Long COVID

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Long COVID
Other namesLong-haul COVID, post-COVID-19 syndrome, post-COVID-19 condition, post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome [1]
Symptoms Highly varied, including post-exertional malaise (symptoms worsen with effort), fatigue, muscle pain, shortness of breath, chest pain and cognitive dysfunction ("brain fog") [2]
DurationWeeks to years, possibly lifelong [3]
Causes COVID-19 infection
Risk factors Female sex, age, obesity, asthma, more severe COVID-19 infection [4]
Frequency50–70% of hospitalised COVID-19 cases, 10–30% of non-hospitalised cases, and 10–12% of vaccinated cases [3]

Long COVID or long-haul COVID is a group of health problems persisting or developing after an initial period of COVID-19 infection. Symptoms can last weeks, months or years and are often debilitating. [3] The World Health Organization defines long COVID as starting three months after the initial COVID-19 infection, but other agencies define it as starting at four weeks after the initial infection. [2]

Contents

Long COVID is characterised by a large number of symptoms that sometimes disappear and then reappear. Commonly reported symptoms of long COVID are fatigue, memory problems, shortness of breath, and sleep disorder. [5] [6] [7] Several other symptoms, including headaches, mental health issues, loss of smell or taste, muscle weakness, fever, and cognitive dysfunction may also present. [5] [7] Symptoms often get worse after mental or physical effort, a process called post-exertional malaise. [5] There is a large overlap in symptoms with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). [2]

The causes of long COVID are not yet fully understood. Hypotheses include lasting damage to organs and blood vessels, problems with blood clotting, neurological dysfunction, persistent virus or a reactivation of latent viruses and autoimmunity. [3] Diagnosis of long COVID is based on (suspected or confirmed) COVID-19 infection or symptoms—and by excluding alternative diagnoses. [8] [9]

Estimates of the prevalence of long COVID vary based on definition, population studied, time period studied, and methodology, generally ranging between 5% and 50%. [10] Prevalence is less after vaccination. [11] Risk factors are higher age, female sex, having asthma, and a more severe initial COVID-19 infection. [4] As of 2023, there are no validated effective treatments. [3] [5] Management of long COVID depends on symptoms. Rest is recommended for fatigue and pacing for post-exertional malaise. People with severe symptoms or those who were in intensive care may require care from a team of specialists. [12] Most people with symptoms at 4 weeks recover by 12 weeks. Recovery is slower (or plateaus) for those still ill at 12 weeks. [12] For a subset of people, for instance those meeting the criteria for ME/CFS, symptoms are expected to be lifelong. [3]

Classification and terminology

Long COVID is a patient-created term coined early in the pandemic by those suffering from long-term symptoms. [13] [14] While long COVID is the most prevalent name, the terms long-haul COVID, post-COVID-19 syndrome, post-COVID-19 condition, [1] [15] post-acute sequelae of COVID-19 (PASC), and chronic COVID syndrome are also in use. [5]

Long COVID may not be a single disease or syndrome. It could be an umbrella term including permanent organ damage, post-intensive care syndrome, post-viral fatigue syndrome and post-COVID syndrome. [2]

Long COVID has been referred to by the scientific community as "Post-Acute Sequelae of SARS-CoV-2 infection (PASC)". [16] These terms are synonyms and are often used interchangeably. [17] [18] [19] [20] [21] Both terms refer to the range of symptoms that continue for weeks or even months after the acute phase of the SARS-CoV-2 infection. [16] [20]

Clinical case definitions

There are multiple definitions of long COVID, depending on country and institution. The most accepted is the World Health Organization (WHO) definition. [22]

The definitions differ in when long COVID starts, and how long persistent symptoms must have lasted. [22] For instance, the WHO puts the onset of long COVID at three months post-infection, if there have been at least 2 months of persistent symptoms. [1] [15] In contrast, the US Centers for Disease Control and Prevention (CDC) puts the onset of "Post-COVID Conditions" at 4 weeks "to emphasize the importance of initial clinical evaluation and supportive care during the initial 4 to 12 weeks after acute COVID-19" [8] According to National Institutes of Health (NIH), postacute sequalae of SARS-CoV-2 (PASC) refers to ongoing, relapsing, or new symptoms, or other health effects that occur 4 or more weeks after the acute phase of SARS-CoV-2 infection. [16]

The British National Institute for Health and Care Excellence (NICE) divides long COVID into two categories: [23]

The case definitions specify symptom onset and development. For instance, the WHO definition indicates that "symptoms might be new onset following initial recovery or persist from the initial illness. Symptoms may also fluctuate or relapse over time." [1]

The NICE and WHO definition further require the exclusion of alternative diagnoses. [22]

Specifically for children, a group of experts from UCL Great Ormond Street Institute of Child Health Population in the UK and from other institutions in the UK defines post–COVID-19 condition as a condition characterized by at least 1 physical symptom persisting for a minimum of 12 weeks after initial confirmed infection, unexplained by an alternative diagnosis, affecting everyday functioning, and may fluctuate or relapse over time. [16]

Many symptoms have similar severity in long COVID and ME/CFS Similar degrees of ME-CFS and long Covid symptoms.webp
Many symptoms have similar severity in long COVID and ME/CFS

Long COVID is a post-acute infection syndrome (PAIS) and shares similarities with other such syndromes. [24] For instance, there are similarities with post-Ebola syndrome and aftereffects of the chikungunya virus. These conditions may have similar pathophysiology to long COVID. [24] [25]

Long COVID has many symptoms in common with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and research estimates half of people with long COVID meet ME/CFS diagnostic criteria. [26] Like long COVID, ME/CFS is often triggered by infections, and some biological changes overlap. [27] [2] Dysautonomia and postural orthostatic tachycardia syndrome (POTS) are also potential shared aspects of long COVID and ME/CFS. [2]

Signs and symptoms

A scientific review identified over 50 apparent long-term effects - including those of 'long COVID' - along with their estimated prevalence and estimated that 80% of included patients had at least one overall effect beyond two weeks. Long-term effects of COVID-19.webp
A scientific review identified over 50 apparent long-term effects – including those of 'long COVID' – along with their estimated prevalence and estimated that 80% of included patients had at least one overall effect beyond two weeks.
External videos
Nuvola apps kaboodle.svg "Long Covid: A parallel pandemic", Akiko Iwasaki and others, Knowable Magazine , 8 August 2022.

There is a large set of symptoms associated with long COVID, impacting many different organs and body systems. Long COVID symptoms can differ significantly from person to person. [2] Symptom severity ranges from mild to incapacitating. [29]

Common symptoms reported in studies include fatigue, muscle pain, shortness of breath, chest pain, cognitive dysfunction ("brain fog") and post-exertional malaise (symptoms worsen after activity). [2] This symptom worsening typically occurs 12 to 48 hours after activity and can be triggered by either mental or physical effort. It lasts between days and weeks. [8]

Neurological symptoms

Common neurological symptoms in long COVID are difficulty concentrating, cognitive impairment and headaches. [3] [7] People also frequently experience loss of taste and loss of smell. [7]

Some people with long COVID experience dysautonomia, a malfunction of the central nervous system. [30] People with dysautonomia may experience palpitations and tachycardia (raised heart rate) after minor effort or upon standing up. This can be associated with dizziness and nausea. If the heart rate is raised by 30 beats per minute or more after standing in a sustained way, this is described as postural orthostatic tachycardia syndrome. [31]

In terms of mental health, people with long COVID often experience sleep difficulties. [7] A large study showed that depression and anxiety levels are raised in the first two months after infection, but return to normal afterwards. This was in contrast to other neurological symptoms, such as brain fog and seizures, which lasted at least two years. [3]

Lungs, heart and digestive system

A 2022 review found difficulty breathing as the second-most common symptom of long COVID. [32] People can also experience a persistent cough. [7] Less frequently, people with long COVID experience diarrhea and nausea. [7]

In the cardiovascular system, effort intolerance and chest pain occur often in people with long COVID. [7] People are at increased risk of stroke, pulmonary embolism and myocardial infarction after recovering from an acute COVID infection, but there is disagreement as to whether this should be seen as part of long COVID or not. [2]

Reproductive system

In the female reproductive system, Long COVID may disrupt fertility, the menstrual cycle, menopause, gonadal function, and ovarian sufficiency. [33] Exacerbation of other Long COVID symptoms around menstruation has also been documented. [33]

Other symptoms

Joint pain and muscle pain are frequently reported as symptoms of long COVID. [7] Some people experience hair loss and skin rashes. [34] People are at increased risk of type I and II diabetes after recovering from acute COVID. [2]

Subgroups

Because the symptom combinations of long COVID vary significantly from person to person, one approach to researching the condition is to define subgroups or clusters of long-haulers. This would allow for more targeted clinical care. [2]

Causes and mechanisms

Possible causes of long COVID Long Covid possible causes.webp
Possible causes of long COVID

The causes of long COVID are not yet fully understood. It is likely that there is no single cause, but instead multiple, and possibly overlapping, mechanisms that all contribute to the development of long COVID. [3] Organ damage from the acute infection can explain a part of the symptoms, but long COVID is also observed in people where organ damage seems to be absent. [35] Several hypotheses have been put forward explaining long COVID. A 2023 review article included: [3]

Further hypotheses include a dysfunction of the mitochondria and the cellular energy system, [36] persistent systemic inflammation, and the persistence of SARS-COV-19 antigens. [37]

Pathophysiology

Organ damage from the acute infection may explain symptoms in some people with long COVID. Radiological tests such as lung MRIs often show up as normal even for people who show clear desaturation (lowered blood oxygen level) after mild exercise. Other tests, such as a dual-energy CT scan, do show perfusion defects in a subset of people with respiratory symptoms. Imaging of the heart show contradictory results. Imaging of brains show changes after COVID infection, even if this has not been studied in relation to long COVID. For instance, some show a smaller olfactory bulb, a brain region associated with smell. [2]

In a subset of people with long COVID, there is evidence that SARS-COV-2 remains in the body after the acute infection. [38] This evidence comes from biopsies, studies of blood plasma, and by the indirect immune effects of persistent virus. Viral DNA or proteins have been found months to a year after acute infection in various studies. A small study demonstrated viral RNA up to nearly two years after an acute infection in people with long COVID. Persistent virus has also been found in people without long COVID, even though at a lower rate. [39] Persistent virus could lead to symptoms via possible effects on coagulation and via microbiome and neuroimmune abnormalities. [40]

During or after acute COVID infection, various dormant viruses can become reactivated. For instance, SARS-COV-2 can reactivate the Epstein-Barr virus, the virus that is responsible for mono. This virus lies dormant in most people. There is some evidence of a relationship between its reactivation and long COVID. A correlation was also found between reactivation of endogenous retroviruses and severity of active COVID-19. [41]

Autoimmunity is another potential cause of long COVID. Some studies report auto-antibodies (antibodies directed against an individual's own proteins) in people with long COVID, but they are not found in all studies. [37] Autoantibodies are often induced during acute COVID, with a moderate relationship to disease severity. Evidence from electronic health care records show that people develop auto-immune diseases, such as lupus and rheumatoid arthritis, more frequently after a COVID-19 infection, compared to controls. [2]

Issues with increased blood clotting are another potential driver of long COVID development. During acute infection, there is direct damage to the linings of blood vessels (endothelial damage), [2] and the risk of thrombosis-related diseases stays elevated longer-term after infection. Issues with blood clotting can include hyperactive platelets and microclots. These microclots may induce oxygen shortage (hypoxia) in tissues. [38] The clotting may potentially be driven by autoantibodies. [2]

Risk factors

Women are more at risk than men. [4] Age has been identified as another risk factor, with older people seemingly more at risk. [4] This is also true for children, with older children at a higher risk than younger children. [22] Most diagnoses of long COVID are in the 36–50 age bracket. [3] Risks of developing long COVID are also higher for people with lower incomes, people with fewer years of education and those from disadvantaged ethnic groups. [22] [38] People who smoke also have a higher risk of developing long COVID. [22]

Various health issues raise the risk of long COVID. For instance, people with obesity more often report long COVID. [4] Asthma and chronic obstructive pulmonary disease are also risk factors. [22] [4] In terms of mental health, depression and anxiety raise risks. [22]

Finally, characteristics of the acute infection play a role in developing long COVID. People who experience a larger number of symptoms during the acute infection are more likely to develop long COVID, as well as people who require hospitalisation. [4] Finally, long COVID risks may have been higher with the SARS-CoV2 Delta variant compared to the Omicron variant. The higher infection rate from the Omicron variant means that it is still responsible for a large group of long-haulers. [22]

Diagnosis

There are no standardised tests to determine if symptoms persisting after COVID-19 infection are due to long COVID. [5] [9] Diagnosis is based on a history of suspected or confirmed COVID-19 symptoms, and by considering and ruling out alternative diagnoses. [8] [9] Diagnosis of long COVID can be challenging because of the wide range of symptoms people with long COVID may display. [9]

Early diagnostic criteria of long COVID required a laboratory-confirmed COVID-19 infection, but current criteria do not require this anymore, given that people may not get tested during the acute infection. [9] For instance, people who develop long COVID after asymptomatic infection would have little reason to get tested. [8] Furthermore, tests for COVID are not foolproof, and can come back negative. [8] False negatives are more common for children, women and people with a low viral load. [3]

There are diagnostic tools available for some elements of long COVID, such as the tilt table test for POTS and MRI scans to test for cardiovascular impairment. Routine tests offered in standard care often come back normal. [3]

Prevention

Preventing a COVID-19 infection is the most effective way to prevent long COVID, for instance by improving ventilation, avoiding contact with people who test positive for COVID, washing hands, and wearing a properly-fitted N95 mask. [42] Treatment during the acute phase may also reduce the risk of long COVID. [5]

COVID-19 vaccination reduces the risk of long COVID, but by how much is unclear, as the available studies differ widely and are of limited quality. [11] One complication is that healthy people more often opt to get vaccinated, which makes it more difficult to draw conclusions on the effect of vaccination. [43] A 2023 review found that three doses of a COVID-19 vaccine offer 69% effectiveness against long COVID, while two doses had 37% efficacy, for those who had not been infected with COVID-19 before. [44] [45]

Clinical care

As of 2023 there are no established effective treatments for long COVID, [3] however several countries and medical organizations have produced guidelines on long COVID for clinicians and the public. [5] [46] [47]

People with long COVID may need care within several clinical disciplines for long-term monitoring or intervention of ongoing symptoms, and to implement social services, physical therapy, or mental health care. [47] In some countries, such as the UK and Germany, specialised long COVID outpatient clinics have been established to assess individual cases for the extent of surveillance and treatment needed. [48] Two reviews indicated that primary physicians should provide the first assessment of people with long COVID symptoms, leading to specialist referrals for more complex long COVID symptoms. [47] [48]

Management of long COVID depends on symptoms. [5] Rest, planning and prioritising are advised for people with fatigue. People who get post-exertional malaise may benefit from activity management with pacing. People with allergic-type symptoms, such as skin rashes, may benefit from antihistamines. [12] Those with autonomic dysfunction may benefit from increased intake of fluids, electrolytes and compression garments. [12]

Long-term follow-up of people with long COVID involves outcome reports from the people themselves to assess the impact on their quality of life, especially for those who were not hospitalised and receiving regular clinical follow-up. [47] [48] Digital technologies, such as videoconferencing, are being implemented between primary care physicians and people with long COVID as part of long-term monitoring. [47]

Prognosis

Around two in three with symptoms at four weeks are expected to recover fully by week twelve. [12] However, the prognosis varies by person, and some may find symptoms worsen within the first three months. [8] Recovery after twelve weeks is variable: some people plateau, whilst others see a slow recovery. [12]

The prognosis also varies by symptom: neurological symptoms may have a delayed onset, and some get worse over time. Symptoms of the gut and lungs are more likely to reduce over time. Pain in muscles and joints seems worse at 2 years than at 1 year after infection. If people meet the diagnostic criteria for ME/CFS or for dysautonomia, it is possible that symptoms are lifelong. [3]

Epidemiology

Long COVID's prevalence varies by age and gender US long COVID demographics.jpg
Long COVID's prevalence varies by age and gender

Estimates of the prevalence of long COVID vary widely. The estimates depend on the definition of long COVID, the population studied, [4] as well as a number of other methodological differences, such as whether a comparable cohort of individuals without COVID-19 were included, [49] what kinds of symptoms are considered representative of long COVID, [50] and whether long COVID is assessed through a review of symptoms, through self-report of long COVID status, or some other method. [51] A conservative estimate based only on confirmed COVID cases puts the global number of people with long COVID at 65 million, corresponding to 10% of more than 651 million documented COVID-19 cases worldwide. [3] While hospitalised people have higher risks of getting long COVID, most long-haulers had a mild infection and were able to recover from the acute infection at home. [3]

An April 2022 meta-analysis estimated that the pooled prevalence of post-COVID conditions after infection was 43%, with estimates ranging between 9% and 81%. People who had been hospitalised with COVID saw a higher prevalence of 54%, while 34% of nonhospitalised people developed long COVID after acute infection. [4]

In the United States in June 2023, 6% of the population indicated having long COVID, as defined as symptoms that last for 3 months or more. [52] This percentage had stayed stable since January that year, but was a decrease compared to June 2022. [52] Of people who had had a prior COVID infection, 11% indicated having long COVID. A quarter of those reported significant limitation in activity. [52]

In a large population cohort study in Scotland, 42% of respondents said they had not fully recovered after 6 to 18 months after catching COVID, and 6% indicated they had not recovered at all. The risk of long COVID was associated with disease severity; people with asymptomatic infection did not have increased risk of long COVID symptoms compared to people who had never been infected. Those that had been hospitalised had 4.6 times higher odds of no recovery compared to nonhospitalised people. [53]

Children and adolescents

Long COVID is less common in children and adolescents than in adults. [54] A 2023 systemic review estimated the differences in persistent symptom frequency between children and adolescents who tested positive for COVID, and controls. The pooled proportion of children and adolescents experiencing three or more persistent symptoms after a COVID infection was 17% more than the controls. The largest differences were found for loss of smell or distorted smell, anxiety and fatigue. [55] Another 2023 review found a prevalence of 16.2% in children and adolescents at least 3 months after infection. The most common symptoms found in this review were a persistent fever, sore throat, problems with sleep, muscle weakness and fatigue. [56] Although Long COVID is less common in children and adolescents, a 2023 study found that children and adolescents can experience serious symptoms and long-term adverse health effects, including serious mental health impacts related to persistent COVID-19 symptoms. [57]

Society and culture

Patient community and activism

Early in the pandemic, official guidance made a distinction between those with mild illness who did not require hospitalisation, and those with severe illness which did require hospitalisation. The typical recovery time for those with mild illness was said to be around two weeks [58] and media attention was mostly focused on those with a severe infection. Patients with long-lasting systems after a mild infection started to describe their symptoms on Twitter and blogs, [59] challenging official assumptions. [60]

The term long COVID was reportedly first used in May 2020 as a hashtag on Twitter by Elisa Perego, a health and disability researcher at University College London. [13] [60] A month later, #LongCovid became a popular hashtag, alongside hashtags from non-English budding communities (for instance, #AprèsJ20 in French, and #koronaoire in Finnish). [60]

Experiences shared online filled a gap in knowledge in how the media talked about the pandemic. [59] Via the media, the knowledge reached governments and health officials, making long COVID "the first illness created through patients finding one another on Twitter". [60]

Some people experiencing long COVID have formed community care networks and support groups on social media websites. [48] [61] Internationally, there are several long COVID advocacy groups. [47] [62] [63] [64] Clinical advice on self-management and online healthcare programs are used to support people with long COVID. [48]

Stigma and discrimination

Many people with long COVID have difficulty accessing appropriate healthcare. The severity of their symptoms may be disbelieved, they may be subject to unsympathetic care, and their symptoms may not be investigated properly or may be falsely attributed to anxiety. [65] [47] People with long COVID may be misdiagnosed with mental disorders. Anxiety and depression questionnaires not designed for people with medical conditions can contribute to this; for example, a questionnaire may assume fatigue is due to depression or that palpitations are due to anxiety, even if explained by another condition like ME/CFS or POTS. [3]

The impact of long COVID on people's ability to work is large. Estimates vary on how many people are out of work, or work reduced hours because of long COVID. For those with mild or moderate disease, between 12% and 23% had had long periods of absence or remained absent from work at 3 to 7 months. The share of people working adjusted hours or tasks after mild or moderate COVID, was around 8% to 45% after three to eight months. [66] The percentage of people returning to work after hospitalisation was lower. [66] Return to work after hospitalisation differed by country. In China and the US a higher percentage went back to work. In the US this could be partially explained by a lack of paid sick leave for some workers. [67] The Institute for Fiscal Studies studied labour impacts of long COVID in the UK in 2021. They concluded that of people who worked before contracting long COVID, one in ten had stopped working. Most of them were on sick leave rather than unemployed. [68]

Research

As long COVID is a novel condition, open questions abound. Research is ongoing in many areas, including developing more accurate diagnostic criteria, refining estimates of its likelihood, identifying risk factors, gathering data for its impact on daily life, discovering which populations face barriers to adequate care, and learning how much protection vaccination provides. [69] [70]

Many experimental and repurposed drugs are being investigated as possible treatments for different aspects of long COVID. [3] [71] These include the anti-inflammatory colchicine, the anticoagulant rivaroxaban, the antihistamines famotidine and loratadine, various immune-modulating drugs, and the experimental aptamer compound BC-007. [2] [3]

In 2021, the US National Institutes of Health started funding the RECOVER Initiative, backed by $1.15 billion over four years, [72] to identify the causes, prevention and treatment of long COVID. [29] In 2023, the Office of Long COVID Research and Practice was created to coordinate research across US government agencies. [73] At the same time, RECOVER announced which clinical trials it will fund: these include a trial of Paxlovid against potential persistent infection, one for sleep disorder, one for cognitive impairment and one for problems with the autonomic nervous system. [74]

In a 2023 survey of 3,700 people with long COVID, fatigue was the symptom most closely associated with poor everyday functioning, while quality of life, depression and brain fog also occurred. [75] Some 20% of people with long COVID were unable to work. [75] [76]

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A 2-day CPET is a cardiopulmonary exercise test given on two successive days to measure the effect of post-exertional malaise (PEM) on a patient's ability to exercise. PEM is a cardinal symptom of myalgic encephalomyelitis/chronic fatigue syndrome and is common in long COVID as well.

Post-acute infection syndromes (PAISs) or post-infectious syndromes are medical conditions characterized by symptoms attributed to a prior infection. While it is commonly assumed that people either recover or die from infections, long-term symptoms—or sequelae—are a possible outcome as well. Examples include long COVID, chronic fatigue syndrome (ME/CFS), and post-Ebola virus syndrome. Common symptoms include post-exertional malaise (PEM), severe fatigue, neurocognitive symptoms, flu-like symptoms, and pain. The pathology of most of these conditions is not understood and management is generally symptomatic.

Amy Proal is an American microbiologist who studies the effects of bacterial, fungal, and viral pathogens on human health at the molecular level. She is one of the founders of PolyBio Research Foundation, a company investigating the basis of chronic infection-associated illnesses, and currently serves on the company's board of directors. She has recently been noted for her work investigating the causes of long covid.

Carmen Scheibenbogen is a German immunologist who is the acting director of the Institute for Medical Immunology of the Charité university hospital in Berlin. She specialises in hematology, oncology and immunology. She leads the Outpatient Clinic for Immunodeficiency and the Fatigue Centre at the Charité hospital. She is one of the few doctors specialised in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in Germany, and also researches long COVID.

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