Long COVID

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

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.

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

The definitions differ in when long COVID starts, and how long persistent symptoms must have lasted. For instance, the WHO puts the onset of long COVID at three months post-infection, if there have been at least two months of persistent symptoms. In contrast, the US Centers for Disease Control and Prevention (CDC) puts the onset of "Post-COVID Conditions" at four weeks "to emphasize the importance of initial clinical evaluation and supportive care during the initial 4 to 12 weeks after acute COVID‑19" According to the US 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 four or more weeks after the acute phase of SARS-CoV-2 infection.

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

The clinical 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."

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

Specifically for children and young people, a group of experts in the UK have published the only research definition which complements the clinical case definition in adults proposed by the WHO. …

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. Symptom severity ranges from mild to incapacitating. Many symptoms reported in long COVID are non-specific, which makes it difficult to definitively attribute them to prior SARS-CoV-2 infection.

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). 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.

Children and adolescents can also experience serious symptoms and long-term adverse health effects, including serious mental health impacts related to persistent COVID‑19 symptoms. The most common symptoms in children are persistent fever, sore throat, problems with sleep, headaches, shortness of breath, muscle weakness, fatigue, loss of smell or distorted smell, and anxiety. Children and adolescents with long COVID experience three or more symptoms more frequently than control groups, but this has low certainty.

Common neurological symptoms in long COVID are difficulty concentrating, cognitive impairment and headaches. People also frequently experience loss of taste and loss of smell. Likewise children and young people may also experience cognitive impairment.

Some people with long COVID experience dysautonomia, a malfunction of the autonomic nervous system. 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 continuous standing, this is described as postural orthostatic tachycardia syndrome.

In terms of mental health, people with long COVID often experience sleep difficulties. 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. …

The causes of long COVID are not understood. Hundreds of potential blood biomarkers have been investigated, but no single blood biomarker has been shown to reliably identify long COVID. There are potentially many overlapping mechanisms that all contribute to the development of long COVID. 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. Several hypotheses have been put forward explaining long COVID, including:

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

Organ damage from the acute infection may explain symptoms in some people with long COVID. Radiological tests such as lung magnetic resonance imaging (MRI) 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.

In a subset of people with long COVID, there is evidence that SARS-COV-2 remains in the body after the acute infection. 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, but at a lower rate. Persistent virus could lead to symptoms via possible effects on coagulation and via microbiome and neuroimmune abnormalities.

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 infectious mononucleosis. This virus lies dormant in most people. There is some evidence of a relationship between its reactivation and long COVID. …

There is currently no diagnostic test for long COVID, and there is no consensus on diagnostic criteria. There are no standardised tests to determine if symptoms persisting after COVID‑19 infection are due to long COVID. Diagnosis is based on a history of suspected or confirmed COVID‑19 symptoms, and by considering and ruling out alternative diagnoses. Diagnosis of long COVID can be challenging because of the wide range of symptoms people with long COVID may display. Many of the symptoms are not specific to long COVID and can occur in other medical conditions.

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

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

Preventing a COVID-19 infection is the most effective way to prevent long COVID, for instance by wearing a properly fitted N95 mask, improving ventilation, avoiding contact with people who test positive for COVID, and washing hands. Treatment during the acute phase may also reduce the risk of long COVID. For example, in two large, randomised, placebo-controlled clinical trials, treatment with metformin during acute infection lowered risk of diagnosis with Long COVID by 41-50%.

COVID-19 vaccination seems to reduce risk of long COVID. Three doses of a COVID-19 vaccine may reduce the risk by 70%, while two doses give 43% protection and one dose gives 19% protection. The evidence is based on observational studies, rather than on randomised clinical trials. The large randomised control trials on COVID-19 vaccines did not include long COVID as an outcome measure. An analysis involving more than 20 million adults found that vaccinated people had a lower risk of long COVID compared with those who had not received a COVID‑19 vaccine; they were also protected against blood clots and heart failure development after the infection.