After the rapid rollout of COVID-19 vaccines, life has returned to a semblance of normalcy. For COVID long-haulers, however, their lives have veered away from their original tracks. While some people have recovered from the illness within weeks, long-haulers are still grappling with the harsh reality of “chronic COVID-19,” even months after the symptom onset.
The first paper on long-haulers was published in April 2020 , and their presence started to gain more attention during June 2020 . While many medical professionals had not acknowledged their symptoms as COVID-19-related, long-haulers began to form support groups on Slack and Facebook, sharing their symptoms and experiences. Among the earliest scientific reports of persistent symptoms, Carfi et al. (2020) distributed follow-up questionnaires to around 140 individuals discharged from the hospital in July 2020 , and the results were worrisome. Only 18% of patients were free of any COVID-19-related symptoms two months after the symptom onset, even though their RT-PCR tests for the SARS-Cov-2 virus were already negative. 53.1 % of patients reported fatigue and 43.4% reported dyspnea (shortness of breath). Other persistent symptoms include joint pain, cough and anosmia, and 44% of patients reported that their quality of life had worsened .
Subsequently, numerous follow-up studies began to roll out. By the end of 2020, around 30 relevant papers were published per month . As such, the chronic symptoms of COVID-19 gradually gained more recognition by the scientific and the medical community. The accumulating evidence also highlighted the need to standardize the definition and name of the identified chronic symptoms . In February 2021, the National Institute of Health (NIH) began to use proposed the name “Post-Acute Sequelae of COVID-19” (PASC) to describe the collection of symptoms , where “sequelae” means “the aftereffect of a disease” . The scientific community have received the naming positively, although other names like “long COVID-19” “post-COVID-19 syndrome” “chronic COVID syndrome” “late sequelae” are also common in the literature . Such naming not only legitimizes the existence of such syndrome but also facilitates information sharing and treatment standardization. NIH also launched the RECOVER (Researching COVID to Enhance Recovery) Initiative in the same month . It aims to support nationwide large-scale studies addressing critical questions of PASC, including the range of symptoms, risk factors, prevention and treatment .
While the delayed recognition of PASC portrays it as a novel phenomenon, chronic symptoms of a viral infection are not unexpected. Although coronavirus infections are known as respiratory diseases, coronaviruses SARS-CoV-1 and MERS both resulted in multiorgan chronic symptoms . Similarly, SARS-CoV-2 can damage more than the respiratory system. Mechanistically, it gains access to the cells via binding of the human angiotensin-converting enzyme 2 (ACE2) receptor after being primed by cellular protease TMPRSS2. Both proteins are enriched on various cell types in the human body, including neurons, cardiomyocytes, gastrointestinal epithelial cells and renal cells . Given their ubiquitous expression and the entry mechanism of SARS-CoV-2, it is not surprising that acute symptoms occur across systems, and PASC may be the aftermath of inflammation and organ impairment . However, the mechanism of PASC maybe more complicated. Recent findings discovered evidence that the virus may persist in the body after the acute symptom receded . Infected organs may also serve as viral reservoirs that cannot be detected by nasal swabs. Both Li et al. (2020)  and Vibholm et al. (2021)  observed that a subset of patients still have viral RNA present in their respiratory tract three months after they had recovered from acute symptoms. However, their immune system appeared to be exhausted [12, 19]. Aside from viral persistence, some theories emphasize the contribution of immune dysregulation. Viruses like herpesviruses that are normally kept in check by the immune surveillance may “re-emerge” and wreak havoc on already devastated cells . SARS-CoV-2 may also induce immune system to attack “self” cells and proteins, causing autoimmune symptoms. Other suspected mechanisms include disruptions in host microbiome [14, 16] and the renin-angiotensin system .
It is worth noting that PASC is distinct from the “post-intensive care syndrome” (PICS), which describes declines in physical, cognitive and psychological capacities after patients are discharged from the intensive care unit (ICU)  that is severe enough to interfere with their ability to perform daily tasks. Worriedly, the clinical profile of people vulnerable to PICS overlaps with that of COVID-19 patients who need intensive care, meaning that PICS is likely to cause another wave of crisis in the post-COVID era .
In contrast to PICS, PASC has a higher prevalence and affects a broader range of individuals. A systematic review, which included 47,910 individuals, identified 55 long-term symptoms demonstrated in respiratory, neuropsychiatric and cardiovascular systems. They estimated that 80% of patients would develop at least one . Over half of the individuals experienced fatigue. Headache (44%), attention disruption (27%), dyspnea (25%) and ageusia (loss of taste, 23%) are among the most common. In addition to physical symptoms, a six-month follow-up study on more than 1700 patients reported that one in five patients experienced depression or anxiety .
Although severe symptoms may imply a higher risk of PASC, PASC also develops in people with milder acute symptoms of COVID-19. A large-scale study in preprint found that 36.1% of the COVID-19-positive individuals surveyed have at least one symptom persisting till 30 days and 14.8% till 90 days. This rate of occurrence was much higher than the hospitalization rate (2%) . For people who had severe acute symptoms, the rate reached 44.9% at 30 days and 20.8% at 90 days. Such findings are corroborated by a study performed by Carvalho-Schneider et al. (2021), which only surveyed adults with non-critical symptoms . Two months after the initial onset of symptoms, two-thirds of the individuals still experience persisting symptoms, namely dyspnea (40%) and anosmia (loss of smell)/ageusia (23%). In addition, they found that PASC was significantly associated with hospital admission and older age .
With ongoing studies on the multifaceted mechanism of COVID-19, the prospect of patients with PASC is still uncertain. Although numerous reports and studies have provided a growing body of evidence, the statistical evidence has not demonstrated consistency across populations. Heterogeneity in symptoms reported poses challenges on reaching a consensus on the definition of PASC or the framework of diagnosis. A preprint meta-analysis of PASC literature demonstrated little consistency among PASC definitions . Studies selected different symptoms, and even the same symptom can be described using different nomenclature. For example, anosmia and ageusia are sometimes tallied as one collective symptom or being viewed as separate. Parameters also vary, with some studies considering the severity of acute symptoms while others did not. Standardization of symptom criteria and evaluation is the next hurdle to overcome in PASC research .
Edited by: Alexandra Dram
Illustrated by: Angela Chen