6

Overall Conclusions

This chapter presents nine conclusions derived by the committee from evidence presented throughout the report. This chapter does not include references. Citations to support the text and conclusions herein are provided in previous chapters of the report.

DIAGNOSIS OF LONG COVID

Long COVID is associated with a wide range of new or worsening health conditions and encompasses more than 200 symptoms involving nearly every organ system. There currently are no consensus-based diagnostic criteria for the condition; criteria for diagnosis are evolving as experience and research findings develop. Diagnosis of Long COVID is generally based on a known or presumed history of acute SARS-CoV-2 infection (as indicated by a positive viral test or patient self-report; as of this writing, no diagnostic test for Long COVID is available), the presence of Long COVID health effects and symptoms, and consideration of other conditions and etiologies that could be causing the symptoms.

Testing to diagnose acute SARS-CoV-2 infection, as well as testing capacity and behaviors, has changed dramatically over the course of the COVID-19 pandemic. Testing was constrained during the early phase of the pandemic, although it subsequently became increasingly available, and the introduction of at-home testing meant that many people may not have reported their positive results to health care systems. As a result of these two drivers, many individuals infected with SARS-CoV-2 never received formal

documentation of their diagnosis. Sole reliance on a documented history of SARS-CoV-2 infection when diagnosing Long COVID will miss these individuals. Therefore, the presence of signs and symptoms and self-reported prior infection are generally considered sufficient to establish a diagnosis of SARS-CoV-2 infection. Continued research on and discussion of Long COVID will help inform a case definition and standardized diagnosis.

Based on its review of the literature, the committee reached the following conclusion:

1. Long COVID is a complex chronic condition caused by SARS-CoV-2 infection that affects multiple body systems. Because of wide variability in testing practices over the course of the pandemic, many people experiencing Long COVID have not received a formal diagnosis of prior SARS-CoV-2 infection. A positive test for SARS-CoV-2 is not necessary to consider a diagnosis of Long COVID.

EPIDEMIOLOGY

Long COVID can impact people across the lifespan, from children to older adults, as well as across sex, gender, racial, ethnic, and other demographic groups. Women are twice as likely as men to experience Long COVID. Population surveys suggest that in 2022 the overall prevalence of Long COVID was around 3.4 percent in U.S. adults and 0.5 percent in children. Estimates of the prevalence of specific long-term health effects of SARS-CoV-2 vary in the literature. This variation reflects the dynamic nature of the pandemic itself, as the virus has evolved and spawned many variants and subvariants (likely with different propensities to cause Long COVID), as well as the introduction of vaccines and treatments for acute infection (e.g., antivirals, steroids), both of which have been shown to reduce the risk of long-term health effects. Variation in incidence and prevalence estimates also stem from the heterogeneity of study designs, including choice of control groups, methods used to account for the effect of baseline health, specification of outcomes, and other methodological differences.

In addition, the broad multisystem nature of Long COVID and the fact that the associated health effects are expressed differently by age group and sex and by baseline health compound the challenge of identifying and quantifying affected populations. Symptoms of SARS-CoV-2 infection range in severity from mild to severe, and the literature suggests that the severity of acute SARS-CoV-2 infection is a risk factor for Long COVID. For example, a large Scottish population-based study found that 5 percent of those with mild infection had not recovered at least 6 months following infection, compared with 16 percent of those who required hospitalization—a ratio of approximately 1:3.

Based on its review of the literature, the committee reached the following conclusion:

2. The risk of Long COVID increases with the severity of acute infection. By the committee’s best estimate, people whose infection was sufficiently severe to necessitate hospitalization are 2–3 times more likely to experience Long COVID than are those who were not hospitalized, and among those who were hospitalized, individuals requiring life support in the intensive care unit may be twice as likely to experience Long COVID. However, people with mild disease can also develop Long COVID, and given the much higher number of people with mild versus severe disease, they make up the great majority of people with Long COVID.

HEALTH EFFECTS

Long COVID is associated with hundreds of symptoms and new or worsening health effects that manifest in many different body systems. In keeping with the three domains of functioning in the International Classification of Functioning, Disability and Health model of disability, health effects experienced in Long COVID may manifest as impairments in body structures and physical and psychological functions, with resulting activity limitations and restrictions on participation. Evidence on clustering of the post-acute and long-term health effects of SARS-CoV-2 infection remains inconsistent across studies. Consensus is needed on terms, definitions, and methodological approaches for generating better-quality and more consistent evidence.

Based on its review of the literature, the committee reached the following conclusion:

3. Long COVID is associated with a wide range of new or worsening health conditions impacting multiple organ systems. Long COVID can cause more than 200 symptoms and affects each person differently. Attempts to cluster symptoms have yielded heterogeneous results.

FUNCTIONAL IMPACT AND RISK FACTORS

Some of the symptoms and health effects associated with Long COVID can be severe enough to interfere with an individual’s day-to-day functioning, including participation in work and school activities. Functional disability associated with Long COVID has been characterized as the inability to return to work, poor quality of life, diminished ability to perform activities of daily living, decreased physical and cognitive function, and overall disability.

The severity of acute COVID-19 is a major risk factor for poor functional outcomes, but even people with mild initial illness can experience long-term functional impairments. Increased number and severity of long-term symptoms correlate with decreased quality of life, physical functioning, and ability to work or perform in school. Other risk factors for poor functional outcomes include female sex, lack of vaccination against SARS-CoV-2, baseline disability or comorbidities, and smoking.

There is some overlap between SSA’s current Listing of Impairments (Listings) and health effects associated with Long COVID, such as impaired lung and heart function. However, it is likely that most individuals with Long COVID applying for Social Security disability benefits will do so based on health effects not covered in the Listings. Three frequently reported health effects that can significantly interfere with the ability to perform work or school activities and may not be captured in the SSA Listings are chronic fatigue and post-exertional malaise, post-COVID-19 cognitive impairment, and autonomic dysfunction, all of which can be difficult to assess clinically in terms of their severity and effects on a person’s functioning.

Based on its review of the literature, the committee reached the following conclusion:

4. Long COVID can result in the inability to return to work (or school for children and adolescents), poor quality of life, diminished ability to perform activities of daily living, and decreased physical and cognitive function for 6 months to 2 years or longer after the resolution of acute infection with SARS-CoV-2. Increased number and severity of long-term health effects correlates with decreased quality of life, physical and mental functioning, and ability to participate in work and school. Health effects that may not be captured in SSA’s Listing of Impairments yet may significantly affect an individual’s ability to participate in work or school include, but are not limited to, post-exertional malaise and chronic fatigue, post-COVID-19 cognitive impairment, and autonomic dysfunction.

LONG COVID IN CHILDREN AND ADOLESCENTS

While there are various definitions of children, adolescents, and young people, for the purposes of this report, “children” or “pediatrics” refers to the entire pediatric age range and “adolescents” to children at the older end of the spectrum (i.e., ages ~11 to 18 years). Even though most children experience mild acute COVID-19 illness, they can experience Long COVID regardless of the severity of their acute infection. As with adults, they may experience health effects across many body systems. Commonly reported symptoms include fatigue, weakness, headache, sleep disturbance, muscle

and joint pain, respiratory problems, palpitations, altered sense of smell or taste, dizziness, and dysautonomia. Although pediatric presentations and intervention options may overlap with those in adults—particularly among adolescents, who may be more likely than children to mimic the adult presentation and trajectory—pediatric management of Long COVID entails specific considerations related to developmental age and/or disabilities and history gathering. In general, children have fewer preexisting chronic health conditions compared with adults; thus, Long COVID may represent a substantial change from their baseline, particularly for those who were previously healthy.

Limited data are available on long-term outcomes in children. Some youth with persistent symptoms experience difficulties that affect their quality of life and result in increased school absences, as well as decreased participation and performance in school, sports, and other activities. Risk factors for the development of Long COVID include acute-phase hospitalization, preexisting comorbidity, and infection with pre-Omicron variants. Most children with Long COVID recover slowly over time, but not all. In one prospective cohort study of 1,243 children (ages 4–10) with Long COVID, for example, 48 percent remained symptomatic at 6 months, 13 percent at 12 months, and 5 percent at 18 months after infection. Importantly, severity of symptoms and functional impairment from Long COVID symptoms were not correlated with traditional clinical testing (e.g., lung ultrasound, standard systolic and diastolic function on echocardiogram).

It is important to note that in pediatrics, because of typical development, the baseline for performance of skills is constantly changing, especially among young children. This can make deviations in their performance during Long COVID challenging to assess, and there may be a delay in recognition of any deviations (e.g., lack of developing a skill at the appropriate age). Additionally, the duration of symptoms (e.g., 1 or 3 months) can feel very different to and have a greater impact on children compared with adults. Currently, there is a dearth of prospective and cross-sectional studies on the prevalence, risk factors, and time course and pattern of Long COVID in children. More research is needed to identify the long-term functional implications of Long COVID in children, because information from adult studies may not be directly applicable to the pediatric population.

Based on its review of the literature, the committee reached the following conclusion:

5. Although the large majority of children recover fully from SARS-CoV-2 infection, some develop Long COVID and experience persistent or intermittent symptoms that can reduce their quality of life and result in increased school absences as well as decreased participation and performance in school, sports, and other activities. Overall, the trajectory

1. for recovery is better among children compared with adults. More research is needed to understand the long-term functional implications of Long COVID in children, as information from adult studies may not be directly applicable.

DISEASE MANAGEMENT

Currently there are no Food and Drug Administration (FDA)–approved drugs or disease-modifying treatments for Long COVID. As with other complex multisystem conditions, management of Long COVID relies on techniques for controlling symptoms and improving functional ability, such as pacing (i.e., balancing periods of activity and rest in daily life), mobility support, social support, diet modulation, pharmacological treatment of secondary health effects, cognitive-behavioral therapy, and rehabilitation. Management often requires a multidisciplinary team. Because of the multisystem nature of the condition, different approaches may be needed to address the variety of clinical presentations and environmental factors (e.g., living situation, work requirements, family support) among individuals. Numerous randomized controlled trials are currently being undertaken to determine the efficacy of a number of identified pharmacological agents; however, limited data have been published, and trials are yet to be finalized.

Based on its review of the literature, the committee reached the following conclusion:

6. There currently is no curative treatment for Long COVID itself. Management of the condition is based on current knowledge about treating the associated health effects and other sequelae. As with other complex multisystem chronic conditions, treatment focuses on symptom management and optimization of function and quality of life.

DISEASE COURSE AND PROGNOSIS

Recovery from Long COVID varies among individuals, and data on recovery trajectories are rapidly evolving. Initial data suggest that people with persistent Long COVID symptoms generally improve over time, although preliminary studies suggest that recovery can plateau 6–12 months after acute infection. Studies have shown that only 18–22 percent of those who have persistent symptoms at 5–6 months following infection have fully recovered by 1 year. Among those who do not improve, most remain stable, but some worsen. More information on recovery trajectories at 1 year or longer may become available in the next few years. Rehabilitation and symptom management, including pacing, may improve function in some people with Long COVID, regardless of the severity of disease or duration

of symptoms, although the benefits are greater for those who are younger and who have had Long COVID for a shorter period of time.

Based on its review of the literature, the committee reached the following conclusion:

7. Recovery from Long COVID varies among individuals, and data on recovery trajectories are rapidly evolving. There is some evidence that many people with persistent Long COVID symptoms at 3 months following acute infection, including children and adolescents, have improved by 12 months. Data for durations longer than 12 months are limited, but preliminary data suggest that recovery may plateau or progress at a slower rate after 12 months.

HEALTH EQUITY

The burden of seeking care and finding adequate services for Long COVID is challenging and can impact the potential for recovery. Patients with Long COVID may encounter skepticism about their symptoms when they present in medical settings, which discourages care seeking. This is particularly true for individuals disadvantaged by their social or economic status, geographic location, or environment, and can result in preventable disparities in the burden of disease and opportunities to achieve optimal health. Disadvantaged groups include members of some racial and ethnic minorities, people with disabilities, women, LGBTQI1 (lesbian, gay, bisexual, transgender, queer, intersex, or other) individuals, people with limited English proficiency, and others.

Individuals with Long COVID have increased health care utilization and financial burden, which may be exacerbated if they are unable to work to gain income and or receive health insurance coverage. Members of disadvantaged groups, especially early in the pandemic, were more likely to contract SARS-CoV-2, more likely to be hospitalized with acute COVID-19, more likely to have adverse clinical outcomes, and less likely to be vaccinated, potentially increasing their risk of developing Long COVID. In addition, these groups are more likely to be uninsured or underinsured. Even for those with insurance coverage, some of the services that have been shown to improve function may not be covered by their benefits. Moreover, the availability of specialized Long COVID services is limited, and capacity does not match the demand for rehabilitation specialists. Limited transportation, distance from clinics, and the inability to take time away from work or school are known barriers to care. The availability issue is particularly problematic for individuals living in medically underserved areas.

Information about COVID is rapidly evolving, and this dynamic nature of the science may contribute to some patient hesitancy regarding

prophylactic and therapeutic management for acute infection or Long COVID. Low levels of health literacy may also place some individuals at increased risk for misinformation, which may prevent them from fully taking advantage of health care resources to protect and improve their health. Low health literacy may also impact individual self-management of the symptoms and conditions associated with Long COVID.

Based on its review of the literature, the committee reached the following conclusion:

8. Social determinants of health, such as socioeconomic status, geographic location, health literacy, and race and ethnicity, affect access to health care. With respect to acute SARS-CoV-2 infection and Long COVID, adverse social determinants of health have contributed to disparities in access to SARS-CoV-2 testing; vaccination; and therapeutics, including treatments for acute infection and specialized rehabilitation clinics for Long COVID. In addition, the demand for specialty care exceeds capacity, resulting in waitlists for the receipt of services.

SIMILAR CHRONIC CONDITIONS

Long COVID shares many features with other complex multisystem conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, and postural orthostatic tachycardia syndrome (POTS). The mechanism of action for infection-associated chronic illnesses remains unclear, and further investigation is needed. Current theories regarding potential mechanisms of action include viral persistence, immune dysregulation (including cytokine dysregulation or mast cell activation), neurological disturbances (e.g., neuroinflammation), cardiovascular damage (e.g., endothelial dysfunction, coagulation issues, orthostatic intolerance), gastrointestinal dysfunction (e.g., secondary to gut microbiome dysbiosis), metabolic issues (energy insufficiency, reactive oxygen species production, mitochrondrial dysfunction), and genetic variations.

Currently, there are no specific laboratory-based diagnostic tests for Long COVID or ME/CFS, and diagnosis involves consideration of other potential causes of the symptoms. In general, Long COVID (especially that which does not meet criteria for ME/CFS) has a better prognosis than ME/CFS. Some manifestations of Long COVID are similar to those of ME/CFS, and like ME/CFS, Long COVID appears to be a chronic illness, with few patients achieving full remission. Studies comparing Long COVID and ME/CFS have several limitations, however. Because Long COVID is a new disease, study participants are usually newly diagnosed, while ME/CFS study participants often have had the condition for longer and so are less likely to improve. Moreover, the definition of ME/CFS requires that symptoms

be ongoing for 6 months or more, whereas the duration criteria for Long COVID vary in the literature from 2 to 6 months, making the two conditions difficult to compare.

Based on its review of the literature, the committee reached the following conclusion:

9. Complex, infection-associated chronic conditions affecting multiple body systems are not new, and Long COVID shares many features with such conditions as myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, and postural orthostatic tachycardia syndrome. Current theories about the pathophysiology of these conditions include immune dysregulation, neurological disturbances, cardiovascular damage, gastrointestinal dysfunction, metabolic issues, and mitochondrial dysfunction. More research is needed to understand the natural history and management of complex multisystem chronic conditions, including Long COVID.

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