Hariharan Regunath, MD, Vamsi P. Guntur, MD Mo Med. 2023 Mar-Apr; 120(2): 102–105.PMCID: PMC10121126 PMID: 37091941 Copyright and License information PMC Disclaimer NCBI
The term “COVID Long-Hauler” or “Long-Haul COVID” was first created by patients within few months of the onset of the pandemic.1,2 The first publication of persistent symptoms following acute COVID-19 was from Italy in July 2020, where-in, 143 hospitalized patients with acute COVID-19 between April and May 2020, who eventually tested negative by polymerase chain reaction (PCR), were followed for two months as out-patient and 87.4% had at least one persistent symptom.3 The database study from the United States (U.S.) Department of Veterans Affairs (VA) was the first largest study to show that beyond a month of illness, there existed a higher risk for death and healthcare utilization because of a variety of incident respiratory, cardiovascular, neurological, musculoskeletal, gastrointestinal and metabolic disorders.4 Subsequently, multiple other observational studies have been published.5–10 The systematic reviews that followed, were limited by the low quality of such studies, lack of standardized definition and representative biologic markers for the different organ systems involved as a part of this syndrome.
To date, “long COVID” remains loosely defined by the Centers for Disease Control and Prevention (CDC) as new-onset, persistent or evolving symptoms that linger beyond four weeks following recovery from a documented acute COVID illness or diagnosis, and characterized by persistent physical or mental health issues.11 The World Health Organization (WHO) uses a longer interval of 12 weeks in the absence of an alternative explanation or diagnosis.12, 13 Consensus continues to be lacking for a unified definition due to wide variations in study criteria, measures, and quality.14 Long COVID, post-COVID conditions, post-acute sequelae of SARS CoV-2 (PASC), chronic COVID-19, ongoing symptomatic COVID-19, post-COVD-19 persistent symptoms, and post COVID-19 syndrome are all merely different terms for a set of continued symptoms that linger after recovery from acute illness. Table 1 displays the different terms, definitions still in use as proposed by organizations and website references.14, 15 Clinically useful and meaningful definitions based on the organ system of greatest involvement, or prolonged manifestations from initial illness (e.g. post-ARDS, lack of pulmonary involvement, minimal URI involvement) are yet to be sorted out.
Table 1
Proposed Long COVID Definitions
| Terms | Developed or proposed | Definition | Suggested website references |
|---|---|---|---|
| Long COVID* | Patients and people with lived experience; patient-researchers | Can be broadly defined as signs, symptoms, and sequelae that continue or develop after acute COVID-19 or SARS-CoV-2 infection for any period; are generally multisystemic; might present with a relapsing–remitting pattern and a progression or worsening over time, with the possibility of severe and life-threatening events even months or years after infection. | https://www.sciencedirect.com/science/article/pii/S0277953620306456?via%3Dihub |
| Persistent symptoms or COVID-19 consequences | Commonly used research term | Persistent signs and symptoms that continue or develop after acute COVID-19 for any period. | https://www.sciencedirect.com/science/article/pii/S0163445321005557; https://gh.bmj.com/content/6/9/e005427.long |
| Post-COVID-19 condition | WHO | Post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis; common symptoms include fatigue, shortness of breath, and cognitive dysfunction, and generally have an impact on everyday functioning; symptoms might be new onset after initial recovery from an acute COVID-19 episode or persist from the initial illness; symptoms might also fluctuate or relapse over time; a separate definition might be applicable for children | https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00703-9/fulltext |
| Ongoing symptomatic COVID-19 | NICE† | Signs and symptoms of COVID-19 from 4 weeks up to 12 weeks. | https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-thelongterm-effects-of-covid19-pdf-51035515742 |
| Post-COVID-19 syndrome | NICE† | 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 might be considered before 12 weeks while the possibility of an alternative underlying disease is also being assessed. | https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-thelongterm-effects-of-covid19-pdf-51035515742 |
| Post-COVID conditions | CDC | An umbrella term for the wide range of physical and mental health consequences experienced by some patients that are present four or more weeks after SARS-CoV-2 infection, including by patients who had initial mild or asymptomatic acute infection. | https://www.cdc.gov/coronavirus/2019-ncov/long-termeffects/index.html |
| Post-acute sequelae of SARS CoV-2 infection* | NIH | Persistent or new symptoms after COVID-19 infection; the definition will be revised in an iterative manner based on existing data, medical literature, and feedback from patient representatives, patients, and the scientific community; updated definitions might be used to implement a strategy to modify deeper phenotyping. | https://recovercovid.org/docs/RECOVER-Adult-Protocol_02-02-2022.pdf |
CDC – Centers for Disease Control and Prevention; NIH – National Institutes of Health; COVID – Coronavirus disease; SARS CoV 2 – Severe acute respiratory syndrome coronavirus 2; NICE=National Institute for Health and Care Excellence (UK).
†NICE also states that: “In addition to the clinical case definitions, the term ‘long COVID’ is commonly used to describe signs and symptoms that continue or develop after acute COVID-19. It includes both ongoing symptomatic COVID-19 (from 4 to 12 weeks) and post-COVID-19 syndrome (12 weeks or more).” [Reproduced from The Lancet Respiratory Medicine, Vol 10, Issue 7, Daniel Munbit et al, “Long COVID: aiming for a consensus”, p 632–634, July 2022, with permission from Elsevier©2022]
Recent estimates from the CDC, report a wide range of 5–30% for the incidence of post-COVID conditions, attributed to the variability in reported symptoms, follow-up duration, study settings (inpatient or outpatient) and whether data is generated by self-report or health records database.16 The wide variety of symptoms (an increasing list of >200 symptoms) in the long COVID studies have been classified by two systematic reviews into three common clusters, ongoing respiratory issues; fatigue with bodily pain or mood swings; and cognitive problems.17, 18 Another data-driven study used a machine learning approach to analyse two large electronic health databases (INSIGHT comprising 20,881 patients out of 12 million in New York City and OneFlorida+ with 13,724 out of 19 million patients from Florida, Alabama, and Georgia). They abstracted and refined a list of 137 diagnosis categories listed by the VA study and evaluated their incidence after 30–180 days of a documented SARS CoV-2 infection. They reported four sub-phenotypes that differed in their demographics, comorbidities, and severity of the preceding acute COVID illness: cardiac and renal; respiratory, sleep and anxiety; musculoskeletal and nervous system; and digestive and respiratory system sequelae.19 The first two sub-phenotypes predominated over the latter two.
An elusive variety of direct (viral) and indirect pathophysiological hypotheses for long COVID, included viral persistence/reservoir in different tissues, mitochondrial dysfunction, immune dysregulation as a continuation from the initial infection, persistent vascular endothelial or other organ injury, triggering or exacerbation of auto-immunity, gut dysbiosis and certain co-morbidities that increase the risk for long COVID.20–24 The most interesting of these mechanisms is evidence for persistent SARS CoV-2 in the human body from a few small studies predating the omicron period, purporting a potential target for treatment or surrogate marker for clinical trials.
One study from the University of California San Francisco, showed higher levels of plasma neuronal exosomes (extracellular vesicles released by neuronal cells25) containing nucleocapsid and spike protein levels in long COVID patients with neuropsychiatric symptoms.26 Another retrospective study measured plasma SARS CoV-2 antigens (S1, spike or N) in samples gathered from a biorepository (two or more samples gathered up to 12 months) and noted that antigens were detected in >70% of those who reported cardiovascular, systemic, head-eye-ear-nose-throat and musculoskeletal symptoms.27 Spike protein was most often detected in 60% of those with long COVID at multiple time points. The authors concluded by indicating that a reservoir of active virus may endure in the body, as an explanation for the continued antigenemia (not viremia).27 An autopsy study from the NIH has also demonstrated that SARS CoV-2 can be widely distributed in different extra-pulmonary tissues of the body and can persist for months, providing further rationale for more research to decipher mechanisms of viral persistence in contributing to long COVID.28 Yet, these findings require confirmation by larger studies. Hence, a unifying pathophysiology remains enigmatic, because persistent symptoms could represent various other disease processes as well.
Designing clinical trials for long COVID has been difficult because it is still a syndrome (and not a disease) with many symptoms that differ between patients and within the same patient (waxing and waning or new symptoms), many long COVID symptoms are akin to myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). The lack of a diagnostic confirmatory marker (lab test) is another major impediment. Eventually, surrogate biomarkers whose levels, correlate with disease activity, are also essential for conducting trials on treatment. Our treatment approaches to Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) diseases took decades to evolve, revolutionized by molecular diagnostics that provided reliable surrogate markers, namely HIV and HCV RNA levels, most of those spurring from concerted efforts by the CDC, National Institutes of Health, and the global community of translational and clinical research. Similar combined efforts are pacing towards the goal of testing and ultimately identifying effective candidates for surrogate biomarkers (lab tests) in long COVID.
The CDC’s Household Pulse survey and the RECOVER [Researching COVID to Enhance Recovery] initiative by the NIH have been laying the foundations for clinical trials on long COVID, several of which started in early 2023, including the testing of various biomarkers and possible interventions including the use of antiviral therapy.29 This has become possible because of their continued efforts to support observational studies, pathobiology studies, evaluation of potential biomarkers and analyses of millions of electronic health records in the National COVID Cohort Collaborative (N3C) data using machine learning approach, which have now informed endpoints and enabled trial designs.30, 31 The Research Review (R3) Seminar Series from the RECOVER initiative, provides useful periodic updates by experts researching on the different aspects of long COVID, to promote a shared understanding of the continued progress in long COVID research.30