Dear Editor,
Coronavirus disease-2019 (COVID-19) has devastated healthcare systems and public health
globally [1]. Many patients develop a wide spectrum of persisting or new symptoms
3 months after the acute COVID-19 illness (long-COVID-19), and these symptoms can
persist for at least 2 months [2, 3]. There is significant variability in the definitions
with the lack of standardization and hence the reported frequency of long-COVID-19
also varies.
Furthermore, there is sparser data with a significant heterogeneity on neurological
long-COVID-19 symptoms [4].
Neurological manifestations represent a possible presentation of long-COVID-19 [5–7].
Data on the type of symptoms and prevalence of neurological long-COVID-19 are still
in evolution [1, 5]. Hence, a clear understanding of neurological long-COVID-19 would
aid healthcare systems in implementing health resources to measure and manage this
global healthcare burden.
Herein, in this study we aimed to characterize the type and prevalence of neurological
symptoms related to neurological long-COVID-19 from a large international multicenter
cohort of adults after discharge from hospital for acute COVID-19.
This is an international, multicenter, prospective, observational cohort using the
ISARIC WHO COVID-19 Clinical Characterization Protocol, approved by the WHO Ethics
Committee (RPC571 and RPC572).
Local Ethics approval was obtained from participating centers according to local regulatory
rules as appropriate.
Inclusion criteria were: patients ≥ 18 years-old; patients previously admitted to
hospital with COVID-19; follow-up data available at least 1-month post- discharge
from hospital or health center; person (or family member/next of kin for patients
who lack capacity) consent to participate.
The case report form (CRF) was completed as a patient self-assessment through an online
link, telephone interview, or in-clinic. Data were collected as first presentation
of symptoms and persistent presentation. First presentation described participants
who did not have neurological symptoms at hospitalization. Persistent presentation
is persistence of symptoms among those who had neurological symptoms evaluated at
initial hospitalization. Survey follow-up was defined as three monthly intervals from
post-discharge follow-up, up to 12 months. Six main neurological symptoms were collected
during hospitalization and follow-up. Additional neurological symptoms were collected
at follow-up only. Specifics of survey schematic overview of the follow-up data time
frame are reported in Supplementary Material (SM) Item S1. Follow-up asking for new
or persistent neurological symptoms has been performed by phone call or in-person
interview at each time point: 1–3 months, 4–6 months, 7–9 months, and 10–12 months.
Main neurological symptoms included confusion, anosmia, ageusia, fatigue/malaise,
muscle aches/joint pain, and seizures. Additional neurological symptoms included dizziness,
erectile dysfunction, fainting/ blackouts, headache, loss of sensation, muscle weakness,
paresthesia, problems seeing, problems speaking or communicating, problems swallowing
or chewing, problems with balance, tinnitus, and tremors.
Observed prevalence of neurological symptoms were estimated based on survey follow-up
time, age at disease onset and sex. Unadjusted symptom prevalence by survey follow-up
period was summarized as percentages with 95% confidence intervals (CIs), assuming
a Gamma distribution. Symptom prevalence estimates were stratified by initial versus
repeat follow-up assessment. Period prevalence by follow-up was also calculated. Symptom
prevalence by age and sex was examined by logistic regression. Regression models with
neurological symptoms as an outcome included fixed effects for sex and age, and their
interaction, nested within the survey follow-up period. Age was modelled by polynomial
terms up to order of 3. Analyses were completed in R using the lmerTest package.
Overall, 11,357 adults (median age = 56 (IQR = 45 to 67) years; 42% female) with acute
COVID-19 hospitalization from January 2020 to December 2022 were analyzed (SM Item
S2). Frequencies are stratified by the availability of neurological signs and symptoms
evaluated at disease onset/hospital admission as shown in SM Item S3. Baseline characteristics
are presented in SM Item S4.
Fatigue/malaise was the most frequent neurological manifestation reported at acute
hospitalization with 54.9% (95%CI 53.6–56.2%), followed by muscle aches/joint pain
35.8% (95%CI 34.5–37.0%), ageusia 20.7% (95%CI 19.6–21.8%), anosmia 18.3% (95%CI 17.2–19.3%),
confusion 7.9% (95%CI 7.1–8.7%), and seizures 0.9% (95%CI 0.5–1.2%).
More than half (55.3%) of participants had one or more neurological symptoms during
their hospitalization. At follow-up, first presentation of symptoms was found in 40.6%
(95%CI = 38.0–43.4%) at 1–3 months, 39.1% (95%CI = 36.5–41.9%) at 4–6 months, 23.1%
(95%CI = 19.0–27.8%) at 7–9 months, and 4.4% (95%CI = 2.4–7.4%) at 10–12 months had
1 or more neurological symptoms. Persistent presentation of symptoms was found in
53.3% (95%CI = 50.6–56.1%) at 1–3 months, 58.4% (95%CI = 56.0–60.9%) at 4–6 months,
55.4% (95%CI = 52.1–58.8%) at 7–9 months, and 40.4% (95%CI = 37.3–42.8%) at 10–12 months
had 1 or more neurological symptoms.
At 1–3 months, estimates of first presentation of symptoms were: fatigue/malaise 51.8%
(95%CI = 48.0–55.9%), muscle aches/joint pain 18.6% (95%CI = 16.9–20.4%), ageusia
5.2% (95%CI = 4.1–6.4%), anosmia 4.1% (95%CI = 3.1–5.2%), and confusion 10.9% (95%CI = 9.6–12.4%).
Estimates of persistent presentation of symptoms were: fatigue/malaise 41.9% (95%CI = 39.4–44.5%),
muscle aches/joint pain 27.6% (95%CI = 25.6–29.7%), ageusia 7.9% (95%CI = 6.8–9.2%),
anosmia 7.7% (95%CI = 6.6–8.9%), and confusion 19.4% (95%CI = 17.2–21.7%).
At 4–6 months, estimates for first presentation of symptoms were: fatigue/malaise
50.8% (95%CI = 46.9–54.9%), muscle aches/joint pain 19.4% (95%CI = 17.6–21.3%), ageusia
3.5% (95%CI = 2.6–4.7%), anosmia 4.4% (95%CI = 3.3–5.6%), and confusion 11.5% (95%CI = 10.1–13.1%).
Estimates of persistent presentation of symptoms were: fatigue/malaise 44.3% (95%CI = 42.2–46.5%),
muscle aches/ joint pain 34.2% (95%CI = 32.3–36.1%), ageusia 6.7% (95%CI = 5.9–7.6%),
anosmia 6.9% (95%CI = 6.1–7.8%), and confusion 29.4% (95%CI = 27.3–31.6%).
At 7–9 months, estimates of first presentation of symptoms were: fatigue/malaise 26.1%
(95%CI = 20.5–32.8%), muscle aches/joint pain 20.5% (95%CI = 16.9–24.7%), ageusia
3.9% (95%CI = 2.1–6.6%), anosmia 4.1% (95%CI = 2.3–6.9%), and confusion 9.4% (95%CI = 7.0–12.5%).
Estimates of persistent presentation of symptoms were: fatigue/malaise 43.6% (95%CI = 40.6–46.7%),
muscle aches/joint pain 30.1% (95%CI = 27.6–32.7%), ageusia 6.2% (95%CI = 5.1–7.5%),
anosmia 7.1% (95%CI = 5.9–8.4%), and confusion 26.6% (95%CI = 23.9–29.5%).
At 10–12 months, estimates of the first presentation of symptoms were: fatigue/malaise
3.1% (95%CI = 1.4–5.8%), muscle aches/joint pain 2.5% (95%CI = 1.1–4.9%), ageusia
and anosmia 0.0%, and confusion in 2.2% (95%CI = 0.9–4.5%). Estimates of persistent
presentation of symptoms were: fatigue/malaise 29.9% (95%CI = 27.6–32.4%), muscle
aches/joint pain 23.1% (95%CI = 21.0–25.2%), ageusia 3.3% (95%CI = 2.6–4.2%), anosmia
3.9% (95%CI = 3.1–4.9%), and confusion 16.9% (95%CI = 15.2–18.8%).
Table 1 shows estimates of first and persistent presentation of symptoms. SM Item
S5 shows period prevalence of neurological symptoms post-hospital discharge. Additional
symptoms assessed by survey only, not evaluated at acute hospitalization, are shown
in SM Item S6. Missing data points were excluded from the analysis of each symptom.
Trajectories of prevalence of neurological symptoms post-hospital discharge between
males and females are shown in Fig. 1. SM Item S7 shows trajectories of prevalence
of neurological symptoms post-acute onset of COVID-19 between males and females.
Table 1
Observed prevalence and persistence of neurological symptoms over survey follow-up
post hospital discharge
Symptom*
Hospitalization
1 – 3 months
4 – 6 months
7 – 9 months
10 – 12 months
First presentation of symptom
First presentation of symptom
Repeat presentation of symptom
First presentation of symptom
Repeat presentation of symptom
First presentation of symptom
Repeat presentation of symptom
First presentation of symptom
Repeat presentation of symptom
Confusion
7.9% (7.1% to 8.7%)
331/4190
10.9% (9.6% to 12.4%)
242/2217
19.4% (17.2% to 21.7%)
289/1493
11.5% (10.1% to 13.1%)
242/2103
29.4% (27.3% to 31.6%)
761/2589
9.4% (7.0% to 12.5%)
49/520
26.6% (23.9% to 29.5%)
351/1319
2.2% (0.9% to 4.5%)
7/323
16.9% (15.2% to 18.8%)
342/2022
Fatigue/malaise
54.9% (53.6% to 56.2%)
3172/5781
51.8% (48.0% to 55.9%)
687/1325
41.9% (39.4% to 44.5%)
1040/2483
50.8% (46.9% to 54.9%)
629/1239
44.3% (42.2% to 46.5%)
1641/3702
26.1% (20.5% to 32.8%)
74/283
43.6% (40.6% to 46.7%)
794/1822
3.1% (1.4% to 5.8%)
9/295
29.9% (27.6% to 32.4%)
618/2067
Anosmia
18.3% (17.2% to 19.3%)
964/5280
4.1% (3.1% to 5.2%)
64/1574
7.7% (6.6% to 8.9%)
173/2252
4.4% (3.3% to 5.6%)
61/1397
6.9% (6.1% to 7.8%)
245/3544
4.1% (2.3% to 6.9%)
14/339
7.1% (5.9% to 8.4%)
124/1756
0.0% (–)
0/305
3.9% (3.1% to 4.9%)
81/2058
Ageusia
20.7% (19.6% to 21.8%)
1092/5271
5.2% (4.1% to 6.4%)
81/1568
7.9% (6.8% to 9.2%)
178/2252
3.5% (2.6% to 4.7%)
50/1409
6.7% (5.9% to 7.6%)
237/3531
3.9% (2.1% to 6.6%)
13/336
6.2% (5.1% to 7.5%)
109/1756
0.0% (–)
0/305
3.3% (2.6% to 4.2%)
68/2053
Muscle aches/joint pain
35.8% (34.5% to 37.0%)
2060/5761
18.6% (16.9% to 20.4%)
439/2366
27.6% (25.6% to 29.7%)
697/2525
19.4% (17.6% to 21.3%)
426/2197
34.2% (32.3% to 36.1%)
1272/3720
20.5% (16.9% to 24.7%)
110/536
30.1% (27.6% to 32.7%)
544/1809
2.5% (1.1% to 4.9%)
8/322
23.1% (21.0% to 25.2%)
476/2063
1 or more neurological symptoms
67.5% (66.4% to 68.7%)
4231/6264
40.6% (38.0% to 43.4%)
897/2207
53.3% (50.6% to 56.1%)
1483/2783
39.1% (36.5% to 41.9%)
809/2067
58.4% (56.0% to 60.9%)
2284/3910
23.1% (19.0% to 27.8%)
112/485
55.4% (52.1% to 58.8%)
1045/1887
4.4% (2.4% to 7.4%)
14/318
40.0% (37.3% to 42.8%)
830/2075
Follow-up defined in months post hospital discharge. Data are reported as observed
prevalence and 95% confidence intervals, assuming a Gamma distribution. (–): confidence
interval not defined due to no cases reported. First assessment of symptoms was defined
as the first time a patient completed a follow-up survey. Follow-up assessment of
symptoms was defined as a patient who already completed their first survey and are
being surveyed again. Estimates are stratified by first versus repeat symptom assessment
to examine symptom persistence following hospital discharge. Observed prevalence at
acute hospitalization is also presented
Fig. 1
Observed prevalence by age and sex, months following hospital discharge. Observed
prevalence of common neurological symptoms by age at hospitalization*, sex, and survey
follow-up time. Follow-up time is defined in months since hospital discharge. Seizures
excluded due to insufficient cases reported. Estimates presented are from a logistic
regression model fitted to each symptom as the dependent variable, with fixed effects
for sex (categorical), age (continuous) and their interaction. Age was modelled using
polynomial terms up to order 3
The main findings of this international, multicenter, observational follow-up study
are that (1) all symptoms declined over follow-up time, except confusion and insomnia;
(2) among symptoms not evaluated during acute hospitalization, estimates of muscle
weakness, headache, problems with balance, paresthesia, problems speaking/ communicating,
dizziness, problems seeing, tremor, tinnitus, fainting, and problems swallowing/chewing
gradually declined from 1–3 months to 10–12 months follow-up, whereas estimates of
loss of sensation, erectile dysfunction, and problems sleeping gradually increased
over time.
To the best of our knowledge, this is one of the largest cohorts (11,357 subjects)
reporting post-COVID-19 neurological symptoms investigating.
It is noteworthy that the median age of our cohort was 56 years (IQR = 45 to 67),
suggesting that most of them were actively working before acute COVID-19. This has
been previously highlighted in another cohort, with many patients having difficulty
returning to work and previous activities, with significant socio-economic consequences
as documented previously how long-COVID-19 impacted employment and working full-time
[6].
Long-term and cognitive symptoms have been previously reported in COVID-19 subjects
[5]. Previous large investigations reported that around 10% of subjects diagnosed
with acute COVID-19 still had symptoms after 1-year of follow-up [7]. In our cohort,
fatigue/malaise, followed by muscle aches/joint pain were the most frequent neurological
symptoms reported at the time of acute illness, with a trend toward decreasing frequency
at each follow-up, suggesting gradual recovery of functional activities and progressive
rehabilitation [8].
Interestingly, we noted a different recovery between symptoms of the central and peripheral
nervous systems. Anosmia and ageusia (peripheral) disappeared completely, whereas
confusion and insomnia (central) persisted. The occurrence of anosmia and ageusia
is supposed to be caused by a local inflammatory response to SARS-CoV-2 infection
targeting peripheral neurons. On the other hand, several systemic factors have been
identified as possible responsible for central nervous system symptoms, some of them
difficult to recover, including hypoxia, cerebrovascular illness, immune response,
medical resources and treatments, social isolation, psychological repercussions of
the pandemic, and the worry of spreading the sickness [9].
Many COVID-19 survivors were bed bound with persistent disconnection from their environment
during their acute illness/hospital admission. Contributors of this status included
prolonged use of sedatives and delirium during hospitalization. This may explain why
we observed a trend toward increased estimates of erectile dysfunction, loss of sensation,
and problems sleeping. Other common explanations for persistent neurological symptoms
include residual tissue damage, viral persistence, and chronic inflammation [10],
but also increasing age in patients with an underlying disease [11].
The major strength of this study is the description of the prognosis of the disease
with inclusion of many subjects across 16 countries, highly representative of the
general population, up to 12 months following hospital discharge [6]. Nevertheless,
it is worth noting that only 22 patients were from the Americas, thus consideration
of our findings in this population should be careful. Inconsistent data capture (sampling
bias) and lack of rigorous definitions are a limitation. Indeed, a protocol for 12-months
follow-up was not systematically implemented in all participating centers, and the
data captured is rather driven by current clinical practice in each site. However,
we use a large cohort with pragmatic data capturing across multiple countries that
represents real-world reported observations. Lack of comparison group is a further
limitation of this study. Moreover, a cluster analysis early on in our study was deemed
infeasible based on the complex patterns of missing data observed (e.g., non-response
to selected symptoms at initial hospitalization and/or survey follow-up; loss to follow-up).
Finally, our results are based on the analysis of individual symptom prevalence. A
more in-depth approach to analysis would be to instead consider patterns in co-occurring
symptoms over time, for example, by cluster analysis. Given complexities in the data
arising from differences in individual follow-up time and loss to follow-up, this
option could not be explored. The application of clustering algorithms should be considered
by future studies pending data availability.
Long-COVID-19 symptoms are common and persist over time. Registry activities and rehabilitation
protocols should be implemented to define the burden of long-COVID-19 globally with
standardized definitions and data capture instruments and ensure adequacy of resource
distribution.
Availability of data and material:
The data that underpin this analysis are highly detailed clinical data on individuals
hospitalized with COVID-19. Due to the sensitive nature of these data and the associated
privacy concerns, they are available via a governed data access mechanism following
review of a data access committee. Data can be requested via the IDDO COVID-19 Data
Sharing Platform (http://www.iddo.org/covid-19). The Data Access Application, Terms
of Access and details of the Data Access Committee are available on the website. Briefly,
the requirements for access are a request from a qualified researcher working with
a legal entity who have a health and/or research remit; a scientifically valid reason
for data access which adheres to appropriate ethical principles. The full terms are
at https://www.iddo.org/document/covid-19-data-access-guidelines. A small subset of
sites who contributed data to this analysis have not agreed to pooled data sharing
as above. In the case of requiring access to these data, please contact the corresponding
author in the first instance who will look to facilitate access.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary file1 (DOCX 1077 KB)