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3 Selected Long-Term Health Effects Stemming from COVID-19 and Functional Implications Long COVID is associated with a wide range of new or worsening health conditions and encompasses more than 200 symptoms involving many different organ systems (Davis et al., 2021; Lubell, 2022). Given the extensive range of symptoms, there have been attempts to cluster these health effects, but to date no consensus in this regard has been reached. This chapter begins with an overview of the full range of symptoms and health effects associated with Long COVID and a summary of the conditionâs epidemiology. The chapter then focuses on three health effects of Long COVID that may not be captured in SSAâs Listing of Impairments but can significantly affect oneâs ability to participate in work or school: chronic fatigue and post-exertional malaise (PEM), postâCOVID-19 cogni- tive impairment (PCCI), and autonomic dysfunction. Although a great num- ber of Long COVID health effects could impact function, the committee thinks it will be useful for SSA to become familiar with these three, as they are particularly challenging to treat because of their multisystem nature (see Chapter 5 for an overview of similar multisystem chronic conditions). These are the novel conditions for which people seek out Long COVID clinics. For each of these three health effects, the chapter provides an overview of ⢠the frequency and distribution of their severity and duration in the general population, as well as any differences along racial, ethnic, sex, gender, geographic, or socioeconomic dimensions, or differences specific to populations with particular preexisting or comorbid conditions; ⢠clinical standards for diagnosis and measurement of each of these health effects; 55 PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 55 5/21/24 10:52 AM
56 LONG-TERM HEALTH EFFECTS OF COVID-19 ⢠any special considerations regarding identification and management of these health effects in special populations, including pregnant people and those with underlying health conditions; ⢠best practices for quantifying the functional impacts of these health effects; and ⢠identified challenges for clinicians in evaluating persons with these health effects. The symptoms and health effects discussed in detail in this chapter do not represent the full range of effects experienced by patients with Long COVID. In an effort to be inclusive, the committee includes at the end of this chapter annex tables organized by body system of selected health effects associated with Long COVID, along with their potential functional impacts and selected management guidelines. OVERVIEW OF HEALTH EFFECTS ASSOCIATED WITH LONG COVID Epidemiology of the Long-Term Health Effects of SARS-CoV-2 Infection Data from the U.S. Centers for Disease Control and Preventionâs (CDCâs) National Health Interview Survey show that in 2022, 6.9 percent of U.S. adults and 1.3 percent of children had Long COVID at some point, while 3.4 percent of adults and 0.5 percent of children had Long COVID at the time of interview (Adjaye-Gbewonyo et al., 2023; Vahratian et al., 2023). Based on these surveys, it is estimated that approximately 8.9 million adults and 362,000 children reported Long COVID symptoms in the United States in 2022 (Adjaye-Gbewonyo et al., 2023; Vahratian et al., 2023). Among adults in the United States, data from the CDCâs Household Pulse Survey show that the prevalence of Long COVID declined from 7.5 percent in June 2022 to 5.9 percent reported in January 2023, then increased to 6.8 percent in January 2024 (NCHS, 2024). Despite an overall decline in prevalence since June 2022, Long COVIDâs disease burden remains sub- stantial. In January of 2024, approximately 22 percent of adults with Long COVID reported significant activity limitations (NCHS, 2024). The body of epidemiological research shows great variation in the incidence and prevalence of the long-term effects of SARS-CoV-2 infection. These variations reflect the dynamic changes in the pandemic itself, as the virus has evolved and spawned many variants and subvariants throughout the pandemicâs course; the effect of vaccines, which were introduced in December 2020 and later shown to reduce the risk of long-term health effects; and the effect of treatments for acute infection (e.g., steroids, PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 56 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 57 antivirals), which may reduce the risk of long-term health effects. In addi- tion, since the awareness about Long COVID in the medical community and the public is still lacking, reported prevalence may be an underestimate. Adding to this complexity is the broad multisystem nature of the long-term health effects of SARS-CoV-2 and the fact that these effects are expressed differently in different age groups and sexes and by baseline health (Maglietta et al., 2022; Rayner et al., 2023; Tsampasian et al., 2023; Wong et al., 2023). Variation in incidence and prevalence estimates also stems from heterogeneities in study designs, including choice of control groups (e.g., whether studies included people with negative SARS-CoV-2 tests or no known SARS-CoV-2 as controls); methods used to account for the effect of baseline health in ascertaining whether the emergence of spe- cific health effects following infection represents new disease; specification of outcomes; and other methodological differences. Because of the considerable variation in estimates of the long-term health effects seen in Long COVID, the committee presents average estimates for different body systems based on the published literature. Among people who had COVID-19, most estimates of long-term cardiovascular health effects, which comprise a broad array of sequelae, regress around 4 percent (Xie et al., 2022b). Neurological and psychiatric conditions are also common among people who had COVID-19, with estimates of around 6 percent (Harrison and Taquet, 2023; Ley et al., 2023; Taquet et al., 2021, 2022; Wulf Hanson et al., 2022; Xie et al., 2022a; Xu et al., 2022). The reported incidence of gastro- intestinal disorders postâCOVID-19 is highly variable, but estimates suggest 6 percent (Xu et al., 2023). Respiratory problems persist in some people fol- lowing SARS-CoV-2 infection, and prevalence studies at 6 months to 2 years suggest estimates of 2â4 percent (Wulf Hanson et al., 2022). Endocrine con- ditions are estimated to affect 1â2 percent of people previously infected with SARS-CoV-2 (Ssentongo et al., 2022). Similarly, estimates of the prevalence of genitourinary disorders is around 1 percent (Kayaaslan et al., 2021). Terminology The committee considers a health condition to be a state, including injury, illness, or physical or mental diagnosis, that adversely affects a per- sonâs physical and/or mental health and well-being. A symptom is a subjec- tive manifestation of disease experienced and reported by a patient, while a sign is an objective manifestation of disease that an examining practitioner can observe or measure (King, 1968; NIH, n.d.). In the context of this study, the committee uses health effects as an umbrella term that includes symptoms, health conditions, and other sequelae caused by or associated with prior infection with SARS-CoV-2. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 57 5/21/24 10:52 AM
58 LONG-TERM HEALTH EFFECTS OF COVID-19 Full Range of Health Effects SARS-CoV-2 infection can lead to post-acute and long-term health effects in nearly every organ system (see Figure 3-1). As described in Chapter 1, the International Classification of Functioning, Disability and Health model of disability identifies three domains of functioning: body functions and structures (i.e., physiological functions of the body, including psychological functions, and functioning of body structures), activity (i.e., actions or tasks), and participation (i.e., performance of tasks in a social context, such as school or work), all of which are mediated by personal and environmental factors that can either enhance or diminish and indi- vidualâs activity and participation (WHO, 2023b). Health effects associated with Long COVID may manifest as impairments in body structures and FIGURE 3-1â Lasting impact of COVID-19. SOURCE: Washington University School of Medicine in St. Louis. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 58 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 59 physiological functions, with resulting activity limitations and restrictions on participation. The impairments associated with Long COVID may affect mental (e.g., cognitive, psychosocial, emotional) functioning as well as physical functioning. In addition, individuals with Long COVID may experience multiple and potentially overlapping symptoms and conditions, including PEM, PCCI, and autonomic dysfunction. A number of preexist- ing conditions (e.g., diabetes, heart failure, chronic obstructive pulmo- nary disease, dementia) can increase the risk of adverse outcomes from SARS-CoV-2 infection, both during and following acute infection (Awatade et al., 2023; Dubey et al., 2023; Núñez-Gil et al., 2023; Steenblock et al., 2022; Treskova-Schwarzbach et al., 2021). Although persistent health effects associated with SARS-CoV-2 infection may include worsening of preexisting conditions, this chapter focuses primarily on newly acquired conditions. Health care providers and patients need to be aware of poten- tial worsening of preexisting conditions and continue to monitor and treat them as needed. Additionally, the variable health effects of Long COVID may have different impacts on different patients depending on the burden of the preexisting condition, further emphasizing the need for a patient- specific approach for monitoring and treatment of health conditions. Annex Tables 3-1 through 3-11 at the end of this chapter list selected health conditions associated with Long COVID in adults, organized by body system. Annex Table 3-12 lists selected health effects that are not organ systemâspecific, including chronic fatigue and PEM, ME/CFS, and fever. These tables include a summary of the potential functional implica- tions of the conditions, selected clinical guidelines for their diagnosis and management, and potentially relevant SSA Listings for adults, where appli- cable. For the functional implications, the committee chose to focus on the kind of information that SSA collects about functioning in adults, which comes from a variety of sources, including the applicant, medical providers, employers, and other third parties with knowledge of the applicant. Infor- mation collected about physical functioning encompasses such activities as sitting, standing, walking, lifting, carrying, reaching, gross manipula- tion (e.g., handling large objects), fine manipulation (e.g., handling small objects, writing, typing), climbing, and low work (e.g., stooping, crouching, kneeling, crawling) (SSA, 2020). Annex Table 3-13 lists the physical; vison, hearing, and speaking; and mental activities the committee considered in populating the tables, along with their definitions. The committee populated the column on potential functional limitations based on the membersâ col- lective expertise. SSA also collects information about the applicantâs ability to perform various daily activities, such as dressing, bathing, self-feeding, and using the toilet, as well as preparing meals, doing house- and yardwork, getting around, and shopping. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 59 5/21/24 10:52 AM
60 LONG-TERM HEALTH EFFECTS OF COVID-19 The long-term health effects associated with Long COVID can affect people across race, ethnicity, sex, gender, and age groups. Generally, the riskâon the relative scaleâof these long-term health effects increases according to the severity of acute infection: the risk is 2â3 times greater in people who were versus were not hospitalized, and greatest in people who required intensive care (Núñez-Seisdedos et al., 2022; Xie et al., 2022b). However, because most people infected with SARS-CoV-2 experience mild or moderate disease that does not require hospitalization, those with mild or moderate cases constitute the majority of individuals with long-term adverse health effects of SARS-CoV-2 (Lai et al., 2023; Spagnuolo et al., 2020). Rates of Long COVID among pregnant women who had COVID-19 during pregnancy are similar to those of the general population (Kandemir et al., 2024). In addition, among pregnant women with COVID-19 at delivery, rates of caesarean delivery and frequency of maternal compli- cations increased (Knight et al., 2020; Prabhu et al., 2020). The risk of Long COVID among adult females is about twice that among adult males (Munblit et al., 2021; Perlis et al., 2022; Sudre et al., 2021). Some pediatric studies also report a higher prevalence of Long COVID in female compared to male children and adolescents, although the exact risk is still undefined (Vahratian et al., 2023; Zheng et al., 2023). Some of the long-term health effects of acute SARS-CoV-2 infection are chronic and can negatively impact individualsâ quality of life; ability to par- ticipate in the labor market or school; and, in some cases, life expectancy. The extent to which the long-term health effects of infection will have a functional impact on a personâs life and ability to work or participate in school can depend on health and functional status prior to COVID-19 and the severity of the medical condition(s). In addition, symptoms and related functional limitations may fluctuate, waxing and waning over time. Clustering of Health Effects Given the vast number of symptoms and health effects associated with Long COVID, several research groups have attempted to cluster patients with similar effects to better understand the disease (see Table 3-1). The committee found that the evidence on clustering of the post-acute and long-term health effects of SARS-CoV-2 remains inconsistent across studies as a result of differences in study designs, populations studied, enrollment criteria, the era in which the study was undertaken (reflecting the possible differential effect of variants, changes in clinical care, and vaccination on phenotypic clusters), specification of post-acute and long- term health effects of SARS-CoV-2 infection, methodological approaches to clustering, and other factors. These differences yielded inconsistent results PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 60 5/21/24 10:52 AM
TABLE 3-1â Research on Clusters of Long COVID Health Effects Time after Initial Population and COVID-19 Clustering Proposed Long COVID Reference Study Type Infection Methodology Symptom Clusters Notes Canas et al. Prospective 84 days Unsupervised clustering (1) cardiorespiratory, Subclusters determined for wild- (2023) cohort study, analysis of time-series (2) central neurological, and type variant in unvaccinated 9,804 UK-based data, additional testing (3) multi-organ systemic people, alpha variant in adults using data from inflammatory unvaccinated people, and delta Covid Symptom Study variant in vaccinated people. BiobankA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 61 Evans et al. PHOSP-COVID 2 and 7 months Clustering large (1) very severe, 46% in the mild cluster. Full (2021) cohort, 1,077 UK applications k-medoids (2) severe, recovery reached in 3% of adults approach (3) moderate with cognitive the very severe cluster, 7% of impairment, the severe cluster, 36% of the (4) mild moderate cluster, and 43% of the mild cluster. Elevated serum C-reactive protein was positively associated with cluster severity. Fischer Predi-COVID 12 months Hierarchical ascendant (1) mild (less severe initial 48% in the mild cluster. Severe et al. cohort in classification infection, fewer comorbidities, cluster had a higher proportion (2022) Luxembourg, 288 fewer persisting symptoms), of women and smokers. PREPUBLICATION COPYâUncorrected Proofs participants (2) moderate (mean of 11 persisting symptoms, poor sleep, poor respiratory quality of life, (3) severe (higher number of symptoms especially vascular, urinary, skin) continued 615/21/24 10:52 AM
TABLE 3-1âContinued 62 Time after Initial Population and COVID-19 Clustering Proposed Long COVID Reference Study Type Infection Methodology Symptom Clusters Notes Frontera 242 patients 12 months Unsupervised (1) few symptoms, mostly The study administered et al. hospitalized with hierarchical cluster headache, psychological therapy and (2022) COVID-19 analysis (2) many symptoms including medications to cluster 2 and PT high levels of depression and or OT to cluster 3. They found anxiety, 100% of those who received (3) shortness of breath, headache, psychiatric therapy, 97% who and cognitive symptoms received PT/OT, and 83% whoA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 62 received few interventions improved over time Goldhaber UC San Diego Unspecified Exploratory factor (1) gastrointestinal, Neurocognitive burden et al. health system, analysis (2) musculoskeletal, associated with depression and (2022) 999 respondents (3) neurocognitive, anxiety. Musculoskeletal burden (4) airway, associated with older age (5) cardiopulmonary Kenny Multicenter 4 weeks or Multiple (1) pain symptoms including joint Clusters 1 and 2 had greater et al. prospective more correspondence pain, myalgia, headache, functional impairment, longer (2022) cohort, 233 analysis on the most (2) cardiovascular symptoms with work absence PREPUBLICATION COPYâUncorrected Proofs individuals, 77% common self-reported chest pain, shortness of breath, mild initial illness symptoms and palpitations, hierarchical clustering (3) significantly fewer symptoms than clusters 1 and 2 Kisiel et al. 506 patients 12 weeks or K-means cluster (1) mild, 59% in the mild cluster. Cluster 3 (2023) from 3 Swedish more analysis and ordinal (2) moderate, had the most reduced work ability. cohorts, mostly logistic regression were (3) severe (predominating Smoking, high BMI, diabetes, and hospitalized used to create PCS symptoms were fatigue, cognitive COVID-19 onset severity were scores impairment, and depression) predictors of cluster 3.5/21/24 10:52 AM
Thaweethai Prospective 6 months or Unsupervised machine (1) post-exertional malaise (PEM) Using least absolute shrinkage et al. cohort study of more learning and fatigue, and selection operator (LASSO), (2023) 9,764 adults at (2) brain fog and PEM, found most representative Long 85 enrolling sites (3) brain fog, PEM, and fatigue, COVID symptoms to be smell/ in 33 states plus (4) fatigue, PEM, dizziness, taste, PEM, chronic cough, brain Washington, DC, brain fog, GI symptoms, and fog, and thirst. and Puerto Rico palpitations Tsuchida Adolescents and 2 months or Cluster analysis was (1) fatigue only, Clusters 2 and 3 had higher et al. adults in an more performed using (2) fatigue, dyspnea, chest pain, proportions of autonomic (2023) outpatient clinic CLUSTER (SAS Ver palpitations, forgetfulness, nervous system disorders and in Japan 9.4, SAS Institute Inc., (3) fatigue, headache, insomnia, leave of absence from work and Cary, NC, USA), and anxiety, motivation loss, low school cluster classification mood, forgetfulness,A02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 63 was performed. (4) hair loss, (5) taste and smell disorders Wulf Pooled 54 studies 3 months Selected based on (1) fatigue, bodily pain, and Among individuals with Hanson and 2 medical reporting frequency in depression and anxiety, COVID-19, 6.2% had long et al. record databases published studies and (2) cognitive problems (inability to COVID at 3 months: 10.6% for (2022) with data for availability of health concentrate and remember), and female adults, 5.4% for male 1.2 million state in Global Burden (3) ongoing respiratory problems adults, 2.8% for children and individuals from of Disease study such as shortness of breath, young people. 22 countries cough, and chest pain Yong and Review of 43 3 months or ânarrative reviewâ (1) non-severe COVID-19 multi- Among individuals with Long Liu (2022) studies on Long more of the literature (not organ sequelae (NSC-MOS), COVID symptoms 3 months PREPUBLICATION COPYâUncorrected Proofs COVID systematic) (2) pulmonary fibrosis sequelae after symptomatic SARS- (PFS), CoV-2 infection, an estimated (3) myalgic encephalomyelitis or 15% continued to experience chronic fatigue syndrome (ME/ symptoms at 12 months. CFS), (4) POTS, (5) post-intensive care syndrome (PICS) and 63 (6) medical or clinical sequelae (MCS)5/21/24 10:52 AM
64 LONG-TERM HEALTH EFFECTS OF COVID-19 across studies, making it challenging to weave the evidence into a coherent narrative to inform policy discussions and clinical care. The heterogeneity of results reflects both the nascency of the field (less than 3.5 years old) and the complexity of Long COVID itself. The generation of better-quality and more consistent evidence will require consensus on terms, definitions, and methodological approaches. SELECTED MULTISYSTEM HEALTH EFFECTS ASSOCIATED WITH LONG COVID Three health effects associated with Long COVID that have a sig- nificant effect on functioning and are particularly challenging to manageâ chronic fatigue and PEM, PCCI, and autonomic dysfunctionâare reviewed in this section. There is significant overlap among the symptoms associated with these conditions. Chronic Fatigue and Post-Exertional Malaise PEM, also called post-exertional symptom exacerbation, is character- ized by a severe worsening of fatigue and other symptoms following physi- cal, mental, social, or emotional exertion that would not typically cause such a reaction in healthy individuals. This exacerbation of symptoms can occur immediately after the stressor or can be somewhat delayed (hours to days). In addition, an episode of PEM can last for days or even weeks. The specific symptoms that worsen vary among individuals, but often can go beyond fatigue to include muscle or joint pain, cognitive difficulties, sleep disturbances, headaches, flu-like symptoms, and/or gastrointestinal distur- bances (Vernon et al., 2023). Fatigue, broadly defined as a distressing or persistent tiredness that is nei- ther proportional to recent activity nor alleviated by rest (Sandler et al., 2021; Twomey et al., 2022), is the most dominant symptom of Long COVID in several studies, ranging from 19 percent to 76.3 percent of patients (Cheung et al., 2023; Hartung et al., 2022; Ho et al., 2023; Kayaaslan et al., 2021; LÃÅ¡ka et al., 2022; Sánchez-GarcÃa et al., 2023; Åteïµpánek et al., 2023). Of the many descriptive studies that have captured fatigue and other symptoms seen in Long COVID, only a small proportion make it a point of measuring PEM. In a large cross-sectional sample of adults who were selected from postâCOVID-19 online groups, PEM was reported by 89.1 percent (95% confidence interval [CI] 88â90%); for most participants, PEM lasted a few days (Davis et al., 2021). A recent analysis of the National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) longitudinal study was aimed at developing and validating a quantitative definition of Long COVID using multiple symptoms. In that study, PEM was reported in 87 percent of patients identified as having Long COVID (Thaweethai et al., 2023). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 64 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 65 Diagnosis Both post-COVID fatigue and PEM are generally diagnosed based on patient-reported symptoms and a detailed medical history. Typically, a thor- ough medical evaluation, which may include blood tests, imaging studies, and other diagnostic tests, is conducted to rule out other possible causes or contributing factors. In clinical settings, health care providers typically evaluate chronic fatigue and PEM by asking patients to describe their symptoms in detail, including by inquiring about the type of exertion (physical, emotional, or mental) that leads to worsening of symptoms; the duration and severity of the symptom worsening that follows those stressors; how long it takes for the symptoms to return to baseline; what symptoms are experienced; and whether there is a prodrome related to the worsening of the symptoms. Multiple validated questionnaires can be used to measure a personâs perception and severity of fatigue and PEM (Davenport et al., 2023; FACIT, 2021), such as the DePaul Symptom QuestionnaireâPost-Exertional Malaise (DSQ-PEM), which cap- tures the frequency and severity of PEM symptoms (Bedree et al., 2019; Cotler et al., 2018; Davenport et al., 2023; FACIT, 2021). One approach to diagnosing PEM, investigated in myalgic encephalitis/ chronic fatigue syndrome (ME/CFS) but not yet in Long COVID, involves two consecutive days of cardiopulmonary exercise testing (CPET) (Stevens et al., 2018). Deconditioned adults and those with other chronic condi- tions show minimal variation between the first and second day of CPET measurement. In ME/CFS patients with PEM, multiple studies reveal a â significant decline in oxygen consumption (VO2) at peak performance and the ventilatory anaerobic threshold on the second day of CPET testing (Davenport et al., 2019; Stevens et al., 2018). The ventilatory anaerobic threshold reflects a personâs ability to sustain continuous work and is more â related to everyday exertion. This drop in VO2 between the first- and sec- ond-day CPET measurements suggests that patients with PEM risk entering anaerobic metabolism during activities they could have completed without it just the day before (Stevens et al., 2018). In ME/CFS, symptoms most associated with PEM after exercise include cognitive dysfunction, reduced self-reported daily functioning, and mood disturbances (Chu et al., 2018). Although 2-day CPET helps with understanding the physiologic response to exercise in patients with PEM generally, there are health system and patient-level barriers that potentially limit the broad implementation of 2-day CPET in diagnosing PEM in Long COVID and ME/CFS. The health system barriers include limited or inequitable access to CPET, with even fewer trained clinicians who can apply and interpret 2-day CPET to diag- nose PEM. Patient-level barriers include prolonged recovery from testing and the prohibitive cost of testing without adequate insurance coverage. Several studies have explored the role of CPET in Long COVID, but not all PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 65 5/21/24 10:52 AM
66 LONG-TERM HEALTH EFFECTS OF COVID-19 have used PEM as an inclusion criterion (Baratto et al., 2021; Durstenfeld et al., 2022; Evers et al., 2022; Wernhart et al., 2023). Although much of the existing research on 2-day CPET in PEM has been in patients with ME/ CFS, the findings should be expected to generalize, regardless of suspected onset. Nevertheless, additional research is needed to compare 2-day CPET results in Long COVID versus ME/CFS. Functional Impacts Chronic fatigue symptoms in Long COVID impact a personâs ability to work and perform activities of daily living, which makes clinical care and rehabilitation a priority for these patients (Walker et al., 2023). They can also impact productivity by preventing a return to pre-COVID functional levels, thereby affecting the social and economic health of the impacted individual. A cross-sectional observational study on the impact of fatigue on function in 3,754 Long COVID patients, conducted at 31 post-COVID clinics in the United Kingdom, found that 94 percent (3,541) were of work- ing age (18â65 years); half (n = 1,321/2,600, 50.8 percent) of those who completed the âworking days lostâ questionnaire reported the loss of at least 1 day of work in the last month. Approximately 20 percent (20.3 percent) reported losing 20â28 days of work, and 20 percent also reported the inabil- ity to work completely. These results were associated mainly with fatigue (Walker et al., 2023). Symptoms of chronic fatigue in Long COVID may also influence a personâs attitudes toward leisure time, thereby impacting mental health functioning and perceived stress. Since PEM is considered a hallmark symptom for diagnosing ME/CFS (CDC, 2021b; IOM, 2015; NICE, 2021d), Long COVID patients with PEM may also fit criteria for ME/CFS. Understanding the functional impact of PEM is made more challenging by the fluctuating nature of the symptom complex and the fact that often people can compensate for limitations in function by first making compensatory changes in the time, effort, and resources they ascribe to certain tasks or by making compensatory changes in their social or leisure activity patterns (NICE, 2021d). One recent study comparing PEM symptoms in Long COVID with those in ME/CFS found that the PEM symptoms were more likely to improve over 1 year in individuals with Long COVID, while there was no improvement in those with ME/CFS. However, 51 percent of the individuals with ME/CFS in this study had already had symptoms for >4 years, while 82 percent of those with Long COVID had had symptoms for <1 year (Oliveira et al., 2023). In a large cross-sectional sample of adults selected from postâCOVID-19 online groups, those participants who had versus those who did not have PEM at 6 months or more after their COVID-19 PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 66 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 67 illness had a significantly higher average number of Long COVID symp- toms that persisted beyond 6 months (Davis et al., 2021). In a smaller cross-sectional analysis of more than 200 adults with at least 4 weeks of persistent symptoms after acute COVID-19 illness, PEM was associated with more severe fatigue and a higher risk of work status limitations, no or low physical activity, lower general health, and lower social functioning (Twomey et al., 2022). In a population-based longitudinal cohort study, PEM was associated with increased risk of other symptoms, such as insom- nia, cognitive impairment, headache, and generalized pain, compared with those with fatigue without PEM. The presence of PEM was also associ- ated with increased risk of functional impairment, reduced work capac- ity, and reduced physical activity (Nehme et al., 2023). Similarly, another population-based longitudinal study conducted in Switzerland describing the long-term trajectory of post-COVID symptoms in adults at 1, 2, 6, 9, 12, 18, and 24 months after SARS-CoV-2 infection found that PEM was more likely in those who had worsening of or no change in their perceived health status compared with those who reported improvement or showed continued recovery (Ballouz et al., 2023). Treatment When PEM is identified, the focus of treatment turns to comprehen- sively assessing and managing the functional impact of these symptoms, along with other Long COVIDârelated symptoms. When PEM is present, rehabilitation interventions and other treatment approaches may need to be personalized to enhance patient safety (Herrera et al., 2021; WHO, 2023a). For physical activity, the anerobic threshold can be used as the physical activity ceiling for safe activity to avoid PEM, recognizing that the nature of PEM is that the anerobic threshold may vary based on the patientâs previous activities and other recent stressors (Davenport et al., 2010). In addition to using self-report questionnaires to capture the severity of patientsâ fatigue and functional limitations, clinicians may ask patients to track their activities in detailed diaries to better capture the types of activi- ties that are most likely to trigger PEM for each individual. Preventing PEM or lessening its severity may require identifying those triggering factors, such as physical, mental, and emotional stressors; orthostatic intolerance; hormonal factors in women; environmental factors (humidity and extreme temperatures); sensory stimuli (light, noise, and smells); certain foods; and infections, including reinfections with SARS-CoV-2. Teaching patients to respect their physiological limits is an important aspect of managing PEM. An important aspect of rehabilitation for people living with PEM is the provision and use of assistive products and environmental modifications to PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 67 5/21/24 10:52 AM
68 LONG-TERM HEALTH EFFECTS OF COVID-19 prevent PEM and its functional impact (WHO, 2023a). Therefore, another important aspect of management is facilitating work or school accommo- dations that may be necessary to prevent PEM (e.g., flexible hours, tele- commuting options, specialized equipment to reduce physical or cognitive exertion). Selected Populations To date, few research studies have explored differences in PEMâs preva- lence, severity, and functional impact by race/ethnicity, rurality, or other social factors. A study using the TriNetX database to look at the use of outpatient rehabilitation for a post-COVID condition did find that Hispanic individuals had a significantly higher incidence of fatigue (Hentschel et al., 2022). There also is a scarcity of information on Long COVID fatigue and PEM and the impact of the condition in pregnant and lactating women, even though women appear to be at higher risk for the condition (Pagen et al., 2023). Post-COVID-19 Cognitive Impairment Cognitive impairment has emerged as one of the most commonly reported health effects associated with Long COVID, potentially portending significant consequences for patient functioning and quality of life. Cogni- tive impairment is defined as difficulties with thinking processes that can impact various cognitive domains, including memory, attention, process- ing speed, language, visuospatial, and executive functions (e.g., multitask- ing, judgment, problem solving). In patients with Long COVID, cognitive impairment has been characterized primarily by deficits in executive func- tioning (Becker et al., 2023). Cognitive impairment associated with Long COVID can vary in severity, from mild to severe, and often has an impact on instrumental activities of daily living. Studies have reported varied rates of PCCI ranging from 8 to 80 percent (Becker et al., 2021), likely the result of varying measurement of cognition, including self-reported versus objective neuropsychological measures; use of cognitive screeners (which are insensitive to milder forms of impairment) (Lynch et al., 2022); and telephonic or online administration of measures versus validated, in-person assessments. However, the most robust studies have found PCCI to occur in approximately 24 percent of patients post COVID-19, across the spectrum of acute COVID severity (Becker et al., 2021). These cognitive deficits have been found to persist several months following SARS-CoV-2 infection (Becker et al., 2021, 2023), with some studies reporting long-term persistence beyond 1 year (Cavaco et al., 2023). While the severity of PCCI is relatively mild in comparison to the deficits PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 68 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 69 seem in neurodegenerative diseases and sever traumatic brain injuries, it can still contribute to significant functional disability in those impacted (Delgado-Alonso et al., 2022). PCCI can occur regardless of age, preexisting comorbidities, vaccina- tion status, and COVID-19 variant. However, vulnerability to the condition appears to be greater in Black, Hispanic, female, and the older-aged popula- tion (Jacobs et al., 2023; Valdes et al., 2022), a finding that has substantial implications for occupational and social functioning. Female sex has also been associated with a greater probability of PCCI (Jacobs et al., 2023; Valdes et al., 2022). Differences have been found among racial and ethnic groups, such that Black and Hispanic individuals may be more likely to experience Long COVID and PCCI compared with non-Hispanic White individuals (Jacobs et al., 2023). Fewer years of education, Black race, and unemployment with baseline disability have likewise been found to confer a greater risk of PCCI (Valdes et al., 2022). Finally, preexisting conditions, including headaches (Jacobs et al., 2023), cognitive impairment (Valdes et al., 2022), neurological disease (Hartung et al., 2022), and renal disease (Bucholc et al., 2022), all appear to confer greater risk of PCCI. Conversely, some data suggest that the COVID-19 vaccine may reduce the risk of PCCI (Gao et al., 2022). While the term âbrain fogâ has been deemed synonymous with cogni- tive impairment in the Long COVID literature, the two may be distinct clinical entities (McWhirter et al., 2023; Orfei et al., 2022). Brain fog is not a recognized medical diagnosis in itself, but rather a debilitating symptom that is usually seen in association with other factors, such as fatigue, psychosocial stress, and both physical and mental conditions (Jennings et al., 2022). Brain fog seen in patients following SARS-CoV-2 infection has anecdotally been described as inattention, forgetfulness, difficulty concentrating, and difficulty finding words (McWhirter et al., 2023). While these difficulties are often observed in formal neuropsycho- logical assessments, it is well known that patientsâ subjective cognitive reports may sometimes be discrepant with objective neuropsychological findings (Schild et al., 2023). Nevertheless, it is important to note that individuals with cognitive impairment may report brain fog as a symp- tom, and that brain fog and PCCI may be equally functionally disabling in patients with Long COVID. Diagnosis The prevalence of cognitive impairment, including mild cognitive impairment (MCI) and more severe forms of cognitive impairment (e.g., dementia), increases with age. It is generally uncommon (i.e., less than 3 percent of the population) before age 65 and increases dramatically PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 69 5/21/24 10:52 AM
70 LONG-TERM HEALTH EFFECTS OF COVID-19 after age 75 (Casagrande et al., 2022; U.S. Preventive Services Task force, 2020). The prevalence of MCI can be difficult to estimate due to several factors. There are varying diagnostic criteria for MCI. Addi- tionally, as the population ages, some cases of MCI return to normal cognition with ongoing follow-up while others progress to dementia (Casagrande et al., 2022; U.S. Preventive Services Task force, 2020). In addition to a comprehensive medical history, the clinical standard for diagnosis of cognitive impairment includes a comprehensive neuropsy- chological evaluation consisting of standardized tests that have well- established normative data (Becker et al., 2023; Casaletto and Heaton, 2017). These tests allow a clinician to compare an individualâs scores with those of a normative population, adjusted for age; education; and sometimes other factors, such as sex. An individualâs performance on these tests is often categorized according to standard deviations (SDs) below the mean of the normative sample. Scores within 1 SD below the mean are considered âaverage,â whereas scores between 1 and 1.5 SDs below the mean are considered âmildly impairedâ or âbelow average,â and those more than 2 SDs below the mean are considered âmoderately to severely impaired.â A neuropsychological evaluation often tests all cognitive domains, including attention, working memory, processing speed, executive functions, language, visuospatial abilities, and learning and memory (Becker et al., 2023). Many clinical challenges are involved in the evaluation and diagnosis of individuals with PCCI. As noted above, some individuals with Long COVID may report brain fog or other cognitive concerns and experience functional impairment, while not necessarily meeting the clinical diagnostic threshold for cognitive impairment (Davis et al., 2023). This may occur for several reasons. First, most neuropsychological measures were developed to assess indi- viduals with neurodegenerative disorders or traumatic brain injury (Casa- letto and Heaton, 2017; Harvey, 2012) and may not adequately capture the often subtle impairment that can result from COVID-19. Similarly, many caveats apply to the normative data with respect to the populations that are considered ânormal,â as norms may not always account adequately for such factors as education, cultural background, language proficiency, and other individual differences. Second, the theory of cognitive reserve posits that individual differ- ences in the ability to cope with brain pathology or damage are influ- enced by the brainâs resilience and adaptability, which is often related to such factors as educational attainment, occupational complexity, lifelong learning and stimulation, and social engagement (Stern et al., 2019). Individuals with a high cognitive reserve may not immediately show PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 70 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 71 impairment on neuropsychological tests for several reasons: (1) they may be adept at using alternative cognitive strategies or recruiting additional brain resources to compensate for those areas that are impaired; (2) they may have started with a higher baseline of cognitive abilities, and thus will still score within the ânormalâ range on tests even if they have expe- rienced some decline; and (3) their brain may be better able to cope with or resist damage because of its adaptability (Stern et al., 2019). At the same time, however, by the time these individualsâ cognitive symptoms become apparent or manifest on neuropsychological tests, the underlying brain pathology may be quite advanced. In some cases, individuals with high cognitive reserve may report subjective cognitive decline; they feel that their cognitive abilities have diminished even if they still score well on formal testing. This subjective feeling may be attributable to patientsâ awareness of subtle changes or difficulties that are not yet detectable with standardized tests, a phenomenon that may be consistent with the concept of brain fog. This phenomenon underscores the importance of considering a comprehensive clinical picture, including subjective reports, daily functioning, and other factors, in conjunction with neuropsycho- logical test scores. Without prior neuropsychological testing, it can be challenging to determine the degree of decline or change from an indi- vidualâs baseline cognitive abilities, especially if those baseline abilities were above-average. Third, performance validity can sometimes be an issue in the clinical evaluation of PCCI. That is, an individualâs performance on neuropsycho- logical tests can be influenced by various factors unrelated to PCCI, such as anxiety, depression, fatigue, or even the specific circ*mstances of the testing day. Such conditions as sleep disorders or chronic pain, medications, or other medical issues can influence cognitive performance and may lead to inconsistent test results, complicating their interpretation. In some cases, an individualâs effort on a test may be called into question; that is, some individuals may have difficulty fully engaging with the evaluation, usu- ally because of psychological or situational factors. It is also possible that individuals may purposely underperform (e.g., for secondary gain, such as disability claims). Fortunately, neuropsychologists have performance valid- ity measures that can detect suboptimal effort. Finally, it is important to note that other conditions can mimic the symptoms of PCCI. For example, depression may increase oneâs perception of brain fog and contribute to poor attention and concentration (Cristillo et al., 2022). Identifying whether cognitive deficits are due to PCCI or other factors can therefore be challenging. For this reason, a thorough medical history can be extremely useful in ruling in or out other potentially con- tributing factors. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 71 5/21/24 10:52 AM
72 LONG-TERM HEALTH EFFECTS OF COVID-19 Functional Impacts Quantifying the functional impacts of PCCI involves integrating a com- prehensive medical history, results of objective neuropsychological tests, subjective symptom reports, and real-world observations. A neuropsycho- logical evaluation can help in identifying specific areas of cognitive strength and weakness and in predicting where an individual may have the most difficulty from day to day. Several instruments (e.g., Instrumental Activities of Daily Living scale) can be used to gauge how PCCI may be impacting daily tasks, such as managing finances, following instructions, or planning activities. Other self- report tools can help capture individualsâ perceptions of their cognitive and functional challenges. For example, numerous self-report instruments have been shown to adequately capture the severity and functional impact of symptoms associated with self-reported brain fog, such as the Neuro-QOL Scale (Shirley Ryan AbilityLab, 2019), the Cogstate (Maruff et al., 2009), or the Everyday Cognition scale (ECog) (Farias et al., 2008). Feedback from family members, coworkers, or educators can also provide a comprehen- sive view of an individualâs functioning by offering insight into observed challenges in task completion, time management, or problem solving in real-world settings. Similarly, review of work performance evaluations or school assessments can be helpful in delineating where an individual may be struggling. Especially in complex cases, a neuropsychologist may work closely with other professionals (e.g., occupational therapists, speech thera- pists, educators, vocational counselors) to provide a holistic understanding of the individualâs functional challenges. Selected Populations Research on PCCI in selected populations is limited. As described above, several studies have found racial and ethnic differences in the inci- dence of PCCI, whereby minoritized populations may be disproportionately impacted (Jacobs et al., 2023). While a neuropsychological evaluation can be extremely valuable in quantifying PCCI and its functional impact, it may not always be accessible to all individuals, and there are many barriers to care. First, because of high demand and a limited number of trained neuro- psychologists, there can be extended wait times for an evaluation. Second, many neuropsychologists practice in urban areas or academic medical cen- ters. Therefore, people living in rural or remote areas may not have easy access to a neuropsychologist and may have to travel significant distances for an evaluation. Third, neuropsychological assessments can be costly, and not all insurance plans cover them adequately; individuals without insur- ance may not be able to afford the evaluation. Finally, in certain cultures PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 72 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 73 or communities, stigma may be associated with seeking psychological or neuropsychological services, preventing some individuals from pursuing an evaluation. In addition, certain populations may not derive the same benefit from an evaluation. Several cultural nuances come into play here. First, indi- viduals who speak languages other than English and those whose cultural background differs from that of the majority U.S. population may not have access to appropriate and culturally sensitive evaluations or even to neu- ropsychologists or interpreters with whom they can communicate, which can lead to misinterpretation of results. Second, most neuropsychological tests were developed and standardized on English-speaking populations, and appropriate normative data may not be available for the individual in question. In this case, an individualâs performance can be over- or under- estimated. Finally, in some cultures, cognitive challenges may be expressed more in somatic or physical terms, which can affect self-report measures, clinical interviews, and even effort on the neuropsychological tests. Thus, data derived from neuropsychological evaluations in such populations must often be interpreted with some caution. Autonomic Dysfunction Orthostatic intolerance and autonomic dysfunction have emerged as a distinct symptom cluster in Long COVID (El-Rhermoul et al., 2023). Autonomic dysfunction is any disturbance of the autonomic nervous sys- tem, inclusive of postural orthostatic tachycardia syndrome (POTS). POTS has increasingly been observed in patients following SARS-CoV-2 infection (Amekran et al., 2022). Other, less frequent types of autonomic dysfunction observed in patients with Long COVID include neurocardiogenic syncope (NCS) and orthostatic hypotension (OH) (Blitshteyn and Whitelaw, 2021). When objective tests do not confirm an established autonomic disorder (i.e., POTS, NCS, or OH), but autonomic symptoms arise upon assuming an upright posture and are relieved by being supine, then the diagnosis of orthostatic intolerance can be given. Some symptoms of autonomic dys- function, such as lightheadedness, improve quickly upon lying down, but other symptoms, such as fatigue and brain fog, can persist for hours or days at a time and can impact activities of daily living (Fedorowski, 2019; Vernino et al., 2021). Although POTS is itself a diagnosable multisystem disorder, it also has emerged as a distinct phenotype of Long COVID (El-Rhermoul et al., 2023). POTS is characterized by a sustained heart rate of 30 beats per minute or more in the absence of orthostatic hypotension (Amekran et al., 2022). Like Long COVID, POTS is a multisystem disorder; common symptoms include PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 73 5/21/24 10:52 AM
74 LONG-TERM HEALTH EFFECTS OF COVID-19 fatigue, nausea, dizziness, palpitations, chest pain, and exercise intolerance. POTS, and autonomic dysfunction generally, often present secondary to viral infections. Some studies have suggested that POTS could contribute to the pathophysiology of Long COVID, explaining the persistence of symp- toms such as fatigue and cognitive issues in Long COVID patients, although the evidence for this hypothesis is limited (Amekran et al., 2022; Barizien et al., 2021; El-Rhermoul et al., 2023; Isaac et al., 2023). Mechanisms of action may include direct tissue damage, immune dysregulation, hormonal disturbances, elevated cytokine levels, and persistent low-grade infection (Carmona-Torre et al., 2022). Autonomic dysfunction appears to play a significant role in Long COVID and its potential neurological complications (Buoite Stella et al., 2022; Diekman and Chung, 2023). The prevalence of POTS in the general U.S. population varies, with estimates ranging from 0.1 to 1 percent and a higher incidence among females, although in the general population is likely significantly under- diagnosed (Arnold et al., 2018; Bhatia et al., 2016; Shaw et al., 2019). POTS occurs most frequently in females aged 12â50 and is less common in young children (Amekran et al., 2022). Among people with Long COVID, one study reports 4.1 percent of respondents had received a diagnosis of POTS by the time of the survey, and 33.9 percent of those who reported tachycardia had symptoms suggestive of POTS (Davis et al., 2021). Another study reported 12 percent of individuals with Long COVID who underwent standard autonomic testing had results consistent with POTS (Bryarly et al., 2022). Studies indicate that 25â66 percent of Long COVID patients report autonomic dysfunction (Ladlow et al., 2022; Larsen et al., 2022). One study found orthostatic hypotension in 14 percent of subjects with Long COVID symptoms (Buoite Stella et al., 2022). Kavi (2022) cites unpublished data indicating that Long COVID clinics report 15â50 percent of patients having postural symptoms. These numbers should be taken as preliminary estimates given that most of the data to date came from small retrospective studies that vary in timing after initial SARS-COV-2 infection, definitions of POTS and autonomic dysfunction, and testing protocols. Diagnosis The diagnostic criteria for POTS are ⢠a sustained increase in heart rate upon assuming an upright position of â¥30 beats per minute in adults or â¥40 beats per minute in adolescents aged 12â19, ⢠the presence of chronic symptoms of orthostatic intolerance for at least 3 months, and ⢠the absence of orthostatic hypotension (Kavi, 2022; Raj et al., 2021, 2022). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 74 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 75 In addition to a detailed medical history and physical examination, evaluating for orthostatic intolerance includes autonomic function tests and questionnaires. Autoantibody testing can provide supporting evidence. Two forms of standing tests are used to diagnose POTS in Long COVID patients. These tests assess heart rate and blood pressure changes upon assuming an upright position, providing insight into autonomic dysfunction and orthostatic intolerance. In the active stand test, patients rest supine for 5 minutes, then immediately stand up, and their blood pressure and heart rate are measured at 2, 5, and 10 minutes. This test captures the immediate response to standing and helps identify orthostatic tachycardia and associ- ated symptoms (Espinosa-Gonzalez et al., 2023). Another potentially useful test is the National Aeronautics and Space Administrationâs (NASAâs) lean test, which involves the patient leaning against a wall after resting supine, with blood pressure and heart rate measured every minute for 10 minutes. This posture minimizes the impact of skeletal muscle pump effects on the cardiovascular system (Espinosa-Gonzalez et al., 2023; Kavi, 2022). These standing tests can be conducted in the primary care setting and may provide valuable information for diagnosing POTS without the need for specialist consultation or specialized equipment (Kavi, 2022). The head-up tilt test is a specialized assessment used in secondary or tertiary health care settings to investigate autonomic dysfunction (Espinosa- Gonzalez et al., 2023). Head-up tilt table testing is usually performed with a motorized table with a foot board for weight bearing (Benditt et al., 1996). The patient lies supine, loosely restrained by safety straps to prevent injury if loss of consciousness occurs. After a variable period of supine rest, usually 15 minutes but in some studies up to 60 minutes, the tilt table is brought upright, usually to 60â70 degrees. This test, designed to explore the underlying causes of loss of consciousness, is the accepted method for investigating fainting in controlled laboratory conditions. During the test, the patient is positioned on a table equipped with motorized tilting capabil- ity. Blood pressure and heart rate measurements are taken while the patient is in a supine position and then gradually tilted upward to approximately 60 degrees for a duration of up to 45 minutes (Espinosa-Gonzalez et al., 2023). If syncope or presyncope occurs, the patient is promptly returned to the supine position. While this specialized test is not essential for a straight- forward diagnosis of orthostatic tachycardia, it is useful in investigating specific symptoms, such as unexplained syncope. Not all individuals with orthostatic symptoms require head-up tilt testing. COMPASS-31 is a standardized, easy-to-complete autonomic question- naire used to screen for autonomic dysfunction and track symptom changes over time (Larsen et al., 2022). Questions fall into one of six domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor function. The questionnaire generates a weighted score from 0 to 100, with a score of â¥20 suggesting moderate to severe autonomic PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 75 5/21/24 10:52 AM
76 LONG-TERM HEALTH EFFECTS OF COVID-19 dysfunction (Larsen et al., 2022). COMPASS-31 is frequently used to assess symptoms of autonomic dysfunction in Long COVID research (Bryarly et al., 2022; Buoite Stella et al., 2022; Seeley et al., 2023). Individuals with Long COVID could benefit from screening for symptoms of autonomic dysfunction (e.g., through use of the COMPASS-31 questionnaire), and those experiencing symptoms of orthostatic intolerance would benefit from further evaluation for disorders such as POTS or orthostatic hypotension (Larsen, Stiles, and Miglis, 2021). Autoantibody testing can provide supporting evidence for diagnosis, although it is currently not particularly sensitive or specific (Carmona- Torre et al., 2022). A feature of POTS following SARS-CoV-2 infection is a high prevalence of specific circulating autoantibodies, including G-protein- coupled receptor (GPCR) antibodies (such as adrenergic, muscarinic, and angiotensin II type-1 receptors) and the ganglionic neuronal nicotinic ace- tylcholine receptor (g-AChR). Other recognized autoantibodies in POTS include circulating antinuclear, antithyroid, anti-NMDA-type glutamate receptor, anticardiac protein, anti-phospholipid, and Sjögrenâs antibodies (Carmona-Torre et al., 2022). Functional Impacts Symptoms resulting from autonomic dysfunction following SARS- CoV-2 infection have a substantial impact on individualsâ functioning and quality of life in the short, medium, and long terms (Carmona-Torre etÂal., 2022). Symptoms are associated with loss of school and work par- ticipation, especially in young women (Bourne et al., 2021). In a study involving 20 adult Long COVID patients (70 percent female), residual autonomic symptoms persisted in 85 percent of participants 6â8 months after SARS-CoV-2 infection, with 60 percent being unable to return to work (Blitshteyn and Whitelaw, 2021). Haloot and colleagues (2022) investigated a sample of 40 Long COVID patients who were diagnosed with POTS and found that disabling symptoms persisted in 100 percent of previously high-functioning participants even after 6 months, indicating the enduring impact of the condition. McDonald and colleagues (2014) assert that young adults with POTS experience a degree of functional impairment compa- rable to that reported in congestive heart failure and chronic obstructive pulmonary disease, leading to a notably low quality of life (McDonald etÂal., 2014). A prospective study of 99 participants, including those with post-acute sequelae of COVID-19 (PASC) (another term used for Long COVID), those with POTS, and healthy controls, revealed a high burden of autonomic dysfunction in those with PASC, leading to poor health-related quality of life and high health disutility (Seeley et al., 2023). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 76 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 77 Approximately 50 percent of patients with POTS recover within 1â3 years, with lifestyle measures aiding recovery (Fedorowski, 2019). Exer- cise therapy, including rowing or cycling, has been shown to be effective in improving functioning in individuals with POTS following COVID-19. A minimum of 3 months of exercise therapy has been recommended, and symptoms often worsen before improving (Fu and Levine, 2018; Shibata et al., 2012). The course of recovery for symptoms associated with autonomic dysfunction in Long COVID entails remitting and relapsing as a result of various factors, such as comorbid conditions, stress, and overexertion (Barizien et al., 2021; Seeley et al., 2023); therefore exercise therapy must be individualized and closely monitored. Assessing the ability to work in individuals experiencing orthostatic intolerance is challenging because of the unpredictable postexertional increase in symptoms for several days after prolonged periods of upright posture. This intolerance can significantly contribute to disability, and the ability to quantify the extent of functional impairments is limited. Self- reported symptom severity is critical in evaluating disability in individuals dealing with both orthostatic intolerance and Long COVID. Overall functioning in chronic illnesses is often assessed in adults through self-report health-related quality of life questionnaires, such as the 36-Item Short Form Survey (SF-36), the EuroQOL, or the Patient- Reported Outcomes Measurement Information (PROMIS) questionnaires (Cook et al., 2012; EuroQol Group, 1990; Ware and Sherbourne, 1992). A newly developed self-report questionnaire, the Malmö POTS symptom score, has shown promise for assessing symptom burden and measuring disease progression in adults with POTS (Spahic et al., 2023). For pediatric patients, age-specific instruments, such as the Functional Disability Inven- tory or Pediatric Quality of Life (PedsQL), are used into young adulthood, effectively distinguishing between healthy and chronically ill individuals (Claar and Walker, 2006; Varni et al., 2001; Walker and Greene, 1991). Self-reported measures of general or cognitive fatigue include the PedsQL, the Multidimensional Fatigue Inventory (MFI), the Wood Mental Fatigue Inventory, the Fatigue Severity Scale, and others (Bentall et al., 1993; Krupp et al., 1989; Varni and Limbers, 2008; Wood et al., 1991). Selected Populations Research on Long COVID-associated POTS in selected populations is limited. In a recent study of pregnant women with POTS not specific to Long COVID (8,941 female patients, 40 percent pregnant), the authors found that the severity of pregnancy symptoms in the first trimester could predict the severity of symptoms in the second and third trimesters PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 77 5/21/24 10:52 AM
78 LONG-TERM HEALTH EFFECTS OF COVID-19 (Bourne et al., 2023). If symptoms improved in the first trimester, they were more likely to continue to improve in the later trimesters, while if symptoms worsened in the first trimester, they were likely to continue to worsen in the second and third trimesters. Other selected populations that may experience autonomic dysfunction from Long COVID and thus require health equity considerations include people with certain condi- tions and/or disabilities, racial and ethnic minorities, people diagnosed as overweight or obese, and uninsured or underinsured individuals. One example of clinical considerations regarding health equity is those with impaired mobility or severe orthostatic intolerance. Some of these patients may be unable to perform standard testing for autonomic dysfunction, such as a 10-minute stand test, requiring testing modifications (Blitshteyn et al., 2022). HEALTH EFFECTS OF LONG COVID IN CHILDREN AND ADOLESCENTS While there are various definitions of children, adolescents, and young people, for the purposes of this report âchildrenâ or âpediatricsâ will refer to the entire pediatric age range and âadolescentsâ to children in the older end of the spectrum (i.e., ages ~11 to 18 years). Although rates vary by age, children infected with SARS-CoV-2 usually have mild disease (COVID-19) with low rates of hospitalization (<2 percent) or death (<0.01 percent) (Bhopal et al., 2020; Bhopal et al., 2021). Nonetheless, persistent health effects following SARS-CoV-2 infection have been reported in children, with multisystem inflammatory syndrome in children (MIS-C) and Long COVID being commonly reported (Lopez-Leon et al., 2022). Addition- ally, Kompaniyets and colleagues (2022) found selected health effects for which children with SARS-CoV-2 infection are at increased risk: pulmonary embolism (adjusted hazard ratio [aHR] 2.01), myocarditis and cardiomy- opathy (aHR 1.99), venous thromboembolic events (aHR 1.87), acute and unspecified renal failure (aHR 1.32), type 1 diabetes mellitus (aHR 1.23), coagulation and hemorrhagic disorders (aHR 1.18), smell and taste distur- bances (aHR 1.17), type 2 diabetes (aHR 1.17), and cardiac dysrhythmias (aHR 1.16). Vaccination has been shown to reduce the risk of infection and protect against COVID-19âassociated illness, including MIS-C, in children (Fowlkes et al., 2022; Tannis et al., 2023; Yousaf et al., 2023; Zambrano et al., 2022), although the majority of children in the United States remain unvaccinated against COVID-19 (AAP, 2023; CDC, 2021a; Zambrano etÂal., 2024). Among the long-term health effects of COVID-19, type 1 diabetes has garnered specific attention, showing a higher incidence rate among children in the first year of the pandemic compared with a prepandemic period PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 78 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 79 (incidence rate ratio [IRR], 1.14; 95% CI, 1.08â1.21) (DâSouza et al., 2023). This finding was mirrored in the months 13â24 of the pandemic, as shown in a meta-analysis (IRR, 1.27; 95% CI, 1.18â1.37) (DâSouza et al., 2023). The increased risk of type 1 diabetes in children after SARS-CoV-2 infection was found even when compared with diagnosis of acute respira- tory infection unrelated to COVID-19 (Barrett et al., 2022; Rahmati et al., 2023; DâSouza et al., 2023). Additional studies are needed to further delineate this phenomenon. MIS-C presents within 2â6 weeks of acute SARSs-CoV-2 infection as a systemic inflammatory illness. Criteria for case definition include sever- ity necessitating hospitalization, fever above 100.4 degrees Fahrenheit, laboratory evidence of systemic inflammation, and multisystemic organ involvement that cannot be explained by another diagnosis (CDC, 2023a). Organ systems affected by MIS-C include gastrointestinal (80â90 per- cent), mucocutaneous (74â83 percent) cardiovascular (66.7â86.5 percent), hematologic (47.5 percent), respiratory (36.5 percent), and neurologic (12.2 percent) (Blatz and Randolph, 2022). Reassuringly, with MIS-Câ directed treatment, the mortality rate has been 1-2 percent (Blatz and Randolph, 2022; Feldstein et al., 2021). Although children with MIS-C present as critically ill, most inflamma- tory and cardiac manifestations resolve rapidly (Rao et al., 2022; Penner et al., 2021). However, some children do experience more long-lasting effects (Penner et al., 2021). One study tested children 6 months after hospitaliza- tion on the 6-minute-walk test and found that 45 percent of the patients scored below the 3rd percentile for age, demonstrating functional impair- ment (Penner et al., 2021). In this same study, 98 percent of the children were able to return to full-time education, but formal neuropsychological testing was not conducted to assess school performance (Penner et al., 2021). More research is needed to characterize the potential long-term effects of MIS-C. Pediatric Long COVID is a separate entity from MIS-C. The true preva- lence of Long COVID symptoms and health effects remains unclear for multiple reasons and varies widely in the literature, including limited stud- ies and heterogeneous samples (Pellegrino et al., 2022). However, rates of pediatric Long COVID are lower than the rates of adult Long COVID (Behnood et al., 2022; CDC, 2023b; Jiang et al., 2023; Rao et al., 2022; Zheng et al., 2023). The risk of Long COVID may be associated with severe symptoms during initial infection, hospitalization, the number of organ systems involved, the number of symptoms at presentation, lack of vacci- nation against COVID-19, medical complexity, and body mass index â¥85th percentile for age and sex (Bygdell et al., 2023; Funk et al., 2022; Rao et al., 2022). Children with MIS-C may also develop Long COVID (Maddux et al., 2022) PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 79 5/21/24 10:52 AM
80 LONG-TERM HEALTH EFFECTS OF COVID-19 Children with Long COVID may have health effects across body sys- tems (Table 3-2). Commonly reported symptoms include fatigue (sometimes with PEM), weakness, headache, sleep disturbance, muscle and joint pain, respiratory problems, palpitations, altered sense of smell or taste, dizzi- ness, and autonomic dysfunction (Morrow et al., 2022; Rao et al., 2022). Guidelines specific to pediatric Long COVID can aid in the diagnosis and management of the condition in children (Malone et al., 2022). A systematic review of 22 studies (n = 23,141) from 12 countries iden- tified fatigue (47 percent) as the most dominant Long COVID symptom in children and young people (age ⤠19 years old), followed by headache (35 percent) (Behnood et al., 2022); these findings are consistent with those of several adult studies (Cheung et al., 2023; LÃÅ¡ka et al., 2022; Sánchez- GarcÃa et al., 2023; ÅteËpánek et al., 2023). In another systematic review and meta-analysis of 21 pediatric studies (n = 80,071), the prevalence of Long COVID was reported as 25.24 percent, with fatigue (9.66 percent) being the second most dominant clinical manifestation, behind mood symptoms (16.50 percent). Sleep disorders (8.42 percent), headache (7.84 percent), and respiratory symptoms (7.62 percent) were among the top-ranked Long COVID manifestations (Lopez-Leon et al., 2022). It is important to note that for this systematic review and meta-analysis, Long COVID criteria included symptoms lasting for at least 4 weeks, which likely contributed to the higher reported prevalence compared with findings of other studies. Studies have shown that isolation, increased stress, and loss of parents and caregivers significantly impacted childrenâs development during the pan- demic and may lead to a future rise in mental illnesses (Lopez-Leon et al., 2022) and other Long COVID sequelae. Fatigue and PEM present similarly in pediatric populations compared to adults and are common in children with Long COVID; however, data from pediatric populations with ME/CFS indicate better long-term recovery compared with adults (Carruthers et al., 2011). In a cohort observational study of nearly 800 children, ME/CFS had a mean duration of 5 years, with 54 percent of patients reporting recovery between 5-10 years, and 68 per- cent of patients reporting recovery after more than 10 years (Rowe, 2019); this issue has not been explicitly studied in children with Long COVID. POTS and other forms of autonomic dysfunction have also been reported in children with Long COVID (Morrow et al., 2022). Presenta- tions and symptomatology, including orthostatic dizziness, palpitations, chest pain, diaphoresis, and nausea, are similar to those in adults. However, the diagnostic criteria for POTS are different in children and in adults: for individuals aged 12â19, the required heart rate increment is an increase of at least 40 beats/minute on a standing tolerance test, compared with 30 beats/minute in adults (Morrow et al., 2022; Vernino et al., 2021). One study compared 29 adolescents with Long COVID who developed PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 80 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 81 TABLE 3-2â Common Long COVID Symptoms in Children and Adolescents by Body System Respiratory Shortness of breath or dyspnea Chest (thoracic) pain or tightness Cough Difficulty with activity/exercise intolerance Cardiovascular Palpitations or tachycardia Dizziness/lightheadedness Syncope Chest pain Difficulty with activity/exercise intolerance Neurological Headache Dizziness/lightheadedness or vertigo Orthostatic intolerance Syncope or presyncope Tremulousness Paresthesia or numbness Difficulty with attention/concentration Difficulty with memory Cognitive impairment or brain fog Special Senses Abnormal or loss of smell or taste Musculoskeletal Weakness Muscle, bone, or joint pain Gastrointestinal Nausea Vomiting/reflux Abdominal pain Bowel irregularities (constipation/diarrhea) Weight loss Lack of appetite Mental Health Anxiety Depression/low mood Increased somatic symptoms School avoidance Regression of academic or social milestones No specific organ system Fatigue (general); Post exertional malaise Exercise intolerance Sleep disturbances Fever SOURCES: Behnood et al., 2022; Borch et al., 2022; Drogalis-Kim et al., 2022; Funk et al., 2022; Jiang et al., 2023; Kompaniyets et al., 2022; Kostev et al., 2022; Leftin Dobkin et al., 2021; Lopez-Leon et al., 2022; Malone et al., 2022; Mariani et al., 2023; Morrow et al., 2022; Pellegrino et al., 2022; Radtke et al., 2021; Riera-Canales and Llanos-Chea, 2023; Roessler et al., 2022; Sansone et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 81 5/21/24 10:52 AM
82 LONG-TERM HEALTH EFFECTS OF COVID-19 an inappropriate sinus tachycardia or POTS with 64 adolescents who developed autonomic dysfunction prior to the COVID-19 pandemic. The authors concluded that, at least with regard to heart-rate variability, ado- lescents with POTS diagnosed following SARS-CoV-2 infection were not significantly different from the prepandemic controls (Buchhorn, 2023). Management of POTS is similar for children and for adults, with lifestyle interventions and physical therapy protocols being first line, augmented by medications when indicated. PostâCOVID-19 cognitive impairment (PCCI) or brain fog is reported in children with Long COVID and may manifest in behavioral changes and declining school performance. Limited research has focused on the chronic cognitive effects of COVID-19 in children. Objective neuropsychological data in pediatric patients have shown increased attention deficits in these patients and elevated mood/anxiety concerns (Luedke et al., 2024; Mor- row et al., 2021; Ng et al., 2022; Tarantino et al., 2022), although these data came from small, single-center studies. In a survey of 510 children with ages ranging from 1-18 years, 61 percent had poor concentration, 46 percent had difficulty remembering information, 40 percent struggled with completing everyday tasks, and 33 percent had difficulties with informa- tion processing (Buonsenso et al., 2022). Importantly, other factors, such as fatigue and mental health problems, should be evaluated when cognitive problems are suspected, as these and other factors can contribute to poor attention and other cognitive difficulties. With respect to management, a cognitive rehabilitation approach should be considered to improve attention regulation and help the child develop compensatory strategies. Whenever possible, support and accommodations should be offered in school settings to prevent the child from falling further behind academically. Periodic reassessment of cognitive functions is also prudent to monitor progress over time. Finally, screening for mental health problems is critical in children with post-COVID cognitive impairment, as PCCI can greatly impact quality of life. Children with Long COVID may experience new or worsening mental health conditions, such as anxiety and depression. One study with 236Âpedi- atric Long COVID patients found that irritability, mood changes, and anxi- ety or depression were found in 24.3 percent, 23.3 percent, and 13.1 percent of the cohort, respectively, suggesting a high prevalence of persistent psychi- atric symptoms (Roge et al., 2021). Children may experience anxiety and depression differently from adults. Signs of depression can include behav- ioral problems at school, changes in eating or sleeping habits, and lack of interest in fun activities, while signs of anxiety in children can include fear of being away from a parent, physical symptoms of panic, and refusal to go to school. Diagnosis involves ruling out other conditions that may affect mood, and often includes interviews with the child and their caregivers (Cleveland PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 82 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 83 Clinic, 2023). Management of mood disorders for pediatric patients with Long COVID is the same as management for those without Long COVID (e.g., psychotherapy, medications); however, special consideration is war- ranted for the other comorbid Long COVID symptoms and how they may interact with mood disorders or their treatment. The most common anti- depressants for children are selective serotonin reuptake inhibitors (SSRIs), which increase the level of serotonin in the brain. Although there may be overlap between pediatric and adult presenta- tions and intervention options, particularly among adolescents, pediatric management of Long COVID entails specific considerations: developmen- tally, some young children and those with developmental disabilities may have difficulty describing their symptoms, and patient histories may come from parents and others outside the home, such as caregivers, coaches, or teachers. Compared with adults, children are healthier, with fewer preex- isting chronic health conditions. Conditions that may increase the risk of Long COVID in adults, such as type 2 diabetes, are rarely seen in pediatrics, and Long COVID may therefore represent a large change from baseline for previously healthy children (Malone et al., 2022). In addition to adverse effects of pediatric Long COVID on participa- tion and performance in school, sports, and other activities (Morello et al., 2023; Pellegrino et al., 2022), it also has been shown to negatively affect family functioning as a whole (Chen et al. 2023). Management of pediatric Long COVID is focused on symptomatic support and from a functional perspective, on activities of daily living, such as participation in school and in activities and hobbies. Additionally, the American Heart Association and American Academy of Pediatrics recommend that those treating pediatric patients with moderate or severe acute SARS-CoV-2 infection or with any prolonged cardiac symptoms (e.g., fatigue, syncope, palpitations) use a screen to assess for the possibility of cardiac complications before recom- mending a return to physical activity (AAP, 2022a). While the trajectory for children affected by Long COVID is more favorable than that for adults, additional studies are needed to better understand and characterize the diversity of presentations in children and long-term implications related to quality of life and function. The National Institutes of Healthâs (NIHâs) Researching COVID to Enhance Recovery (RECOVER) initiative currently has ongoing clinical trials and studies under way aimed at further understanding how to treat and prevent Long COVID in children in addition to adults (NIH, 2023). However, more research is still needed (Long COVID and kids: More research is urgently needed, 2022). As detailed in Chapter 1, SSAâs definition and determination of dis- ability in children and adolescents (<18 years) differs from those in adults. âDisabilityâ for adults in the SSA context centers on work disability or an PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 83 5/21/24 10:52 AM
84 LONG-TERM HEALTH EFFECTS OF COVID-19 inability to perform work-related activities (see, e.g., Annex Table 3-13 at the end of this chapter) and to participate in work âin an ordinary work set- ting, on a regular and continuing basis, and for 8 hours per day, 5 days per week, or an equivalent work scheduleâ (SSA, 2021). In contrast, the defini- tion and determination of disability in children incorporates the concept of functioning more broadly (i.e., a childâs qualifying impairment(s) must cause âmarked and severe functional limitationsâ1). When evaluating the effects of an impairment or combination of impairments on a childâs functioning, SSA considers âhow appropriately, effectively, and independentlyâ the child performs their activities (everything they do at home, at school, and in the community) âcompared to the performance of other children [their] age who do not have impairments.â2 In particular, SSA considers functioning in six domains: acquiring and using information, attending and completing tasks, interacting and relating with others, moving about and manipulating objects, caring for [oneself], and health and physical well-being.3 SELECTED GUIDANCE STATEMENTS SPECIFIC TO LONG COVID In addition to the diagnosis and management guidelines included in Annex Tables 3-1 through 3-12, selected guidance statements specific to Long COVID are listed in Table 3-3. The CDC (2024b) maintains a web- page with information on Long COVID (which the CDC refers to as Post-COVID conditions) for health care providers and the general public, covering the topics of assessment and testing, management, documentation, research, and tools and resources. The latter includes a list of âmedical professional organization expert opinion and consensus statements.â The World Health Organization (WHO) (2023a) also maintains a webpage on âclinical management of COVID-19,â which includes a link to the most recent version of its COVID-19 Clinical Management: Living Guidance document. This publication contains âthe most up-to-date recommenda- tions for the clinical management of people with COVID-19â and includes a section on the âcare of COVID-19 patients after acute illnessâ (WHO, 2023a). In the United Kingdom, the National Institute for Health and Care Excellence, Scottish Intercollegiate Guidelines Network, and Royal College of General Practitioners jointly developed a guideline addressing identifica- tion, assessment, and management of the long-term effects of COVID-19 and offering ârecommendations about care in all healthcare settings for adults, children and young people who have new or ongoing symptoms 1â20 CFR 416.906. 2â20 CFR 416.926a. 3â20 CFR 416.926a. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 84 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 85 TABLE 3-3â Selected Guidance Statements on Long COVID Author Title Last revised Source Centers for Disease Control Post-COVID conditions: February 6, CDC and Prevention Information for healthcare 2024 (2024b) providers World Health Organization Clinical management of August 18, WHO COVID-19: Living guideline, 2023 (2023a) 18 August 2023 National Institute for COVID-19 rapid guideline: November 11, NICE Health and Care Excellence, Managing the long-term effects 2021 (2021a) Scottish Intercollegiate of COVID-19 Guidelines Network, and Royal College of General Practitioners Catalan Society of Family Long Covid-19: Proposed April 20, 2021 Sisó- and Community Medicine Primary Care Clinical Almirall Long COVID-19 Study Guidelines for Diagnosis and et al. Group Disease Management (2021) American Academy of Post-COVID-19 conditions in September 2, AAP Pediatrics children and adolescents 2022 (2022b) American Academy of Multi-disciplinary collaborative August 11, Malone Physical Medicine and consensus guidance statement 2022 et al. Rehabilitation (AAPMR) on the assessment and (2022) PASC Multi-Disciplinary treatment of postacute sequelae Collaborative Pediatric of SARS-CoV-2 infection Work Group (PASC) in children and adolescents AAPMR PASC Multi- Multidisciplinary collaborative July 26, 2021 Herrera Disciplinary Collaborative consensus guidance statement et al. Writing Group on the assessment and treatment (2021) of fatigue in postacute sequelae of SARS-CoV-2 infection (PASC) patients AAPMR PASC Multi- Multi-disciplinary collaborative November 29, Maley Disciplinary Collaborative consensus guidance statement 2021 et al. Writing Group on the assessment and treatment (2022) of breathing discomfort and respiratory sequelae in patients with post-acute sequelae of SARS-CoV-2 infection (PASC) AAPMR PASC Multi- Multi-disciplinary collaborative December 1, Fine et al. Disciplinary Collaborative consensus guidance statement 2021 (2022) Writing Group on the assessment and treatment of cognitive symptoms in patients with post-acute sequelae of SARS- CoV-2 infection (PASC) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 85 5/21/24 10:52 AM
86 LONG-TERM HEALTH EFFECTS OF COVID-19 TABLE 3-3âContinued Author Title Last revised Source AAPMR PASC Multi- Multi-disciplinary collaborative May 27, 2022 Whiteson Disciplinary Collaborative consensus guidance statement et al. Writing Group on the assessment and (2022) treatment of cardiovascular complications in patients with post-acute sequelae of SARS- CoV-2 infection (PASC) AAPMR PASC Multi- Multi-disciplinary collaborative June 3, 2022 Blitshteyn Disciplinary Collaborative consensus guidance statement et al. Writing Group on the assessment and (2022) treatment of autonomic dysfunction in patients with post-acute sequelae of SARS- CoV-2 infection (PASC) AAPMR PASC Multi- Multidisciplinary collaborative March 29, Melamed Disciplinary Collaborative consensus guidance statement 2023 et al. Writing Group on the assessment and (2023) treatment of neurologic sequelae in patients with post- acute sequelae of SARS-CoV-2 infection (PASC) AAPMR PASC Multi- Multidisciplinary collaborative November 8, Cheng Disciplinary Collaborative consensus guidance statement 2023 et al. Writing Group on the assessment and (2023) treatment of mental health symptoms in patients with post-acute sequelae of SARS- CoV-2 infection (PASC) 4 weeks or more after the start of acute COVID-19â (NICE, 2021a). Likewise, a Long COVID study group of the Catalan Society of Family and Community Medicine (Spain) issued proposed primary care clinical guidelines for the diagnosis and management of the condition in 2021 (Sisó- Almirall et al., 2021). The stated primary objective of the guidelines is the identification of individuals âwith signs and symptoms of long COVID-19 . . . through a protocolized diagnostic process that studies possible etiolo- gies and establishes an accurate differential diagnosisâ (Sisó-Almirall et al., 2021, p. 4350). Pediatric guidance on Long COVID in the United States includes statements from the American Academy of Pediatrics (AAP, 2022b) and a pediatric work group in alliance with the American Academy of Physical Medicine and Rehabilitation (AAPMR) PASC Multi-Disciplinary Collab- orative (Malone et al., 2022). The AAP guidance provides information on PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 86 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 87 Long COVID in children and adolescents and evaluation and management of some of the potential ongoing symptoms. To assist primary care physi- cians and assist in initial specialty evaluations for children and adolescents with Long COVID, the AAPMR pediatric guidance statement addresses the initial evaluation of children and adolescents with Long COVID and potential health effects in different body systems, as well as return to play or activity and accommodations for school and activities (Malone et al., 2022). Work groups of the AAPMR PASC Multi-Disciplinary Collaborative have also issued guidance statements on the diagnosis and management of health effects of Long COVID in specific areas: fatigue, breathing discom- fort and respiratory sequelae, cognitive symptoms, cardiovascular compli- cations, autonomic dysfunction, neurologic sequelae, and mental health (Blitshteyn et al., 2022; Cheng et al., 2023; Fine et al., 2022; Herrera etÂal., 2021; Maley et al., 2022; Melamed et al., 2023; Whiteson et al., 2022). OVERVIEW OF BODY SYSTEMS POTENTIALLY AFFECTED IN LONG COVID In addition to the information in Annex Tables 3-1 through 3-12 on selected health effects associated with Long COVID, the following narra- tives, organized by body system, provide a high-level overview of diagnos- tic, management, and other information potentially relevant to adults with Long COVID. It is important to note that symptoms and health conditions may cross two or more body systems. Respiratory System Persistent respiratory symptoms and conditions are common in patients with Long COVID (Evans et al., 2023). The underlying pathophysiology for these symptoms and conditions is complex and multifactorial, encompass- ing persistent cardiac, pulmonary, or vascular dysfunction. The diagnostic approach to patients with these symptoms and conditions in Long COVID involves a clinical history and physical examination, and may include blood, radiologic, and other diagnostic tests, such as the 1-minute sit-to-stand test, chest X-ray, and pulmonary function testing (Daines et al., 2022). Computed tomography pulmonary angiography (CTPA) or ventilation perfusion (VQ) scintigraphy and VQ single-photon emission computed tomography (Daines et al., 2022; Kim et al., 2022) may be used to identify pulmonary vascular manifestations after acute SARS-CoV-2 infection. In general, the manage- ment approaches for all these respiratory symptoms and conditions in Long COVID are not specific to Long COVID, although some studies indicate the use of steroids to improve radiological, subjective, and functional outcomes in selected patients with post-COVID-19 pulmonary involvement (Dhooria PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 87 5/21/24 10:52 AM
88 LONG-TERM HEALTH EFFECTS OF COVID-19 et al., 2022; Goel et al., 2021; Mizera et al., 2024; Myall et al., 2021). Management of respiratory symptoms and conditions associated with Long COVID varies based on the severity of the symptoms, the level of functional impairment, comorbid illnesses, and other clinical factors. Cardiovascular System Cardiovascular symptoms and conditions are common following acute SARS-CoV-2 infection, and can include cardiopulmonary symptoms (e.g., chest pain, dyspnea, or palpitations), cardio-neuro symptoms, cardiac inflammatory diseases (e.g., myocarditis and pericarditis), and collateral damage from acute coronary syndromes (DePace and Colombo, 2022; Satterfield et al., 2022). Diagnostic approaches for cardiovascular symp- toms and conditions related to Long COVID include electrocardiogram (ECG); transthoracic echocardiography; echocardiography; stress testing; event monitoring; and laboratory assessments such as cardiac biomarkers, cell counts, inflammatory markers, and coagulation markers. Functional tests, such as the 3-minute active stand test, 10-minute POTS assessment, and 6-minute walking test, may be administered. Cardiac magnetic reso- nance (CMR) can be used to determine abnormalities in ventricular and systolic function; pericardial effusion; and such abnormalities as myocar- ditis, epicarditis, pericarditis, and endocarditis (Satterfield et al., 2022; Von Knobelsdorff-Brenkenhoff and Schulz-Menger, 2023). Cardiopulmonary exercise testing can be used to better understand the relevant factors con- tributing to post-COVID diminished exercise capacity. As mentioned in the earlier discussion of PEM, two consecutive days of CPET can help diagnose PEM in individuals with ME/CS (Davenport et al., 2019; Stevens etÂal., 2018). Long COVID patients may exhibit various ECG abnormalities, including sinus tachycardia, ST changes, T-wave abnormalities, prolonged QT interval, low voltage, and bundle branch block. Management of cardiovascular issues related to Long COVID currently involves symptom management and rehabilitation. Although there are no specific guidelines for cardiac inflammatory diseases such as myocarditis, ongoing research is exploring the use of antivirals, steroids, and nonsteroidal anti-inflammatory drugs in this condition (Raman et al., 2022). In general, the management approaches for all the cardiovascular symptoms and conditions in Long COVID, are not specific to Long COVID and treatment approaches generally follow the routine guidelines for the underlying condition. Neurological System A growing body of evidence indicates that Long COVID can manifest as neurological sequelae, affecting the central and/or peripheral nervous system. Some manifestations occur during the acute phase in hospitalized PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 88 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 89 patients or as sequelae of a major neurological event, such as a stroke, while other relevant symptoms and conditions either continue or emerge weeks after infection. The neurological abnormalities observed in Long COVID likely arise from a multifaceted interplay of direct viral effects, autoimmunity, inflammation, mitochondrial dysfunction, vascular changes and thrombosis, hormonal imbalances, and persistent viral presence. A comprehensive understanding of these pathophysiological mechanisms is essential for the development of targeted therapeutic strategies for manag- ing and alleviating the neurological sequelae of Long COVID. Manage- ment can include pharmacological interventions; physical therapy; pacing; occupational therapy, including lifestyle modifications; and psychological therapy (Tana et al., 2022). Special Senses Research on the specific abnormalities of the special senses such as vision, hearing, balance, taste, and smell in Long COVID is still emerging, and understanding of these abnormalities is evolving. Some individuals with Long COVID have reported persistent alterations in taste and smell, a condition known as anosmia (loss of smell) and ageusia (loss of taste). Additionally, studies have found visual and auditory disturbances, such as blurry vision, tinnitus, or hearing loss, in some Long COVID patients. These sensory changes can impact quality of life and may persist after acute SARS-CoV-2 infection even after other COVID-19 symptoms have resolved. In addition to diminishing quality of life, impaired or loss of smell and taste may lead to changes in eating habits (Ferrulli et al., 2022), poten- tially resulting in weight loss and worsening of other symptoms, including fatigue. Abnormalities of the special senses should be assessed in patients suspected of having Long COVID; however, a thorough medical history and physical examination are always advisable. There are no well-established treatments for dysfunctions of the special senses due to Long COVID. The authors of a systematic review (Khani et al., 2021) propose several potential medications for treating Long COVID anosmia and ageusia, including pentoxifylline, zinc, omega-3, intranasal fluticasone, intranasal insulin, statins, and melatonin. Musculoskeletal System Individuals with Long COVID frequently report musculoskeletal and pain conditions alongside a range of other symptoms, complicating their pain experience and impacting their function and quality of life. Skeletal muscle abnormalities have been associated with lower exercise capacity, and exercise-induced myopathy has been noted with PEM (Appelman etÂal., 2024). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 89 5/21/24 10:52 AM
90 LONG-TERM HEALTH EFFECTS OF COVID-19 Diagnosis of musculoskeletal manifestations of Long COVID requires a thorough workup that ranges from noninvasive techniques (e.g., radiol- ogy/imaging) to invasive maneuvers (e.g., biopsy). A detailed medical his- tory and physical examination is the first step, before any diagnostic test. Evidence is currently insufficient to recommend or advise against tests including creatine kinase, lactate dehydrogenase, c-reactive protein (CRP), rheumatologic factor, and antinuclear antibody in patients with arthralgia and myalgia lasting more than 12 weeks after COVID-19 (Kim et al., 2022). There currently is no specific treatment for the musculoskeletal man- ifestations of Long COVID; patient-centered symptomatic management aimed at improving the quality of life is the goal by default (Calabrese et al., 2022). In a systematic review, Balcom and colleagues (2021) report that Long COVID myositis showed a favorable response to steroids, intravenous immunoglobulin, and tocilizumab. Baricitinib, an anti-inflammatory drug used to treat rheumatoid arthritis, has shown promising results; however, its association with increased risk for the development of malignancy has warranted further investigation (Assadiasl et al., 2021). Physical therapy (low-intensity aerobic training exercises) and psychological measures have proven to be effective in improving muscle strength (Nambi et al., 2022). Of note, people with Long COVID can exhibit changes in skeletal muscle mitochondrial function and metabolism that can further deteriorate with PEM; therefore, engaging in intense exercise is not advisable for some indi- viduals with Long COVID (Appelman et al., 2024). Endocrine System Several conditions consistent with endocrine dysfunction, including diabetes mellitus (DM), dyslipidemia, thyroid dysfunction, adrenal dysfunc- tion, and reproductive hormone dysfunction, have been noted in patients with Long COVID. The interplay between the endocrine system and Long COVID can be bidirectional: studies have shown a higher risk of develop- ing Long COVID in patients with DM or overweight, but have also shown that treatments, such as corticosteroids, potentially used both for acute SARS-CoV-2 infection and Long COVID may increase the risk of develop- ing endocrine and metabolic disease (Bornstein et al., 2022). Thyroid dysfunction has also been reported in Long COVID. Findings are mixed, however, as to the true role played by thyroid dysfunction and even the presence of antithyroid antibodies in Long COVID patients (Lui et al., 2023; Sunada et al., 2022). Adrenal dysfunction has also been postulated as a relevant feature in patients with Long COVID. Of note, lower levels of serum cortisol have been described in patients with Long COVID compared with nonâLong COVID healthy controls (Klein et al., 2023). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 90 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 91 Finally, the presence of reproductive hormonal dysfunction in patients with Long COVID has been hypothesized, due mainly to epidemiological factors and to a high incidence (74 percent of females) of patient-reported changes in menstrual cycle as part of the Long COVID complex of symp- toms. However, no clear entity has been identified to define a clear diagnos- tic pathway (Lott et al., 2023). The diagnosis and treatment of endocrine dysfunction is similar for individuals with and without Long COVID. Immune System The immune system is an integral part of the response to SARS-CoV-2 infection itself, as its proper function is critical for the ability to contain and eliminate the infection prior to any additional therapeutic support. Given its role in the control and containment of the primary infection, it is not surprising that dysregulation of the immune system has been reported by patients with Long COVID. Different levels of immune dysregulation have been identified in patients with Long COVID, including differences in the levels of circulating myeloid and lymphocyte populations compared with control patients with- out Long COVID; increased levels of antibody response to SARS-CoV-2; and increased levels of antibody response to other pathogens, especially Epstein-Barr virus (Klein et al., 2023). Notably, these abnormalities are not diagnostic of Long COVID, but are observations that support immune dysregulation among Long COVID patients. Immune dysregulation is a broad theme. The immune system overlaps with all the other body systems and functions, and so the dysregulation noted in patients with Long COVID is hypothesized to potentially affect viral persistence and replication and gut microbiota dysbiosis, and to lead to autoimmunity and immune priming, blood clotting and endothelial abnor- malities, and dysfunctional neurological signaling (Bellanti et al., 2023). Patients with Long COVID frequently report symptoms compatible with mast cell activation syndrome (MCAS). Several of the symptoms fre- quently seen in Long COVID overlap with those seen in MCAS, which can lead to diagnostic confusion. The diagnostic criteria for MCAS are well established by international societies and are applied similarly in Long COVID patients (Valent et al., 2021). Treatment of MCAS depends on the individualâs symptoms. It involves, first, guaranteeing anaphylaxis management ability through education and permanent availability of an epinephrine auto-injector and additionally controlling the different mast cell mediators. Treatment is standardized by society guidelines and applies to all patients with MCAS, regardless of the presence of Long COVID (Valent et al., 2020). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 91 5/21/24 10:52 AM
92 LONG-TERM HEALTH EFFECTS OF COVID-19 Gastrointestinal System Individuals with Long COVID frequently report gastrointestinal symp- toms, in isolation or combined with other symptoms. These symptoms may be compatible with such diagnoses as gastroesophageal reflux disease and irritable bowel syndrome, with similar presentations and management. Genitourinary System The relationship between chronic kidney disease and COVID-19 is bidirectional: chronic kidney disease increases susceptibility to COVID-19 infection and risk for severe disease, and Long COVID increases the risk of chronic kidney disease, even independently of acute kidney injury (Schiffl and Lang, 2023). The risk of renal dysfunction increases proportional to the severity of the acute COVID-19 infection (nonhospitalized, hospital- ized, or ICU), although the risk extends to all patients, including those with milder cases of COVID-19 (Bowe et al., 2021). Kidney dysfunction is often a silent problem that can progress without being discovered. It is therefore important to monitor kidney function in Long COVID patients who are at higher risk of kidney disease. Diagnosis involves a combination of medical history, physical examination, laboratory tests, and imaging studies, as used in the general population. Kidney care is an integral part of post-acute care for COVID-19. Treat- ment and management depend on the disease (i.e., chronic kidney disease or acute kidney injury) and stage, and those protocols are also applied to patients with and without Long COVID according to standardized guidelines. Integumentary System Cutaneous manifestations of Long COVID are relatively mild and last an average of 7 to 15 days (Freeman et al., 2023; Martora et al., 2023 Mass General, 2022; Polly and Fernandez, 2022). These conditions would most likely not rise to the level of a disabling impairment. Mental Health Because SARS-CoV-2 infection can affect the brain, some of its post- acute sequelae may manifest in the form of neuropsychiatric disorders, including depression, anxiety, and adjustment and stress disorders. These disorders are likely driven by structural and/or functional brain alterations following infection and should not be misconstrued as evidence of a psy- chological basis for Long COVID. That said, mental health problems can also arise as a secondary or tertiary effect of Long COVID, as well as of PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 92 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 93 the global pandemic more broadly. That is, with the rapid spread of SARS- CoV-2 arose the strict implementation of widespread social restrictions (e.g., quarantine, social distancing measures), often coupled with occupa- tional loss and economic hardships. These factors should also be considered, as they could certainly play a role in initiating and/or exacerbating mental health problems in a subset of individuals. Along those lines, having Long COVID may predispose individuals to mental health problems by virtue of their new onset limitations. Finally, preexisting mental health problems may also be exacerbated following SARS-CoV-2 infection. Overall, determining whether mental health problems in those infected by SARS-CoV-2 differ from those not infected but merely affected by the global pandemic remains an ongoing challenge. Regardless of their precise etiology, it is advisable for all clinicians to screen for new-onset anxiety and depression in Long COVID patients as they can have profound functional implications. Diagnosis of mental health prob- lems may range from brief screening assessments in medical settings to more thorough clinical assessments by mental health professionals. Thorough assessments involve a review of symptoms, medical history, and psychoso- cial context. Criteria for diagnosis of mental health disorders are outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) (APA, 2022) or the International Classification of Diseases, Eleventh Revision (ICD-11) (WHO, 2023b). These criteria are used to diagnose anxiety, depression, posttraumatic stress disorder (PTSD), and other metal health disorders that may be pertinent in Long COVID. The treatment of mental health disorders in patients with Long COVID can vary widely depending on the specific disorder, its severity, and the individualâs unique needs and comorbid symptoms. The most common, evi- dence-based approaches include psychotherapy (e.g., cognitive-behavioral therapy), medications (e.g., antidepressants, antipsychotics), or a combina- tion of the two (Cleveland Clinic, 2023). Importantly, given the multimor- bidity of Long COVID, it is critical for clinicians to consider the potential interaction effects of certain medications, as well as their impact on other Long COVID symptoms. SUMMARY AND CONCLUSIONS Long COVID comprises hundreds of health effects caused by or asso- ciated with acute SARS-CoV-2 infection that manifest in many different body systems. Evidence on clustering of the post-acute and long-term health effects of SARS-CoV-2 remains inconsistent across studies, and consensus is needed on terms, definitions, and methodological approaches for generat- ing better-quality and more consistent evidence. Health effects associated with Long COVID may manifest as impairments in body structures and PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 93 5/21/24 10:52 AM
94 LONG-TERM HEALTH EFFECTS OF COVID-19 physiological functions, potentially affecting mental (e.g., cognitive, psycho- social, emotional) functioning as well as physical functioning. In addition, individuals with Long COVID may experience multiple and potentially overlapping symptoms and conditions, including PEM, PCCI, and auto- nomic dysfunction. Some health effects can be sufficiently severe to interfere with an individualâs day-to-day functioning, including participation and performance in work and school activities. There is some overlap between SSAâs 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 on the basis of 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 SSAâs Listings are chronic fatigue and PEM, PCCI, and autonomic dysfunction, all of which can be difficult to assess clinically in terms of their severity and effects on a personâs functioning. Children with Long COVID also may experience health effects across many body systems. Commonly reported symptoms include fatigue, weak- ness, headache, sleep disturbance, muscle and joint pain, respiratory prob- lems, palpitations, altered sense of smell or taste, dizziness, and autonomic dysfunction. Although pediatric presentations and intervention options may overlap with those in adults, particularly among adolescents, who may be more likely to mimic adult presentation and trajectories, pediatric manage- ment of Long COVID entails specific considerations related to developmen- tal age and/or disabilities and history gathering. In general, children have fewer preexisting chronic health conditions than adults; thus, Long COVID may represent a substantial change from their baseline, particularly for those that were previously healthy. Management of pediatric Long COVID, as with adults, is focused on symptomatic support and, from a functional perspective, on activities of daily living, such as participation in school and in activities and hobbies. REFERENCES AAP (American Academy of Pediatrics). 2022a. COVID-19 interim guidance: Return to sports and physcial activity. https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19- infections/clinical-guidance/covid-19-interim-guidance-return-to-sports/#:~:text=The%20 AAP%20recommends%20not%20returning,physician%20evaluation%20has%20 been%20completed (accessed January 12, 2024). AAP. 2022b. Post-COVID-19 conditions in children and adolescents https://www.aap.org/ en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/post-covid-19- conditions-in-children-and-adolescents/ (accessed January 17, 2024). AAP. 2023. Children and COVID-19 vaccination trends. https://www.aap.org/en/pages/2019- novel-coronavirus-covid-19-infections/children-and-covid-19-vaccination-trends/ (accessed January 16, 2024). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 94 5/21/24 10:52 AM
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120 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-1â Selected Respiratory Conditions Associated with Long COVID Potential Social Security Health Potential Functional Selected Diagnostic and Administration Effects Limitations Management Guidelines Listing Pulmonary Standing, walking, ââ¢â Idiopathic Pulmonary 3.02 fibrosis strenuous physical Fibrosis (an Update) and activity, lifting, carrying, Progressive Pulmonary pushing/pulling, climbing, Fibrosis in Adults: An low work, speaking Official ATS/ERS/JRS/ ALAT Clinical Practice Guideline (Raghu et al., 2022 ââ¢â Idiopathic pulmonary fibrosis in adults: diagnosis and management (NICE, 2017) Hypoxemia Standing; walking; N/A None strenuous physical activity; lifting; carrying; pushing/pulling; overhead reaching; climbing; low work; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace Pneumonitis Walking, strenuous ââ¢â Diagnosis of None physical activity, lifting, hypersensitivity carrying, pushing/pulling, pneumonitis in adults: An overhead reaching, official ATS/JRS/ALAT climbing, low work clinical practice guideline (Raghu et al., 2020) Chronic Strenuous physical â â¢âERS guidelines on the None cough activity, speaking diagnosis and treatment of chronic cough in adults and children (Morice et al., 2020) â â¢âChronic cough: Evaluation and management (Michaudet and Malaty, 2017) PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 120 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 121 ANNEX TABLE 3-1âContinued Potential Social Security Health Potential Functional Selected Diagnostic and Administration Effects Limitations Management Guidelines Listing Chronic Standing; walking; â â¢â2022 ESC/ERS guidelines 3.09 pulmonary strenuous physical for the diagnosis and hypertension activity; lifting; carrying; treatment of pulmonary pushing/pulling; overhead hypertension (Humbert reaching; climbing; low etÂal., 2022) work; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace Asthma Walking, strenuous â â¢â2020 Focused Updates to None physical activity, carrying, the asthma management pushing/pulling, overhead guidelines: A report from reaching, climbing, low the National Asthma work, speaking Education and Prevention Program Coordinating Committee Expert Panel Working Group (Expert Panel Working Group, 2020) â â¢âManagement of severe asthma: a European Respiratory Society/ American Thoracic Society guideline (Holguin et al., 2020) Dyspnea Walking, strenuous ââ¢â Chronic dyspnea: None physical activity, carrying, Diagnosis and evaluation pushing/pulling, overhead (Badhwar and Syed, 2020) reaching, climbing, low work, speaking SOURCES: Maley et al., 2022; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 121 5/21/24 10:52 AM
122 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-2â Selected Cardiovascular Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Heart failure Standing, walking, ââ¢â 2022 AHA/ACC/ 4.02 strenuous physical HFSA guideline for the activity, lifting, management of heart carrying, pushing/ failure: A report of the pulling, reaching, foot/ American College of leg controls, climbing, Cardiology/American Heart low work, speaking Association joint committee on clinical practice guidelines (Heidenreich et al., 2022) Coronary disease Walking, strenuous ââ¢â 2023 AHA/ACC/ACCP/ 4.04 physical activity, ASPC/NLA/PCNA guideline lifting, carrying, for the management of pushing/pulling, patients with chronic reaching, climbing, coronary disease: A report low work of the American Heart Association/American College of Cardiology joint committee on clinical practice guidelines (Virani et al., 2023) Dysrhythmia Standing, walking, ââ¢â 2018 ACC/AHA/HRS 4.05 (tachycardia and strenuous physical guideline on the evaluation bradyarrhythmia) activity, lifting, and management of patients carrying, pushing/ with bradycardia and pulling, reaching, cardiac conduction delay: climbing, low work A report of the American College of Cardiology/ American Heart Association task force on clinical practice guidelines and the heart rhythm society (Kusumoto et al., 2019) Pulmonary Walking, strenuous â â¢âAmerican society of 7.08 embolism physical activity, hematology 2020 guidelines lifting, carrying, for management of pushing/pulling, venous thromboembolism: overhead reaching, Treatment of deep vein climbing, low work thrombosis and pulmonary embolism (Ortel et al., 2020) PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 122 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 123 ANNEX TABLE 3-2âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Venous Standing, walking, â â¢âVenous thromboembolic 4.11 thrombosis strenuous physical diseases: Diagnosis, activity, foot/leg management and controls thrombophilia testing: NICE Clinical Guidelines, no. 158 (NICE, 2023b) â â¢âAmerican society of hematology 2020 guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism (Ortel et al., 2020) Vasculitis Strenuous physical â â¢âVasculitis clinical practice 14.03 activity, lifting, guidelines (ACR, 2021) carrying, pushing/ pulling, reaching, overhead reaching Cardiac Walking, strenuous â â¢âManagement of acute None inflammatory physical activity, myocarditis and disease lifting, carrying, chronic inflammatory (myocarditis and/ pushing/pulling, cardiomyopathy: An Expert or pericarditis) reaching, foot/leg Consensus Document controls, climbing, low (Ammirati et al., 2020) work â â¢âManagement of acute and recurrent pericarditis (Chiabrando et al., 2020) SOURCES: Whiteson et al, 2022; Xie et al., 2022; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 123 5/21/24 10:52 AM
124 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-3â Selected Neurological Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Dysautonomia/ Sitting; standing; walking; ââ¢â Multi-disciplinary None Postural strenuous physical activity; collaborative consensus tachycardia lifting; carrying; pushing/ guidance statement syndrome pulling; reaching; climbing; on the assessment and low work; near visual treatment of autonomic acuity; understanding, dysfunction in patients remembering, and applying with post-acute information; concentrating, sequelae of SARS- persisting, or maintaining CoV-2 infection (PASC) pace; problem solving (Blitshteyn, 2022) ââ¢â Diagnosis and management of postural orthostatic tachycardia syndrome (Raj et al., 2021) Dizziness Sitting; standing; walking; ââ¢â Dizziness: Evaluation 2.07 (vestibular/ strenuous physical activity; and management orthostatic) lifting; carrying; pushing/ (Rogers et al., 2023) pulling; reaching; climbing; low work; near visual acuity; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace; problem solving Encephalitis/ Sitting; standing; walking; â â¢âAutoimmune None Encephalopathy strenuous physical activity; Encephalitis (Gole and lifting; carrying; pushing/ Anand, 2023) pulling; reaching; gross ââ¢âDiagnosis and and fine manipulation; management of foot/leg controls; climbing; acute encephalitis: A low work; vision; hearing; practical approach speaking; understanding, (Venkatesan and remembering, and applying Geocadin, 2014) information; concentrating, ââ¢âConsensus Clinical persisting, or maintaining Guidance for pace; problem solving; Diagnosis and adapting or managing Management of oneself; interacting with Adult COVID-19 others Encephalopathy Patients (Michael et al., 2023) PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 124 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 125 ANNEX TABLE 3-3âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Neurodegenerative Sitting; standing; walking; ââ¢â Dopaminergic therapy 11.17 disease strenuous physical activity; for motor symptoms in lifting; climbing; low work; early Parkinson disease speaking; understanding, practice guideline remembering, and applying summary: A report information; concentrating, of the AAN guideline persisting, or maintaining subcommittee pace; problem solving; (Pringsheim et al., adapting or managing 2021) oneself; interacting with â â¢âAducanumab use others in symptomatic Alzheimer disease evidence in focus: A report of the AAN guidelines subcommittee (Day et al., 2022) Neurocognitive Speaking; understanding, ââ¢â Multi-disciplinary None disorders/post- remembering, and applying collaborative consensus COVID cognitive information; concentrating, guidance statement impairment persisting, or maintaining on the assessment and pace; problem solving; treatment of cognitive adapting or managing symptoms in patients oneself; interacting with with post-acute others sequelae of SARS- CoV-2 infection (PASC) (Fine et al., 2022) â â¢âPractice guideline update summary: Mild cognitive impairment: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology (Petersen et al., 2018) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 125 5/21/24 10:52 AM
126 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-3âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Abnormal Standing, walking, ââ¢â Evidence-based 12.07 movements/ strenuous physical guideline update: Tremors activity, lifting, carrying, Treatment of essential reaching, gross and fine tremor: Report of manipulation, foot/leg the quality standards controls, climbing, low subcommittee of the work, speaking American Academy of Neurology (Zesiewicz et al., 2011) ââ¢â Differentiation and diagnosis of tremor (Crawford and Zimmerman, 2011) ââ¢â Movement Disorder Societyâs evidence-based review of treatments for essential tremor (Ferreira et al., 2019) ââ¢â COVID-19-associated new-onset movement disorders: A follow-up study (Schneider et al., 2023) Dysphagia Eating, drinking, ââ¢â Dysphagia: Evaluation None swallowing and collaborative management (Wilkinson et al., 2021) Guillain-Barré Sitting, standing, walking, ââ¢â Practice parameter: 11.14 lifting, low work, Immunotherapy reaching, gross and fine for Guillain-Barré manipulation, climbing, syndrome: Report of foot/leg controls, strenuous the quality standards physical activity, speaking, subcommittee of the vision American Academy of Neurology (Hughes et al., 2003) ââ¢â European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of Guillain- Barré syndrome (Van Doorn et al., 2023) PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 126 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 127 ANNEX TABLE 3-3âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Stroke Sitting; standing; walking; â â¢âGuidelines for the 11.04 strenuous physical activity; early management of lifting; carrying; pushing/ patients with acute pulling; reaching; gross ischemic stroke: 2019 and fine manipulation; update to the 2018 foot/leg controls; climbing; guidelines for the low work; vision; hearing; early management speaking; understanding, of acute ischemic remembering, and applying stroke: A guideline information; concentrating, for healthcare persisting, or maintaining professionals from pace; problem solving; the American Heart adapting or managing Association/American oneself; interacting with Stroke Association others (Powers et al., 2019) ââ¢â Guidelines for adult stroke rehabilitation and recovery: A guideline for healthcare professionals from the American Heart Association/American Stroke Association (Winstein et al., 2016) Spinal cord Standing, sitting, walking, N/A None infarction strenuous physical activity, lifting, carrying, pushing/ pulling, reaching, gross and fine manipulation, foot/leg controls, climbing, low work Peripheral/small Standing, walking, â â¢âCurrent view of 11.14 fiber neuropathy strenuous physical activity, diagnosing small fiber carrying, reaching, gross neuropathy (Raasing and fine manipulation, et al., 2021) foot/leg controls, climbing ââ¢â Small fiber neuropathy: A clinical and practical approach (Geerts et al., 2023) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 127 5/21/24 10:52 AM
128 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-3âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Bellâs palsy/cranial Vision, hearing, speaking â â¢âBell palsy: Rapid 11.14 neuropathies evidence review (Dalrymple et al., 2023) ââ¢â Clinical practice guideline: Bellâs palsy (Baugh et al., 2013) Migraine and Strenuous physical activity; ââ¢â Outpatient primary None other chronic vision; understanding, care management of headaches remembering, and applying headaches: Guidelines information; concentrating, from the VA/DoD persisting, or maintaining (Ford et al., 2021) pace; interacting with â â¢âHeadaches in over others 12s: Diagnosis and management (NICE, 2021b) Pain Standing; walking; ââ¢â Clinical guidelines None strenuous physical activity; (AAPM, 2023) lifting; carrying; pushing/ pulling; climbing; low work; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace Proprioception Standing, walking, lifting, ââ¢â Diagnosis and None and balance carrying, pushing/pulling, management of disorders reaching, gross and fine balance vestibular manipulation, foot/leg disorder (ASHA, 2016) controls, climbing, low work Seizure Climbing; strenuous â â¢âAES clinical practice 11.02 physical activity; guideline development understanding, manual (American remembering, and applying Epilepsy Society, 2019) information; concentrating, persisting, or maintaining pace PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 128 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 129 ANNEX TABLE 3-3âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Transverse Sitting, standing, walking, â â¢âTransverse myelitis 11.08 myelitis or other strenuous physical activity, (Simone and Emmady, demyelinating lifting, carrying, pushing/ 2020 disease pulling, reaching, gross and fine manipulation, foot/leg controls, climbing, low work, vision Raynaudâs Fine manipulation ââ¢â Raynaudâs 114.04 phenomenon (NIAMSD, 2021) Paresthesia Fine manipulation, foot/leg â â¢âA comprehensive None controls algorithm for management of neuropathic pain (Bates et al., 2019) Critical illness Standing, walking, ââ¢â Critical illness None myopathy and/or strenuous physical activity, myopathy: Diagnostic neuropathy lifting, carrying, pushing/ approach and pulling, reaching, gross and resulting therapeutic fine manipulation, foot/leg implications controls, low work (Rodriguez et al., 2022) SOURCES: Melamed et al., 2023; Premraj et al., 2022; Xu et al., 2022; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 129 5/21/24 10:52 AM
130 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-4â Selected Special Senses and Speech Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listings Anosmia/ N/A â â¢âClinical diagnosis and current None dysnosmia management strategies for olfactory dysfunction: A review (Whitcroft and Hummel, 2019) â â¢âManagement of new onset loss of sense of smell during the COVID-19 pandemic - BRS consensus guidelines (Hopkins et al., 2021) Ageusia/ N/A â â¢â Dysgeusia (ENT Health, 2020) None dysgeusia â â¢âClinical practice guidelines for the assessment of uninvestigated esophageal dysphagia (Liu et al., 2018) Dysarthria/ Speaking â â¢âGuidelines of clinical practice 2.09 dysphonia for the management of swallowing disorders and recent dysphonia in the context of the COVID-19 pandemic (Mattei et al., 2020) Visual, ocular Near or far visual â â¢âClinical management guidelines 2.02, 2.03, 2.04 symptoms acuity, peripheral (The College of Optometrists, (changes in vision 2022) vision/dry eye) Tinnitus Hearing â â¢âClinical practice guideline: 2.07 Tinnitus (Tunkel et al., 2014) â â¢âTinnitus: Assessment and management (NICE, 2020) â â¢âHearing loss, tinnitus, and dizziness in COVID-19: A systematic review and meta- analysis (Jafari et al., 2022) â â¢âSelf-reported tinnitus and vertigo or dizziness in a cohort of adult long covid patients (Degen et al., 2022) SOURCES: Melamed et al., 2023; Premraj et al., 2022; Xu et al., 2022. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 130 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 131 ANNEX TABLE 3-5â Selected Musculoskeletal Conditions Associated with Long COVID Potential Social Security Health Potential Functional Selected Diagnostic and Administration Effects Limitations Management Guidelines Listing Myopathy Standing, walking, strenuous ââ¢â Current classiciation None physical activity, lifting, and mangement of pushing/pulling, overhead inflammatory myopathies reaching, gross and fine (Schmidt, 2018) manipulation, climbing, low work, vision Muscle Standing, walking, strenuous â â¢âMuscle weakness in adults: None weakness physical activity, lifting, Evaluation and differential pushing/pulling, reaching, diagnosis (Larson and gross and fine manipulation, Wilbur, 2020) climbing, low work ââ¢â Musculoskeletal complications in long COVID-19: A systematic review (Swarnakar et al., 2022) Sarcopenia Standing, walking, strenuous ââ¢â International clinical None physical activity, lifting, practice guidelines for pushing/pulling, reaching, sarcopenia (ICFSR): gross and fine manipulation, Screening, diagnosis and climbing, low work management (Dent et al., 2018 Myositis Standing, walking, strenuous â â¢âBritish society for 14.05 physical activity, lifting, rheumatology guideline on pushing/pulling, reaching, management of paediatric, gross and fine manipulation, adolescent and adult climbing, low work patients with idiopathic inflammatory myopathy (Oldroyd et al., 2022) Myalgia Standing, walking, strenuous ââ¢â Nonpharmacologic None physical activity, lifting, and pharmacologic pushing/pulling, reaching, management of acute gross and fine manipulation, pain from non-low back, climbing, low work musculoskeletal injuries in adults: A clinical guideline from the American College of Physicians and American Academy of Family Physicians (Qaseem et al., 2020) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 131 5/21/24 10:52 AM
132 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-5âContinued Potential Social Security Health Potential Functional Selected Diagnostic and Administration Effects Limitations Management Guidelines Listing Arthralgia Standing, walking, strenuous â â¢â2019 American College of None physical activity, lifting, Rheumatology/Arthritis pushing/pulling, reaching, Foundation guideline gross and fine manipulation, for the management of climbing, low work osteoarthritis of the hand, hip, and knee (Kolasinski et al., 2020) Arthritis Sitting, standing, walking, â â¢âAmerican College of 14.09 strenuous physical activity, Rheumatology guideline lifting, pushing/pulling, for the treatment of reaching, gross and fine rheumatoid arthritis manipulation, climbing, low (Fraenkel et al., 2021) work SOURCES: Swarnakar et al., 2022; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 132 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 133 ANNEX TABLE 3-6â Selected Endocrine Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Diabetes type 1 Standing; walking; â â¢âClassification and diagnosis of None (diabetes strenuous physical diabetes: Standards of care in complications activity; lifting; pushing/ diabetes- 2023 (ElSayed et al., are included pulling; reaching; gross 2023) under organ- and fine manipulation; specific climbing; low work; listings) vision; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace Diabetes type 2 Standing; walking; â â¢âClassification and diagnosis of None (diabetes strenuous physical diabetes: Standards of care in complications activity; lifting; pushing/ diabetes- 2023 (ElSayed et al., are included pulling; reaching; gross 2023) under organ- and fine manipulation; specific climbing; low work; listings) vision; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace Dyslipidemia Vision â â¢âAmerican Heart Association/ None American College of Cardiology/American Association of Cardiovascular and Pulmonary Rehabilitation/ American Academy of Physician Assistants/Association of Black Cardiologists/ American College of Preventive Medicine/American Diabetes Association/American Geriatrics Society/American Pharmacists Association/American Society for Preventative Cardiology/ National Lipid Association/ Preventive Cardiovascular Nurses Association guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines (Grundy et al., 2019) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 133 5/21/24 10:52 AM
134 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-6âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Thyroid gland Standing; walking; â â¢âThyroid disease: Assessment None disorders strenuous physical and management (NICE, activity; lifting; pushing/ 2023a) pulling; reaching; gross and fine manipulation; climbing; low work; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace; problem solving; interacting with others Hypothalamic, Standing; walking; â â¢âDiagnosis and treatment of None pituitary, strenuous physical primary adrenal insufficiency: adrenal axis activity; lifting; pushing/ An Endocrine Society clinical dysfunction pulling; reaching; gross practice guideline (Bornstein et and fine manipulation; al., 2016) climbing; low work; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace; problem solving; interacting with others Reproductive Low testosterone: â â¢âSex hormones in SARS-CoV-2 None hormone Understanding, susceptibility: Key players or dysfunction remembering, and confounders? (Lott et al., 2023) applying information; concentrating, persisting, or maintaining pace; problem solving SOURCES: Xie and Al-Aly, 2022; Xu et al., 2023; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 134 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 135 ANNEX TABLE 3-7â Selected Immune Conditions Associated with Long COVID Potential Selected Diagnostic Social Security Potential Functional and Management Administration Health Effects Limitations Guidelines Listing Mast cell activation Strenuous physical activity; â â¢âSelecting the right None syndrome low work; understanding, criteria and proper remembering, and applying classification to information; concentrating, diagnose mast persisting, or maintaining cell activation pace; problem solving; syndromes: A adapting or managing critical review oneself (Gülen et al., 2021) ââ¢â Diagnosis, classification and management of mast cell activation syndromes (MCAS) in the era of personalized medicine (Valent et al., 2020) Autoimmune Sitting; standing; walking; ââ¢â Diagnostic testing 14.00D disorders (including strenuous physical activity; and interpretation rheumatoid lifting; carrying; pushing/ of tests for arthritis, ankylosing pulling; reaching; gross and autoimmunity spondylitis, fine manipulation; foot/ (Castro and systemic lupus leg controls; climbing; Gourley, 2010) erythematosus, low work; vision; hearing; myositis, systemic speaking; understanding, sclerosis, Sjögrenâs remembering, and applying syndrome, mixed information; concentrating, connective tissue persisting, or maintaining disease, and pace, problem solving; inflammatory interacting with others; bowel disease) adapting or managing oneself NOTE: Myositis and rheumatoid arthritis are discussed in Annex Table 3-5 (musculoskeletal conditions). SOURCES: Chang et al., 2023; Lim et al., 2023; Sumantri and Rengganis, 2023; Weinstock et al., 2021. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 135 5/21/24 10:52 AM
136 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-8â Selected Gastrointestinal Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Gastroesophageal N/A â â¢âAmerican College of None reflux and peptic Gastroenterologyâs ulcer disease gastroenterology guidelines (American College of Gastroenterology, 2023) Gastritis/enteritis Strenuous physical â â¢âAmerican None activity Gastroenterological Association clinical practice update on the diagnosis and management of atrophic gastritis: Expert review (Shah et al., 2021) Ischemic colitis Strenuous physical â â¢âACG clinical guideline: None activity Epidemiology, risk factors, patterns of presentation, diagnosis, and management of colon ischemia (CI) (Brandt et al., 2015) Irritable bowel Strenuous physical â â¢âACG clinical guideline: None syndrome/ activity; lifting; carrying; Management of irritable motility disorders pushing/pulling; bowel syndrome (Lacy reaching; gross and fine etÂal., 2021) manipulation; foot/leg controls; climbing; low work; vision; hearing; speaking; understanding, remembering, and applying information; concentrating, persisting, or maintaining pace; problem solving; interacting with others; adapting or managing oneself Gut dysbiosis N/A N/A None PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 136 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 137 ANNEX TABLE 3-8âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Cholestasis N/A â â¢âGuidelines for the 5.05 management of cholestatic liver diseases (2021) (Lu, 2022) â â¢âACG clinical guideline: Diagnosis and management of biliary strictures (Elmunzer etÂal., 2023) â â¢âACG clinical guideline: Evaluation of abnormal liver chemistries (Kwo etÂal., 2017) â â¢âEASL clinical practice guidelines: Management of cholestatic liver diseases (EASL, 2009) Chronic liver Standing, walking, â â¢âEASL Clinical Practice 5.05 disease strenuous physical activity Guidelines for the management of patients with decompensated cirrhosis (Angeli et al., 2018) Cholangitis N/A â â¢âTokyo guidelines 2018: None Diagnostic criteria and severity grading of acute cholangitis (with videos) (Kiriyama et al., 2018) ââ¢â Primary biliary cholangitis: 2021 practice guidance update from the american association for the study of liver diseases (Lindor et al., 2022) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 137 5/21/24 10:52 AM
138 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-8âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Pancreatitis N/A â â¢âAmerican None Gastroenterological Association institute guideline on initial management of acute pancreatitis (Crockett etÂal., 2018) â â¢âAmerican College of Gastroenterology guideline: Management of acute pancreatitis (Tenner et al., 2013) Weight Strenuous physical N/A 5.08 loss due to activity gastrointestinal disease Chronic Strenuous physical â â¢âEvaluation of acute None abdominal pain activity, overhead abdominal pain in reaching adults (Cartwright and Knudson, 2008) â â¢âRome IV criteria (Rome Foundation, n.d.) Nausea or Strenuous physical â â¢âAGA clinical practice None vomiting activity, climbing update on management of medically refractory gastroparesis: Expert review (Lacy et al., 2022) SOURCES: Xu et al., 2023; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 138 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 139 ANNEX TABLE 3-9â Selected Genitourinary Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Sexual N/A ââ¢â Clinical practice None dysfunction guidelines for management of sexual dysfunction (Avasthi etÂal., 2017) Dysmenorrhea/ Standing; walking; ââ¢â Dysmenorrhea and None menstrual strenuous physical activity; endometriosis in the irregularities lifting; carrying; pushing/ adolescent â Committee (with moderate pulling; foot/leg controls; opinion number 760 to severe pain) climbing; low work (ACOG, 2018) â â¢âThe initial management of chronic pelvic pain: Green top guideline 41 (RCOG, 2012) Oligospermia N/A ââ¢â Diagnosis and None treatment of infertility in men: AUA/ASRM guideline part I (Schlegel et al., 2020) Orchitis/ Standing; walking; ââ¢â Sexually transmitted None epididymitis strenuous physical activity; infections treatment (with moderate lifting; carrying; pushing/ guidelines, 2021 (CDC, to severe pain) pulling; climbing; low 2021c) work Acute kidney N/A ââ¢â Kidney Disease None injury (<12 Improving Global months) Outcomes (KDIGO) clinical practice guideline for acute kidney injury (KDIGO, 2012) â â¢âKDIGO 2021 clinical practice guideline for the management of glomerular diseases (Rovin et al., 2021) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 139 5/21/24 10:52 AM
140 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-9âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Chronic kidney Standing; walking; ââ¢â KDIGO clinical 6.05 disease strenuous physical activity; practice guideline for (>12 months) lifting; carrying; pushing/ the evaluation and pulling; reaching; fine management of chronic manipulation; foot/leg kidney disease (KDIGO, controls; climbing; low 2013) work; understanding, remembering, and applying information; concentrating, persisting, and maintaining pace; problem solving Overactive Sitting; standing; walking; ââ¢â Diagnosis and None bladder strenuous physical activity; treatment of overactive syndrome lifting; carrying; pushing/ bladder (non- pulling; climbing; low neurogenic) in adults: work; concentrate, persist AUA/SUFU guideline or maintain pace; adapting amendment 2019 or managing oneself (Lightner et al., 2019) SOURCES: Bowe et al., 2021; Schiffl et al., 2023; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 140 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 141 ANNEX TABLE 3-10â Selected Skin Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Hair loss N/A â â¢âHair loss: Common None causes and treatment (Phillips et al., 2017) â â¢âGuidelines for the management of alopecia areata (MacDonald Hull et al., 2003) Livedo N/A â â¢âLivedo reticularis and None reticularis livedoid vasculopathy (Primary Care Dermatology Society, 2023) ââ¢â Livedo reticularis: An update (Gibbs et al., 2005) Pernio Sitting, strenuous ââ¢â Clinical characteristics, 8.05 physical activity, lifting, etiologic associations, carrying, pushing/pulling, laboratory findings, reaching, gross and fine treatment, and proposal manipulation, foot/leg of diagnostic criteria of controls, low work pernio (chilblains) in a series of 104 patients at mayo clinic, 2000 to 2011 (Cappel and Wetter, 2014) Retiform Sitting, strenuous ââ¢â Retiform purpura: A 8.05 purpura physical activity, lifting, diagnostic approach carrying, pushing/pulling, (Georgesen et al., 2020) reaching, gross and fine manipulation, foot/leg controls, low work Chronic Sitting, strenuous â â¢âThe diagnosis and None urticaria physical activity, lifting, management of acute and carrying, pushing/pulling, chronic urticaria: 2014 reaching, gross and fine update (Bernstein et al., manipulation, foot/leg 2014) controls, low work SOURCES: Grover et al., 2022; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 141 5/21/24 10:52 AM
142 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-11â Selected Neuropsychiatric Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Loss of sexual N/A ââ¢â Diagnostic and None desire statistical manual of mental disorders, fifth edition, text revision (DSM-5-TR) (APA, 2022) Attention deficit/ Sitting; concentrating, ââ¢âDSM-5-TR None hyperactivity persisting, or maintaining disorder pace; interacting with others; adapting or managing oneself Anxiety/panic Speaking; concentrating, â â¢â DSM-5-TR (APA, 2022) 12.06 disorders persisting, or maintaining pace; interacting with others; adapting or managing oneself Depression Speaking; concentrating, â â¢â DSM-5-TR (APA, 2022) 12.04 persisting, or maintaining pace; interacting with others; adapting or managing oneself Post-traumatic Speaking; concentrating, â â¢â DSM-5-TR (APA, 2022) 12.15 stress disorder persisting, or maintaining pace; interacting with others; adapting or managing oneself Psychotic Speaking; understanding, â â¢â DSM-5-TR (APA, 2022) 12.03 disorder remembering, and applying information; concentrating, persisting, or maintaining pace; problem solving; interacting with others; adapting or managing oneself Stress Concentrating, persisting, â â¢â DSM-5-TR (APA, 2022) 12.06 or maintaining pace; interacting with others; adapting or managing oneself PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 142 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 143 ANNEX TABLE 3-11âContinued Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Adjustment Concentrating, persisting, â â¢â DSM-5-TR (APA, 2022) 12.15 disorder or maintaining pace; interacting with others; adapting or managing oneself Eating disorder Standing; strenuous â â¢â DSM-5-TR (APA, 2022) None physical activity; climbing; concentrating, persisting, or maintaining pace; interacting with others; adapting or managing oneself Obsessive Concentrating, persisting, â â¢â DSM-5-TR (APA, 2022) None compulsive or maintaining pace; disorder interacting with others; adapting or managing oneself Disordered sleep Understanding, â â¢â DSM-5-TR (APA, 2022) None remembering, and applying information; concentrating, persisting, or maintaining pace; problem solving; interacting with others; adapting or managing oneself SOURCES: Cheng et al., 2023; Premraj et al., 2022; Xie et al., 2022; Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 143 5/21/24 10:52 AM
144 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-12â Multisystem Conditions Associated with Long COVID Potential Social Security Potential Functional Selected Diagnostic and Administration Health Effects Limitations Management Guidelines Listing Chronic fatigue/ Walking; strenuous ââ¢â Multidisciplinary None post-exertional physical activity; lifting; collaborative consensus malaise carrying; pushing/pulling; guidance statement reaching; climbing; low on the assessment and work; understanding, treatment of fatigue in remembering, and applying post-acute sequelae of information; adapting or SARS-CoV-2 infection managing oneself (PASC) patients (Herrera et al., 2021) Myalgic Sitting; standing; walking; ââ¢âBeyond myalgic None encephalitis/ strenuous physical activity; encephalomyelitis/ chronic fatigue lifting; carrying; pushing/ chronic fatigue syndrome pulling; reaching; gross syndrome: Redefining and fine manipulation; an illness (IOM, 2015) foot/leg controls; climbing; ââ¢â Myalgic low work; vision; hearing; encephalomyelitis/ speaking; understanding, chronic fatigue remembering, and applying syndrome: Essentials information; concentrating, of diagnosis and persisting, or maintaining management (Bateman pace; problem solving; et al., 2021) interacting with others; ââ¢â Myalgic adapting or managing encephalomyelitis oneself (or encephalopathy)/ chronic fatigue syndrome: Diagnosis and management (NICE, 2021c) ââ¢â Diagnosis and management of myalgic encephalomyelitis/ chronic fatigue syndrome (Grach et al., 2023) Fever N/A â â¢âFever (Mayo Clinic, None 2022) SOURCE: Zang et al., 2023. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 144 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 145 ANNEX TABLE 3-13â Physical Activities; Vision, Hearing, and Speech; and Mental Activities Activity Definition Physical Activities Sitting For the purpose of collecting occupational data, the U.S. Bureau of Labor Statistics considers sitting to be present when any of the following conditions exists: â â¢âWorkers remain in a seated position. This includes active sitting. For example, bicyclists sit but push/pull with their feet/legs. â â¢âWorkers are lying down. This includes active lying down. For example, a mechanic lying on a dolly working underneath a vehicle is sitting. â â¢âWorkers may choose between sitting and standing for a given task. For example, office workers can choose a standing desk. (BLS, 2020, p. 112) From a functional perspective, however, sitting as a physical activity involves resting oneâs lower body (buttocks) on a seat or the ground, while maintaining oneâs upper body (torso, neck, head) in an upright position. In addition to strong neck, shoulder, and core muscles, sitting requires balance and good proprioception. Although lying on a raised surface (e.g., a bed) may be grouped with sitting, sitting is distinct from lying down on the ground (e.g., lying on a dolly underneath a vehicle), which this report groups under low work. Standing For the purpose of collecting occupational data, the Occupational Requirements Survey distinguishes only between sitting (as defined previously) and standing/walking defined as âwhenever workers are not sitting or lying down,â including âtime spent stooping, crawling, kneeling, crouching, or climbingâ (BLS, 2020, p. 112). In other words, âa worker is always either sitting or standing/walkingâ (BLS, 2020, p. 112). From a functional perspective, standing is distinct from walking, which in turn is distinct from low work (stooping, crawling, kneeling, crouching), or climbing. For the purpose of this report, standing is defined as being âin an upright position with all of [oneâs] weight on [oneâs] feetâ (Stand, n.d.). Walking Moving along on foot or advancing by steps, with one foot always on the ground. Distance (long or short) and surface type (uneven, rough) can affect an individualâs ability to walk. Strenuous physical Strenuous physical activity captures activities that require exertion activity and staminaâfor example, running, jumping, swimming, throwing, catching, and the like. It potentially includes all other physical activities, in addition to running and other impact activities. Lifting (floor Use of upper and/or lower extremities to raise or lower an object from to waist and nother, including upward pulling (BLS, 2020, p. 118). one level to an overhead) continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 145 5/21/24 10:52 AM
146 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-13âContinued Activity Definition Carrying âTransporting an object, usually by holding it in the hands or arms, or wearing it on the body, usually around the waist or upper torsoâ (BLS, 2020, p.118). Carrying usually also requires the ability to stand, lift, and walk. Pushing/pulling Use of upper and/or lower extremities to exert force upon an object so that the object moves away from or toward the origin of the force (BLS, 2020, p. 125). Reaching âExtending the hand(s) and arm(s) in any direction, requiring the straightening and extending of the arm(s) and elbow(s) and the engagement of the shoulder(s)â (BLS, 2020, p. 130). Reaching may require standing. Overhead reaching Extending the arm(s) with the hand(s) higher than the head and (1) the elbow is bent and the angle at the shoulders is about 90 degrees or more or (2) the elbow is extended and the angle at the shoulder is about 120 degrees or more (BLS, 2020, p. 130). Overhead reaching requires neck extension and may require standing. At/below the Reaching that does not meet the threshold for overhead reaching shoulder reaching described above (BLS, 2020, p. 130). At/below the shoulder reaching may require standing. Gross Gross manipulation involves âseizing, holding, grasping, turning, or manipulation otherwise working with the hand(s). Fingers are involved only to the extent that they are an extension of the hand to hold or operate an object or tool, such as hammerâ (BLS, 2020, p. 187). It includes handling of large objects. Fine manipulation Fine manipulation involves âtouching, picking, pinching, or otherwise working primarily with fingers rather than with the whole hand or armâ (BLS, 2020, p. 133). It includes writing, typing, or handling small objects (fingering). Foot/leg controls Refers to the âuse of one or both feet or legs to move controls on machinery or equipment. Controls include, but are not limited to, pedals, buttons, levers, and cranksâ (BLS, 2020, p. 133). Climbing âThe act of ascending or descending stairs, ramps, ladders, ropes or scaffolding and similar structures using feet, legs, hands, and/or armsâ (BLS, 2020, p. 142). PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 146 5/21/24 10:52 AM
SELECTED LONG-TERM HEALTH EFFECTS 147 ANNEX TABLE 3-13âContinued Activity Definition Low work Low work is a group of activities that includes stooping, crouching, kneeling, crawling, and lying on the ground. Stooping is the act of âbending the body forward and down while bending the spine at the waist 45 degrees or more either over something below waist level or down towards an object on or near the groundâ (BLS, 2020, p. 193). Must be performed standing. Crouching is âbending the body downward and forward by bending the legs and spineâ (BLS, 2020, p. 138). Kneeling is âbending the legs at the knees to come to rest on the knee or kneesâ (BLS, 2020, p. 139). Crawling is âmoving about on hands and knees or hands and feetâ (BLS, 2020, p. 139). Lying on the ground includes the need to get down and up from the ground (e.g., lying down on a trolley on the ground). Clustering the low work activities is appropriate because one generally has to be able to stoop, crouch, and kneel to be able to crawl. There might be an occasion when someone only has to kneel momentarily (e.g., to lift a child) that might be less difficult for some people, but most of the difficulties are shared among these activities. From a functional perspective, lying on the ground has more in common with other low work activities in that it includes the need to get up and down from the ground and potentially squirming around to do work while on the ground. These are difficult tasks that are equivalent to the other low work activities. Vision, Hearing, and Speaking Activities Near visual acuity âClarity of vision at approximately 20 inches or less, as when working with small objects or reading small printâ (BLS, 2020, p. 154), including the use of a computer in support of a critical job function, regardless of distance. Far visual acuity âClarity of vision at a distance of 20 feet or more, involving the ability to distinguish features of a person or objects at a distanceâ (BLS, 2020, p. 154). Peripheral vision âWhat is seen above, below, to the left or right by the eye while staring straight aheadâ (BLS, 2020, p. 154). Hearing âAbility to hear, understand, and distinguish speech and/or other soundsâ (BLS, 2020, p. 149). Includes hearing in-person one-on-one and group or conference communication; telephones and similar devices, such as radios, walkie-talkies, intercoms, and public address systems; and other such sounds as machinery alarms and equipment sounds. Passing a hearing test may be required for certain jobs. Speaking âExpressing or exchanging ideas by means of the spoken word to impart oral information to clients or the public and to convey detailed spoken instructions to other workers accurately, loudly, or quicklyâ (BLS, 2020, p. 149). continued PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 147 5/21/24 10:52 AM
148 LONG-TERM HEALTH EFFECTS OF COVID-19 ANNEX TABLE 3-13âContinued Activity Definition Mental Activities Understand, The abilities to learn, recall, and use (apply) information (SSA, n.d.-a, remember, and n.d.-b). apply information Concentrate, The abilities to focus attention on work/school activities and stay on persist, or task at a sustained rate (SSA, n.d.-a, n.d.-b). maintain pace Problem solve âAnalyze issues and make decisions that have a moderate to significant level of difficulty (e.g., the full extent of issues may not be readily apparent and requires independent judgment and research or investigation). The defining characteristics of problem solving are that there is no obvious, immediate solution to a problem or issue, and the worker must identify and weigh alternatives to arrive at a solutionâ (BLS, 2020, p. 99). Interact with The abilities to relate to and work with supervisors, coworkers, the others public, teachers, peers, and othersâfor example, âcooperating with others; asking for help when needed; handling conflicts with others; stating [oneâs] point of view; initiating or sustaining conversation; understanding and responding to social cues (physical, verbal, emotional); responding to requests, suggestions, criticism, correction, and challenges; and keeping social interactions free of excessive irritability, sensitivity, argumentativeness, or suspiciousness. (SSA, n.d.-a; see also SSA, n.d.-b) Adapt or manage The abilities to âregulate emotions, control behavior, and maintain oneself well-beingâ in a work or school settingâfor example, âresponding to demands; adapting to changes; managing [oneâs] psychologically based symptoms; distinguishing between acceptable and unacceptable work performance; setting realistic goals; making plans for [oneself] independently of others; maintaining personal hygiene and [appropriate attire]; and being aware of normal hazards and taking appropriate precautions. (SSA, n.d.-a; see also SSA, n.d.-b) SOURCES: BLS, 2020; SSA, n.d.-a, n.d.-b; table reprinted from NASEM, 2022, p. 197. PREPUBLICATION COPYâUncorrected ProofsA02506-Long-Term_Health_Effects_of_COVID-19_Ch03.indd 148 5/21/24 10:52 AM
