Journal Reading Oleh Paishal Mizan

Kepada
YTH: dr. Vesri Yoga,

Sp.PD
Journal Reading
Prevalence of Post-COVID-19 Symptoms in

Hospitalized and Non-Hospitalized COVID-19
Survivors: A Systematic Review and
Meta-analysis
Nama : dr. Paishal Mizan

NIM : 2150302207
Tanggal presentasi : 30 Desember 2021
Program Studi Pendidikan Dokter Spesialis I

Bagian Penyakit Dalam RSUP Dr. M. Djamil Padang
Fakultas Kedokteran Universitas Andalas
2021
European Journal of Internal Medicine 92 (2021) 55–70
Contents lists available at ScienceDirect
European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
Original article
Prevalence of post-COVID-19 symptoms in hospitalized and

non-hospitalized COVID-19 survivors: A systematic review and
meta-analysis
César Fernańdez-de-las-Penãs a, *, Domingo Palacios-Cenã a, Víctor Go´mez-Mayordomo b,
Lidiane L Florencio a, María L. Cuadrado b, c, Gustavo Plaza-Manzano d, e, Marcos Navarro-
Santana d
a
Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos (URJC),
Avenida de Atenas s/n, Madrid, Alcorcón 28922 Spain
b
Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain
c
Department of Medicine, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
d
Department of Radiology, Rehabilitation and Physiotherapy, Universidad Complutense de Madrid, Madrid, Spain
e
Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain
A R T I C L E I N F O
A B S T R A C T
Keywords:
Covid-19 Background: Single studies support the presence of several post-COVID-19 symptoms; however, no meta-analysis
Symptoms differentiating hospitalized and non-hospitalized patients has been published to date. This meta-analysis analyses
Fatigue the prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized patients recovered from COVID-
Dyspnea 19
Meta-analysis
. Methods: MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medR Xiv and bioRXiv
Prevalence
preprint servers were searched up to March 15, 2021. Peer-reviewed studies or preprints reporting data on post-
COVID-19 symptoms collected by personal, telephonic or electronic interview were included. Methodological
quality of the studies was assessed using the Newcastle-Ottawa Scale. We used a random-effects models for meta-
analytical pooled prevalence of each post-COVID-19 symptom, and I2 statistics for heterogeneity. Data synthesis
was categorized at 30, 60, and ≥90 days after
. Results: From 15,577 studies identified, 29 peer-reviewed studies and 4 preprints met inclusion criteria. The
sample included 15,244 hospitalized and 9011 non-hospitalized patients. The methodological quality of most
studies was fair. The results showed that 63.2, 71.9 and 45.9% of the sample exhibited ≥one post-COVID-19
symptom at 30, 60, or ≥90days after onset/hospitalization. Fatigue and dyspnea were the most prevalent
symptoms with a pooled prevalence ranging from 35 to 60% depending on the follow-up. Other post-COVID-19
symptoms included cough (20–25%), anosmia (10–20%), ageusia (15–20%) or joint pain (15–20%). Time trend
analysis revealed a decreased prevalence 30days after with an increase after 60days
. Conclusion: This meta-analysis shows that post-COVID-19 symptoms are present in more than 60% of patients
infected by SARS-CoV-2. Fatigue and dyspnea were the most prevalent post-COVID-19 symptoms, particularly 60
and ≥90 days after.
1. Introduction
such as respiratory (cough, sore throat, rhinorrhea, dyspnea), muscu-
The world is suffering a dramatic situation of catastrophic pro- loskeletal (myalgias), gastrointestinal (diarrhoea, vomiting), and
portions due to the rapid worldwide spread of the coronavirus disease neurological (headaches, myopathy, ageusia, anosmia) [2].
2019 (COVID-19) caused by the pathogen acute respiratory syndrome Understandably, most literature has concentrated on the potential
coronavirus 2 (SARS-CoV-2) [1]. Symptoms associated with SARS- pathophysiology of the disease and on the management of acute cases
at hospitalization periods. However, a second pandemic has emerged:
CoV-2 infection are heterogeneous and affect different systems
post- COVID-19 sequalae and “long-haulers” [3]. Since millions of
people will
* Corresponding author.
E-mail address: c esar .f erna ndez@ urj c. es (C. Fernańdez-de-las-Penãs).
https://doi.org/10.1016/j.ejim.2021.06.009
Received 20 April 2021; Received in revised form 21 May 2021; Accepted 5 June 2021
Available online 16 June 2021
0953-6205/© 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Downloaded for Matdoan Rifkiah Aisyah (matdoan.rifkiah@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on
October 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
Intervention: Not applicable
C. Fernańdez-de-las-Penãs et al.
Comparison: Not applicable
survive to SARS-CoV-2 infection; the number of individuals suffering Outcomes: Monitorization or collection of the presence of multiple
COVID-19 sequelae, i.e., long hauler, will dramatically increase with
time [4]. Therefore, identification of the COVID-19 aftermaths will be
crucial for healthcare professionals.
Current evidence suggests the presence of a plethora of symptoms
in subjects recovered from COVID-19. However, literature
investigating the symptoms after SARS-CoV-2 infection is on its infancy
in comparison with the literature available on the acute COVID-19
phase. Different terms are currently used for describing the presence of
post-COVID-19 symptoms (e.g., post-COVID-19 syndrome, persistent
post-COVID), being “long COVID” probably the most expanded
term [5]. “Long COVID” is used to describe illness in people who
have recovered from COVID-19 but still exhibit symptoms for far
longer than would be ex-
pected [5]. In the last months, an increasing number of studies assessing
the presence of post-COVID-19 symptoms have been published. In fact, a
meta-analysis has been recently published as a preprint [6]. This meta-
analysis found that 80% of COVID-19 survivors exhibited at least one
post-COVID-19 symptom, being fatigue (58%), headache (44%),
attention disorders (27%), hair loss (25%), and dyspnea (24%) the
most frequent [6]. However, this review pooled prevalence rates
without considering follow-up periods after symptoms and did not
differentiate between hospitalized and non-hospitalized patients [6].
These two considerations are highly important to properly determine
the presence of post-COVID-19 symptoms [7].
This study presents a systematic review and meta-analysis pooling
prevalence data of post-COVID-19 symptoms differentiating between
hospitalized and non-hospitalized COVID-19 survivors and analysing
the prevalence of post-COVID-19 symptoms at different timepoints.
The research questions of this systematic review and meta-analysis
were: what is the prevalence of post-COVID-19 symptoms in
individuals recovered from SARS-CoV-2 infection?, is there any
difference in post- COVID-19 between hospitalized and non-
hospitalized patients? and, what is the time-course of post-COVID-19
symptoms in the next months following SARS-CoV-2 infection?
2. Methods
This systematic review and meta-analysis adheres to the Preferred

Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement as appropriate [8]. It was also prospectively registered in the
Open Science Framework Registry database with the following link
https://doi.org/10.17605/OSF.IO/ESWQZ.
2.1. Systematic literature search
Electronic literature searches were conducted on MEDLINE,

CINAHL, PubMed, EMBASE, and Web of Science databases, as well as on
preprint servers medRXiv and bioRXiv, for studies published to March
20, 2021. We also screened the reference list of the identified papers.
Database search strategies were conducted with the assistance of an
experienced health science librarian. Searches were limited to human
studies by using the following terms: “long COVID syndrome”,
“long
COVID symptoms”, “long haul COVID”, “long hauler COVID”, “chronic
COVID syndrome”, “chronic COVID symptoms”, “post-acute COVID
syndrome”, “post-acute COVID symptoms”, “persistent COVID
syndrome”, “post-COVID”, “COVID sequalae” OR “persistent
COVID symptoms”. The inclusion/exclusion criteria were formulated
by using the Population, Intervention, Comparison, Outcome (PICO)
questions:
Population: Adults (>18 years), positively diagnosed of SARS-CoV-
2
infection with real-time reverse transcription-polymerase chain reaction
(PCR) assay of nasopharyngeal/oral swab samples, during the first
wave of the pandemic (from January 1 to June 30, 2020). We included
both hospitalized and non-hospitalized patients.
5 6
categorized by time after onset/hospitalization into three follow-up
European Journal of Internal Medicine 92 (2021) 55–70
periods (symptoms at 30 days, 60 days, and 90 days). To determine
symptoms in COVID-19 survivors after SARS-CoV-2 infection, i.e., the time-course of post-COVID-19 symptoms over time (from onset to
hospital discharge or symptoms onset, by either personal, 90 days after), Freeman-Tukey double arcsine transformation was
telephonic, or electronical interview. Studies monitoring just changes conducted using the escalc function in the metafor package. The
in immunolog- rma.mv (meta-analytic
ical, serological or radiological outcomes without assessment of post- C. Fernańdez-de-las-Penãs et al.
European Journal of
COVID —19 symptoms were excluded. Internal Medicine 92
multilevel random effect model (2021) 55–70
3. Re
2.2. Screening process, study selection and data extraction with moderators via linear
sul
miXed-effect models) was used ts
This review/meta-analysis considered original research including to carry out a multilevel
observational cohort or case-control studies where samples of COVID-19 metanalysis with three levels to 3.1. S
survivors, either hospitalized or non-hospitalized, were followed for identify time and time *subgroup t
the presence of symptoms for more than two weeks after infection. effect. For meta-analyses of u
Based on pre-existing data and timeframes [7], we selected 30, 60, studies reporting outcomes at d ≥
and 90 days after symptoms onset as pre-endpoints selected for the multiple time points, it may be y
analysis. Edito- rials, opinion, and correspondence articles were reasonable to s
e
excluded.
l
Two authors reviewed the title and abstract of publications identified e
in the databases. First, the duplicates were removed. Second, title and c
abstract of the articles were screened for potential eligibility and pos- ti
terior full-read text. Data including authors, country, sample size, o
clinical data, settings (hospitalization/no hospitalization), n
symptoms at onset, and post-COVID-19 symptoms at different follow-up assume that the true effects are The selection process is
periods were extracted from each study. Both authors had to achieve a correlated over time according to shown in Fig. 1. The electronic
consensus on data-extraction. Discrepancies between the reviewers at an autoregressive structure; search identified 15,577
any stage of the screening process were resolved by asking a third therefore, a heteroscedastic potential titles. After removing
author, if necessary. autoregressive (HAR) model was duplicates and papers not
adopted. Grouping by gender directly related to post-COVID-
2.3. Methodological quality was not possible due to lack of 19 symptoms, 64 studies
data (see discussion section). remained. Twenty-siX (n 26)
The methodological quality of the studies was independently For quantitative data (age, were excluded after
assessed by two authors using the Newcastle-Ottawa Scale, a star days at hospital), overall means title/abstract examination. One
rating system that evaluates the risk of bias of case-control and cohort and standard deviations (SD) preprint was excluded because it
studies [9]. This scale, when applied to cohort studies, includes the were calculated using the analysed risk factors and
following sections: case selection, comparability, and exposure. Case pool.groups function from the clusters but not detailed specific
selection includes representativeness of cohort, selection of non- dmetar package. Median and post-COVID-19 symptoms [11];
exposed cohort, ascertainment of exposure (case definition), and interquartile range (IQR) were one study was excluded because
outcome of interest no present at start. Comparability evaluates the converted to =mean and SD as it was a case series [12]; another
analysis of comparison (e. g., controlled for age, gender, or other described by Luo et al. [10]. one because mor- tality rate, not
When necessary, data were post-COVID-19 symptoms, was
factors) between groups (exposed and non-exposed). EXposure
estimated from graphs with the analyzed [13]; and the last one
includes outcome assessment, long enough follow-up period, and
GetData Graph Digitizer because it included children,
adequate follow-up. In longitudinal cohort studies or case-control
v.2.26.0.20 software. not adults, with COVID-19 [14].
studies, a maximum of 9 stars can be awarded. In cross-sectional
cohort studies, a maximum of 3 stars can be awarded. Studies scoring A total of 29 published studies
3 are considered of good quality, those scoring 2 are of fair quality 2.5. Role of the funding source [15–43] and five medRXiv
preprints
and studies scoring 1 are of poor quality [9]. Methodological quality
There was no funding source [44–48] were initially included
of the included studies was determined by two authors and the
for this study. in the review/meta-analysis
differences, if existed, were discussed. In the case of disagreement, a
(Fig. 1). One preprint [44] was
third researcher arbitrated a consensus decision.
excluded because the same
2.6. Patient and public
study has been pos- teriorly
2.4. Data synthesis and analysis involvement
published in a peer-reviewed
journal [30]. Therefore, a total
The meta-analysis was conducted with the R software 4.0.0 using Patients were not involved in
of 29 peer-reviewed studies [15–
meta and dmetar packages. Percentages and frequencies of each symp- the study since this was a meta-
43] and four medRXiv preprints
tom at onset/hospitalization and each symptom were extracted from analysis of the literature.
[45–48] were included in the
studies and an overall proportion was calculated reporting a systematic review and meta-
single analysis.
proportion using the metaprop function. We used a random-effects model
because potential heterogeneity was expected. An I2 value 75% was ≥
considered to indicate serious heterogeneity. We were not able to 3.2. Sample characteristics
assess
funnel plot asymmetry due to an insufficient number of studies inves- The characteristics of the
tigating the same post-COVID-19 symptom at a particular follow-up. We COVID-19 populations of the
included
calculated sample size-weighted mean scores for each study reporting
data alongside 95% confidence intervals (95%CI) in addition to any
potential meta-analytical summary effect on the pooled prevalence
data for each post-COVID-19 symptom. Data synthesis was
5 7
≥
Downloaded for Matdoan Rifkiah Aisyah (matdoan.rifkiah@ui.ac.id) at University of Indonesia from ClinicalKey.com by Elsevier on ≥
3.3. Methodological quality
Europe
an
Journal
Thirty studies (88%) were of
cross-sectional, just one was of Internal
Medicin
good quality (3/3 stars), 28 were e 92
considered of fair quality (2/3 (2021)
55–70
stars), and two of poor quality
(1/3 stars). One was a
3.4. Symptoms at onset or
longitudinal cohort study with
hospital admission experienced
high methodological quality (8/9
by COVID-19 patients
stars), and two were case-control
studies of poor quality (5/9 stars,
Supplementary Table
with 0 stars in the comparability
summarizes which study assessed
domain). No disagreement
each COVID- 19 onset symptom
between authors was observed.
and each post-COVID-19
Table 3 presents the Newcastle-
symptom. SiXteen studies
Ottawa Scale scores for each
(48.5%) collected the post-
study and a summary of every
COVID-19 data by telephonic
item.
interviews, whereas ten studies
(30%) collected data face-to-
Table 1 face interviews.
Characteristics of the included
Pooled data of symptoms at
studies investigating post-COVID-19
symptoms. onset and post-COVID-19
symptoms experienced by the
total sample, including both
hospitalized and non-
hospitalized COVID-19 patients,
are shown in Table 4. In the
total sample, the most common
symptoms experienced at SARS-
CoV-2 infection were fatigue
(63.4%), cough (60.2%), fever
(55.3%), ageusia
(46.0%), anosmia (45.7%) and
dyspnea (44.1%). Among
hospitalized patients, the most
common onset symptoms at
hospital admission included
cough (65.2%), fever
(59.45%), fatigue (48.0%),
Fig. 1. dyspnea
Preferred (50.9%), anosmia (34.3%) and
reporting
items for ageusia (34.0%). In non-
systematic hospitalized patients, the most
reviews and common onset symptoms were
meta-analyses
(PRISMA) fatigue (71.89%), myalgia
flow diagram. (59%), cough (56%), fever
C. Fernańdez-de-las-Penãs et al.
(52.5%), anosmia (51.9%), and
26.3%, 95%CI 25.3–28.0%;
ageusia (51.8%). Most pooled
two: 17.6%, 95%CI data showed high level of
studies are shown in Table 1. 15.1–20.5%; ≥ three: 25.6%, ≥
The total sample comprised heterogeneity (I2 75%).
95%CI ±11.4 —47.8%) with
24,255 COVID-19 survivors Interestingly, non-
hypertension hospitalized patients
(52.26% female; mean SD (22.9%, 95%CI 16.2–31.5%) — and experienced chest pain (28.0%
age: 47.8 16.6 obesity (22.2%, 95%CI 13.9 vs. 10.1%, P = 0.008), myalgias
years); 15,244 were 33.5%) ±
hospitalized (42.7% female; (59.0% vs. 15.6%, P = 0.004),
being the most prevalent. Pre-
age: 48.6 17.4) sore throat (45.8% vs. 5.6%, P =
existing comorbidities were, in
whereas 9011 (70.2% female; ± 0.009), anosmia (51.9% vs.
general, more prevalent in
age: 44.3 14.8) were non- 34.36%, P
hospitalized patients than in
hospitalized patients. The mean = 0.006), ageusia (51.8% vs.
non-hospitalized patients.
length of hospital stay due to 34.0%, P = 0.022), diarrhoea
± 2 summarizes the pooled
Table
SARS-CoV-2 infection was 12.5 (36.0% vs.
prevalence of demographic and
days (SD 6.8). From those 14.1%, P = 0.014), vomiting
clinical data of COVID-19
hospitalized, 402 patients (8%) (12.2% vs. 2.7%, P = 0.011),
survivors separated by
required ICU admission (mean nausea
hospitalization. Hos- pitalization
stay: 15 14.6 days). (24.16% vs. 4.3%, P = 0.007),
data were collected from medical
Almost 50% of the total palpitations (28.37% vs. 7.2%, P =
records in all studies.
sample exhibited at least one 0.022)
pre-existing comorbidity (one: and vertigo (31.9% vs. 5.74%, P =
5 8
0.045) significantly more frequently Hospitali Non- talized Overall, siXty days after±onset
Country
zed Hospitaliz and or hospitalization (mean: 60.4
(n¼15,2 non-
Hospitalizatio D Days onset ed
44)
n a to follow-up (n¼9,011 hospit days), the most frequent post-
48.7
Carvalho et al. 2020 [15] (SD)
France 150 (66
t / 84) (median) YES )49 (15) alized
Telephone 30-60
COVID-19 symptoms were
Garrigues et al. 2020 [16] France 120 a(73 / 47) YES (17.4)N=1 63.2 (15.7) Telephone 100
44.3 patien fatigue
Carfi et al 2020 [27] Italy 143 (90
a / 53) YES 2,595 - 22 56.5 (14.6)
(14.8)N= ts Face-to-face 60 (56.2%), dyspnea
studies
Mandal et al. 2020 [37] UK 384 s(239 / 145) YES 59.9 (16.1)
8,792 - 11 Telephone
(Table (27.2%),
54 chest pain (23.6%),
Arnold et al. 2020 [40] UK 110 (68
s / 42) YES studies
60 IQR 46-73
4).Face-to-face headache
90 (19.8%), joint
9,189 2,584
(57.5 (29.7%)
Jacobs et al. 2020 [41] Italy 183 e(112 / 71) YES 57 IQR 48-681%) /6,107
/6,79 Telephone
pain 35
(19%), and cough (18.9%).
Townsend et al. 2020 [42] Ireland 128 (59
s / 69) YES 49.5 (15) (70.3%)
Face-to-face 63
(%) * Non-hospitalized individuals
Wang et al. 2020 [43] China 131 (59
s / 72) YES Medical co- 49 (36, 62) Face-to-face showed28
Halpin et al. 2021 [18] UK 100 m(54 / 46) YES morbidities 66.66 55.2%
Telephone 50
higher prevalence of sore throat
Xiong et al. 2021 [22] China 538 e(245 / 293) YES Without comorbidities *
52 IQR 41-62 [48.0;
Telephone 97
(67%), headache (48%) and
Huang et al. 2021 [23] China 1,733n (897 / 836) YES 57 IQR 47-65 62.2]N Face-to-face 186
Kamal et al. 2020 [29] Egypt 287 t(103 /184) YES 32.3 (8.5)2,799= Postal
anosmia
60
Moreno-Pe´rez et al. 2021 [24] Spain 277 (146 /131) YES 56 (42-67.5) / 2,062 /
Face-to-face (37%)77than hospitalized
2
977
Perlis et al. 2021 [47] USA 5,437 (3,189/2,248) YES 37.87 (11.92) 3,507I Website patients
60 (4%, 11%, and 11.5%,
= = 93% -
Jacobson et al. 2021 [26] USA 22 (14 /8) YES 50.6 (15.1) Face-to-face 138
respectively), but the
88% -
Sykes et al. 2021 [25] UK 134 (88 / 46) YES 59.6 (14) 2 Virtual 113
differences did not reach
Zhou et al. 2021 [32] China 89 (46 / 43) YES 43 (31-52) Face-to-face 21
Venturelli et al. 2021 [33] Italy 767 (515/ 252) YES 63 (13.6) Telephone statistical
81 significance due to
Suarez-Robles et al. 2021 [34] France 134 (515 / 252) YES 58.5 (18.5) Telephone the het-
90
COMEBAC Study Group et al. 2021 France 478 (277 / 201) YES 60.9 (16.1)
studies Telephone
4 studies 113
1
[35] co 27.7% 25.6%
erogeneity in the comparison
Mumblit et al. 2021 [46] Russia 2,649 (1,296/1,353) YES m 56 (46-66)
[26.1; Telephone
[24.0; (Table 4).
217.5
or More
60 than ninety days after
Chopra et al. 2021 [36] USA 1250 (648 / 602) YES
bi
62 (50-72)
29.4] Telephone
27.2]N ±
Nehme et al. 2020 [38] Switzerland 669 (268 / 401) NO 42.8
N (13.7)
= = Telephone 40
onset/hospitalization (mean:
di
Tenforde et al. 2020 [39] USA 270 (130 / 140) NO ty 42.5 IQR
755 / 31- 726Telephone
/ 21
118.4
2,799I 2,838I
2
40.0 days), the most frequent
2
= = 61% - post-COVID-19 symptoms
74% - 3
included fatigue
2 studies
studies
2 comorbidities 15.8% (35.3%), dyspnea (26.3%),
20.9]N = [12.3;
2
698 / 3,566I = 0% - 3
anosmia (11%), myalgia
20.0]N
=
(10.9%), joint pain (10.3%),
413 / and ageusia (10%). At this
2
2,838I follow-up period, non-
= 89% -
54 3 hospitalized
Goertz et al. 2020 [17] Netherland Website 80
2113 (310 / 3 or more studies studies
1,803) NO comorbid 29.6% 16.1% patients reported significantly
54.0 ities [10.9; [12.2; higher prevalence of anosmia
Galvań-Tejada et al. 2020 [19] Mexico 219 (111 / 108) 59.0]N = 20.9]N (15.5% vs. 8.1%, P
Stavem et al. 2020 [20] Norway 451 (198 / 253) 591 / = pain (14.9% vs. 7.7%; P
Petersen et al. 2020 [21] Faroe Islands 180 (82 / 98) Obesity 2
44 /
2,883I
Cirulli et al. 2020 [45] USA 357 (NR) = 2 sputum (10.7
= 98% - 274I =
Sudre et al. 2020 [30] Multi- 4,182 (1,192 / 2,990) = vs. 3.4, P 0.002), and
3 N/A -1
country Hyperten
studies study vertigo (12.7% vs. 4.2%, P
sion *
Logue et al. 2021 [28] USA 177 (76 /101) 29.0% 12.7 than hospitalized patients
Jacobson et al. 2021 [26] * USA 96 (49 / 47) [4.3;
[21.2; (Table 4).
Iqbal et al 2021 [31] Pakistan 158 (71 / 87) 38.2]N = 32.0]N
Peluso et al. 2021 [48] USA 135 (100 / 79) 841 / =
2 1,155 /
3.6. Post-COVID-19 symptoms
SD: standard deviation; IQR: Interquartile range; NR: Not Reported 3,687I
* = 96% - 4,491I
2 classified by groups:
Jacobson et al included both hospitalized and non-hospitalized patients
5 = 93% - hospitalized/non- hospitalized
studies 3 studies
C. Fernańdez-de-las-Penãs et al. 30.9% 13.0%
Europe
an [21.6; [7.9;
Table 2 Journa 42.1]N = 20.7]N
Pooled means of demographic and l of 3,548 / =
Intern 2
clinical data differentiated by 9,127I = 224 /
al 2
hospitalized (n=15,244) and non- Medici 98% - 1,375I
ne 92 15 = 81% -
hospitalized (n=9,011) COVID-19 (2021) studies 6
patients. 55–70
studies
Diabetes * 8,864 4.1% [2.1; 8.1]N = 180 /
days), the most frequent post- 20.1]N = 2
5,106I = 90% - 6
COVID-19 symptoms were 1,557 studies
cough (18.6%), anosmia / 2.3% [1.3; 4.0]N = 100 /
2
(16.5%), ageusia (15.7%), 9,128 4,929I = 78% - 5
dyspnea (13.2%), fatigue I

(11.7%) and confusion (8%), 97%
-
without significant differences 15
between the hospi- studi
es
Heart Disease *
mean years * male/femalen
[7.8; 17.0]N = 487
Age,
/
(SD), Gender,
5 9
Of the inve of post-COVID-19 symptoms studies, I2: 94%) 60 days days after hospitalization (Fig. 2).
twenty-one stiga in hospitalized patients, after, and 45.9% (95%CI 28.2–
Within non-hospitalized
studies ting four analyzed symptoms 30 64.7, 7 studies, I2: 96%) ≥90
the days after hospital days after. Most comparisons patients, the most common
[15,16,18,22–
pres discharge [15,33,41,43], nine showed serious/large post-COVID-19 symptoms were
25,27,29,32– showed a follow-up period of 60
ence heterogeneity (I2 ≥75%). A anosmia (19.9%), ageusia
37,40–43,46, 47] days [15,
greater proportion of (18.3%), dyspnea (15.7%),
studi studies 18,24,27,29,36,37,42,47], hospitalized patients (P =
Ast es 12.0% cough (13.9%), fatigue (11.8%),
hm 9.3% [8.8; whereas ten reported 0.003) showed one or more and headache (10.9%) 30 days
a [5.5; 16.1]N symptoms ≥90 days after post-COVID —19 symptoms 60
15.4] = after the onset of symptoms;
N= discharge [16,22,23,25,26,33– days after (78.5% 95%CI 60.1–
88.9) as compared to non- sore throat (67.0%), fatigue
219 35,40,46]. Overall,
hospitalized patients (56.2% (63.2%), headache ≥(48.2%),
hospitalized 95%CI 48.5–63.72), without
/5, 562 / 2
5,245I
cough (40.7%), dyspnea
CO
61
9I = 89% COVID-19 patients were differences at 30 days (P = (39.9%), and anosmia (37.7%)
2 -5
PD
* = studies assessed a mean of 83.6 ± 48.4 0.186) or ≥90 days (P
9 60 days after symptom onset;
6
% after hospital = 0.305) after.
- and fatigue (29.8%), dyspnea
8
st Overall, thirty days after (19.1%), anosmia (15.5%), chest
u
di onset/hospital admission pain (14.9%), and ageusia
es
6.0% 2.2% discharge. Among twelve (mean: 30.3 ± 6.3 (13.2%) 90 days
[4.1; [1.2; studies [17,19– after (Fig. 2).
8.7] 4.0]N = 21,26,28,30,31,38,39,45,48] Fig. 2 graphs the time-course
Can N= 10 /
2
with non-hospitalized patients, of ≥the eight most prevalent
cer 195 / 454I =
8,25
four studies evaluated post- symptoms from onset/
0% - 2
2I
2
studies
COVID-19 symptoms 30 days ≥ 60 and 90
hospitalization to 30,
= after onset [19,31,38,45] two days after in hospitalized and
94% 1.9% had a follow-up of 60 days ± non-hospitalized patients. The
[0.8;
- 11 [30,45], whereas seven random effect model showed
studi 4.2]N =
es 6/
analysed symptoms after 90 sig-
4.4% 2
315I = days [17, 20,21,26,28,45,48]. nificant effect for time (all,
[2.5; 0% - 2 The sample of non- P<0.001) for fatigue, dyspnea,
7.7] studies hospitalized patients was
N= headache,
140 myalgias, cough, anosmia and
/ ageusia symptoms, but not for
7,975 ≥ chest pain: symptoms dropped
2
I = at 30 days relative to baseline
95%
and raised up again at 60 and
- 10
studi 90 days after. Significant group
es *time effects were also found
Kidney disease * 0.6% assessed a mean of 73.9 46.4 showing that this tendency was
[2.7; 9.8]N = 567 / [0.4; days after onset of symptoms.
0.9]N =
7,504 Within hospitalized more pronounced in
I 27 / patients, the most common hospitalized than non-
98%4,475I2 =
post-COVID-19
10 0% - 3
hospitalized patients.
studies
studies
Immune 3.3% [1.3; 4.6%
symptoms included: cough
Disorders 7.3]N = [3.0; (26.6%), skin rashes (14%),
92 / 7.2]N = ageusia (11.4%), anosmia
Stay at 2
4,707I = 19 / (11.1%), confusion (9.3%) and
the 2
93% - 8 409I =
hospita dyspnea (9.2%) 30 days after
studies 0% - 2
l, mean hospitalization; fatigue
12.6 studies
(SD),
(6.8)N=7 (53.9%), dyspnea (24.4%),
days
,299 - 15 joint pain (22.8%), chest pain
ICU)
admissi
studies (21.0%), cough (13.8%), and
492
onYes/ anosmia (11.5%) 60 days after
(8%)N=4,
No, n hospitalization; and fatigue
507 - 12
(%)Stay (38.5%), dyspnea (33.3%),
studies14.
at ICU, 97 cough
mean (14.6)N= (10.4%), myalgia
pain (9.4%) and (9.7%), joint
palpitations
(9.1%) ≥90
(SD), days 391 - 7
studies
COPD: Chronic Obstructive 3.5. Post-COVID-19

Pulmonary Disease; ICU: Intensive symptoms experienced by
Care Unit; SD: Standard Deviation COVID-19 survivors (Total
*
Significant differences between sample)
non-hospitalized and hospitalized
COVID-19
A total of 63.2% of the sample
patients
(95%CI 43.9–78.9, 7 studies, I2:
97%) exhibited one or more
than hospitalized COVID-19 post-COVID-19 symptoms 30
patients. days after onset/ hospitalization,
71.9% (95%CI 53.3–85.2, 3
5 1
C.
Table 3 Fer
Newcastle - ottawa quality assessment scale - quality appraisal cohort/cross-sectional studies. na
ńd
Selection Comparability Exposure ez-
de-
Cohort Study Representativeness of Selection of non- Ascertainment of Outcome of Study controls Study controls Assessment of Long enough Adequate Score las-
exposed cohort exposed cohort exposure interest nor for age/gender for additional outcome follow-up follow-up Pen
present at start factor ãs
Carvalho et al. ★ ★ 2/3 et
Dow 2020 [15]
al.
nl
o Garrigues et al. ★ ★ 2/3
a 2020 [16]
d Carfi et al 2020 ★ ★ 2/3
e [27]
d
f Mandal et al. ★ ★ 2/3
o 2020 [37]
r Arnold et al. ★ ★ 2/3
M 2020
at [40] ★ ★ 2/3
d
o Jacobs et al.
a 2020 ★ ★ 2/3
n [41]
R Townsend et al. ★ ★ 3/3
if 2020 [42]
ki
Wang et al. 2020 ★ ★ 2/3
a
h [43]
A Halpin et al. 2021 ★ ★ 2/3
is [18]
y
a Xiong et al. 2021 ★ ★ 2/3
h [22]
( Huang et al. 2021 ★ ★ 2/3
m 60 [23]
at Nehme et al. ★ ★ 2/3
d 2020
o
a [38] ★ 1/3
n. Tenforde et al.
ri 2020 [39] ★ ★ 2/3
f Goertz et al. 2020
ki
a [17] ★ ★ 2/3
h Stavem et al.
@ 2020 [20] ★ ★ ★ ★ ★ ★ ★ ★ 8/9
ui Petersen et al.
.a
c. 2020 [21] ★ ★ 2/3
id Cirulli et al. 2020
) [45] ★ 1/3 Eur
at Sudre et al. 2020 ope
U ★ ★ 2/3 an
ni [30]
Jou
v Kamal et al. 2020 rna
er [29] ★ ★ 2/3 l of
si Chopra et al. Inte
ty ★ ★ 2/3 rna
2021 [36]
o l
f Jacobson et al. Me
I 2021 [26] ★ ★ 2/3 dici
n Sykes et al. 2021 ne
[25] ★ ★ 2/3 92
(20
Moreno-Pe´rez 21)
et al. 2021 [24] ★ ★ 2/3
55–
Iqbal et al 2021 70
[31] ★ ★ 2/3
Zhou et al. 2021
[32] (continued on next page)
Venturelli et al.
2021 [33]
Score
2/3
5/9
C. Fernańdez-de-las-Penãs et European Journal of Internal Medicine 92 (2021) 55–70
al.
4. Discussion This
Non- response rate

review/m
4.1. Findings that more
19 survivo
post-COV
Same method for cases and controls

more tha
≥ or ho
prevalenc
isolation
days and
longer aft
(Fig. 2).
were the
COVID-19
hospitaliz
hospitaliz
particular
of follo
prevalenc
e.g., h
ageusia,
palpitatio
highly va
The p
Ascertainment of exposure
by Lopez
that fa-
attention
dyspnea
frequent
symptom
overall p
for additional factors
COVID-19
distinctio
hospitaliz
patients
follow-up
the co
for age
prevalenc
Controlled
Another s
Controlled
reported
COVID-19
infectious
reduced
carditis;
Selection of controls Definitions of controls
did not
COVID
focused
impairme
meta-ana
most com
COVID-19
by hos
survivors
dyspnoea
cough sho
of 52%,
respective
and 3 m
discharge
prevalenc
our pool
60days
Cares-Ma
pooled
distinctio
periods.
review/m
6 1
the prevalence of post-COVID-19 symptoms T 9.4; 34.9
H NH 2
considering if patients were I 99% 98.0% 99%
T H 96% 95% 97%
also separated by follow-up periods. We were NH T 99% 99% 99%
to identify 29 peer-reviewed studies as well as four H NH Fever 99% 97% 99%
medRXiv preprints providing prevalence data on 55.3 Event 48 2,6 27 76 / 1,2 79 41 2, 48 1
% 59.4% /Tota
post-COVID-19 symptoms from l
3/ 40 9 464 11 2 9 61 3/ ,
52.5 1,3 / / 203 / 7,2 71 7 4,3 6
and non-hospitalized % - /5,815 97 4,4 1,7 / 7,9 46 6 / 85 7
different follow-up periods; the highest number of - - 18 41 1,27 62 4, 7
7 38 /
studies pooled to date; how- - -
5 3
were of fair methodological quality and also showed - - ,
- - 3
high heterogeneity in their results. Nevertheless, it9 41.4; 63.4 1
should be remarked that 5 - 4
% - - Studies 17 8 9 8
assessing post-COVID-19 CI - - 3 5 10 8 2
published and future updated - - 15 8 7
- - Fatigue 63.4% 48.0% 71.9%
be needed. 4
11.7% 7.7%# 11.8%
2.
The most common symptoms experienced by 9;
56.2% 53.9% 63.2%
35.3% 38.4% 29.8%
patients at onset/hospitalization in the overall6
95%CI
★
7. 48.3; 76.2 3.1; 1.9;25.3 1

sample were fatigue, cough, fever, ageusia, 1 76.2 35.3 7.1; ; 2
99.
and dyspnoea in agreement 67.8 8.0 6.5; 3 46. .
Representativeness of cases
20.5 28.3; 8 3
analysis showing similar symptoms at SARS-CoV-23 80.7 40.5; ;
3.
infection [51]. Neverthe- 7; 66.8
30.
prevalence rates can be 8 4; 5
0 6
current meta-analysis, Alimohamadi et al. found .9
47.
4 .
similar prevalence of cough (58.5%), but higher I2 98% 3
2
prevalence of fever (81.2%) and lower rate of 99% 98% I 99% 98% 99%
- - 95% 0% 88%
fatigue (38.5%) [51]. There is clear evidence - - 98.0% 96% 99%
supporting that clinical manifestations - - 99% 99% 99%
19 are highly heterogeneous. - - Event 45 3,0 230 114 116 74 55 4, 1, 2
- /Tota
A relevant finding was that post-COVID-19 8 73 / / / 0/ 5 40 75 ,
Event/Total 3,1 l
symptoms experienced 2,0 - - 1,1 / 1,2 40 894 1,3 71 9 3 0
72
45 - - /5,134 05 4,0 97 3 19 0 / / 0
onset/hospitalization decreased // - - 29 / 9, 6, 0
5, 6,5
prevalence as compared to the acute phase but21 4,4 -- - 2,02
9
87
6
56
7
/
3
49
18
increased 60days after ( 7/ ,
3
these findings are still unknown
Adequate case definitions
10 0
confirmed in well-designed longitudinal studies; ,9 9
67 Studies 13 5 8 6
however, it should be noted that Studies 15 3 3 8 6 2
data were based on a small number of studies and 6 7 17 10 7
- -
comparisons had large - -
Chest Pain 16.5% 10.1% 28.0%
* 6.6% 1.1% 10.9%
studies conducted in - - 23.6% 21.0% 28.5%
- -
prevalence rates of fatigue -
9.4% 7.7% 14.9%
*
(30–40%) as post-COVID-19 Dyspnea 44.1%
★
95%CI 8.0; 30.9 3.5; 5.8; 6.7; 13.1

18,20,27,37, 40–42] 50.9% 38.9% 25.6 14.4; 47.3 1.5; 72. 5.2; 11
13.2% 9.2% 25.2 0.0; 77.1 3.3;
whereas Chinese studies reported, in general, lower 15.7% 27.2% 2 9.9; 21.7
30.6 11.9; 41.5
Table 3 (continued )
prevalence rates of these 24.5% 39.9% 14.4;

26.3% 33.3%
[22,23,32,43]. Factors such 19.1% 29.7
2
I 99 97 99 94%
lower pre-existing medical comorbidities in 95 23.0; 9
% 100% 97% 98% 84%
Chinese studies could explain these discrepancies; 57.5 .
CI 6.6; 4 99% 94.6% 93%
however, the magnitude of these different 5 89%
29.3
prevalence rates would suggest other relevant2 2.0; Event 115 1,4 106 / 832 27 131 35 92 252 5
33.0 /Tota
factors e.g., racial disparities 9. / 46 / 28179 / / 0 0/ / 5
7.7; l
3;
29.3 1,0 / 551 481 560 71 8,9 6,4 3
[53]. Future studies investigating 6 /3,990 72 2,9 1,27 8 45 37
of post-COVID-19 symptoms 0. 18
44.4 /
1
factors are 2
41.9 ,
C 25 5
. E .8 0
; 8
7 Studies 9 5 4 5
T 5 2 3 5 3 2
a . 13 9 4
Pooled prevalence of 5
symptoms at onset, and Myalgia 37.0% 15.6% 59.0%
#
Post-COVID-19 Symptoms * 4.9% 2.0% 9.6%
14.7% 8.1% 32.1%
30, 60, and ≥90 days after
10.9% 9.7% 12.6%
Onset/Hospitalization.
95%CI 21.2; 56.1 4.3; 6.6; 17.7
Onset 30 days after 42.9 53.2; 64.6 1.3; 3.9; 22
17.2 0.0; 27.8 7.0; 7.8; 19.9
60 days after 12.9 5.1; 35.5 3.5;
≥90 days dafter 17.3 6.8;
75.3
T 2
I 98% 95% 90%
81% 82% 0% 99%
H 98% 99% 99% 98%
97%
NH Event l 2,556 25 8 25 2,2 9

/Tota /4,956 1,2 8
/ 7 28 3 131,119187 2 5 - 2 99%
Event 15% 99% N/A
3 8 6 , , 43 11 / 310 0 28 - 1
7 98/ 8 7 /Tota / N/A
131 11 94%
0 / 94% -
, 6 9 2 5
4 l
7 , 5,8 / 5,83,3 1 , 6 94% 27 N/A 280 / 95%
5,5 2,7
57 / 5,226 12 1,892 4 /
3 6 / 4 5,580 80 67
1 7 86
Studies 5 /
Studies 13 6 2
2 3 1,6
7 5 2
4 2 18
3 2 64 /
2 1
5 3
1 - 2
2 14
2 - ,
7 7 7
2
Headache 36.7% 4
Sputum 18.9%
11.8% 5
51.6% 14.8% 25.5%
Studies 8 2 6 2
7.4% 1.1% 4.7% 4.7% 1 1 2 2 -
11.0% - 7.7% 6 1 5
19.8%
11.3% 7.7% - Sore Throat 26.7% 5.6% 45.8%
# #
48.2% 6.5% 3.4% * 1.0% 1.5% 0.6%
#
6.3% 3.6% 10.7% * 15.2% 4.2% 67.0%
10.9% 4.9% 4.5% 7.3%
95%CI 13.0; 26.7
95%CI 3. 9.2; 22.9 17.1; 95%CI 12.1; 49.1 0.1; 29.6 2.7; 8.7
2; 36.1 0.0; 49.5 38.1; 53.7 0.3; 3.0 1.9; 10
12 0.0; 49.5 - 0.4; 5.9 0.01; 3.9
18.5; 59.8 1.2; 2.0; 23.0
.0 3.9; 13.3 3.9; 2.4; 56.4 3.7; 4.7
60.3 13.3 - 63.0;
3.1; 13.1 2.2; 5.1 70.8
1. 4.5; 23.3 2
32.9; 69.8 2.3; 2 I 98% 98% 96% 0%
3; I 96%
21.5 0.0; N/A N/A 99% 36%
9. 86% 96%
72.9 4.2;
9 N/A 98% 97 97%
25.7 5.3; 99% 99%
52.4 4.7; N/A N/A Event 71 / 3 / 3102 / 235 37 69 103 5
24.8 3.1; /Tota 812 131 1 / 4 2/ / 8
5. 96% 38%
96.5 l 609 / 9
7; 94% 5,5 55 5,5 3,1
19 /4,269 6,138 80 8 23 96
.7 E 8 49 / 2 1,90 /
2 v 6 403 3 4/ 3
I 98% 99% e 9 49 / 3,4 ,
99% 95% n 57
/ 403 1
99% 97% t / 9
2, 11 /
99% 99% / 6
6 143
99% 99% T 5 / 143 Studies 9 3 6 2
o 0 413 / 6
97% 97% 1 1 3 2 1
t 7
E 2,965 9 3 6
142,714 2 8331521 1,195 86 a 2
v l Cough 60.2% 65.2% 56.0%
3 232 9 3 2 / 57/ 7
e 18.6% 26.5% 13.9%
56/ 1,3 6, 6,1714
/ 5,7 / 18.9% 13.8% 40.7%
nt 3
7 4,370 85 44 8,675 2, 1 9 8.6% 10.4% 6.7%
/ 22 / 8 37 86 , 0
T 2 95%CI 48.2; 6.2; 28.3 5.3; 13.7
ot 0 66.8 63.5 10.1; 5.7; 18
al 3 2 74.3
/ 10.6; 8.3; 22.0 3.0; 14.3
1 5
30.7 11.9;
4 / 2
2, , 43.8 77.8
3 2
8 , 2 I 95% 92% 97%
6 1 6 9 96% 92% 97%
6 1 4 3 99% 98% 99%
/ 3 5 98.6% 97% 97%
4,8 Studies 7 Event/Total
89 4 3
/ (continued on next page)
3 3
1 - 1
, C
1 -
0 .
4 2
5 2
6
Rhinitis 27.3% T
Studies 1 4 3,438
8 4 1.2% 38.9% 838 2,6 334 153 181 812 401 411 1,0 374 6
2 4 /5,697
0.1% 0.0% / 00 / / / / / / 61 / 8
6 4
2 12 0.006% 7.3% 1,37 / 1,82553 1,2 7,29 6,57718 / 4,9 7
6 6 7.3% - 5 4,3 9 76 3 5 8,2 04 /
4.0% 4.5% 22 19 3
E 15.3% 17.7% ,
y 13.9% 4.0%
3
e 7.0% 95 1
#
0.0; 3.7;
irri 5.3% % 1.0 14.0 5
tati 9.7% 9.8% CI Studies 15 7 8 9
on 9.8% - 5.1% 14.0 4 5 4 5 2
- 5.1% 0.0 - 8 15 7
12 03;
95%CI 8.6; 25.6 9.3 Anosmia 45.7% 34.4% 51.9%
.6;
9.0; 32.0 10.7 #
49 * 16.5% 11.1% 19.9%
6.0; 28.8 26.1
.6 17.3% 11.8% 37.6%
3.4;24.6
9.8 11.0% 8.1% 15.5%
2.2; 12.5
3.4; 24.6 0. *
5.9; 15.8 0; 595%CI 45.7; 58.1 8.3; 8.0; 15.0
5.9; 15.8 - 9. 9.9;
32.1 5.0; 12
1.4; 17.2 - 0 24.9; 8.2; 15.0 18.1 12.5;
1.4; 17.2 45.3 10.3; 19.0
2
I 96% 93% 34.8 80.2
36
97% 88% 2
.5; I 95.6% 89% 95%
68% 94% 41 95% 26% 96%
N/A N/A .3 99% 97% 99%
97% -
95% 96% 77%
97%
0. Event 197 1,7 198 37 / 42 41 84 302 4
E / 59 0 /Tota
ve / 30 / 333 8 2 1/ / 6
3,242 / 02 l
nt 6 586 / 1,0 766 6,4 71 9.3 6,0 0
32 ; /4,317 /
/T 8 3,7 99 75 6 57 42
6 34.6 31
ot 8 7,191
629 I
2
31% /
al /
6 3
3 ,315 E 81.9% Event 22 1,4 49 / 945 36 38 / 40 15 2
1, 1 1 549 /Tota
Studies 11 4 v 91%
2 3 6 /N/A 3/ 46 553 13 550 4/ 51 4
7 6 e 6 l 331 / / 9
97%
0 2 94%
3,0 1,3 / 8,4
2 4 n 3 , /5,106 75 3,7 1,267 59 5,1
94% 38
7 5 t 31 293 43 /
2 16 / /
/ / 3
3,
9 7 T 71 ,
28
Ageusia 46.0% o 0 7 3
34.0% t 9 1
a 9 6
51.8% *
l 6 Studies 14 7 7 6
15.7%
# 4 2 5 3 2
11.4% 11 4 47
18.3% 1 4 #
, 0 Vomiting 7.5% 2.7% 12.2%
9.0% 8.93
3 * 0.9% 0.0% 2.8% -
9.6% 4 - - 0.8% 0.3%
10.0% 8 / #
1.3%
7.6% /
3 95%CI 3.7; 14.5 0.1; 8.5 8.2;
13.2% 4
, 17.8 0.05; 14.0 0.0; 1.0 0.3;
95% 43.7; 59.0 6. 7 2 21.4 - - - 0.3;
CI 9.2; 25.6
6; 1 2 2.2 0.01; 0.6 0.7; 2.3
2
8.4; 15.3 8.8; 15 6 I 958% 64% 95%
54.9 34.16.3; .1
9 77% N/A 89% -
12.7 5.8; - - 83% N/A
46.9 2
5.9;
3. 61%
15.3
8; Event 23 24 / 529 0 / 131 247
/
14 /Tota / / 398 - -
.6 l 66 - 40 /
5 3,686 9 5,448 /
4
10
4 /
.0 2
; 3,0
,
17 17
1 6
.1 6 0
2
I 95% 91% 8 9
96% 96% 33
32% 97%
/
94% 95% /
N/A 95% 2
96% 77% 7 ,
1 8
E 161,823 3 37361 17 34 4 3
v 1 700 8 7 2 /5 6 2 9
e / /
47/ 1,4 6, 6,1 Studies 6 2 4 3
n 1
6 3,928 35 98 4, 2, 1 2 - - -
t/ 66 / 4 / 5
69 95 5 1 4
T 7 8 2
ot Nausea 15.5% 4.3% 24.2%
al 3 1 * 3.8% 0.8% 5.4% *
3 5 / 3.1% - 3.1%
3 6 560 4.9% - 4.9%
2,
Studies 8 95%CI 8.6; 26.2 1.1; 15.3 18.4;
0
3 5 31.0 1.5; 9.0 0.1; 5.2 2.8;
3 1 5
6 3 10.7 1.3; 7.3 - 1.3; 7.3
1 9 6
3 4 2.4; 9.5 - 2.4; 9.5
/ 2 1 2
3 1 I 96% 91% 94%
4,4
42 9 4 81% N/A 82%
/ / 5 N/A - N/A
1 7 Diarrhoea 23.9% 86% - 86%
, , 14.1% 36.0%
0 6 Event 40 39 / 743 1 / 13138 -
4.1% 4.2% /Tota
9 5 # / / 612 5 / 160 - 280
5 5 3.3% 8.5% l 779 5 / 160 280 /
Studies 9 3 5.3% 18.2% /4,510 2,769
6 6 3.1% 2.2% / /
2 4 3.9% 3,73 2
5 4 1 ,
95%CI16.2; 1 7
1 11 33.8
6 5 . 6
32.2; 40.0 9 9
Joint Pain 30.0% 9.7 ; Studies 10 3 7 4
32.0% 1.9; 5.62.7;
28.7% 4 1 3 1 - 1
23.7 .
6.9% 6.8% 5 - 5
2.4; 9
7.3% Skin Rashes 5.7% - 5.7%
67.0
19.0% 4.6% 14.0% 2.5%
#
22.9%
1 6.7% 9.4% * 2.5%
10.4%
. 2.7% 3.0% 2.4%
10.3%
9.4% 1
; 95%CI 4.1; 7.9 - 4.1; 7.9
11.2% 1.6; 12.6 9.3; 20.5 0.1; 4.6
4
95% 17.0; 45.8 6.5 7. . 3.4; 12.7 6.9; 12.6 0.9; 6.7
CI ; 1; 3 1.8; 4.0 1.8; 5.1 1.3; 4.3
2
2.7; 16.2 16 14 I 78% - 78%
42.1 .3 .7 91% N/A 0% 75%
10.7; 31.5 2 8% N/A 76% 83%
48.7 .
3 76%
37.4 5.
0; ; Event - 31 / 545 21 / 150 10117 6
16 6 /Total / 395 42 / 569 / 2
.7 . / 38 / 407 4 4,5
7 3,376 / 162 179 / 32
2
3,3
I 94% 76 7,303 /
7. 2
2; 87% 77%
81% 78% ,
17 7
.1 0% 98% 7
2
I 95% 94% 80% 98% 1
95% 96% 94% 90% Studies 6 - 6 3
85% 97% 87% 1 2 2 2 1
9 4 5
Palpitations 15.2% Vertigo 17.7%
7.2% 5.7% 31.9%
28.4% * 2.3% 0.0%
3.5% 0.9% #
4.6% 3.0% 4.3% 6.2%
2.1% 4.9% 6.3% 6.2%
10.0% 7.9% 4.2%
9.1% 12.6% *
11.1%
95%CI6.3; 3
95%CI3.7; 2.9; 7.1 0.6; 40.7
45.80.1; .
13.8 0.1; 18.7; 48.9 8
42.9 22.9 2.5; 9.6 8.2 ;
6.4; 15.3 2.7; 6.84.0; 1
5.6; 14.5 9.6 5
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2
I 99% 95% 11.2 8
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2
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E 7
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n
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Studies 4 2
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2 4
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1 9 v 7 5240 /
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# 2,4
Confusion 13.2% n 17 / 13
9.6% t / 393
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6;
11.1 9 4
14
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8
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Studies 5
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8 1 1
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11.9 3
2
I 52.0% 77% T: Total sample,
0% 0% H: Hospitalized
N/A N/A COVID-19
0% - patients; NH:
0% 99% Non-hospitalized
93% 98% COVID-19
E patients; CI:
32 / 303 104 45 71
ve / 725 32 9 5
Confidence
nt / 3981 17 / / interval
5,7
/ 183 15 *
11 2, Statistically
T / 215 11 / 96 significant
ot 161 - 1
al differences
161
between
hospitalized
13 1,174/ and non-
6
/
8,672 hospitalized
1, patients; # No
0 heterogeneity
2 between
8 studies
Studies 4 2 (I2<75%)
2 1
1 1
1 -
1 10
5 5
6 5
C. Fernańdez-de-las-Penãs et al. European Journal of Internal Medicine 92 (2021) 55–70
Supplementary Table S1 Supplementary Table S1 (continued )

: Studies investigating each post-COVID-19 symptom at onset and at Jacobson
different follow-up periods. et al. 2021
[26]Peluso
et al. 2021
Symptom Onset Follow-up [48]Peluso
Period
30 60 >90 Carvalho - - et al. 2021
et al. 2020 - [48]
[15] Jacobs et al.
Fatigue Carfi et al Arnold et al.
Arnol 2020 [41] 2020 [27] 2020et[40]
Carfi al
d Wang et al. Mandal et al. Garrigues
et 2020 [43] 2020 [37] et al. 2020
2020 2 Townsend
Nehme et al. [16]Xiong
[40] 0 et al. 2020
2020 [38] et al. 2021
Jacob 2 [42]Halpin
Cirulli et al. [22]Huang
s
2020 [45] 0 et al. 2021 et al. 2021
et
Peluso et al. [18]Cirulli [23]Goertz
2020
2021 [48] et al. 2020 et al. 2020
[41] [
[45]Sudre [17]Petersen
Wang 2
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et 7
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2020 ]
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[43] Arnold
[29] [45]Logue
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Moreno-P et al. 2021
rde [40]
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al. Jacobs
2021 et al. 2021
2020 e
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[21]
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2020 [41] 2020 [27] 32020 [40]
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2020 [43] 2020 [45] X2021 [22]
Cirulli et al. Sudre et al. i Huang et al.
2020 [45] 2021 [30] o2021 [23]
Peluso et al. Moreno-Pérez nGoertz et al.
2021 [48] et al. 2021 g2020 [17]
[24]Zhou Stavem et al.
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[32] ePetersen et al.
t 2020 [21]
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(continued on next page)
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20[42]Wang 2 et al. 2021
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55–
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et
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0 2 Jacobson et al. Goertz Supplementary Table S1
2020 [20]
[38]
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etTenforde Peluso et al. [17]
et al. 2020 2020
et [21]
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ma [17] [34]
[39] l et Venturelli et al. 2020
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COMEBAC
Goertz al. et al. 2021 [20]
et al. 2020 Jacobson
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Group
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al. 2021
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Petersen Peluso
[35] et al.
Stavem et al. 2020 [21]Cirulli
et al. 2020 2021 [48]
et al. 2020 [34] et al. 2020
[21]Cirulli Sykes et al.
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et al. 2020 2021 [25]
Petersen Study Group et al. 2021
[45]Logue
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[21]Cirulli [35] et al. 2021
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et al. 2020 et al. 2021
A
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et al. 2021 [48] et al. 2020 2020 [15] 2020 [15] 2020 [40]
n e
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alho 2020
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[15] [15] al.
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4 [41] 2020 [27] 2021 [22] et al. 2021 ] et al. 2021
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2020 [43] 2020
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et al 2020 [19]Cirulli Sudre et al. [23]Goertz
[27] et al. 2020 2021 [30] et al. 2020
Jacobs [45]Iqbal et al Chopra et al. [17]Stavem
et al. 2020 2021 [31] 2021 [36] et al. 2020
[41] Peluso et al. Moreno-Pérez [20]Petersen
Tenforde 2021 [48] et al. 2021 et al. 2020
et al. 2020 [24] [21]Cirulli
[39] et al. 2020
Goertz [45]Logue
et al. 2020 et al. 2021
[17] [28]Jacobson
Stavem et al. 2021
et al. 2020 [26]Peluso
[20] et al. 2021
Petersen [48]Sykes
et al. 2020 et al. 2021
[21]Cirulli [25]Venturelli
et al. 2020 et al. 2021
[45]Logue [33]
et al. 2021 Sua´rez-Robles
[28]Peluso et al. 2020
et al. 2021 [34]Mumblit
[48] et al. 2021
[46]
COMEBAC
Study Group
et al. 2021
[35]
Ageusia Carvalho Carvalho et al. Carvalho et al. Garrigues
et al. 2020 2020 [15] 2020 [15] et al. 2020
[15]Carfi Jacobs et al. Carfi et al [16]Huang
et al 2020 2020 [41] 2020 [27] et al. 2021
[27] Nehme et al. Cirulli et al. [23]Goertz
Mandal 2020 [38] 2020 [45] et al. 2020
et al. 2020 Galván-Tejada Chopra et al. [17]Stavem
[37] et al. 2020 2021 [36] et al. 2020
Jacobs [19]Cirulli [20]Petersen
et al. 2020 et al. 2020 et al. 2020
[41] [45]Iqbal et al [21]Cirulli
Nehme 2021 [31] et al. 2020
et al. 2020 [45]Jacobson
[38] et al. 2021
Goertz [26]Sykes
et al. 2020 et al. 2021
[17] [25]
Stavem Sua´rez-Robles
et al. 2020 et al. 2020
[20] [34]Mumblit
Petersen et al. 2021
et al. 2020 [46]
[21]Cirulli
et al. 2020
[45]
Joint Pain Arnold Carvalho et al. Carvalho et al. Arnold et al.
et al. 2020 2020 [15] 2020 [15] 2020 [40]
[40]Carfi Jacobs et al. Carfi et al Goertz et al.
et al 2020 2020 [41] 2020 [27] 2020 [17]
6 9
Supplementary Table S1 (continued ) Supplementary Table S1 (continued )

et al. 2021 et al. 2020 2020 [21] Verti
[22] [45]Peluso Cirulli et al.
Tenforde et al. 2021 2020 [45]
et al. 2020 [48] Logue et al.
[39] 2021 [28]
Goertz Peluso et al.
et al. 2020 2021 [48]
[17]
Stavem
et al. 2020
[20]
Petersen
e
t[ needed.
4
The occurrence
of respiratory
symptoms following
SARS-CoV-2
Cut
an
infection is similar
eo
us to that present in
severe acute
respiratory syn-
drome (SARS)
survivors, who also
exhibit symptoms
6–12 months after
the infection [54],
but contrasts with
that observed after
communi-
ty-acquired bacterial
pneumonia where
almost all patients
al.
are asymp-
Goert [22]Carv W
z Goertz
alho a
sign et al. et al. 2020 n
et al.
2020 [17] 2020 g
[17] al. [15] e
Stave [48]Cirull t
m
i et a
et
al. l.
2020
2020 2
[20]
[45] 0
Peter
Pel 2
sen
us 0
al.
o [
2020
et 4
[21]
al. 3
irulli
20 ]
et al. Con
fusi
on 21 Cirul
2020
[4 li et
[45] Gar
rigu
es 8] al.
ogue
202
et
0
2021
[45]
[28]
Pe
eluso
lu
et
so
2021
et
[48]
al.
20
21
[4
8]
Palpitation
s
al. Carv
2020 alho
[43] et al.
Xiong 2020
et [15]
2021 Jaco
bs et
6 1
Car C l. 1 [48]Sykes
tomati c s n ot. These considerations are
val i 2 et al. 2021
ho r 0 [25]Venturelli et c 10 o y t highly important to properly
et u 2 al. 2021 days n st h define the timeframe of post-
al. l 0 [33] after fi e e COVID-19 symptoms [7].
20 l Sua´rez-Robles
the r m f To determine the
20 i et al. 2020
[15 [ [34]Mumblit et infecti m ic o underlying mechanisms behind
] 2 al. 2021 on s i ll these symptoms is beyond the
Cir e 0 [46] [55]. t n o scope of the current review, but
ulli t ] Xiong et al.
C In h v w two main hypotheses are
et ir P 2021 [22]
al.
u
ll e Huang et al.
additio e ol - currently discussed, although
ie
20
ta
l.
a t 2021 [23] n, a p v u not alone. First, a prolonged
20 l e Goertz et al. main r e p pro- inflammatory response
. r 2020 [17]
[45 differe e m p (hyper-inflammatory cytokine
] s Cirulli et al.
e
nce s e e storm) related to SARS-CoV-2
Mo 2020 [45]
ren 2 n Jacobson et al. betwee e n r infection can provoke an
o-P 0 n n t; i atypical response of the im-
2021 [26]
ér 2
ez e Peluso et al. SARS- c it o mune system and mast cells,
0 t 2021 [48]
et
H CoV-2 e al d promoting a cascade of events
al. a Venturelli et
20 u l. al. 2021
and o s a affecting the respiratory,
21 a 2 other f o n immune, and central nervous
[33]
[24 n
]
0 Sua´rez-Robles respira s s d systems [56]. Second, social
g 2 et al. 2020 tory e h w and emotional factors around
0 [34]Mumblit et
infecti v o h COVID-19 pandemic, e.g.,
al. 2021
e ous e w e posttraumatic stress,
[46]
t [ disease r s t hospitalization, treatments
2
s is the a t h received, catastrophic social
1
a
]
presen l h e alarm, lockdown, laboral and
l ce of a p at r familiar situations, and
C
.
i plethor o ti t psychological disorders, such as
r a of s m h anxiety or depression, may
u
2 post- t- e- e contribute to these post-
l
0 infecti C c C COVID-19 symptoms.
l
2
i ous O o O Although the underlying
1
e sympto V u V mechanisms explaining this
t
ms, I rs I plethora of symptoms are
[ a
e.g., D e D unknown, their complexity and
2 l.
Car
3 2
joint - of - heterogeneity supports that
val
] 0 pain, 1 s 1 post-COVID-19 sequalae will
ho
G 2 ageusia 9 y 9 need from a multidisciplinary
et
o 0 , s m p approach [57].
al.
e [
20 anosmi y p a
r 4
20 a, chest m t ti 4.2. Strengths and weaknesses of
t 5
[15
z ] pain, p o e the review
]
e L nausea, t m n
Cir
t o The results of this review and
ulli g
headac o s t
et u hes or m fl w meta-analysis summarizing
al. prevalence rates of post-
a e palpitat s u a
20
l e ion, s ct s COVID-19 symptoms should be
20
. t considered according to its
[45 affectin u u h
a
] l g p at o strengths and weaknesses. The
K 2 . system p e s main strength was the rigorous
a 0 2 s other o s p methodology applied for
m 2 0
a than rt d it literature search, study
0 2
l the i e a selection, screening for
1
e [ respira n p li eligibility, assessment of
t [ 2 methodological quality, and
tory g e z
a 1 8
system a n e pooling analysis of prevalence
l 7 ]
. ] P . This m di d data from more than 30
2 S e meta- u n o studies. Nevertheless, some
0 t l analysi lt g r weak-
2 a u nesses should be also recognized.
s i- o n First, a meta-regression could
0 v s not be
e o
m e et rde Stavem et al.
[ 2020 [39] 2020 [41] 2020 [45] 2020 [20]
t [16]
2 Stavem
Cirulli et al. Cirulli et al. 2020
a Jacob
9 e l et 2020 [45] [45]
s
] t [20] Logue et al. 2021
. et
2020 [28]
2
[41] Mumblit et al. 2021
0
a [46]
2 Tenfo
6 1
c udie p lence data
o s. In o separately
n fact, p by gender
d mos u [22,25];
u t of l however,
c com a they
t pari t reported
e sons i different
d sho o follow-
b wed n ups and
e larg different
c e c post-
a hete a COVID-19
u roge n symptoms
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i
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,
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e Simi w
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i
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e n p
- was o
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e no e
e conc d
n lusi
t ons p
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6 1
Fig. 2. Time course of the eight most prevalent COVID-related symptoms at onset/hospital admission and 30days, 60days and ≥90 days after.
* Statistically significant effect (P<0.001) showing a time trend during the different follow-up periods.
presence of post-COVID-19 symptoms remains unknown. Finally, into the designs since COVID-19 patients are highly active and their
post-COVID-19 symptoms were mostly self-reported by the patients point of view may be crucial for designing studies according to their
themselves and collected by telephonic interview, electronical needs [59]. Studies investigating underlying mechanisms explaining
websites, postal or face-to-face interviews (table 1). Development of post-COVID-19 symptoms are needed for better management of this
specific patient-reported outcome measures (PROM) for COVID-19 group of individuals, the long-haulers [4].
will be helpful to obtain homogeneous data. Interestingly, Tran et al.
have recently developed the long COVID Symptom and Impact Tools, 5. Conclusions
which could help for more standardized collection of post-COVID-19
symptoms [58]. This review/meta-analysis has revealed that more than 60% of in-
dividuals infected by SARS-CoV-2 exhibited at least one post-COVID-
4.3. Future research direction 19
symptom after onset or hospital admission. Fatigue and dyspnea were
This systematic review and meta-analysis investigating prevalence the most prevalent post-COVID-19 symptoms experienced by both
rates of post-COVID-19 symptoms provides updated data on the pres- hos- pitalized and non-hospitalized patients, particularly 60≥ and 90
ence of persistent post-COVID-19 symptoms in COVID-19 survivors; days after onset/ hospitalization. The prevalence rate of other post-
however, it opens several questions for future studies. First, due to the COVID-19 symptoms including headache, anosmia, ageusia, chest pain,
relapsing and remitting nature of post-COVID-19 symptoms, it is joint pain or palpitations was lower and more variable. Early
identification of post- COVID-19 symptoms will ensure immediate
important to identify those time frames where these symptoms should be
considered as residual (post-acute COVID) or as real (long-term) post- action and counselling of these “long haulers”, who may otherwise
COVID-19 symptom. In fact, time frames are important for proper struggle with unrecognized and unmanaged symptoms.
description of post-COVID-19 symptomatology [7]. For instance,
symptoms appearing soon (i.e., the first 30 days after symptoms onset) Role of the funding source
after recovery from acute infection have been considered as post-acute
sequelae of COVID-19 (PASC), whereas symptoms appearing later, i.e., No funds were received for this study
3 months or longer, after infection could be considered as the real
post-COVID-19 syndrome [7]. Second, identification of risk factors Data sharing statement
associated with post-COVID-19 symptoms is crucial. Some studies
included in this review identified, by using multivariate analyses, po- This study will not share any individual data or document from any
tential risk factors, such as older age [15,17,38], female gender [22,23, participant.
25,41,46], longer hospital stance [15], pre-existing comorbidities [17],
or number of symptoms at the acute stage [15,17] associated with a Transparency declaration
higher number of post-COVID-19 symptoms. However, contradictory
findings were also observed. For instance, whereas some studies re- The lead author affirms that the manuscript is an honest, accurate,
ported that females were more prone to exhibit post-COVID-19 symp- and transparent account of the study being reported; that no important
toms when compared with males [22,23,25,41,46], others did not find aspects of the study have been omitted; and that any discrepancies
such association with female gender [21,24,26,30,45,47]. The hetero- from the study as originally planned have been explained
geneity in the methodology between the studies could explain these
discrepancies in the results and does not permit to determine firm CRediT authorship contribution statement
conclusions. Studies investigating risk factors associated with
post-COVID-19 symptoms are urgently needed to promote focus on Ce´sar Fernańdez-de-las-Penãs: Conceptualization,
this issue in healthcare systems and, thereby, facilitate counselling and Visualization, Writing – review & editing, Data curation, Writing –
management strategies for these patients. A relevant topic for consid- original draft. Domingo Palacios-Cenã: Conceptualization,
ering in future studies would be a potential participation of the Visualization, Data curation. Víctor Go´mez-Mayordomo:
patients Conceptualization, Visualization, Data curation, Writing – original
draft. Lidiane L Florencio:
C. Fernańdez-de-las-Penãs et al. 82:378–83.
Conceptualization, Visualization, Formal analysis, Data curation,

Writing – original draft. María L. Cuadrado: Conceptualization, Visu-
alization, Formal analysis, Data curation, Writing – original draft.
Gustavo Plaza-Manzano: Conceptualization, Visualization, Writing –
review & editing, Data curation. Marcos Navarro-Santana: Conceptu-
alization, Visualization, Writing – review & editing, Formal analysis,
Data curation.
Declaration of Competing Interest
No conflict of interest is declared by any of the authors
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70
Prevalensi gejala pasca-COVID-19 pada penyitas COVID-19 yang dirawat
inap dan yang tidak dirawat inap: Tinjauan sistematis dan meta-analisis
Latar belakang : Penelitian tunggal yang mendukung kehadiran beberapa gejala

pasca COVID-19; Namun, tidak ada Penelitian meta analisis yang membedakan
pasien yang di rawat inap dan yang tidak dirawat inap yang telah di terbitkan
sampai saat ini. Meta-analisis ini menganalisis prevalensi gejala pasca-COVID-19
pada pasien yang dirawat inap dan tidak dirawat inap yang pulih dari COVID.
Metode : Database MEDLINE, CINAHL, PubMed, EMBASE, dan Web of

Science, serta medRxiv dan bioRxiv server pracetak dicari sampai dengan tanggal
15 Maret 2021. Penelitian peer-review atau pracetak yang melaporkan data
tentang gejala pasca COVID-19 yang dikumpulkan melalui wawancara pribadi,
telepon, atau elektronik dimasukkan. Kualitas metodologis Penelitian dinilai
menggunakan Skala Newcastle-Ottawa. Kami menggunakan model efek acak
untuk prevalensi gabungan meta analitik dari setiap gejala pasca-COVID-19, dan
statistik I2 untuk heterogenitas. Sintesis data dikategorikan pada 30, 60, dan 90
hari setelahnya
Hasil : Dari 15.577 Penelitian yang diidentifikasi, 29 Penelitian peer-review dan 4

pracetak memenuhi kriteria inklusi. Sampel termasuk 15.244 pasien yang dirawat
inap dan 9011 pasien yang tidak dirawat inap. Kualitas metodologis dari
kebanyakan Penelitian adalah sedang. Hasil penelitian menunjukkan bahwa 63,2%
, 71,9% dan 45,9% sampel menunjukkan satu gejala pasca-COVID-19 pada 30,
60, atau 90 hari setelah onset/rawat inap. Kelelahan dan sesak napas napas adalah
gejala yang paling umum dengan prevalensi gabungan mulai dari 35% hingga
60% tergantung pada follow up. Gejala pasca-COVID-19 lainnya termasuk batuk
(20– 25%), anosmia (10–20%), ageusia (15–20%) atau nyeri sendi (15–20%).
Analisis tren waktu menerangkan penurunan prevalensi setelah 30 hari dengan
peningkatan setelah 60 hari.
1
Kesimpulan : Meta-analisis ini menunjukkan bahwa gejala pasca-COVID-19
pada lebih dari 60% pasien yang terinfeksi oleh SARS-CoV-2. Kelelahan dan
sesak napas adalah gejala pasca-COVID-19 yang paling umum, terutama setelah
60 dan 90 hari.
1. Pendahuluan
Dunia sedang mengalami situasi dramatis dengan proporsi bencana karena

penyebaran penyakit coronavirus 2019 (COVID-19) yang cepat di seluruh dunia
yang disebabkan oleh patogen sindrom pernapasan akut coronavirus 2 (SARS-
CoV-2)1. Gejala yang terkait dengan infeksi SARS-CoV-2 bersifat heterogen dan
mempengaruhi sistem yang berbeda seperti pernapasan (batuk, sakit tenggorokan,
rinore, sesak napas), muskuloskeletal (mialgia), gastrointestinal (diare, muntah),
dan neurologis (sakit kepala, miopati, ageusia, keadaan kekurangan penciuman)2.
Dapat dipahami, sebagian besar literatur telah berkonsentrasi pada

patofisiologi potensial penyakit dan pengelolaan kasus akut pada periode rawat
inap. Akan tetapi, pandemi kedua telah muncul: gejala sisa pasca-COVID-19 dan
“long-hauler”3. Karena jutaan orang akan selamat dari infeksi SARS-CoV-2;
jumlah orang yang menderita gejala sisa COVID-19, yaitu long hauler, akan
meningkat secara dramatis seiring waktu4. Oleh karena itu, identifikasi dampak
COVID-19 akan sangat penting bagi para tenaga kesehatan.
Bukti saat ini menunjukkan adanya sejumlah besar gejala pada subjek yang
pulih dari COVID-19. Akan tetapi, literatur yang menyelidiki gejala setelah
infeksi SARS-CoV-2 masih dalam tahap awal dibandingkan dengan literatur yang
tersedia tentang fase akut COVID-19. Istilah yang berbeda saat ini digunakan
untuk menggambarkan adanya gejala pasca-COVID-19 (misalnya, sindrom pasca-
COVID-19, pasca-COVID yang persisten), menjadi "long covid" mungkin istilah
yang paling luas5. "Long COVID" digunakan untuk menggambarkan penyakit
pada orang yang telah pulih dari COVID-19 tetapi masih menunjukkan gejala jauh
lebih lama dari yang diperkirakan5. Dalam beberapa bulan terakhir, semakin
banyak penelitian yang menilai adanya gejala pasca-COVID-19 telah diterbitkan.
Faktanya, sebuah meta-analisis baru-baru ini diterbitkan sebagai pracetak 6. Meta-
analisis ini menemukan bahwa 80% penyintas COVID-19 menunjukkan
setidaknya
satu gejala pasca-COVID-19, yang paling sering yaitu kelelahan (58%), sakit
kepala (44%), gangguan perhatian (27%), rambut rontok (25%) , dan sesak napas
(24%)6. Akan tetapi, tinjauan ini mengumpulkan tingkat prevalensi tanpa
mempertimbangkan periode follow up gejala setelahnya dan tidak membedakan
antara pasien yang dirawat inap dan yang tidak dirawat di inap6. Kedua
pertimbangan ini sangat penting untuk menentukan dengan benar adanya gejala
pasca-COVID-197.
Penelitian ini menyajikan tinjauan sistematis dan meta analisis yang

mengumpulkan data prevalensi gejala pasca-COVID-19 yang membedakan antara
penyintas COVID-19 yang dirawat inap dan yang tidak dirawat inap dan
menganalisis prevalensi gejala pasca-COVID-19 pada titik waktu yang berbeda.
Pertanyaan penelitian dari tinjauan sistematis dan meta-analisis ini adalah:
bagaimana prevalensi gejala pasca COVID-19 pada individu yang sembuh dari
infeksi SARS-CoV-2?, apakah ada perbedaan pasca COVID-19 antara pasien
yang rawat inap dan yang tidak rawat inap? dan, bagaimana perjalanan waktu
gejala pasca-COVID 19 dalam beberapa bulan ke depan setelah infeksi SARS-
CoV-2?
2. Metode
Tinjauan sistematis dan meta-analisis ini mematuhi pernyataan Item Pelaporan

Pilihan untuk Tinjauan Sistematis dan Meta-Analisis (PRISMA) sebagaimana
mestinya8. Hal ini juga terdaftar secara prospektif di database Open Science
Framework Registry dengan tautan berikut https://doi.org/10.17605/OSF.IO/ESWQZ
2.1 Pencarian Literarur Sistematis
Pencarian literatur elektronik dilakukan pada database MEDLINE,

CINAHL, PubMed, EMBASE, dan Web of Science, serta pada server pracetak
medRxiv dan bioRxiv, untuk Penelitian yang diterbitkan sampai tanggal 20 Maret
2021. Kami juga menyaring daftar referensi dari makalah yang diidentifikasi.
Strategi pencarian basis data dilakukan dengan bantuan pustakawan ilmu
kesehatan yang berpengalaman. Penelusuran dibatasi pada penelitian pada
manusia dengan menggunakan istilah berikut: “long COVID syndrome”, “long
COVID symptoms”,
“lomng haul COVID”, “long hauler COVID”, “chronic COVID syndrome”,
“post-acute COVID symptoms”, “persistent COVID syndrome”, “post-COVID”,
“COVID sequale”, atau “persistent COVID symptoms”. Kriteria inklusi/eksklusi
dirumuskan dengan menggunakan pertanyaan Population, Intervention,
Comparison, Outcome (PICO):
Population: dewasa (>18 tahun), terdiagnosis positif terinfeksi SARS-

CoV- 2 dengan real-time reverse transcription-polymerase chain reaction (PCR)
assay dari sample swab nasofaring atau orofaring, selama gelombang pertama
pandemic (dari 1 Januari sampai 30 Juni 2020). Kami memasukkan pasien yang
dirawat inap dan yang tidak dirawat inap.
Intervention : tidak di lakukan
Comparison: tidak dilakukan
Outcomes : Pemantauan atau pengumpulan adanya gejala ganda pada

penyintas COVID-19 setelah infeksi SARS CoV-2, yaitu timbulnya gejala keluar
dari rumah sakit baik melalui wawancara pribadi, telepon, atau elektronik.
Penelitian yang memantau hanya perubahan dalam hasil imunologis, serologis,
atau radiologis tanpa penilaian gejala klinis pasca-COVID 19 dikeluarkan.
2.2. Proses penyaringan, pemilihan Penelitian dan ekstraksi data
Tinjauan/meta-analisis ini mempertimbangkan penelitian asli termasuk

Penelitian kohort observasional atau kasus kontrol di mana sampel orang dari
penyintas COVID-19, baik yang dirawat inap maupun yang tidak dirawat inap,
diikuti untuk mengetahui adanya gejala selama lebih dari dua minggu setelah
infeksi. Berdasarkan data dan kerangka waktu yang sudah ada sebelumnya 7, kami
memilih 30, 60 dan > 90 hari setelah timbulnya gejala sebagai titik akhir yang di
pilih untuk analis. Artikel editorial, opini dan korespodensi dikeluarkan. Dua
penulis meninjau judul dan abstrak publikasi yang diidentifikasi dalam database.
Pertama, duplikasi dihapuskan. Kedua, judul dan abstrak artikel disaring untuk
kelayakan potensial dan teks bacaan lengkap akhir. Data termasuk penulis, negara,
ukuran sampel, data klinis, pengaturan (rawat inap/tanpa rawat inap), gejala saat
onset, dan gejala pasca-COVID-19 pada periode follow up yang berbeda diambil
dari setiap penelitian. Kedua penulis harus mencapai kesepakatan tentang
ekstraksi data. Perbedaan antara pengulas pada setiap tahap proses penyaringan
diselesaikan dengan meminta penulis ketiga, jika perlu.
2.3. Kualitas Metodologis
Kualitas metodologis Penelitian dinilai secara independen oleh dua penulis

menggunakan Skala Newcastle-Ottawa, sistem peringkat berbintang yang
mengevaluasi risiko bias pada Penelitian kasus-kontrol dan Penelitian kohort 9.
Skala ini, jika diterapkan pada Penelitian kohort, mencakup bagian berikut:
pemilihan kasus, komparabilitas, dan paparan. Pemilihan kasus mencakup
keterwakilan kohort, pemilihan kohort yang tidak terpapar, kepastian paparan
(definisi kasus), dan hasil yang diinginkan tidak ada di awal. Komparabilitas
mengevaluasi analisis perbandingan (misalnya, kontrol untuk usia, jenis kelamin,
atau faktor lain) antar kelompok (terpapar dan tidak terpapar). Paparan meliputi
penilaian hasil, lamanya periode follow up, dan memadainya follow up. Pada
Penelitian kohort longitudinal atau Penelitian kasus-kontrol, maksimal 9 bintang
dapat diberikan. Pada Penelitian kohort potong lintang, maksimal 3 bintang dapat
diberikan. Penelitian dengan skor 3 dianggap berkualitas baik, skor 2 berkualitas
sedang dan Penelitian dengan skor 1 berkualitas buruk9. Kualitas metodologis dari
Penelitian yang disertakan ditentukan oleh dua penulis dan perbedaannya, jika
ada, didiskusikan. Dalam kasus ketidaksepakatan, peneliti ketiga menengahi
keputusan konsensus.
2.4. Analisis dan Sintesis Data
Meta-analisis dilakukan dengan perangkat lunak R 4.0.0 menggunakan

paket meta dan dmetar. Persentase dan frekuensi setiap gejala saat onset/rawat
inap dan setiap gejala diambil dari penelitian dan proporsi keseluruhan dihitung
dengan melaporkan proporsi tunggal menggunakan fungsi metaprop. Kami
menggunakan model efek acak karena potensi heterogenitas diharapkan. Nilai I2 >
75% dianggap menunjukkan heterogenitas yang serius. Kami tidak dapat menilai
asimetri plot corong karena jumlah penelitian yang tidak mencukupi yang
menyelidiki gejala pasca-COVID-19 yang sama pada follow up tertentu. Kami
menghitung besar skor rata-rata sampel untuk setiap penelitian melaporkan
data dengan interval
kepercayaan 95% (95% CI) sebagai tambahan efek ringkas meta-analitik potensial
pada data prevalensi yang dikumpulkan untuk setiap gejala pasca-COVID-19.
Sintesis data dikategorikan berdasarkan waktu setelah onset / rawat inap menjadi
tiga periode follow up (gejala pada 30 hari, 60 hari, dan 90 hari). Untuk
menentukan perjalanan waktu gejala pasca-COVID-19 dari waktu ke waktu (dari
awal hingga
90 hari setelahnya), transformasi busur ganda Freeman-Tukey dilakukan
menggunakan fungsi escalc dalam paket metafor. rma.mv (model efek acak
multilevel meta-analitik dengan moderator melalui model efek campuran linier)
digunakan untuk melakukan metaanalisis bertingkat dengan tiga level untuk
mengidentifikasi waktu ke waktu 'efek subkelompok'. Untuk meta-analisis studi yang
melaporkan hasil pada beberapa titik waktu, masuk akal untuk mengasumsikan bahwa
efek sebenarnya berkorelasi dari waktu ke waktu sesuai dengan struktur autoregresif; Oleh
karena itu, model heteroscedastic autoregressive (HAR) diadopsi. Pengelompokan
berdasarkan gender tidak dimungkinkan karena kurangnya data (lihat bagian diskusi).
Untuk data kuantitatif (usia, hari di rumah sakit), rata-rata keseluruhan dan
standar deviasi (SD) dihitung menggunakan fungsi pool groups dari paket dmetar.
Rentang median dan interkuartil (IQR) diubah menjadi mean dan SD seperti yang
dijelaskan oleh Luo et al10. Jika diperlukan, data diestimasi dari grafik dengan perangkat
lunak GetData Graph Digitizer v.2.26.0.20.
2.5. Peran Sumber Pendanaan
Tidak ada sumber pendanaan pada penelitian ini
2.6. Keterlibatan Pasien dan publik
Pasien tidak terlibat dalam penelitian karena ini adalah meta-analisis dari literatur.
3. Hasil
3.1. Pilihan studi
Proses seleksi ditunjukkan pada Gambar 1. Pencarian elektronik

mengidentifikasi 15.577 judul potensial. Setelah menghapus duplikat dan makalah
yang tidak terkait langsung dengan gejala pasca-COVID-19, 64 penelitian tetap
ada. Dua puluh enam (n = 26) dikeluarkan setelah pemeriksaan judul/abstrak. Satu
pracetak dikeluarkan karena menganalisis faktor risiko dan kelompok tetapi tidak
merinci gejala spesifik pasca-COVID-19[11]; satu studi dikeluarkan karena itu
adalah seri kasus12; satu lagi karena tingkat kematian, bukan gejala pasca-COVID-
19, yang dianalisis13; dan yang terakhir karena termasuk anak-anak, bukan orang
dewasa, dengan COVID-1914.
15–43 44–48
Sebanyak 29 studi yang diterbitkan dan lima pracetak medRxiv
awalnya dimasukkan dalam ulasan / meta-analisis (Gambar 1). Satu pracetak 44
dikeluarkan karena penelitian yang sama telah diterbitkan secara posterior dalam
jurnal peer-review 30. Oleh karena itu, total 29 studi peer-review15–43 dan empat
pracetak medRxiv 45–48dimasukkan dalam tinjauan sistematis dan meta-analisis.
Gambar 1. item pelaporan yang dirujuk untuk tinjauan sistematis

dan diagram alir meta-analisis (PRISMA)
3.2. Karakteristik sampel
Karakteristik populasi COVID-19 yang disertakan studi ditampilkan dalam

Tabel 1. Total sampel terdiri dari 24.255 orang penyintas COVID-19 (52,26%
perempuan; rata-rata ± SD Usia: 47.8 ± 16,6 tahun); 15.244 dirawat inap (42,7%
perempuan; usia: 48,6± 17,4) sedangkan 9011 tidak dirawat inap (70,2%
perempuan; usia: 44,3 ± 14.8). Rata-rata lama rawat inap di rumah sakit akibat
infeksi SARS-CoV-2 adalah 12,5 hari (SD 6.8). Dari mereka yang dirawat inap,
402 pasien (8%) memerlukan perawatan ICU (rata-rata rawat inap: 15± 14,6 hari).
Hampir 50% dari total sampel menunjukkan setidaknya satu komorbiditas

yang sudah ada sebelumnya (satu: 26,3%, 95% CI 25,3-28,0%; dua: 17,6%, 95%
CI 15,1-20,5%; ≥ tiga: 25,6%, 95% CI 11,4 47,8%) dengan hipertensi (22,9%, 95%
CI 16,2–31,5%) dan obesitas (22,2%, 95%CI 13,9 33,5%) menjadi yang paling
umum. Komorbiditas yang sudah ada sebelumnya, secara umum, lebih umum
pada pasien rawat inap dari pada pasien yang tidak dirawat di rumah sakit. Tabel
2 merangkum kumpulan data demografi dan klinis dari para penyintas COVID-19
yang dipisahkan oleh rawat inap. Data rawat inap dikumpulkan dari rekam medis
di semua penelitian.
Tabel 1. Karakteristik studi yang disertakan meneliti gejala pasca-COVID-19
Tabel 2. Kumpulan sarana data demografi dan klinis yang dibedakan berdasarkan
pasien rawat inap (n = 15.244) dan pasien tidak dirawat inap (n=9011) COVID-19
* Perbedaan signifikan antara pasien rawat inap dan bukan rawat inap
COVID19
3.3. Kualitas metodologis
Tiga puluh penelitian (88%) bersifat cross-sectional, hanya satu yang

berkualitas baik (3/3 bintang), 28 dianggap berkualitas sedang (2/3 bintang), dan
dua berkualitas buruk (1/3 bintang). Salah satunya adalah studi kohort
longitudinal dengan kualitas metodologi tinggi (8/9 bintang), dan dua adalah studi
kasus-kontrol dengan kualitas buruk (5/9 bintang, dengan 0 bintang dalam domain
komparatif). Tidak ada perbedaan pendapat antara penulis yang diamati. Tabel 3
menyajikan skor Skala Newcastle-Ottawa untuk setiap studi dan ringkasan setiap
item.
Tabel 3.Newcastle - skala penilaian kualitas ottawa - studi kohort/penelitian

cross- sectional penilaian kualitas
3.4. Gejala saat onset atau masuk rumah sakit yang dialami pasien COVID-19
Tabel Tambahan merangkum penelitian mana yang menilai setiap gejala

awal COVID-19 dan setiap gejala pasca-COVID-19. Enam belas studi (48,5%)
mengumpulkan data pasca-COVID-19 melalui wawancara telepon, sedangkan
sepuluh studi (30%) mengumpulkan data wawancara tatap muka.
Kumpulan data gejala saat onset dan gejala pasca COVID-19 yang dialami
oleh total sampel, termasuk pasien COVID-19 yang dirawat di rumah sakit dan
yang tidak dirawat di rumah sakit, ditampilkan pada Tabel 4. Dari total sampel,
gejala yang paling umum dialami pada infeksi SARS-CoV-2 adalah kelelahan
(63,4%), batuk (60,2%), demam (55,3%), ageusia (46,0%), anosmia (45,7%) dan
dyspnea ( 44,1%). Di antara pasien rawat inap, gejala awal yang paling umum saat
masuk rumah sakit termasuk batuk (65,2%), demam (59,45%), kelelahan (48,0%),
sesak napas (50,9%), anosmia (34,3%) dan ageusia (34,0%). Pada pasien yang
tidak dirawat di rumah sakit, gejala awal yang paling umum adalah kelelahan
(71,89%), mialgia (59%), batuk (56%), demam (52,5%), anosmia (51,9%), dan
ageusia (51,8%). Sebagian besar data yang dikumpulkan menunjukkan tingkat
heterogenitas yang tinggi (I2≥ 75%).
Menariknya, pasien yang tidak dirawat inap mengalami nyeri dada (28,0%
vs 10,1%, P = 0,008), mialgia (59,0% vs 15,6%, P = 0,004), sakit tenggorokan
(45,8% vs 5,6%, P = 0,009), anosmia (51,9% vs 34,36%, P= 0,006), ageusia (51,8%
vs 34,0%, P = 0,022), diare (36,0% vs 14,1%, P = 0,014), muntah (12,2% vs 2,7%,
P = 0,011), mual (24,16% vs 4,3%, P = 0,007), jantung berdebar (28,37% vs
7,2%, P = 0,022) dan vertigo (31,9% vs 5,74%, P = 0,045) secara signifikan lebih
sering dibandingkan pasien COVID-19 yang dirawat inap.
Tabel 4. Prevalensi gabungan gejala saat onset, dan Gejala Pasca-COVID-19 30,
60, dan ≥90 hari setelah Onset / Rawat Inap
Tabel Tambahan S1. Studi yang menyelidiki setiap gejala pasca-COVID-19 saat
onset dan pada periode follow up yang berbeda.
3.5. Gejala pasca COVID-19 yang dialami oleh penyintas COVID-19 (Total
sampel)
Sebanyak 63,2% sampel (95% CI 43,9-78,9, 7 studi, I 2: 97%) menunjukkan

satu atau lebih gejala pasca-COVID-19 30 hari setelah onset/ rawat inap, 71,9%
(95% CI 53,3–85,2, 3 studi, I2: 94%) 60 hari setelahnya, dan 45,9% (95% CI
28,2– 64,7, 7 studi, I2: 96%) ≥90 hari setelahnya. Sebagian besar perbandingan
menunjukkan heterogenitas yang serius/besar (I2 ≥75%). Proporsi yang lebih besar
dari pasien rawat inap (P = 0,003 menunjukkan satu atau lebih gejala pasca-
COVID-19 60 hari setelahnya (78,5% 95% CI 60,1–88,9) dibandingkan dengan
pasien yang tidak dirawat inap (56,2% 95% CI 48.5–63.72), tanpa perbedaan
pada 30 hari (P = 0,186) atau ≥90 hari (P=0,305) setelahnya.
Secara keseluruhan, tiga puluh hari setelah onset/rawat inap (rata-rata: 30,3
± 6.3 hari), gejala pasca COVID-19 yang paling sering adalah batuk (18,6%),
anosmia (16,5%), ageusia (15,7%), dyspnea (13,2%), kelelahan (11,7%) dan
kebingungan (8%), tanpa perbedaan yang signifikan antara pasien rawat inap dan
non rawat inap (Tabel 4).
Secara keseluruhan, enam puluh hari setelah onset atau rawat inap (rata-
rata: 60,4 ± 6,6 hari), gejala pasca COVID-19 yang paling sering adalah kelelahan
(56,2%), sesak napas (27,2%), nyeri dada (23,6%), sakit kepala (19,8%), nyeri
sendi (19%), dan batuk (18,9 %). Individu yang tidak dirawat inap menunjukkan
prevalensi yang lebih tinggi dari sakit tenggorokan (67%), sakit kepala (48%) dan
anosmia (37%) dibandingkan pasien yang dirawat inap (masing-masing 4%, 11%,
dan 11,5%), tetapi perbedaannya tidak mencapai signifikan secara statistic karena
heterogenitas dalam perbandingan (Tabel 4).
Lebih dari sembilan puluh hari setelah onset / rawat inap (rata-rata: 118,4 ±
40,0 hari), gejala pasca COVID-19 yang paling sering termasuk kelelahan
(35,3%), sesak napas (26,3%), anosmia (11%), mialgia (10,9%), nyeri sendi
(10,3%), dan ageusia (10%). Pada periode follow-up ini, pasien yang tidak dirawat
inap melaporkan prevalensi yang secara signifikan lebih tinggi dari anosmia
(15,5% vs 8,1%,P = 0,012), nyeri dada (14,9% vs 7,7%; P=0,02), dahak (10,7
vs 3,4, P =
0,002), dan vertigo (12,7% vs 4,2%, P = 0,02) dibandingkan pasien rawat inap
(Tabel 4).
3.6. Gejala pasca-COVID-19 diklasifikasikan berdasarkan kelompok:

dirawat di rumah sakit/tidak dirawat di rumah sakit
15,16,18,22–25,27,29,32–37,40–43,46,47
Dari dua puluh satu studi menyelidiki adanya
gejala pasca-COVID-19 pada pasien rawat inap, empat menganalisa gejala 30 hari
15,33,41,43
setelah keluar dari rumah sakit , sembilan menunjukkan follow-up 60 hari
15,18,24,27,29,36,37,42,47
, sedangkan sepuluh melaporkan gejala ≥90 hari setelah keluar
rumah sakit16, 22,23,25,26,33–35,40,46. Secara keseluruhan, pasien COVID-19 yang dirawat
di inap dinilai rata-rata 83,6± 48.4 setelah keluar dari rumah sakit. Di antara dua
17,19–21,26,28,30,31,38,39,45,48
belas studi dengan pasien yang tidak dirawat inap, empat
penelitian mengevaluasi gejala pasca-COVID-19 30 hari setelah onset 19,31,38,45 dua
30,45
memiliki follow-up 60 hari , sedangkan tujuh menganalisis gejala setelah ≥90
17,20,21,26,28,45,48
hari . Sampel pasien yang tidak dirawat inap dinilai rata- rata 73,9±
46,4 hari setelah timbulnya gejala.
Pada pasien rawat inap, gejala pasca-COVID-19 yang paling umum

termasuk: batuk (26,6%), ruam kulit (14%), ageusia (11,4%), anosmia (11,1%),
kebingungan (9,3%) dan sesak napas (9,2%). ) pada 30 hari setelah rawat inap;
kelelahan (53,9%), sesak napas (24,4%), nyeri sendi (22,8%), nyeri dada (21,0%),
batuk (13,8%), dan anosmia (11,5%) pada 60 hari setelah rawat inap; dan
kelelahan (38,5%), sesak napas (33,3%), batuk (10,4%), mialgia (9,7%), nyeri
sendi (9,4%) dan palpitasi (9,1%) pada ≥90 hari setelah rawat inap ( Gambar 2.).
Pada pasien yang tidak dirawat inap, gejala paling umum pasca-COVID-19
anosmia (19,9%), ageusia (18,3%), dyspnea (15,7%), batuk (13,9%), kelelahan
(11,8%), dan sakit kepala (10,9%) pada 30 hari setelah timbulnya gejala; sakit
tenggorokan (67,0%), kelelahan (63,2%), sakit kepala (48,2%), batuk (40,7%),
sesak napas (39,9%), dan anosmia (37,7%) pada 60 hari setelah timbulnya gejala;
dan kelelahan (29,8%), dyspnea (19,1%), anosmia (15,5%), nyeri dada (14,9%),
dan ageusia (13,2%) pada ≥90 hari setelah (Gambar 2.).
Gambar 2. grafik perjalanan waktu dari delapan gejala yang paling umum
dari onset / rawat inap hingga hingga 30, 60 dan ≥90 hari setelah pasien rawat
inap dan non rawat inap. Model efek acak menunjukkan efek yang signifikan
untuk waktu (semua, P<0,001) untuk gejala kelelahan, sesak napas, sakit kepala,
mialgia, batuk, anosmia dan ageusia, tetapi tidak untuk nyeri dada: gejala turun
pada 30 hari relatif terhadap baseline dan meningkat lagi pada 60 dan ≥90 hari
setelahnya. Kelompok yang signifikan *efek waktu juga ditemukan yang
menunjukkan bahwa kecenderungan ini lebih menonjol pada pasien yang dirawat
di rumah sakit daripada pasien yang tidak dirawat di rumah sakit.
Gambar 2. Perjalanan waktu dari delapan gejala terkait COVID yang

paling umum saat onset/masuk rumah sakit dan 30 hari, 60 hari, dan 90
hari setelahnya.
* Efek signifikan secara statistik (P<0,001) menunjukkan tren waktu
selama periode follow up yang berbeda.
4. Diskusi
4.1. Temuan
Tinjauan sistematis/meta-analisis ini mengungkapkan bahwa lebih dari 60%

penyintas COVID-19 menunjukkan setidaknya satu gejala pasca-COVID-19
selama lebih dari 30 hari setelah onset atau rawat inap. Prevalensi setiap gejala
dalam isolasi adalah 10-15% pada 30 hari dan 40-60% pada 60 hari atau lebih
setelah onset / rawat inap (Gambar 2.). Kelelahan dan sesak napas adalah gejala
pasca-COVID-19 yang paling umum pada pasien rawat inap dan non-rumah sakit,
terutama pada usia 60 dan≥90 hari follow-up, sedangkan prevalensi gejala lain,
misalnya sakit kepala, anosmia, ageusia, nyeri dada, atau palpitasi, lebih rendah
dan sangat bervariasi.
Meta-analisis pracetak oleh Lopez-Leon et al. mengamati bahwa kelelahan,

sakit kepala, gangguan perhatian, rambut rontok, atau sesak napas adalah gejala
pasca-COVID-19 yang paling sering6. Mereka melaporkan prevalensi keseluruhan
gejala pasca-COVID-19 tanpa perbedaan antara pasien yang dirawat inap/tidak
dirawat inap atau mempertimbangkan periode follow-up6; oleh karena itu,
perbandingan antara tingkat prevalensi tidak layak. Tinjauan sistematis lainnya
telah melaporkan bahwa gejala sisa utama pasca-COVID-19 adalah kelelahan
pasca-infeksi, penurunan fungsi paru-paru yang persisten, dan karditis; akan
tetapi, ulasan ini tidak mengumpulkan data tentang gejala pasca-COVID karena
berfokus pada gangguan fungsional49. Meta-analisis lain melaporkan bahwa gejala
pernapasan pasca-COVID-19 yang paling umum dilaporkan oleh pasien COVID-
19 yang dirawat inap termasuk kelelahan, sesak napas, nyeri dada, dan batuk yang
menunjukkan tingkat prevalensi masing-masing 52%, 37%, 16% dan 14%. antara
3 minggu dan 3 bulan setelah keluar dari rumah sakit 50. Data prevalensi ini serupa
dengan kumpulan data kami yang diamati pada 60 hari follow-up; akan tetapi,
Cares-Marambio et al.50 mengumpulkan studi tanpa perbedaan pada periode
follow up. Tinjauan / meta-analisis sistematis kami memeriksa prevalensi gejala
pasca- COVID-19 dengan mempertimbangkan apakah pasien dirawat di rumah
sakit atau
tidak dan juga dipisahkan oleh periode follow-up. Kami dapat mengidentifikasi 29
studi peer-review serta empat pracetak medRxiv yang menyediakan data
prevalensi gejala pasca-COVID-19 dari penyintas COVID-19 yang dirawat inap
dan yang tidak dirawat inap pada periode follow-up yang berbeda; jumlah studi
tertinggi yang dikumpulkan hingga saat ini; namun, sebagian besar penelitian
memiliki kualitas metodologis yang sedang dan juga menunjukkan heterogenitas
yang tinggi dalam hasil mereka. Namun demikian, perlu dicatat bahwa semakin
banyak penelitian yang menilai gejala pasca-COVID-19 akan diterbitkan dan
meta-analisis yang diperbarui di masa depan akan diperlukan.
Gejala yang paling umum dialami oleh pasien saat onset/rawat inap dalam
sampel keseluruhan adalah kelelahan, batuk, demam, ageusia, anosmia dan sesak
napas sesuai dengan meta-analisis sebelumnya yang menunjukkan gejala serupa
pada infeksi SARS-CoV-251. Namun demikian, beberapa perbedaan dalam tingkat
prevalensi dapat ditemukan. Dibandingkan dengan meta-analisis saat ini,
Alimohamadi et al. menemukan prevalensi batuk yang sama (58,5%), tetapi
prevalensi demam lebih tinggi (81,2%) dan tingkat kelelahan yang lebih rendah
(38,5%)51. Ada bukti jelas yang mendukung bahwa manifestasi klinis COVID-19
sangat heterogen.
Temuan yang relevan adalah bahwa gejala pasca-COVID-19 yang dialami

30 hari setelah onset/rawat inap menurun drastis dalam prevalensi dibandingkan
dengan fase akut tetapi meningkat 60 hari setelahnya (Gambar 2.). Alasan dari
temuan ini masih belum diketahui dan perlu dikonfirmasi dalam studi longitudinal
yang dirancang dengan baik; akan tetapi, perlu dicatat bahwa sebagian besar data
prevalensi didasarkan pada sejumlah kecil studi dan perbandingan memiliki
heterogenitas yang besar. Faktanya, penelitian yang dilakukan di Eropa
melaporkan tingkat prevalensi kelelahan yang lebih tinggi (50-70%) atau sesak
napas (30-40%) sebagai gejala pasca-COVID-1915–18,20,27,37, 40–42
sedangkan
penelitian Cina melaporkan, secara umum, tingkat prevalensi yang lebih rendah
dari gejala-gejala ini (12-20%)22,23,32,43. Faktor-faktor seperti usia yang lebih muda
dan komorbiditas medis yang sudah ada sebelumnya dalam penelitian di Cina
dapat menjelaskan perbedaan ini; namun, besarnya tingkat prevalensi yang
berbeda ini akan menyarankan faktor lain yang relevan misalnya, perbedaan
ras52 atau golongan
darah53. Studi masa depan yang menyelidiki epidemiologi gejala pasca-COVID-19
yang memperhatikan faktor-faktor ini diperlukan.
Terjadinya gejala pernapasan setelah infeksi SARS-CoV-2 mirip dengan

yang ada pada penderita sindrom pernapasan akut berat (SARS), yang juga
menunjukkan gejala 6-12 bulan setelah infeksi54. tetapi kontras dengan yang
diamati setelah pneumonia bakteri komunitas yang didapat di mana hampir semua
pasien tidak menunjukkan gejala 10 hari setelah infeksi55. Selain itu, perbedaan
utama antara SARS-CoV-2 dan penyakit menular pernapasan lainnya adalah
adanya sejumlah besar gejala pasca-infeksi, misalnya nyeri sendi, ageusia,
anosmia, nyeri dada, mual, sakit kepala atau palpitasi, yang mempengaruhi system
organ lain daripada sistem pernapasan. Meta-analisis ini mengkonfirmasi adanya
beberapa gejala pasca-COVID-19 yang mendukung keterlibatan multisistem; itu
juga menunjukkan bahwa perjalanan waktu gejala berfluktuasi tergantung pada
periode follow-up dan apakah pasien COVID-19 dirawat di rumah sakit atau tidak.
Pertimbangan ini sangat penting untuk menentukan jangka waktu gejala pasca-
COVID-19 dengan benar7.
Untuk menentukan mekanisme yang mendasari di balik gejala-gejala ini

berada di luar cakupan tinjauan saat ini, tetapi dua hipotesis utama saat ini
dibahas, meskipun tidak sendiri. Pertama, respons proinflamasi yang
berkepanjangan (badai sitokin hiperinflamasi) terkait terhadap infeksi SARS-
CoV-2 dapat memicu respons atipikal dari sistem kekebalan dan sel mast,
mendorong serangkaian kejadian yang memengaruhi sistem pernapasan,
kekebalan, dan sistem saraf pusat56. Kedua, faktor sosial dan emosional di sekitar
pandemi COVID-19, misalnya stres pasca trauma, rawat inap, perawatan yang
diterima, alarm sosial bencana, lockdown, situasi kerja dan keluarga, dan
gangguan psikologis, seperti kecemasan atau depresi, dapat berkontribusi pada
gejala pasca-COVID-19 ini.
Meskipun penjelasan mekanisme yang mendasari sejumlah besar gejala ini

tidak diketahui, kompleksitas dan heterogenitasnya mendukung bahwa sequalae
pasca-COVID-19 akan diperlukan dari pendekatan multidisiplin57.
4.2. Kekuatan dan kelemahan ulasan
Hasil tinjauan dan meta-analisis ini yang merangkum tingkat prevalensi

gejala pasca-COVID-19 harus dipertimbangkan sesuai dengan kekuatan dan
kelemahan. Kekuatan utama adalah metodologi ketat yang diterapkan untuk
pencarian literatur, pemilihan studi, penyaringan untuk kelayakan, penilaian
kualitas metodologi, dan pengumpulan analisis data prevalensi dari lebih dari 30
studi. Namun demikian, beberapa kelemahan juga harus diakui. Pertama, meta-
regresi tidak dapat dilakukan karena adanya heterogenitas yang serius/besar antara
studi. Bahkan, sebagian besar perbandingan menunjukkan heterogenitas yang
besar. Kedua, sejumlah kecil studi dalam beberapa perbandingan membatasi hasil
umum saat ini. Demikian pula, jumlah pasien yang membutuhkan rawat inap ICU
kecil, sehingga tidak ada kesimpulan mengenai populasi ini yang dapat dicapai.
Ketiga, hanya dua penelitian yang melaporkan prevalensi data secara terpisah
menurut jenis kelamin22,25; namun, mereka melaporkan follow-up yang berbeda
dan gejala pasca-COVID-19 yang berbeda; oleh karena itu, perbedaan gender
tidak mungkin untuk dianalisis. Keempat, sebagian besar penelitian termasuk
subyek Kaukasia, dengan hanya empat termasuk orang Cina dan tidak ada yang
termasuk orang Afrika; oleh karena itu, pengaruh ras pada keberadaan gejala
pasca-COVID-
19 masih belum diketahui. Akhirnya, gejala pasca-COVID-19 sebagian besar
dilaporkan oleh pasien sendiri dan dikumpulkan melalui wawancara telepon, situs
web elektronik, wawancara pos atau tatap muka (Tabel 1). Pengembangan ukuran
hasil yang dilaporkan pasien (PROM) spesifik untuk COVID-19 akan membantu
untuk mendapatkan data yang homogen. Menariknya, Tran et al. baru-baru ini
mengembangkan Alat Gejala dan Dampak long-COVID, yang dapat membantu
pengumpulan gejala pasca-COVID-19 yang lebih terstandarisasi58.
4.3. Arah penelitian masa depan
Tinjauan sistematis dan meta-analisis yang menyelidiki tingkat prevalensi

gejala pasca-COVID-19 ini memberikan data terbaru tentang adanya gejala pasca-
COVID-19 yang persisten pada penyintas COVID-19; Namun, ini membuka
beberapa pertanyaan untuk studi masa depan. Pertama, karena gejala pasca-
COVID-19 yang kambuh dan mereda, penting untuk mengidentifikasi kerangka
waktu di mana gejala-gejala ini harus dianggap sebagai gejala sisa (pasca-akut)
atau sebagai nyata (jangka panjang) gejala pasca-COVID-19. Faktanya, kerangka
waktu penting untuk deskripsi simtomatologi pasca-COVID-19 yang tepat 7.
Misalnya, gejala yang muncul segera (yaitu, 30 hari pertama setelah timbulnya
gejala) setelah pemulihan dari infeksi akut telah dianggap sebagai gejala sisa
pasca-akut COVID- 19 (PASC), sedangkan gejala yang muncul kemudian, yaitu,
3 bulan atau lebih, setelah infeksi dapat dianggap sebagai sindrom pasca-COVID-
19 yang sebenarnya7. Kedua, identifikasi faktor risiko yang terkait dengan gejala
pasca- COVID-19 sangat penting. Beberapa penelitian yang termasuk dalam
tinjauan ini mengidentifikasi, dengan menggunakan analisis multivariat, faktor
15,17,38 22,23, 25,41,46
risiko potensial, seperti usia yang lebih tua , jenis kelamin wanita ,
lama masa rawat rumah sakit 15, komorbiditas yang sudah ada sebelumnya17, atau
jumlah gejala pada stadium akut15,17 terkait dengan jumlah gejala pasca-COVID-
19 yang lebih tinggi. Namun, temuan yang bertentangan juga diamati. Misalnya,
beberapa penelitian melaporkan bahwa perempuan lebih rentan menunjukkan
22,23,25,41,46
gejala pasca-COVID-19 jika dibandingkan dengan laki-laki , yang lain
tidak menemukan hubungan seperti itu dengan jenis kelamin perempuan
21,24,26,30,45,47
. Heterogenitas dalam metodologi antara studi bisa menjelaskan
perbedaan ini dalam hasil dan tidak memungkinkan untuk menentukan kesimpulan
tegas. Studi yang menyelidiki faktor risiko yang terkait dengan gejala pasca-
COVID-19 sangat diperlukan untuk mempromosikan fokus pada masalah ini
dalam sistem perawatan kesehatan dan, dengan demikian, memfasilitasi strategi
konseling dan manajemen untuk pasien ini. Topik yang relevan untuk
dipertimbangkan dalam studi masa depan akan menjadi partisipasi potensial dari
pasien ke dalam desain karena pasien COVID-19 sangat aktif dan sudut pandang
mereka mungkin penting untuk merancang studi sesuai dengan kebutuhan
mereka59. Studi yang menyelidiki mekanisme mendasar yang menjelaskan gejala
pasca-COVID-19 diperlukan untuk manajemen yang lebih baik dari kelompok
individu ini, long haulers4.
5. Kesimpulan
Tinjauan/meta-analisis ini mengungkapkan bahwa lebih dari 60% orang

yang terinfeksi SARS-CoV-2 menunjukkan setidaknya satu gejala pasca-COVID-
19 setelah onset atau masuk rumah sakit. Kelelahan dan sesak napas adalah gejala
pasca-COVID-19 yang paling umum dialami oleh pasien rawat inap dan tidak
dirawat inap, terutama 60 dan≥90 hari setelah onset / rawat inap. Tingkat
prevalensi gejala pasca COVID-19 lainnya termasuk sakit kepala, anosmia,
ageusia, nyeri dada, nyeri sendi, atau palpitasi lebih rendah dan lebih bervariasi.
Identifikasi dini gejala pasca-COVID-19 akan memastikan tindakan dan konseling
segera dari “long haulers” ini, yang mungkin berjuang dengan gejala yang tidak
dikenali dan tidak dikelola.
PICO
Population 24.255 COVID-19 survivor (15,244 in hospitalized and

9,011 non-hospitalized, adult (>18 years), positively
diagnosed of SARS-CoV2 infection with real-time PCR
during the first wave of the pandemic ( January 1 to June
30, 2020)
Intervention Not applicable
Comparison Hospitalized and non-hospitalized COVID-19 Survivors
at 30, 60, 90 days after onset/hospitalized
Outcomes Collection of the presence of multiple symptoms of
COVID-19 survivors in hospitalized and non-hospitalized
after SARS CoV-2 Infection at 30, 60, 90 days after
onset/hospitalized
CRITICAL APPRAISAL
DOES THIS REVIEW ADDRESS A CLEAR QUESTION?
1. Did the review address a clearly focussed issue? Yes Can’t No

tell
Was there enough information on: ·
- The population studied √
- The intervention given √
- The outcomes considered √
2. Did the authors look for the appropriate sort of
papers?
The ‘best sort of studies’ would?

- Address the review’s question √
- Have an appropriate study design √
ARE THE RESULTS OF THIS REVIEW VALID?
3. Do you think the important, relevant studies Yes Can’t No

were included? tell
Look for
- Which bibliographic databases were used √
- Follow up from reference lists √
- Personal contact with experts √
- Search for unpublished as well as published
studies √
- Search for non-English language studies √
4. Did the review’s authors do enough to assess the √
quality of the included studies?
The authors need to consider the rigour of the
studies they have identified. Lack of rigour may
affect the studies results
5. If the results of the review have been combined,
was it reasonable to do so?
Consider whether
- The results were similar from study to study √
- The results of all the included studies are √
clearly displayed
- The results of the different studies are similar √
- The reasons for any variations are discussed √
WHAT ARE THE RESULTS ?
6. What is the overall result of There is one or more post covid-19 symptoms
the review? in 30 days, 60 days, and > 90 days after
onset/ hospitalized
7. How precise are the results ? YES
Are the results presented with Total 63.2% of sample (95% CI 43.9-78.9, I2
confidence intervals? = 97%) exhibited one or more post-covid-19
symptoms in 30 days after onset, 71.9% (95%
CI 53.3-85.2, I2 = 94) 60 days after, and
45,9% (95% CI = 28,2 -64,7, I2 = 96%) > 90
days after. A greater proportion of
hospitalized patients (P= 0.003) showed one
or more 60 days after onset (78,5% CI : 60.1
– 88.9) as compered to non-hospitalized
patients (56,2% CI : 48,5 -63,72), and
without differences at 30 days (p : 0,186) or
> 90 days (p = 0.305) after onset
WILL THE RESULTS HELP LOCALLY?
Yes Can’t No
8. Can the results be applied to the local tell
population?
Consider whether
- The patients covered by the review could √
be sufficiently
- Your local setting is likely to differ much
from that of of the review √
9. were all important outcomes considered? √
10. Are the benefits worth the harms and costs? √
Even if this is not addressed by the review,
what do you think?

Journal Reading Oleh Paishal Mizan

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Kepada

YTH: dr. Vesri Yoga,

Prevalence of Post-COVID-19 Symptoms in

Nama : dr. Paishal Mizan

Program Studi Pendidikan Dokter Spesialis I

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Prevalence of post-COVID-19 symptoms in hospitalized and

This systematic review and meta-analysis adheres to the Preferred

2.1. Systematic literature search

Electronic literature searches were conducted on MEDLINE,

dyspnea (13.2%), fatigue I

COPD: Chronic Obstructive 3.5. Post-COVID-19

Non- response rate

Same method for cases and controls

7. 48.3; 76.2 3.1; 1.9;25.3 1

95%CI 8.0; 30.9 3.5; 5.8; 6.7; 13.1

prevalence rates of these 24.5% 39.9% 14.4;

NH Event l 2,556 25 8 25 2,2 9

Supplementary Table S1 Supplementary Table S1 (continued )

(continued on next page)

Supplementary Table S1 (continued ) Supplementary Table S1 (continued )

Conceptualization, Visualization, Formal analysis, Data curation,

Declaration of Competing Interest

No conflict of interest is declared by any of the authors

Latar belakang : Penelitian tunggal yang mendukung kehadiran beberapa gejala

Metode : Database MEDLINE, CINAHL, PubMed, EMBASE, dan Web of

Hasil : Dari 15.577 Penelitian yang diidentifikasi, 29 Penelitian peer-review dan 4

Dunia sedang mengalami situasi dramatis dengan proporsi bencana karena

Dapat dipahami, sebagian besar literatur telah berkonsentrasi pada

Penelitian ini menyajikan tinjauan sistematis dan meta analisis yang

Tinjauan sistematis dan meta-analisis ini mematuhi pernyataan Item Pelaporan

2.1 Pencarian Literarur Sistematis

Pencarian literatur elektronik dilakukan pada database MEDLINE,

Population: dewasa (>18 tahun), terdiagnosis positif terinfeksi SARS-

Intervention : tidak di lakukan

Comparison: tidak dilakukan

Outcomes : Pemantauan atau pengumpulan adanya gejala ganda pada

2.2. Proses penyaringan, pemilihan Penelitian dan ekstraksi data

Tinjauan/meta-analisis ini mempertimbangkan penelitian asli termasuk

2.3. Kualitas Metodologis

Kualitas metodologis Penelitian dinilai secara independen oleh dua penulis

2.4. Analisis dan Sintesis Data

Meta-analisis dilakukan dengan perangkat lunak R 4.0.0 menggunakan

2.5. Peran Sumber Pendanaan

Tidak ada sumber pendanaan pada penelitian ini

2.6. Keterlibatan Pasien dan publik

3.1. Pilihan studi

Proses seleksi ditunjukkan pada Gambar 1. Pencarian elektronik

Gambar 1. item pelaporan yang dirujuk untuk tinjauan sistematis

Karakteristik populasi COVID-19 yang disertakan studi ditampilkan dalam

Hampir 50% dari total sampel menunjukkan setidaknya satu komorbiditas

3.3. Kualitas metodologis

Tiga puluh penelitian (88%) bersifat cross-sectional, hanya satu yang

Tabel 3.Newcastle - skala penilaian kualitas ottawa - studi kohort/penelitian

Tabel Tambahan merangkum penelitian mana yang menilai setiap gejala

Sebanyak 63,2% sampel (95% CI 43,9-78,9, 7 studi, I 2: 97%) menunjukkan

3.6. Gejala pasca-COVID-19 diklasifikasikan berdasarkan kelompok:

Pada pasien rawat inap, gejala pasca-COVID-19 yang paling umum

Gambar 2. Perjalanan waktu dari delapan gejala terkait COVID yang

Tinjauan sistematis/meta-analisis ini mengungkapkan bahwa lebih dari 60%

Meta-analisis pracetak oleh Lopez-Leon et al. mengamati bahwa kelelahan,