https://orcid.org/0000-0003-3991-470X
Figures
Abstract
Purpose
The aim was to longitudinally explore changes in fatigue- and cognition-related symptoms during the first year after hospital treatment for COVID-19.
Method
Patients hospitalized for COVID-19 in Gothenburg, Sweden, were consecutively included from 01-07-2020 to 28-02-2021. Patients were assessed at the hospital (acute) and at 3 and 12 months after hospital discharge. Cognition was assessed with the Montreal Cognitive Assessment (MoCA), the Trail Making Test B (TMTB), and the Cognitive Failure Questionnaire (CFQ). Fatigue was assessed using the Multidimensional Fatigue Inventory-20 (MFI-20) and the Mental Fatigue Scale (MFS). Data was analyzed with demographics and changes over time calculated with univariable mixed-effects models.
Result
In total, 122 participants were included. Analyzes of Z-scores for MoCA indicated improvement over the year, however the results were 1 SD below norm at all assessments. Alertness (TMTB scores) improved significantly from the acute assessment to the 12- month follow-up (p = <0.001, 95% CI 34.67–69.67). CFQ scores indicated cognitive impairment, and the sum scores for MFI reflected a relatively high degree of fatigue at follow-up.
Citation: Andreasson I, Persson HC, Björkdahl A (2024) Fatigue and cognitive dysfunction in previously hospitalized patients with COVID-19: A 1-year follow-up. PLoS ONE 19(11): e0314131. https://doi.org/10.1371/journal.pone.0314131
Editor: Tanja Grubić Kezele, University of Rijeka Faculty of Medicine: Sveuciliste u Rijeci Medicinski fakultet, CROATIA
Received: July 17, 2024; Accepted: November 5, 2024; Published: November 25, 2024
Copyright: © 2024 Andreasson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The datasets analysed during the current study are not publicly available due to ethical restrictions. According to the Swedish regulation https://etikprovningsmyndigheten.se/ the permission to use data is only for what has been applied for and then approved by the Swedish Ethical Review Authority. Data is available from the Department of Clinical Neuroscience, SU/Sahlgrenska, Blå stråket 7, plan 3, SE-413 45 Gothenburg, Sweden, by email (inf@neuro.gu.se) upon reasonable request.
Funding: This study was funded in part by the Swedish government under an agreement between the Swedish government and the county councils (ALFGBG-965653, ALFGBG-942914), Forte/Formas (2020-02775), Västragötaland regional research funding (VGFOUREG-969261, VGFOUREG-940508, VGFOUREG-969267), Västragötaland local research funding (VGFOUGSB-977360), and the Sahlgrenska University Hospital research funds (SU-961051). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
COVID-19 affects multiple organs with a variety of symptoms, and cases vary from being asymptomatic (about 20%) to involving severe illness and death [1]. A meta-analysis with over 1000 participants and 32 countries showed that at 12 months post-COVID infection 50% had at least one symptom still present, with the most common being memory impairment, fatigue, and depression [2]. Both patients who required hospital admission, including care in Intensive care unit (ICU), and those with a milder COVID-19 infection may have significant residual disabilities after a long period of time [3–5]. The condition with long-lasting problems was defined by the World Health Organization (WHO) as “post-COVID-19 condition” (PCC), which “occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis” [6]. A Swedish study using data from national registers and primary health care databases for all adult inhabitants of the two largest regions in Sweden (4.1 million inhabitants) found that of all registered COVID-19 cases, 2.0% (n = 10196) had been diagnosed with PCC [7].
It seems that different pathways are involved in the PCC sequelae, ranging from persistence of systemic inflammation, virus‐driven cellular alterations, dysregulated immune reaction, metabolic disturbances and coagulation and fibrosis pathways activation [8]. Structural and functional brain changes have been found after COVID-19, which provide insights to the understanding of neural underpinnings of cognitive dysfunction of PCC and the pathophysiology of this disorder [9–12].
Health status is generally poor for people with PCC, particularly in the domains of functional impairment (64%) and quality of life (72%) [13]. Fatigue and cognitive deficits are key features of PCC affecting daily activities for several patients over a long time [14]. A recent meta-analysis found fatigue to be the most frequent symptom of neurological post-COVID-19 syndrome (37%) followed by brain fog (32%), sleep disturbances (31%) and memory issues (28%) [15]. In a study of patients reporting major difficulties in everyday life following COVID-19, neuropsychological tests revealed cognitive impairment in 46%, whereas magnetic resonance imaging showed multiple areas of affected white matter in 71% [16]. Global impairment in cognition across the spectrum of COVID-19 disease severity has been shown, but no clear pattern of deficits in specific domains post-acute [17]. A recent study, with patients eight months post-COVID-19 infection, showed significantly lower performance on tests of attention, executive functions, and naming abilities, as well as subjective memory complaints of prospective and retrospective memory, with respect to a normative sample [18].
Fatigue is a multidimensional problem that is difficult to assess [19]. Studies of post-COVID fatigue focus on physical or mental fatigue or both using various scales, making results difficult to compare [20]. Cognitive impairment in people with post-COVID has been assessed with various neurological tests, but the most common screening is the Montreal Cognitive Assessment (MoCA) [21].
Fatigue and cognitive impairment limit everyday activities and cause disability that leads to the need for support and rehabilitation [13, 22]. People with PCC also can experience difficulties in understanding and managing their symptoms and in gaining insight from the healthcare system and accessing adequate rehabilitation efforts [23]. These difficulties emphasize the need for improved knowledge about the severity and progression of fatigue and cognitive impairment in people with post-COVID.
The aim of the present study was to longitudinally explore changes in fatigue- and cognition-related symptoms during the first year after hospital treatment for COVID-19.
Materials and methods
Patients
This longitudinal cohort study included patients enrolled in two studies, “Life in the time of Covid study in Gothenburg” (i.e., GOT-LOCO) and “Long-term Evaluation of the implication of COGnitive and other symptoms on everyday life” (i.e., LECOG-COVID-19). The two studies were coordinated regarding inclusion and follow-up. A total of 146 patients were consecutively included at Sahlgrenska University Hospital (four units), Gothenburg, Sweden, from 01-07-2020 to 28-02-2021 (first and second waves of the pandemic). Inclusion criteria were age ≥18 years and treatment in the hospital ≥5 days after (if needed) intensive care unit (ICU) treatment and a completed MoCA test during the hospital stay (designated here as the acute assessment). Exclusion criteria were cognitive or physical inability to perform cognitive screening, and not an independent living before the onset of COVID-19 infection.
Non-residents of Sweden were excluded. The study was approved by the Swedish Ethical Review authority (Drn: GOT-LOCO: 2020–03046, 2020–03922, 2021–00444, 2021–03556. LECOG: 2020–03222, 2021–03824) and complies with the Declaration of Helsinki. All patients signed written informed consent prior to inclusion. This manuscript was developed according to the STROBE guidelines [24].
Procedure—data collection
A study coordinator reviewed medical records daily to recruit patients. Patients were subsequently informed and enrolled in the study by physiotherapists and occupational therapists at the hospital. The acute assessment was carried out at the hospital. The two in-person follow-ups were carried out at 3 and 12 months after hospital discharge. The follow-up was performed by an occupational therapist, mostly as an outpatient visit at the hospital or in the patient’s home if the patient could not travel. All assessments followed a standardized procedure and test protocol. Characteristics of the study population in the acute setting were retrived from the medical charts. Severity of COVID-19 was assessed according to the World Health Organizations Clinical Progression Scale [25, 26] moderate disease infection corresponding to hospital treatment with or without oxygen therapy (level 4–5), and severe disease was defined as needed more advanced respiratory or medical support (level 6–9) [25, 26]. For each patient the Charlson comorbidity index was calculated on data from the hospital medical records [27]. The Charlson comorbidity index is a weighted score, based on specific comorbid conditions, and was grouped as no comorbidity (0 points), mild comorbidity (1–2 points), and severe comorbidity (2 points).
Measurement of cognitive function and fatigue.
Three measurements were used to assess different aspects of cognitive function. The MoCA is a brief screening test for cognitive impairment, with a maximum score of 30 points. Higher scores indicate less impairment, and a score <26 indicates cognitive impairment. The MoCA has high reliability and validity in patients with cognitive impairment [21]. To evaluate mental flexibility, speed of processing, and executive functions, the Trail Making Test B (TMTB) was used [28].
The Cognitive Failure Questionnaire (CFQ), consisting of 25 questions (each rated 0–4), was used for self-assessment of cognitive impairment. The total CFQ score range is 0–100, and higher scores indicate a worse degree of symptoms [29]. A standardized question also was used to explore whether participants experienced cognitive deficits that affected everyday life, with responses dichotomized as yes or no.
Three measurements were used to assess different aspects of fatigue. Self-perceived fatigue was assessed with the Swedish version of the Multidimensional Fatigue Inventory-20 (MFI-20). The MFI-20 includes five dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Each dimension contains four items, each rated 0–5. A higher score indicates more fatigue, and the maximum total score is 100 points [30]. Self-perceived mental fatigue was assessed using the Mental Fatigue Scale (MFS), with 14 questions that are rated 0–3 and one question on daily variation that is rated 0–2. The score is based on the first 14 questions, and a score ≥10.5 points indicates mental fatigue in need of further examination [31]. The participants also rated fatigue on a visual analogue scale (VAS; 0–100 mm), where 100 mm indicated the worst possible fatigue. Furthermore, standardized questions were used to investigate the presence of sleepiness, lack of energy, and mental fatigue, and responses were dichotomized as yes or no.
The MoCA and TMTB, were used at all three timepoints and MFI-20, and MFS at 3 and 12 months. The CFQ was used only at the 12-month follow-up. Standardized questions regarding cognitive impact and different aspects of fatigue were asked at the 3- and 12-month follow-ups.
Statistical analysis.
Data were analyzed using the Statistical Package for Social Sciences version 28.0 (IBM Corp., Armonk, NY, USA). Demographic and parametric data are presented as mean (standard deviation, SD), and non-parametric data as median [min, max]. To adjust for sex and age, Z-scores were calculated for MoCA [32], and t-scores were calculated for TMTB [33]. To investigate differences between groups, the Mann–Whitney U test was used. Two separate univariable mixed-effects models were used to evaluate changes in TMT-B and MoCA over time. The models were fitted using the lme function from the nlme package in R version 4.4.1 (R Foundation for Statistical Computing, Vienna, Austria), with random intercepts to account for individual variability across subjects. To address heteroscedasticity, separate variance structures were modelled for each time point.
Results
Of the 146 patients originally included in the studies, 122 met the inclusion criteria for the present study (Fig 1), with a mean age of 64 (standard deviation [SD] 13.2) years, and 75% were men. Most (70%) of the participants were born in Sweden, and almost half had an exam from secondary school (49%). All participants had been treated for COVID-19 in the hospital, for a mean of 40 (SD 42.1) days, including care in the ICU. More than half (55%) of the participants had been treated in the ICU (Table 1).
A total of 94 participants attended the 3-month follow-up, and 74 attended at 12 months. Not all participants were assessed at both follow-ups, and some participated in only one assessment (Fig 1).
Cognition
At the acute assessment, the median MoCA score was <26, indicating impaired function. The median score was 26 at both the 3- and 12-month follow-ups. When using the Z-scores for MoCA, i.e. considering age, sex, and education, the results were > 1 SD below the norm for the sample at all three assessments. Regarding TMT B at the acute assessment, 41% had a t-score <T40 (1 SD below the mean), and at the 12-month follow-up, 15% had a t-score <T40 (Table 2).
The proportion of participants with an unchanged MoCA score between the acute and 3-month follow-up was 11%, whereas 35% had a worse score and 54% had an improved score. Between the acute assessment and the 12-month follow-up, 8% had no change, 37% had worse scores, and 55% had an improved score (Fig 2). For the TMTB scores, 86% had an improved score at the 12-month follow-up, 12% had a worse score, and for 2%, scores were unchanged (Fig 3).
Improvement is implied for values above the reference line (solid black line).
Improvement is implied for values below the reference line.
Cognitive function (TMT B and MoCA) improved significantly over time, both at 3- and 12-months follow-up for both TMT B and MoCA (Table 3). Cognitive function (assessed with MoCA) did not differ significantly depending on treatment in the ICU or not.
Assessment with CFQ indicated experiences of cognitive impairment at 12 months (Table 2). Most problematic were questions related to attention and working memory (questions 2, 7, 9, 20, and 22). More than 20% of participants scored 3 or 4, indicating “quite often or often,” and <10% scored 0, meaning that they “never” experienced difficulties related to these questions.
Regarding the standardized question about the presence of cognitive impairment, 64% indicated experiencing cognitive impairment at 3 months and 61% did so at 12 months. The rates did not differ significantly between the two timepoints (Table 2).
Fatigue
The level of fatigue (MFI) was reported as high (≥10 out of 20) in all but one of the dimensions at the 3- and 12-month follow-ups. The reported level of fatigue was approximately similar at both timepoints, with only “reduced activity” being less frequently reported at 12 months (Table 4).
Proportions of participants experiencing increased fatigue or reduced fatigue were similar at 12 months (Fig 4).
Improvement is implied for values below the reference line (solid black line).
The changes in fatigue for the total group of participants, assessed with MFI at 3 and 12 months, is illustrated in Fig 5. Fatigue (MFI dimension) did not differ with versus without ICU care at 12 months, except for “physical fatigue” scores, which were higher for patients who had not been treated in the ICU (p = 0.045, 95% CI -4.84 to -0.06).
Boxplots show the five dimensions of MFI-20 at the 3- and 12-month follow-ups.
When participants estimated fatigue using the VAS, the means were 48 (SD 26.0) at the 3-month follow-up and 42 (SD 25.7) at the 12-month follow-up (Table 3). The decrease was not significant (p = 0.297, 95% CI -2.69 to 8.69; Fig 6).
For each, the box represents interquartile ranges and contains 50% of the cases, the line represents the median, and the whiskers indicate the smallest and largest values.
The median MFS score at 12 months was 9 [0–32] points. The proportion scoring ≥10.5, indicating mental fatigue, was 39%.
For the standardized question about presence of sleepiness, lack of energy, or mental fatigue, more than 50% stated that they had experienced all three at both 3 and 12 months (Table 4). At 3 months, 85% reported that they experienced a lack of energy, which had declined significantly to 69% at 12 months (p = 0.005, z = -2.83). For sleepiness and mental fatigue, the differences between 3 and 12 months were minimal (Table 4).
Discussion
In this Swedish cohort study, among patients treated at the hospital for COVID-19, cognitive impairment was common within the first year. There was an improvement but results for global cognition (MoCA) was still >1 SD below norm at 12-months follow-up. Although alertness improved in the first year, which was indicated in improved results on TMT B, the improvement was insufficient to positively influence global cognitive function, which remained diminished. At one year after hospitalization for COVID-19, the prevalence of fatigue also was high.
MFI-scores indicated a higher degree of fatigue and below the norm for all other dimensions except for motivation [34]. This pattern might indicate that the motivation to be active had increased but that fatigue remained an obstacle. In line with our results, others have reported that fatigue may be persistent up to one year following COVID-19 [35–38]. Calabria et. al. [39] found that reports of clinically significant fatigue were present at eight months for most of the participants (82.3%) in their study, with physical fatigue rated highest, similar to the present study. We also found that mental fatigue (measured by MFS) was present in 4 of 10 participants at one year after COVID-19. Previous work from a post-COVID clinic in Primary care also has identified mental fatigue as one of the most severe consequences and a major persistent problem after COVID-19. Patients at this clinic needed special interventions because of residual symptoms, and the study categorized 75% of the participants as suffering from moderate to severe mental fatigue at about 9 months after infection [40]. Moreover, fatigue can reduce quality of life following COVID-19 [41].
Cognitive consequences after COVID-19 are common [42, 43], with persisting symptoms for one year or longer [44]. The current results indicated improvement in cognition during the year after COVID-19, on MoCA tests, calculated as z-scores, but based on self-reports of cognitive dysfunction the experience was that there was no improvement. Self-reported cognitive functions have been shown to correlate with the results of cognitive tests, and the experiences of cognitive difficulties persist confirmed by objective tests [43]. Although, even if there was an improvement in cognitive function the results were still below the general norm, which could correspond to the self-reported lack of improvement in cognitive function. A study in Italy assessed whether self-reports of cognitive impact could be verified neurophysiologically by altered electroencephalography patterns and showed a pattern characterized by a predominant slowing in 65% of cases [45]. Kopanska et. al. [10] compared Quantitative Electroencephalography (QEEG) findings before and after onset of PCC cognitive dysfunction and found objective changes in the QEEG profile in relation to the cognitive complaints. They concluded that a QEEG examination may be a supportive tool for post-COVID clinical workup and for monitoring the treatment effects.
Several studies of COVID-19 have used MoCA to explore the impact of the disease on global cognitive function, most using a cut-off score of <26 for impairment, regardless of age [5, 45–47]. However, age, sex, and level of education have been significantly associated with total MoCA score and are relevant to consider, rather than using a common cut-off [48]. For this reason, we performed z-score calculations, which could better be compared to normative data. The analyzes showed a small significant improvement between timepoints, but the results remained below the expected. There is an important difference between the reporting of results from raw scores as a mean at the cut -off (26 points) and using standard scores of Z, with a result for the sample of >-1SD meaning a performance below the norm, indicating that difficulties in daily life and work may be expected.
Our findings suggesting persistent problems are in line with a recent study of post-COVID patients treated in primary care, with results indicating neurocognitive disorders in more than 75% at 15 months after the infection [44]. However, flexibility and tempo, both aspects of cognitive function, were measured with the TMTB in the present study and showed significant improvement from the acute assessment to the 12-month follow-up, which is to be expected if alertness improves. Our results indicate that although the general cognitive impact persists, alertness increases, suggesting that to some extent, specific functions such as attention can be improved over time.
Fatigue and cognitive impairment are likely to affect each other, and they both seem to persist in the first year after COVID-19. Different symptoms in relation to long-term cognition have been explored, and fatigue has been identified in several domains associated with cognitive aspects [49]. Executive and attentional difficulties on cognitive tests have been found to be important predictors among different types of fatigue [39]. In PCC, neurocognitive symptoms and fatigue have also been associated with alterations in electroencephalographic (EEG) activity [9]. Cognitive impairment has considerable consequences for occupational performance, and fatigue also can heavily limit day-to-day activities [50] and be disabling [51, 52]. Even if the ability to work increases over time after COVID-19, fatigue and cognitive impairment may still greatly affect the ability to work [53]. Six months after infection, many patients need workplace accommodations or may not be able to resume their original employment [54–56]. According to one study of patients treated in the hospital for COVID-19, although most had returned to work by one year after infection, many still experienced various symptoms [57].
Given the great burden of post-COVID fatigue and cognitive impairment at both the individual and societal levels, the need is ongoing to investigate how long such problems persist or whether they will do so. Furthermore, effective interventions are needed to improve functioning and to discern which aspects of fatigue and cognitive impairment most affect the ability to perform activities of daily living. These aims are important to ensure the most appropriate rehabilitation measures that will allow people affected by COVID-19 to return to activity and work.
Strengths and limitations
A strength of the present study is the longitudinal design, with the first assessment prior to discharge after in-hospital treatment for COVID-19 and follow-up at two timepoints during the first year after onset. As the study was conducted in an ongoing pandemic, however, rapid, and unforeseen ward changes became necessary for patients during their stay, so that it was difficult to adjust and carry out assessments as intended in a timely manner. For this reason, some data are missing, which is a limitation.
Another strength is that Z-scores were used for MoCA which not is the case in most COVID articles using MoCA. The most common is the use of raw sum score with adjustment of one point for participants with education less than 12 years. The use of z-scores takes into account sex, age, and level of education, offering a more solid assessment that does not have to rely on a cut-off which could be expected to be different in relation to sex, age and education. Furthermore, we used reliable and valid instruments complemented with self-ratings of fatigue and cognitive impairment to capture different aspects of these symptoms. For measuring cognitive impairment, however, more complete neuropsychological test batteries would have been preferable to a global screening instrument such as MoCA. As COVID was a new diagnosis, it was difficult to foresee that cognition would represent a significant residual impairment requiring deeper analysis. In hindsight, the choice of instruments would have been different to gain a deeper understanding of the impact of the disease on everyday life and work.
Conclusion
In the first year after hospitalization with COVID-19, most patients in this study experienced fatigue and reduced cognitive function. Alertness improved over time, but other improvements were few. Because both fatigue and impaired cognitive function have a major impact on daily life, the results highlight the importance of further research with respect to treatment for these persistent problems, including rehabilitation.
Acknowledgments
We would like to thank all the physical and occupational therapists at Östra University Hospital, Mölndal University Hospital, Högsbo University Hospital, and Sahlgrenska University Hospital for their contributions to the study and data collection. We also thank Marie Engwall, Alexandra Larsson, Hilda Öhlén, Iolanda Santos Tavares Silva, and Cecilia Boustedt for their extensive contributions to the follow-up data collection. We also thank the patients included in this study.
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