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The physical space of the MSK Library is permanently closed to visitors as of Friday, May 17, 2024. Please visit this guide for more information.
"Long COVID" is a term coined by patients early in the pandemic to describe the broad number of issues they were experiencing after infection. These post-COVID conditions are a wide range of new, returning, or ongoing physical and mental health problems that some people experience after being infected with the virus that causes COVID-19. Most people with COVID-19 get better within a few days to a few weeks after infection, so at least four weeks after infection is the start of when post-COVID conditions could first be identified. Anyone who was infected can experience post-COVID conditions. Most people with post-COVID conditions experienced symptoms days after first learning they had COVID-19, but some people who later experienced post-COVID conditions did not know when they got infected.
There is no test that determines if your symptoms or condition is due to COVID-19. Post-COVID conditions are not one illness. Your healthcare provider considers a diagnosis of post-COVID conditions based on your health history, including if you had a diagnosis of COVID-19 either by a positive test or by symptoms or exposure, as well as doing a health examination.
Post-COVID conditions are associated with a spectrum of physical, social, and psychological consequences, as well as functional limitations that can present substantial challenges to patient wellness and quality of life.
In April 2020, shortly after the beginning of the pandemic, anecdotal reports from patients started to emerge that previously healthy individuals were experiencing lingering symptoms and were not fully recovering from an infection with SARS-CoV-2. These patients started to refer to themselves as “Long Haulers,” and they coined the term “Long COVID.” This early recognition by the patient community, and their efforts to organize, colloquially name the condition, and alert the world to study it, galvanized the scientific community to pursue research programs in this area, which in a short period of time have resulted in substantial conceptual advances and significant breakthroughs.
“Long COVID is broadly defined as signs, symptoms, and conditions that continue or develop after initial COVID-19 or 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 worsening 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.”
This working definition was developed by the U.S. Department of Health and Human Services in collaboration with other departments including with subject matter experts at HHS Office of the Secretary, CDC, and NIH and coincident with engagement of patient groups, medical societies, and experts inside and outside the government.
The definition builds on CDC’s definition of Post-COVID-19 Conditions (PCC), conceptually first described by CDC in November 2020 and first labeled PCC in February 2021. Terms and definitions for these conditions have evolved since the beginning of the pandemic and will continue to evolve as we learn more about the symptoms and conditions associated with Long COVID. In addition to Long COVID and PCC, an additional term had emerged in parallel and is in general usage in the United States: Post-Acute Sequelae of SARS-CoV-2 infection (PASC).
While Long COVID is largely a lay term, PCC and PASC are two scientific technical terms. PCC covers a wide range of health consequences that are due to all effects of COVID-19, including secondary and tertiary effects. PASC refers to the direct and indirect consequences of SARS-CoV-2 on human health.
Below are some of the 50+ identified signs and symptoms associated with Long COVID. This is far from an exhaustive list, but these are the most common reported symptoms in the weeks and months following acute COVID-19 infection.
Researchers are working to understand which people or groups of people are more likely to have Post-COVID Conditions, and why. Studies have shown that some groups of people may be affected more by Post-COVID Conditions. These are examples and not a comprehensive list of people or groups who might be more at risk than other groups for developing Post-COVID Conditions:
Some people are at increased risk of getting sick from COVID-19 because of where they live or work, or because they can’t get health care. Health inequities may put some people from racial or ethnic minority groups and some people with disabilities at greater risk for developing Post-COVID Conditions. Scientists are researching some of those factors that may place these communities at higher risk of both getting infected or developing Post-COVID Conditions.
The prevalence of post-COVID conditions has been challenging to estimate, with estimates ranging widely (5–30%). Reasons for these wide-ranging estimates include:
NVSS National Vital Statistics Reporting Guidance, Expanded February 2023
In the acute phase, clinical manifestations and complications of COVID-19 of varying degrees have been documented, including death. However, patients who recover from the acute phase of the infection can still suffer long-term effects. Post-acute sequelae of COVID-19 (PASC), commonly referred to as “long COVID,” refers to the long-term symptoms, signs, and complications experienced by some patients who have recovered from the acute phase of COVID-19.
Emerging evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, can have lasting effects on nearly every organ and organ system of the body weeks, months, and potentially years after infection.
Documented serious post-COVID-19 conditions include cardiovascular, pulmonary, neurological, renal, endocrine, hematological, and gastrointestinal complications, as well as death.
As we enter year four (4) of the COVID-19 pandemic, we are still only at the tip of the iceberg when it comes to experiencing, documenting, and understanding the long-term health consequences that SARS-CoV-2 infection has on humans. What scientists and clinicians do know is that the depth and breadth of consequences is expanding daily. The symptoms of many of these conditions can last for years, and many are believed to likely be life-long. Millions of Long COVID sufferers are unable to return to work, and the scale of disability caused by long-term consequences of COVID-19 infections will continue to contribute to labor shortages which will only increase with time and number of infections.
Long COVID (also known as Post-Acute COVID-19 Sequelae or Post-COVID-19 Conditions) is a broad set of signs, symptoms, and conditions that persist or appear after an acute COVID-19 infection. Since most people with COVID-19 get better within a few days to a few weeks after infection, Long COVID cannot be identified until at least four weeks after initial infection. The prevalence of Long COVID and it's wide range of conditions has been challenging to estimate, with estimates ranging widely (5–30%).
What scientists still do not understand is the connection between Long COVID and the long-term consequences of COVID-19 infections. Few people with long COVID demonstrate full recovery, with one study finding that 85% of patients who had symptoms 2 months after the initial infection still reported symptoms 1 year after symptom onset. Future prognosis is uncertain, although diagnoses of ME/CFS and dysautonomia are generally lifelong.
COVID-19 infection has been implicated in causing damage and dysfunction to nearly every organ system in the body, including:
This is just a short list of the types of medical conditions that COVID-19 infections increase the risk of developing after infection. These are all new-onset conditions in patients after COVID-19 infections, that have been documented in the medical literature.
Various studies around the world are documenting clusters of Long Covid symptoms, often tied to specific SARS-CoV-2 variants. Below are some the large-scale studies.
The multi-system cluster included significant levels of laboratory abnormalities. The group is dominated by heart, kidney and circulation-related symptoms.
Patients in this group, compared with those in other groups, were older on average, more likely to be male, had a relatively high rate of COVID hospitalization and had relatively more pre-existing conditions. Data suggests this cluster may actually be ongoing residual clinical manifestations of severe acute infection. These patients also were at the highest risk for mortality in the post-acute period.
The majority of patients in the cluster were patients sickened by SARS-CoV-2 during the first big U.S. wave from March to June 2020.
Neuropsychiatric symptom cluster included headaches, respiratory and sleep issues, anxiety, and mood disorders.
Patients with this pattern were mostly female and a much lower rate of COVID hospitalization.
Most of these patients tested positive for COVID-19 in later waves, from November 2020 to November 2021. Pre-existing conditions in this cluster centered on respiratory problems such as chronic obstructive pulmonary disorder and asthma.
This cluster included patients with a high degree of tachycardia, palpitations and hypoxemia. It also included pulmonary embolism.
Patients with this phenotype had higher frequencies of cough and hypoxemia.
This cluster included significant fatigue symptoms included ME/CSF.
Dominated by musculoskeletal and nervous system symptoms including arthritis pain. This cluster includes multi-system pain with significant overlap with the multi-system cluster, but without the laboratory abnormalities.
Unlike the multi-system cluster, the cluster is predominantly female. Evidence available prior to our study suggests that sex differences exist that influence the clinical course of COVID-19. For instance, although males are more likely to be hospitalized or die with acute COVID-19, females are more likely to develop long COVID
These patients had higher baseline comorbidity burdens of autoimmune and allergy conditions, such as rheumatoid arthritis and asthma, as well as other musculoskeletal and nervous system conditions, including soft tissue, bone and sleep disorders.
This cluster included patients with significant digestive symptoms. While patients in this cluster had the lowest risk of severe acute COVID-19 infection and lower overall burden of underlying conditions, their symptoms were centered around the digestive system, such as hematemesis, stomach and duodenum disorders and digestive system neoplasm, and more incident prescription digestive system medications.
One of the most concerning long-term impacts of COVID-19 is immune dysregulation and dysfunction. Immune system impacts were heavily documented, even in the first waves of the pandemic, however there was a lack of understanding as to what exactly COVID-19 infections were doing to the immune system, and what that might mean both during acute infection and long-term.
Early on in the pandemic, there were two main hypotheses for the pathophysiology of COVID-19 severe disease and death:
Early on it was noted that many patients with severe COVID-19 ended up developing ARDS. This was reminiscent of the cytokine release syndrome - induced ARDS and secondary hemophagocytic lymphohistiocytosis. Therefore it lead researchers to believe that severe infections were the results of an overactive immune response caused by excessive inflammatory cytokines, which lead to inflammatory lung and vascular injuries, and that death was from subsequent respiratory failure or coagulopathy. The second hypothesis took the exact opposite hypothesis, that COVID-19 caused immune collapse. In this hypothesis, COVID-19 causes the patient's protective immunity to collapse, causing uncontrolled viral replication and dissemination which lead to cytotoxicity and death. Support for this contrasting theory was based on the observed progressive and profound lymphopenia, often to levels seen in patients with AIDS.
More recent research has concluded that COVID-19 causes dysregulation to both the innate and the adaptive immune systems. Paradoxically, in COVID-19 pneumonia, the innate immune system fails to mount an effective antiviral response while also inducing potentially damaging inflammation.
Severe COVID cases were found to have decreased production of early immune responses (INF) which in turn lead to the virus replicating and causing severe cellular lung damage. Not only is was the antiviral response of IFN delayed and reduced, but it was also accompanied an over-exaggerated inflammatory response with excessive cytokines. This resulting hyper-inflammation caused edema, fibrosis, and thromboses in the lungs that ultimately lead to hypoxia, ARDS, and death.
Although COVID-19 patients may exhibit elevated levels of inflammatory cytokines compared to non-critically-ill patients, a study comparing the immune profiles of COVID-19 and influenza noted that while a 3–4% subset of COVID-19 patients exhibited hyperinflammation characteristic of a cytokine storm, they more commonly demonstrated immunosuppression.
CD4+ helper T cells and CD8+ cytotoxic T cells have been identified as crucial in the immunologic response to SARS-CoV-2 infection. CD4+ T cells are responsive to the virus's spike protein, and the presence of CD8+ T cell expansion in bronchoalveolar lavage is correlated with illness moderation. However, one of the most remarkable characteristics of immune dysregulation in COVID-19 is an immense depletion of CD4+ and CD8+ T cells associated with disease severity.
While lymphopenia is observed in other respiratory viral illnesses such as influenza A H3N2 viral infection, COVID-19 induced lymphocytic depletion is distinctive for its magnitude and longevity. Additionally, CD8+ T cells, crucial for their cytotoxic activity against virally infected cells, may experience the more stark reduction.
The lack of intense lymphocytic infiltration found in the lungs of critical COVID-19 patients demonstrates that the peripherally observed lymphopenia may be occurring through a mechanism beyond simply recruitment to the infection site.
In the early days of the pandemic, it was well documented that patients with severe COVID-19 infections had pronounced immune dysregulation with lymphopenia and increased expression of inflammatory mediators.
Patients with severe acute COVID-19 infection exhibit increased T-cell activation and subsequent T-cell exhaustion. This T-cell reduction of functional T-cells was pronounced and sustained beyond the acute infection. Early research found that in non-hospitalized COVID-19 patients, these immune cells returned to baseline fairly quickly, but were sustained in those with severe COVID-19 infection.
Now, three years into the pandemic, with millions of infections and immunizations behind us, severe acute COVID-1 infections are becoming significantly less common -- though COVID-19 is still causing significant hospitalizations and mortality across the globe. But generally speaking most individuals are no longer concerned with the acute infection stage of COVID-19. To the point that getting the virus may seem unremarkable and not a cause for concern.
However, a new idea about how COVID can affect immunity has emerged: that even mild infections routinely cause consequential damage to our bodies’ defenses. This degradation was referred to as “immunity theft” by T. Ryan Gregory, an evolutionary biologist, as a counterargument to "immunity debt" being the reason why respiratory infections were more severe than usual this past fall.
So while the acute infection may be one reason to not want to keep getting infected with SARS-CoV-2 over and over again, the idea that it can increasingly cause damage to the immune system should be a significant reason. Throughout the pandemic, scientific evidence has mounted that even mild COVID infections may be doing something to our immune systems, as well as our collective immunity.
For example, what if SARS-CoV-2 infection causes the immune system to be able to respond to SARS-CoV-2 in such a way that we no longer experience severe COVID infections, but rather it causes a subtler, long-term immunological changes that leave us more vulnerable to other infections or even chronic disease?
A March 2023 study published in the journal Immunity looked at how the immune system responded to both COVID-19 infection and COVID-19 vaccination. What the researchers found was that the magnitude and quality of CD8+ T cell activation and expansion after two COVID-19 vaccine doses were considerably lower in people with prior SARS-CoV-2 infection compared to people without prior infection, suggesting that previous infection can influence the T cell response to vaccination.
Taken together, the researchers write, "these findings suggest that SARS-CoV-2 infection damages the CD8+ T cell response, an effect akin to that observed in earlier studies showing long-term damage to the immune system after infection with viruses such as hepatitis C or HIV. The new findings highlight the need to develop vaccination strategies to specifically boost antiviral CD8+ T cell responses in people previously infected with SARS-CoV-2, the researchers conclude."
COVID-19 has been reported to present immunological features that resemble those of autoimmune diseases, such as over-activation of mature natural killer cells, CD8+ T cells, and dysregulation of B cells and T cells. Also, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to dysregulation of immune response and increased inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6.
There have already been many documented cases of autoimmune disease following COVID-19 infections, including:
A retrospective cohort study published in February 2023 in the journal eClinicalMedicine found that those who had documented COVID-19 infection had significantly higher risks of the following autoimmune diseases compared those without COVID-19:
Other viruses that are capable of latent phases are:
A large majority of people have been infected with lymphotropic herpesviruses, including Epstein–Barr Virus (EBV), cytomegalovirus (CMV), and Human Herpesviruses-6 (HHV-6) and -7 (HHV-7), which can remain latent within an individual’s cells throughout their lifetime. These viruses can emerge from latency when the infected host cells are triggered by various cues, including viral infections.
More recent research has been focusing on whether SARS-CoV-2 can remain latent in the body and become reactivated at a later time, similar to herpesviruses.
RNA viruses such as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) are capable of inducing immune dysfunction through hijacking host immune cell epigenomes and altering transcriptional programs to evade immune defenses. Epigenetics offers a window into understanding host‐pathogen interactions decoding the biologic dialogue between host and pathogen and understanding pathogen‐related disease outcomes.
Increasing evidence has shown that various components of the host immune system are dramatically altered during SARS‐CoV‐2 infection and the extent of immune dysregulation relates to severe COVID‐19 disease and mortality.
In order for SARS-CoV-2 to be successful in entering human cells and causing infections it must be able to continuously use the cell's metabolism machinery to replicate and invade. To do that it hijacks the host epigenetic mechanisms like DNA-methylation, acetylation, histone modifications etc.
Aging is a biological process related to diseases and mortality. Previous research has identified certain viral infections (including HIV, HBV, CMV) and bacterial infections can increase the rate at which the cells in the body age.
The biological process in aging is reflected by molecular hallmarks, which include epigenetic modifications and telomere shortening. DNA methylation correlates with aging process and can be used to estimate epigenetic aging across tissues. The deviation between DNA methylation age (DNAm age) and chronological age has been proposed as a biomarker for aging and has been related to risk and survival outcomes in age-related diseases.
In humans, telomere shortening is associated in the body with the aging process and, in the cells, with cellular replicative senescence (decreased cellular replication and cellular "death"). Telomeres possess properties that make them suitable as biomarkers in several diseases or conditions, including cancer, CVDs, and aging. The inverse correlation between telomere length (TL) and chronological age has been used for age prediction.
Interestingly, telomere length and the epigenetic clock do not correlate with one another, suggesting that DNAm age and TL measure different aspects of biological aging.