Symptom-Targeted Rehabilitation for Cognitive Complaints in Long COVID (STAR-C3)

Cognitive complaints are one of the most common, pervasive, and debilitating outcomes for adults with Long COVID. In a study of 3762 adults from 56 countries who were 7 months post-diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS Coronavirus 2, referred to here as COVID) 85% reported cognitive problems, including brain fog, word-finding problems, difficulty communicating their thoughts, and a reduced ability to solve serious problems. In the Great British Intelligence Test, an online study of 81,337 individuals the subgroup of 12,689 who reported having had COVID had significantly lower cognitive test scores than those who had not, providing objective support for the symptoms that adults with Long COVID are reporting. These persistent cognitive symptoms, which the investigators refer to as Post-COVID Cognitive Symptoms (PCCS), do not appear to spontaneously resolve, with many patients in Canada and worldwide reporting cognitive impairments more than 1 year after infection. PCCS can have severe effects on usual functioning, particularly given that most survivors are working age. Two large studies estimated that at 7-9 months post-infection, between 40-75% of adults either could not work at all or were working fewer hours than they did pre-COVID. Although emerging data indicate that PCCS may be less common after infection with the Omicron variant, there continues to be concern about future "super-variants" that may have more virulent effects. Even if infection rates stabilize, i.e., COVID becomes endemic, the disease does not become harmless.

Usual care for those with PCCS is, at best, providing information about how to manage symptoms (e.g., this handout from the Public Health Authority of British Columbia). The literature on treatment of cognitive problems in other patient groups, however, shows that providing general information alone does not "fix" cognitive impairments. To improve cognitive function in everyday life, intervention must be individualized and provide opportunities for high-dose practice of target behaviours. The investigators do not, however, have interventions like this with demonstrated effectiveness for PCCS. The literature related to cognitive rehabilitation after COVID includes three types of papers: 1) studies of COVID effects on people who had cognitive diagnoses pre-COVID (e.g., how lack of services has affected patients with Alzheimer's Disease) 2) a small number of case reports of rehabilitation for COVID patients, in which cognitive rehabilitation is mentioned in general terms (e.g., patient received "skill training for basic activities of living" and "evaluation of adaptive devices", and 3) urgent calls for cognitive rehabilitation of adults with PCCS (e.g., 13-15). To the investigators knowledge, there are no published controlled studies of cognitive rehabilitation methods for adults with PCCS. One of the investigators recently completed a pilot pre-post study with 34 adults with Long COVID to examine if physical therapy for physical symptoms and occupational therapy for cognitive symptoms was safe and feasible (protocol completed, under analysis). The cognitive intervention was 6 hours of combined individual and group cognitive rehabilitation over 12 weeks, including education about managing cognitive challenges. The pilot data showed a reduction in intensity and frequency of cognitive symptoms, but no effect on everyday functioning. The study investigators concluded that to improve everyday function, therapy must be targeted at individual complaints, and it is this type of intervention that the investigators propose for a randomized control trial (RCT).

A recent paper in Science 16 called for cognitive rehabilitation to be part of the health system response to Long COVID, but rehabilitation was not included in the category of research needs - i.e., the paper implied that investigators already know how to treat patients with PCCS, and that investigators just need to increase access to therapy. However, it is unclear if standard cognitive rehabilitation methods used for other patient groups are effective for people with PCCS. One source of guidance for PCCS rehabilitation methods is the literature on cognitive rehabilitation for adults with traumatic brain injury (TBI), especially patients with mild TBI (aka concussion). Adults with mild TBI (mTBI) have symptoms that are commonly reported by adults with PCCS, such as word-finding problems, slow thinking, "brain fog", trouble following instructions, forgetting medications, difficulty in conversations, complaints about mental fatigue, and difficulty making decisions. There also is anecdotal evidence from clinicians who have overseen treatment of more than 3400 adults with Long COVID - that PCCS characteristics are very similar to patients with mild TBI. COVID and TBI share pathophysiological features such as inflammation, hypoxia, microvascular lesions and disruption of the blood-brain barrier, cortical thinning, and diffuse white-matter damage, particularly in anterior cortical regions. Best practices in cognitive rehabilitation also should be similar in both groups: treatments must be tailored to the patients needs, focused on solving everyday thinking challenges rather than 'fixing' deficits, and given in a relatively high dose.

In summary, PCCS is prevalent, debilitating, and persistent, and there is a lack of evidence-based methods to treat adults with these problems. TBI and COVID share pathophysiological features, survivors report similar cognitive symptoms, and best practices apply to both populations, thus the investigators predict that cognitive rehabilitation methods developed for adults with mTBI will also be effective for adults with PCCS.

Study design will follow recommendations in the CONSORT extension for randomized pilot and feasibility trials, so that data from the Vanguard study can be used in the main trial analysis. Results of the main study will significantly advance the investigators understanding of health consequences of COVID-19, delivery of health care, and health outcomes for adults with Long COVID. It is interdisciplinary research by a Canadian-led research team representing speech-language pathology, occupational therapy, physiotherapy, healthcare administration, and stakeholders with lived experience; and includes US collaborators representing the largest national company providing a cognitive rehabilitation program developed specifically for adults with Long COVID. The investigators collaboration with US partners is a step toward globalization of the rehabilitation methods.