Key points

Introduction

The severity of acute SARS-CoV-2 infections has dropped significantly since the initial onset of the pandemic, with hospitalizations and deaths due to coronavirus disease 2019 (COVID-19) declining 60% and 83% respectively, as of 2023. Though there has been a reduction in the severity of acute COVID-19 complications, the long-term impacts of the disease remain a concern to many. These long-term consequences are referred to collectively as “Long-COVID,” or post-acute sequelae of COVID-19 (PASC). PASC has become well known among the biomedical community and general public alike, as the condition was the subject of a dedicated committee hearing held by the US Senate in January 2024. This recognition is due in large part to the prevalence of PASC, with estimates ranging from under 10% to over 40% of those who have been infected with COVID-19. These estimates vary based on the population in question as well as the definition and criteria used for PASC, as there is not yet consensus regarding a singular definition of the condition. There are variations across the literature in the definitions of PASC, risk factors, ^, manifestations, and potential pathophysiologic explanations for PASC. ^, An understanding of each of these core components of PASC can provide insight into how to better predict and manage the manifestations of this condition, both of which are especially pertinent for high-risk patients with systemic autoimmune rheumatic diseases (SARDs), who may be more susceptible to COVID-19 infection and its complications due to use of immunosuppressive medications.

Variations in defining post-acute sequelae of coronavirus disease 2019

Definitions of PASC vary across national and international public health agencies and research studies, with differences related to both chronology and timing as well as the manifestations included in the definition. In terms of timing, 2 definitions are most commonly used. The first definition, used by the Centers for Disease Control and Prevention (CDC), describes PASC as encompassing one or more symptoms that either last or develop 28 or more days after the time of initial infection. ^, The other common definition of PASC, adopted by both the World Health Organization and the National Institute for Health and Care Excellence (NICE) in the United Kingdom, describes the condition as any symptom that lasts or develops at least 90 days from the time of initial infection. ^, Others have proposed more precise time points and distinguish “post-acute COVID” (between 5 and 12 weeks following infection), “long post-COVID” (between 12 and 24 weeks following infection), and “persistent post-COVID” (>24 weeks following infection).

Beyond the timeline and duration of either persistence or development of symptoms, various definitions encompass differing extent of symptoms and differing severity of findings. For example, some definitions require a determination of whether symptoms can be attributed specifically to COVID-19 infection. While definitions of PASC often refer to “prolonged symptoms” or “COVID-related symptoms,” in practice, it can be challenging to discern whether or not signs or symptoms experienced following infection are truly due to COVID-19 infection as opposed to an alternative etiology. For example, the NICE guidelines state that PASC symptoms are those that develop “during or after” acute COVID infection and are “not explained by an alternative diagnosis.” This broad language stems from our continuously evolving understanding of the condition, but it poses challenges for clinical diagnosis. The RECOVER (Researching Covid to Enhance Recovery) Consortium proposed a symptom-specific definition based on a model that identified symptoms that were more likely to be present in infected as opposed to uninfected individuals. They identified 12 symptoms (altered smell/taste, post-exertional malaise, chronic cough, brain fog, thirst, palpitations, chest pain, fatigue, altered sexual desire or capacity, dizziness, gastrointestinal symptoms, abnormal movements, and hair loss), each of which receives a score ranging from 1 to 8, with a total score threshold of 12 or more determined to be the optimal threshold to identify PASC. Given the variability in the manifestations of PASC, this definition could potentially exclude significant but less common phenotypes, and these findings require further validation. Additionally, though some signs and symptoms coded in the electronic health record can be easily retrieved from administrative data, relying on these data to define PASC may both result in the underestimation of symptoms that may not be reported to clinicians and also may overestimate the overall incidence of PASC as an electronic health record-based definition of PASC does not require attribution of symptoms to COVID-19 infection and may not be representative of symptoms actively affecting an individual. These challenges in diagnosing PASC are especially apparent for individuals with SARDs, as multiple symptoms of PASC (eg, joint pain, headache, cough, shortness of breath) can also indicate manifestations of the underlying SARD. The American College of Rheumatology recommends that individuals with rheumatic diseases generally hold their immunosuppressive medications during presumed or documented COVID-19 infection, which may place them at risk for flare of their rheumatic disease. In fact, one study found that 41% of individuals with SARDs reported disease flares following COVID-19 infection. Given that the timelines of PASC and SARD flare can coincide and that there are no specific tests for PASC given that the diagnosis remains primarily symptom based, accurate identification of PASC can be particularly challenging in this patient population.

Prevalence and epidemiology of post-acute sequelae of coronavirus disease 2019

Estimates of the prevalence of PASC in the general population range from 8% to over 30% of those with a history of COVID-19 infection ( Table 1 ). One estimate suggests a global prevalence of 43%, with significant variation across geographic regions. PASC may also be more prevalent in regions of lower socioeconomic status and has also been reported to be more prevalent in female individuals, both within and outside of the United States. ^{, , , ,}

Multiple studies have also demonstrated a higher prevalence of PASC in individuals with SARDs. ^, Estimates regarding the prevalence in this population range from approximately 10% to greater than 40%, with higher estimates typically employing a 28 day definition of the condition. ^{, , ,} Reassuringly, the risk of PASC has declined since the start of the pandemic. Among the general population, CDC statistics show that the proportion of patients developing PASC following COVID-19 infection has declined from 18.9% in June 2022 to 11.0% the following year. Similarly, individuals with SARDs infected during the Delta-dominant and Omicron-dominant periods had a lower risk of PASC than those infected earlier on in the pandemic (adjusted odds ratio of 0.5 [95% CI: 0.41–0.62] for those infected in the Omicron era compared to the early pandemic).

Risk factors for post-acute sequelae of coronavirus disease 2019

Multiple modifiable and non-modifiable risk factors for PASC have been identified in both the general population and in those with SARDs ( Box 1 ). Several factors, including older age ^, and high severity of acute COVID infection, are associated with greater risk of PASC in the general population. Among individuals with SARDs, specific clinical and demographic factors predispose patients to increased risk of PASC. Greater severity of acute infection, which encompasses a greater number of acute symptoms, hospitalization, and intensive care unit admission are associated with a higher risk of PASC in this population as well. Also, as is the case in the general population, female individuals with SARDs are more likely to develop PASC than their male counterparts. This is important to note given that many rheumatic diseases disproportionately affect female individuals. ^, In both the general population and among those with SARDs, greater body mass index is associated with greater risk of PASC. ^, Greater comorbidity burden (encompassing asthma, depression, liver disease, stroke, and others) has also been associated with a greater risk of PASC in individuals with SARDs in multiple studies. ^,

Many studies have examined the differential risk of PASC in patients with SARDs based on the type of immunomodulatory medications that they were using at the time of COVID-19 infection. Multiple studies have found an increased risk of PASC in those using cluster of differentiation 20 (CD20) inhibitors (adjusted odds ratio of 2.69 [95% CI: 1.23–5.88] compared to those using conventional synthetic disease modifying anti-rheumatic drugs [DMARDs]). ^, Aside from CD20 inhibitors, there are limited data to support associations between other immunosuppressive medications and risk of PASC among patients with SARDs, and multiple studies have shown no increase in risk with a variety of different oral and biologic medications. ^{, ,} Glucocorticoid use at the time of COVID-19 infection has also been identified as a risk factor for PASC (adjusted hazard ratio of 1.19 [95% CI: 1.05–1.34] compared to no glucocorticoid use). Both glucocorticoid use and CD20 inhibitor use prior to COVID-19 infection have been identified as risk factors for more severe acute COVID-19 outcomes (eg, hospitalization, mortality) among patients with rheumatic and musculoskeletal diseases ; thus, the relationship between the use of these medications and PASC may be in part mediated by hospitalization and other acute care requirements.

As earlier, the prevalence of PASC has declined overtime since the onset of the pandemic. It is unclear whether this lower risk is the result of vaccination prior to infection, given that vaccines became available in December 2020, or whether the intrinsic virulence and properties of circulating variants may contribute to this decreased risk as well. Indeed, SARS-CoV-2 vaccination prior to infection was associated with a lower risk of developing PASC in individuals with SARDs and in those in the general population. However, the majority of the infections in vaccinated individuals occurred during the Delta/Omicron phases of the pandemic, making it difficult to eliminate confounding factors and determine whether vaccination itself versus differences in the variants overtime contributed to differences in the risk of PASC.

Pathophysiologic mechanisms underlying post-acute sequelae of coronavirus disease 2019

Though the pathophysiology of PASC remains unclear, various potential explanations have been proposed. One potential explanation suggests that the post-COVID condition is the result of viral persistence in tissues or organs. The persistence of the virus in tissue reservoirs may contribute to chronic inflammation exhibited by some patients with PASC. This hypothesis is also potentially supported by the fact that viral RNA can persist in fecal matter of patients up to months following COVID-19 infection, suggestive of possible ongoing infection in the gastrointestinal tract. Similarly, other data have demonstrated prolonged detection of SARS-CoV-2 viral RNA in multiple tissues including the brain and lungs, even in the absence of viral detection by either blood test or nasopharyngeal swab. However, other studies have not demonstrated this association between viral persistence in tissue samples and PASC. Differences in time from infection to sample collection, severity of acute infection, and demographics of the patient populations may explain discrepant findings across studies.

Second, organ damage originating during or shortly following the acute phase of the infection may contribute to the risk of PASC. For example, Bussani and colleagues identified alveolar damage in the pulmonary parenchyma of patients with PASC. Additionally, some studies have suggested that persistent damage to the central nervous system could drive neurologic manifestations of PASC. ^,

Third, immune dysfunction may also contribute to PASC, with some data indicating the presence of autoantibody responses in individuals with PASC. Herman and colleagues identified a dysfunctional immune response in those with PASC, thought to be in part due to antibodies against prior common non-SARS-CoV-2 coronaviruses, indicating that prior exposure to other coronavirus strains may contribute to PASC risk. Ultimately, the development of PASC is likely multifactorial and the pathophysiology may differ between individuals, based on factors such as viral persistence, organ damage, or possibly preexisting autoimmunity or autoantibody development.

Researchers have also aimed to identify specific biomarkers associated with PASC. Though there is significant variability in the literature, several pro-inflammatory cytokines and vascular growth factors have been found to be elevated in those with PASC. Multiple studies have identified elevated levels of interleukin 6 and tumor necrosis factor-alpha in individuals with PASC. ^, Angiopoietin-1 (ANG-1), p-selectin, and other angiogenic factors have been found to be elevated in individuals with PASC. ^, One study in particular found that while ANG-1 was elevated in PASC, this biomarker was either unchanged or depressed in those with various autoimmune diseases, suggesting distinct processes driving these different conditions. It is unclear if different biologic medications used by patients with SARDs that affect circulating levels of cytokines may contribute to increased or decreased risk of PASC. As earlier, aside from CD20 inhibitors, no particular associations between other DMARDs and PASC have been consistently identified.

Furthermore, it is unclear whether, among individuals with PASC, differing levels of biomarkers and pro-inflammatory cytokines may contribute to differing presentations or manifestations. Ganesh and colleagues found that IL-6 was higher among PASC patients with a “central sensitization” phenotype, consisting of predominant symptoms including fatigue, myalgia, and orthostasis. Despite similarities in presentation with other conditions including fibromyalgia and myalgic encephalitis/chronic fatigue syndrome, it is not clear whether these conditions share similar biomarker profiles with PASC.

Clinical manifestations of post-acute sequelae of coronavirus disease 2019 in individuals with and without systemic autoimmune rheumatic diseases

PASC has the potential to involve almost any organ, with symptoms ranging from mild to severe. In the general population, the most common symptoms include dyspnea, ^{, , ,} fatigue, ^{, ,} myalgia, post-exertional malaise, brain fog, depression, and cough. The prevalence of each of these symptoms varies across studies; the prevalence of dyspnea varies from 53% in patients evaluated a median of 54 days after hospital discharge for COVID-19 infection to 8% in patients assessed 9 months following COVID-19 infection, suggesting that the prevalence may diminish overtime. Another study evaluating individuals 90 days following COVID-19 infection found a prevalence of 15% of those with “pulmonary PASC.” Studies have similarly found a decrease in prevalence of fatigue overtime, ranging from greater than 80% earlier on to 11%, months following COVID-19 infection. ^{, ,}

Similar to in the general population, dyspnea and fatigue are also among the most common manifestations of PASC in individuals with rheumatic diseases. ^{, ,} In fact, Dreyer and colleagues reported that individuals with PASC who use medication for an autoimmune disease were at 2 fold greater risk for dyspnea and fatigue than those who did not. Among a prospective cohort of various patients with SARDs, the majority of whom did not require hospitalization, 27% reported fatigue and 12% reported dyspnea at least 28 days following COVID-19 infection ( Fig. 1 ). Among a cohort of patients with rheumatic and musculoskeletal diseases who required hospitalization due to COVID-19 infection, 4 to 7 months after discharge, significantly higher proportions—approximately 36% and 26%—reported dyspnea and fatigue, respectively, consistent with the increased risk of persistent symptoms in those with greater severity of acute infection.

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