<scp>Multi‐disciplinary</scp> collaborative consensus guidance statement on the assessment and treatment of p<scp>ostacute</scp> sequelae of <scp>SARS‐CoV</scp>‐2 infection (<scp>PASC</scp>) in children and adolescents

Abstract

Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are generally asymptomatic or have mild acute symptoms with low rates of hospitalization (<2%) and death (<0.03%).1 After initial infection, some children, including those who experienced mild or asymptomatic disease, develop other postacute manifestations of COVID, including multisystem inflammatory syndrome in children (MIS-C, not discussed in this statement) or postacute sequelae of SARS-CoV-2 infection. The latter post-COVID condition may be known as long COVID, long-haul COVID, postacute COVID-19, long-term effects of COVID, or chronic COVID.2 This guidance statement uses the terminology of postacute sequelae of SARS-CoV-2 infection (PASC). Data are limited on the epidemiology of and risk factors for PASC in children and adolescents. The prevalence of PASC symptoms in children varied considerably between studies from 4 to 66%.1, 3-5 There is also large variation in the reported frequency of persistent symptoms. Recent studies have suggested that possible risk factors for PASC in pediatric patients may be older age, female gender, and history of allergic disease.6 In general, Hispanic or Latino (Hispanic) and non-Hispanic Black (Black) children had higher cumulative rates of COVID-19-associated hospitalizations (16.4 and 10.5 per 100,000, respectively) than did non-Hispanic White (White) children (2.1), although it is not currently known if hospitalization is a risk factor for PASC in children.6 Studies have also investigated the effects of the pandemic itself on the care of children with developmental disabilities,7-10 with a recent study finding that, other than age, intellectual disability was the strongest independent risk factor for COVID-19 mortality.11 More studies in this area are needed. Limited guidance exists regarding the assessment and treatment of manifestations of PASC in children and adolescents. Additional challenges in the diagnosis of PASC include the overlap of psychosocial effects (eg, social isolation, loss of routine with school and activities, fear of illness, loss of family members or friends) of the pandemic on children.12-14 Although there may be overlap with adult presentations and intervention options, pediatric management and rehabilitation of PASC have unique considerations, and adult guidance cannot be systematically transcribed to pediatrics. First, the approach to the child may differ; developmentally, some young children or those with developmental disabilities may have difficulty describing their symptoms. Pediatric histories from vested parties (parents, caregivers, coaches, teachers) are vital and subsequently help guide diagnosis and management. Compared to adults, children have fewer preexisting chronic health conditions, and some conditions that may increase risk of PASC, such as type 2 diabetes, are uncommon in pediatrics.15 Therefore, children may not require the same laboratory or radiographic tests as adults. Finally, from a psychosocial perspective, children are often previously healthy; thus, the symptoms of PASC can represent a stark departure from baseline for individuals and their families and present with increased stress or urgency to address. With this in mind, the American Academy of Physical Medicine and Rehabilitation (AAPM&R) Multi-Disciplinary PASC Collaborative (PASC Collaborative) convened a pediatric workgroup to address the urgent need for interim assessment and treatment guidance in the care of children and adolescents with PASC. The following information is meant to assist the primary care physician and initial specialty evaluations for children and adolescents with PASC. The PASC Collaborative was created, in part, to develop expert recommendations and guidance from established PASC centers with extensive experience in managing patients with PASC. The PASC Collaborative is following an iterative modified Delphi approach to achieve consensus on assessment and treatment recommendations for a series of Consensus Guidance Statements focused on the most prominent PASC symptoms.16-18 As with other PASC Collaborative guidance statements, a detailed literature review was performed before initiation of the modified Delphi approach, and the full description of our methodology has been published in detail previously.19 As the assessment and treatment recommendations for each systemic section of this specific guidance statement were developed and refined, review of emerging studies and current literature was conducted on an ongoing basis. This monitoring of the literature occurred until finalization of the manuscript and throughout the review process to ascertain that the best available and current evidence was used. In the expansion of the PASC Collaborative to include a Pediatric Workgroup the intent was to recognize that assessment and treatment standards differ in younger populations requiring a pediatric specialization focus. Achieving consensus on the assessment and treatment recommendations for children and adolescents with PASC followed the same published modified Delphi approach with one adjustment to reflect the specialized expertise of the Pediatric Workgroup. The second wave of voting, to ensure the completeness and evidence base of recommendations, was conducted at the workgroup level as opposed to the full PASC Collaborative level. The Pediatric Workgroup then referred their consensus-based recommendations to the full PASC Collaborative for a final consensus vote prior to finalization. The PASC Collaborative Pediatric Workgroup is composed of approximately 30 pediatric specialists representing eight clinics or institutions from across the United States with engagement from patients or caregivers to gain the patient perspective in the care process. The Pediatric Workgroup recognizes that patients with health manifestations due to PASC typically present with a cluster of symptoms that cross multiple body systems and may overlap. The recommendations and discussion presented in this report are intended to reflect common presenting symptoms and organ system manifestations seen by pediatric specialists and those that pediatricians, family medicine practitioners, and pediatric subspecialists may encounter (Table 1). Importantly, the recommendations provided in the Guidance Statement should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors. As with any treatment plan, clinicians treating patients with PASC are encouraged to discuss the unknowns of PASC treatments and prognosis, as well as the benefits and risks of any treatment approach. Fatigue (generalized, exercise intolerance, or postexertional malaise) Sleep disturbances Fever Anxiety Depression/low mood Increased somatic symptoms unexplained by systemic findings School avoidance Regression of academic or social milestones Dizziness/lightheadedness Orthostatic intolerance Headache Nausea Syncope or presyncope Headache Tremulousness Paresthesias or numbness Dizziness and vertigo Difficulty with attention/concentration Difficulty with memory Cognitive fatigue or "brain fog" Shortness of breath or dyspnea Chest (thoracic) pain or tightness Cough Difficulty with activity/exercise intolerance Palpitations or tachycardia Dizziness/lightheadedness Syncope Chest pain Difficulty with activity/exercise intolerance Weakness Muscle, bone, or joint pain Nausea/vomiting/reflux Abdominal pain Bowel irregularities (constipation/diarrhea) Weight loss Lack of appetite The primary care system is often the first point of contact for patients with PASC and may provide the bulk of therapeutic management. For patients with complex medical needs, multidisciplinary and interdisciplinary approaches are often beneficial.20-27 Multidisciplinary clinics to treat the population with PASC first opened in the spring of 2020, and as the pandemic continued, clinics focusing on the needs of the pediatric population emerged although they may not be accessible to all,28 in which case the primary care clinician will have a larger role in coordinating the specialty evaluation(s) and care. Previsit symptom checklists or screening tools may help facilitate information gathering and optimize the time providers have with patients and their caregivers at the initial evaluation.21, 27, 29, 30 Goals of the initial visit are to (1) determine symptoms and their impact on patient function; (2) assess what additional detailed evaluations may be helpful; (3) identify "red flag" symptoms that warrant urgent further testing and/or referral to subspecialists; and (4) differentiate PASC from preexisting or new conditions that require a different therapeutic approach. PASC is a clinical diagnosis and can be supported by positive polymerase chain reaction (PCR), antigen, and/or antibody testing for SARS-CoV-2; however, negative testing may not rule out PASC for multiple reasons. Some patients with PASC will not have a positive test for SARS-CoV-2 because of lack of testing, waning antibody levels, or false-negative testing.31, 32 As pediatric SARS-CoV-2 vaccination rates increase; the role of antibody testing may decrease unless providers specifically order antinucleocapsid antibodies. A strong epidemiological link (eg, SARS-CoV-2 positive close contact) or distinctive clinical features of COVID-19 (anosmia/ageusia) without an alternative diagnosis may also be considered evidence of prior infection. The evaluation should begin with a thorough history and review of systems, followed by a comprehensive physical examination and additional studies as warranted. Key areas to focus on in an initial evaluation are summarized in Table 2. This initial evaluation can guide the need for additional assessment considerations and treatment options based on findings (Tables 3–11). Description of the acute SARS-CoV-2 infection or "inciting event" Characterize pertinent PASC symptoms1, 20, 25, 34 Factors that limit activity or result in fatigue should be noted, with attention to nutrition, sleep, exercise, and mental health.2, 27 Refer to Tables 3-11 for further guidance on assessment parameters. Assess for level of functional activity limitations Past medical, surgical, family, and social history Review the past medical history. Specific attention should be placed on preexisting conditions including mental and behavioral health,2, 35 surgeries or hospitalizations, and vaccination status including for SARS-CoV-2. Physical examination: Assessment: Clinicians should incorporate history, prior laboratory or microbiological testing, and physical exam findings in making a diagnosis of PASC. Concerning symptoms and signs ("red flags") should be addressed and may require additional targeted evaluation prior to further therapies or management strategies related to PASC. Labs/radiology (2) Follow-up plan and referrals – Follow symptom-based treatment strategies as outlined in the specific sections that follow (Tables 3-11 ). Evaluation: •Full physical exam including thorough neuromuscular exam and provocative musculoskeletal tests specific to any areas of pain •Consider orthostatic vital signs/standing test if experiencing lightheadedness/ dizziness (See Autonomic Dysfunction/POTS section in Table 5 for more information) •Consider formal testing of physical functioning and endurance (examples include 6-minute walk test (40), 30 second sit to stand test if feasible) •Bloodwork: complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone/free T4, iron panel, ferritin, vitamin D •Consider magnesium, vitamin B12, erythrocyte sedimentation rate/C-reactive protein, celiac screening based on additional symptoms. Refer to Tables 4-10 for additional testing recommendations if concerned for comorbid conditions contributing to fatigue or EI. Interventions/considerations: Medications: Lifestyle modifications: Physical activity: Sleep difficulty symptoms may include insomnia (difficulty falling asleep, sleep deprivation), difficulty with sleep maintenance, sleep events (eg, restless leg syndrome, sleep apnea), hypersomnia (excessive daytime sleepiness) Interventions/considerations: Behavioral sleep interventions: When to Refer and to Whom: Psychology or therapist for cognitive behavioral therapy for insomnia if behavioral interventions are not sufficient and/or to treat comorbid mental health concern (anxiety, depression) Sleep medicine specialist if abnormalities on PSG or concern for sleep disorder Fatigue is a common symptom in children with PASC with a broad differential.20, 25-27, 41 Physical activity/exercise intolerance is also reported, which often overlaps with symptoms of fatigue.3, 20, 42 Physical inactivity is a well-documented risk to both overall physical and mental health43; thus, it is important to help mobilize those with physical activity intolerance in a timely fashion to minimize lasting effects of decreased activity or poor exercise tolerance. Some patients with prolonged fatigue may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is a clinical diagnosis of exclusion. ME/CFS is characterized by profound fatigue occurring for at least 6 months with significant impairment in day-to-day functioning including physical functioning, school performance, and extracurricular activities.44 Postexertional malaise and unrefreshing sleep are hallmarks of the disorder, and cognitive impairment and orthostatic intolerance are also commonly cooccurring conditions.45 The relationship between ME/CFS and SARS-CoV-2 infection is unclear at this point, but ME/CFS has been noted after other viral illnesses, most prominently primary infection with Epstein–Barr virus.37, 46 If patients with PASC report symptoms of postexertional malaise or "crashing" after mild physical or cognitive activity, they should be educated on "pacing" and careful attention should be made to avoid postexertional malaise and exacerbation of symptoms; patients may benefit from referral to pediatric rehabilitation medicine. (See Appendix 1 for a link to Centers for Disease Control and Prevention resources for ME/CFS.) Recommendations for physical activity programs should be tailored to each individual patient and take into account access to exercise opportunities and equipment (ie, gym class, recess, safe neighborhood, bicycle). There have been some suggested protocols for return to play in pediatric and adult recreational athletes following mild-to-moderate COVID43, 47 using a graduated exercise approach48; however, these types of programs may cause symptom exacerbation in those with postexertional malaise. A more gradual approach of slowly increasing physical activity through a subsymptom threshold exercise program similar to protocols recommended for postconcussion syndrome may be better tolerated.49 Oversight by a physical therapist or occupational therapist (in those with more significant symptoms limiting activities of daily living) may be helpful for more specific guidance. Recommendations for physical activity including any restrictions may need to be translated to school and other settings such as sports and extracurriculars (see Pediatric Accommodations section). Sleep is critical for optimal function and development across multiple body systems. Insufficient sleep may be associated with mood changes, impaired attention and concentration, and decreased immune response. Post-COVID sleep difficulties are often reported in children.3, 50-52 It is unclear whether sleep difficulties are a manifestation of having COVID-19, related to other psychological or medical conditions, a product of increased psychosocial distress, or some combination of factors.53 Mental health concerns for individuals with PASC (Table 4) can be influenced by biological (direct effects of infection) and psychosocial (disrupted quality of life, isolation, loss of loved ones and routine) factors.54 This has resulted in an increase in the prevalence of anxiety, depression, irritability, boredom, inattention, and new-onset psychological symptoms in youth during the COVID-19 pandemic.55 Many children have undergone the trauma of losing a loved one to COVID-19 and may experience symptoms of grief, exacerbating psychological and physical symptoms of PASC. Additionally, the pandemic has exacerbated difficulty with access to mental health care for many populations such as racial and ethnic minority groups and gender/sexual minority individuals.56 One study demonstrated that children, girls, those with Hispanic ethnicity, those with public versus private insurance, and those with more significant medical comorbidity were more likely to exhibit PASC neuropsychiatric symptoms,57 although these demographic and socioeconomic factors need to be studied further. With the increase in mental health problems since the start of the pandemic it is particularly important to screen for mental health symptoms in all youth with PASC, and in particular, screen for suicidal ideation especially if there are known past attempts, past suicidal ideation, or changes in mood. Of note, emergency room visits for suicidal ideation and attempts started increasing in early 2020 for adolescents (ages 12–17 years) in the United States and have sustained at higher levels, especially for adolescent females.58 Patient history and symptom assessment: Anxiety Depression Evaluation/scales to consider: *Note: the PHQ-9 contains a suicidality question; clinicians should be prepared with a plan if score is positive. Suicidality Anxiety is the most common mental health concern in adults with PASC symptoms54 and studies have supported newly emerging anxiety symptoms in youth.55 Children with primarily social anxiety may have a recurrence of symptoms upon return to in-person school after a prolonged absence (which may be prolonged due to PASC). Therefore, school avoidance should be monitored closely. Adolescents and young adults with disabilities may have differential impacts related to anxiety during the pandemic, especially if they identify with a minoritized racial/ethnic group and should be screened and monitored closely.59 Depression has been documented in adult PASC and to a lesser extent in some pediatric studies, both in patients with and without premorbid depression.60, 61 These symptoms are occasionally also associated with changes in behavior that may be uncharacteristic for the youth (eg, increased irritability, social withdrawal). Clinical experience suggests there may be an increase in somatization and SSRDs in some pediatric cases of PASC; however, one should not assume PASC symptoms are all related to a SSRD and thorough medical investigation into any newly emerging physical symptom is always recommended. If considering a diagnosis of a somatic symptom disorder or functional neurological symptom disorder, it is recommended to refer and collaborate with medical subspecialties (eg, neurology, rheumatology, pediatric rehabilitation medicine, and gastroenterology) prior to diagnosis. When the diagnosis of functional neurologic symptoms disorder or other somatic disorder is made, patients should be referred to a specialized multi-disciplinary clinic or program and/or psychology when available.62 In adult studies, 25% of patients experiencing PASC had posttraumatic symptoms up to 50 days post COVID-19 infection.63 To date, rates of PTSD for youth with PASC have not been reported. PTSD symptoms may be elevated in children with history of hospitalization, prolonged period in intensive care, or history of multiple procedures.64 In addition, one of the unfortunate outcomes of the pandemic has been the increase in prevalence of child maltreatment.63, 65 In a small study, the amassing of COVID-19 stressors was found to be a key risk factor implicated in higher parent-perceived stress, whereas anxiety and depression were associated with both higher parent-perceived stress and child abuse potential.66 This consequently increases the odds of PTSD and is critical for physicians to be vigilant for signs of PTSD and potential underlying maltreatment both in patients with and without PASC. When mental health concerns are identified and have a negative impact on functioning or are associated with significant distress, referral for evidence-based therapy (eg, cognitive behavioral therapy) is warranted and in some cases consideration of medication and/or referral to may be on and resources of symptoms can be based on symptom and level of the primary care a perspective, families may benefit from in a who has experience with individuals with chronic and cognitive behavioral such as for chronic which may also be helpful to for this may also benefit from to for their youth or behavioral management strategies for young orthostatic tachycardia syndrome is a chronic disorder of the system characterized by symptoms (Table which are orthostatic in It is a condition primarily between the of and is commonly by infection, or can be in decreased quality of and limited to in school and/or Interventions/considerations: Lifestyle modifications: Physical activity with When to refer and to In to there are other of such as orthostatic orthostatic tachycardia and treatment for of management (see Table and on orthostatic symptoms and quality of with increased and has been to orthostatic and quality of in some patients with there are and for although that increase blood decrease and increase are often In children with orthostatic symptoms who not meet full criteria for management should be and can be considered to help with symptom management. Although there are case the of following COVID-19 infection in there is limited literature available on pediatric presenting symptoms of PASC, including and overlap with symptoms of and In addition, it is important to screen for mental health concerns as symptoms of may present to somatic symptoms of anxiety and depression for which referral to mental health may be and concerns of fatigue and attention generally increased attention in these with and and elevated those with children with PASC should (see Table 6 and Accommodations and intervention (eg, behavioral therapy) to ensure these cognitive and mood difficulties not the to in school settings or in the testing is recommended to assist in the level and types of school these children may benefit from and to therapeutic A comprehensive evaluation is not always unless a child had preexisting developmental disabilities or neurological conditions (eg, history, A targeted evaluation be (eg, for most a cognitive assessment until symptoms function increases the risk for additional and Patient history and symptom assessment: Anxiety and mood symptoms Patient Anxiety and pediatric symptom mental health and symptoms section for further Interventions/considerations: in with comorbid medical conditions School may be warranted with a of as symptoms (eg, test in decreased cognitive during These school may be tailored or modified following formal testing when needed. When to refer and to in cognitive status (eg, increased or concerns on screening based on clinical Accommodations and/or strategies are after months of for "red as well as signs of by an underlying are common in children with 20, 27, Recommendations for evaluation and management are in with pediatric from the American Academy of and American Headache neurological examination or a history for system A primary type (eg, in patients with PASC has not been identified and some patients multiple Orthostatic are common in children with (Table The of treatment and for patients and families on behavioral and factors that may Clinicians should as in children with PASC and may require a approach treatment may to treatment with a daily medication to decrease or many patients with PASC experience a of of treatment may be by treatments commonly for other PASC symptoms. For a of cognitive which a symptoms. such as which some providers in treatment of and orthostatic intolerance in a child with PASC. in children with or other body can treat both and other possible pain symptoms. for for sleep and appetite or for anxiety may be for when these comorbid conditions are When a daily medication for it is important to start at low be of and treatment based on comorbid symptoms. In children and adolescents with PASC, respiratory symptoms are commonly reported (Table has been found to be associated with a higher risk of evaluation of patients with PASC and persistent symptoms should at and with a low threshold to refer to a Some studies have function tests are most often in children with whereas more than of children had mild and In patients with evaluation for or intolerance (eg, 6-minute walk test or 1 sit to stand is Additional tests may be if symptoms or there are findings on exam or an initial Assess frequency of Assess activity Review respiratory post-COVID Review of symptoms should of if or which Evaluation: of decreased breath of If history of optimize treatment with and per If history of of on or therapy and per respiratory should also be