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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Suggested Citation:"4 Global Functioning in Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

4 Global Functioning in Long COVID For many individuals, the effects of SARS-CoV-2 infection persist well beyond the acute phase and can result in considerable disability. A 2-year prospective cohort study of 548 individuals meeting the World Health Organization’s definition of Post–COVID-19 Condition found that at the end of the 23-month follow-up period, only 7.6 percent of the subjects (38 percent hospitalized) had recovered (Mateu et al., 2023). The U.S. Household Pulse Survey revealed that 26.4 percent of adults with Long COVID experienced substantial activity limitations (Ford et al., 2023). Similarly, the Public Health Agency of Canada reported that 21.3 percent of adults with the condition “often” or “always” experienced substantial activity limitations (Public Health Agency of Canada, 2023), and the UK Office for National Statistics reported that 20 percent indicated their daily activity performance had been “limited a lot” (Rea et al., 2023). Addition- ally, a study of U.S. veterans (older, male population) followed for 2 years found that Long COVID contributed 80.4 disability-adjusted life years (DALYs) per 1,000 persons, compared with 50 and 52 DALYs for cancer and heart disease, respectively (Bowe et al., 2023). This chapter provides an overview of the literature on patterns and trends of work- or school-related functional changes associated with Long COVID in adults and children. The chapter addresses global functioning, meaning an individual’s overall ability to function, in people with Long COVID. The committee reviewed prospective cohort studies that followed Long COVID patients and assessed their functioning for 6 months or more. 149 PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 149 5/22/24 11:11 PM

150 LONG-TERM HEALTH EFFECTS OF COVID-19 For less well-studied topics, cohorts followed for a shorter duration and cross-sectional studies were also reviewed (the committee did not conduct a systematic review; see Appendix A for the literature search strategy). Functional disability post–COVID-19 has been characterized as inability to return to work, poor quality of life, diminished ability to perform activi- ties of daily living (ADLs), decreased physical and cognitive function, and overall disability (Ahmad et al., 2023; J. Becker et al., 2021; Frontera et al., 2022, 2021; Ghossein-Doha et al., 2022; Hartung et al., 2022; Rass et al., 2022). The committee notes that outcomes differ for people hospitalized for COVID-19 and those with milder cases; those with more severe initial infection who were admitted to the intensive care unit (ICU) may have dif- ferent outcomes still. Thus, this chapter groups studies by nonhospitalized, hospitalized, and ICU patients. The committee notes that it recognizes the need to separate the effects of hospitalization or critical illness from effects unique to COVID-19, as their recovery trajectories and pathophysiologies may differ. The chapter also provides a table of selected assessment mea- sures used to quantify the impact of Long COVID, sections on unique con- siderations for children and other special populations with Long COVID, and a summary of how rehabilitation can affect functioning in individuals with the condition. LONG-TERM FUNCTIONAL OUTCOMES IN PATIENTS NOT HOSPITALIZED FOR COVID-19 Although severe initial infection with SARS-CoV-2 is one of the stron- gest predictors of poor long-term functional outcomes, individuals with mild initial illness make up the great majority of the population with long-term functional impairments, simply because of their greater num- bers relative to those with severe infection (Ahmad et al., 2023; Banic et al., 2022; Hodgson et al., 2021). A large Scottish population-based study, for example, found that 5 percent of those with mild COVID-19 had not recovered at least 6 months following infection, compared with 16 percent of those who required hospitalization—a ratio of approximately 1:3 (Hastie et al., 2022). Other studies have found a similar degree of increased risk among those hospitalized for COVID-19 (Jassat et al., 2023). However, the proportion of people not hospitalized for acute SARS-CoV-2 infection compared with those hospitalized is approximately 95–98:1, dwarfing the increased risk of Long COVID conveyed by hospitalization (Angulo et al., 2021; Mahajan et al., 2021; Menachemi et al., 2021). Thus, consideration of functional impairment from Long COVID must include those with mild initial illness. Symptom burden is closely associated with functional impairment, with numerous studies demonstrating a correlation between an increased number PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 150 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 151 and severity of long-term symptoms and decreased quality of life, physical functioning, and ability to work (Bahmer et al., 2022; Cazé et al., 2023; Chatys-Bogacka et al., 2022; Dennis et al., 2021, 2023; Graham et al., 2021; Gutiérrez-Canales et al., 2022; Han et al., 2022; Hastie et al., 2022; Hossain et al., 2021; Kenny et al., 2022; O’Kelly et al., 2022; Perlis et al., 2023; Seeßle et al., 2022). People not hospitalized for COVID-19 are less likely to experience severe organ dysfunction (e.g., kidney failure requir- ing dialysis, disabling stroke, or measurable reduction in lung function) compared with those initially hospitalized. In one study of 337 patients, for example, 20 percent of individuals initially hospitalized had reduced diffusing capacity of the lungs for carbon monoxide (DLCO) after 3–6 months compared with only 4 percent of those not requiring hospitalization (Björsell et al., 2023). Instead, the population with mild initial illness more typically experiences long-term symptoms such as fatigue, sleep distur- bance, brain fog, headaches, and muscle pains. Breathlessness is common, often despite the lack of measurable abnormalities in lung function (Bahmer et al., 2022; Björsell et al., 2023; Dennis et al., 2021; Graham et al., 2021; Gutiérrez-Canales et al., 2022; Hossain et al., 2021; Y. Kim et al., 2022; Perez Giraldo et al., 2023; Seeßle et al., 2022). Long-term loss of smell or taste is particularly disproportionate in the population with mild infection compared with those hospitalized (Graham et al., 2021; Hossain et al., 2021; Perez Giraldo et al., 2023). While some- times dismissed as a minor impairment, loss of smell or taste can have important functional consequences and decrease quality of life. In a study of 322 people with COVID-19–related olfactory loss, 96 percent reported at least one quality-of-life impact, including reduced enjoyment of food (87 percent) and reduced enjoyment of life (56 percent) (Coelho et al., 2021). More than 57 percent reported at least one safety-related event, such as inability to smell smoke (45 percent), burning food (28 percent), ingesting spoiled food (15 percent), and being unable to detect a gas leak (7 percent). Moreover, loss of olfactory function may correlate with other neurological abnormalities (Coelho et al., 2021). A study of 23 patients with persistent olfactory dysfunction found that the degree of that sensory loss was corre- lated with impaired visuospatial memory and executive function (Muccioli et al., 2023). Risk Factors Risk factors for long-term symptoms in the nonhospitalized population are similar to those for the hospitalized population. They include female sex, lack of vaccination against SARS-CoV-2, baseline disability or comor- bidities, and smoking (Ayoubkhani et al., 2022; Björsell et al., 2023; Dennis et al., 2023; Gutiérrez-Canales et al., 2022; Jassat et al., 2023; Y. Kim et al., PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 151 5/22/24 11:11 PM

152 LONG-TERM HEALTH EFFECTS OF COVID-19 2022; Mateu et al., 2023; Mohamed Hussein et al., 2021; Tanguay et al., 2023). People with elevated heart rate at 3 months are more likely still to have symptoms at 1 year (O’Kelly et al., 2022). Some work suggests that people suffering specific symptoms in the acute phase are more likely to suffer those symptoms long term (Golla et al., 2023; Tanguay et al., 2023; Thronicke et al., 2022). In contrast with hospitalized patients, however, older age is less consistently a risk factor for Long COVID symptoms in the nonhospitalized population. Some studies have found higher rates of Long COVID in older nonhospitalized patients compared with younger patients (Y. Kim et al., 2022). However, a study of 2,198 people in Bangladesh found that Long COVID was associated with younger age, while two stud- ies collectively involving 427 people in the United Kingdom and Germany, mostly with mild disease, found that cognitive dysfunction and dyspnea were more common in younger than in older patients (Dennis et al., 2023; Hossain et al., 2021; Seeßlle et al., 2022). Other studies similarly have found dyspnea to be more common in people <60 years of age compared with those that are older (Björsell et al., 2023). Finally, a study of 1,173 nonhospitalized patients in Canada found that age was not a significant predictor of the development of Long COVID, whereas older age was a predictor among hospitalized patients (Tanguay et al., 2023). Additionally, environmental exposures including certain air pollutants and toxicants have been found to be associated with increased risk of Long COVID, though data vary regionally (Zhang et al., 2023). Recovery Trajectories Many nonhospitalized people with persistent symptoms following acute SARS-CoV-2 infection improve over time. In one study of 331 people with per- sistent symptoms at about 6 months following infection, symptom prevalence was found to be reduced at 1 year: fatigue decreased from 98 to 64 percent, myalgia from 89 to 35 percent, shortness of breath from 90 to 47 percent, headache from 85 to 34 percent, chest pain from 81 to 38 percent, fever from 73 to 2 percent, cough from 75 to 11 percent, and sore throat from 71 to 11 percent (Dennis et al., 2023). However, only 18 percent had fully recovered by 1 year (Dennis et al., 2023). Similarly, a study of 96 people with symptoms at 5 months found that only 22 percent had fully recovered by 1 year (Seeßle et al., 2022). Another study found that approximately one-quarter of those who initially lost the sense of smell or taste had not regained those functions by 1 year (Fortunato et al., 2022), and in another study, objective measures of lung function were found to improve only slightly between 3 months and 1 year after mild infection (Lenoir et al., 2023). In the NIH RECOVER study, approximately two-thirds of 409 adults who met criteria for persistent symp- toms at 6 months still met those criteria at 9 months (Thaweethai et al., 2023). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 152 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 153 Among those who do not improve, most remain stable, but some worsen. In one study, for example, 13 percent of Long COVID patients who had mild initial disease experienced worsening quality of life scores between 3 and 12 months following infection (Tanguay et al., 2023). A survey of 4,510 U.S. adults found that Long COVID patients with disabilities were not significantly more likely to experience long-term symptoms compared with respondents without disabilities (adjusted odds ratio [aOR]=1.65 [0.78–3.50]) (Miller et al., 2023). Seeking health care for reported symp- toms was higher among respondents with disabilities (40 percent) than among those without disabilities (18%) (Miller et al., 2023). LONG-TERM FUNCTIONAL OUTCOMES IN PATIENTS HOSPITALIZED FOR COVID-19 Functional disability is highly prevalent in individuals surviving hos- pitalization for COVID-19. In the majority of the studies summarized here, hospitalization for COVID-19 is defined as a hospital stay with a symptomatic PCR-confirmed COVID-19 test. A few studies define it as discharge from the hospital with a diagnosis of confirmed or suspected COVID-19. One prospective longitudinal study of adults hospitalized for COVID-19 in 44 hospitals across the United States found that approxi- mately 75 percent of survivors experienced cardiopulmonary, financial, and functional problems 6 months after hospitalization (Admon et al., 2023). Other cohort studies have similarly suggested that approximately 50–87 percent of patients hospitalized for COVID-19 may continue to experience functional disability through 6- to 12-month follow-up periods (D’Ettorre et al., 2022; S. Kim et al., 2022; McAuley et al., 2023; Menges et al., 2021; Rass et al., 2022; Sahanic et al., 2023; Schlemmer et al., 2023; Shirakawa et al., 2023; Sonnweber et al., 2022; Steinbeis et al., 2022; Taboada et al., 2022; Valdes et al., 2022; Weber et al., 2022). Emerging evidence indicates that once established, symptoms can persist even longer than 1 year. In a prospective study, 54 percent of 1,359 hospital- ized patients in China still had at least one symptom at 3 years postinfec- tion, and 13 percent of those who were employed prior to infection were still unable to work after 3 years (Zhang et al., 2024). The high symptom burden of Long COVID is particularly contributory (Kersten et al., 2022). One study found that 44 percent of patients hospitalized for COVID-19 reported three or more persistent symptoms at 6 months follow-up, and that disability was widespread across all areas of functioning in these patients (Hodgson et al., 2021). This finding is echoed across studies, encompass- ing significant decreases in health-related quality of life, significant physi- cal limitations, impairing fatigue, difficulties performing ADLs, changes in occupation, and cognitive impairment (C. Becker et al., 2021; J. Becker PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 153 5/22/24 11:11 PM

154 LONG-TERM HEALTH EFFECTS OF COVID-19 et al., 2021; Bellan et al., 2022; Daher et al., 2020; Damanti et al., 2022; Evans et al., 2021; Miskowiak et al., 2023; Stavem et al., 2022). Risk Factors COVID-19 severity is among the greatest risk factors for poor functional outcomes following recovery from acute infection (Ahmad et al., 2023; Banic et al., 2022; Hodgson et al., 2021). Studies have shown that patients hospitalized for COVID-19 are more likely to have more severe symptoms and worse functional outcomes on average compared with those who were not hospitalized (Björsell et al., 2023; Jassat et al., 2023; Krysa et al., 2023; Niedziela et al., 2022; Xie et al., 2022; Xu et al., 2022). In a cross-sectional study conducted in Alberta, Canada, that included 330 respondents, Krysa and colleagues (2023) found that twice as many previously hospitalized than nonhospitalized patients reported Long COVID symptoms (49 per- cent vs. 26 percent), and about four times as many hospitalized patients were unable to return to work (19 percent vs. 5 percent). In addition, in a U. S. Department of Veterans Affairs (VA) cohort of more than 150,000 individuals, Xie and colleagues (2022) and Xu and colleagues (2022) found that, compared with those who were not hospitalized, those who were hospitalized experienced approximately twice as great an excess burden of neurological outcomes and more than four times greater excess burden of cardiovascular outcomes at 12 months. While severity of acute COVID-19 has been found consistently to be a strong risk factor for Long COVID and associated sequelae, individu- als who experience mild SARS-CoV-2 infection can still develop Long COVID. Baseline demographic factors, including female gender, older age, obesity, and baseline disability, have also been identified as risk factors for functional disability (Asadi-Pooya et al., 2021; Damanti et al., 2022; Fernández-De-Las-Peñas et al., 2022). Additionally, neurological compli- cations, psychological morbidity (e.g., depression, anxiety, posttraumatic stress disorder), and psychosocial stressors (e.g., financial insecurity, food insecurity, death of close contact, new disability) have been found to confer risk for poor functional outcomes (Claflin et al., 2021; Frontera et al., 2021, 2022; McAuley et al., 2023; Sahanic et al., 2023; Sonnweber et al., 2022). Recovery Trajectories With respect to recovery trajectories, only a few studies have exam- ined the functional disability burden of Long COVID longitudinally. Such studies have found that approximately half of patients hospitalized for severe COVID-19 may recover, whereas others may remain with persistent PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 154 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 155 functional impairment at 12 months and beyond (Huang et al., 2021). One study found that among those reporting difficulty managing occupational or school responsibilities at 4 months, half continued to report difficulty at 2 years follow-up (Wahlgren et al., 2023). Another study found that approximately 47 percent of participants (n = 825) had at least one new impairment in ADLs or instrumental ADLs (IADLs) at 6 months follow- ing acute infection—a decrease from the reported 55 percent of patients reporting such impairments at 1 month (Admon et al., 2023). Approxi- mately 26 percent of participants reported three or more new ADL or IADL impairments at 6 months (Admon et al., 2023). Overall, these findings suggest that functional recovery is limited for patients hospitalized for COVID-19 (Admon et al., 2023; Wahlgren et al., 2023). Among those who do not recover by 6 months following acute infec- tion, recovery appears to plateau between 6 and 12 months (Fernandez- de-Las-Penas et al., 2023; Sahanic et al., 2023; Schlemmer et al., 2023; Steinbeis et al., 2022; Zhang et al., 2024). In the above-referenced study of 1,359 patients from China, the proportion with any post-COVID symptom at 3 years (54 percent) was nearly identical to that at 2 years (55 percent) (Zhang et al., 2024). Factors associated with not recovering included female sex, middle/older ages, two or more comorbidities, and more severe ini- tial infection (Ahmad et al., 2023; Banic et al., 2022; Evans et al., 2021; Hodgson et al., 2021; Qin et al., 2023; Sahanic et al., 2023). Given the relatively brief time since the onset of the pandemic, the long-term trajectories for recovery remain unclear. Extrapolating from other research areas and critical illnesses (e.g., post-intensive care syndrome [PICS]; acute respiratory distress syndrome), the likelihood of long-term functional recovery may be limited in a subset of individuals. Studies of PICS and acute respiratory distress syndrome have found that many affected individuals experience persistent functional disability up to 5 years later (Herridge et al., 2011; Hodgson et al., 2021). Research is needed to answer question about variations in functional status or long-term effects in people hospitalized for COVID-19 based on different viral variants and vaccination status. However, studies have shown that even for the milder Omicron variant, rates of COVID-19 hospitalization have remained high, and vaccination and patient immune status have been the greatest predic- tors of poor health outcomes (Nevejan et al., 2022). LONG-TERM FUNCTIONAL OUTCOMES IN PATIENTS RECEIVING INTENSIVE CARE FOR COVID-19 PICS, a term used to describe new or worsening health impairments across physical, mental, cognitive, or social domains of health in survivors of critical illnesses that required hospitalization in an ICU, is a useful rubric PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 155 5/22/24 11:11 PM

156 LONG-TERM HEALTH EFFECTS OF COVID-19 for understanding the long-term functional outcomes in individuals with COVID-19 who were treated in ICUs (Needham et al., 2012). However, most of the studies examining long-term outcomes in COVID-19 survivors treated in the ICU are small case series or single-center inception cohort studies (Erber et al., 2021; Fischer et al., 2022; Gonzalez et al., 2022; Núñez-Seisdedos et al., 2022; Sassi et al., 2022). Since most people who survive the discharge from the ICU spend a significant time after discharge in hospital wards, disentangling post-ICU from posthospital effects is chal- lenging (Admon et al., 2023a; Iwashyna et al., 2021). Other methodological challenges to interpreting the literature on long-term outcomes after ICU treatment for COVID-19 include (1) a high degree of patient heterogene- ity in many of the studies; (2) the absence of pre-ICU functional status in most studies; (3) variation in mortality in the months following hospital discharge, which can impact the estimates of impairments, particularly when the follow-up time is long; and (4) loss to follow-up (whether due to severe symptoms or impairments or to functional recovery), which can contribute to the study population’s not being representative of the popula- tion of interest (Murphy et al., 2018). Compared with COVID-19 survivors who were hospitalized but not treated in the ICU, COVID-19 ICU survivors have been shown to have higher rates of cardiovascular outcomes (Xie et al., 2022), neuromuscular weakness (Núñez-Seisdedos et al., 2022), abnormalities in pulmonary func- tion (Erber et al., 2021; Schlemmer et al., 2023), mood disorders (Portacci et al., 2022), posttraumatic stress symptoms (Neville et al., 2022), and dysphagia (Sassi et al., 2022). In the above-cited VA cohort of more than 150,000 individuals with COVID-19, approximately twice as many ICU patients experienced cardiovascular outcomes compared with patients hos- pitalized but not admitted to the ICU (Xie et al., 2022). In a small cohort of 70 adult survivors, ICU-acquired neuromuscular weakness and gait dependence at hospital discharge were present in 31 percent and 54 percent, respectively (Núñez-Seisdedos et al., 2022). In a Spanish cohort of 97 adults treated for COVID-19 in the ICU, Gonzalez and colleagues found that about 60 percent of survivors reported either cognitive concerns, severe dyspnea, or fatigue at 12 months after hospital discharge, and that a high proportion of these survivors were also diagnosed with new medical con- ditions during the follow-up period (Gonzalez et al., 2022). In a French cohort of 41 adult COVID-19 ICU survivors who underwent a neurological consultation 4 months following ICU discharge, ICU-acquired weakness was present in 16 percent, depression or anxiety in 26 percent, and post- traumatic stress symptoms in 7 percent (Jaquet et al., 2022). In a Dutch cohort of 96 adult survivors of severe COVID-19, 30 percent met criteria for objective cognitive impairment 6 months after ICU discharge based on abnormalities in two or more neuropsychological tests, and 20 percent PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 156 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 157 reported subjective cognitive concerns; there was no strong correlation between the subjective concerns and the objective cognitive impairment (Duindam et al., 2022). In a U.S. cohort of 132 ICU COVID-19 survivors from two academic institutions who were assessed at 6 months after hos- pital discharge, levels of anxiety, depression, fatigue, sleep disturbance, social activity participation, pain interference, and cognitive function were not significantly different from those found in the general U.S. population, but physical function was worse among the ICU survivors than in the average U.S. adult population (Neville et al., 2022). This study found that about 24 percent of the COVID-19 ICU survivors reported very low health status, as reflected by a health utility score ≤0.2 (Neville et al., 2022). In a large sample of more than 2,590 critically ill adult COVID-19 survivors who were eligible for follow-up at 180 days after hospital discharge, 1 in 3 reported at least moderate disability that persisted at 6 months after hospital discharge, and 37.9 percent reported moderate, severe, or complete disability (Higgins et al., 2023). Risk Factors Few risk factors have been elucidated by the studies examining health impairments in ICU-hospitalized COVID-19 survivors. Demographic fac- tors such as older age and more comorbidities have been associated with a higher risk of neuromuscular weakness (Núñez-Seisdedos et al., 2022). Older age, the need for invasive mechanical ventilation, and/or longer stays in the hospital or ICU are factors associated with lower quality life or a higher risk of disability in the months after hospital discharge (Jaquet et al., 2022). Rapid resolution of both lung injury and multiorgan dysfunc- tion have been found to be associated with better functional status 1 year after hospital discharge. Individuals who had low health status at 6 months after discharge were more likely to require supplemental oxygen, to have been rehospitalized, and to need informal caregivers (Neville et al., 2022). Risk factors for persistent postintubation dysphagia at hospital discharge include older age, greater severity of illness upon ICU admission, presence of neurological comorbidities, type 2 diabetes mellitus, and severe swallow- ing impairment shortly after extubation (Sassi et al., 2022). In one study, women were more likely than men to report subjective cognitive concerns, and type 2 diabetes was associated with objective cognitive impairment (Duindam et al., 2022). Recovery Trajectories Few studies have examined recovery trajectories in COVID-19 sur- vivors beyond 1 year after ICU treatment. Information on the long-term PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 157 5/22/24 11:11 PM

158 LONG-TERM HEALTH EFFECTS OF COVID-19 outcomes in populations with acute respiratory distress syndrome from before COVID-19 indicates that physical, mental, and cognitive impair- ments improve steadily during the first year following hospital discharge but can persist for up to 5 years. Recent data from a cohort of 428 critically ill COVID-19 survivors through 1 year suggest that many of the health impairments peak in prevalence around 3 months after hospital discharge but persist in a minority of patients even at 1 year after discharge (Taniguchi et al., 2023). In a Danish cohort of about 200 ICU survivors, the prevalence of cognitive impairment decreased from 26 percent at 6 months after ICU admission to 17 percent at 12 months after admission. The prevalence of frailty and fatigue was similar at both time points (Weihe et al., 2022). LONG-TERM FUNCTIONAL OUTCOMES IN CHILDREN AND ADOLESCENTS WITH COVID-19 Limited data are available on long-term outcomes in children and adolescents with Long COVID. Even though most children and adolescents experience a mild acute COVID-19 illness, Long COVID can occur in chil- dren with or without hospitalization (Fink et al., 2021; Jamaica Balderas et al., 2023; see Chapter 3). Some youth with persistent symptoms experi- ence difficulties that affect their quality of life (Fink et al., 2021) and result in more school absences (Kikkenborg Berg et al., 2022). Risk factors for the development of Long COVID include acute-phase hospitalization, pre- existing comorbidity, re-infection, and infection with pre-Omicron variants (Morello et al., 2023; Osmanov et al., 2022; Pazukhina et al., 2022; Pinto Pereira et al., 2023). Common symptoms of Long COVID in children and adolescents include tiredness, sleep difficulties, shortness of breath, and headaches (Pinto Pereira et al., 2023). One study in a pediatric Long COVID clinic found that 60 percent of children with a mean age of 12 years reported functional impairment, which was assessed by self-report anywhere between 1 and 7 months after SARS-CoV-2 infection (Ashkenazi-Hoffnung et al., 2021). In this study, only 12 percent of the children were hospitalized during the acute phase of illness (Ashkenazi-Hoffnung et al., 2021). A more recent cohort study inves- tigated symptom trajectory at 3, 6, 12, and 18 months after SARS-CoV-2 infection (Morello et al., 2023). In this study, 23 percent of children with a median age of 7.5 years met the definition of Long COVID, defined as symptoms persisting for at least 3 months after initial infection, symptoms having a negative impact on daily life, and other possible diagnoses being excluded (Morello et al., 2023). Of those with Long COVID, 48 percent remained symptomatic at 6 months, 13 percent at 12 months, and 5 percent (1 in 20) at 18 months after infection (Morello et al., 2023). A study con- ducted in the UK that included 20,202 11-to-17-year-olds found that at the PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 158 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 159 12-month follow-up, 24 percent of those who were reinfected compared to 10 percent of those who had no later infection experienced 5-plus symp- toms (Pinto Pereira et al., 2023). A Canadian cohort study at 14 pediatric emergency departments studied long-term effects of COVID-19 in younger children (ages 0.9 to 5.0 years, median age 2.0 years). They found that in this population of young children, out of over 5,000 participants, only 10 children at the 6-month follow-up and 8 children at the 12-month follow- up had Long COVID-related symptoms (Dun-Dery et al., 2023). 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 echocar- diogram) (Ashkenazi-Hoffnung et al., 2021; Grager et al., 2023; Sabatino et al., 2022). However, one study found persistent subclinical changes in systolic cardiac impairment approximately 5 months after acute SARS- CoV-2 infection that was worse in children who were infected in the second wave versus the first wave of infections (Sabatino et al., 2022). This subtle impairment in myocardial function (with findings still within the “normal” range) was worse in children who recovered during the second compared with the first wave (i.e., those who had the alpha variant rather than the original strain), although functional impact and cardiopulmonary symp- toms were not assessed in this cohort (Sabatino et al., 2022). At this time, 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 and adolescents. It is also important to note that in pediatrics, because of typical development, the baseline for comparison is constantly changing. Additionally, the duration of symptoms (e.g., 1 or 3 months) can feel very different to and have a greater impact on children and adolescents compared with adults. Overall, more research is needed to identify the long- term functional implications of Long COVID in pediatric populations, to whom information from adult studies may not be directly applicable. LONG-TERM FUNCTIONAL OUTCOMES IN OTHER SELECTED POPULATIONS WITH COVID-19 Functional impacts from Long COVID vary among individuals, and there is no standardized approach for evaluation and treatment. Some populations that may disproportionally experience greater severity and prevalence of COVID-19 and of long-term symptoms after infection include but are not limited to racial and ethnic minorities, women (pregnant and nonpregnant), and individuals with disabilities (CDC, 2022). These differ- ences in severity and prevalence could be due to a wide range of social or biopsychological factors, such as poor access to health care, repeat infec- tions from workplaces, and higher rates of comorbidities (Jolley et al., PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 159 5/22/24 11:11 PM

160 LONG-TERM HEALTH EFFECTS OF COVID-19 2022; Mora et al., 2023). Although racial and ethnic minority populations experience greater severity of disease and complications from COVID-19, more data are needed on how race/ethnicity and other social factors impact the risk of long-term functional impairment after infection (Jolley et al., 2022; Khullar et al., 2023). Importantly, the same marginalized popula- tions that are disproportionally impacted by higher rates of infection and severity of illness from COVID-19—racial and ethnic minorities, women, children, and individuals with disabilities—have also been shown to be at risk for less access to rehabilitation care (N. Katz et al., 2023). The combi- nation of increased risk for and/or severity of COVID-19 and poor access to rehabilitation care may well translate into inequities in the severity and duration of Long COVID. Data gathered by the Centers for Disease Control and Prevention (CDC) using household survey methods suggest that LGBTQIA persons may have higher rates of Long COVID, and may have distinct health issues in addition to experiencing challenges in accessing care during the pandemic (Jarrett et al., 2021; NCHS, 2023), Pregnant women can have more severe COVID- 19 and may experience fatigue related to both pregnancy and Long COVID (Lassi et al., 2021). Considerations required for this at-risk population include diagnostic testing without radiation exposure; exercise prescriptions that may be limited by large girth, back pain, or preeclampsia; and return to work with appropriate accommodations. Individuals with versus those without disabilities have a higher fatality rate from COVID-19, a finding suggesting that impaired cognitive and physical function may be associated with COVID-19 mortality (Katz et al., 2023). Even before the COVID-19 pandemic, persons with disabilities already had reduced access to health care, resources, and social services (Lebrasseur et al., 2021). Stereotypes and biases toward these individuals can further lead to their disparate treatment (Fuentes et al., 2021). When appropriate, clinicians need to advocate for persons with disabilities to obtain appropriate therapy, accommodations (per the Americans with Disabilities Act and the Rehabilitations Act), home health aides, and/or medical equipment. Additionally, one study among farmworkers in California showed that a significant proportion experienced Long COVID and associated persistent symptoms, limiting their ability to continue working (Mora et al., 2023). Finally, though not a population of interest to SSA, it is worth mentioning that nursing home residents tend to experience modest declines in cognition after COVID-19 infection and may need more help with activities of daily living than their peers who were not infected. One study of nursing home residents aged 80 years or older found that most residents experienced improved functional status and cognition within one year after their illness (Harris, 2024). Overall, research is limited on functional impacts and impairments from Long COVID affecting specific populations. A comprehensive approach to PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 160 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 161 addressing the varying and unique needs of these populations is critical for the achievement of health equity. EFFECTS OF REHABILITATION ON FUNCTIONAL TRAJECTORIES IN INDIVIDUALS WITH LONG COVID Rehabilitation can be helpful in improving functional outcomes, as has been demonstrated in a variety of health conditions. In the rehabilitation literature, measuring function involves a variety of components, including cardiovascular and pulmonary fitness, muscle strength, coordination, cog- nitive function, and quality of life. The specific benefits of rehabilitation in individuals with Long COVID may vary depending on the individual’s symptoms and severity of disease, but small studies consistently show improvements in physical function, fatigue, dyspnea, and quality of life (Calvo-Paniagua et al., 2022; de la Plaza San Frutos et al., 2023; Gloeckl et al., 2021; Nopp et al., 2022; Ostrowska et al., 2023; Parker et al., 2023; Spielmanns et al., 2023). A recent systematic review and meta-analysis by Pouliopoulou and colleagues (2023) analyzed 14 randomized clinical trials involving 1,244 patients with Long COVID. The authors found improvements in functional exercise capacity, yet there was significant uncertainty regarding the prob- ability of experiencing exercise-induced adverse events during rehabilita- tion. Additionally, studies have shown that the benefits of rehabilitation for people with Long COVID are greater for those who are younger and who have had Long COVID for a shorter period of time (Nopp et al., 2022; Ostrowska et al., 2023). However, people who have had Long COVID for a longer period of time may still benefit from an individualized, targeted rehabilitation program that monitors for any post-exertional symptom exacerbation. It is important to note that these studies are relatively small, and more research is needed to confirm their findings. Given the multidisci- plinary nature of human function, the variables measured in studies of reha- bilitation of persons with Long COVID may not provide a comprehensive understanding of their true functional capacity. Furthermore, the variables used to look at function in these studies need to be interpreted cautiously and alongside other variables that capture the multidisciplinary nature of functional capacity and quality of life. At the beginning of the pandemic, health care systems recognized the urgent need for specialized rehabilitation programs to aid individuals in their recovery from COVID-19. Several types of rehabilitation programs have been used for recovering individuals (Table 4-1). The early reliance on evidence from post–intensive care syndrome rehabilitation was a prag- matic approach, given the similarities in the clinical trajectories of severe COVID-19 cases and patients with other critical illnesses. These established PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 161 5/22/24 11:11 PM

162 LONG-TERM HEALTH EFFECTS OF COVID-19 TABLE 4-1  Types of Rehabilitation Programs Used in Long COVID Recovery Type of therapy Description Physical Therapy Addresses physical symptoms and uses personalized exercise programs Occupational Therapy Addresses challenges in activities of daily living and can develop strategies and accommodations to manage these tasks Speech and Language Pathology Addresses speech, swallow, and cognitive impairments Pulmonary rehabilitation Aims to improve respiratory function and endurance Neurocognitive rehabilitation Manages and improves cognitive function Pacing Program that instructs in a phased pacing protocol to decrease post-exertional symptom exacerbation. Cardiac Rehabilitation Monitored multi-phase program to improve cardiovascular health Autonomic conditioning therapy Adapted program to manage autonomic dysregulation Multidisciplinary rehabilitation programs Comprehensive rehabilitation program involving a team of professions working together NOTE: Many professionals from different backgrounds can provide the forms of rehabilitation listed. SOURCE: Carda et al., 2020b. strategies targeted respiratory, muscular, and neurological impairments that arise from prolonged hospitalization. Moreover, insights gleaned from past pandemics informed the design of those rehabilitation programs, aiding in the anticipation of potential long-term sequelae that Long COVID survivors might face (Carda et al., 2020a,b). Rehabilitation programs have evolved over time as more data have become available on the unique effects of COVID-19 on various populations. Recommendations on the safe provision of rehabilitation for persons with Long COVID have been published (DeMars et al., 2023). The World Health Organization has created a Living Guideline for the Clinical Manage- ment of COVID-19 with up-to-date recommendations for clinical manage- ment, which includes a section on rehabilitation for patients with COVID-19 (WHO, 2023). Regardless of disease severity, individuals with COVID-19 can present with persistent symptoms and functional decline. The guideline PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 162 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 163 provides suggestions across the continuum of care for persons with COVID- 19 from the ICU to the outpatient setting for persons with persistent symp- toms. Additionally, authors from the National Institute for Occupational Safety and Health published best practices for handling return to work in Long COVID patients (Howard et al., 2024). The guidelines suggest that returning to work too early may result in health deterioration, and a gradual return to work plan may be advised, especially in cases involving post-exertional malaise. They also address the importance of communica- tion among affected workers and their employers and health care providers, as well as the potential role of workplace accommodations in facilitating return to work. Research on the long-term effects of COVID-19 and the most effective rehabilitation approaches is incomplete, and limited understanding of the impacts of Long COVID rehabilitation is limited. Because some patients report post-exertional symptom exacerbation following physical exertion or have a phenotype of Long COVID consistent with myalgic encephalomy- elitis/chronic fatigue syndrome (ME/CFS) (see Chapter 5), clearer guidelines are needed on safe rehabilitation for these individuals (Appelman et al., 2024). There is no one-size-fits-all approach to rehabilitation, and each individual will need a program tailored to their complex needs. ASSESSING GLOBAL FUNCTIONING Table 4-2 provides an overview of selected assessments that can be used to quantify the functional impacts of Long COVID. The assessments in the table can contribute to an overall picture of individuals’ functioning, but given the heterogeneity of Long COVID, there are no gold standard tests specific for this population. The assessments are divided into domains of functioning, including full-body functioning, work-related functioning, pain, fatigue, and cognitive functioning. The assessments in the table include both performance-based and self-report measures and are just examples of ones that might be reported in the medical record. Performance-based measures assess the individual’s ability to perform specific tasks, such as walking or climbing stairs, while self-report measures ask the individual to rate their symptoms and how those symptoms affect their daily life. Of note, these selected assessments are commonly used to assess disability based on specific complaints; however, the three newer, more unique symptoms described earlier in Chapter 3 (chronic fatigue and post-exertional malaise, post– COVID-19 cognitive impairment, and autonomic dysfunction) may not be adequately captured with these assessments. There also may be wide day- to-date variability in performance on these tests, which may make using the tests to assess disability challenging. More research is needed to develop and validate additional disability and functioning assessments for Long COVID. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 163 5/22/24 11:11 PM

164 LONG-TERM HEALTH EFFECTS OF COVID-19 TABLE 4-2  Global Functioning Associated with Long COVID Domain Selected Assessments Full-Body functioning, Performance-based measures: walking, standing • Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (physical) (BOT-2)* (Bruininks and Bruininks, 2005) [pediatric population] • Bruininks Motor Ability Test (BMAT)* (Bruininks and Bruininks, 2012) [adult version of BOT-2] • Functional capacity evaluation (Chen, 2007; Fore et al., 2015; Genovese and Galper, 2009; Jahn et al., 2004; Kuijer et al., 2012; Soer et al., 2008) • Exercise testing to include aerobic capacity and neuromuscular performance (Liguori and American College of Sports Medicine, 2021) •  6-minute walk test •  10-meter walk test (Physiopedia, n.d.) •  Functional Gait Assessment • Sensory Organization Test (Shirley Ryan Ability Lab, 2013e) • 30-second, 5x, or 10x sit-to-stand test (Shirley Ryan Ability Lab, 2013a) • Romberg (Shirley Ryan Ability Lab, 2013d) Self-reported measures: • Composite Autonomic Symptom Score-31 (COMPASS-31) (Sletten et al., 2012) • Lower extremity Functional Scale (LEFS) (Shirley Ryan Ability Lab, 2013b) • Foot and Ankle Ability Measures (FAAM) (Shirley Ryan Ability Lab, 2015) • The Activities-specific Balance Confidence (ABC) Scale (Powell and Myers, 1995) • Patient-Reported Outcomes Measurement Information System (PROMIS)—Physical Function (HealthMeasures, 2020) Work-related Performance-based measures: functioning, activities of • ADL Profile (head injury and stroke) (Dutil et al., 1990) daily living (ADLs), and • ADL-Focused Occupations-Based instrumental activities of Neurobehavioral Evaluation (Gardarsdottir and Kaplan, 2002) daily living (IADLs) • Assessment of Motor and Processing Skills [adult and pediatric populations] (Fisher and James, 2012; Shirley Ryan Ability Lab, 2019) • Bay Area Functional Performance Evaluation (Houston et al., 1989) • Executive Function Performance Test (Baum et al., 2008) • Functional Independence Measure (Ottenbacher et al., 1996) • Katz ADL Scale (elderly and chronically ill) (Katz, 1983; Katz and Akpom, 1976) • Kohlman Evaluation of Living Skills (IADLs—psychiatric geriatric) (Burnett et al., 2009; Kohlman-Thomson, 1992) Observation and interview-based measures: • Performance Assessment of Self-Care Skills (Chisholm et al., 2014) PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 164 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 165 TABLE 4-2 Continued Domain Selected Assessments Self-reported measures: • Work Disability Functional Assessment Battery (WD-FAB) Physical Function (Meterko et al., 2015; Meterko et al., 2019) •  Work Ability (Illmaren, 2007; Tuomi et al., 1998) •  Sheehan Disability Scale (Sheehan, 1983) •  Barthel Index (Quinn et al., 2011) • Frenchay Activities Index (IADLs) (Schuling et al., 1993) •  The Lawton IADL Scale (Graf, 2008) • Manual Ability Measure (neurological and musculoskeletal conditions) (Chen and Bode, 2010) Caregiver-reported measures: • Cleveland Scale of Activities of Daily Living (dementia) (Patterson and Mack, 2001) Pain Self-reported measures: •  Visual Analog Scale (VAS) for Pain (Bijur et al., 2001) • Numeric Rating Scale (NRS) for Pain (Shirley Ryan Ability Lab, 2013c) • PROMIS—Pain Interference Instruments (HealthMeasures, 2021) • Functional Disability Inventory (Claar and Walker, 2006; Walker and Greene, 1991) [pediatric population] Fatigue Performance-based measures: • Polysomnography • Exercise testing to include aerobic capacity and neuromuscular performance (Liguori and American College of Sports Medicine, 2021) Self-reported measures: •  Brief Fatigue Inventory [BFI] •  Fatigue Severity Scale [FSS] •  Fatigue Symptom Inventory •  Multidimensional Assessment of Fatigue •  Fatigue Impact Scale (modified) •  Multidimensional Fatigue Symptom Inventory • Multidimensional Fatigue Symptom Inventory Short Form •  Profile of Mood States-Brief, • PedsQL Multidimensional Fatigue Scale [pediatric and young adult population] •  Multi-Dimensional Fatigue Scale •  Profile of Fatigue •  Functional Assessment Chronic Illness •  Therapy Checklist Individual Strength • Patient-Reported Outcomes Measurement Information System – Fatigue • Pittsburgh Sleep Quality Assessment (Buysse et al., 1989) •  VAS to Evaluate Fatigue Severity •  PROMIS—Fatigue (Shirley Ryan Lab, 2018) continued PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 165 5/22/24 11:11 PM

166 LONG-TERM HEALTH EFFECTS OF COVID-19 TABLE 4-2 Continued Domain Selected Assessments Cognitive dysfunction Attention and Working Memory • Weschler Adult Intelligence Scale-IV (WAIS-IV) Digit Span •  Continuous Performance Test-3 (CPT-3) •  Digit Vigilance Test •  Paced Auditory Serial Addition Test (PASAT) Processing Speed •  Trail Making Test- Part A •  Symbol Digit Modalities Test •  WAIS-IV Coding Executive Functioning •  Trail Making Test- Part B •  Wisconsin Card Sorting Test-64 (WCST-64) •  Stroop Color and Word Test •  Delis-Kaplan Executive Function System (DKEFS) Tower Test • Self-reported:   0  Frontal Systems Behavior Scale (FrSBe)   0 Behavior Rating Inventory of Executive Functioning (BRIEF) •  PROMIS Short Form v2.0—Cognitive Function Language • Controlled Oral Word Association Test (COWAT) or DKEFS Verbal Fluency •  Multilingual Naming Test or Boston Naming Test Memory • Verbal:   0  California Verbal Learning Test-II (CVLT-II)   0  Hopkins Verbal Learning Test-Revised (HVLT-R)   0  Rey Auditory Verbal Learning Test (RAVLT) • Nonverbal:   0  Brief Visual Memory Test-Revised (BVMT-R) Visuospatial Ability •  Judgment of Line Orientation •  Rey-Osterrieth Complex Figure Test Estimated Premorbid Ability • Wide Range Achievement Test-4 (WRAT-4) Reading subtest •  Test of Premorbid Functioning (TOPF) NOTES: *Multi-dimensional assessment: Balance, coordination, dexterity, functional mobility, gait, strength, upper-extremity, function, vestibular. SOURCES: Hodgson et al., 2021; Raj et al., 2018. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 166 5/22/24 11:11 PM

GLOBAL FUNCTIONING IN LONG COVID 167 SUMMARY AND CONCLUSIONS For many individuals, the effects of SARS-CoV-2 infection persist well beyond resolution of the acute infection and can result in significant dis- ability. Functional disability associated with Long COVID has been char- acterized as inability to return to work, poor quality of life, diminished ability to perform ADLs, decreased physical and cognitive function, and overall disability. Severity of acute COVID-19 is a major risk factor for poor functional outcomes. By the committee’s best estimate, people hospitalized for COVID-19 are two to three times more likely to have higher rates of Long COVID and more severe disease and to experience longer disease duration compared with nonhospitalized people. In addition, those whose severe COVID-19 required life support treatments in the ICU may be twice as likely to experience the aforementioned outcomes compared with those hospitalized without such intensive treatment. However, even people with mild initial illness can experience long-term functional impairments. In fact, those with mild initial illness make up the great majority of the population with long-term functional impairments simply because there are many times more people with mild than with severe initial infection. Increased number and severity of long-term symptoms correlates 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. Data on recovery trajectories are rapidly evolving, and recovery is heterogenous. Initial data suggest that people with persistent Long COVID symptoms generally improve over time, although preliminary studies sug- gest that recovery can plateau between 6 and 12 months after acute infec- tion. More information on recovery trajectories at 1 year or longer may become available in the next few years. Long COVID in children and adolescents is a poorly understood condi- tion. While most children recover from COVID-19 with no long-term prob- lems, some may experience persistent symptoms that can affect their quality of life and result in more school absences. Risk factors for Long COVID in children include acute-phase hospitalization, preexisting comorbidity, being infected with pre-Omicron variants, and older age. More research is needed to identify the long-term functional implications of Long COVID for chil- dren, as information from adult studies may not be directly applicable to the pediatric population. Rehabilitation can improve functional outcomes in people with Long COVID, regardless of the severity of disease or duration of symptoms, although the benefits are greater for people who are younger and who have had Long COVID for a shorter period of time. It is important to choose the right type of rehabilitation for the individual. Access to rehabilitation can be difficult, and there are often long waitlists. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch04.indd 167 5/22/24 11:11 PM

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Since the onset of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, many individuals infected with the virus that causes COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have continued to experience lingering symptoms for months or even years following infection. Some symptoms can affect a person's ability to work or attend school for an extended period of time. Consequently, in 2022, the Social Security Administration requested that the National Academies convene a committee of relevant experts to investigate and provide an overview of the current status of diagnosis, treatment, and prognosis of long-term health effects related to Long COVID. This report presents the committee conclusions.

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