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Long COVID's Long Road: The Muddled Map at 4 Years


Long COVID affects approximately 20 million people in the US and that number may be conservative. Here, a snapshot, through the fog, of the route they are on.

Long COVID's Long Road / image credit mystery road:  ©Rawpixel.com/stock.adobe.com

March 11, 2024, marked the 4th anniversary of the official declaration of COVID-19 as a global pandemic. And while there is no actual date to mark the occurrence, the 4th anniversary of the first experiences of the lingering symptoms now called long COVID will follow.

Long COVID, in just 2 words, has come to stand for myriad constellations of multisystem symptoms experienced by individuals who have recovered from active infection with SARS-CoV-2. Symptoms can be lingering versions of those experienced during the acute infection or can be altogether new and different from them; they can follow resolution of the infection closely or emerge weeks, even months, after what appears to be recovery from the acute illness. The symptoms range from irritating to debilitating and manifest in persons whose infection was mild or even asymptomatic in addition to those who were hospitalized and critically ill. What has become clear since shortly after the world closed in March 2020 is that an experience of COVID-19 that falls anywhere along the continuum of severity poses a risk for post-acute sequelae of SARS-CoV-2 infection (PASC).

Long COVID, defined

The World Health Organization defines long COVID as “the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.”1

A description from the US Centers for Disease Control and Prevention is more detailed and nuanced2:

“Long COVID is a patient-created term broadly defined as signs, symptoms, and conditions that continue or develop after initial SARS-CoV-2 infection. The signs, symptoms, and conditions are present four weeks or more after the initial phase of infection; may be multisystemic; and may present with a relapsing–remitting pattern and progression or worsen over time, with the possibility of severe and life-threatening events even months or years after infection. Long COVID is not one condition. It represents many potentially overlapping entities, likely with different biological causes and different sets of risk factors and outcomes.”2

The CDC description closely reflects the real-world experience of health care professionals who assess and treat people living with long COVID and also of the researchers around the globe who have worked since the earliest days to characterize the nature of the syndrome, potential underlying causes, and possible trajectories of an illness for which there is documented evidence of an effect on every organ system in the human body.

Current scope, impact

The majority of people infected with COVID-19 recover completely from the virus, but as of February 2024, more than 17% of US adults reported having ever experienced symptoms of long COVID. If extrapolated to the US population, the data, which come from the US Census Bureau’s most recent Household Pulse Survey,3 would mean that more than 45 million adult Americans are living with long COVID. Estimates of prevalence from the Government Accounting Office4 are that between 7 million and 23 million Americans “are suffering from the long-term effects of infection with the virus.” Within that population are an estimated 1 million individuals who are no longer able to work.4 One million US adults out of the workforce at any given time translates to an annual loss in income of $50 billion, according to Harvard economist David Cutler, PhD, in an analysis of long COVID costs in JAMA.5 Another estimate of disability, from the Brookings Institution, increases the number to 1.6 million, a number analysts there described as “conservative” in January 2022.6 Based on the number of unfilled jobs at that time, “long Covid potentially accounted for 15% of the labor shortage,” according to the report.6


For as much as is yet to be learned about the whys of long COVID, reliable patterns have emerged around populations most affected. By age prevalence approximates a bell shaped curve with the greatest proportion reporting having long COVID between ages 35 to 49 years and the lowest among those aged 65 years and older.3 The CDC reports that among those who have ever reported symptoms and with current symptoms, women were significantly more likely to report long COVID vs men. The CDC Household Pulse survey specifically reported 20.6% of women compared with 14.4% of men reported ever having long COVID.3 Pulse also found that Hispanic respondents were the most likely to report long COVID symptoms and non-Hispanic Asian respondents were the least likely.3 Respondents self-reporting as Black were less likely than Hispanic respondents to report long COVID but more likely than respondents self-reporting as White or Asian.3 Other correlates associated with long COVID include lower education level and household income.3 Among the many risk factors identified for long COVID are: current smoking, higher body mass index, and presence of comorbidities including mental health, respiratory disease, and metabolic disease.8

Symptoms, pathophysiology

Research to date has documented more than 200 symptoms associated with long COVID, the most familiar of those including fatigue, post exertional malaise, heart palpitations, blood clots, hair loss, persistent cough, loss of lung function, muscle pain and joint aches, brain fog, headache, depression, anxiety, sleep disturbances, loss of smell, and gastrointestinal problems.9

Consensus in the scientific community is coalescing around long COVID as not one disease but as numerous disease subtypes albeit driven originally by a single virus. The picture grows more complex and fragmented, too, with observations that the subtypes can overlap in one person.

“Physiologic perturbations are often the result of many intersecting pathways,” Bruce Levy, MD, the Parker B. Francis Professor of Medicine at Harvard Medical School and an investigator at the HMS-led Massachusetts Consortium on Pathogen Readiness, said in a recent interview with Harvard Medical School.10 Levy explains that while signs and symptoms may be defined with clinical precision, that process and the result may not help identify the underlying mechanisms. Persistent low-grade inflammation, for example, may lead to chronic blood clots, fatigue, poor exercise tolerance, and decreased lung function. The chronic inflammation, however, may be the result of several distinctly different pathways, eg, low levels of circulating virus, reactivation of dormant infections, immune dysfunction, and more.10

David A Putrino, PhD, is among the foremost physician scientists investigating the multiple pathophysiologic aberrations under the umbrella term of long COVID. Putrino is director of rehabilitation innovation at the Mount Sinai Health System in New York and Professor in the department of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai. “If we follow the literature, we know that there are many underlying mechanisms that are associated with long COVID. Some individuals are showing clear signs of SARS-CoV-2 persistence. We've found replicable virus and reservoirs of virus in multiple tissue samples, especially in the gut,” said Putrino in an interview with Patient Care. He says researchers have observed circulating spike proteins in blood samples and have seen “replicable virus in other forms of tissue, such as breast tissue and muscle and neurological tissue,” evidence that viral persistence is occurring in at least a proportion of individuals with long COVID.

“We know, too, that immune dysregulation is occurring, sometimes very serious immune dysregulation,” Putrino continued. He describes a paper he published in Nature11 with Aki Iwasake from Yale that investigated features of long COVID through immune profiling. The team of researchers found evidence of reactivation of coinfections including Epstein-Barr, other herpes viruses, and Lyme disease.11 He also highlighted research published in January 2024 in the journal Science12 by Cervia-Hasler and colleagues showing that the complement system is “completely dysregulated by SARS-CoV-2 in long COVID,” the condition found to be marked by “increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis.”12

“We have documented microbiome dysfunction and gut dysbiosis,” Putrino continued. “We see autonomic nervous system dysfunction, coagulation issues in the blood. We have learned so much about what’s going wrong.”

A closer look at the leading hypotheses

Viral persistence. Viral proteins and/or RNA has been found in multiple systems, including cardiovascular and reproductive, in lymph nodes, the eyes, hepatic tissue, lung tissue, plasma, stool and urine. Circulating SARS-CoV-2 spike antigen was found in 60% of a cohort with long COVID up to 1 year after diagnosis compared with no members of a group of virus-infected individuals.9 The findings all suggest a persistent reservoir of active virus in some individuals that allows viral RNA to trigger innate immune response and viral proteins to cause tissue damage, activating lymphocytes, and setting up chronic inflammation.9

Autoimmunity. Infection with SARS-CoV-2 may trigger autoimmune conditions that manifest with symptoms linked to long COVID. Increased rates of rheumatoid arthritis and lupus have been identified in individuals who have recovered from the virus. Although this post-acute effect of infection is not a novel finding, the increase in the overall incidence and range of autoimmune conditions observed in the aftermath of COVID-19 distinguishes this experience.13 A systematic review in Nature in November 202314 found multiple studies documenting upregulation of autoantibodies in individuals with long COVID, including antibodies to ACE2, anti-nuclear autoantibodies, and immunomodulatory factors including complement components, chemokines, cytokines, and cell-surface proteins.14

Reactivation of dormant chronic infections. Recent research suggests significant immune dysregulation, both with and without reactivation of underlying pathogens, including herpesviruses such as Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) among others. More than half (58.7%) of participants over the age of 18 years in one study met the criteria for EBV.14 Work yet to be published led by Harvard researcher Jennifer Snyder-Cappione suggests that memory T cell response highly specific to EBS increases significantly over the months following a diagnosis of COVID-19 among many people with long COVID but not in those who have fully recovered from the infection.10

Gut dysbiosis. GI symptoms of long COVID include nausea, abdominal pain, loss of appetite, heartburn, and constipation. Significant alterations have been seen in the composition of the gut microbiota.9 Studies focused on the potential for persistence of SARS-CoV-2 in the gastrointestinal tract have revealed viral RNAs and proteins in both gut and stool tissue up to 12 months after COVID-19 diagnosis.14 Studies have also found that some individuals are left with a condition in which molecular channels in the gut, ie, tight junctions, loosen and become susceptible to leaking. The microbes released into the bloodstream result in immune activation and chronic inflammation.10

New disease?

Evidence of influence of SARS-CoV-2 on the cardiovascular and endocrine systems has been observed since early in the COVID-19 pandemic when reports of incident cardiovascular disease and diabetes began proliferating. Two large studies supported by the US Department of Veterans Affairs, Office of Research and Development and published by Xie et al in Nature Medicine15 and Lancet Diabetes Endocrinology16 support the initial descriptions. The investigators found that beyond the first 30 days of infection with COVID-19, individuals exhibited “increased risks and 12-month burdens of incident cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, and other cardiac disorders.15 The risks were consistent across age, race, sex, and other CV risk factors and were evident in those without any CVD before SARS-CoV-2 exposure.15 The team reported similar findings for the risk of diabetes and use of antihyperglycemic medications, with risk and burdens regardless of hospitalization.16

A game of Scrabble

At the Post-COVID-19 Program at the University of Texas Health in Austin, clinical data collected over time shows that individuals present with a median of 18 new symptoms. A collection of symptoms vs a single or even 2 or 3 appears to be the norm. “I’ve never seen 2 long COVID patients that look exactly alike…it’s like you’re picking Scrabble letters but there are 200 of them,” said Noah Greenspan, PT, DPT, CCS, EMT-B, a specialist in pulmonary and cardiovascular rehabilitation in New York City. Greenspan is the founder of the Pulmonary Wellness and Rehabilitation Center and the Pulmonary Wellness Foundation in NYC and established a clinic to care for individuals with long COVID early in the pandemic. He describes long COVID rehabilitation as a lot like the Cryptex from the DaVinci code—you’re trying to find the solution to each patient’s particular Rubik’s Cube.

“We may not have cures right now, but there are many things we can do to make people feel better,” Putrino said. That is where part 2 of this “Long COVID’s Long Road” feature will pick up, with a review of approaches to assessment and treatment for the many manifestations of the vexing syndrome, including current medications being used to treat symptoms and the wide range of nondrug interventions proven helpful in the physical rehabilitation setting. The status of the research underway and the role of federal agencies in moving the science forward will also be reviewed.

1. Post COVID-19 condition (long COVID). World Health Organization. Fact sheets. Decemeber 7, 2022. Accessed March 21, 2024. https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
2. Post-COVID conditions: information for healthcare providers. Centers for Disease Control and Prevention. Updated February 6, 2024. Accessed March 1, 2024. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.htm
3. National Center for Health Statistics. US Census Bureau, Household Pulse Survey, 2022–2024. Long COVID. Last reviewed March 21, 2024. Accessed March 15, 2024. https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm
4. US Government Accountability Office. Science and tech spotlight: long COVID. Fast facts. March 2, 2024. Accessed March 15, 2024. Available at: https://www.gao.gov/products/gao-22-105666
5. Cutler D. The costs of long COIVD. JAMA Health Forum. 2022;3(5):221809. doi:10.1001/jamahealthforum.2022.1809
6. Bach K. Is long COVID worsening the labor shortage? Brookings. January 11, 2022. Accessed March 15, 2024. https://www.brookings.edu/articles/is-long-covid-worsening-the-labor-shortage/
7. Adjaye-Gbewonyo D, Vahratian A, Perrine CG, Bertolli J. Long COVID in adults: United States, 2022. NCHS Data Brief, no 480. Hyattsville, MD: National Center for Health Statistics. 2023. doi: https://dx.doi.org/10.15620/cdc:132417.
8. Tsampasian V, Elghazaly H, Chattopadhyay R, et al. Risk Factors Associated With Post−COVID-19 Condition. A Systematic Review and Meta-analysis. JAMA Intern Med. 2023;183(6):566-580. doi:10.1001/jamainternmed.2023.0750
9. Davis HE, McCorkell L, Moore J, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133–146. https://www.nature.com/articles/s41579-022-00846-2
10. Pesheva E. The most important questions about long COVID. Harvard Medicine News. August 9, 2023. https://hms.harvard.edu/news/most-important-question-about-long-covid
11. Klein J, Wood J, Jaycox J, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023;623:139-148. https://doi.org/10.1038/s41586-023-06651-y
12, Cervia-Hasler C, BrÜningk SC, Hoch T, et al. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science. 2024;383(6680). doi:10.1126/science.adg7942
13. Sharma, C., Bayry, J. High risk of autoimmune diseases after COVID-19. Nat Rev Rheumatol 19, 399–400 (2023). https://doi.org/10.1038/s41584-023-00964-y
14. Li, J., Zhou, Y., Ma, J. et al. The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID. Sig Transduct Target Ther. 2023;8(416). doi:10.1038/s41392-023-01640-z
15.Xie Y, Xu E, Bowen B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022; 28(3):583–590. doi:10.1038/s41591-022-01689-3
16. Xie Y, Al-Aly Z. Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabetes Endocrinol. 2022;10(5):311-321. doi:10.1016/S2213-8587(22)00044-4

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