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\begin{document}

\title{Impact of long-COVID on health-related quality of life in Japanese
COVID-19 patients}



\author[1]{Shinya Tsuzuki}%
\author[1]{Yusuke Miyazato}%
\author[1]{Mari Terada}%
\author[1]{Shinichiro Morioka}%
\author[1]{Norio Ohmagari}%
\author[2]{Philippe Beutels}%
\affil[1]{National Center for Global Health and Medicine}%
\affil[2]{University of Antwerp Faculty of Medicine and Health Sciences}%


\vspace{-1em}



  
  \date{May 20, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: The empirical basis for a quantitative assessment of the
disease burden imposed by long-COVID is currently scant. We aimed to
assess the disease burden caused by long-COVID in Japan. Methods: We
conducted a cross sectional self-report questionnaire survey. The
questionnaire was mailed to 530 eligible patients, who were recovered
from acute COVID-19 in April 2021. Answers were classified into two
groups; participants who have no symptom and those who have any ongoing
symptoms that lasted longer than four weeks at the time of the survey.
We compared health-related quality of life scores estimated by the
EQ-5D-3L questionnaire between these two groups after adjusting basic
characteristics of the participants by propensity score matching.
Results: 349 participants reported no symptoms and 108 reported any
symptoms at the time of the survey. The participants who reported any
symptoms showed a lower value on a Visual Analogue Scale (median 70
{[}IQR 60-80{]}) and on the EQ-5D-3L (median 0.81 {[}IQR 0.77-1.0{]})
than those reporting no symptoms (median 85 {[}IQR 75-90{]} and 1.0
{[}IQR 1.0-1.0{]}, respectively). After adjusting for background
characteristics, these trends did not change substantially (Visual
Analog Scale: median 70 {[}IQR 60-80{]} vs 80 {[}IQR 77-90{]}, EQ-5D-3L:
median 0.81 {[}IQR 0.76-1.0{]} vs 1.0 {[}IQR 1.0-1.0{]}). Conclusions:
Due to their long duration, long-COVID symptoms represent a substantial
disease burden expressed in impact on health-related quality of life.%
\end{abstract}%



\sloppy


Title: Impact of long-COVID on health-related quality of life in
Japanese COVID-19 patients

Running title: HRQOL of long-COVID

Shinya Tsuzuki, MD, MSc\textsuperscript{1,2*}; Yusuke Miyazato,
MD\textsuperscript{3}; Mari Terada, MPH\textsuperscript{3,4}, Shinichiro
Morioka, MD\textsuperscript{3}; Norio Ohmagari, MD,
PhD\textsuperscript{1,3}; Philippe Beutels, PhD\textsuperscript{2}

\textsuperscript{1} AMR Clinical Reference Center, National Center for
Global Health and Medicine, Tokyo, Japan

\textsuperscript{2} Faculty of Medicine and Health Sciences, University
of Antwerp, Antwerp, Belgium

\textsuperscript{3} Disease Control and Prevention Center, National
Center for Global Health and Medicine, Tokyo, Japan

\textsuperscript{4} Center for Clinical Sciences, National Center for
Global Health and Medicine, Tokyo, Japan

*Corresponding author: Shinya Tsuzuki, MD, MSc

National Center for Global Health and Medicine

1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan

Tel: +81(0)3-3202-7181

Email:\emph{stsuzuki@hosp.ncgm.go.jp}

\textbf{Abstract}

\textbf{Background:} The empirical basis for a quantitative assessment
of the disease burden imposed by long-COVID is currently scant. We aimed
to assess the disease burden caused by long-COVID in Japan.

\textbf{Methods:} We conducted a cross sectional self-report
questionnaire survey. The questionnaire was mailed to 530 eligible
patients, who were recovered from acute COVID-19 in April 2021. Answers
were classified into two groups; participants who have no symptom and
those who have any ongoing symptoms that lasted longer than four weeks
at the time of the survey. We compared health-related quality of life
scores estimated by the EQ-5D-3L questionnaire between these two groups
after adjusting basic characteristics of the participants by propensity
score matching.

\textbf{Results:} 349 participants reported no symptoms and 108 reported
any symptoms at the time of the survey. The participants who reported
any symptoms showed a lower value on a Visual Analogue Scale (median 70
{[}IQR 60-80{]}) and on the EQ-5D-3L (median 0.81 {[}IQR 0.77-1.0{]})
than those reporting no symptoms (median 85 {[}IQR 75-90{]} and 1.0
{[}IQR 1.0-1.0{]}, respectively). After adjusting for background
characteristics, these trends did not change substantially (Visual
Analog Scale: median 70 {[}IQR 60-80{]} vs 80 {[}IQR 77-90{]}, EQ-5D-3L:
median 0.81 {[}IQR 0.76-1.0{]} vs 1.0 {[}IQR 1.0-1.0{]}).

\textbf{Conclusions:} Due to their long duration, long-COVID symptoms
represent a substantial disease burden expressed in impact on
health-related quality of life.

Keywords: COVID-19; disease burden; Quality of life; long-COVID

Word count: 3,001

\textbf{Acknowledgment}

We thank all the people who participated in our survey and study,
``Collection and antibody measurement of Convalescent plasma foreseeing
the use for COVID-19 treatment''.

\textbf{Author contributions}

Shinya Tsuzuki: Conceptualization, Funding Acquisition, Data Curation,
Formal Analysis, Methodology, Visualization, Original Draft Preparation.
Yusuke Miyazato: Data Curation, Review and Editing. Mari Terada: Data
Curation, Review and Editing. Shinichiro Morioka: Data Curation, Project
Administration, Review and Editing. Norio Ohmagari: Conceptualization,
Funding Acquisition, Project Administration, Review and Editing.
Philippe Beutels: Supervision, Project Administration, Review \&
Editing.

\textbf{Data availability}

The data that support the findings of this study are available upon
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

\textbf{Funding}

This research was funded by JSPS KAKENHI {[}Grant number 18K17369{]}, a
grant for the National Center for Global Health and Medicine
{[}20A05{]}, AMED under Grant Number JP20fk0108502 and the Health and
Labour Sciences Research Grant, ``Research for risk assessment and
implementation of crisis management functions for emerging and
re-emerging infectious diseases.''

\textbf{Conflict of interest}

PB reports grants from the EU's SC1-PHE-CORONAVIRUS-2020 programme,
Pfizer, GlaxoSmithKlein, and European Commission IMI, unrelated to
this~work.

\textbf{Ethics approval}

This study was reviewed and approved by the Ethics Committee of the
Center Hospital of the NCGM (NCGM-G-004121-00)

\textbf{Patient consent}

According to local ethical guidelines, responses to questionnaire were
regarded as patient consent.

\textbf{Permission to reproduce material from other sources}

Not applicable.

\textbf{Introduction}

Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus, has
become a global health threat.\textsuperscript{1} Not only its acute
phase of disease, but so-called ``long-COVID'' is also a cause of
substantial disease burden.\textsuperscript{2,3} A systematic review
reported that 80\% of patients developed one or more long-term symptoms
and the prevalence of 55 long-term effects of
COVID-19.\textsuperscript{4}

There is no clear definition of long-COVID so far, however, the National
Institute for Health and Care Excellence (NICE) in The UK defined it as
``signs and symptoms that develop during or following an infection
consistent with covid-19 and which continue for more than four weeks and
are not explained by an alternative diagnosis''.\textsuperscript{5} This
term includes ongoing symptomatic COVID-19, from four to 12 weeks
post-infection, and post-COVID-19 syndrome, beyond 12 weeks
post-infection.\textsuperscript{6}

The symptoms of long-COVID are various and often different from the
acute phase of COVID-19. Miyazato and colleagues reported that the mean
time from COVID-19 symptom onset to the emergence of alopecia was 58.6
days and one of patients presented dysosmia after 92 days after symptom
onset.\textsuperscript{7} Other symptoms such as general
fatigue,\textsuperscript{8,9} respiratory
symptoms,\textsuperscript{10,11} cognitive and mental health
disorder,\textsuperscript{12,13} and so forth\textsuperscript{14,15}have
been reported as long-COVID.

Considering its chronic phase, the disease burden of COVID-19 should be
larger than that of other respiratory infections due to length and
variety of the symptoms. However, the empirical basis for a quantitative
assessment of the disease burden imposed by long-COVID is currently
scant. An important element towards disease burden assessment is
health-related quality of life impact. The objective of the present
study is to collect and analyse empirical information on the
health-related quality of life (HRQoL) due to long-COVID.

\textbf{Methods}

\textbf{Settings}

We conducted a survey in which a self-report questionnaire was mailed to
eligible patients who had recovered from COVID-19 in April 2021 with two
reminders 2 weeks and 1 month later. Potential participants were
recruited from patients who had recovered from COVID-19 and visited the
outpatient service of the Disease Control and Prevention Center (DCC) in
the NCGM in order to obtain pre-donation screening test for COVID-19
convalescent plasmapheresis (Another study named ``Collection and
antibody measurement of Convalescent plasma foreseeing the use for
COVID-19 treatment''). 530 patients who had recovered from COVID-19 (70
out of 448 needs supplementary oxygen support) and visited the
outpatient service of the Disease Control and Prevention Center (DCC) in
National Center for Global Health and Medicine (NCGM), Tokyo, Japan from
1\textsuperscript{st} February 2020 to 31\textsuperscript{st} March
2021. Participation in the survey was voluntary and not anonymous.
Participants were requested to complete and return the questionnaire.
457 of 530 (86.2\%) patients completely answered the questionnaire and
were included in the analysis.

\textbf{Statistical analysis}

Answers were classified into two groups; participants who have no
symptom and those who have any ongoing symptoms that lasted longer than
four weeks at the time of the survey. We compared visual analogue scale
(VAS) and HRQoL values estimated by the EQ-5D-3L
questionnaire\textsuperscript{16} by Japanese value
set\textsuperscript{17} between two groups using Mann-Whitney U test,
after adjusting basic characteristics of the participants by one-to-one
propensity score matching (nearest neighbour pair matching, caliper =
0.2) calculated by multivariate logistic regression model predicting the
likelihood of having ongoing symptoms.\textsuperscript{18,19} We
included age, sex, BMI, smoking, drinking, hypertension, diabetes,
chronic obstructive lung diseases, malignancy, use of antivirals, use of
systemic steroids, and severe COVID-19 disease during admission (use of
mechanical ventilation or extracorporeal membrane oxygenation during
admission, according to the definition by a report of national registry
data in Japan\textsuperscript{20}). The standardized mean difference was
used to measure covariate balance, and an absolute standardized
difference above 20\% was interpreted as a meaningful imbalance.
Two-sided p values of \textless{}0.05 were considered to show
statistical significance. All analyses were conducted by R, version
4.0.5.\textsuperscript{21}

\textbf{Ethics approval}

According to local ethical guidelines, responses to questionnaire were
regarded as patient consent. This study was reviewed and approved by the
Ethics Committee of the Center Hospital of the NCGM (NCGM-G-004121-00).

\textbf{Results}

Table 1 shows the basic characteristics of the participants. 457
patients recovered from acute phase of COVID-19 and 108 of them
presented at least one symptom. The proportion of female was larger in
``Any symptom'' group than that in ``No symptom'' group. There was no
substantial difference between the two groups in terms of their age and
medical history. Crude comparison of VAS and QOL showed that ``Any
symptom'' group had lower VAS and QOL values than the ``No symptom''
group did (VAS: 70 vs 85, QOL: 0.81 vs 1.0, respectively).

(Table 1)

Table 2 describes the characteristics of the data after propensity score
matching. 91 pairs included in the matched data and 17 of ``Any
symptom'' group were discarded. Adjusted comparison of VAS and QOL
showed a similar trend to the results of crude comparison. Both VAS and
QOL were lower in the ``Any symptom'' group (VAS: 70 vs 80, QOL: 0.81 vs
1.0, respectively).

(Table 2)

Table 3 describes the characteristics of ``long-COVID'' symptoms. We
defined ``long-COVID'' as the status in which any symptoms attributed to
SARS-nCoV-2 infection lasting more than four weeks in the present study.
201 of 457 (44.0\%) participants reported at least one symptom after
four weeks have passed since their symptom onset due to COVID-19. The
most common symptom of long-COVID was general fatigue. 58 of 457
(12.7\%) participants have had general fatigue longer than four weeks.
The second most common symptom was alopecia. 55 of 457 (12.0\%)
participants have experienced hair loss worse than usual.

(Table 3)

Figure 1 and 2 show a violin plot of VAS and QOL value, respectively.
The ``Any symptom'' group showed greater variance in both indicators.

(Figure 1)

(Figure 2)

\textbf{Discussion}

The present study demonstrated that the phenomenon we called
``long-COVID'' can impair the HRQOL substantially. This would be another
important aspect of COVID-19 to consider because it implies a heavier
disease burden to us than other influenza like illnesses (ILIs) do, not
only due to its severity but also the characteristics of its chronic
phase. In the first place, COVID-19 showed higher case-fatality than
other ILIs.\textsuperscript{22--24} Additionally, it might cause a
substantial burden through accumulated mild disease only.

Furthermore, the frequency and the duration of symptoms due to
``long-COVID'' are also noteworthy. Our results showed that nearly half
of the patients who recovered from acute COVID-19 (201/457) experienced
any symptoms lasting more than four weeks. As for patients who required
supplementary oxygen support, 32 out of 70 (45.7\%) presented any
symptoms longer than four weeks. The precise duration of such symptoms
was not obvious because more than 100 participants reported that their
symptoms were still ongoing, nevertheless, we can say that the symptoms
attributed to ``long-COVID'' often continue several months. Albeit the
HRQOL value of the participants who have any ``long-COVID'' symptoms was
higher than that of the acute phase of other ILIs reported by a previous
study in Japan (0.81 vs 0.66, respectively)\textsuperscript{25}, QOL
lost attributed to ``long-COVID'' should be greater than that due to the
acute phase of other ILIs because of its duration.

These results suggest that prevention is more important in COVID-19
countermeasures than other ILIs because effective treatment of
``long-COVID'' is not clearly established
yet.\textsuperscript{6,26}Although there is no doubt that vaccination
against SARS-CoV-2 will reduce the risk of fatal and severe
COVID-19,\textsuperscript{27--29}its effectiveness against
``long-COVID'' is not demonstrated yet. This may provide an additional
incentive to prevent SARS-CoV-2 infection even in the absence of known
risk factors of severe illness.

There are several limitations in our study. First, our results are based
on the questionnaire survey then there are some recall biases in
participants' responses. . Similarly, the potential participants were
enrolled from the visitors of outpatient department at the national
center hospital of infectious diseases in Japan, then the study
population might be influenced by selection biases. In addition, we
could not take ``new variants'' into consideration. The difference in
severity, infectiousness, and so forth between such new variants and old
ones were already reported,\textsuperscript{30--32} however, there is no
solid evidence about the frequency and the severity of ``long-COVID''
symptoms in new variants. This should be the subject of future study.

In addition, we should be careful about the representativeness of the
data when we interpret the results because our survey includes a
comparatively small number of participants from Japan. However, the
response rate of our survey was extremely high (86.2\%), and
non-response bias may therefore be limited. Furthermore, we compared VAS
and EQ-5D-3L values after adjusting participants' background by
propensity score matching.

In conclusion, what we call ``long-COVID'' brings us substantial disease
burden in addition to the burden attributed to the acute phase of
COVID-19. This additional burden makes the whole disease burden of
COVID-19 heavier, making prevention strategies all the more important.
The influence of vaccination and variants on ``long-COVID'' should be
examined in the near future.

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\textbf{Table 1. Characteristics of participants}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& \textbf{No symptom} & \textbf{Any symptom} & \emph{P} \textbf{value*}
& \textbf{SMD}\tabularnewline
\midrule
\endhead
\textbf{Number} & 349 & 108 & &\tabularnewline
\textbf{Age} & 48 {[}39-55{]} & 47 {[}40-54{]} & 0.724 &
0.001\tabularnewline
\textbf{Male} & 188 (53.9) & 38 (35.2) & 0.001 & \textless{}
0.383\tabularnewline
\textbf{BMI} & 23.2 {[}21.1-25.6{]} & 23.4 {[}20.9-26.9{]} & 0.453 &
0.163\tabularnewline
\textbf{Smoking} & 130 (37.2) & 38 (35.5) & 0.819 & 0.036\tabularnewline
\textbf{Drinking} & 290 (83.1) & 86 (79.6) & 0.471 &
0.089\tabularnewline
\textbf{Hypertension} & 52 (14.9) & 14 (13.0) & 0.754 &
0.056\tabularnewline
\textbf{Diabetes} & 23 (6.6) & 5 (4.6) & 0.646 & 0.085\tabularnewline
\textbf{COPD} & 3 (0.9) & 0 (0.0) & 1.0 & \textless{}
0.132\tabularnewline
\textbf{Malignancy} & 6 (1.7) & 0 (0.0) & 0.343 & 0.187\tabularnewline
\textbf{Use of antivirals} & 62 (18.8) & 22 (20.8) & 0.672 &
0.049\tabularnewline
\textbf{Use of steroids} & 40 (12.8) & 13 (13.3) & 0.865 &
0.013\tabularnewline
\textbf{Severe disease\textsuperscript{+}} & 7 (2.1) & 6 (5.6) & 0.092 &
0.183\tabularnewline
\textbf{Oxygen support} & 44 (12.6) & 13 (13.3) & 0.870 &
0.027\tabularnewline
\textbf{VAS} & 85 {[}75-90{]} & 70 {[}60-80{]} & \textbf{\textless{}
0.001} & \textbf{0.810}\tabularnewline
\textbf{QOL} & 1.0 {[}1.0-1.0{]} & 0.81 {[}0.77-1.0{]} &
\textbf{\textless{} 0.001} & \textbf{0.845}\tabularnewline
\bottomrule
\end{longtable}

Median {[}interquartile range{]} for continuous variables, number (\%)
for categorical variables.

*Mann-Whitney U test for continuous variables, Fisher's exact test for
categorical variables.

\textsuperscript{+}Use of mechanical ventilation or extracorporeal
membrane oxygenation during admission.

SMD: standardized mean difference, BMI: Body Mass Index, COPD: chronic
obstructive pulmonary disease, VAS: Visual Analogue Scale, QOL: Quality
of Life

\textbf{Table 2. Characteristics of participants after propensity score
matching}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& \textbf{No symptom} & \textbf{Any symptom} & \emph{P} \textbf{value*}
& \textbf{SMD}\tabularnewline
\midrule
\endhead
\textbf{Number} & 91 & 91 & &\tabularnewline
\textbf{Age} & 46 {[}39-52{]} & 46 {[}39-54{]} & 0.515 &
0.123\tabularnewline
\textbf{Male} & 29 (31.9) & 29 (31.9) & 1.0 & \textless{}
0.001\tabularnewline
\textbf{BMI} & 22.7 {[}20.8-26.8{]} & 23.4 {[}20.9-26.5{]} & 0.801 &
0.051\tabularnewline
\textbf{Smoking} & 30 (33.0) & 30 (33.0) & 1.0 & \textless{}
0.001\tabularnewline
\textbf{Drinking} & 68 (74.7) & 74 (81.3) & 0.371 & 0.160\tabularnewline
\textbf{Hypertension} & 7 (7.7) & 10 (11.0) & 0.612 &
0.113\tabularnewline
\textbf{Diabetes} & 5 (5.5) & 5 (5.5) & 1.0 & \textless{}
0.001\tabularnewline
\textbf{COPD} & 0 (0.0) & 0 (0.0) & NA & \textless{}
0.001\tabularnewline
\textbf{Malignancy} & 0 (0.0) & 0 (0.0) & NA & \textless{}
0.001\tabularnewline
\textbf{Use of antivirals} & 16 (17.6) & 16 (17.6) & 1.0 &
0.063\tabularnewline
\textbf{Use of steroids} & 14 (15.4) & 12 (13.2) & 0.833 & \textless{}
0.001\tabularnewline
\textbf{Severe disease\textsuperscript{+}} & 3 (3.3) & 3 (3.3) & 1.0 &
\textless{} 0.001\tabularnewline
\textbf{VAS} & 80 {[}77-90{]} & 70 {[}60-80{]} & \textbf{\textless{}
0.001} & \textbf{0.763}\tabularnewline
\textbf{QOL} & 1.0 {[}1.0-1.0{]} & 0.81 {[}0.76-1.0{]} &
\textbf{\textless{} 0.001} & \textbf{0.80}\tabularnewline
\bottomrule
\end{longtable}

Median {[}interquartile range{]} for continuous variables, number (\%)
for categorical variables.

*Mann-Whitney U test for continuous variables, Fisher's exact test for
categorical variables.

\textsuperscript{+}Use of mechanical ventilation or extracorporeal
membrane oxygenation during admission.

SMD: standardized mean difference, BMI: Body Mass Index, COPD: chronic
obstructive pulmonary disease, VAS: Visual Analogue Scale, QOL: Quality
of Life

\textbf{Table 3. Details of symptoms lasted longer than four weeks in
the participants}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& \textbf{Number} & \textbf{Duration (days)}\tabularnewline
\midrule
\endhead
\textbf{Number of symptoms} & 457 &\tabularnewline
\textbf{At least 1} & 201 (44.0) &\tabularnewline
\textbf{1} & 73 (16.0) &\tabularnewline
\textbf{2} & 46 (10.1) &\tabularnewline
\textbf{3} & 47 (10.3) &\tabularnewline
\textbf{4 and more} & 34 (7.4) &\tabularnewline
\textbf{Fatigue} & 58 (12.7) & 50 {[}30-60{]}\tabularnewline
\textbf{Hair loss} & 55 (12.0) & 60 {[}30-90{]}\tabularnewline
\textbf{Cough} & 54 (11.8) & 40 {[}30-60{]}\tabularnewline
\textbf{Dysosmia} & 47 (10.3) & 45 {[}30-60{]}\tabularnewline
\textbf{Dysgeusia} & 47 (10.3) & 35 {[}30-60{]}\tabularnewline
\textbf{Shortness of breath} & 36 (7.9) & 42.5
{[}30-60{]}\tabularnewline
\textbf{Loss of concentration} & 34 (7.4) & 40
{[}30-90{]}\tabularnewline
\textbf{Depression} & 29 (6.3) & 40 {[}30-60{]}\tabularnewline
\bottomrule
\end{longtable}

Absolute number (\%) for the number of participants, median
{[}interquartile range{]} for the duration of symptoms.

\textbf{Figure 1. Violin plot of visual analogue scale}

Red colour represents ``No symptom'' group and blue colour represents
``With symptom'' group.

\textbf{Figure 2. Violin plot of Quality of Life}

Red colour represents ``No symptom'' group and blue colour represents
``With symptom'' group.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig1/Fig1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig2/Fig2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

