The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). While the word “acute” implies a brief illness (2), many patients experience persisting symptoms (3). These ongoing and sometimes debilitating symptoms were initially brought to public attention by online social support groups that quickly proliferated early in the pandemic (4); these groups coined the terms “Long-Hauler and ‘Long-COVID.” Since then, prolonged symptoms have been additionally referred to as post-COVID syndrome, long-haul COVID-19, and post-acute sequelae of SARS-COV-2 (PASC) (4). The labels initially referred to patients with symptoms lasting more than one month following diagnosis of SARS-CoV-2 (5–8), and now typically refer to symptoms lasting three or more months (9–11). Here, we use the term PASC because it is explicit in its focus on long-lasting symptoms of COVID-19 without etiological assumptions of symptoms.

Like the acute illness, enduring symptoms of COVID-19 are often multi-faceted (12–15). Origins of symptoms may be central neurological (e.g., cognitive impairment, depression/anxiety, loss of sense of smell/taste) (14, 16), cardiovascular (e.g., chest pain/tightness, tachycardia) (17, 18), respiratory (e.g., dyspnea, cough) (14, 19–23), gastrointestinal (e.g., nausea, abdominal pain, altered gut microbiota) (24–26) and/or musculoskeletal (e.g., joint/muscle pain) (27). Symptoms may also have their origins in the autonomic nervous (28) or immune systems (inflammatory and neuroinflammatory) (29). While some symptoms can be ascribed to specific etiology, there are also symptoms where the pathophysiology and causes are uncertain (30).

The exact prevalence of PASC remains uncertain, but given the vast numbers of patients sustaining SARS-CoV-2 – nearly 500 million at the time of writing (31) – even the smallest estimates are concerning, especially as protracted sequelae occur even in mild acute illness and in young and fit patients. One of the largest meta-analyzes to date, pooling 54 studies and almost 1.2 million patients’ data from around the world, found that 6.2% of patients experienced symptoms lasting beyond 4 weeks (32). Other smaller-scale studies have reported prevalence rates varying between 10 and 65% (33–35).

Not surprisingly, the societal impact of PASC is significant. For instance, SARS-CoV-2 is estimated to share a similar mortality rate to that of seasonal influenza, causing an estimated doubling proportion of deaths annually (36). Moreover, the increased healthcare utilization places a notable strain on a system already burdened by large numbers of patients and healthcare workers with acute COVID-19 (28, 37). A retrospective cohort study in Canada found that the mean days in hospital per-person-year increased by 47–53%, 8 weeks or more after a COVID-19 infection (38). Moreover, the array of cognitive, physical and emotional sequelae of PASC impede social, academic and vocational functioning with deleterious financial consequences (39). A large-scale survey of >3,000 patients with PASC (40) found 71% of respondents endorsing compromise to family life and relationships, with 31% endorsing reduced ability to care for children and dependents. Work-related impacts were endorsed by 81% of people, and 36% endorsed financial impact. Similarly, Davis and colleagues (14) in a survey of 3,762 participants with PASC found that 45% needed a reduced work schedule, and 22% were not working due to illness at 6 months post-diagnosis.

Given the above consequences, a treatment for PASC is needed to reduce its burden on patients and society. However, the wide-ranging non-specific and specific nature of symptoms has made this a significant treatment challenge (41).

One path for treating PASC is to identify other disorders with an overlapping clinical presentation that have treatments with demonstrated efficacy (42). PASC shares a likeness with several conditions in which a discrete organic event is followed by a cluster of prolonged and non-specific symptoms. These include “chemo brain” (43–47), post-viral syndromes such as post influenza, SARS (48), Middle East Respiratory Syndrome (49), myalgic encephalomyelitis/chronic fatigue syndromes (50), and the prolonged symptoms of concussion (51). In all of these disorders, symptoms can include fatigue, sleep disturbance, brain fog, headache and mood disturbance, for example, which are some of the more common non-specific PASC sequelae.

Of particular relevance to PASC is the idea of symptom interplay and exacerbation. This has been described in the concussion literature from a “network perspective,” whereby non-specific symptoms amplify and reinforce one another (52). For example, fatigue may cause or exacerbate cognitive symptoms, which may cause or escalate mood symptoms, which may in turn worsen sleep (53).

The diagnostic challenges of non-specific and trans-diagnostic symptoms in post-viral syndromes, chemo brain and prolonged symptoms of concussion have led to treatment approaches that do not necessitate a mapping between symptom and cause at the individual patient level. One such approach is education and strategies for symptom self-management (e.g., educating about the disorder and expectations regarding symptom recovery; providing strategies for managing one’s own symptoms), which has shown efficacy for managing non-specific and specific symptoms associated with post-viral syndromes, and chemo-brain (54). Education has also been found to be prophylactic against the development of prolonged symptoms of concussion (55). Not surprisingly, education and strategies have been advocated for managing prolonged COVID-19 symptoms (56), but remain to be empirically tested in this population. Another approach with efficacy for non-specific and specific symptoms is Mindfulness (referring to increasing one’s awareness of the present moment) (57), and which can enhance an individual’s internal locus of control for optimizing health (58). Mindfulness treatments have been shown to improve: fatigue in patients with cancer (59–61); anxiety, depression and quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndromes (62); chronic pain, depression relapse, addiction (57); and, symptoms of fatigue and depression in concussion (54, 63). Mindfulness interventions have also shown to improve prolonged symptoms of concussion (63–65). In the context of PASC, however, Mindfulness has limitations for certain physical symptoms such as shortness of breath, lung function, or exercise intolerance (66).

While a number of clinical recommendations have been made for PASC patients, there is a paucity of treatment research to date. The recommended pharmacological approach is symptom-based; this has mainly included the repurposing of drugs that are employed for similar conditions and symptoms (5, 67). For example, medications for chemotherapy and brain fog [e.g., methylphenidate, donepezil, modafinil, and memantine (68)] are under consideration for brain fog in PASC (69). However, currently, no drugs have been found to effectively target subjective cognitive symptoms of PASC, and studies investigating their efficacy are still limited to case-studies (70).

A number of recommendations have been made to promote self-education and strategy use. The National Institute for Health and Care Excellence (NICE) guidelines recommend directing patients to online resources and apps to optimize self-management, for example referring to behavioral guidelines published by the WHO (71) and a PASC self-management web-page created by the Provincial Health Services Authority in Canada (72). As well, a recent guide published for primary care physicians advocated educating patients with PASC with concrete strategies and recommendations for managing their respiratory, cognitive, neurological, and somatic symptoms (73). To date, there are no published multidisciplinary education, strategy and self-management approaches for PASC.

In sum, while management of acute COVID is being studied extensively, there is no candidate treatment that targets, let alone alleviates, all or most symptoms of PASC across patients. In response to this gap in care, we developed an education and strategies intervention inspired by findings in related populations that have shown efficacy. This intervention synthesized by psychiatrists and clinical psychologists provides practical recommendations to manage both the specific and non-specific symptoms of PASC. The current study aims to (i) demonstrate the feasibility and efficacy of a novel education and strategies intervention for self-management of PASC symptoms that can be delivered cost-effectively, (ii) and to disseminate an intervention package to aid symptom self-management free-of-charge to licensed therapists for delivery to their patients with PASC. The intervention package will be fully manualized, with (i) videos of presentations from clinician-scientists (cardiology, neurology, respirology, rheumatology, psychology) with experience in PASC that includes frequently asked questions from patients and answers from clinicians; and (ii) PowerPoint presentations plus scripts to be delivered by the facilitator.

The treatment under development employs remote delivery, which has shown to be cost-effective (74, 75), and can tackle the scale and geographic distance of patients from treatment centers. Remote delivery also prevents infection risk, employing a group-based approach which has shown to be cost-effective (76), and may be psychologically optimal given the proliferation of online groups for individuals with PASC, suggesting a need for mutual support. Importantly, group-based approaches for related disorders have been proven effective and feasible (77) as have telerehabilitation and education approaches (78).

We will undertake a two-phase randomized controlled trial (RCT) to determine feasibility and effect size (Phase 1) and efficacy (Phase 2) for a novel 8-week Education and Self-Management Strategies group compared to a mindfulness skills program. Phase 2 is a full-scale quantitative-only RCT, with refinements and power analysis based on Phase 1 results, and an additional third no-treatment control arm. Outcomes of interest include confidence and ability to self-manage symptoms, quality of life, healthcare utilization. Hypotheses: Both interventions will be associated with enhanced mood, anxiety, quality of life and management of dyspnea symptoms. The education and self-management strategies program will additionally increase confidence to self-manage symptoms, decrease intrusiveness of Long-COVID symptoms in everyday life, and decrease medical visits, more so than the mindfulness group.

Individuals (N = 90; >18 years) with previously diagnosed COVID-19 and experiencing symptoms lasting for more than 3 months (i.e., persisting symptoms) are currently being recruited for Phase 1. Sample size is based on paired tests from our prior concussion study (79) (N = 61; under review) that used the same primary outcome. With effect size 0.59 and standard alpha and beta values, 26 pairs are needed. Factoring (i) 20% attrition (conservative given 7% attrition in a similar concussion study [79; under review] and 9% in the pilot group for the present study), and (ii) a further 25% for 1-month follow-up, we will recruit N = 45 for education of self-management strategies group and N = 45 for mindfulness skills group. Key inclusion criteria are: positive COVID-19 diagnosis a minimum of 3 months prior to study participation; proof of COVID-19 diagnosis through PCR, rapid antigen or serology test; self-report experiencing 3 or more persisting symptoms from 2 or more categories of mood, cognitive and somatic domains; age > 18; and English speaking. Key exclusion criteria include past acute ventilator support; past or present major neurological/psychiatric conditions including dementia, mild cognitive impairment, psychotic illness, mania, chronic fatigue syndrome, fibromyalgia, chronic Lyme disease, and/or traumatic brain injury.

The Phase 1 trial is a block randomized, controlled, parallel group, two arm, assessor-blinded trial with a 1:1 allocation. Participants will be randomly assigned to either the Education and Self-Management Strategies or the Mindfulness Skills groups. The allocation sequence is determined using the random function in Microsoft Excel by the study coordinators prior to recruitment. The study coordinators will screen, consent, enroll, and assign participants to their study identity numbers. Qualitative assessment of N = 20 patients from the Education and Self-Management group will be purposively (i.e., subjectively) sampled to attain a heterogeneous subset of patients. Qualitative information will be combined with quantitative to permit a more thorough understanding of the outcomes and to aid in further program refinement before undertaking the Phase 2 full-scale RCT. This study design is summarized in COSORT flow diagram presented in Figure 1.

Phase 2 will be a full-scaled trial with an additional third arm (1:1:1 allocation) as a non-treatment, standard-of-care group, with refinements and power analysis based on Phase 1 results.

For both groups, 8 weekly sessions will be delivered remotely on Microsoft Teams by licensed therapists (e.g., Psychologist, Occupational Therapist) with mental health experience; discipline experts will also deliver content for the Education and Self Management Strategies Group. Sessions will last 1.5 h, with 10–15 patients per group (factoring in attrition).

After providing informed consent to participate in the study and prior to commencing the intervention groups, participants will be asked to complete an online background questionnaire in order to assess potential moderators. This background questionnaire collects demographic information (e.g., age race, sex, gender, highest education, occupation), previous and current medical and psychiatric history, current symptoms and healthcare supports.