Long-COVID: diagnosis and epidemiology
The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. While the word ‘acute’ may imply 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, 10]. Here, we use the term PASC because it is explicit in its non-attribution of a specific etiology to a given persisting symptom.
Like the acute illness, enduring symptoms of COVID-19 are often multi-faceted [11, 12], Origins of symptoms may be central neurological (e.g., cognitive impairment, depression/anxiety, loss of sense of smell/taste), cardiovascular (e.g., chest pain/tightness, tachycardia), respiratory (e.g., dyspnea, cough), gastrointestinal (e.g., nausea, abdominal pain) and/or musculoskeletal (e.g., joint/muscle pain). Symptoms may also have their origins in the autonomic nervous [13] or immune systems (inflammatory and neuroinflammatory) [14]. However, many symptoms such as fatigue, headache and brain fog for example, are non-specific, and cannot be ascribed to a single system/organ.
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[15]. - 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-analyses to date, pooling 40 studies and almost 1 million patients’ data from around the world, found that 43% of patients experienced symptoms lasting beyond 4 weeks [3]. Other smaller-scale studies have reported prevalence rates varying between 10–65% [16–18].
Not surprisingly, the societal impact of PASC is significant. 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[13, 19]. Moreover, the array of cognitive, physical and emotional sequelae of PASC impede social, academic and vocational functioning, and with deleterious financial consequences [20]. A large-scale survey of > 3000 patients with PASC [21] 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 [22] in a survey of 3762 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, treatment of PASC is needed to reduce its burden on patients and society. However, the non-specific etiology and wide-ranging sequelae made this a significant treatment challenge.
Identifying Treatment Options: Overlap of PASC with Related Disorders with Prolonged Symptoms
One path for treating PASC is to identify other disorders with overlapping clinical presentation that have treatments with demonstrated efficacy. 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” [23–27], post-viral syndromes such as post influenza, SARS [28], Middle East Respiratory Syndrome [29], myalgic encephalomyelitis/chronic fatigue syndromes [30], and the prolonged symptoms of concussion [31]. 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 PAC sequelae.
As in PASC, both psychogenic and organic causes are hypothesized for the non-specific symptoms in these disorders [32]. Pathophysiological drivers include immune and autoimmune factors [33] as well autonomic dysfunction [34]. Psychogenic (and psychogenic plus organic) factors influencing clinical presentation include mental health disturbances (e.g., depression, anxiety [35] as well as pre-morbid factors like headache [36].
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 [37]. For example, fatigue may cause or exacerbate cognitive symptoms, which may cause or escalate mood symptoms, which may in turn worsen sleep [38].
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 symptoms associated with post-viral syndromes, and chemo-brain [39]. Education has also been found to be prophylactic against the development of prolonged symptoms of concussion [40]. Not surprisingly, education and strategies has been advocated for managing prolonged COVID-19 symptoms [34], but remains to be empirically tested in this population. Another approach with efficacy for non-specific symptoms is Mindfulness (referring to increasing one’s awareness of the present moment [41], and which can enhance an individual’s internal locus of control for optimizing health [42]. Mindfulness treatments have been shown to improve: fatigue in patients with cancer [43–45]; anxiety, depression and quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndromes [46]; chronic pain, depression relapse, addiction [41]; and, symptoms of fatigue and depression in concussion [47] [39]. Mindfulness interventions have also shown to improve prolonged symptoms of concussion [47–49]. In the context of PASC, Mindfulness has limitations for certain physical symptoms such as shortness of breath, lung function, or exercise intolerance [50]. Graded Exercise Therapy (GET) has also been shown to benefit people living with chemo brain [51, 52] and postural orthostatic tachycardia syndrome (POTS) [53, 54]; it is particularly promising for concussion, and the only treatment with evidence of speeding recovery from concussion [55–57]. With regard to myalgic encephalomyelitis/chronic fatigue syndromes, the NICE guidelines (2021) recommends a personalized GET that is overseen by a physiotherapist who has expertise in the condition [58]. Finally, in some cases, clinical guidelines and studies have shifted to a symptom-based approach whereby individual symptoms rather than their underlying cause are targeted on a symptom by symptom basis; this is increasingly employed in concussion [59].
Limited research into current approaches to treatment of PASC
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 [60]. For example, medications for chemotherapy and brain fog (e.g., methylphenidate, donepezil, modafinil, and memantine [61] are under consideration for brain fog in PASC [62]. 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 [63].
Although rehabilitation is being employed around the world [64, 65], only one small-scaled observational study has shown that a rehabilitation program targeting breathing, mobilisation, and psychological interventions improved lung function and physical capacity [66].
With regard to exercise, a recent narrative review [67] supported its potential role for PASC symptoms; however, exercise can cause post-exertional malaise and worsening of symptoms in some individuals [22]. Thus, a recent collaborative multidisciplinary consensus recommended conservative use of exercise in PASC, namely a cautious, titrated return to physical activity with close monitoring of symptoms [68, 69].
Lastly, education and strategies for self-management have yet to be empirically examined to our knowledge. However, 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 behavioural guidelines published by the WHO [70] and a PASC self-management web-page created by the Provincial Health Services Authority in Canada [71]. 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 [72]. To date, these educational resources have yet to be empirically evaluated to our knowledge.
Gaps in research and aims of current study
In sum, while management of acute COVID is being studied extensively, there is currently a dearth of evidence-based treatment for PASC. The drivers of PASC are multi-faceted and heterogeneous, and the etiology of any and all symptoms at the single case level is unclear. Thus, as yet there is no candidate treatment to emerge that targets, let alone alleviates, all or most symptoms across patients. Efficacy of pharmaceuticals is being studied [5], and rehabilitation recommendations for PASC symptoms are largely based on clinical observations rather than empirical findings [73].
In response to this gap in care, we have developed an intervention that was inspired by findings in related populations that have shown efficacy, and synthesized by psychiatrists and clinical psychologists for the current study. The aims of the current study are two-fold: (i) to demonstrate feasibility and efficacy for a novel education and strategies intervention for self-management of PASC symptoms that that can be delivered cost-effectively, (ii) 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 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 centres. Remote delivery also prevents infection risk. It also employs a group-based approach, which has also 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](under review).
To date, there are no published multidisciplinary education, strategy and self-management approaches for PASC.
Objectives and hypotheses
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.