Long Coronavirus 2019 (COVID-19) 

Updated: Jul 26, 2022
Author: Russell W Steele, MD; Chief Editor: John L Brusch, MD, FACP 

Overview

Practice Essentials

Postviral syndromes have been described as sustained presence of symptoms after an acute viral infection, for months or years.[1]  COVID-19 infection, like other viruses (eg, Epstein-Barr virus), can result in lingering symptoms and complications after an acute infection.

A small number of individuals develop long term clinical residua following acute coronavirus 2019 (COVID-19) infection, sometimes persisting for months. Officially called post-acute sequelae of SARS-CoV-2 (PASC), it more commonly is referred to as “Long COVID,”(LC).[2, 3, 4, 5]  Adults who have received the complete vaccination series but experienced breakthrough infection are 50% less likely to develop LC or chronic 1-3 month COVID-19 residua. The virus can damage the lungs, heart, and brain, which increases the risk for long-term health problems, particularly in patients with preexisting organ dysfunction.[6, 5]

The most commonly reported sequela is persistent fatigue, very similar to the medical illness referred to as chronic fatigue syndrome (CFS) or more recently termed myalgic encephalomyelitis (ME). Some aspects of our understanding and management of CFS/ME have already been applied to LC, and the overlap should direct clinicians to consider a diagnosis of CFS/ME in patients who have documented evidence of COVID-19 infection and subsequent clinical symptoms without the more unusual features of LC. It is the unique features of each that help differentiate them (eg, loss of taste and smell, cardiac dysrhythmia, shortness of breath or difficulty breathing, and loss of memory for LC vs orthostatic intolerance and information processing for CFS/ME).[5]

Long COVID-19

The entity now referred to as LC has not been officially defined, but published cases offer some background for identifying this entity. Such cases have not been followed beyond 2 years as the pandemic has only been in existence since April 2020. A study of 28,118 people in the Kaiser Permanente program who tested positive for SARS-CoV-2 by PCR before the Omicron wave were evaluated and presented at the Conference on Retroviruses and Opportunistic Infections 2022.[7]  These data may help guide the diagnoses of LC. CDC continues to work to identify how common post-COVID-19 conditions are, who is most likely to get them, and why some symptoms eventually improve for some people and last longer for others. Rapid and multi-year studies are underway to further investigate post-COVID-19 conditions in more detail.[8] These studies will help us better understand the long term effects of COVID-19 infection and how to treat patients with these long-term clinical changes.

Observations in the United States and elsewhere indicate there is a higher percentage of females, predominantly middle-aged females, as compared with males who are more likely to develop LC; this difference is also seen in most countries in Europe and Asia, and similar trends are being seen in other countries.[9, 10]  

Also ongoing is a nationwide clinical trial called Researching COVID to Enhance Recovery (RECOVER) being conducted by the National Institutes of Health.[8]  No data are yet available from this study.

For purposes of this review of the literature, LC will be defined as an illness lasting longer than 3 months, although some experts use the term for symptoms lasting as short as 3 weeks. 

Fatigue is the most common symptom, and it may continue for 3 months to 2 years. Symptoms in order of frequency are as follows[2, 3, 4, 8, 9] :

  • Fatigue
  • Cough
  • Loss of taste and smell (the most unique feature of LC)
  • Insomnia
  • Headache
  • Shortness of breath or difficulty breathing (a unique feature)
  • Joint pain
  • Muscle pain
  • Difficulty concentrating
  • Loss of memory (a unique feature)
  • Chest pain
  • Palpitations
  • Fluid and electrolyte disorders (a unique feature)
  • Cardiac dysrhythmia (a unique feature)
  • Dysuria (a unique feature)
 

Chronic COVID-19

COVID-19: Long-term effects

Most people who have coronavirus disease 2019 (COVID-19) completely recover within a few weeks, but some, even those who had mild disease, continue to experience symptoms for 2-12 weeks after their initial recovery.[11, 5]

Terminology in the lay press has been variable, further confusing the issue. People are sometimes described as "long haulers" and the conditions have been called post-COVID-19 syndrome or COVID-19 conditions rather than LC. They are generally lumped together as effects of COVID-19 that persist for 2-12 weeks after documentation of COVID-19 virus infection, without separating the categories as described below.

Patients older than 65 years and younger patients with serious medical conditions are the most likely to experience lingering COVID-19 symptoms, but even young, otherwise healthy people experience illness for weeks to months after infection.[10]  Common signs and symptoms that linger over time include[5] :

  • Fatigue
  • Shortness of breath or difficulty breathing
  • Cough
  • Joint pain
  • Chest pain
  • Difficulty concentrating
  • Loss of memory
  • Insomnia
  • Muscle pain or headache
  • Palpitations
  • Loss of taste and smell (similar to LC)
  • Depression or anxiety
  • Fever
  • Dizziness when standing
  • Worsened symptoms after physical or mental activities

Organ damage caused by COVID-19

Both adults and children who have had COVID-19 can later develop a post-COVID-19 condition lasting fewer than 3 months as contrasted with LC, which we have defined in the present review as more than 3 months.[12]  Although post-COVID-19 conditions appear to be less common in children and adolescents than in adults, long-term effects after COVID-19 do occur in the younger age groups.

Although COVID-19 is reported as a virus that primarily affects the lungs, it can also damage many other organs, including the heart, kidneys, and the brain, not apparent until weeks after infection. Organ damage may lead to health changes that linger after the COVID-19 acute illness, including long-term respiratory illness, heart complications, chronic kidney impairment, stroke, and Guillain-Barre syndrome.

Some adults and children are diagnosed with multisystem inflammatory syndrome during acute COVID-19 infection.[10]  In this condition, many organs and tissues become severely inflamed. This appears to be most consistent with an autoimmune process and therefore has led clinicians to consider treating these conditions with prolonged steroids and NSAIDs although the illness often resolves after initial treatment.

Information on post-COVID-19 conditions in children and adolescents is limited because young children often have trouble describing the problems they are experiencing. Studies have reported long-term symptoms in children with both mild and severe COVID-19, during or immediately after a COVID-19 infection and particularly in children who previously had multisystem inflammatory syndrome in children (MISC).[13]  MISC is a condition in which different organs become inflamed, particularly the heart, with laboratory and MRI findings compatible with myocarditis. MISC can lead to post-COVID-19 chronic residua if a person continues to experience multiorgan effects or other symptoms associated with LC. Similar to the changes seen in adults, the most common changes reported in children have been tiredness or fatigue, headache, trouble sleeping (insomnia), trouble concentrating, muscle and joint pain, and cough. 

Some younger patients experience new or ongoing symptoms that can last weeks but fewer than 3 months after first being infected with COVID-19 and then resolve spontaneously.

Please see Coronavirus 2019 (COVID-19) in Children.

Non-specific changes related to hospitalization itself

Hospitalizations for any illness as well as for COVID-19 can cause health effects including severe weakness and exhaustion during the recovery period. Effects of hospitalization for LC can also result in post-intensive care syndrome (PICS), which refers to health effects that begin when a person is in an intensive care unit (ICU) and can remain after the patient is discharged.[14]  These effects include severe weakness, problems with thinking and judgment, and post-traumatic stress disorder (PTSD), which occurs as a long-term reaction to any very stressful event.

Some symptoms that can occur after hospitalization are similar to symptoms that people with initially mild or no symptoms may experience many weeks after COVID-19. It is therefore difficult to separate changes that are a consequence of hospitalization itself, the long-term effects of the virus, or a combination of both. These conditions might also be complicated by other effects related to the COVID-19 pandemic, including mental health effects from isolation, negative economic situations, and lack of access to healthcare for managing underlying conditions. These factors have affected both people who were infected with COVID-19 and those who have had many other illnesses.

 

Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis

It is important to define CFS/ME using the Institute of Medicine 2015 diagnostic criteria for adults and children,[15]  because of the considerable overlap with LC:

Three symptoms and at least 1 of 2 additional manifestations are required for diagnosis. The frequency and severity of these symptoms need to be carefully evaluated by the examining physician.

The 3 required symptoms are:

  1. A reduction or impairment of greater than 50% in the ability to perform at pre-illness levels of essential activities such as work related, educational, social, and personal life. This impairment lasts for more than 6 months and is associated with or caused by fatigue that is severe, new onset, not the result of extreme exercise or activities requiring excessive exertion, and is not significantly alleviated by rest.
  2. Post-exertional malaise (PEM)—worsening of symptoms after physical, mental, or emotional exertion that were not experienced prior to the onset of the current changes. This PEM often puts the patient in relapse that may last days, weeks, or even longer. For some patients, sensory overload (light and sound) can induce PEM. The symptoms typically get worse 12 to 48 hours after the activity or exposure and can last for days or even weeks.
  3. Unrefreshing sleep—patients with ME/CFS may not feel better or less tired even after a full night of sleep despite the absence of specific objective sleep alterations.

At least 1 of the following 2 additional manifestations must be present:

  1. Cognitive impairment—patients have problems with thinking, memory, executive function, and information processing, as well as attention deficit and impaired psychomotor functions. All can be exacerbated by exertion, effort, prolonged upright posture, stress, or time pressure, and may have serious consequences on a patient’s ability to maintain a job or attend school full time.
  2. Orthostatic intolerance (a unique feature)—patients develop a worsening of symptoms upon assuming and maintaining upright posture as measured by objective heart rate and blood pressure abnormalities during standing, bedside orthostatic vital signs, or head-up tilt testing. Orthostatic symptoms including lightheadedness, fainting, increased fatigue, cognitive worsening, headaches, or nausea are worsened with quiet upright posture (either standing or sitting) during day-to-day life and are improved (though not necessarily fully resolved) with lying down. Orthostatic intolerance is often the most bothersome manifestation of CFS/ME among adolescents.

The IOM committee specified that “The diagnosis of CFS/ME should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.”

Other Common Symptoms of CFS/ME

Many people with CFS/ME also have other symptoms, including the following:

  • Muscle pain
  • Pain in the joints without swelling or redness
  • Headaches of a new type, pattern, or severity
  • Swollen or tender lymph nodes in the neck or armpit
  • A sore throat that is frequent or recurring
  • Chills and night sweats
  • Visual disturbances
  • Sensitivity to light and sound
  • Nausea
  • Allergies or sensitivities to foods, odors, chemicals, or medications

Please see Coronavirus 2019 (COVID-19) in Children.

 

 

Cardiovascular Sequelae

ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19

Recognizing the long-term impacts of COVID-19 on the cardiovascular system, the American College of Cardiology (ACC) convened a group of clinical experts to develop content addressing new and evolving information regarding heart health. The group wrote an expert consensus decision pathway (ECDP) to guide clinicians in caring for patients with myocarditis or other myocardial involvement or post-acute sequelae of SARS-CoV-2 (PASC). Additionally, the ECDP addresses when and how to resume physical activity after SARS-CoV-2 infection. The ECDP provides a framework for evaluation and management of adults with cardiovascular sequelae for clinicians.[16]  

 

Nonpharmacologic Treatment

Multi-disciplinary post-COVID care centers have opened across the country to enable management of patients with lingering symptoms. Rehabilitation centers have developed physical therapy programs for patients with LC. 

There are no basic nor clinical research studies to support any treatment for the few months of lingering symptoms after COVID-19 nor for LC, but healthcare providers may be able to help reduce or manage symptoms through simpler measures of rehabilitation services, symptomatic medications, and coordinated care. Mild disease is more likely to resolve without aggressive therapy. Particularly with milder illness, it is important to consider other possible diagnoses masquerading as LC. Conventional interventions can be used to address issues such as pain, poor appetite, headache, nausea, and diarrhea. Specialists are needed for patients with chronic kidney disease who may need long-term dialysis after COVID-19 infection. Clotting abnormalities have been reported that require consultation and treatment by hematologists.

Although registries to assess LC are being launched, there is an absence of research on self-management practices among individuals with LC. Patients and patient advocacy groups have reported an absence of timely support and poor recognition and definition of LC, partly attributable to insufficient understanding of LC infection and overwhelmed healthcare systems. The lack of support for these patients has led to loss of faith and disappointment in healthcare service delivery, leading people with LC to seek alternative sources of support and treatment.

Exercise is currently being evaluated as early management of these patients with encouraging results.[10]  Specific treatment for defined organ involvement should include specialists such as cardiologists, pulmonologists, gastroenterogists, psychologists, neurologists, and physical therapists, as well as specialists in other fields of medicine.

The various presentations of LC are accounted for by variations in the effect of the virus on the immune system and other organs and the extent of the host inflammatory response. This interaction is currently being evaluated.

There are now published series of LC in children, although treatment data are lacking.[13, 17]  A major difference between LC in adults and children is that the percent of COVID-19 infected children developing LC is significantly lower and the duration of illness is shorter. Early symptoms appear to be similar to adults, with fatigue and difficulty concentrating being most common. Difficulty concentrating is of greatest concern because of the interference with optimal learning and school performance. One contrasting feature is that insomnia is much less common than in adults. Some series have suggested that in addition to the duration of illness being shorter, long-term outcome is better than for adults.

Some people with LC have symptoms of CFS/ME, postural orthostatic tachycardia syndrome (POTS), dysautonomia, fibromyalgia, autoimmune disease, mast cell activation syndrome (MCAS), and other health conditions that require management that has been shown to be effective in clinical trials. When someone suspected of having LC receives a new diagnosis of these other conditions, medical and rehabilitation specialists may then be able to apply the appropriate treatments and therapies.

For some patients, their LC symptoms improve over time. It is unclear which LC patients have symptoms that are likely to be permanent or are reversible with time. 

Cardiovascular therapies

In a retrospective study presented in February 2022 at the American College of Cardiology's virtual Cardiovascular Summit, scientists from Cleveland Clinic reviewed their data that used enhanced external counterpulsation (EECP).[18]  This intervention compresses the blood vessels in the lower limbs to increase blood flow to the heart. EECP uses contracting and relaxing pneumatic cuffs on the calves, thighs, and lower hip area to provide oxygen-rich blood to the heart muscle, brain, and the rest of the body. Each session takes 1 hour, and patients may undergo as many as 35 sessions over 7 weeks. The researchers evaluated the effect of the therapy in 50 COVID-19 survivors. Twenty patients had coronary artery disease (CAD), whereas 30 did not; average age was 54 years.

All patients completed the Seattle Angina Questionnaire-7 (SAQ7), Duke Activity Status Index (DASI), PROMIS Fatigue Instrument, Rose Dyspnea Scale (RDS), and the 6-minute walk test (6MWT) before and after they completed 15 to 35 hours of EECP therapy.

The analysis showed statistically significant improvements in all areas assessed, including 25 more points for health status on the SAQ7 (range, 0 to 100), 20 more points for functional capacity on DASI (range, 0 to 58.2), 6 fewer points for fatigue on PROMIS (range, 4 to 20), 50% lower shortness of breath score on the RDS, and 178 more feet on the 6MWT.

The change from baseline among participants who had LC but not CAD was significant for all end points, but there was no difference between LC patients with or without CAD. 

Registries and databases for LC 

Recover Initiative 

The United States National Institutes of Health has launched the RECOVER Initiative (Researching COVID to Enhance Recovery). The New York University Grossman School of Medicine will take the lead in building the RECOVER research consortium, harmonizing and coordinating data within the consortium, and developing methods for monitoring protocols, including recruitment, data quality, and safety measures to identify adverse events. Additionally, they will guide communication and engagement efforts with key stakeholders, including patients and healthcare providers. 

The Biostatistics Center at Massachusetts General Hospital will support the data resource core, which will help enable tracking and searchability of results across all sources of data, from clinical studies to electronic health records. In addition, they will provide expertise in statistical analyses and play a key role in ensuring data standardization, access, and sharing among RECOVER projects. 

Therapies for LC (TLC) study

The Therapies for LC study will begin to explore self-management practices through a central database that surveys people with LC.[8, 19] This study aims to be a first step towards understanding this important and under-researched public health issue.

Finally as a warning: there are potential risks of self-prescription, such as harmful drug–drug interactions and use of inappropriate treatments. Research is needed to understand the self-management practices that are being used to manage LC symptoms; factors influencing their uptake; and the benefits, harms, and costs. There is also a need to assess the potential harmful effects of polypharmacy and drug–drug interactions in these individuals. 

 

Pharmacologic Treatment

Vaccines

People who are fully vaccinated against SARS-CoV-2 are less likely to develop LC. Findings from the COVID Symptom Study allowed citizens in the United Kingdom to download a smartphone app and self-report data on their infection, symptoms, and vaccination status over a long period of time. Results collected before availability of COVID vaccines found 1 in 20 (5%) people who got COVID-19 had COVID symptoms for 8 weeks or longer. Data collected after vaccines became available (December 9, 2020 to July 4, 2021) analyzed nearly 1 million individuals who were fully vaccinated during this period. These data show only 0.2% of fully vaccinated individuals who later tested positive for COVID-19. The researchers also found that fully vaccinated individuals who developed breakthrough infections were about half (49%) as likely as unvaccinated people to report symptoms of Long COVID lasting at least 4 weeks after infection.[20]   

The above data are supported by other studies described in an evidence briefing of effectiveness of vaccinations against long COVID. 

Therapeutics

Besides vaccination, it is currently unknown whether any existing COVID-19 therapies have an effect on risk of developing long COVID. 

In the NIH ACTIV-6 treatment protocol for outpatient repurposed drugs, if a drug demonstrates efficacy in reducing symptoms of mild-to-moderate COVID-19, it will be further evaluated for effects on clinical outcomes (hospitalization, mortality) and long-term COVID-19 symptoms. 

A national study using University of Utah’s Intermountain real-world MAB-treatment registry and control group to prospectively evaluate COVID-19 symptoms for 120 days after diagnosis is planned. 

The World Health Organization’s SOLIDARITY trial has tracked study participants for 1 year who were hospitalized with COVID-19 and treated with the antiviral drug remdesivir. Results are expected mid-2022. This study is also following up on patients who received infliximab or imatinib during hospitalization, although the studies had low enrollment and may not end up being useful to determine reliable answers if these drugs lower risk for LC.[21]   

The PANORAMIC trial (University of Oxford, United Kingdom) is evaluating outpatient oral antiviral agents for COVID-19 (ie, molnupiravir, nirmatrelvir/ritonavir) to determine if these agents prevent hospitalization and lead to a quicker recovery. 

Uncontrolled Studies and Case Reports

Uncontrolled studies and case reports have suggested a wide range of self-prescribed medications employed for the prevention and management of acute LC, including steroids, ivermectin, anti-retrovirals, montelukast, hyperbaric oxygen, penicillin, vitamin C, traditional medicines, chloroquine, and hydroxychloroquine.[9, 10, 12, 22, 23]  Self-prescribing practices are unsurprising given the concern of LC patients based on the well reported high incidence of morbidity and mortality from acute COVID-19 infection, restricted access to healthcare during lockdowns, and few treatments and preventive therapies for COVID-19 infection itself.

Unfortunately medicines are being used off label, in unsafe doses, and are sometimes purchased in an unregulated manner overseas. Harmful drug–drug interactions are enhanced due to the complexity and multiple symptoms of LC, leading to the sequential addition of multiple treatments when earlier ones fail.

In the absence of information for effective treatments, some individuals with LC seek advice from social media platforms (eg, Facebook), where others share their self-management experiences, regardless of the outcome, and online resources, including medical blogs and journals. Owing to the limited evidence base, these platforms are a potential source of conflicting information and unfortunately, misinformation.[24]  

Self-management can be costly, and some patients use a substantial proportion of their income, which threatens to increase existing health costs. Further obstacles to care (eg,  geographical disparities in access to clinics for LC, access to private healthcare, health literacy) jeopardize patient recovery and overall health.[24]  

Promotion of unproven medications (eg, ivermectin), vitamins, and therapies for LC can further hinder gaining evidence as to which drugs may provide benefit and delay needed medical care. Infectious disease experts and physicians at many medical centers treating patients with documented LC have expressed concern for unproven treatment plans[25]  since controlled clinical trials have not been completed to provide evidence of efficacy. Instead, they recommend patience until possible treatments have been more fully examined and confirmed. 

 

Investigational Drug Trials for Long COVID

Table 1. Investigational Drug Trials for Long COVID (Open Table in a new window)

Drug Description
Leronlimab (CytoDyn) [26]   CCR5-binding antibody. Phase 2 trial treating long COVID observed significantly increased blood cell surface CCR5 in treated symptomatic responders, but not in nonresponders or placebo-treated participants. Findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab.
RSLV-132 (Resolve Therapeutics) [27] Enzymatically active ribonuclease designed to digest the ribonucleic acid contained in autoantibodies and immune complexes and thereby render them biologically inert. The compound consists of a catalytically active human RNase moiety fused to a human IgG1 Fc domain that digests RNA circulating in the blood and thereby decreases inflammation. Phase 2 trial. 
Zofin (Organicell Regenerative Medicine) [28] Acellular, biologic therapeutic derived from perinatal sources and is manufactured to retain naturally occurring microRNAs without the addition or combination of any other substance or diluent. Phase I/II trial.  
Ampion (Ampio Pharmaceuticals) [29]   Low molecular weight filtrate of human serum albumin with the in vitro ability to modulate inflammatory cytokine levels. Phase 1 trial.