Long-Term Risks FAQ

FAQ: Long-Term Effects of COVID-19

Summary: Takeaways for prospective challenge trial participants

Prepared for 1Day Sooner by Steffen Kamenicek, Jupiter Adams-Phipps, and Danny Toomey

Long COVID is a condition in which acute symptoms of COVID-19 persist for at least 12 weeks without an alternative diagnosis. Rates estimating the incidence of Long COVID widely vary, with most studies approximating 30% of acute COVID cases persisting into Long COVID. However, a major study observed comparable rates of Long COVID symptoms, such as fatigue, in people who never had COVID, suggesting these symptoms may be partially attributable to the general strain of the pandemic. A leading hypothesis of Long COVID holds that it is caused by tiny blood clots that can lead to a broad array of symptoms, such as fatigue and difficulty breathing, concentrating, or sleeping. Older individuals, women, people with preexisting conditions, and people with more severe initial COVID symptoms are more likely to develop Long COVID. There are currently no definitive tests or treatments for Long COVID.

What is “Long COVID”?
Long COVID is the popular term for a condition characterized by long-term complications following an acute COVID-19 infection, i.e. an infection with SARS-CoV-2 virus. Due to the novelty of the condition, research on long-term effects is ongoing, and it should be understood that reported findings remain preliminary. Other terms for Long COVID that have been highlighted by the US Centers for Disease Control and Prevention (CDC) include post-COVID conditions, long-haul COVID, post-acute COVID-19, post-acute sequelae of SARS CoV-2 infection, long-term effects of COVID, and chronic COVID.^[1]

The US CDC suggests that post-COVID conditions can first be identified starting four weeks after infection.¹ This is consistent with guidelines published by the UK’s National Institute for Health and Care Excellence (NICE),^[2] which recommends using the following clinical case definitions:

Acute COVID-19: Used to describe signs and symptoms of COVID-19 that last for up to 4 weeks.
Ongoing symptomatic COVID-19: Used to describe signs and symptoms of COVID-19 that last from 4 weeks up to 12 weeks.
Post-COVID-19 syndrome: Used to describe signs and symptoms of COVID-19 that continue for more than 12 weeks and that are not explained by an alternative diagnosis.

According to NICE, the term “Long COVID” is used to encapsulate both “ongoing symptomatic COVID-19” (4-12 weeks) and “post-COVID-19 syndrome” (12+ weeks).²

The World Health Organization (WHO) has also developed a definition, using the term “post COVID-19 condition” to describe cases in which individuals with a probable or confirmed history of SARS-CoV-2 infection have persistent symptoms 3 months (around 13 weeks) from the initial infection that last for at least two months (around 8 and a half weeks) and that are not explained by an alternative diagnosis.^[3]

Taken together, the CDC, NICE, and WHO definitions can be synthesized to define Long COVID as symptoms of acute COVID-19 that persist for at least 12 weeks and are not explained by another diagnosis.

How many people experience Long COVID?
The percentage of people who suffer from long-term symptoms after COVID-19 infection varies greatly between studies. A meta-analysis of 41 studies by Chen et al. found that estimates ranged from 9 to 81%.^[4] This wide range could be the result of differences in terms of study design. Studies that include only originally hospitalized cases, for example, tend to show a higher prevalence. However, even within meta-analyses and analyses of large datasets, there is still considerable variation. According to CDC data from June 2022 based on the “Household Pulse Survey”, 19% of adults in the U.S. with a confirmed history of COVID-19 report symptoms of Long COVID.^[5] A meta-analysis of 18 studies by Han et al., which looks at the average prevalence of individual symptoms across studies found that the prevalence for the most commonly reported symptom – fatigue – was 28%.^[6] A review article from September 2022 by Mantovani et al. that provides an overview of the current state of knowledge on Long COVID gives a more defensive estimate, stating that it affects “over 10% of patients”, without giving an estimated upper limit.^[7] However, a survey performed by the UK office for National Statistics observed a lower range of 3.0-11.7% of COVID patients reporting Long COVID symptoms.^[8]

An important caveat to estimates of Long COVID prevalence was provided by a study highlighting the importance of control groups in Long COVID studies^[9]. This study found comparable rates of symptoms attributed to Long COVID in people who had never had COVID, suggesting that the high prevalence of common symptoms such as fatigue may be attributable to the strain of the pandemic broadly, rather than prior acute COVID infection. This suggests that the true incidence of Long COVID may lie closer to the lower estimates studies have identified.

What are the commonly reported symptoms of Long COVID, and how common are they?
Long COVID can manifest in many different ways. Organizations such as the WHO, CDC, and NICE have compiled lists of commonly reported symptoms. The following table organizes these symptoms by category; however, these symptoms should not be used for self-diagnosis due to their wide variety. If you are concerned that you are experiencing symptoms of Long COVID, you should consult with a doctor.

Symptom Category	Commonly Reported Symptoms
General Symptoms	Fatigue/tiredness,^1,2,^[10] fever,^1,2,7 general pain,² symptoms that worsen after physical or mental effort (“post-exertional malaise”)¹
Respiratory Symptoms	Difficulty of breathing or shortness of breath (dyspnea),^1,2,7 cough^1,2,7
Cardiovascular Symptoms	Chest tightness and/or pain,^1,2,7 heart palpitations¹^,2
Neurological Symptoms	“Brain fog” (including issues with memory and/or concentration),^1,2,7 sleep problems,^1,2,7 change in or loss of smell and/or taste,^1,2,7 symptoms of depression/anxiety,^1,2,7headache,^1,2 dizziness,^1,2 “pins and needles” feeling and/or numbness,^1,2 symptoms of PTSD,² trouble speaking⁷
Gastrointestinal Symptoms	Diarrhea,^1,2 stomach/abdominal pain,^1,2 nausea and vomiting,² weight loss and reduced appetite²
Musculoskeletal Symptoms	Joint and/or muscle pain/aches¹^,2,7
Ear/Nose/Throat Symptoms	Ringing in ears (“tinnitus”),² earache,² sore throat,² nasal congestion²
Dermatological Symptoms	Rash,^1,2 hair loss²
Other Symptoms	Changes in menstrual cycles¹

Additionally, there have been a number of systematic reviews and other studies investigating the frequency and prevalence of Long COVID symptoms, with most in agreement that fatigue, shortness of breath, and sleep disorders are among the most commonly reported symptoms of Long COVID.

A systematic review and meta-analysis performed by Alkodaymi et al.^[11] (May 2022) included 63 studies published prior to October 2021, with a total population of 257,348 individuals with confirmed SARS-CoV-2 infection. The prevalence of the most commonly reported symptoms was determined at four different follow-up time intervals:

3-6 months: fatigue (32%), dyspnea (25%), sleep disorder (24%), and difficulty concentrating (22%)
6-9 months: effort intolerance (45%), fatigue (36%), sleep disorder (29%), and dyspnea (25%)
9-12 months: fatigue (37%) and dyspnea (21%)
>12 months: fatigue (41%), dyspnea (31%), sleep disorder (30%), and myalgia (22%)

A retrospective study of 8 healthcare centers in India found that among 679 health care workers who had primary COVID infection, 30.3% had Long COVID within a timeframe of 12-52 weeks.¹⁰ The most commonly reported symptoms were fatigue (11.5%), insomnia (8.5%), difficulty breathing (6.0%), and joint pain (5.0%).^[12]

A systematic review performed by van Nasserie et al.^[13] included 45 studies published from January 2020 to March 2021, with a total of 9,751 participants. The most frequently occurring individual symptoms included fatigue/exhaustion (40.0% median frequency among 25 studies), dyspnea (36.0% median frequency among 26 studies), and sleep disorders or insomnia (29.4% median frequency among 8 studies).¹¹

Is there a test for Long COVID?
There is no definitive test for Long COVID. The CDC has provided guidelines for healthcare providers to help assess what tools they should use to diagnose Long COVID.^[14] These tools include:

Physical exam findings
Lower blood oxygen while walking or when standing up may be observed in Long COVID. Testing to determine exercise capacity may also help identify Long COVID. Otherwise, the broad array of symptoms that can compose Long COVID make physical exam findings equally broad and individualized.

Laboratory and Imaging findings
There is no known combination of blood, metabolic, or imaging abnormalities that clearly define Long COVID. Laboratory or radiologic studies in Long COVID patients may be normal. Antigen and PCR testing are intended to identify acute COVID and do not identify Long COVID. Due to the broad array of symptoms that Long COVID can present with, an equally broad array of laboratory examinations may be indicated. These tests are often to rule out a medical emergency and not to explicitly diagnose Long COVID. Imaging studies in Long COVID patients are similarly more likely to be performed to rule out a medical emergency, rather than diagnose Long COVID.

What causes these effects?
An array of mechanisms has been proposed to explain the neurological, cardiovascular, pulmonary, immunological, and musculoskeletal symptoms of Long COVID.^[15] Tiny blood clots called microthromboses often serve as a common thread for these various pathological mechanisms, with one study finding that Long COVID patients experiencing a broad range of symptoms tended to exhibit increased platelet dysfunction.^[16] These effects are magnified in patients with hypertension and high cholesterol, which are known to impair endothelial cell function, further supporting the evidence for this possible mechanism.^[17]

At an individual system level, proposed pathological mechanisms of Long COVID become more granular, though key similarities remain. Neurological, cardiovascular, and pulmonary symptoms have been proposed to relate the effects of microthromboses on endothelial cells in these separate systems. Endothelial cells line the walls of arteries and veins and act as gatekeepers between molecules in the blood and molecules in tissues. Microthromboses may disrupt this lining, causing the immune system to invoke an inflammatory response in these tissues. Inflammation is a common and ubiquitous tool of the immune system, but prolonged inflammation can damage the body.

In the nervous system, Long COVID can manifest as psychiatric disorders, headaches, loss of smell or taste, and fatigue. One possible mechanism of these symptoms is that microthromboses may lead to endothelial cell dysfunction, inducing chronic neuroinflammation by way of prolonged microglial cell activation.^[18] Microglial cells are immune cells of the nervous system and induce inflammation in response to threats, such as endothelial cell disruption.^[19] If microglial cells persistently react to microthromboses in the nervous system, cells in the nervous system could be impacted by the resulting immune response, leading to neurological and psychiatric symptoms.^[20]

In the heart, key cardiac symptoms of chest pain, palpitations, and syncope (fainting, loss of consciousness) may be due to inflammation secondary to endothelial cell dysfunction caused by microthromboses. Prolonged inflammation in heart tissue can cause the death of cardiac muscle cells, leading to fibrosis (scarring) and decreased function.^[21] In the lungs, microthromboses have been proposed to interfere with oxygen exchange at capillaries, leading to difficulty breathing and hypoxia (low oxygen levels).^[22]^,^[23] Musculoskeletal symptoms of excessive fatigue when exercising and muscle pain are proposed to be similarly caused by decreased oxygen exchange due to microthromboses.^[24]

Additionally, Long COVID patients appear to exhibit systemic chronic low grade inflammation, which may contribute to Long COVID symptoms that are difficult to isolate to a single system, such as weakness or fatigue.^[25]

Biological system	Key symptoms	Possible mechanism
Nervous	Mental disorders, Headaches, Loss of smell or taste, Persistent fatigue	Chronic neuroinflammation caused by microglial activation, possibly in reaction to microthromboses and endothelial cell dysfunction^15-17
Cardiovascular	Chest pain, palpitations, syncope	Cardiac fibrosis induced by inflammation in cardiac muscle tissue, possibly secondary to microthromboses and endothelial cell dysfunction¹⁸
Pulmonary	Dyspnea, Hypoxia	Pulmonary fibrosis secondary to epithelial cell damage, possibly in reaction to microthromboses¹⁹^{, 20}
Musculoskeletal	Exercise intolerance and muscle pain	Decreased peripheral oxygen transport²¹
Immune	Chronic low grade inflammation	Increase in proinflammatory cytokines, interferons, and autoantibodies²²

How long could we expect the symptoms of Long COVID to last?
A survey of 5,163 people with prior symptomatic COVID infection identified 101 persistent symptoms.^[26] Among respondents, 78.9% experienced fatigue with a median duration of 105 days, 55.3% experienced headache with a median duration of 56 days, 55.3% experienced shortness of breath for a median of 84 days, 53.6% experienced difficulty concentrating for a median duration of 105 days, and 49.6% experienced inability to exercise for a median of 112 days.

There is no definitive upper limit on the duration of Long COVID symptoms. Under the WHO clinical case definition of post COVID-19 condition, symptoms are expected to last for at least 2 months after initial infection with SARS-CoV-2.³ Studies have reported symptoms lasting for 12 months or longer,^8,9 with some even reporting increased risks for various symptoms after 2 years.^[27] New symptoms can manifest after recovering from the initial infection, or symptoms can persist from the original illness, with the possibility of fluctuating or relapsing over time.³ A study of patients in France found that the prevalence of some symptoms decreased throughout the first 6-8 months after onset, while the prevalence of other symptoms increased 6 months after onset.^[28]

What are risk factors for Long COVID?
Sex
Despite the fact that men are more likely than women to suffer from a severe course of COVID-19 infection, and also have a higher mortality rate, women are at a significantly stronger risk of developing Long COVID. Almost all studies point out that female sex is a risk factor for developing long-term symptoms. One review that explicitly compared different studies with regard to sex differences in Long COVID came to the conclusion that women are at a 22% higher risk of developing long-term symptoms,^[29] while two other studies even arrive at an approximate 50% increased risk for women compared to men.^[30] ^[31]

There is still no definite answer to the phenomenon of why Long COVID affects women more than men, while acute COVID hits males harder than females. However, it has been suggested that the differences in immune system function could play an important role. Women generally have a stronger immune response, which can protect them from initial infection and severity, but at the same time also leaves them more vulnerable to autoimmune reactions.^[32]

Comorbidities or Preexisting conditions

There are several underlying conditions which are associated with a higher risk of developing long-term symptoms following COVID-19 infection. Several conditions have been cited as increasing the risk for Long COVID, including pulmonary conditions such as COPD^[33] and asthma,^[34] psychological conditions such as depression, anxiety and perceived stress,^[35] neurological conditions such as migraine^[36] and fibromyalgia, as well as a range of other conditions including benign prostatic hyperplasia, erectile dysfunction, multiple sclerosis, and celiac disease.^[37] Moreover, higher BMI, as well as being a current or former smoker, also lead to a higher risk of suffering from long-term symptoms following COVID-19 infection.^[38]^,^[39]

Severity of initial disease

People who had a more severe episode of acute COVID-19 also seem to be at a higher risk of developing long-term symptoms. A study comparing hospitalized and non-hospitalized patient cohorts of people who had acute COVID-19 found that people who were hospitalized had a 49% higher risk of suffering from Long COVID.^[40] A systematic review of literature on long-term COVID-19 symptoms found that most studies, although not all of them, showed a higher risk of long-term symptoms in patients with severe or critical acute COVID-19 compared to people who had a non-severe course of initial infection.^[41]

Age

The relationship between age and the likelihood of developing Long COVID symptoms is not straightforward, according to the currently available data. While some studies see a weak, albeit linear connection between increasing age and the risk of developing Long COVID, others see the highest risk among middle-aged populations,^[42] while yet another study says that older age was associated with a higher risk of reporting symptoms in the univariate analysis, but with a lower risk after adjusting for baseline covariates such as underlying health conditions^[43]. In other words, while older people suffer from more debilitating symptoms in general, these symptoms do not seem to be specifically tied to COVID-19 infection. In the case of age, this lack of a clear correlation is particularly surprising, as older age is widely proven to be one of the most important risk factors for severity of acute COVID-19 disease, with older people being much more likely to encounter severe illness, hospitalization, intensive care, and death.

Other possible risk factors

To what extent risks for Long COVID correlate with ethnicity is unclear, with different studies pointing in different directions. An analysis of ten longitudinal studies in the UK found that people of South Asian or Black ethnicity were at a lower risk of developing Long COVID symptoms compared to people of White ethnicity^[44], while another large-scale study, also from the UK, arrived at the opposite conclusion, listing “belonging to an ethnic minority” as a risk factor for developing Long COVID.^[45] The CDC, in turn, reports the highest Long COVID rates among Hispanic adults, followed in this order by non-Hispanic White, Black and Asian.^[46] Yet another study says that ethnicity is not associated with developing long-term symptoms.^[47]

There is some evidence that social deprivation is associated with a higher risk for Long COVID, but the evidence is comparatively weak. One large review found that those who were most socioeconomically deprived are at a 11% higher risk of developing long-term symptoms compared to those who are least deprived.^[48] Another study, meanwhile, found that social vulnerability was not associated with developing long-term symptoms.^[49] One of the largest datasets by the UK’s Office for National Statistics, which is updated every month, listed social deprivation as a risk factor in earlier versions, but has suspended the publication of this and some other risk factors in its latest edition (October 2022) pending a review of their quality.^[50]

Does reinfection increase your chances of Long COVID?

To date, there have been no studies that definitively conclude the risk of developing Long COVID after multiple COVID infections. One large survey^[51] conducted by Long COVID Kids and Long COVID Support found that participants who self-reported Long COVID symptoms and self-reported having been infected with COVID multiple times tended to indicate a worsening of Long COVID symptoms. However, the self reported nature of these data makes drawing any meaningful clinical conclusions difficult. A recent meta-analysis^[52] of reinfection in COVID patients identified several case reports of worsening COVID symptoms after reinfection. Although, these findings were not in the setting of Long COVID and the majority of case reports identified did not find an increase in symptom severity.

An analysis of patients enrolled in the CDC INSPIRE trial identified the importance of including a COVID negative control group in studies evaluating the severity of Long COVID. This study found no difference between COVID negative viral illnesses and COVID positive patients in decrements in physical, mental, or social well being 3 months after symptomatic infection, suggesting these effects may be attributable to the strain of the ongoing pandemic rather than the viruses themselves.^[53] Another longitudinal study of children and young people with previous COVID infection compared to those who had never tested positive for COVID found a comparable incidence of common Long COVID symptoms between the groups at matched time intervals.^[54] Taken together, these studies suggest that the strain of the pandemic alone may contribute to the presence and severity of Long COVID-like symptoms, even in people who never had COVID.

What kind of treatment or care is available for these symptoms?
There is no known effective therapy or cure for Long COVID and no known timeframe for resolution of symptoms. Because of the variety of Long COVID symptoms patients experience, appropriate clinical care tends vary by individual. Common treatments include oxygen supplementation for dyspnea, corticosteroid therapy for pneumonia, and anticoagulants to prevent blood clots.^[55] Anticoagulants have additionally been shown to reduce mortality of hospitalized COVID patients after discharge, regardless of the symptoms they experienced.^[56] However, broad recommendations maintain that antithrombotic prophylaxis should be prescribed based on individual assessment for bleeding or venous thromboses.^[57] The NIH is currently enrolling participants in a series of large cohort studies as part of the RECOVER Initiative in order to better understand Long COVID how it may be treated.^[58]

There has been substantial research evaluating methods to reduce dyspnea in Long COVID patients. Several studies have evaluated breathing exercises as an intervention for prolonged difficulty breathing. The working theory behind the efficacy of these treatments is that improving control of inspiratory muscles can help patients alleviate breathlessness, which was supported by a recent randomized controlled trial.^[59] Another study found that breathing exercises in conjunction with yoga or stretching significantly improved pulmonary function and exercise capacity in Long COVID patients, as well as reducing anxiety.^[60]

Treatments have also been evaluated for weakness and chronic fatigue in Long COVID patients. Few definitive treatments have been identified, but several have emerged as possible therapeutic strategies to be more thoroughly researched. A non-randomized control trial showed that treatment with oxaloacetate in Chronic Fatigue Syndrome and Long COVID patients reduced fatigue symptoms in both, suggesting that oxaloacetate may be effective against pathological fatigue arising from different conditions.^[61] Additionally, a randomized controlled trial identified that sedum gluconate improves olfactory function in patients with diminished sense of smell.^[62]

Paxlovid has been proposed as a therapy for COVID and Long COVID, however the risks and benefits must be weighed in an individual context to determine if treatment with Paxlovid is appropriate.^[63] In patients at high risk for severe complications of COVID, Paxlovid may reduce the likelihood of death.^[64] An increase in viral load has been observed after Paxlovid therapy is finished, leading to “rebound” COVID, though the symptoms of rebound COVID appear to be less severe than acute COVID or Long COVID.^[65] Oral antiviral therapies are generally effective in treating COVID, however more research is required to establish a standard of care for COVID and Long COVID.^[66]

Can vaccination improve symptoms for people with Long COVID?

Despite the fact that vaccination against Sars-CoV-2 has a well-proven and large impact on reducing mortality rates and severe disease, it is controversial whether it has a significant effect on Long COVID. The answer also depends on the timing of vaccination – does it occur before or after SARS-CoV-2 acute infection?

Vaccination followed by breakthrough infection

The first systematic review aimed at summarizing data about the impact of COVID-19 vaccine on Long COVID found that vaccination before infection reduces the risk of developing Long COVID after.^[67] However, it also says that the level of evidence is still low, not least because the studies included differed in their definition of Long COVID and the duration of follow-up periods, and because they did not differentiate between virus variants. The largest individual study so far, which compares more than 30,000 breakthrough infections with infections among unvaccinated people, also concluded that the risk of developing long-term symptoms after vaccination is somewhat lower.^[68] However, it should also be noted that another larger study^[69] as well as several smaller studies^[70]^[71] found no association between vaccination and long-term symptoms.

Infection followed by vaccination
According to the only available systematic review, evidence is mixed for cases where infection came first and vaccination second. In this case, while the majority of individual studies reported improved Long COVID symptoms, around ⅓ of studies found no improvement or even worsening in some patients.^[72]

Does the vaccine used make a difference?
The evidence is still limited, but one study, which looked at the risk of post-acute sequelae of breakthrough infections at 6 months, found that the risk of Long COVID symptoms was lower in people who were vaccinated with Pfizer/BioNTech’s and Moderna’s mRNA vaccines, compared to those receiving the Johnson & Johnson shot.^[73] Moreover, there is evidence that receiving at least two shots has a larger positive effect on potential Long COVID symptoms, compared with only one shot.^[74] There is no available data yet on the efficacy of booster shots in preventing Long COVID.^[75]

Do Long COVID outcomes vary with different virus variants?

Initial evidence suggests that the Omicron variant could lead to lower Long COVID rates, but not necessarily to less Long COVID cases compared to previous virus variants, because it is at the same time more infectious than earlier variants. Intriguingly, the Omicron variant did appear to impact olfactory at a much lower rate than other variants.^[76]

There are two studies, one from the UK^[77] and one from Japan,^[78] that compare Long COVID outcomes of the Omicron variant to those of previous variants. Both studies found that the prevalence of long-term symptoms is lower in people who were infected with the Omicron variant. However, both studies are limited in their scope as well as their methodology. Larger studies are still needed to confirm these results. As Omicron only started to appear in late 2021, it will take some more time until the results of studies with longer follow-up periods will be published.

At the same time, it should be noted that the Omicron variant is more infectious. The higher number of overall infections means that even if the individual risk of suffering from long-term symptoms might be lower with Omicron compared to, say, Delta, this does not necessarily mean that there will be less Long COVID cases in general.

What institutions like the CDC exist outside the U.S. that gather authoritative data useful for answering questions on long-term complications?

The US CDC partners with various kinds of organizations around the world (https://www.cdc.gov/globalhealth/partnerships.htm ), and most countries have a Ministry of Health that oversees government health programs, including data collection. Below you can find a list of some of the most important institutions and their findings on Long COVID: