The root causes of long-COVID still a mystery

In a recent article posted to the journal Annals of Internal Medicine, researchers presented baseline outcomes from a longitudinal assessment of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), also known as long-COVID.

Study: A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings. Image Credit: tilialucida / Shutterstock


SARS-CoV-2 is a new coronavirus that has not previously been detected infecting humans. The clinical illness produced by SARS-CoV-2 infection, coronavirus disease 2019 (COVID-19), was first identified in China in late December 2019. To date, SARS-CoV-2 has infected more than 526 million people globally. 

After an initial illness, a large percentage of those infected with SARS-CoV-2 experience chronic symptoms. The etiology of PASC has been linked to several pathophysiologic processes. Furthermore, existing PASC research relies heavily on assessing electronic medical records and questionnaire data.

About the study

The goal of the present ongoing longitudinal cohort study conducted in the National Institutes of Health Clinical Center, Bethesda, Maryland, which began in June 2020, was to examine the medical consequences and long-term symptoms of SARS-CoV-2 infection in a group of COVID-19 survivors and controls. In a longitudinal cohort of patients recuperating from COVID-19 and control subjects without a record of SARS-CoV-2 infection, the researchers aimed to more critically examine the long-term mental¬†and medical health implications of COVID-19. They attempted to classify PASC’s clinical findings, risk factors, natural history, and laboratory aspects.¬†¬†

The study volunteers were self-referred adults with laboratory-confirmed SARS-CoV-2 infection. The eligible subjects were those nearly six weeks post-COVID-19 symptom onset, did not have deteriorating respiratory manifestations and had no fever in the week before enrolment. Moreover, regardless of whether or not PASC was present, these individuals were enrolled. Besides, those with asymptomatic COVID-19 were also eligible four weeks following the initial SARS-CoV-2-positive reverse transcriptase-polymerase chain reaction (RT-PCR) laboratory report.

People without COVID-19 history or serologic proof of SARS-CoV-2 infection were selected irrespective of their current health state as a control cohort. Both study cohorts were recruited simultaneously and were from the exact geographic location.

Regardless of whether or not they experienced symptoms, all subjects had the same assessments, such as a physical examination, questionnaires, laboratory tests, cardiopulmonary evaluation, and cognitive function screening. Additionally, a fraction of the participants had exploratory virologic and immunologic testing.

The authors defined PASC as any medical condition or symptom that worsened or started after the beginning of COVID-19 or the initial SARS-CoV-2-positive RT-PCR test in individuals with an asymptomatic infection and was still there at the research enrolment visit.


The baseline findings from this ongoing study showed the research included 189 subjects with laboratory-confirmed COVID-19, and of that, 12% were hospitalized during acute SARS-CoV-2 infection. In addition, there were 120 SARS-CoV-2 antibody-negative control volunteers. Of note, the participant recruitment for the study was still ongoing. 

The authors noted that at enrolment, 55% of the SARS-CoV-2 cohort and 13% of control individuals exhibited symptoms compatible with PASC, such as chest discomfort, dyspnea, and memory impairment. They found that women and individuals with a history of anxiety conditions were at higher risk for PASC.

On standardized assessments, subjects with findings that met the description of PASC documented a worse quality of life than control subjects. Abnormal diagnostic testing and physical examination findings were infrequent and were comparable between the two study cohorts. Although SARS-CoV-2 spike (S) protein neutralizing antibody levels were absent in 27% of the non-vaccinated COVID-19 group, it was substantially present in the vaccinated SARS-CoV-2 cohort. These data imply that there might be a subset of COVID-19-recovered individuals with antibody concentrations beneath the protective range and that vaccination following natural infection boosts viral neutralizing antibodies significantly. Additionally, in people with PASC, exploratory investigations showed no indication of persisting autoimmunity, aberrant immune activation, or viral infection.

Furthermore, the researchers reported that a significant portion of those infected with SARS-CoV-2 had mild to moderate acute symptoms that did not need hospital admission. The frequency of reported PASC in this group was likely overstated since those with PASC might have been more driven to enroll. Besides, the present research did not include PASC that was resolved before enrolment. 


According to the study findings, COVID-19-recovered subjects had a significant burden of chronic symptoms. However, a detailed diagnostic investigation showed no particular reason for reported symptoms in most instances. Further, after infection with SARS-CoV-2, antibody titers against the virus were highly varied in COVID-19 vaccinated individuals.

Given the scarcity of publications containing detailed diagnostic data and clinical information on PASC, the scientists believe that the data gleaned so far by this study will offer a better understanding of the severity and nature of the syndrome and will be beneficial for physicians treating and evaluating such patients. Unfortunately, the pathophysiology of PASC is still unknown and needs more research.