Long-Term Sequelae of COVID-19 - A Systematic Review and Meta-Analysis of One-Year Follow-Up Studies On Post-COVID Symptoms
Long-Term Sequelae of COVID-19 - A Systematic Review and Meta-Analysis of One-Year Follow-Up Studies On Post-COVID Symptoms
Long-Term Sequelae of COVID-19 - A Systematic Review and Meta-Analysis of One-Year Follow-Up Studies On Post-COVID Symptoms
Systematic Review
Long-Term Sequelae of COVID-19: A Systematic Review and
Meta-Analysis of One-Year Follow-Up Studies on
Post-COVID Symptoms
Qing Han 1 , Bang Zheng 2,3,4, * , Luke Daines 2 and Aziz Sheikh 2
1 Department of Social Policy and Intervention, University of Oxford, Oxford OX1 2ER, UK;
[email protected]
2 Usher Institute, University of Edinburgh, Edinburgh EH16 4UX, UK; [email protected] (L.D.);
[email protected] (A.S.)
3 Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine,
London WC1E 7HT, UK
4 Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London W6 8RP, UK
* Correspondence: [email protected]
Abstract: Emerging evidence has shown that COVID-19 survivors could suffer from persistent
symptoms. However, it remains unclear whether these symptoms persist over the longer term.
This study aimed to systematically synthesise evidence on post-COVID symptoms persisting for at
least 12 months. We searched PubMed and Embase for papers reporting at least one-year follow-up
results of COVID-19 survivors published by 6 November 2021. Random-effects meta-analyses were
conducted to estimate pooled prevalence of specific post-COVID symptoms. Eighteen papers that
reported one-year follow-up data from 8591 COVID-19 survivors were included. Fatigue/weakness
(28%, 95% CI: 18–39), dyspnoea (18%, 95% CI: 13–24), arthromyalgia (26%, 95% CI: 8–44), depression
Citation: Han, Q.; Zheng, B.; Daines, (23%, 95% CI: 12–34), anxiety (22%, 95% CI: 15–29), memory loss (19%, 95% CI: 7–31), concentration
L.; Sheikh, A. Long-Term Sequelae of difficulties (18%, 95% CI: 2–35), and insomnia (12%, 95% CI: 7–17) were the most prevalent symptoms
COVID-19: A Systematic Review and
at one-year follow-up. Existing evidence suggested that female patients and those with more severe
Meta-Analysis of One-Year
initial illness were more likely to suffer from the sequelae after one year. This study demonstrated
Follow-Up Studies on Post-COVID
that a sizeable proportion of COVID-19 survivors still experience residual symptoms involving
Symptoms. Pathogens 2022, 11, 269.
various body systems one year later. There is an urgent need for elucidating the pathophysiologic
https://doi.org/10.3390/
pathogens11020269
mechanisms and developing and testing targeted interventions for long-COVID patients.
Academic Editors: Wenjun Ma and Keywords: post-acute sequelae of COVID-19; long-COVID; prevalence; symptom; meta-analysis
Alexander W.E. Franz
at 30, 60, and ≥ 90 days after hospitalisation or onset, of which fatigue, dyspnoea, cough,
anosmia, ageusia, and joint pain were the most prevalent symptoms. A meta-analysis [5] of
39 studies with up to seven months follow-up showed that the most frequently reported
symptoms included weakness, fatigue, concentration impairment, and breathlessness. An-
other meta-analysis [2] of 15 papers reported over 50 persistent symptoms of COVID-19
experienced by COVID-19 survivors between 14–110 days post infection.
However, no previous systematic review and meta-analysis has focused on longer-
term persistent symptoms of COVID-19, and it remains unclear to what extent these broad
classes of symptoms still persist after one year post infection. With the emerging data
of longer-term follow-up of COVID-19 patients, it is important to investigate the natural
history of COVID-19 symptomatology and whether the spectrum of long-lasting symptoms
is different from that of the short- or medium-term manifestations previously described.
We sought to systematically synthesise existing evidence on long-term post-COVID
symptoms. We estimated the pooled prevalence and also summarised potential risk factors
of post-COVID symptoms lasting for one year after infection.
3. Results
3.1. Search Results and Study Characteristics
The literature search in PubMed and Embase yielded 1425 records. After screening
of abstract and full text, 18 eligible papers with a total of 8591 COVID-19 survivors were
included in this systematic review and meta-analyses. Details of the literature screening
process are displayed in the PRISMA flowchart (Figure 1).
Characteristics of the 18 papers are summarised in Table 1. These one-year follow-up
studies of COVID-19 patients were conducted in China (n = 7), Italy (n = 5), Spain (n = 4),
and Germany (n = 2), with the longest follow-up time being a median of 401 days from the
first SARS-CoV-2 positive swab [9]. All COVID-19 patients recruited by the 18 studies had
confirmed SARS-CoV-2 infection. The sample size of the included studies varied from 51
to 2433 (median = 146). Thirteen studies recruited hospitalised COVID-19 patients, two
studies with home-isolated COVID-19 patients with mild-to-moderate symptoms, and
three studies with mixed samples of hospitalised and non-hospitalised patients. Thirteen
studies only included adult patients, and the other five did not report the age range; no
study focused on the long-term sequelae of children or adolescents with COVID-19.
Pathogens 2022, 11, x FOR PEER REVIEW 4 of 14
Pathogens 2022, 11, 269 4 of 14
Identification
Figure 1. PRISMA
Figure flowchart.
1. PRISMA flowchart.
Characteristics of thepost-COVID
When assessing 18 papers aresymptoms,
summarised in Table
eight 1. These
studies usedone-year follow-up
clinical scales, including
studies
AcuteofRespiratory
COVID-19 patients were conducted
Tract Infection in China [10],
Questionnaire (n = 7), Italy (n =WHO
five-item 5), Spain (n = 4), Index
Wellbeing
and Germany (n [11],
questionnaire = 2), modified
with the longest
Medicalfollow-up
Research time being
Council a median
dyspnoea of 401
scale [12],days fromSeverity
Fatigue
theScale
first SARS-CoV-2
[13], Montrealpositive swab Assessment
Cognitive [9]. All COVID-19
[14], patients
Hospitalrecruited
Anxietyby andtheDepression
18 studies Scale
had confirmed
(HADS) SARS-CoV-2
subscales infection.Hamilton
[15], 14-item The sample size of the
Anxiety included
Rating studies
Scale varied from
[16], 24-item Hamilton
51 Depression
to 2433 (median
Rating Scale [17], post-traumatic stress disorder (PTSD) checklisttwo
= 146). Thirteen studies recruited hospitalised COVID-19 patients, for DSM-
studies
5 [18],with
andhome-isolated COVID-19
Insomnia Severity Indexpatients
[19]. Thewith mild-to-moderate
follow-up symptoms,
method included and visit
in-person
three
(n =studies with
11) and mixed
phone samples(n
interview of=hospitalised
7). and non-hospitalised patients. Thirteen
studies only included adult patients, and the other five did not report the age range; no
study focused on the long-term sequelae of children or adolescents with COVID-19.
When assessing post-COVID symptoms, eight studies used clinical scales, including
Acute Respiratory Tract Infection Questionnaire [10], five-item WHO Wellbeing Index
Pathogens 2022, 11, 269 5 of 14
Table 1. Cont.
Figure2.2.Forest
Figure Forestplot
plot for
for prevalence
prevalence of post-COVID
post-COVIDfatigue
fatigueand
andrespiratory
respiratorysymptoms.
symptoms.Note:
Note: There
There
weremissing
were missingvalues
valuesfor
fordyspnoea
dyspnoeaand
andfatigue
fatiguein
inpapers
papers of
of Huang
Huang et
et al.
al. [25]
[25] and
and Latronico
Latronico et
et al.
al. [26].
[26].
Pathogens 2022, 11, x FOR PEER REVIEW 9 of 14
Pathogens 2022, 11, 269 9 of 14
Figure3.3.Forest
Figure Forest plot for prevalence
plot for prevalenceofofpost-COVID
post-COVIDmental
mental health
health and
and cognitive
cognitive symptoms.
symptoms. Note:
Note:
There
Therewere
weremissing
missingvalues
valuesfor
for depression
depression and insomnia in the
insomnia in the paper
paperofofLatronico
Latronicoetetal.
al.[26].
[26].
Pathogens 2022, 11, x FOR PEER REVIEW 10 of 14
Pathogens 2022, 11, 269 10 of 14
Figure4.4.Forest
Figure Forestplot
plotfor
forprevalence
prevalenceofofother
otherpost-COVID
post-COVIDsymptoms.
symptoms.
4. Discussion
We conducted a comprehensive evidence synthesis of the prevalence and risk factors
for post-COVID symptoms lasting for one year after acute infection. The meta-analyses on
prevalence data showed that common residual symptoms among COVID-19 survivors at
one-year post infection included fatigue/weakness (28%), dyspnoea (18%), arthromyalgia
(26%), depression (23%), anxiety (22%), memory loss (19%), concentration difficulties (18%),
and insomnia (12%). The qualitative review of evidence on risk factors suggested that
females [20,25,32,35] and those with severe/critical COVID-19 infection [25,34,35] were at
higher risk of experiencing long-term post-COVID symptoms.
Reliable estimates for the prevalence of long-COVID symptoms among COVID-19
survivors are essential for policy makers and clinicians to anticipate associated healthcare
burden and inform decisions on the allocation of healthcare resources. To be noted, some
major COVID-19 symptoms at the acute phase of infection, such as cough, fever, and sore
throat [37], were not frequently experienced one year later. Although loss of taste or smell
was a common symptom at the acute phase [37] and also during short- and medium-term
follow-up [4], it seemed to improve over time. In addition, consistent with a previous meta-
analysis on prolonged gastrointestinal symptoms in COVID-19 survivors [38], we found
a low prevalence of nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite at
one-year follow-up.
Several studies included in this meta-analysis examined the evolution of post-COVID
symptoms by comparing data from multiple follow-up visits. A large-scale cohort study
of hospitalised COVID-19 patients in Wuhan, China [25], showed that the percentage of
having at least one persisting symptom significantly decreased from 68% at 6 months to
49% at 12 months post COVID, but mixed results were found for the trajectory of individual
symptoms. Another Chinese cohort study [27] also found that the percentage of having at
least one symptom decreased from 51.2% at 3 months post-discharge to 40.0% and 28.4%
at 6-month and 12-month visits. However, a small-scale cohort study in Germany [32]
Pathogens 2022, 11, 269 12 of 14
showed that between 5 months and 12 months post COVID, the prevalence of hair loss
decreased significantly from 26.1% to 10.4%, but the prevalence of fatigue and dyspnoea
increased (from 41.7% to 53.1% and from 27.1% to 37.5%, respectively). Another small-scale
Italian cohort study of survivors after intensive care unit discharge [26] found that cognitive
impairment significantly improved (from 28% at 3 months to 16% at 12 months), but no
significant changes were observed for severe fatigue, depression, anxiety, insomnia, and
PTSD symptoms.
One important methodological concern when interpreting these studies on post-
COVID symptoms is how to distinguish post-COVID symptoms from pre-COVID symp-
toms or the population’s baseline level, especially for symptoms with a relatively low
prevalence. In fact, six of the included studies [21,23,28,32,35,36] asked participants to
take into account their pre-COVID state when reporting post-COVID symptoms (i.e., new
or worsening symptoms compared with pre-COVID baseline) though such measurement
relied on participants’ recall accuracy. The afore-mentioned large-scale cohort study in
Wuhan, China [25], included a matched non-COVID-19 control group, which showed that
COVID-19 survivors had a significantly higher prevalence of all individual symptoms
assessed at the one-year follow-up visit than the control population (proportion of having
any one of the symptoms: 66% vs. 33%, p < 0.001).
The current body of evidence suggested that female sex [20,25,32,35] and severe/critical
acute infection [25,34,35] could be risk factors for experiencing long-term post-COVID
symptoms. A cohort study with 342 COVID-19 patients [39] found that time to complete
recovery (no ongoing symptoms) was significantly longer in those with moderate and
severe/critical initial illness than mild cases, and at least one persistent symptom was
reported by 16.4%, 49.5%, and 52.5% of participants in mild, moderate, and severe/critical
groups at one year after infection, respectively. However, the pathophysiologic mechanisms
of those long-lasting post-COVID symptoms remained unclear.
Several limitations of this study should be noted. This systematic review and meta-
analysis focused on subjective symptoms of COVID-19 patients. Future systematic evidence
syntheses on other types of potential long-term sequelae, such as persistent pulmonary
function impairment, lung imaging abnormalities, limited exercise capacity, systemic
inflammation, and incident clinical complications, are needed. In addition, caution is
needed in interpreting pooled estimates of symptom prevalence (especially those with
wide confidence intervals) due to the heterogeneity across studies. Little evidence was
available for long-term follow-up of children or adolescents with COVID-19, making future
research into the evolution of symptoms for this population warranted. Finally, it is likely
that the one-year follow-up studies included in this meta-analysis covered the initial waves
of the pandemic; thus, our findings mainly applied to those who experienced infection in
the Wild and Alpha eras. Future research on infection by the Delta or Omicron variant
and its long-term consequences could help elucidate how the COVID-19 pandemic evolves
over time.
In conclusion, this systematic review and meta-analysis demonstrated that multiple
physical, cognitive, and mental health symptoms persist for at least one year in a sizeable
proportion of COVID-19 survivors. Persistent symptoms could be more evident in females
and those with more severe acute COVID-19 infection. There is an urgent need to elucidate
the underlying pathophysiologic mechanisms and for trials of interventions to treat or
prevent the persistence of these long-lasting symptoms.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/pathogens11020269/s1, Supplementary methods; Figure S1:
Funnel plot of meta-analysis for prevalence of post-COVID fatigue/weakness; Figure S2: Funnel
plot of meta-analysis for prevalence of post-COVID dyspnoea/breathlessness; Figure S3: Funnel plot
of meta-analysis for prevalence of post-COVID headache; Table S1: Risk of bias assessments of 18
eligible papers; Table S2: Information on other reported post-COVID symptoms; Table S3: Sensitivity
analyses for prevalence of post-COVID symptoms.
Pathogens 2022, 11, 269 13 of 14
Author Contributions: Conceptualization, B.Z. and Q.H.; methodology, B.Z.; formal analysis, B.Z.
and Q.H.; writing—original draft preparation, Q.H. and B.Z.; writing—review and editing, L.D. and
A.S. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by PHOSP-COVID grant from UK Research and Innovation and
National Institute of Health Research (grant number: MR/V027859/1 and COV0319), and the Chief
Scientist Office of the Scottish Government (grant number: COV/LTE/20/15). The APC was funded
by UK Research and Innovation.
Conflicts of Interest: The authors declare no conflict of interest.
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