week.
- While the data on long COVID is still evolving, the current literature faces some drawbacks in the form of lack of consensus on the definition, name, duration, and symptoms, selection bias in studies due to online recruitment with self-reported symptoms without a laboratory-confirmed diagnosis of COVID-19. The studies also lack appropriate control groups and failing to represent the general population, thus suggesting the need for more well-conducted longitudinal studies.
Long-term neurological manifestations of COVID-198-10: Studies show that post COVID-19 infection, patients suffer from long-term neurological manifestations like anosmia, cognitive and attention deficits (brain fog), new-onset anxiety, depression, psychosis, seizures, etc., even after resolution of respiratory symptoms.
- SARS-CoV-2’s effect on the brain: Similar to other respiratory viruses, SARS-CoV-2 also has been found to have neuro-invasive capacities and can spread to the central nervous system, which is suggested to be occurring by retrograde axonal transport along the sensory and olfactory nerves in the cribriform plate; crossing the blood-brain barrier (BBB); its invasion of endothelial cells by interacting with the angiotensin-converting enzyme 2 (ACE2) receptors; and its ability to alter tight junction proteins formed by endothelial cells. Brain imaging studies of COVID-19 patients have detected several diverse lesions. Also, brain autopsy studies have revealed SARS-CoV-2 RNA or its proteins in various neuroanatomical regions, astrogliosis, and microglial activation and infiltration of cytotoxic T lymphocytes. Despite this neuro-invasive ability, the neurological signs and symptoms associated are believed to be more likely due to systemic reactions such as hypoxemia, hypercoagulability, systemic inflammation, and multiorgan failure.
- Neurofilament light chain (NFL) levels: Studies have found that NFL, a biomarker reflecting neuroaxonal damage, shows an early and pronounced elevation in serum, plasma, and cerebrospinal fluid (CSF) of COVID-19 patients and correlates with worse clinical outcomes - need for mechanical ventilation (intubation), ICU admission, longer periods of hospitalization and worse functional outcomes. Moreover, these levels were found to be lower in patients treated with remdesivir. In keeping with these observations, it has been suggested that monitoring NFL levels in COVID-19 patients could facilitate the early detection of neuronal damage and prevent long-term adverse effects.
Causes of long COVID : Akiko Iwasaki, an immunobiologist from Yale University, hypothesized three possible mechanisms causing long COVID, after which several studies have been conducted that support these mechanisms. The mechanisms are as follows:
- a persistent viral reservoir;
- Fragments of the virus (RNA, proteins, etc) known as the ‘viral ghost,’ - that linger on and are capable of stimulating the immune system even after the infection has been cleared; and
- an autoimmune response induced by the infection.
How vaccines could improve long COVID [11-13]
Studies conducted on recovered seropositive individuals have demonstrated an excellent immune response to vaccination compared to seronegative individuals. So far, several studies have been conducted on long COVID patients to assess if their symptoms improve post-vaccination with either an mRNA or adenoviral vector vaccine. Most of the patients from these studies reported an overall improvement in their long COVID symptoms, except for a few who found that their symptoms worsened while others observed no change in symptoms. Importantly, it was observed that receiving vaccination was not associated with a reduction in quality of life, thus reassuring that vaccines could be safe for long COVID patients.
Along with her team, Akiko Iwasaki is conducting a study on unvaccinated long COVID patients. The objective is to track how their bodies react to the vaccine and determine which mechanism(s) are responsible for the vaccine-mediated improvement in long COVID patients. She hypothesizes that all the three mechanisms of long COVID mentioned above could benefit from the vaccines.
- In the case of a persistent viral reservoir, vaccine-induced T cells and antibody responses may eliminate this reservoir.
- In case of lingering viral components associated with spike proteins (used by the virus to enter cells), vaccine-induced immunity may be able to eliminate such viral ghosts.
- In case of an autoimmune response induced by infection, the vaccine might divert the autoimmune cells [vaccine-induced transient inflammation or adaptive immune responses might divert the leucocytes (immune cells) that cause long COVID].
Conclusion: The lack of evidence-based guidelines necessitates addressing long COVID and its manifestations with more longitudinal studies that would represent the general population. Up till now, COVID-19 vaccines have only been considered as a measure to prevent disease severity. Thus, its role in improving or treating long COVID certainly comes as a surprise. Studies have suggested that vaccines are safe for use in long COVID patients, and as more and more data evolves, we hope to have answers as to how vaccines could also benefit individuals with long COVID.
- Post-COVID Conditions - https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html#print
- The four most urgent questions about long COVID. Nature 594, 168-170 (2021) doi: https://doi.org/10.1038/d41586-021-01511-z
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- Boldrini M, Canoll PD, Klein RS. How COVID-19 Affects the Brain. JAMA Psychiatry. 2021;78(6):682–683. doi:10.1001/jamapsychiatry.2021.0500
- M. Prudencio et al., Sci. Transl. Med. 10.1126/scitranslmed.abi7643 (2021).
- Sutter, R., Hert, L., De Marchis, G.M., Twerenbold, R., Kappos, L., Naegelin, Y., Kuster, G.M., Benkert, P., Jost, J., Maceski, A.M., Rüegg, S., Siegemund, M., Leppert, D., Tschudin-Sutter, S. and Kuhle, J. (2021), Serum Neurofilament Light Chain Levels in the Intensive Care Unit: Comparison between Severely Ill Patients with and without Coronavirus Disease 2019. Ann Neurol, 89: 610-616. https://doi.org/10.1002/ana.26004
- How Vaccines Might Improve Long Covid. https://elemental.medium.com/how-vaccines-might-improve-long-covid-c1f41c4d7378
- The impact of COVID vaccination on symptoms of Long Covid. An international survey of 900 people with lived experience. https://3ca26cd7-266e-4609-b25f-6f3d1497c4cf.filesusr.com/ugd/8bd4fe_7301ed588cc44d1483e9fc8df7989a03.pdf
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