Over the last 17 months, the world has been dealing with the burden caused by the COVID-19 pandemic that led to the deaths of over 4 million people globally. While most people completely recover from COVID-19 illness, a subset of patients experience symptoms that persist beyond the acute phase of infection. The persistence of symptoms or development of new symptoms beyond four weeks from the onset symptoms is colloquially known as Long COVID. The observation that some patients experience symptoms beyond their recovery from acute COVID-19 prompted studies into the epidemiology and biology of Long COVID to gain a better understanding of possible mechanisms of its development. While this pandemic has only been around for roughly two years, the effects of Long COVID on our public health system and economy will be felt for many years to come.
Symptoms and Epidemiology of Long COVID
Long COVID can be further broken down into two subcategories: (1) subacute COVID-19, where symptoms persist or are present 4-12 weeks beyond acute COVID-19 and (2) chronic or post-COVID-19 syndrome, where symptoms persist or are present 12 weeks beyond acute illness but are not related to other health conditions. Some common symptoms of Long COVID include fatigue, joint pain or discomfort, muscular weakness, shortness of breath, and persistent oxygen requirements. Other reported symptoms include brain fog and cognitive impairments, anxiety, depression, hair loss, skin rashes, chronic kidney disease, and thromboembolism – all contributing to a reduced quality of life, with some patients requiring subsequent admittance to the ICU due to persisting symptoms. In a cross-sectional study by Halpin et al., at 4-8 weeks post-COVID-19 diagnosis, associations existed between the presence of dyspnea and pre-existing respiratory diseases, higher body mass index, older age, and participants of Black, Asian or other undisclosed minority ethnicities. Several studies also attributed a reduction in lung diffusion capacity(the amount of oxygen that passes through the lungs and into the bloodstream) as the most prominent physiological impairment in patients with Long COVID and correlated with worsened severity of acute illness. Additionally, Huang et al., suggested sex differences in the development of Long COVID symptoms, where women were more likely to experience fatigue, anxiety, and depression at the 6-month follow-up mark. How comorbidities such as cancer, diabetes, obesity, and chronic cardiovascular or kidney disease impact the development of Long COVID is still being investigated.
Biology of Long COVID
It is now understood that SARS-CoV-2 , the virus responsible for causing COVID-19 infection, impacts several organs in the body (lung, brain, heart, kidneys) and this likely play a role in the persistence or development of symptoms beyond acute COVID-19. Several mechanisms have been proposed to play a role in the development of Long COVID symptoms: 1) virus-specific aberrations, 2) immunologic abnormalities resulting from acute COVID-19 infection, and 3) post-intensive care syndrome.
Virus-specific aberrations. While it has not yet been determined if a long-term reservoir exists for SARS-CoV-2, this virus has been detected in several organs in the body during acute infection. SARS-CoV-2 has the capacity to invade and damage the barrier cells of the lungs (epithelial cells and endothelial cells), which, in combination with immunologic abnormalities (discussed below), can result in fluid leakage into the lungs. This ultimately results in shortness of breath, a common symptom in Long COVID patients. COVID-19 infection has also been reported to cause difficulty in heart pumping, leading to arrhythmias in Long COVID patients.
Immunologic abnormalities. It was reported that patients with critically severe COVID-19 have circulating B cells, or antibody-producing cells, that are similar to those found in patients with autoimmune diseases such as Systemic lupus erythematosus. The presence of these B cells correlated with markers of inflammation and organ damage. In December 2020, Wang et al. identified a wide range of autoantigens (or self proteins) that were targeted by antibodies in patients with COVID-19. These autoantibodies were specific to self proteins including signaling molecules such as cytokines, interferons, and chemokines. Additional autoantibodies specific for antigens in the central nervous system, cardiac tissue, hepatic tissue, and intestinal tract were also detected in patients with COVID-19. These autoantibodies were also found in patients experiencing Long COVID. The presence of these autoantibodies may impact natural anti-viral immunity, while the presence of the organ-specific autoantibodies may contribute to antibody-mediated organ damage in COVID-19 patients. In addition, increased inflammation and invasion of the lungs by inflammatory immune cells can lead to the breakdown of the lung barrier, contributing to difficulties in breathing for many Long COVID patients.
Post-intensive care syndrome. Statistically, 80% of patients that survive acute respiratory failure after experiencing ventilation in the ICU experience new or worsened physical, psychiatric and/or cognitive symptoms; this is known as post-intensive care syndrome. The pathophysiology of post-intensive care syndrome has been proposed to include factors such as microvascular injury, immobility, and metabolic modifications. Patients that experience severe COVID-19 requiring admittance into the ICU often require long durations of mechanical ventilation, deep sedation, and immobility. These factors can contribute to new long-term physical impairments (muscle weakness, diaphragm dysfunction)that persist beyond the acute phase of infection, leading to symptoms of Long COVID. Similarly, prolonged isolation from family members and healthcare staff due to infection control precautions have been implicated in cognitive and psychiatric impairments in post-intensive care syndrome. Overall, there are a multitude of factors that could contribute to the development of Long COVID. Understanding these mechanisms may inform the decisions made by healthcare professionals to prevent or ameliorate Long COVID symptoms.
Treatment for Long COVID
Depending on the symptoms experienced by patients, the treatment plan varies. In most cases, patients require regular monitoring, particularly if respiratory symptoms are detected. In a small cohort study from the UK, treatment with corticosteroids was beneficial for a subset of patients with post-COVID inflammatory lung disease. In addition to medical management of symptoms, patients with Long COVID also require rigorous self management of their symptoms. It is highly recommended that patients use a daily pulse oximeter to monitor their blood oxygen levels. Additionally, limiting consumption of alcohol and caffeine, as well as quitting smoking are advised. Finally, a gradual increase in physical activity can support recovery of physical strength and a return to an active lifestyle.
Impact on the Economy and Public Health
Both public health and the economy are affected by the increasing cases of Long COVID.As a result of symptoms that impact various organ systems (cardiovascular, respiratory, etc.), there is an increased demand on healthcare professionals to develop unique treatment plans for patients. Additionally, Long COVID patients require regular monitoring, compounding the burden on the healthcare system. Long COVID also impacts patients in other aspects of life, such as preventing their return to work because of the prolonged symptoms. This can directly affect the financial stability of families of patients. The disabilities caused by Long COVID directly impacts the labour force due to increasing numbers of people requiring extended medical leaves of absences. Furthermore, there is an increased demand in disability benefits for these patients to directly support themselves and their families.
Conclusion
The effects of the COVID-19 pandemic will be felt for many years to come as a result of the Long COVID. Despite this, researchers across the globe are continuing their efforts to investigate the causes of Long COVID through large cohort studies. These seminal studies will provide the necessary information to build an effective standard of care for people experiencing post-acute COVID-19 symptoms.
References
- Nalbandian, A., Sehgal, K., Gupta, A. et al.Post-acute COVID-19 syndrome. Nat Med27, 601–615 (2021). https://doi.org/10.1038/s41591-021-01283-z
- PHAC: https://www.canada.ca/en/public-health/news/2021/07/statement-from-the-chief-public-health-officer-of-canada-on-july-7-2021.html
- Carvalho, T., Krammer, F. & Iwasaki, A. The first 12 months of COVID-19: a timeline of immunological insights. Nat Rev Immunol21, 245–256 (2021). https://doi.org/10.1038/s41577-021-00522-1
- Marx, V. Scientists set out to connect the dots on long COVID. Nat Methods18, 449–453 (2021). https://doi.org/10.1038/s41592-021-01145-z
- Wang, E. Y. et al. Diverse functional autoantibodies in patients with COVID-19. Preprint at medRxivhttps://doi.org/10.1101/2020.12.10.20247205(2020).
- Bhadelia, N. et al. Distinct autoimmune antibody signatures between hospitalized acute COVID-19 patients, SARS-CoV-2 convalescent individuals, and unexposed pre-pandemic controls. Preprint at medRxivhttps://doi.org/10.1101/2021.01.21.21249176(2021).
- Needham, D. M. et al. Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding. EDENtrial follow-up. Am. J. Respir. Crit. Care Med.188, 567–576 (2013).
- Hosey, M.M., Needham, D.M. Survivorship after COVID-19 ICU stay. Nat Rev Dis Primers6, 60 (2020). https://doi.org/10.1038/s41572-020-0201-1
- Myall, K. J. et al. Persistent post-COVID-19 inflammatory interstitial lung disease: an observational study of corticosteroid treatment. Ann. Am. Thorac. Soc.https://doi.org/10.1513/AnnalsATS.202008-1002OC(2021).
- Watson, P. The “Long COVID” Economy. https://www.forbes.com/sites/patrickwwatson/2021/06/14/the-long-covid-economy/
Baweleta Isho
