Editorial: Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). Updated Terminology for the Long-Term Effects of COVID-19

At an early stage in the COVID-19 pandemic, long-term respiratory and neurological effects in adults were identified in some patients who recovered from the initial infection with SARS-CoV-2 [1]. As more long-term clinical sequelae were identified, long COVID or post-COVID syndrome were used as clinical terms for patients with long-term respiratory, cardiovascular, hematologic, renal, neuropsychiatric, endocrine, gastrointestinal, and dermatologic sequelae [2]. Disease surveillance modeling showed that in 2020 and 2021, in 1.2 million patients with symptomatic COVID-19, symptoms of persistent fatigue, cognitive impairment, or persistent respiratory problems persisted for a mean duration of 9.0 months in hospitalized patients and 4.0 months in non-hospitalized patients [3]. Among individuals with at least one long COVID symptom at three months, an estimated 15.1% continued to experience symptoms at 12 months [3]. From April 2021, clinical guidelines were proposed to define, diagnose, and manage long COVID [4]. At that time, long COVID was defined as signs and symptoms of illness four weeks after the initial infection with SARS-CoV-2, which were not explained by other causes [4]. Populations studies showed that the prevalence of long COVID was between 10–30% [4,5]. As the pandemic continued, longer follow-up of affected populations also identified long-term cardiovascular complications in patients without prior cardiovascular comorbidities and previously healthy individuals [6]. Children with asymptomatic or symptomatic SARS-CoV-2 infection also suffer from direct long-term effects of COVID-19, including chronic multisystem inflammatory syndrome in children (MIS-C) [7]. Children and adolescents have also experienced the impact of COVID-19 on the changing pathogenesis of other infections that have occurred since the start of the COVID-19 pandemic [8].

Most studies on the long-term effects of SARS-CoV-2 infection have been retrospective, have lacked an uninfected comparison group, and have focussed on the prevalence of individual symptoms, resulting in different estimates of prevalence. However, the long-term effects of SARS-CoV-2 infection can overlap and involve multiple organs, systems, and physiological and immunological functions and show differences in children, adolescents, pregnant women, adults, and the elderly [9]. Therefore, the term, long COVID, is too simplistic, and there are reasons to replace it with the term, post-acute sequelae of SARS-CoV-2 infection (PASC) [9,10]. PASC is defined as new, ongoing, or relapsing symptoms or conditions present 30 or more days after the diagnosis of SARS-CoV-2 infection or the onset of symptoms of COVID-19 [9]. In June 2023, Gross and Lo Re supported the use of PASC and ongoing studies on the sequelae of SARS-CoV-2 infection, with multidisciplinary clinical, scientific, and patient collaboration to identify whether multiple phenotypes arise after COVID-19 to individualize and improve clinical care for patients with late effects of SARS-CoV-2 infection [10].

The National Institutes of Health (NIH) have established the Researching COVID to Enhance Recovery (RECOVER) Consortium, a prospective longitudinal cohort initiative to learn about the long-term effects of COVID-19 [9]. As of June 23, 2023, RECOVER enrolled 12,057 non-pregnant adults, 1,917 pregnant women, and 9,599 children with long-term symptoms after SARS-CoV-2 infection [9]. RECOVER has registered 85 sites that include hospitals and health centers, which are located in 33 US states, in Washington, DC, and in Puerto Rico [9]. Participants enrolled in the RECOVER adult cohort before April 2023 completed a symptom survey at 6 months or more after a positive SARS-CoV-2 test or the onset of symptoms [9].

On May 25, 2023, Thaweethai and colleagues reported the findings from data analysis of 9,764 adult participants in the RECOVER study [11]. This study aimed to identify symptoms present in SARS-CoV-2–infected individuals at 6 months or more after infection compared with uninfected individuals and to identify symptom-based criteria for PASC [11]. There were 37 symptoms involving multiple systems identified as present more often in SARS-CoV-2-infected participants at 6 months compared to uninfected participants [11]. In this recent study, the 9,764 study participants included 71% women, 16% Hispanic/Latino patients, and 15% non-Hispanic Black patients, with a median age of 47 years (IQR, 35–60 years) [11]. The most common symptoms included brain fog (64%), fatigue (85%), post-exertional malaise (PEM) (87%), dizziness (62%), palpitations (57%), and gastrointestinal symptoms (59%), followed by chronic cough, change in smell or taste, changes in libido, thirst, chest pain, and abnormal movements [11]. Of 2,231 participants first infected with SARS-CoV-2 on or after December 1, 2021, and enrolled within 30 days of infection, 10% (N=224) (95% CI, 8.8–11%) had PASC at 6 months [11]. Among infected participants in the full cohort, the proportions of PASC positivity were 39% (299/757) in hospitalized participants and 22% (1636/7387) in non-hospitalized participants during acute infection [11]. The proportions of PASC positivity were 19% (442/2,377) in men and 25% (1,540/6,221) in women, 20% (885/4389) in patients aged 18–45 years and 28% (904/3175) in patients aged between 46–65 years [11]. Four PASC cluster groups were identified: Cluster 1 (N=477) – change in smell and taste (100%); Cluster 2 (N=405) – PEM (99%) and fatigue (84%); Cluster 3 (N=587) – brain fog (100%), PEM (99%), and fatigue (94%); and Cluster 4 (N=562) – fatigue (94%), PEM (94%), dizziness (94%), brain fog (94%), GI (88%), and palpitations (86%) [11]. These findings indicate that PASC is heterogenous and may reflect a group of individual phenotypes, which is supported by recent findings from the National COVID Cohort Collaborative [12]. Therefore, the remaining factors that require investigation include the identification of biomarkers for PASC to inform therapy and further studies on phenotypes associated with PASC. Because more than 500 million people worldwide have now had COVID-19, there likely is more to learn about PASC from future epidemiological studies [9].

Conclusions

PASC is associated with a significant and increasing global economic and health burden [2]. Recognizing the range and complex interactions between the many long-term effects of COVID-19 is essential before effective prevention or management strategies can be investigated and implemented. A symptom-based definition of PASC that also combines biological and laboratory factors, patient age, ethnicity, gender, vaccination status, pregnancy, comorbidities, and social determinants of health at the time of SARS-CoV-2 infection is now a possible approach to identify patients at risk for PASC and to identify PASC subgroups.