Long COVID

Long COVID or long-haul COVID (also known as post-COVID-19 syndrome, post-COVID-19 condition,[1][2] post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS)[3][4][5]) is a condition characterized by long-term health problems persisting or appearing after the typical recovery period of COVID-19. Although studies into long COVID are under way, as of May 2022 there is no consensus on the definition of the term.[6] Long COVID has been described as having the potential to affect nearly every organ system, causing further conditions (sequelae) including respiratory system disorders, nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, musculoskeletal pain, and anemia.[7]

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The most commonly reported symptoms of long COVID are fatigue and memory problems.[8][9] Many other symptoms have also been reported, including malaise, headaches, shortness of breath, anosmia (loss of smell), parosmia (distorted smell), muscle weakness, low fever and cognitive dysfunction.[10] Overall, it is considered by default to be a diagnosis of exclusion.[11]

Estimates of the prevalence of long COVID vary based on definition, population studied, time period studied, and methodology, generally ranging between 5% and 50%.[12] Health systems in some countries and jurisdictions have been mobilized to deal with this group of patients by creating specialized clinics and providing advice.[13][14][15]

Terminology and definitions

Overview

Long COVID is a patient-created term which was reportedly first used in May 2020 as a hashtag on Twitter by Elisa Perego, an archaeologist at University College London.[16][17]

Long COVID has no single, strict definition.[18][19] It is normal and expected that people who experience severe symptoms or complications such as post-intensive care syndrome or secondary infections will take longer to recover than people who did not require hospitalization (called mild COVID-19[20]) and had no such complications. It can be difficult to determine whether an individual's set of ongoing symptoms represents a normal, prolonged convalescence, or extended 'long COVID'. One rule of thumb is that long COVID represents symptoms that have been present for longer than two months, though there is no reason to believe that this choice of cutoff is specific to infection with the SARS-CoV-2 virus.[18]

World Health Organization clinical case definition

The World Health Organization (WHO) established a clinical case definition in October 2021,[1] published in the journal The Lancet Infectious Diseases:[2]

post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction, and generally have an impact on everyday functioning. Symptoms might be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms might also fluctuate or relapse over time.

British definition

The British National Institute for Health and Care Excellence (NICE) divides COVID-19 into three clinical case definitions:

  • acute COVID-19 for signs and symptoms during the first four weeks after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the first, and
  • long Covid for new or ongoing symptoms four weeks or more after the start of acute COVID-19, which is divided into the other two:
    • ongoing symptomatic COVID-19 for effects from four to twelve weeks after onset, and
    • post-COVID-19 syndrome for effects that persist 12 or more weeks after onset.

NICE describes the term long COVID, which it uses "in addition to the clinical case definitions", as "commonly used to describe signs and symptoms that continue or develop after acute COVID-19. It includes both ongoing symptomatic COVID-19 (from four to twelve weeks) and post-COVID-19 syndrome (12 weeks or more)".[21]

NICE defines post-COVID-19 syndrome as "Signs and symptoms that develop during or after an infection consistent with COVID‑19, continue for more than 12 weeks and are not explained by an alternative diagnosis. It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body. Post‑COVID‑19 syndrome may be considered before 12 weeks while the possibility of an alternative underlying disease is also being assessed".[21]

American definition

In February 2021, the U.S. National Institutes of Health (NIH) director Francis Collins indicated long COVID symptoms for individuals who "don't recover fully over a period of a few weeks" be collectively referred to as "Post-Acute Sequelae of SARS-CoV-2 Infection" (PASC). The NIH listed long COVID symptoms of fatigue, shortness of breath, brain fog, sleep disorders, intermittent fevers, gastrointestinal symptoms, anxiety, and depression. Symptoms can persist for months and can range from mild to incapacitating, with new symptoms arising well after the time of infection.[22] The Centers for Disease Control and Prevention (CDC) term Post-Covid Conditions qualifies long Covid as symptoms four or more weeks after first infection.[4]

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.[23][24]
External video
“Long Covid: A parallel pandemic”, Akiko Iwasaki and others, Knowable Magazine, 8 August 2022.

A multinational online survey with 3,762 adult participants with illness lasting more than 28 days found that recovery takes longer than 35 weeks for 91% of them. On average, participants experienced 56 symptoms (standard deviation ± 25.5) in nine organ systems. Symptoms varied over time, and the most common symptoms after six months were fatigue, post-exertional malaise and cognitive dysfunction.[25][26]

Symptom relapse occurred in 86% of adult participants triggered by physical or mental effort or by stress. Three groups of symptoms were identified: initial symptoms that peak in the first two to three weeks and then subside; stable symptoms; and symptoms that increase markedly in the first two months and then stabilize.[25]

Symptoms reported by adults with long COVID include:[27][28][29][30][31][7][32]

Epidemiology

Estimates of the prevalence of long COVID vary widely. The estimates depend on the definition of long COVID and the population studied. An April 2022 meta-analysis estimated that the pooled prevalence of post-COVID conditions was 43%, with estimates ranging between 9% and 81%. People who had been hospitalised with COVID saw a higher prevalence of 54%, while this number dropped to 34% for nonhospitalised people. Prevalence generally decreased with a longer follow-up time.[37] In people age 0–18 years the prevalence of long COVID conditions – like mood symptoms, CFS and sleep disorders – appears to be at ~25% overall.[38][39]

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 nonhopitalised people.[40]

In June 2022, a CDC study based on electronic health records showed that "one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19" or long COVID.[41][42] An analysis of private healthcare claims showed that of 78,252 patients diagnosed with 'long COVID', 75.8% had not been hospitalized for COVID-19.[43][44]

Children

Long COVID is uncommon in children and their features differ from adults: In a retrospective cohort study from October 2022 of almost 660,000 US children tested for SARS-CoV-2 by antigen or polymerase chain reaction, the incidence of at least 1 systemic, syndromic, or medication feature of long COVID (1-6 months afterwards) was 42% among viral test–positive children versus 38% among viral test–negative children, that is there was an incidence proportion difference of only 3.7%. Long COVID was identified more in those cared for intensive care unit during the acute illness phase, children younger than 5 years, and those with complex chronic conditions. Neurological symptoms, such as headache, vertigo, and paresthesiae were not significant findings in this study, as opposed to in adults.[45]

A 2021 study from the UK Office for National Statistics with 20,000 participants, including children and adults, found that, in children who tested positive, at least one symptom persisted after five weeks in 9.8% of children aged two to eleven years and in 13% of children aged 12 to 16 years.[46] A 2022 University College London study in the UK, found that children ages 11–17 who had a positive PCR test were more likely to have three or more symptoms three months after their diagnosis compared to those with a negative test.[47]

Causes

It is currently unknown why most people recover fully within two to three weeks and others experience symptoms for weeks or months longer.[48] The exact processes that cause long COVID remain uncertain, but research has established that long COVID is associated with changes in fatty acid metabolism and mitochondrial dysfunction.[49][50]

A number of mechanisms have been suggested.[26]

A March 2021 review article cited the following pathophysiological processes as the predominant causes of long COVID:[51]

  • direct toxicity in virus infected tissue, especially the lungs
  • ongoing inflammation due to post-infection immune system dysregulation
  • vascular injury and ischemia caused by virus induced hypercoagulability (tendency to form internal clots) and thromboses (internal blood clots)
  • impaired regulation of the renin-angiotensin system related to the effect of SARS-CoV-2 on ACE2 containing tissue

In October 2020, a review by the United Kingdom's National Institute for Health and Care Research hypothesized that ongoing long COVID symptoms may be due to four syndromes:[52][53]

Other situations that might cause new and ongoing symptoms to include:

Similarities to other syndromes

Long COVID is similar to post-Ebola syndrome and the post-infection syndromes seen in chikungunya and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is often triggered by infection and immune activation and was previously also known as "post-viral fatigue". The pathophysiology of long COVID may be similar to these other conditions.[18] Some long COVID patients in Canada have been diagnosed with ME/CFS, a "debilitating, multi-system neurological disease that is believed to be triggered by an infectious illness in the majority of cases". Lucinda Bateman, a US specialist in ME/CFS in Salt Lake City, believes that the two syndromes are identical. There is need for more research into ME/CFS; Anthony Fauci, chief medical adviser to the US government, said that COVID-19 is a "well-identified etiologic agent that should be very helpful now in getting us to be able to understand [ME/CFS]".[59]

Risk factors

Several risk factors have been found for long COVID:

  • Gender – Women are more likely to develop long COVID than men.[37] Some research suggests this is due primarily to hormonal differences,[60][61] while other research points to other factors, including chromosomal genetics, sex-dependent differences in immune system behavior; non-biological factors may also be relevant.[18]
  • Age, with older people more at risk[37][40]
  • Obesity[37]
  • Asthma[37]
  • Depression or anxiety[40]
  • The number of symptoms during acute COVID[37]

Diagnosis

Xenon MRI is being used to study long COVID, because it provides patients and physicians with explanations for previously unexplained observations. Xenon MRI can measure gas exchange and provide information on how much air is taken up by a patient's bloodstream, which is being researched in long-haul COVID patients.[62][63]

Xenon MRI can quantify three components of lung function: ventilation, barrier tissue uptake and gas exchange. Xenon-129 is soluble in pulmonary tissue, which allows the evaluation of lung functions such as perfusion and gas exchange (an advantage over helium). Ventilation measures how the air is distributed in the lung and can provide the locations of potentially compromised lung areas if no xenon reaches those areas. Barrier tissue uptake and gas exchange measure how much air diffuses across the alveolar-capillary membrane. Xenon MRI helps determine how well air is taken in by the lungs, absorbed into lung tissue, and taken up by the blood.[64][63]

Prevention

A September 2021 study published in The Lancet found that having two doses of a COVID-19 vaccine halved the odds of long COVID.[65] However, a May 2022 study published by Nature that examined VA Saint Louis Health Care System records from January to December 2021 of more than 13 million people, including 34,000 people vaccinated against COVID-19 who had breakthrough infections, found that COVID-19 vaccination reduced long COVID risk by about 15%.[66]

Treatment and management

As of May 2022, there is no established treatment for long COVID. There are however trials in progress for possible treatments.[67]

Management of long COVID depends on symptoms, and can often be done in primary care. Rest, planning and prioritising is advised for people with fatigue. People who suffer from post-exertional system exacarbation may benefit from activity management with pacing. People with allergic-type symptoms such as rashes on the skin may benefit from antihistamines.[68]

Health system responses

Australia

In October 2020, a guide published by the Royal Australian College of General Practitioners (RACGP) says that ongoing post-COVID-19 infection symptoms such as fatigue, shortness of breath and chest pain will require management by GPs, in addition to the more severe conditions already documented.[69]

In December 2021, research by a health economics expert at Deakin University suggests that even without fully understanding the Omicron variant's effects yet, a further 10,000 to 133,000 long COVID cases are likely to emerge on top of the current approximately 9450 in New South Wales and 19,800 in Victoria, after border and other restrictions had been recently lifted. The RACGP released new guidelines for general practitioners to manage a large number of new long COVID patients.[70]

South Africa

In October 2020, the DATCOV Hospital Surveillance Department of the National Institute for Communicable Diseases (NICD) looked into a partnership with the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) (an open-access research and data resource)[71] in order to conduct clinical research into the impact PASC may have within the South African context. As of 30 January 2021, the project has yet to receive ethical approval for the commencement of data collection. Ethics approval was granted on 3 February 2021 and formal data collection began on 8 February 2021.

United Kingdom

In Britain, the National Health Service set up specialist clinics for the treatment of long COVID.[72] The four Chief Medical Officers of the UK were warned of academic concern over long COVID on 21 September 2020 in a letter written by Trisha Greenhalgh published in The BMJ[73] signed by academics including David Hunter, Martin McKee, Susan Michie, Melinda Mills, Christina Pagel, Stephen Reicher, Gabriel Scally, Devi Sridhar, Charles Tannock, Yee Whye Teh, and Harry Burns, former CMO for Scotland.[73]

In October 2020, NHS England's head Simon Stevens announced the NHS had committed £10 million to be spent that year on setting up long COVID clinics to assess patients' physical, cognitive, and psychological conditions and to provide specialist treatment. Future clinical guidelines were announced, with further research on 10,000 patients planned and a designated task-force to be set up, along with an online rehabilitation service[74] – "Your Covid Recovery".[75] The clinics include a variety of medical professionals and therapists, with the aim of providing "joined-up care for physical and mental health".[76]

The National Institute for Health Research has allocated funding for research into the mechanisms behind symptoms of long COVID.[76][6]

In December 2020, University College London Hospitals (UCLH) opened a second long COVID clinic at the National Hospital for Neurology and Neurosurgery for patients with post-COVID neurological issues. The first clinic had opened in May, primarily focused on respiratory problems, but both clinics refer patients to other specialists where needed, including cardiologists, physiotherapists and psychiatrists.[77] By March 2021 there were 69 long COVID clinics in the English NHS, mostly focussing on assessing patients, with more planned to open. There were fears that community rehabilitation services did not have capacity to manage large numbers of referrals.[78]

On 18 December 2020, the National Institute for Health and Care Excellence (NICE), the Royal College of General Practitioners (RCGP) and the Scottish Intercollegiate Guidelines Network (SIGN) published a guide to the management of long COVID.[79] The guideline was reviewed by representatives of the UK doctors #longcovid group, an online support group for COVID long-haulers, who said that it could be improved by introducing a more comprehensive description of the clinical features and physical nature of long COVID, among other changes.[80]

In November 2021 complaints were reported from NHS staff that neither their employers nor their trades unions were supportive, though the British Medical Association was pushing for long COVID to be classed as an occupational disease.[81]

In May 2022 demand for occupational therapy led rehabilitation services in Britain was reported to have increased by 82% over the previous six months as occupational therapists were supporting people whose needs have become more complex because of delays in treatment brought about by the pandemic. Half of occupational therapists surveyed were supporting people affected by lasting Covid symptoms.[82]

United States

On 23 February 2021, the National Institutes of Health director, Francis Collins, announced a major initiative to identify the causes and ultimately the means of prevention and treatment of people who have long COVID.[22] Part of this initiative includes the creation of the COVID-19 Project,[83] which will gather data on neurological symptoms associated with PASC.

On 28 April 2021, the Subcommittee on Health of the U.S. House of Representatives' Committee on Energy and Commerce held a hearing about long COVID.[84][85] In February 2022, it was announced that at least sixty-six hospitals and health systems had launched COVID recovery programs to aid patients who experience long term or lingering symptoms.[86]

Society and culture

Some people experiencing long COVID have formed groups on social media sites.[87][88][89][90] In many of these groups, individuals express frustration and their sense that their problems have been dismissed by medical professionals.[89][90] There is an active international long COVID patient advocacy movement.[91][92]

Founded by Lisa McCorkell and other scientists who are also long COVID patients, the Patient-Led Research Collaborative has carried out surveys to gather data on long COVID symptoms,[26][25] and has received funding for five long Covid research projects led by patients themselves.[26][93][94]

See also

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