key: cord-0994922-0tq39aez authors: Garjani, A.; Middleton, R. M.; Nicholas, R.; Evangelou, N. title: Pre-existing anxiety, depression, and neurological disability are associated with long COVID: A prospective and longitudinal cohort study of the United Kingdom Multiple Sclerosis Register date: 2021-06-25 journal: nan DOI: 10.1101/2021.06.25.21259256 sha: ccf3a0b31d3bd4fb08830a173a88d0ebd3e23ae3 doc_id: 994922 cord_uid: 0tq39aez Objectives: To assess the prevalence of and factors associated with developing long COVID among patients with multiple sclerosis (MS), a condition which shares the neurological and psychological symptomatology of long COVID Design: Community-based prospective and longitudinal observational study Setting: The United Kingdom (UK) MS Register (UKMSR) COVID-19 study Participants: A national cohort of MS patients with COVID-19 Main outcome measures: Participants used the online questionnaire-based platform of the UKMSR to update their COVID-19 symptoms and recovery status. Questionnaires were date-stamped for estimation of COVID-19 symptom duration. The UKMSR also holds demographic and up-to-date clinical data on participants including comorbidities, MS type, date of MS diagnosis, disease-modifying therapies, web-based Expanded Disability Status Scale scores (a measure of physical disability in MS), and Hospital Anxiety and Depression Scale. The association between these factors and recovery from COVID-19 was assessed using multivariable Cox regression analysis. Results: Out of 7,977 MS patients who participated in the UKMSR COVID-19 study, 599 had COVID-19 and updated their recovery status prospectively. At least 181 participants (31.1%) had long-standing COVID-19 symptoms for [≥]4 weeks and 76 (13.1 %) for [≥]12 weeks. Participants with higher levels of pre-COVID-19 physical disability, participants with anxiety and/or depression prior to COVID-19 onset, and women were less likely to recover from COVID-19. Conclusions: Long COVID appears to affect patients with a pre-existing chronic condition, especially those with physical disabilities or mental health problems disproportionately when compared to reports in the general population. Long COVID research and the development of post-COVID-19 rehabilitation services need to be inclusive of these at-risk populations. Trial Registration: ClinicalTrials.gov: NCT04354519 Long-term sequelae of COVID-19, or long COVID, has become a focus of research to inform the transformation of healthcare services for providing post-COVID-19 rehabilitation. Identification of long COVID risk factors will ensure that care is delivered more efficiently amid the burden of the COVID-19 pandemic on healthcare systems. 1 A study has reported that asthma patients are at increased risk of experiencing long COVID. 2 This finding may not be unexpected as respiratory symptoms constitute one of the most common symptoms of long COVID. 2 3 It could be anticipated that people with other chronic conditions and symptoms similar to long COVID may also be vulnerable to the long-term effects of infection. Neurological symptoms are common in long COVID with fatigue being the single most prevalent symptom. 2 3 Fatigue is a prominent feature of many neurological conditions including multiple sclerosis (MS) with an estimated prevalence of 65.6%. 4 Cognitive deficits, which are commonly reported in post-acute COVID-19, 5 are estimated to affect 43-70% of people with MS. 6 Similarly, studies have suggested a bidirectional association between psychiatric disorders and COVID-19 in that they can be both a risk factor for and a sequela of This study aimed to assess the prevalence and predictors of long COVID among people with MS. This community-based prospective and longitudinal cohort study was conducted as part of the United Kingdom (UK) MS Register (UKMSR) COVID-19 study (ClinicalTrials.gov, Identifier: NCT04354519). Ethical approval for UKMSR studies was obtained from . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Web-EDSS measures neurological impairment in MS and is an ordinal scale, scored from 0 to 10, with higher scores indicating more physical disability. 9 10 Participants were grouped into those with a web-EDSS score of (1) 0-2.5 (ambulatory without assistance-no or minimal neurological impairment), (2) 3-3.5 (ambulatory without assistance-moderate neurological impairment), (3) 4-5.5 (ambulatory without assistance-severe neurological impairment), (4) 6-6.5 (ambulatory with assistance), and (5) ≥ 7 (restricted to wheelchair or bed). HADS is scored from 0 to 21 for anxiety and depression separately. Participants with scores ≥ 11 were considered as having probable anxiety or depression. 11 Participants with anxiety, depression, or both were considered as one group ('with anxiety and/or depression') because . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 25, 2021. ; these conditions frequently co-exist in people with MS, 12 Univariable and multivariable Cox regression analysis, with time (days) from reporting COVID-19 to full recovery ('event') as the dependent variable, were performed to assess the association between demographic and clinical variables and recovery from COVID-19. Participants with persistent symptoms at their last follow-up were 'censored'. A directed acyclic graph was produced (Supplemental Material) to identify potential confounding factors, which were subsequently accounted for in the multivariable Cox regression analysis. This method avoids the introduction of bias in the analysis by the erroneous inclusion of colliders and mediators as confounding factors. 14 Listwise deletion was implemented for missing data. Results are presented as adjusted hazard ratios with 95% confidence intervals. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 25, 2021. ; Out of 7,977 people with MS who participated in the UKMSR COVID-19 study, 1,096 reported COVID-19. A total of 599 people with MS and COVID-19 updated their recovery status (participants) and 497 did not (non-participants). Participants did not differ in their baseline characteristics from non-participants (Table 1) . Twenty-four participants had been hospitalised during their acute infection, 12 because of COVID-19 and 12 for non-COVID-19 reasons. Table 2 . . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 25, 2021. ; Web-EDSS score of 4 to 5.5, n (%) (Table 1) . Participants with higher web-EDSS scores or anxiety and/or depression before COVID-19 onset and women were less likely to recover (Table 3) . . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 25, 2021. ; 11 for anxiety or depression were considered as having probable anxiety or depression, respectively. c Prior to COVID-19 onset New or worsening fatigue was the most common long COVID symptom followed by lower respiratory tract symptoms (Figure 1 ). Studies have suggested that pre-existing neurological and psychiatric disorders are predisposing factors for In this prospective and longitudinal study, we report an association between pre-existing anxiety and depression and long COVID. Although the results of this study are from a population with higher prevalence of anxiety and depression than the general population, 15 they highlight that patients with pre-COVID-19 mental health problems could be disproportionately affected by long COVID. The links between psychological stress and the function of the immune system could be one explanation for this observation. 16 We also report a higher rate of long COVID in people with MS compared to a study of the general population with a similar methodology, using prospective data collection (2.3% for ≥ 12 weeks). 2 Other studies are emerging that report much higher rates of long COVID (38% for ≥ 12 weeks) in the general population, but they have used retrospective data collection that can be affected by recall bias. 17 Although the lack of a direct control group, for example recording any new symptoms in people with MS without COVID-19, is a limitation of this study, we feel that it is unlikely to affect these results. These findings in a study population comprised of mostly non-hospitalised people with MS and COVID-19 highlight previous observations that people with COVID-19 treated in the community can also experience prolonged symptoms of COVID-19. 2 18 An association between pre-COVID-19 physical disability in people with MS and adverse acute COVID-19 outcomes has been previously reported. 19 Our study shows that higher levels of physical disability predispose them to long COVID as well. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 25, 2021. ; It is possible that long-lasting symptoms of COVID-19 in populations with asthma or MS be a deterioration of their pre-existing condition triggered by the infection rather than persistent new symptoms of COVID-19? It is known that respiratory infections can trigger asthma exacerbations, 20 and we have previously shown that COVID-19 can lead to MS exacerbations. 21 New or worsening fatigue was the most common persisting symptom in our population followed by lower respiratory tract symptoms, a pattern similar to the general population. 2 3 Fatigue, however, is also prevalent in MS. 4 Further research is needed to understand what is long COVID and whether it presents with different symptom patterns in populations with other pre-existing disorders. We think these observations are important as healthcare services are being reformed to address the consequences of the pandemic. This study adds to studies of long COVID in the general population, 2 22 highlighting that, in long-term, COVID-19 could affect people with pre-existing conditions differently. These findings have implications for long COVID research-to be inclusive of at-higher risk populations, and for provision of post-COVID-19 rehabilitation-as individualized pathways to accommodate the needs of these potentially more vulnerable populations are needed. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) systems network-United States Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis Asthma exacerbations· 2: Aetiology COVID-19 is associated with new symptoms of multiple sclerosis that are prevented by disease modifying therapies. Multiple Sclerosis and Related Disorders Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study None. The study was funded by the United Kingdom Multiple Sclerosis Society (131). .