pathogens

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

Received: 15 January 2022

Accepted: 15 February 2022
Published: 19 February 2022 1. Introduction
Publisher’s Note: MDPI stays neutral
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still rapidly spread-
with regard to jurisdictional claims in ing around the world, fuelled by the emergence of new variants. According to the World
published maps and institutional affil- Health Organization (WHO) Coronavirus (COVID-19) Dashboard [1], there have been over
iations. 300 million confirmed cases of COVID-19 worldwide. A feature of COVID-19 that differs
from other respiratory infections could be its multi-system symptomatology, complications,
and long-term sequelae [2].
A growing body of evidence has shown that COVID-19 survivors may experience
Copyright: © 2022 by the authors. persistent symptoms affecting different organ systems after the acute phase of infection
Licensee MDPI, Basel, Switzerland. (also known as long-COVID [3]). Several previous systematic reviews and meta-analyses
This article is an open access article on long-COVID [2,4,5] estimated the prevalence of short- and medium-term persistent
distributed under the terms and symptoms after COVID-19 infection, involving respiratory, cardiovascular, musculoskeletal,
conditions of the Creative Commons
integumentary, gastrointestinal, endocrine, and neurological systems. A meta-analysis [4]
Attribution (CC BY) license (https://
of 33 papers investigating hospitalised and non-hospitalised COVID-19 survivors demon-
creativecommons.org/licenses/by/
strated that 63.2%, 71.9%, and 45.9% of patients experienced at least one persistent symptom
4.0/).

Pathogens 2022, 11, 269. https://doi.org/10.3390/pathogens11020269 https://www.mdpi.com/journal/pathogens

Pathogens 2022, 11, 269 2 of 14

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.

2. Materials and Methods

2.1. Search Strategy
The reporting of this study followed the Preferred Reporting Items for Systematic
Reviews and Meta-analyses (PRISMA) reporting guideline [6]. We systematically searched
PubMed and Embase databases for studies reporting one-year follow-up data for COVID-19
survivors published between 1 January 2021 and 6 November 2021, in English or Chinese.
Studies were identified using search terms related to COVID-19, sequelae, and long-term
follow-up. Medical Subject Headings (MeSH) terms and free text words were combined for
the searches. Reference lists of relevant papers were checked for additional studies. Our
detailed search strategies are presented in the Supplementary Methods.
Two authors (Q.H. and B.Z.) independently screened the papers and performed data
extraction and quality assessment. Any discrepancies were resolved following review of
the corresponding papers by both authors and consensus discussion.

2.2. Inclusion/Exclusion Criteria

Studies were included if they used a cohort, cross-sectional, or case series design and
reported data required for the estimation of pooled prevalence of post-COVID symptoms
(i.e., sample size of COVID-19 survivors and the prevalence or proportion of specific
symptoms). Eligible studies were required to have a mean/median follow-up time of at
least 12 months. For studies with overlapping or identical participants, we included the
study with the largest sample size. Studies were excluded from meta-analysis if they only
recruited participants with reported residual symptoms or complications post COVID-19
or only recruited participants with a specific comorbidity (e.g., cancer patients). We also
excluded studies with less than 50 COVID-19 survivors because of concerns regarding the
precision and potential bias of prevalence estimates. Review papers without original data
and conference abstracts without full text were excluded from this study.

2.3. Data Extraction

We extracted the following information from eligible studies: (1) sample size and
prevalence or number of patients with specific post-COVID symptoms; (2) types and
definitions of post-COVID symptoms; (3) follow-up period and follow-up method; and (4)
population characteristics (country, age, sex, and severity of COVID-19 infection). We used
the Cochrane recommended software PlotDigitizer (www.plotdigitizer.sourceforge.net/,
accessed on 15 January 2022) to extract graphically presented prevalence data from two
papers.
We also extracted results of risk factor analyses (if available) for a qualitatively synthe-
sis of the risk factors for long-term post-COVID symptoms.
Pathogens 2022, 11, 269 3 of 14

2.4. Study Quality Assessment

The study quality of eligible papers was evaluated using the “Joanna Briggs Institute
(JBI) Critical Appraisal Checklist for Studies Reporting Prevalence Data” [7]. This checklist
consists of nine items with four options (i.e., yes, no, unclear, not applicable). We assigned
an overall quality rating of high, moderate, or low to each paper based on a qualitative
evaluation of the nine items.

2.5. Statistical Analyses

Random-effects meta-analyses with inverse-variance method were conducted to es-
timate the pooled prevalence and its confidence interval (CI) of specific post-COVID
symptoms in COVID-19 survivors [8]. The study-specific confidence intervals were esti-
mated using the Wilson’s score method [8]. The meta-analyses were conducted only for
symptoms assessed by three or more studies. The heterogeneity of prevalence estimates
across studies was assessed by the I2 statistic and Q test in each analysis. For each symptom
with > 10 studies, a funnel plot for prevalence estimates after logit transformation was
created to graphically identify publication bias, followed by an Egger’s test of asymmetry.
To examine the robustness of the main findings, several sensitivity analyses were
performed by: (1) excluding studies rated as poor quality and (2) repeating the meta-
analyses using prevalence estimates after logit transformation or Freeman–Tukey double-
arcsine transformation [8]. We also assessed the influence of each study on the overall
estimate by recalculating the pooled prevalence after removing that study.
Statistical analyses were performed using Stata (version 14, StataCorp, College Station,
TX, USA). All statistical tests were two-sided with the significance threshold of p < 0.05.

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

Records identified through Records identified through

PubMed (n = 1164) Embase (n = 570)

Records after duplicates removed

(n = 1425)
Screening

Records excluded by ab-

Records screened
stract (n = 1364)
(n = 1425)

Full-text articles excluded (n = 43):

Full-text articles as-
Eligibility

sessed for eligibility No symptom prevalence data (17)

(n = 61) Follow-up time < 12 months (11)
Sample size ≤ 50 (9)
Inappropriate study population (5)
Duplicated study participants (1)
Included

Studies included in meta-analysis

(n = 18)

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. Study characteristics of 18 papers included in the meta-analyses.

Sample Mean/Median Only Male Single-/ Follow-Up

First Author Country Scale for Symptoms Hospitalisation Follow-Up Period
Size Age, Year Adults Proportion Multi-Centre Method
Boscolo-Rizzo, Acute Respiratory Tract non- 12 months after
304 Italy 47 Yes 0.39 single centre phone
P. [20] Infection Questionnaire hospitalised symptom onset
5-item World Health median of 401 days
Boscolo-Rizzo, Organization Wellbeing Index, non- from the first
100 Italy 49 Yes 0.61 multi-centre in-person visit
P. [9] Acute Respiratory Tract hospitalised SARS-CoV-2
Infection Questionnaire positive swab
Catalán, I. P. one year after
76 Spain 64 Yes 0.62 - single centre hospitalised phone
[21] hospital admission
median follow-up
time from hospital
Chai, C. [22] 432 China 65 - 0.49 - multi-centre hospitalised in-person visit admission was 12.2
(IQR 12.1-12.6)
months
Fernández-de-
one year after
las-Peñas, C. 1950 Spain 61 - 0.53 - multi-centre hospitalised phone
hospital discharge
[23]
Gamberini, L. one year after ICU
178 Italy 64 - 0.73 mMRC multi-centre ICU in-person visit
[24] discharge
12 months after
Huang, L. [25] 1272 China 59 Yes 0.53 mMRC single centre hospitalised in-person visit
symptom onset
Fatigue Severity Score,
Montreal Cognitive
Latronico, N. Assessment, Hospital Anxiety 12 months after ICU
51 Italy 60 Yes 0.77 single centre ICU in-person visit
[26] and Depression Scale subscales, discharge
PTSD checklist for DSM-5,
Insomnia Severity Index
12 months after
Liu, T. [27] 486 China 63 - 0.46 - single centre hospitalised in-person visit
discharge
Maestre-
12 months after
Muñiz, M. M. 543 Spain 65 Yes - - single centre mixed phone
discharge
[28]
mean of 347 ± 10
Maestrini, V.
118 Italy 71 - 0.57 - single centre hospitalised phone days from
[29]
COVID-19 diagnosis
Pathogens 2022, 11, 269 6 of 14

Table 1. Cont.

Sample Mean/Median Only Male Single-/ Follow-Up

First Author Country Scale for Symptoms Hospitalisation Follow-Up Period
Size Age, Year Adults Proportion Multi-Centre Method
a battery of standardised
instruments for the cognitive
Méndez, R. 12 (±1) months after
171 Spain 58 Yes 0.58 functioning; subjective single centre hospitalised phone
[30] hospital discharge
cognitive complaints; anxiety,
depression, and PTSD
12 months after
Rank, A. [31] 83 Germany 42 Yes 0.76 - single centre mixed in-person visit
onset of COVID-19
12 months after
Seeßle, J. [32] 96 Germany 57 Yes 0.45 - single centre mixed in-person visit
symptom onset
12 months after
Wu, X. [33] 83 China 60 Yes 0.57 mMRC single centre hospitalised in-person visit
discharge
one year after
Zhan, Y. [34] 121 China 49 Yes 0.41 - single centre hospitalised in-person visit
diagnosis
median (IQR) time
from discharge to
Zhang, X. [35] 2433 China 60 Yes 0.50 - multi-centre hospitalised phone
follow-up was 364
(357–371) days
median duration
from symptom onset
to follow-up visit
14-item Hamilton Anxiety
was 366 (355, 376)
Rating Scale, 24-item Hamilton
Zhao, Y. [36] 94 China 48 Yes 0.57 multi-centre hospitalised in-person visit days; median time
Depression Rating Scale,
from hospital
mMRC
discharge to
follow-up visit was
345 (333, 349) days.
Note: “-“ refers to information unclear or not applicable. IQR, interquartile range; ICU, intensive care unit; mMRC, modified Medical Research Council dyspnoea scale; PTSD,
post-traumatic stress disorder; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.
Pathogens 2022, 11, 269 7 of 14

3.2. Assessment of Risk of Bias

The study quality of eight papers was rated as high, while another eight papers were
rated moderate quality, and two with low quality (Supplementary Table S1). Sources of
potential bias among these studies were lack of representativeness of the study sample
(12 studies were single-centre studies), small sample size, low response rate, lack of vali-
dated scales for symptom assessment, and lack of standard and reliable follow-up methods
(especially for phone interviews).

3.3. Prevalence of One-Year Post-COVID Symptoms among COVID-19 Survivors

Random-effects meta-analyses were conducted for 27 individual symptoms separately.
Fifteen and sixteen papers assessed fatigue/weakness and dyspnoea/breathlessness at one-
year follow-up, the pooled prevalence of which were 28% (95% CI: 18–39) and 18% (95%
CI: 13–24), respectively (Figure 2). Substantial heterogeneity across studies was observed
(I2 = 99.3% and 98.5%, both p < 0.001). Other post-COVID respiratory symptoms were
also reported but with much lower prevalence. The pooled prevalence was 5% for cough
(n = 8; 95% CI: 4–7; I2 = 86.7%), 5% for chest pain (n = 10; 95% CI: 3–7; I2 = 91.3%), 2%
for sore throat/difficulty swallowing (n = 7; 95% CI: 1–3; I2 = 82.3%), and 2% for sputum
production (n = 6; 95% CI: 1–3; I2 = 82.1%; Figure 2).
Mental health and cognitive symptoms were frequently reported among COVID-19
survivors (Figure 3). The pooled prevalence for depression and anxiety symptoms were 23%
(n = 5; 95% CI: 12–34; I2 = 89.6%) and 22% (n = 7; 95% CI: 15–29; I2 = 95.4%), respectively.
Memory loss/memory complaints/forgetfulness and concentration difficulties were also
commonly experienced, with the pooled prevalence of 19% (n = 5; 95% CI: 7–31; I2 = 98.3%)
and 18% (n = 3; 95% CI: 2–35; I2 = 95.8%), respectively. Insomnia/sleep difficulties had
a pooled prevalence of 12% (n = 9; 95% CI: 7–17; I2 = 97.1%). In addition, the pooled
prevalence of anosmia/loss of smell/smell disorder and ageusia/loss of taste/taste disorder
were 6% (n = 9; 95% CI: 4–8; I2 = 94.1%) and 4% (n = 10; 95% CI: 3–6; I2 = 94.0%), respectively.
As for other classes of symptoms (Figure 4), the pooled prevalence was 26% for
arthromyalgia (n = 4; 95% CI: 8–44; I2 = 96.8%), 8% for muscle pain/myalgia (n = 8; 95% CI:
5–11; I2 = 95.1%), 10% for joint pain (n = 5; 95% CI: 5–15; I2 = 94.5%), 4% for backache/waist
pain (n = 3; 95% CI: 1–6; I2 = 69.9%), 7% for headache (n = 11; 95% CI: 5–9; I2 = 93.2%), 4%
for dizziness (n = 6; 95% CI: 2–5; I2 = 70.1%), 3% for skin rash (n = 3; 95% CI: 2–4; I2 = 41.2%),
7% for hair loss/alopecia (n = 5; 95% CI: 2–11; I2 = 97.8%), and 5% for palpitations (n = 9;
95% CI: 3–7; I2 = 89.7%).
Fever, vomiting/nausea, diarrhoea, abdominal pain, and loss of appetite were uncom-
mon symptoms at one-year follow-up, with the pooled prevalence of 0.3% (n = 7; 95% CI:
0.0–1.2; I2 = 79.8%), 0.7% (n = 5; 95% CI: 0.0–2.2; I2 = 83.5%), 1.3% (n = 6; 95% CI: 0.2–2.8;
I2 = 80.7%), 0.4% (n = 3; 95% CI: 0.0–1.8; I2 = 70.8%), and 1.0% (n = 4; 95% CI: 0.0–3.4;
I2 = 90.8%), respectively (Supplementary Table S2). Other symptoms, such as hearing loss,
PTSD symptom, rhinorrhoea/runny nose, and chest tightness, were only reported by one or
two studies with one-year follow-up, the details of which are displayed in Supplementary
Table S2.
The funnel plots (Supplementary Figures S1–S3) and Egger’s tests for meta-analyses of
fatigue/weakness, dyspnoea/breathlessness, and headache (where n > 10) showed no evi-
dence of publication bias (p > 0.10). Results of the sensitivity analyses were consistent with
the main findings (Supplementary Table S3). The influential analysis indicated no single
study had a major impact on the pooled prevalence estimate (Supplementary Table S3).
 Pathogens 2022, 11, x FOR PEER REVIEW 8 of 14
Pathogens 2022, 11, 269 8 of 14

Figure2.2.Forest
Figure Forestplot
plot for
for prevalence
prevalence of post-COVID
post-COVIDfatigue
fatigueand
andrespiratory
respiratorysymptoms.
symptoms.Note:
Note: There
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were missingvalues
valuesfor
fordyspnoea
dyspnoeaand
andfatigue
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inpapers
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of Huang
Huang et
et al.
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and Latronico
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et al.
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[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:
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There
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for depression
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insomnia in the paper
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[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.

3.4. Evidence of Risk Factors for One-Year Post-COVID Symptoms

Pathogens 2022, 11, 269 11 of 14

3.4. Evidence of Risk Factors for One-Year Post-COVID Symptoms

Of the 18 included studies, 10 examined potential risk factors for post-COVID symp-
toms at one-year follow-up. Three studies [25,32,35] found that female patients had signifi-
cantly higher risk of experiencing symptoms one-year post-COVID than males, and one
study [20] detected a borderline statistical significance. Inconsistent results were reported
for age, with two studies [25,35] showing a positive association with post-COVID symp-
toms, one showing a negative association [32], one showing a higher risk in the middle age
group (40–54 years old) [20], and one reporting no association [36]. One study [20] found a
positive association between body mass index (BMI) and risk of long-term symptoms.
Three studies [25,34,35] showed a higher risk of long-term symptoms in severe/critical
patients than non-severe patients in terms of the acute infection status, one study [36] found
such association only for muscle fatigue but not for other symptoms, and another study [32]
did not detect the association. In addition, one study [28] reported higher prevalence of
long-term symptoms in hospitalised patients than non-hospitalised patients, and another
study [24] found a positive association between duration of invasive mechanical ventilation
and post-COVID dyspnoea at one-year follow-up.
A large-scale cohort study in China [25] found no association of education level,
smoking status, and comorbidity with one-year post-COVID symptoms. Another large-
scale study in Spain [23] investigating persistent cough (which was reported by 2.5% of
recruited COVID-19 survivors) showed no association between cough and sex, age, BMI,
initial disease severity, days at hospital, and smoking status. One study [21] found that
corticosteroids therapy received during hospitalisation was associated with lower risk of
headache, dysphagia, chest pain, and depression at one-year follow-up; however, the afore-
mentioned Chinese cohort study [25] showed that corticosteroids therapy was associated
with increased risk of fatigue or muscle weakness and had no association with anxiety or
depression one year later.

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.

References
1. World Health Organization. World Health Organization (WHO) Coronavirus (COVID-19) Dashboard. Available online: https:
//covid19.who.int/ (accessed on 17 January 2022).
2. Lopez-Leon, S.; Wegman-Ostrosky, T.; Perelman, C.; Sepulveda, R.; Rebolledo, P.A.; Cuapio, A.; Villapol, S. More than 50
long-term effects of COVID-19: A systematic review and meta-analysis. Sci. Rep. 2021, 11, 16144. [CrossRef] [PubMed]
3. National Institute for Health and Care Excellence. COVID-19 Rapid Guideline: Managing the Long-Term Effects of COVID-19.
Available online: https://www.nice.org.uk/guidance/ng188 (accessed on 17 January 2022).
4. Fernandez-de-Las-Penas, C.; Palacios-Cena, D.; Gomez-Mayordomo, V.; Florencio, L.L.; Cuadrado, M.L.; Plaza-Manzano, G.;
Navarro-Santana, M. Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: A
systematic review and meta-analysis. Eur. J. Intern. Med. 2021, 92, 55–70. [CrossRef] [PubMed]
5. Michelen, M.; Manoharan, L.; Elkheir, N.; Cheng, V.; Dagens, A.; Hastie, C.; O’Hara, M.; Suett, J.; Dahmash, D.; Bugaeva, P.; et al.
Characterising long COVID: A living systematic review. BMJ Glob. Health 2021, 6, e005427. [CrossRef]
6. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA
statement. PLoS Med. 2009, 6, e1000097. [CrossRef]
7. Munn, Z.; Moola, S.; Lisy, K.; Riitano, D.; Tufanaru, C. Methodological guidance for systematic reviews of observational
epidemiological studies reporting prevalence and cumulative incidence data. Int. J. Evid. Based Healthc. 2015, 13, 147–153.
[CrossRef] [PubMed]
8. Nyaga, V.N.; Arbyn, M.; Aerts, M. Metaprop: A Stata command to perform meta-analysis of binomial data. Arch. Public Health
2014, 72, 39. [CrossRef] [PubMed]
9. Boscolo-Rizzo, P.; Hummel, T.; Hopkins, C.; Dibattista, M.; Menini, A.; Spinato, G.; Fabbris, C.; Emanuelli, E.; D’Alessandro, A.;
Marzolino, R.; et al. High prevalence of long-term olfactory, gustatory, and chemesthesis dysfunction in post-COVID-19 patients:
A matched case-control study with one-year follow-up using a comprehensive psychophysical evaluation. Rhinology 2021, 59,
517–527. [CrossRef]
10. Aabenhus, R.; Thorsen, H.; Siersma, V.; Brodersen, J. The development and validation of a multidimensional sum-scaling
questionnaire to measure patient-reported outcomes in acute respiratory tract infections in primary care: The acute respiratory
tract infection questionnaire. Value Health 2013, 16, 987–992. [CrossRef]
11. Topp, C.W.; Ostergaard, S.D.; Sondergaard, S.; Bech, P. The WHO-5 Well-Being Index: A systematic review of the literature.
Psychother. Psychosom. 2015, 84, 167–176. [CrossRef]
12. Mahler, D.A.; Wells, C.K. Evaluation of clinical methods for rating dyspnea. Chest 1988, 93, 580–586. [CrossRef]
13. Krupp, L.B.; LaRocca, N.G.; Muir-Nash, J.; Steinberg, A.D. The fatigue severity scale. Application to patients with multiple
sclerosis and systemic lupus erythematosus. Arch. Neurol. 1989, 46, 1121–1123. [CrossRef] [PubMed]
14. Nasreddine, Z.S.; Phillips, N.A.; Bedirian, V.; Charbonneau, S.; Whitehead, V.; Collin, I.; Cummings, J.L.; Chertkow, H. The
Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment. J. Am. Geriatr. Soc. 2005, 53,
695–699. [CrossRef] [PubMed]
15. Zigmond, A.S.; Snaith, R.P. The hospital anxiety and depression scale. Acta. Psychiatr. Scand. 1983, 67, 361–370. [CrossRef]
[PubMed]
16. Hamilton, M. The assessment of anxiety states by rating. Br. J. Med. Psychol. 1959, 32, 50–55. [CrossRef]
17. Hamilton, M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 1960, 23, 56–62. [CrossRef]
18. Blevins, C.A.; Weathers, F.W.; Davis, M.T.; Witte, T.K.; Domino, J.L. The Posttraumatic Stress Disorder Checklist for DSM-5
(PCL-5): Development and Initial Psychometric Evaluation. J. Trauma. Stress 2015, 28, 489–498. [CrossRef]
19. Bastien, C.H.; Vallieres, A.; Morin, C.M. Validation of the Insomnia Severity Index as an outcome measure for insomnia research.
Sleep Med. 2001, 2, 297–307. [CrossRef]
20. Boscolo-Rizzo, P.; Guida, F.; Marcuzzo, A.V.; D’Alessandro, A.; Zanelli, E.; Marzolino, R.; Lazzarin, C.; Antonucci, P.; Sacchet, E.;
Tofanelli, M.; et al. Sequelae in adults at 12 months after mild-to-moderate coronavirus disease 2019 (COVID-19). Int. Forum
Allergy Rhinol. 2021, 59, 517–527. [CrossRef]
21. Catalan, I.P.; Marti, C.R.; Sota, D.P.; Alvarez, A.C.; Gimeno, M.J.E.; Juana, S.F.; Rodriguez, G.H.; Bajo, E.D.; Gaya, N.T.; Blasco,
J.U.; et al. Corticosteroids for COVID-19 symptoms and quality of life at 1 year from admission. J. Med. Virol. 2022, 94, 205–210.
[CrossRef]
Pathogens 2022, 11, 269 14 of 14

22. Chai, C.; Feng, X.; Lu, M.; Li, S.; Chen, K.; Wang, H.; Wang, W.; Tang, Z.; Cheng, G.; Wu, X.; et al. One-year mortality and
consequences of COVID-19 in cancer patients: A cohort study. IUBMB Life 2021, 73, 1244–1256. [CrossRef]
23. Fernández-de-Las-Peñas, C.; Guijarro, C.; Plaza-Canteli, S.; Hernández-Barrera, V.; Torres-Macho, J. Prevalence of Post-COVID-19
Cough One Year After SARS-CoV-2 Infection: A Multicenter Study. Lung 2021, 199, 249–253. [CrossRef] [PubMed]
24. Gamberini, L.; Mazzoli, C.A.; Gordini, G.; Prediletto, I.; Sintonen, H.; Scaramuzzo, G.; Volta, C.A.; Spadaro, S.; Allegri, D.;
Colombo, D.; et al. Health-related quality of life profiles, trajectories, persistent symptoms and pulmonary function one year
after ICU discharge in invasively ventilated COVID-19 patients, a prospective follow-up study. Respir. Med. 2021, 189, 106665.
[CrossRef] [PubMed]
25. Huang, L.; Yao, Q.; Gu, X.; Wang, Q.; Ren, L.; Wang, Y.; Hu, P.; Guo, L.; Liu, M.; Xu, J.; et al. 1-year outcomes in hospital survivors
with COVID-19: A longitudinal cohort study. Lancet 2021, 398, 747–758. [CrossRef]
26. Latronico, N.; Peli, E.; Calza, S.; Rodella, F.; Novelli, M.P.; Cella, A.; Marshall, J.; Needham, D.M.; Rasulo, F.A.; Piva, S. Physical,
cognitive and mental health outcomes in 1-year survivors of COVID-19-associated ARDS. Thorax 2022, 77, 300–303. [CrossRef]
27. Liu, T.; Wu, D.; Yan, W.; Wang, X.; Zhang, X.; Ma, K.; Chen, H.; Zeng, Z.; Wang, H.; Xing, M.; et al. Twelve-month systemic
consequences of COVID-19 in patients discharged from hospital: A prospective cohort study in Wuhan, China. Clin. Infect. Dis.
2021, ciab703. [CrossRef]
28. Maestre-Muniz, M.M.; Mata-Vazquez, E.; Martin-Toledano, M.; Lopez-Larramona, G.; Ruiz-Chicote, A.M.; Nieto-Sandoval, B.;
Arias, A.; Lucendo, A.J. Long-term outcomes of patients with coronavirus disease 2019 at one year after hospital discharge. J.
Clin. Med. 2021, 10, 2945. [CrossRef]
29. Maestrini, V.; Birtolo, L.I.; Francone, M.; Galardo, G.; Galea, N.; Severino, P.; Alessandri, F.; Colaiacomo, M.C.; Cundari, G.;
Chimenti, C.; et al. Cardiac involvement in consecutive unselected hospitalized COVID-19 population: In-hospital evaluation
and one-year follow-up. Int. J. Cardiol. 2021, 339, 235–242. [CrossRef]
30. Mendez, R.; Balanza-Martinez, V.; Luperdi, S.C.; Estrada, I.; Latorre, A.; Gonzalez-Jimenez, P.; Bouzas, L.; Yepez, K.; Ferrando, A.;
Reyes, S.; et al. Long-term neuropsychiatric outcomes in COVID-19 survivors: A 1-year longitudinal study. J. Intern. Med. 2022,
291, 247–251. [CrossRef]
31. Rank, A.; Tzortzini, A.; Schmid, C.; Claus, R.; Kling, E.; Loll, E.; Hoffmann, R.; Dennehy, K.M.; Burger, R.; Grutzner, S.; et al.
One year after mild covid-19: The majority of patients maintain specific immunity, but one in four still suffer from long-term
symptoms. J. Clin. Med. 2021, 10, 3305. [CrossRef]
32. Seeßle, J.; Hippchen, T.; Lim, A.; Merle, U.; Waterboer, T.; Simon, J.; Kirchner, M.; Muller, B. Persistent symptoms in adult patients
one year after COVID-19: A prospective cohort study. Clin. Infect. Dis. 2021, ciab611. [CrossRef]
33. Wu, X.; Liu, X.; Zhou, Y.; Yu, H.; Li, R.; Zhan, Q.; Ni, F.; Fang, S.; Lu, Y.; Ding, X.; et al. 3-month, 6-month, 9-month, and 12-month
respiratory outcomes in patients following COVID-19-related hospitalisation: A prospective study. Lancet Respir. Med. 2021, 9,
747–754. [CrossRef]
34. Zhan, Y.; Zhu, Y.; Wang, S.; Jia, S.; Gao, Y.; Lu, Y.; Zhou, C.; Liang, R.; Sun, D.; Wang, X.; et al. SARS-CoV-2 immunity and
functional recovery of COVID-19 patients 1-year after infection. Signal Transduct. Target. Ther. 2021, 6, 368. [CrossRef] [PubMed]
35. Zhang, X.; Wang, F.; Shen, Y.; Zhang, X.; Cen, Y.; Wang, B.; Zhao, S.; Zhou, Y.; Hu, B.; Wang, M.; et al. Symptoms and Health
Outcomes Among Survivors of COVID-19 Infection 1 Year After Discharge From Hospitals in Wuhan, China. JAMA Netw. Open
2021, 4, e2127403. [CrossRef] [PubMed]
36. Zhao, Y.; Yang, C.; An, X.; Xiong, Y.; Huang, L.; Jia, J.; Xu, Q.; Zhang, L.; Zhao, J.; Xu, A.; et al. Follow-up study on COVID-19
survivors one year after discharge from hospital. Int. J. Infect. Dis. 2021, 112, 173–182. [CrossRef]
37. Centers for Disease Control and Prevention. Symptoms of COVID-19. Available online: https://www.cdc.gov/coronavirus/2019
-ncov/symptoms-testing/symptoms.html (accessed on 17 January 2022).
38. Yusuf, F.; Fahriani, M.; Mamada, S.S.; Frediansyah, A.; Abubakar, A.; Maghfirah, D.; Fajar, J.K.; Maliga, H.A.; Ilmawan, M.; Emran,
T.B.; et al. Global prevalence of prolonged gastrointestinal symptoms in COVID-19 survivors and potential pathogenesis: A
systematic review and meta-analysis. F1000Res 2021, 10, 301. [CrossRef]
39. Wynberg, E.; van Willigen, H.D.G.; Dijkstra, M.; Boyd, A.; Kootstra, N.A.; van den Aardweg, J.G.; van Gils, M.J.; Matser, A.; de
Wit, M.R.; Leenstra, T.; et al. Evolution of COVID-19 symptoms during the first 12 months after illness onset. Clin. Infect. Dis.
2021, ciab759. [CrossRef]