Author: Dr. Ann Hardy and Dr. Sherry Mills
Date: August 9, 2022

Long COVID: The Pandemic Within the Pandemic?

In 2020, a new acute respiratory infectious disease rapidly became the global COVID-19 pandemic, causing widespread illness and death. Early on, clinicians noted that some patients continued to have a range of symptoms long after their acute infection had resolved. This more sustained form of COVID-19 goes by several names, including Long COVID (used in this blog) and, more recently, Post COVID-19 Condition (PCC) and Post-acute Sequelae SARS-CoV-2 infection (PASC).

There are currently critical gaps in our understanding of Long COVID. Because this condition is occurring in many countries in the aftermath of the global COVID pandemic, there is an ongoing worldwide research effort to study it. This blog reviews what is currently known about Long COVID and identifies priorities for future clinical research.

What Do We Know about Long COVID?

Definition
As with any new condition, it is important to have a standard case definition that can be used in epidemiological and clinical research studies. Both the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have published similar case definitions although the WHO definition is more detailed. As there is no test at present for Long COVID, these case definitions are based primarily on temporal patterns of a constellation of symptoms:

  • CDC: Some people who have been infected with the virus that causes COVID-19 can experience long-term effects from their infection which can include a wide range of ongoing health problems and can last weeks, months, or years (1).
  • WHO: Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time (2).

Incidence and Prevalence
Just like acute COVID-19, Long COVID is occurring worldwide. Estimates of the proportion of those with a COVID-19 infection who go on to develop Long COVID range from 6 to 50 percent, in part because of variation in population-related factors used to make estimates, such as demographics or hospitalization rates (3). Based on data from a national household survey collected in June 2022, CDC estimated that 14 percent of all adults in the United States have had long COVID with 7.5 percent still experiencing this condition (4). There are concerns currently that we may be undercounting acute COVID-19 cases with the increased use of home testing that is not captured by public health monitoring systems and the increase in people with mild to no symptoms who are seeking medical care. This may result in future undercounts of Long COVID cases as well.

The American Academy of Physical Medicine and Rehabilitation’s PASC Dashboard shows daily estimates of the number of both COVID and Long COVID cases in the United States and by state. The dashboard also demonstrates the sobering reality that as the number of new COVID infections goes up, so does the number of individuals with Long COVID. When one considers the global incidence of acute COVID-19, Long COVID is affecting millions worldwide and has become what some call a pandemic within the pandemic.

Risk Factors Associated with Long COVID
Based on observational human subjects research studies, Long COVID appears to be more common in women, older adults, those who have a more severe initial course of COVID, and those who are unvaccinated. However, Long COVID has been diagnosed in patients of all ages (including children), as well as in those with very mild initial infections and those who have been fully vaccinated (5-9). It is notable that some individuals with Long COVID, especially children, were healthy before their acute COVID infection.

Symptoms and Clinical Presentation
The symptoms of Long COVID can quite variable. Those commonly reported include fatigue, post-exertional malaise, shortness of breath, and cognitive dysfunction (often referred to as “brain fog”), but can include an array of other symptoms such as insomnia, changes in smell and taste, chest pain, heart palpitations, headaches, dizziness, depression, and anxiety. Symptoms vary based on factors such as age and presence of underlying health conditions (5-9).

Symptoms can be present most of the time or can occur intermittently with new symptoms appearing over time. In more severe cases, patients may be limited or unable to perform their usual daily activities (10). In 2021, the U.S. Department of Health and Human Services (HHS) released guidance for considering Long COVID as a disability under the Americans with Disabilities Act (ADA) if it substantially limits at least one major life activity.

What are Gaps in Our Understanding of Long COVID?
Pathogenesis
Currently, the etiology Long COVID is unknown but there are several theories being investigated. Some scientists believe there may be multiple possible causes (11). The most prevalent theories include:

  • Long-term hospitalization, especially in the ICU. The recognition that chronic hospitalization can cause generalized symptoms such as muscle weakness and confusion that last well beyond discharge pre-dates the COVID pandemic. Early in the pandemic when large numbers of patients required hospitalization, this factor received more attention. However, the proportion of patients hospitalized with COVID has decreased over time, making this factor less likely to be a cause of Long COVID.
  • Cell and tissue damage. Direct damage from COVID infection to cells and tissues can lead to chronic problems like micro clots that have been noted in the lungs of some Long COVID patients.
  • Immune dysregulation. During the acute phase of COVID, as with any acute infection, the body’s immune system ramps up in response. However, the immune systems in some Long COVID patients remain overly activated after the acute phase has ended. This can lead to chronic inflammation. Additionally, COVID seems to trigger an autoimmune response in some patients that can have long-lasting consequences.
  • Persistent infection. Another prominent Long COVID theory is that the SARS-CoV-2 virus is not completely eliminated after the acute phase in some individuals. Such patients show continued evidence of viral RNA and proteins in various cells and can have viral antigen detectable in blood tests.

It is plausible that in some cases these causative factors are interrelated; for example, persistent infection can result in continued immune activation. Similarities between Long COVID and other post-viral syndromes, such as those seen after acute mononucleosis, as well as syndromes like Chronic Fatigue Syndrome may provide clues about pathogenesis and potential approaches to symptom management.

Clinical Course and Prognosis

Because COVID-19 is a new disease, there has been limited time to study the natural course of Long COVID. While some patients appear to have recovered completely from Long COVID, others have had this condition for over two years. More clinical research is needed to better determine recovery rates and associated factors.

As noted above, symptoms can be persistent or recurring and can impact those with Long COVID in a variety of ways. However, the long-term clinical course remains to be defined. While there are now two antivirals approved to treat the acute phase of COVID infection, it is not yet known whether the use of these antivirals will also prevent or decrease the likelihood of progression to Long COVID. COVID-19 vaccination also appears to offer some protection against Long COVID (6,7) but it is not known whether this protection will continue as new strains of the virus that causes COVID-19 continue to arise.

What are Clinical Research Priorities for Long COVID?
Globally, scientists will likely continue studying both acute and Long COVID for many years. Clinical research priorities for Long COVID include:

  • A more precise case definition and diagnostic criteria that can be used universally and which are applicable to both adults and children will help better quantify the incidence of Long COVID and identify who is most likely to be affected by it. The CDC and WHO case definitions are a good start but will likely need to be refined going forward to incorporate new clinical findings. In June 2021, the American Medical Association passed a resolution supporting the development of an ICD-10 code or family of codes for Long COVID as a distinct diagnosis which would greatly facilitate records-based research (12).
  • Increased active surveillance of Long COVID would provide more robust estimates of incidence and prevalence that can facilitate effective planning and resource allocation
  • Studies are needed to more precisely define the pathophysiology of this disease, including identification of factors that trigger Long COVID, and more precises clinical/biological measures to predict who is more likely to progress to this condition, and what determines symptoms, clinical course, and prognosis. Results of these studies would, in turn, suggest potential treatment strategies.
  • Clinical research studies and controlled clinical trials to evaluate effective treatments for Long COVID and its varied symptoms are critically needed.
  • Identification of appropriate health care and support models for those with this disorder, including social and mental health services, are also important.
  • Development of more effective ways to communicate with the public, patients, and the health care community about Long COVID will enhance the management and uptake of clinical and public health strategies.

What Research is Currently Underway?
Scientists across the globe are working on various aspects of Long COVID (13). In terms of ongoing clinical research, as of August 2, 2022, the Clinicaltrials.gov data base listed 160 active Long COVID human subjects research studies, 102 of which are recruiting participants in the United States and internationally. These include observational studies to identify possible biomarkers, develop diagnostics, characterize the condition’s pathophysiology, and/or measure its impact on patients and families, as well as clinical trials to test approaches to treating this syndrome or managing associated symptoms.

Notable international Long COVID research efforts include:

  • One of the first studies on Long COVID was published in May 2020 by the Patient-led Research Collaborative that was organized by Long COVID patients who are also researchers. This group continues to conduct Long COVID research (14).
  • The UK Biobank is a large population-based registry that successfully enrolled 20,000 of its participants plus their families for a longitudinal study of COVID-19, including Long COVID (15).
  • The Real Time Assessment of Community Transmission (REACT) Study, also based in the United Kingdom, is following a cohort of 120,000 individuals to determine infection rates, symptoms, and other aspects of COVID -19 infection (16).

In the United States, COVID research efforts initially focused on disease surveillance and development of therapeutics, vaccines, and diagnostic tests. In April 2022, HHS was formally tasked with coordinating a government-wide effort to develop a national research action plan on Long COVID, focusing on delivery of high quality health care to affected individuals, making needed services and supports broadly available, and advancing our understanding of this condition (17).

Three large-scale studies in the U.S. are currently recruiting volunteers to study Long COVID:

  1. RECOVER (REsearching COVID to Enhance Recovery) is an NIH-funded human subjects research initiative that is enrolling individuals of all ages, including those who have had COVID and those who have not. Participants will provide periodic bio-samples and surveys at one of over 60 sites across the US and in Puerto Rico. Find out more at the RECOVER website.
  2. INSPIRE (Innovative Support for Patients with SARS-CoV-2 Infection) is a CDC effort to establish an online clinical research cohort of recently infected individuals to better understand the long-term effects of COVID-19 infection by collecting periodic surveys and other medical information. To enroll, visit the INSPIRE website.
  3. The Johns Hopkins COVID Long Study is a survey of COVID patients that focuses on their symptoms. This study is currently enrolling participants with a target of 25,000 respondents across the United States and plans to expand the survey internationally in the future. Visit the COVID Long Study website for study and enrollment information.

In summary, Long COVID is a serious consequence of COVID-19 infection that has been observed worldwide and will likely remain a problem, even with effective vaccines and treatments for acute COVID infection. While we now have basic knowledge about Long COVID, many important aspects of this disorder—including its pathogenesis, clinical course, and effective care and treatment approaches–remain to be determined. We applaud the response of scientists who are studying this condition around the world and remain hopeful that these global clinical research efforts and collaborations will fill in the critical gaps in our understanding of Long COVID.

Informational Resources

References

  1. CDC case definition: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
  2. WHO Case Def: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1
  3. Ledford, H. How common is long COVID? Why studies give different answers. NatureNews.20 June 2022
  4. CDC Long Covid Household Pulse Survey https://www.cdc.gov/nchs/covid19/pulse/long-covid.htmData from June 2022.
  5. Sudre, C.H., Murray, B., Varsavsky, T. et al. Attributes and predictors of long COVID. Nat Med 27, 626–631 (2021). https://doi.org/10.1038/s41591-021-01292-y
  6. Antonella, M., Pujot, J.C., Spector, T.D., et. al.  Risk of long COVID associated with delta versus omicron variants of SARS-CoV2. Lancet 399, 2263-2264; June 18, 2022 https://doi.org/10.1016/S0140-6736(22)00941-2
  7. Al-Aly, Z., Bowe, B., and Xie, Y. Long Covid after breakthrough SARS-CoV-2 infection. Nat Med 28, 1461-1467; 2022 https://doi.org/10.1038/s41591-022-01840-0
  8. Antonella, M., Pujot, J.C., Spector, T.D., et. al.  Risk of long COVID associated with delta versus omicron variants of SARS-CoV2. Lancet 399, 2263-2264; June 18, 2022 https://doi.org/10.1016/S0140-6736(22)00941-2
  9. Funk, A.L., Kupperman, N., Florin, T.A., et. al. Post-Covid19 Conditions Among Children 90 Days After SARS-CoV-2 Infection. JAMA Netw Open. 5(7): e2223253; 2022 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794484
  10. Davis, H.E., Assaf, G.S., McCorkell, L., et. al. Characterization of Long Covid in an International Cohort: 7 Months of Symptoms and their Impact. eClinical Medicine 38 (101019); July 15, 2021 https://doi.org/10.1016/j.eclinm.2021.101019
  11. Couzin-Frankel, J. Clues to Long COVID. Scientists strive to unravel what is driving disabling conditions. Science News, 16 June 2022.
  12. American Medical Association; June 2021 AMA Special Meeting. Adoption of policy support for “the development of an ICD-10 code or family of codes to recognize Post-Acute Sequelae of SARS-CoV-2 infection (‘PASC’ or ‘long COVID’) and other novel post-viral syndromes as a distinct diagnosis.”
  13. Jin H., Lu L., and Fan H. Global Trends and Research Hotspots in Long COVID: A Bibliometric Analysis. Int J Environ Res Public Health 19(6):3742; March 21, 2022. 10.3390/ijerph19063742
  14. Patient-led Research Collaborative. Report: What Does COVID-19 Recovery Actually Look Like? May 11, 2020. https://patientresearchcovid19.com/research/report-1/
  15. UK Biobank Covid-19 Hub: https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/covid-19-hub
  16. UK Real Time Assessment of Community Transmission Long COVID Study (REACT+ LC): https://www.imperial.ac.uk/medicine/research-and-impact/groups/react-study/studies/react-long-covid/
  17. Presidential Memorandum on Addressing the Long-term Effects of COVID-19. April 5, 2022. https://www.whitehouse.gov/briefing-room/presidential-actions/2022/04/05/memorandum-on-addressing-the-long-term-effects-of-covid-19/

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