ISSN 0030- 6096

O S A K A
C I T Y

Vol.

68

No.1

M E D I C A L

2022

J O U R N A L

V o l . 6 8 ,N o . 12 0 2 2

PUBLISHED BYOSAKA CITY MEDICAL ASSOCIATIONOSAKA JAPANOsaka City Medical Journal
Vo l . 6 8 , N o . 1 ,Ju n e 2 0 2 2

CONTENTS
Comparing the Effects of Intravenous Methylpredonisolone Pulse Therapy

pagewith the Conventional dose of Corticosteroids for the Treatment of
Acute Facial Nerve Palsy: A Propensity Score Analysis
MASAHIRO OISHI, YUKI KOUDA, HISAO AMATSU, HISAKO YOSHIDA,
AYUMI SHINTANI, and KISHIKO SUNAMI ････････････････････････････････････････････････････････････

1

Somatic Symptoms as Stress Responses among Japanese Workers
Measured by the Brief Job Stress Questionnaire
AYA KADOWAKI, SHINICHI IWASAKI, YASUHIKO DEGUCHI,TOMOE MITAKE, YUKAKO OKUDA, AKIHIRO NIKI, TOMOYUKI HIROTA,YOSHIKI SHIRAHAMA, YOKO NAKAMICHI, and KOKI INOUE ･･････････････････････････････････ 11
Association between Depression and Anxiety Symptoms and Changes in
Neighborhood Interaction among Community-dwelling Older Adults
before and after the COVID-19 Pandemic
HIDEO KUROZUMI, KENTARO UCHIDA, JUMPEI MARUTA,
SATOSHI NOGI, SATOSHI AKADA, and KOKI INOUE ･･････････････････････････････････････････････ 19
Comparison of Clinical Test Results in Pollen-food Allergy Syndrome:Multicenter Case Series StudyTAISUKE HASHIMOTO, SAKI KASUGA, SAKURA ANDO, NAHO YAMAMOTO,SHIORI FUJIKAWA, HIROKO FUJITANI, and TAKASHI HAMAZAKI ･････････････････････････････ 29
Association between Job Stressors and Extended Long-term Sickness
Absence due to Mental Disorders among Public Servants in JapanYOSHIKI SHIRAHAMA, SHINICHI IWASAKI, YASUHIKO DEGUCHI,AYA KADOWAKI, AKIHIRO NIKI, TOMOYUKI HIROTA,
YOKO NAKAMICHI, and KOKI INOUE ･････････････････････････････････････････････････････････････････ 39

Osaka City Med. J. Vol. 68, 1-10, 2022

Comparing the Effects of Intravenous Methylpredonisolone Pulse
Therapy with the Conventional dose of Corticosteroids for theTreatment of Acute Facial Nerve Palsy: A Propensity Score Analysis
MASAHIRO OISHI1), YUKI KOUDA1), HISAO AMATSU2), HISAKO YOSHIDA3), AYUMI SHINTANI3), and
KISHIKO SUNAMI1)
Department of Otorhinolaryngology1) and Medical Statistics3), Osaka City University
Graduate School of Medicine; and Department of Otorhinolaryngology2), Tane general hospital

Abstract
BackgroundTo evaluate and compare the effectiveness of intravenous methylpredonisolone pulse therapy withconventional dose of corticosteroids for the treatment of facial nerve palsy.
Methods
The recovery rate and treatment period were compared between the intravenous
methylpredonisolone pulse therapy and conventional dose of corticosteroids in this retrospective
observational study. Patients with acute facial nerve palsy were treated within 7 days after onset.
Results
A total of 74 patients with facial nerve palsy were included: 48 were treated with intravenous
methylpredonisolone pulse therapy and 26 with conventional doses of corticosteroids. The recovery
rates were 70.8% and 84.6% in the intravenous methylpredonisolone pulse therapy and conventional
treatment, respectively. The median treatment periods were 61 days and 30 days in the intravenous
methylpredonisolone pulse therapy and conventional treatment, respectively. A statisticallysignificant difference was observed between the two groups (log-rank test p ＝0.014), with theconventional treatment group having a shorter treatment period.
Conclusions
In conclusion, no results showed that intravenous methylpredonisolone pulse therapies were more
effective than the conventional steroid treatment.
Key Words: ‌Facial nerve palsy; Bellʼs palsy; Ramsay Hunt syndrome; Zoster sine
herpete; Intravenous methylpredonisolone pulse therapy

Introduction
Facial nerve palsy may occur due to various reasons; however, its primary causes are Bellʼs palsy
Received August 18, 2021; accepted November 30, 2021.
Correspondence to: Masahiro Oishi, MD.
Depertment of Otorhinolaryngology Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3871; Fax: +81-6-6646-0515
E-mail: oishi1128@omu.ac.jp-1-

Oishi et al

and Ramsay Hunt syndrome (RHS). Bellʼs palsy, defined as an acute facial nerve paralysis of
unknown origin, is recently presumed to be caused by reactivation of herpes simplex virus type 1(HSV1)1). RHS occurs with vesicular eruption around the affected ear and with facial palsy caused by
the reactivation of varicella-zoster virus (VZV)2). Zoster sine herpete (ZSH) is one of the atypicalclinical manifestations of herpes zoster. ZSH is caused by the reactivation of VZV but without
vesicular eruption. ZSH is one of the causes of facial nerve paralysis; however, distinguishing it fromBellʼs palsy is difficult. Therefore, it is commonly misdiagnosed as Bellʼs palsy3-5）. ZSH is diagnosed
with the detection of virus deoxyribonucleic acid (DNA) using polymerase chain reaction (PCR) or
anti-VZV antibody in the serum 3,4). It has also been reported in 8%-19% of patients clinicallydiagnosed with Bellʼs palsy5). Serological or PCR examinations should be performed to distinguishBellʼs palsy from ZSH.
The prognosis of Bellʼs palsy is favorable, with approximately 70% of patients being completely
resolved without treatment6). However, the prognosis of facial palsy caused by RHS and ZSH is worse
than Bellʼs palsy7). Only 10% of complete facial palsy caused by RHS is resolved without treatment.
Reactivation of HSV1 or VZV in the geniculate ganglion causes facial nerve inf lammation andedema, which resulted in facial nerve compression as it travels through the fallopian canal, theleading posited mechanism of Bellʼs palsy and facial paralysis of RHS. Corticosteroids target theinf lammatory process and decrease nerve edema, thereby resulting in the return of facial nerve
function.
Some randomized control trials (RCT) of the effectiveness of corticosteroid treatment for Bellʼspalsy, with higher recovery rate and shorter recovery time8,9). Some reports have described theeffectiveness of corticosteroids for facial nerve palsy in RHS and ZSH4,10).
Clinical practice guideline in the American Academy of Otolaryngology-Head, and Neck Surgery(AAO-HNS) recommends a 10-day course of oral steroids with at least 5 days at high dose
[prednisolone {PSL} 50 mg/day for 10 days or 60 mg/day for 5 days then tapered for ＞5 days] to treat
Bellʼs palsy6). The French Society of ENT (SFORL) recommends the PSL administration of 1 mg/kg/
day for 7-10 days for the treatment of Bellʼs palsy and PSL 2 mg/kg/day for 10 days for the treatment
of severe Bellʼs palsy11). The international guidelines for facial palsy in RHS are not yet established.
The Japan Society of Facial Nerve Research proposed a dose of steroids according to the severity of
facial palsy. PSL of 120-200 mg/day tapered within 10 days in complete facial palsy (＜10 points in
the Yanagihara score), PSL of 60 mg/day tapered in moderately facial palsy (18-10 points), PSL of 30
mg/day tapered in mild facial palsy (＞20 points) are proposed in both Bellʼs palsy and RHS based on
this guideline12).
The efficacy of the intravenous methylprednisolone pulse therapy (methylprednisolone 1000 mg/
day for 3-5 days) for central inf lammatory diseases, such as multiple sclerosis, neuromyelitis optica,
and acute transverse myelitis, has been already reported13-15). The intravenous methylpredonisolone
pulse therapy is considered effective for acute facial nerve palsy but reports of their advisability havenever been done before.

The intravenous methylpredonisolone pulse therapy is a higher dose than

the administration of the high dose steroids reported so far. There is no report comparing the effects
of high-dose steroid administration and intravenous methylpredonisolone pulse therapy.
It is necessary to study whether ultra-high dose steroids have more effects to acute facial nerve
palsy especially Bellʼs palsy and RHS than ever reporting.
In this study, we evaluated the effectiveness of intravenous methylprednisolone pulse compared-2-

Effect of Intravenous Methylpredonisolone Pulse Therapy for Acute Facial Nerve Palsy

with the conventional dose of corticosteroids.

Methods
Study design and setting
A retrospective observational study was conducted at the Osaka City University Hospital andTane General Hospital from April 2014 to March 2016. The ethical committee of Osaka City
University Graduate School of Medicine approved this study (No. 2021-087). We included patientswith acute facial palsy aged ≧16 years that occurred within 7 days of symptom onset. Precise history
taking, thorough physical examination, stapedius ref lex assessment, and serum test were performedon the first day. Electroneurography (ENoG) was measured 7-10 days after the symptom onset.
Anti-HSV1 IgG and anti-VZV IgG in the serum were examined. A positive diagnosis was made when
the HSV1 or VZV antibody was found to be 50 times higher. If both HSV1 and VZV antibodies were
low, antibody testing was repeated 2 weeks after. If the increase doubled or higher, it was judged to
be positive. HSV1-positive patients were diagnosed with Bellʼs palsy, VZV-positive with vesicular
eruption as RHS, and VZV-positive without vesicular eruption as ZSH.
Patients were treated with (1) conventional dose of corticosteroid (PSL of -200 mg and 10 days
tapering) or (2) intravenous methylpredonisolone pulse therapy (intravenous methylprednisolone
1000 mg for 3 days at 1-3 times). All the intravenous methylpredonisolone pulse therapy were
performed at the Department of Neurology, Tane General Hospital.
Outcome measures
The facial movement was examined using the Yanagihara facial nerve grading system score at thefirst visit, one week after onset, the first month, and every month thereafter for up to 6 months.
Recovery from the palsy was defined as a score ≧36 using the Yanagihara 40-point scoring system
without facial contracture or synkinesis.
Statistical analysis
Continuous variables are represented by the median (interquartile range), and nominal variables
are represented by the percentage (frequency). The chi-square test and Mann-Whitney test wereused to describe the difference between the two groups. When ≧36 points indicated completely
treated by the Yanagihara score, the duration for complete treatment between the normal treatment
and steroid pulse groups was compared using the log-rank test with censoring. Patients who were
not completely treated after 6 months or those who were lost to follow-up before 6 months were
excluded. Next, we compared the time to complete treatment between the two groups using a Cox
proportional hazards model with age, gender, and score at the start of treatment as regulators. In
addition, a diagnosis was added to the model as interaction term and examined whether a differencein the therapeutic effect depends on the diagnosis. All statistical processing was performed using R(version 4.0.1), and the significance level was set to 5% on two sides.

Results
Among 80 patients diagnosed with acute facial nerve palsy, three were excluded because ofdiagnosis (facial nerve tumor, temporal bone fracture, and multiple sclerosis). Of 77 patients withfacial nerve palsy, 52 were diagnosed as Bellʼs palsy and 25 as RHS and ZSH. Three of the patientswith Bellʼs palsy not treated with steroid therapy were excluded from the analysis. Twenty-six
patients in the conventional treatment group (17 with Bellʼs palsy, 9 with RHS and ZSH) and 48 in-3-

Oishi et al

the steroid pulse therapy group (32 with Bellʼs palsy, 16 with RHS and ZSH) were investigated. The
baseline characteristics are shown in Table 1.
In the conventional treatment group, 17 patients (65.4%) were diagnosed with Bellʼs palsy and 9(34.6%) as RHS and ZSH. In the steroid pulse therapy group, 32 patients (66.7%) were diagnosed
with Bellʼs palsy and 16 (33.3%) as RHS&ZSH. No difference in the diagnosis was observed between
the steroid pulse and conventional treatment groups. Stapedius ref lex was negative in 14 patients(53.8%) in the conventional treatment group and 32 (66.7%) in intravenous methylpredonisolone
pulse therapy group. No difference in the ratio of negative stapedius ref lex between the steroid pulse
therapy and conventional treatment groups. With regard to the ENoG value, the median value of
ENoG in the conventional treatment and the intravenous methylpredonisolone pulse therapy was
37.4% and 33.3%, respectively, showing no significant difference. The proportion of patients with
ENoG of ＜10% was 3.8% (1 patient) and 10.4% (5 patients) in the conventional treatment and theintravenous methylpredonisolone pulse therapy groups, respectively, showing no significant
difference. The median values of the Yanagihara score observed at the start of treatment were 15.00
Table 1.
Without steroid pulse With steroid pulsepOverall

Number26

48

74

Age (median [IQR])

49.00 [34.50-65.00]

61.00 [47.00-71.00]

0.006

58.00 [43.00-68.75]

Sex% (freq)

malefemale61.5 (16)38.5 (10)54.2 (26)45.8 (22)0.541

56.8 (42)43.2 (32)

Diagnosis% (freq)

Bell
RHS &ZSH

65.4 (17)34.6 (9)66.7 (32)33.3 (16)0.911

66.2 (49)33.8 (25)SR%

negative
positive53.8 (14)46.2 (12)66.7 (32)33.3 (16)0.278

62.2 (46)37.40 [24.45-61.23]

33.30 [18.12-59.90]

0.365

33.75 [19.38-60.30]

89.6 (43)10.4 (5)0.323

91.9 (68)
8.1 (6)10.00 [6.00-14.00]

0.106

10.00 [6.00-17.50]

ENoG%
ENoG 10%more than 10% 96.2 (25)less than 10% 3.8 (1)Baseline score15.00 [7.50-18.00]

Baseline characteristics of all patients. Steroid pulse is intravenous methylpredonisolone pulse therapy. IQR,
Interquartile Range; RHS, Ramsay Hunt syndrome; ZSH, Zoster sine herpete; SR, stapedius ref lex; and ENoG,
electroneurography.

Table 2.

Treat with conventional treatment
Treat with steroid pulse

Percentage of cure22 (84.6%)
34 (70.8%)

Treatment period
30 (95% CI 30-61)
61 (95% CI 30-122)

RHS &ZSH
Bell

Percentage of cure18 (72.0%)
33 (77.6%)

Treatment period
61 (95% CI 30--)
61 (95% CI 30-61)

The recovery rate and the treatment period. Steroid pulse is intravenous methylpredonisolone
pulse therapy. RHS, Ramsay Hunt syndrome; and ZSH, Zoster sine herpete.

-4-Effect of Intravenous Methylpredonisolone Pulse Therapy for Acute Facial Nerve Palsy

Figure 1. A Kaplan-Meier curve according to the treatment period of the steroid pulse therapy and the conventional
treatment group. A statistically significant difference was observed between the two groups (log-rank test p＝0.014),
suggesting that the duration of for complete treatment the conventional treatment group is shorter than that in the sintravenous methylpredonisolone pulse therapy group. Pulse is intravenous methylpredonisolone pulse therapy. RHS,
Ramsay Hunt syndrome; and ZSH, Zoster sine herpete.

Figure 2. A Kaplan-Meier curve according to the treatment period of Bellʼs palsy and RHS and ZSH. Any difference
between Bellʼs palsy and RHS and ZSH based on the treatment period were not detected.

-5-Oishi et al

and 10.00 points in the normal treatment and the intravenous methylpredonisolone pulse therapy
groups, respectively, showing no significant difference.
The recovery rate of patients receiving the conventional treatment and the intravenous
methylpredonisolone pulse therapy are shown in Table 2. Of 74 patients, 56 were completely treatedwith a Yanagihara score of ≧36 points. The rate of complete treatment was 70.8% (34 patients) and
84.6% (22 patients) in the intravenous methylpredonisolone pulse therapy and conventional
treatment groups, respectively. The meaning values of the treatment period were 61 days and 30
days in the intravenous methylpredonisolone pulse therapy and conventional treatment groups,
respectively. The rate of complete treatment was 77.6% (33 patients) and 72% (18 patients) in theBellʼs palsy and RHS and ZSH, respectively. The median treatment period were 61 days in both
Bellʼs palsy and RHS and ZSH groups (Table 2).
A Kaplan-Meier curve according to the treatment period of each group is shown in Figure 1. A
statistically significant difference was observed between the two groups (log-rank test p＝0.014),
suggesting that the duration of for complete treatment in the conventional treatment group is shorter
than that in the intravenous methylpredonisolone pulse therapy group.
Analysis of each disease is shown in Figure 2. We could not detect any difference between Bellʼspalsy and RHS and ZSH based on the treatment period.
Next, as a result of the Cox proportional hazard model adjusted for gender, age at the start oftreatment, and Yanagihara score at the start of treatment, the hazard ratio for complete treatment in
the intravenous methylpredonisolone pulse therapy to the conventional treatment group was 0.787(95% confidence interval 0.359-1.722, p＝0.548) (Fig. 3). Finally, when diagnostic were added asinteraction, no difference was observed between the presence and absence of intravenous
methylpredonisolone pulse therapy for complete treatment in patients with Bellʼs palsy (HR 1.051,
95% CI 0.504-2.194, p＝0.894), but not in those with RHS and ZSH (HR 0.151, 95% CI 0.053-0.427,
p＜0.001) for complete treatment of the intravenous methylpredonisolone pulse therapy group,suggesting that the effectiveness of the intravenous methylpredonisolone pulse therapy differs
depending on the cause of paralysis (p for interaction＝0.003) (Fig. 4). In RHS and ZSH, treatment
duration was longer when steroid pulse was administered.

Discussion
We evaluated the effectiveness of the intravenous methylpredonisolone pulse therapy for thetreatment of Bellʼs palsy and RHS and ZSH. The results showed the steroid pulse therapy was not
more effective than conventional therapy using 30-200 mg of prednisolone with several days of dosetapering.
Bellʼs palsy is one of the most common causes of acute facial nerve palsy with an annual incidenceof 15-30/100000. Various diseases caused facial nerve paralysis (Table 3)6). Among them, Bellʼs palsy
was considered as acute facial nerve palsy with unknown etiology but is currently considered as thereactivation of HSV11). The prognosis of Bellʼs palsy is favorable, with approximately 70% of patientscompletely resolved without treatment6).
RHS is acute facial nerve palsy with auricular vesicular eruptions and pain around the affected
ear, with an annual incidence of 5/100000, and is caused by the reactivation of VZV. Its prognosis isworse than Bellʼs palsy, and spontaneous remission is available in only 30% of patients10,16,17). ZSH is
an atypical clinical manifestation of herpes zoster, causing acute facial nerve palsy without vesicular-6-

Effect of Intravenous Methylpredonisolone Pulse Therapy for Acute Facial Nerve Palsy

Figure 3. The hazard ratio for complete treatment in the intravenous methylpredonisolone pulse therapy and theconventional treatment group. The hazard ratio for complete treatment in the steroid pulse, intravenous
methylpredonisolone pulse therapy to the conventional treatment group was 0.787 (95% CI 0.359-1.722, p=0.548). CI,
confidence interval.

Figure 4. The hazard ratio for complete treatment in the steroid pulse, intravenous methylpredonisolone pulse
therapy and the conventional treatment group depending on the cause of paralysis. No difference was observed
between the presence and absence of the steroid pulse therapy for complete treatment in patients with Bellʼs palsy(HR 1.051, 95% CI 0.504-2.194, p＝0.894), but not in those with RHS and ZSH (HR 0.151, 95% CI 0.053-0.427, p＜
0.001) for complete treatment of the steroid pulse, intravenous methylpredonisolone pulse therapy group. Steroid
pulse is intravenous methylpredonisolone pulse therapy. HR, hazard ratio; RHS, Ramsay Hunt syndrome; ZSH, Zostersine herpete; and CI, confidence interval.

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Oishi et al

eruptions and is also caused by the reactivation of VZV18). ZSH is diagnosed by increased anti-VZV
antibody titer or virus DNA in the cerebrospinal f luid or serum3). ZSH is observed in 8%-19% of
patients diagnosed with Bellʼs palsy5) and involves pain around the affected ear; however, Bellʼs palsy
is also sometimes accompanied by pain, and the degree of pain did not differ in both diseases4).
Distinguishing Bellʼs palsy from ZSH is difficult based on physical findings alone. The prognosis of
ZSH and RHS is poor. The poor prognosis of patients with Bellʼs palsy might be the presence of ZSH.
In this study, RHS and ZSH accounted for 31% of acute facial nerve palsy. The ratio of facial
nerve palsy associated with VZV was higher than that of previous reports. Robillard et al reported
that 185 (12.3%) of 1507 patients with facial nerve palsy were diagnosed as RHS17) In our study, antiVZV antibody titer and anti-HSV1 antibody titer were determined to diagnose acute facial nerve
palsy; therefore, ZSH could be diagnosed as facial palsy associated with VZV. ZSH is likely to bediagnosed with Bellʼs palsy when testing for antibodies or PCR was not performed. Furuta et alreported that of 142 patients with acute facial nerve palsy, 56 were caused by reactivation of VZV and
86 by HSV1. They were diagnosed based on increased anti-VZV antibody titer in the serum or virus
DNA in the saliva19). Our results of the RHS and ZSH ratio in acute facial nerve palsy were consistent
with their findings.
Sullivav et al reported a double-blind, RCT about the effect of prednisolone (50 mg for 10 days) for
the treatment of Bellʼs palsy. In their trial, 551 patients were divided into four groups (acyclovir plus
prednisolone, acyclovir plus placebo, prednisolone plus placebo, and placebo). About 83% of patientsrandomized to prednisolone had recovered their facial nerve function, whereas 63.6% of thoserandomized to placebo had recovered 3 months after treatment (p＜0.01). Moreover, 94.4% of patientsrandomized to prednisolone had recovered their facial nerve function, whereas 81.6% of thoserandomized to placebo had recovered 9 months after treatment 8). Engström et al also had asubstantially similar trial and reported a significant shortening of the treatment period byadministering prednisolone (60 mg for 5 days with a 5-day taper)9).
Based on these results, the AAO-HNS guideline recommends a 10-day course of oral steroid
treatment (prednisolone of 50 mg for 10 days or prednisolone of 60 mg for 5 days with a 5-day taper)
to treat Bellʼs palsy6). Conversely, Fujiwara et al reported that 50-60 mg prednisolone cannot
adequately treat severe Bellʼs palsy. In their report, 120 mg of prednisolone (2 mg/kg) for 3 days witha 6-day taper can more effectively treat Bellʼs palsy than 60 mg of prednisolone20,21).
No studies have reported the effectiveness of steroid pulse therapy for Bellʼs palsy to date. In ourstudy, no significant effect was observed in administering conventional treatment and steroid pulse
therapy, whereas short treatment periods were not observed. The steroid pulse therapy might not benecessary even for severe Bellʼs palsy.
Several studies have reported the effects of steroids in RHS; however, no RTC or meta-analysis
has been conducted on steroid doses. In the review, Monsanto et al reported the difference in theeffect of steroid type, each recovery rate was 69.2% in prednisone, 61.4% in prednisolone, 76.2% inhydrocortisone, and 81.3% in methylprednisolone10). Various reports have investigated steroid dosages
for the treatment of RHS. Kinishi et al reported that 93.4% of patients had recovered facial nerve
function using methylprednisolone of 500 mg for 1 day with a 6-day taper combined with acyclovir16).
Only a few case reports have been published on intravenous methylpredonisolone pulse therapy for
RHS. Donani et al reported that the patient who did not improve with initial therapy of oral
prednisone (50 mg/day) recovered with the intravenous methylpredonisolone pulse therapy 37 days
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Effect of Intravenous Methylpredonisolone Pulse Therapy for Acute Facial Nerve Palsy

after the onset22). The intravenous methylpredonisolone pulse therapy is possibly effective for RHS.
However, in this study, intravenous methylpredonisolone pulse therapy did not effectively improveand reduce the treatment period compared to conventional treatment to treat RHS and ZSH.
The facial nerve grading system score identifies HSV-1 or VZV and ENoG as factors to predict the
prognosis of facial movement. Antibody testing to confirm the cause takes approximately 1-2 weeks.
The ENoG is considered as a valid prognosis from the 7th day to 14th days23). The administration ofsteroids to treat facial nerve palsy should be initiated within 72 h of symptom onset. Therefore,
steroid doses are determined using the facial nerve grading system score only. In the guideline for
facial paralysis of the Japan Society of Facial Nerve Research, the setting of the steroid doses isrecommended by score, and if it is ≦8 points in the Yanagihara score, 120-200 mg of prednisolone isrecommended12）. Administration of steroids more than necessary should be avoided to prevent side
effects, such as gastrointestinal disturbance, reactivation peptic ulcer disease, and loss of control of
glucose level, elevated blood pressure, peripheral edema, and mood swings or episodes of acute
psychosis.
In conclusion, the intravenous methylpredonisolone pulse therapy cannot be recommended for
RHS and Bellʼs palsy. Bellʼs palsy does not require the intravenous methylpredonisolone pulse
therapy because it has a good prognosis, but RHS & ZSH has a poor prognosis, so we considered theintravenous methylpredonisolone pulse therapy might be effective. However, the effectiveness of thesteroid pulse therapy was not confirmed even in RHS ＆ ZSH. Corticosteroids target theinf lammatory process and decrease nerve edema, thereby resulting in the return of facial nerve
function. For that purpose, even with severe paralysis, it is likely to be sufficient with 2 mg/kg/day
prednisolone, and the steroid pulse therapy are not necessary.
Acknowledgements
All authors have no COI to declare regarding the present study.
The authors would gratefully acknowledge Dr. Shouichi Shiraishi and Ms. Mai Nakano for help
with data collection.
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13. Miller DM, Weinstock-Guttman B, Béthoux F, et al. A meta-analysis of methylprednisolone in recovery frommultiple sclerosis exacerbations. Mult Scler 2000;6:267-273.
14. Yamasaki R, Matsushita T, FukazawaT, et al. Efficacy of intravenous methylprednisolone pulse therapy inpatients with multiple sclerosis and neuromyelitis optica. Mult Scler 2016;22:1337-1348.
15. Defresne P, Meyer L, Tardieu M, et al. Efficacy of high dose steroid therapy in children with severe acutetransverse myelitis. J Neurol Neurosurg Psychiatry 2001;71:272-274.
16. Kinishi M, Amatsu M, Mohri M, et al. Acyclovir improves recovery rate of facial nerve palsy in Ramsay Hunt
syndrome. Auris Nasus Larynx 2001;28:223-226.
17. Robillard RB, Hilsinger RL Jr, Adour KK. Ramsay Hunt facial paralysis: clinical analyses of 185 patients.
Otolaryngol Head Neck Surg 1986;95:292-297.
18. Nagel MA, Gilden DH. The protean neurologic manifestations of varicella-zoster virus infection. Cleve Clin J
Med 2007;74:489-494, 496, 498-499 passim.
19. Furuta Y, Ohtani F, Mesuda Y, et al. Early diagnosis of zoster sine herpete and antiviral therapy for thetreatment of facial palsy. Neurology 2000;55:708-710.
20. Fujiwara T, Haku Y, Miyazaki T, et al. High-dose corticosteroids improve the prognosis of Bellʼs palsy comparedwith low-dose corticosteroids: a propensity score analysis. Auris Nasus Larynx 2018;45:465-470.
21. Fujiwara T, Namekawa M, Kuriyama A, et al. High-dose corticosteroids for adult Bellʼs palsy: systematic
review and meta-analysis. Otol Neurotol 2019;40:1101-1108.
22. Donati D, De Santi L, Ginanneschi F, et al. Successful response of non-recovering Ramsay Hunt syndrome to
intravenous high dose methylprednisolone. J Neurol Sci 2012;318:160-162.
23. Mancini P, De Seta D, Prosperini L, et al. Prognostic factors of Bellʼs palsy: multivariate analysis ofelectrophysiological findings. Laryngoscope 2014;124:2598-2605.

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Osaka City Med. J. Vol. 68, 11-18, 2022

Somatic Symptoms as Stress Responses among Japanese Workers
Measured by the Brief Job Stress Questionnaire
AYA KADOWAKI, SHINICHI IWASAKI, YASUHIKO DEGUCHI, TOMOE MITAKE, YUKAKO OKUDA,
AKIHIRO NIKI, TOMOYUKI HIROTA, YOSHIKI SHIRAHAMA, YOKO NAKAMICHI, and KOKI INOUE
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine

Abstract
BackgroundOccupational stressors cause physiological stress responses representing somatic symptoms andpsychological stress responses such as a depressive mood and anxiety. However, few studies haveinvestigated factors related to workersʼ physiological stress responses. Thus, this study examined thefactors associated with stress-related somatic symptoms among Japanese workers.
Methods
Data were collected from 18513 Japanese public servants through the Brief Job Stress
Questionnaire (BJSQ) in 2017, which was developed based on the National Institute for Occupational
Safety and Health (NIOSH) stress model. Factors predicting higher physiological stress responses
among demographic variables (sex and age), work-related variables (job title and job category),
psychological stress responses, and two BJSQ factors (occupational stressors and social support) wereidentified using multiple linear regression analysis.
Results
After adjusting for demographic and work-related variables, higher psychological stress responses,
being female, and being older were associated with having higher physiological stress responses. A
higher score on psychological stress responses was the most potent factor. Neither greater occupational
stressor nor lower social support was associated with a higher score of physiological stress responses
when confounding was reduced.
Conclusions
Efforts should be made to identify employeesʼ psychological stress responses in order to reduce
workersʼ stress-related somatic symptoms.
Key Words: ‌Physiological stress response; Psychological stress response; Occupational
stress; Somatic symptom; Brief Job Stress Questionnaire

Received September 1, 2021; accepted November 30, 2021.
Correspondence to: Aya Kadowaki, MD.
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3821; Fax: +81-6-6636-0439
E-mail: ak.peridot@gmail.com- 11 -

Kadowaki et al

Introduction
Work-related stressors are widely known as major risk factors for physical and mental healthproblems among workers. For instance, burnout1) is a well-known syndrome of exhaustion anddisinterest typically in the work context, which can result in various negative effects such as anxiety,depression, and increased health problems2). In the meta-analysis by Alarcon3), several studies haveshowed an association between workload and negative physical and psychological health outcomes.
Other prospective studies suggested that high job demands, low job control, low co-worker support,
low supervisor support, low procedural justice, low relational justice, and a high effort-reward
imbalance predicted the incidence of stress-related diseases4). Limited to physical symptoms, researchshowed that most psychosocial stressors had small but significant lagged effects on the developmentof musculoskeletal problems, especially highly monotonous work and lower back pain5). The
longitudinal and cross-sectional results from another meta-analysis provided some evidence oftemporal consistency of the occupational stressor and physical symptom relationship6).
According to the occupational stress model proposed by the National Institute for Occupational
Safety and Health (NIOSH)7), occupational stressors bring physiological stress responses whichconstitute somatic symptoms and psychological stress responses such as a depressive mood andanxiety. These stress responses are inf luenced by several factors such as individual (e.g., age, sex,
and personality), non-work (e.g., domestic and family demands), and buffer factors (e.g., social support
from supervisors, co-workers). Above all, somatic symptoms such as abdominal discomfort andmusculoskeletal pain are frequent among the working population, as past studies have shown thatnearly 80% of people have complaints about their health8,9). Somatic symptoms have a significantly
negative impact on individuals and companies in the long term. They are a substantial cause forphysician visits, multiple medical examinations, working disability, and other consequences withconsiderable socioeconomic impact 10). Regarding occupational outcomes, high somatic symptom
severity was a determinant of prolonged sick leave, prolonged disability, and health-related job loss11).
In addition, compared to psychological stress responses such as depressive mood and anxiety,research on physiological stress response is scant, and there is no standard coping method that can beprescribed to both companies and individuals12), which may make coping with it more difficult.
Despite the increasing number of workers in Japan who suffer from somatic symptoms13), few
studies have investigated the factors related to workersʼ somatic symptoms. Many questionnaires
were developed to evaluate workersʼ occupational stress, including the Brief Job Stress Questionnaire(BJSQ)14). This questionnaire was based on the NIOSH occupational stress model mentioned above7)
and the job content questionnaire (JCQ)15). These occupational stress models and the validity ofquestionnaire categories and evaluation methods have already been established. Additionally, BJSQ
is widely-used in Japan, known for the main component of the Stress Check Program16), launched in2015 as a Japanese annual survey aimed at identifying employees who experience high psychosocial
stress in the workplace. Thus, this study aimed to examine the factors related to workersʼ somatic
symptoms using the BJSQ among Japanese participants. According to the NIOSH occupational
stress model7), both of occupational stressors and social supports affect physiological and psychologicalstress response. Besides, occupational stressors is the only factor which directly affect physiologicaland psychological stress responses. Hence, it was hypothesized that workersʼ somatic symptoms werepotently affected by occupational stressors and social supports, and they were most potently affectedby occupational stressors.
- 12 -

Somatic Symptoms of Stress among Japanese Workers

Methods
ParticipantsThis study employed a cross-sectional design. Initially, 18513 public servants at the municipal or
the ward office of City A, located in the Kinki region of Japan were approached. In 2015, theJapanese government launched an occupational health policy to screen for workers with highpsychosocial stress in a workplace with 50 or more employees17). The researchers of this study
requested the municipal government of City A for the relevant study data in 2017. After acquiring
the secondary data (already anonymized by the office staff), questionnaires with incomplete responses(n＝1223) were excluded. Therefore, data from 17290 workers (93.4%) were analyzed for inclusion
eligibility.
Demographic and work-related variables
The demographic variables were sex and age. Sex was included as a demographic variable as paststudies have reported sex differences in the frequency of somatic symptoms18,19). The work-related
variables were job title (non-manager and manager) and job category (clerical workers, technicalworkers, professional workers, and others). Clerical workers were defined as those who carried out
clerical tasks related to construction, design, and management (among different roles) of buildings in
the municipality; technical workers were those who carried out technical tasks requiring physicalendeavors in the municipality; and professional workers comprised of nurses, care workers, publichealth nurses, and childcare workers, among others.
Brief Job Stress Questionnaire
The BJSQ 14) was originally created from the JCQ 15) and Generic Job Stress Questionnairedeveloped by the NIOSH7). It is a 57-item questionnaire that comprises four subscales and is
responded to by using a 4-point Likert-type scale (1＝disagree to 4＝agree). Its factors are as follows:
occupational stressors (17 items; score range: 17-68), which includes questions on work-related
stressors (e.g., job demands; physical, psychological, social, or organizational aspects of the job that
require sustained physical and/or psychological effort or skills and job control; the ability of a person
to inf luence what happens in their work environment); stress responses (29 items; score range: 29116) which has two subscales, namely psychological stress responses (PSY: 18 items; score range: 1872) which includes 6 items for depression, 3 for anxiety, 3 for hostility, 3 for fatigue, and 3 for vigor;
physiological stress responses (PHY: 11 items; score range: 11-44) which includes one item each fordizziness, body pain, headache, stiff shoulder, lower back pain, tired eyes, palpitation or shortness ofbreath, gastrointestinal symptoms, loss of appetite, constipation or diarrhea, and insomnia; social
support (9 items; score range: 9-36), which includes questions on social support in the workplace (e.g.,supervisor and co-worker support); and work and life satisfaction (2 items; score range: 2-8), which
includes questions on employeesʼ satisfaction with their work and personal lives. While calculating
the BJSQ score, reversed scoring was used where necessary; higher scores indicated greater stress.
A large-scale investigation confirmed the reliability and validity of the BJSQ and its usefulness inassessing Japanese workersʼ mental health20). Another study conducted with a Japanese sample
highlighted that the BJSQ is a well-established and widely used instrument for evaluating occupational
stress. It has sufficient reliability and validity in the Japanese setting21).
In the present study, the Cronbachʼs alpha coefficients for the factors and subscales were as
follows: 0.80 for occupational stressors, 0.93 for psychological stress response (PSY), 0.85 forphysiological stress response (PHY), 0.89 for social support, and 0.49 for work and life satisfaction. In- 13 -

Kadowaki et al

this study, the 2-item work and life satisfaction subscale were excluded because job dissatisfaction
was regarded as a part of the stress response according to the occupational stress model by the
NIOSH7).
Statistical analysis
To examine whether demographic variables (sex and age), work-related variables (job title and job
category), PSY, and the two BJSQ factors (occupational stressors and social support) predicted higher
PHY, a multiple linear regression analysis was conducted. Differences were considered significant at
p＜0.05. All statistical analyses were performed using SPSS version 26 (SPSS Inc., Chicago, IL, USA).
As aforementioned, we acquired and utilized anonymous secondary data (i.e., workersʼ responses
to the BJSQ, which had encrypted identification) in this study; this dataset had been previously
collected by the healthcare center of City A through the Stress Check Program. Thus, given that thedataset already existed, the review committee waived the need to collect written informed consent
from participants. Moreover, prior to data obtainment, the City A staff had already anonymized andde-identified the whole dataset. We provided a means to opt out of this study on the website. Finally,
the Human Subjects Review Committee of Osaka City University approved the study protocol(authorization number: 2969), and this study conformed to the tenets of the Declaration of Helsinki.

Results
Table 1 shows the participantsʼ characteristics and Brief Job Stress Questionnaire (BJSQ) scores(n＝17290). In total, 64.5% (n＝11145) were men and 35.5% (n＝6145) were women. Participantsʼmean age (± standard deviation [SD]) was 45.6±10.3 years. Among the participants, 70.6% were
non-managers (n＝12215) and 29.4% were managers (n＝5075). The most common job category wasthat of clerical workers (n＝8584, 49.7%).
Table 1. Participants’ characteristics and Brief Job Stress
Questionnaire (BJSQ) scores (n＝17290)
Range
nAge, years, mean (±SD)
Sex (n, %)MaleFemaleTotal
17290
45.6±10.311145 (64.5)
6145 (35.5)

Job Title (n, %)Non-manager
Manager

12215 (70.6)
5075 (29.4)

Job Category (n, %)Clerical worker
Technical worker
Professional worker
Other categories
Stress Response
Psychological stress response
Physiological stress response(18-72)(11-44)36.2±10.3
19.4±5.9

Occupational Stressor(17-68)41.9±6.9

Social Support(9-36)

19.4±5.3

SD, standard deviation.

- 14 -

8584
3341
3328
2037

(49.7)(19.3)(19.2)(11.8)

Somatic Symptoms of Stress among Japanese Workers

Table 2 shows the results of the hierarchical multiple linear regression analyses for higher PHY.
Entering demographic and work-related variables, that is, age, sex, job title, and job category (Step 1)
accounted for 3% of the variance. In Step 1, all variables were significant predictors. Namely, older
age, female sex, a manager, and any job category predicted higher PHY. When the BJSQ subscales(PSY, occupational stressors and social support) were added (Step 2), PSY was the only significant
predictor (explaining an additional 41% of the variance, F＝1512.440, p＜0.05). Namely, higher PSY
predicted higher PHY (standard partial regression coefficient β＝0.661: 95% confidence interval [CI],0.37-0.39). For occupational stressors (β＝−0.01; 95% CI, −0.03 to 0.01) and social support (β＝0.01:
95% CI, −0.01 to 0.02), Step 2 of the model revealed no significant predictors.

Table 2. R elated factors for higher physiological stress response by hierarchical multiple linear regression
analyses (n＝17290)
Step 1

Step 2

B

β

B

β

Age
Sex

0.02
−1.89

0.0304＊＊＊−0.152＊＊＊0.04

0.061＊＊＊−1.28−0.103＊＊＊

Job Title

−0.65

−0.05

−0.20

−0.015＊Range

Job Category
Clerical worker
Technical worker
Professional worker
Other categories
Psychological Stress Response
Occupational Stressor
Social Support
R
R2
R2 Change score
F

＊＊＊

2.38

0.201＊＊＊

0.37

0.031＊＊

2.40

0.16

0.96

0.064＊＊＊

1.66

0.11

−0.10

＊＊＊
＊＊＊

−0.01

(18-72)

0.38(17-68)(9-36)

−0.01

−0.01

0.01
0.66

0.01

0.16
0.03

0.44

0.03
76.591＊＊＊

0.661＊＊＊

0.41
1512.440＊＊＊

Step 1: adjusted for age, sex (reference category: male), job title (reference category: non-manager), and job category(reference category: clerical worker).
Step 2: adjusted for the Brief Job Stress Questionnaire (BJSQ) subscales.
p＜0.05, ＊＊p＜0.01, ＊＊＊p＜0.001.

＊

Discussion
The present study aimed to examine the factors related to somatic symptoms as stress responses
in an occupational context among Japanese workers. The results showed that a higher PSY, femalesex, and higher age were related factors for a higher PHY (meaning somatic symptoms and subjective
somatic complaints). Unexpectedly, neither greater occupational stressors nor lower social support
were significantly associated with higher PHY. In the present study, a higher PSY was the mostpotent factor.
Physiological and psychological stress responses
The current study showed that neither higher occupational stressors nor lower social support wassignificantly associated with a higher PHY when confounding was reduced. This result seems
contradictory to previous studies. Many studies have reported cross-sectional and longitudinal
relationships between somatic symptoms and various occupational stressors. For instance, according- 15 -

Kadowaki et al

to Nixonʼs meta-analysis6), somatic symptoms are related to a wide range of job stressors. Thistendency was seen for both individual symptoms and composite symptom scales, and the effect sizesof these relationships varied by the stressor and the individual symptom. As for the social supports,
studies examining the relationship between burnout 1) and Conservation of Resources theory 22)
suggested work sources of support are strongly related to exhaustion, which is one of three main
dimensions of burnout2). Non-work related sources of support are strongly related to depersonalizationand personal accomplishment, the other two dimensions of burnout.
Unlike previous studies, this study measured PSY and PHY separately and simultaneously, andanalyses were conducted to examine related factor of somatic symptoms, with confound factors
including PSY. Previous studies have showed a close association between psychological symptoms
such as depression and anxiety, and somatic symptoms. For instance, Löwe et al 23) foundcomorbidities between depression, anxiety, and somatization in over 50% of patients in primary careclinics. In a large study, Haug et al18) showed that the number of somatic symptoms and the total
score on the Hospital Anxiety and Depression Scale were linearly correlated. This finding
corroborates the present studyʼs finding that a higher PHY was associated with a higher PSY.
Considering these past findings, there is the possibility that PSY act as mediators when somatic
symptoms as stress responses (PHY) appear. In other words, when one confronted with occupational
stressors, subjective somatic complaints appear secondarily. Indeed, past studies have indicated thepossibility that depression and anxiety lowered the threshold for the perception of somatic
symptoms24), and depressive mood may foster illness-related memories and a negative view of oneʼs
health25). On the contrary, Rudy et al26) suggested that chronic somatic symptoms may play a role ininitiating or provoking depression and anxiety, indicating that somatic symptoms and somatic
complaints can also contribute to psychological problems. Another possibility suggested by thecurrent study is that PHY are more strongly affected by individual factors rather than occupational
stressors or social supports. In any case, this study clarifies the importance of coping with workersʼ
psychological problems to improve their somatic symptoms. Thus, the organizations should make aneffort to care for workersʼ psychological stress responses such as depressive moods or anxiety. Efforts
should be made to reduce somatic symptoms or complaints, and the necessary actions should betaken, such as referring workers to clinical doctors at the right time.
Sex and age
The present study also showed an association between a higher PHY and demographic variables
such as female sex and older age. Regarding sex, many previous studies indicated that women report
more somatic symptoms than men18,19,27), which supports the results of the present study. There seemto be many reasons for the higher prevalence of somatic symptoms in women. First, previous studies
have shown that compared to men, women have a higher prevalence of mental disorders associatedwith somatic symptoms, such as depression and anxiety disorders18,28). Participants in the present
study did not have any active mental disorders; however, some psychological problems, which
partially resembled depression symptoms and anxiety, may have increased their somatic symptoms.
Sex differences in social roles and responsibilities, thresholds for healthcare, and the amplification ofphysical symptoms were considered29,30).
Regarding age, several studies have suggested an association between age and somatic symptoms,
but results are incoherent and difficult to interpret19,28,31). Although physiological functions changewith age, somatic symptoms include medically explained symptoms as well as medically unexplained- 16 -

Somatic Symptoms of Stress among Japanese Workers

symptoms or somatization, meaning the tendency to express psychological distress with somatic
complaints, which results in inconsistent results caused by between-study differences in the definitionof somatization problems, measurement instruments, and the setting of the research population.
Several studies have reported somatization in older people, thereby concluding that clinically relevantsomatization frequently occurring through somatization disorder in itself is rare among the aging
population32). These studies can account for the current studyʼs results, as medically explained andunexplained symptoms were not differentiated in this study.
Strengths and limitations
This study has several limitations. First, a cross-sectional design was employed and data werecollected from self-reported questionnaires. Since this study used self-administered questionnaires,
participants may have included people who exaggerated or diminished their actual degree of
symptoms. Furthermore, the causal relationship between the two stress responses could not be
determined because of the cross-sectional nature of the study design. A study using a structural
equation modelling for two stress responses should be conducted to clarify these mechanisms. Second,as mentioned above, no information regarding the participantsʼ medical history was collected in thisstudy. This will likely increase the PHY in older people, although the participants of this study wereclinically healthy enough to be engaged in full-time work. Third, this studyʼs results may have been
inf luenced by residual and unmeasured confounders such as personality33), temperament34), stresscoping style, and length of employment. However, an understanding of the individual aspects of thestress response is limited. Thus, individual factors were not included in this study, except for age,sex, job title, and job category. Fourth, the data were obtained from public servants of one city inJapan, thus limiting the generalizability of these results to other jobs, regions, and countries. Last,
PSY and PHY were not separately examined for their validity and reliability; though the validity andreliability of whole BJSQ and stress response was well established14).
Despite the limitations, several strengths for our study deserve attention. To the best of authorsʼ
knowledge, this is the first investigation on the relationship between occupational stress and stressresponse dominance, and no previous study has simultaneously examined these two stress responses
together. Though somatic symptoms as stress responses remain unclear and still difficult to deal
with, our findings may be beneficial for individuals, supporters, and organizations to reduce workersʼ
somatic symptoms. Additionally, few studies on occupational stress targeted for this large sample
size in Japan. Moreover, this study utilized the BJSQ, widely-used in Japan as an assessment ofworkersʼ subjective stress response, known for the use of governmentʼs Stress Check Program. Since
it is widely used in Japan, results of the current study is highly versatile for the future studies.
Acknowledgements
All authors have no COI to declare regarding the present study.
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Osaka City Med. J. Vol. 68, 19-28, 2022

Association between Depression and Anxiety Symptoms andChanges in Neighborhood Interaction among Community-dwelling
Older Adults before and after the COVID-19 Pandemic
HIDEO KUROZUMI1), KENTARO UCHIDA1), JUMPEI MARUTA2), SATOSHI NOGI1),SATOSHI AKADA1), and KOKI INOUE1,3)
Department of Neuropsychiatry1) and Center for Brain Science3), Osaka City University
Graduate School of Medicine; and Department of Psychiatry2), Osaka City Kosaiin Hospital

Abstract
BackgroundThe coronavirus disease (COVID-19) pandemic has changed peopleʼs daily lives globally.
Specifically, there is concern regarding older adults who are at high risk of severe disease who havefewer opportunities to go out and interact with others, as they may develop psychological problems.
This study investigated the relationship between changes in neighborhood interactions andpsychological symptoms among older adults during the COVID-19 pandemic.
Methods
We conducted a questionnaire survey from January to May, 2021 and 460 responses wereanalyzed. We assessed depression and anxiety symptoms using the Kessler Psychological Distress
Scale-6 (K6), and the frequency of neighborhood interaction before and after the start of the
COVID-19 pandemic using a 4-point scale (1: always, 2: sometimes, 3: not often, and 4: never).
Results
The frequency of interaction with neighbors among community-dwelling older individuals
decreased after the start of the pandemic, compared to before. Further, after the start of thepandemic, people who interacted less with their neighbors had higher K6 scores. Depression andanxiety symptoms may also have worsened among those whose frequency of interacting withneighbors decreased around the COVID-19 pandemic, compared with those whose frequency ofinteracting with neighbors did not change.
Conclusions
Our results suggest that older adults whose frequency of neighborhood interaction decreased are
more likely to have psychological symptoms than those who do not. To prevent depression andanxiety symptoms among older adults, it is necessary to promote neighborhood interaction and social
activities.
Received September 1, 2021; accepted November 30, 2021.
Correspondence to: Hideo Kurozumi, MD.
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3821; Fax: +81-6-6636-0439
E-mail: d18mb013@hg.osaka-cu.ac.jp- 19 -

Kurozumi et al

Key Words: ‌COVID-19; Depression; Anxiety; Neighborhood; Older adults

Introduction
Japan is a super-aged society with a declining birthrate and an aging population; as of 2020, thenumber of people aged 65 years or older was 36.17 million, accounting for 28.7% of the total
population. It is estimated that this number will reach 38.4% by 2065. The increasing costs ofmedical and nursing care for older adults place an enormous financial burden on Japan. Depression
is a major mental health condition among older adults and in 2013, the prevalence of depression
symptoms among the general older population ranged from 21.5% to 36.2%1). Depression symptoms
are also strongly associated with the development of major depressive disorder2) and suicide ideationin older adults3-6). Therefore, the prevention of depression symptoms in older adults is a crucial issue.
Depression symptoms have been shown to be associated with a lack of interaction with others7,8),
social activities9), and exercise10), and it is recommended to engage in these activities from an earlystage.
Originating in Wuhan, China, the coronavirus disease (COVID-19) has spread globally and was
declared a pandemic by the World Health Organization on March 11, 202011). Pandemics are generally
said to exacerbate anxiety, due to fear of infection12); moreover, the COVID-19 pandemic has led to anincrease in the number of people with depression symptoms in the United States13). In Japan, thepandemic has led to significant changes in various behavioral patterns, such as people preferring tostay home due to fear of being infected. It has been reported that people with comorbidities, such as
diabetes and malignancy, as well as older people are at an increased risk of death from COVID-1914,15).
Therefore, older people at high risk of severe disease are thought to be less likely to go out andinteract with their neighbors. Kimura et al reported that restrictions on gyms, activities, and social
participation may lead to increased depression16). The lockdown measures implemented after the
pandemic began were found to be associated with greater depression and anxiety symptoms than
before the pandemic17-21). Moreover, the prevalence of depression symptoms was reported to increaseby nearly three times after the pandemic started, compared with before the pandemic, due to limitedsocial activities13). Prior studies into these changes mostly consist of online questionnaires13,17-26) andhave not sufficiently examined older populations, who are more likely to lack access to Internet.
Consequently, it is not yet clear how this change has affected the neighborhood relations ofcommunity-dwelling older adults, or whether it has changed or worsened their depression andanxiety symptoms.
To fill the gap in research, this study investigated the relationship between changes inneighborhood social interactions and depression and anxiety symptoms among community-dwellingolder adults before and after the start of the COVID-19 pandemic.

Methods
Target population
The survey was conducted in Daito City in the Kansai region of Japan, a city where the proportionof older adults is 27.3% of the community, as of 2021, and the population is gradually aging. We
obtained the cooperation of 60 stores operated by the drugstore company located in Daito City, and
510 individuals aged 65 years or older who used these drugstores on a daily basis were asked by store
clerks to complete the questionnaire. The participants were not compensated for completing this- 20 -

Depression and Anxiety in Older Adults after the Pandemic

questionnaire, but were informed that they would receive compensation for participating in a future
follow-up study. The store clerks assisted the participants in filling out the questionnaire. Those who
had been diagnosed with dementia or mild cognitive impairment, and those who had visited a medical
institution for cognitive impairment, were excluded from the survey. The questionnaire survey wasadministered from January 2021 to May 2021.
Questionnaire contents
The questionnaire contained items to record age, gender, education, medical history (diabetes,
heart disease, stroke, hypertension, dyslipidemia, cancer, and deafness), drinking habits, smoking
habits, subjective health, living arrangements, frequency of interacting with neighbors before the
COVID-19 pandemic, frequency of interacting with neighbors during frequency of interacting withneighbors during the past three months, and current depression and anxiety symptoms. Diabetes,
heart disease, stroke, hypertension, dyslipidemia, and cancer are some of the diseases listed ascommon among middle-aged and older people in the Japanese governmentʼs Longitudinal Study ofMiddle-aged and Older People27). In addition, it has been reported that older people with hearing loss
have fewer interactions with others, and thus, feel lonelier. Therefore, in this questionnaire, theseseven diseases were identified for the history of disease28). For the question on frequency ofinteraction with neighbors before COVID-19, the questionnaire was administered in a retrospective
manner.
For the frequency of interaction with neighbors, the respondents were asked to choose from four
options: “1: always”, “2: sometimes”, “3: not often”, and “4: never”. Participants were divided into fourgroups based on their answers, from group 1 ʻalwaysʼ to group 4 ʻneverʼ. The question on thefrequency of interactions with neighbors was based on the quadrant method used in the Longitudinal
Study of Middle-aged and Older People27).
For drinking habits, the respondents were asked to choose from seven options: “1: every day”, “2:
5-6 days a week”, “3: 3-4 days a week”, “4: 1-2 days a week”, “5: 1-3 times a month”, “6: rarely drink”,
and “7: never drink”. The responses were tabulated and answers of 1-5 were judged to be “habitual
drinkers”, while answers of 6-7 were judged to be “non-drinkers”.
For smoking habits, the respondents were asked to choose from among five options: “1: over 31
cigarettes a day”, “2: 21-30 cigarettes a day”, “3: 11-20 cigarettes a day”, “4: 1-10 cigarettes a day”, “5:never smoke”. The responses were tabulated, and those who chose the responses 1-4 were determined
to be “habitual smokers”, while those who answered 5 were judged to be “non-smokers”.
For subjective health, the respondents were asked to choose from the following six options: “1: verygood”, “2: good”, “3: rather good”, “4: rather bad”, “5: bad”, and “6: very bad”. The responses weretallied and answers of 1-3 were categorized as “good subjective health” and 4-6 as “poor subjective
health”.
The Kessler Psychological Distress Scale-6 (K6) was used to assess depression and anxiety
symptoms. The K6 is a self-administered scale developed by Kessler et al in 2002 to assess depression
and anxiety symptoms during the previous month29), and its reliability and validity (in Japanese) havebeen confirmed30). K6 items are answered with six items on a five-point scale ranging from “0: not atall” to “4: always”. The score range is from 0 to 24, and scores of 13 or higher has been proposed asindicating serious mental disorders, while scores of 5 or higher has been proposed as indicating
psychological stress in the general population23).
Statistical analysis- 21 -

Kurozumi et al

Statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical
University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for
Statistical Computing, Vienna, Austria, version 2.13.0)31).
To determine whether demographic and health characteristics affect the frequency ofneighborhood interaction, cross tabulations were conducted in the four groups (mentioned below),according to the frequency of interaction in the neighborhood. The p-values of the tabulation tablewere examined for age and years of education using the Kruskal-Wallis test, and a chi-squared test
was used for other categorical data. The pairwise comparisons using a chi-square test were used tocompare the proportions between groups. The p-values were adjusted using the Bonferroni
correction.
The participants were divided into four groups according to the frequency of neighborhoodinteraction in the three months after the start of the COVID-19 pandemic, and an inter-groupcomparison of K6 scores was performed using the Kruskal-Wallis test in the four groups. In addition,a Steel-Dwass multiple comparison correction was used to compare even pairs in the four groups.
A Wilcoxon signed rank test was performed to determine participantsʼ frequency of neighborhoodinteractions before and after the COVID-19 pandemic started.
In addition, the frequencies of neighborhood interactions before and after the COVID-19 pandemic
were compared individually for each person and divided into two groups: decreased, and nondecreased (unchanged or increased), and the groups were compared using the Mann-Whitney U test
for K6 score.
The participants were divided into sixteen combinations according to the type of change in thefrequency of neighborhood interactions before and after the start of the COVID-19 pandemic, and apairwise comparison of K6 scores was performed using the Kruskal-Wallis test for the sixteen
combinations. In addition, a Steel-Dwass multiple comparison correction was used to compare evenpairs in the sixteen combinations.
In this study, the significance level was set at 5%.
Ethical considerations
Participants were provided with an explanatory document containing the details of the study at
the time the questionnaire was provided, and were asked to sign a consent form if they agreed toparticipate. This study was approved by the Ethical Committee of Osaka City University Graduate
School of Medicine (approval number: 2020-238).

Results
Our questionnaire survey produced responses from 510 community-dwelling older adults. A totalof 460 completed questionnaires (125 male and 335 female participants, inclusion rate of 86.8%, mean
age: 73.5 [standard deviation: ±6.8] years) were included in the analysis. Questionnaires withoutliers were excluded from analysis.
Table 1 shows the participantsʼ demographic and health characteristics. Participants were divided
into four groups, based on the frequency of neighborhood interaction before or after the start of the
COVID-19 pandemic. Before the COVID-19 pandemic, gender (p＜0.001) and a history of diabetes (p＝0.049) were both significantly associated with the frequency of neighborhood interaction. After the

COVID-19 pandemic began, gender (p＝0.021), drinking habits (p＝0.032) and K6 score (p＝0.033)
were significantly associated with the frequency of neighborhood interaction. In the group- 22 -

Depression and Anxiety in Older Adults after the Pandemic

comparison, there was a significant difference in the K6 score between “1. always” and “4. never” (p＝0.041).
Table 2 shows the changes in the frequency of interactions with neighbors before and after thestart of the pandemic. The frequency of interaction with neighbors after the start of the pandemic
decreased, compared to before the pandemic (p＜0.001).
Figure 1 shows the association between K6 scores and the change in frequency of interaction withneighbors before and after the start of the COVID-19 pandemic. The median (first quartile point [Q1],third quartile point [Q3]) K6 score was 2 (0, 5) in the decreased group, 1 (0, 3) in the non-decreased
group. The participants in the group with decreased frequency of neighborhood interaction after the
COVID-19 pandemic had significantly higher K6 scores than the non-decreased group (p＝0.002).

Table 1. Descriptive statistics: overall and stratified by the frequency of interaction with neighbors
before and after the start of the pandemic
Frequency of interactions with neighbors
Characteristics
Before or after the COVID-19
pandemic
Demographics
Overall, nGender, n
Male

Total

AlwaysSometimes

Not often

Never

Before After Before After Before After Before After

460

149

89

160

150

98

145

53

76

p
BeforeAfter＜0.001a0.021b

0.137
0.140

0.050
0.636

125

25

15

43

39

33

42

24

29

FemaleAge, mean years
Years of Education, mean years
Health and lifestyle
Medical history, n

335
73.5
12.3

124
74.5
12.1

74
75
12.3

117
73.2
12.4

111
73.6
12.3

65
72.4
12.6

103
72.5
12.4

29
73.3
12.1

47
73
12.1

Diabetes
Heart disease
StrokeHypertension
Dyslipidemia
CancerDeafness
Drinking habit, n
Smoking habit, n

63
43
14
183
84
24
48
180
36

13
14
4
65
31
6
13
49
7

8
7
1
45
23
4
8
27
4

21
15
4
57
29
8
17
70
13

17
18
6
58
24
4
14
72
12

17
8
2
37
15
6
12
39
11

23
10
2
52
24
11
19
51
15

12
6
4
24
9
4
6
22
5

15
8
5
28
13
5
7
30
5

0.049
0.939
0.240
0.406
0.734
0.756
0.835
0.260
0.284

0.151
0.452
0.104
0.133
0.232
0.262
0.655
0.032
0.421

Living arrangements, nMore than one person
Living alone
Subjective health, n

349
111

110
39

70
19

125
35

109
41

71
27

111
34

43
10

59
17

0.529

0.710

416
44

134
15

80
9

146
14

139
11

90
8

133
12

46
7

64
12

0.753

0.206

Good
Bad
K6, n
score (0-4)

362

76

118

113

55

score (5-12)score (13-24)

92
6

12
1

31
1

32
0

17
4

0.033 cCOVID-19, coronavirus disease, SD, standard deviations, and K6, Kessler Psychological Distress Scale-6.
apairwise comparisons of always vs not often, p＝0.022, and pairwise comparisons of always vs. never, p＜0.001.

b

pairwise comparisons of always vs never, p＝0.022.
pairwise comparisons of always vs never, p＝0.041.

c- 23 -

Kurozumi et al
Table 2. C hanges in the frequency of interactions with neighbors before and after the start of thepandemicFrequency of interactions with neighbors after the start of the pandemic, nAlwaysFrequency of interaction with
Sometimes
neighbors before the start ofNot often
the pandemic, n
Never
Total

AlwaysSometimes

Not often

Never

86
3
0
0
89

42
100
6
2
150

17
53
74
1
145

4
4
18
50
76

Total
149
160
98
53
460

Figure 1. Boxplots of distribution of K6 scores stratified by change of frequency around the COVID-19 pandemic. K6,
Kessler Psychological Distress Scale-6, and COVID-19, coronavirus disease.

There were no significant differences found between the 16 combinations according to the type ofchange in frequency of neighborhood interactions before and after the start of the COVID-19
pandemic.

Discussion
This study examined the relationship between the frequency of interacting with neighbors anddepression and anxiety symptoms in community-dwelling older adults during the COVID-19
pandemic. Our study produced two important clinical observations. First, the frequency ofinteraction with neighbors among community-dwelling older adults decreased after the start of thepandemic, compared to before the pandemic. Second, participants who decreased the frequency ofsocializing with their neighbors may have worsened depression and anxiety symptoms, comparedwith those who did not change.
First, we address the decrease in the frequency of interaction with neighbors after the pandemic
started. There are several reasons for community-dwelling older adults to limit their activities, such
- 24 -

Depression and Anxiety in Older Adults after the Pandemic

as interacting with their neighbors. COVID-19 infection carries a very high mortality risk for older
adults22,32); therefore, they may tend to take the governmentʼs request for self-restraint very seriously
and increase the amount of time spent in the home. These requests were not intended to force people
to take specific actions, as is the case with lockdowns in major cities globally, but rather to ask people
to refrain from social activities. In particular, those who regularly consumed alcohol showed adecrease in the frequency of interacting with neighbors after the COVID-19 pandemic started. It has
been reported that the isolation caused by COVID-19 increased drinking alone 23), and people withdrinking habits may have been staying at home and drinking, limiting their interaction with theirneighbors. Our results also showed a correlation between the frequency of neighborhood interactions
and history of diabetes before the COVID-19 pandemic. Older adults with diabetes may have hadless social interaction because many have diabetes-related complications and decreased activities ofdaily living than the general older population.
Our second finding is that the decrease in frequency of socializing with their neighbors may haveworsened depression and anxiety symptoms, compared with those who did not decrease theirfrequency of socialization. The strong correlation between depression symptoms and the frequency ofinteraction with neighbors in older adults has been reported previously8,33-35). In this study, 92 patients(20%) had K6 scores of between 5 and 12, and 6 patients (1.3%) had K6 scores of 13 or higher,
indicating serious mental disorders. In another Japanese study, the former was 36.6%, and the latter
was 11.5%24). The reason for the difference in the results may be that the previous study targeted allages and included a large number of young people who were strongly affected by the COVID-19
pandemic; their survey was conducted around May 2020, when COVID-19 began to spread and people
may have felt more anxious. Many studies have pointed out an increase in depression and anxiety
symptoms in younger people, rather than in older people36,37). One of the factors may be that younger
people, who were more active, were more affected by the behavioral restrictions imposed by COVID-19
than older people. However, it has been reported that psychological distress is higher in older age
groups25,38). This study revealed that depression symptoms worsened in older people who had lessinteraction with their neighbors, suggesting that interaction with others may be important foralleviating depression symptoms.
Less interaction with others could lead not only to depression, but also to an increased risk ofneeding nursing care, developing dementia, and early death39-41). It is therefore clear that a system toassist older adults socially is necessary. A variety of methods have been recommended to cope withthe social isolation caused by the spread of COVID-19, including the use of Internet applications andvideo chat42,43), as well as telephone support lines and support groups26,44,45). It is conceivable thatpreventing older adults from becoming isolated and engaging in social interaction from an early stage
may help prevent depression and limit the progression of dementia.
One of the main strengths of this study is that it targeted older people in the community andinvited them to complete the questionnaire at a location they were likely to use on a daily basis.
Since the start of the pandemic, many studies have used online questionnaires to gather data.
However, this study may have lower participant bias because physical questionnaires wereadministered in a drugstore, which allowed us to target people who do not have Internet access or
who are uncomfortable with electronic devices.
This study had five limitations. First, in the present study, we used a subjective choicequestionnaire, the information before the COVID-19 pandemic was collected retrospectively, the size
- 25 -

Kurozumi et alof the current study was small, and we did not conduct multivariate analysis, which may haveintroduced bias in the study results. However, we consider this study to be valuable because studies
that investigated the actual situation of older people without using the Internet during the COVID-19
pandemic are distinctive. Second, we did not investigate the history of COVID-19 infection in thisstudy. In total, 1151 people were infected with COVID-19 in Daito City from the beginning of the
COVID-19 pandemic to May 2021, which is only 0.96% of the cityʼs population. Therefore, the numberof subjects with depressive symptoms as a reaction to the aftereffects of COVID-19 infection or the
event of being infected was small, and we considered the effect to be minor. Third, during the study
period, both the national and local governments were continuously appealing to people to refrain fromsocial activities; it is therefore possible that the difference in whether the request was made by theJapanese government or the local government may have affected the frequency of peopleʼssocialization. Fourth, the survey was conducted at drugstores and the target population was active
older adults who could come to the drugstore. Therefore, the frequency of depression and anxiety
symptoms may have been lower than that of the total older population. Fifth, we could not determine
an association between the degree of change in the frequency of neighborhood socializing and thechange in K6 score. It is possible that the comparisons did not result in a significant difference due tothe small sample size. Finally, this study did not determine causation between depression andanxiety symptoms worsening and the participants reducing their neighborhood interactions. Further
studies are needed to understand this causation and how neighborhood association and depression
change during the pandemic, including a larger number of participants by using a method toprospectively record neighborhood relations and depression.
This study found that the frequency of interaction with neighbors decreased due to the COVID-19
pandemic, and that depression and anxiety symptoms were exacerbated among those who interactedwith neighbors less. We found that depression symptoms worsened not only in the younger age groupas previous research has shown, but also among older adults whose social interaction with neighbors
decreased. Older adults, who are likely to have limited social activities due to the COVID-19
pandemic, need to maintain neighborhood and social activities to prevent depression and anxiety
symptoms, and social support is important for them to do so.
Acknowledgements
All authors have no COI to declare regarding the present study.
We would like to thank Editage (https://www.editage.com) for English language editing. The
authors acknowledge the role of the Wellness Open Living Lab in conducting this study. We would
also like to express our sincere gratitude to all the people who understood the purpose of this study
and willingly cooperated.
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45. Wang H, Li T, Barbarino P, et al. Dementia care during COVID-19. Lancet 2020;395:1190-1191.

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Osaka City Med. J. Vol. 68, 29-38, 2022

Comparison of Clinical Test Results in Pollen-food Allergy
Syndrome: Multicenter Case Series StudyTAISUKE HASHIMOTO1), SAKI KASUGA1), SAKURA ANDO1), NAHO YAMAMOTO1), SHIORI FUJIKAWA1),
HIROKO FUJITANI2), and TAKASHI HAMAZAKI1)
Department of Pediatrics1), Osaka City University Graduate School of Medicine; andFujitani Clinic2)

Abstract
BackgroundThe crude antigen-specific immunoglobulin E (IgE) test does not necessarily have a highsensitivity and specificity for the diagnosis of pollen-food allergy syndrome (PFAS). The skin prick-toprick test (PPT) has a high sensitivity; however, it can induce allergic symptoms, similar to the oral
food challenge (OFC). A new in vitro test for the diagnosis of PFAS is required. This study aimed tocompare the results of the basophil activation test (BAT) to the results of the other tests in PFAS.
Methods
To compare the sensitivities of the crude antigen-specific IgE test, PPT, and BAT-CD203c fordiagnosing PFAS, we performed these tests on patients with PFAS. To examine the correlation
between threshold doses and basophil CD203c expression levels, we also performed OFC on thepatients and determined their threshold doses according to the results. We compared basophil
CD203c expression levels in patients with oral symptoms and those with systemic symptoms in PFAS.
Results
Ten patients with PFAS induced by eating peach, watermelon, or tomato were analyzed. BATCD203c, crude antigen-specific IgE test, and PPT showed sensitivities of 93.3%, 86.7%, and 60%,
respectively. There was a significant negative correlation between threshold doses and basophil
CD203c expression levels. Basophil CD203c expression levels for the patient with systemic symptoms
induced by eating peach were markedly higher than those for patients with oral symptoms.
Conclusions
BAT-CD203c has a high sensitivity in the diagnosis of PFAS and may be useful for predicting thethreshold doses. BAT-CD203c may distinguish systemic and oral symptoms in peach allergy.
Key Words: ‌Basophil degranulation test; Food allergy; Peach; Tomato; Watermelon

Received September 15, 2021; accepted November 30, 2021.
Correspondence to: Taisuke Hashimoto, MD.
Department of Pediatrics, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3816; Fax: +81-6-6636-8737
E-mail: hashimotot.5591@gmail.com- 29 -Hashimoto et al

Introduction
Pollen-food allergy syndrome (PFAS) is a food allergy based on cross-reactivity between pollens
and food antigens. Its typical symptoms are isolated in the oropharynx, and systemic reactions are
unusual1). The prevalence rates of PFAS have been reported to be 13%-58% in adults and 4.2% inchildren2). There is a concern that the number of children with PFAS will increase in the future aspollinosis develops at a younger age3). The symptoms of PFAS are mostly subjective, and a detailed
medical history is important for the diagnosis of PFAS4,5). However, it is sometimes difficult todiagnose PFAS in children who have difficulty explaining their symptoms and medical history.
Therefore, a superior test to assist the diagnosis of PFAS is needed.
Some objective tests for diagnosing PFAS have been verified, such as the allergen-specificimmunoglobulin E (IgE) test, skin prick test, and oral food challenge (OFC)1,6). The crude antigenspecific IgE test has been reported to have a sensitivity of approximately 20%-70% and a specificity of
approximately 60%-90%7). Therefore, it does not necessarily have high sensitivity and specificity forthe diagnosis of PFAS. In addition, the crude antigen-specific IgE test result may be negative, even if
systemic symptoms appear in PFAS. For example, the sensitivity of the peach-specific IgE test forsevere peach allergy has been reported to be approximately 70%8). Therefore, the crude antigenspecific IgE test is insufficient to predict the risk of systemic symptoms. The allergen componentspecific IgE test has been reported to be useful for predicting the risk of systemic symptoms 9,10).
However, it has not been sufficiently covered by medical insurance in Japan. The skin prick test,
especially the prick-to-prick test (PPT), which is performed using fruit and vegetable pulps, has beenreported to have higher sensitivity in the diagnosis of PFAS than the allergen-specific IgE test 7).
However, it is difficult to predict the risk of systemic symptoms using the skin prick test and crude
antigen-specific IgE test8), and the skin prick test has a high risk of inducing allergic symptoms inpatients who have had systemic symptoms after ingestion of the causative food. If it is difficult todiagnose PFAS even after taking a detailed medical history and performing an allergen-specific IgEtest and skin prick test, OFC is finally performed. A double-blind placebo-controlled food challenge(DBPCFC) is recommended because the symptoms of PFAS are mostly subjective11). Patients withsystemic symptoms can be diagnosed with PFAS even with an open food challenge. Because OFC has
a high risk of inducing allergic symptoms, a new in vitro test for the diagnosis of PFAS is needed.
The basophil activation test (BAT) is a less invasive test than PPT and OFC. In addition, it is amore useful method for identifying rare allergens compared to the allergen-specific IgE test, in which
identifiable allergens are limited12). Basophils are activated by allergen-bound IgE antibodies, release
inf lammatory mediators such as histamine, and produce Th2-type cytokines [interleukin (IL)-4, IL13] to induce allergic symptoms13). The basophil surface markers, CD63 and CD203c, indicate
basophil activation, and BAT detects the levels of these markers using a f low cytometer14). The BAT
has been reported to have high sensitivity and specificity for the diagnosis of peanut, milk, egg, andwheat allergy15-17). Regarding the usefulness of BAT in diagnosing PFAS, there are some reports
demonstrating the sensitivity and specificity of BAT18-21). However, the allergens examined in thesereports are limited. Regarding the usefulness of BAT in predicting the severity of PFAS, some studies
have examined the difference in BAT between systemic and oral symptoms in PFAS20,21). However, theconclusions remain unclear. Furthermore, there are no reports examining the correlation between
threshold doses and basophil CD203c expression levels in PFAS.
This study aimed to compare the result of BAT to the results of the other tests for PFAS.
- 30 -

Clinical Testing for Pollen-food Allergy Syndrome

Methods
Study design and study population
This was a multicenter case series study. Between October 2019 and March 2020, we enrolled
patients who visited the Department of Pediatrics, Osaka City University Hospital or Fujitani Clinic
in Osaka Prefecture and were diagnosed with PFAS. All patients were diagnosed with PFAS because
they had a history of oral symptoms due to ingestion of raw fruits or vegetables and tested positive
for specific IgE against the pollen that had been reported to be cross-reactive with the causative food.
They underwent the crude antigen-specific IgE test, PPT, and BAT against the causative foods, andwe examined the sensitivity of each test for the diagnosis of PFAS. OFC was performed on thepatients who consented to the test, and their threshold doses were determined based on the results of
OFC. We examined the correlation between threshold doses and basophil CD203c expression levels.
Patients with systemic symptoms also underwent the crude antigen-specific IgE test, PPT, and BATagainst the causative foods, and we compared the results with those of patients who had only oral
symptoms. Furthermore, to compare basophil CD203c expression levels in patients with PFAS andhealthy subjects, we also performed BAT-CD203c in healthy subjects who did not have food allergies.
Specific immunoglobulin E test
Allergen-specific IgE was measured using ImmunoCAPTM (Thermo Fisher Diagnostics, Uppsala,Sweden). We defined allergen-specific IgE antibody titers of ＜0.1 UA/mL as 0 UA/mL and of ≧100 UA/
mL as 100 UA/mL. We also defined allergen-specific IgE antibody titer of ≧0.35 UA/mL (CAP class 1)
as positive.
Prick-to-prick test
Patients were instructed to stop taking antihistamines 3 days before undergoing PPT. BifurcatedNeedle® (Allergy Laboratories, Ohio, Inc., USA) was used as the pricking needle. After piercing thepulp of raw fruits or vegetables with a pricking needle, it was pressed against the skin of the patientʼs
forearm 22). Allergen Scratch Extract Positive control (Torii) histamine dihydrochloride ® (Torii
Pharmaceutical Co., Ltd., Japan) and saline were used as positive and negative controls, respectively.
Swelling more than twice the size of the positive control was defined as 4 (＋), equivalent to that of 3(＋), half of that as 2 (＋), less than half of that and larger than the size of the negative control as 1 ( ＋),and equivalent or smaller than that of negative control as 0 (−).We defined 2 (＋) or more as a positive
response.
Extraction of fruit and vegetable allergens
In brief, the pulp of raw fruits or vegetables was minced and pureed in a food processor, andextraction buffer was added to it. The particles were separated by centrifugation for 10 min at 2000
rpm. The supernatant was collected for use as an extract and dialyzed against phosphate-bufferedsaline (PBS) overnight. The extracts were freeze-dried and stored at −80℃ until use. The frozen
extracts were reconstituted in PBS, and the protein concentration in each extract was measured witha spectrophotometer (NanoDropTM 2000c, Thermo Fisher Scientific, Wilmington, DE, USA) and diluted
to 10 and 100 μg/mL with PBS at the time of use.
Basophil activation test (BAT-CD203c)
To quantify basophil CD203c expression, BAT was performed using a commercial kit (Allergenicity
Kit, Beckman Coulter, Fullerton, CA, USA) in a manner similar to that in a previous study17). In brief,
ethylenediaminetetraacetic acid-containing whole blood was incubated with each antigen extract at
protein concentrations of 10 and 100 μg/mL for 10 min at 37℃ after the addition of activation solution- 31 -Hashimoto et al

and the mixture of phycoerythrin-cyanine 7-labeled anti-CD3, f luorescein isothiocyanate-labeled antiCRTH2, and phycoerythrin-labeled anti-CD203c for cell activation and staining of cell surface
antigens. Anti-IgE antibody at 10 μg/mL was used as a positive control, and PBS was used as anegative control. The samples were analyzed using a f low cytometer (GalliosTM, Beckman Coulter).
Basophils were identified based on their forward- and side-scatter properties, the absence of CD3
expression, and the presence of CRTH2 expression. Upregulation of CD203c on basophils wasdetermined using a threshold defined by the f luorescence of unstimulated cells (negative control).
The ratio of CD203c expression level induced by a food allergen to that induced by PBS was expressedas the CD203c stimulation index (SI), and CD203c SI ≧2 was defined as positive16）. Patients with
CD203c expression levels induced by an anti-human IgE antibody ＜10% were defined as low
responders and excluded from the analysis.
Oral food challenge
OFC was performed openly. The patients ingested 20g of raw fruits or vegetables at 5-minintervals and up to 100g. OFC was discontinued if subjective or objective symptoms were observed,
and total intake was defined as the threshold dose.
Statistical analyses
Sensitivity was calculated as the positivity rate for each test in the patients with PFAS. The
correlation between threshold doses and BAT-CD203c SI was analyzed using Spearmanʼs rankcorrelation coefficient. The difference in BAT-CD203c SI between patients with PFAS and healthy
subjects was analyzed using the Mann-Whitney U test. Statistical significance was set at p＜0.05.
Statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical
University, Saitama, Japan).
Ethics statement
This study was approved by the Ethical Committee of Osaka City University Graduate School of
Medicine (#4411). Informed consent was obtained from the patients or their guardians.

Results
Characteristics of patients
Ten patients were enrolled and underwent clinical testing (Table 1). Patients aged 8 to 19(median, 12) years were included, and six (60%) were male. Food allergens included peach (70%),
watermelon (60%), and tomato (20%). Half of the patients had atopic dermatitis and bronchialasthma, and all patients had allergic rhinitis. The median total IgE levels were 1200 (range: 3602700) IU/mL, and the median pollen-specific IgE levels were higher in the order Japanese cedar (83UA/mL), alder (64.7 UA/mL), and orchard grass (2.13 UA/mL). No low responders were found in BAT.
Sensitivity of tests
The sensitivities of the crude antigen-specific IgE antibody test, PPT, and BAT-CD203c against
food allergens in the diagnosis of PFAS were examined (Table 2). The sensitivities of the crude
antigen-specific IgE antibody test were 85.7%, 83.3%, and 100% for peach, watermelon, and tomato,respectively. Similarly, the sensitivities of PPT, BAT-CD203c in the extract at 10 μg/mL, and BATCD203c in the extract at 100 μg/mL were 71.4%, 50%, and 50%; 14.3%, 33.3%, and 100%; and 85.7%,
100%, and 100% for peach, watermelon, and tomato, respectively. For total food allergens, BATCD203c in the extract at 100 μg/mL showed the highest sensitivity (93.3%), followed by the crude
antigen-specific IgE antibody test (86.7%), PPT (60%), and BAT-CD203c in the extract at 10 μg/mL- 32 -

Clinical Testing for Pollen-food Allergy Syndrome
Table 1. Demographics and clinical test results of ten patients with PFAS
Subject Age/Sex

1

8/F

AD

BA

AR

T-IgE

Japanese
cedar
sIgE

Alder
sIgE

Orchard
grass
sIgE

＋

−

＋

2700

90.7

100

11.5

Crude
antigen
sIgE

PPT

Peach

84.4

2

1.02

39.36

Watermelon

5.8

2

4.22

66.79

NA

5.54

3

13.24

76.35

20g

Allergen

BAT-CD203c SI BAT-CD203c SI Threshold(10 μg/mL)(100 μg/mL) doses

NA

2

12/M

−

−

＋

2000

100

86.7

9.14

Watermelon
Tomato

13.3

3

6.32

73.48

NA

3

9/F

＋

＋

＋

1400

57.5

17.8

0.48

Peach

15.0

2

3.13

39.84

40g

4

14/M

＋

＋

＋

576

100

27.8

32.5

Watermelon

1.47

3

0.44

146.79

NA

5

19/F

＋

＋

＋

2339

29.0

0.89

2.16

Watermelon

0.82

0

1.62

157.86

NA

6

18/M

−

−

＋

835

75.3

53.3

2.09

Peach

10.4

2

0.56

21.35

100g

7

12/F

−

−

＋

360

0.14

8.07

0.19

Peach

0.1

0

0.60

1.31

80g

Watermelon

0

0

1.21

81.0

40g

8

11/M

−

−

＋

1207

100

100

24.7

Peach

50.5

4

1.40

15.55

NA

Watermelon

1.78

0

1.47

17.65

NA

9

16/M

−

＋

＋

873

43.7

76.1

2.0

Peach

27.7

0

1.21

16.63

NA

Tomato

1.73

0

2.62

13.76

NA

Peach

59.1

2

1.33

18.03

NA

10

12/M

＋

＋

＋

1192

100

92.9

1.47

PFAS, pollen-food allergy syndrome; AD, atopic dermatitis; BA, bronchial asthma; AR, allergic rhinitis; T-IgE, total
IgE; sIgE, specific IgE; PPT, prick-to-prick test; BAT, basophil activation test; SI, stimulation index; and NA, notavailable.

Table 2. Results and sensitivities of tests in PFAS patients
Test

Median (range)

Sensitivity

Specific IgE (UA/mL)
Peach
Watermelon
TomatoTotal

27.7 (0.1-84.4)
1.63 (0-5.8)
7.52 (1.73-13.3)
5.8 (0-84.4)

85.7%
83.3%
100%
86.7%

PPT (＋)
Peach
Watermelon
TomatoTotal

2 (0-4)
1 (0-3)
1.5 (0-3)
2 (0-4)

71.4%
50%
50%
60%

BAT-CD203c SI (extract at 10 μg/mL)
Peach
Watermelon
TomatoTotal

1.21 (0.56-3.13)
1.54 (0.44-13.24)
4.47 (2.62-6.32)
1.40 (0.44-13.24)

14.3%
33.3%
100%
33.3%

BAT-CD203c SI (extract at 100 μg/mL)
Peach
Watermelon
TomatoTotal

18.03 (1.31-39.84)
78.67 (17.65-157.86)
43.62 (13.76-73.48)
39.36 (1.31-157.86)

85.7%
100%
100%
93.3%

PPT, prick-to-prick test; BAT, basophil activation test; and SI, stimulation index.

(33.3%).
Correlation between BAT-CD203c SI and threshold dose
OFC was performed on four patients who consented to the test (peach: n＝2, watermelon: n＝1,
- 33 -Hashimoto et alboth peach and watermelon: n＝1), and the correlation between threshold doses and BAT-CD203c SI
was examined (Fig. 1). There was a significant negative correlation between threshold doses and
BAT-CD203c SI in the extract at 10 μg/mL (rs＝−0.975, p＝0.005). The correlation between thresholddoses and BAT-CD203c SI in the extract at 100 μg/mL tended to be negative, although not significant(rs＝−0.718, p＝0.172).
Difference in laboratory results between systemic and oral symptoms in peach allergy
The laboratory results of seven patients who had oral allergy symptoms (OAS) (OAS patients)
after eating raw peach were compared with those of a patient who had systemic symptoms [systemic
reaction (SR) patient] (Table 3). Total IgE was normal in the SR patient, but it was high in OAS
patients. Peach-specific IgE was negative in the SR patient; in contrast, it was positive in six of theseven OAS patients. Specific IgEs against Pru p 1, 3, 4, and 7, which are peach allergen components,
was measured in the SR and OAS patients. In the SR patient, Pru p 1-, 3-, and 4-specific IgE levels
were negative, and the Pru p 7-specific IgE level increased to 0.67 UA/mL (CAP class 1). Pru p 7 aspeach gibberellin-regulated protein (GRP) has been identified8), and GRP has been reported as foodantigens that result in systemic symptoms10). Therefore, we diagnosed the SR patient as having peach
GRP allergy. In contrast, among the OAS patients, Pru p 1-specific IgE was positive in six of theseven patients, Pru p 4-specific IgE was positive in two of the seven patients, and Pru p 3- and7-specific IgE were negative in all patients. Alder-specific IgE was negative in the SR patient andpositive in all OAS patients. PPT was positive in the SR patient and in five of the seven OAS
patients. BAT-CD203c was performed on the SR patient, the seven OAS patients, and six healthy
controls (Fig. 2). In healthy controls, BAT-CD203c SI in the extracts at both 10 and 100 μg/mL wasnegative. In the OAS patients, BAT-CD203c SI in the extract at 10 μg/mL was positive in one of theseven patients and in the extract at 100 μg/mL was positive in six of the seven patients. BAT-CD203c

Figure 1. Correlation between BAT-CD203c SI and threshold dose in patients with PFAS. There was a significant
negative correlation between threshold doses and BAT-CD203c SI in the extract at (a) 10 μg/mL (n＝5, rs＝−0.975, p＝0.005). The correlation between threshold doses and BAT-CD203c SI in the extract at (b) 100 μg/mL tended to be
negative, although not significant (n＝5, rs＝−0.718, p＝0.172). BAT, basophil activation test; SI, stimulation index; andPFAS, pollen-food allergy syndrome.

- 34 -

Clinical Testing for Pollen-food Allergy Syndrome

SI in the extract at 100 μg/mL was significantly higher in the OAS patients than in healthy controls.
In the SR patient, BAT-CD203c SI in the extract at both 10 and 100 μg/mL was positive, and BATCD203c SI in the extract at 10 μg/mL was markedly higher than that in the OAS patients andhealthy controls.

Table 3. Demographics and sensitization of patients with peach allergy
Peach allergy
SR (n＝1)

OAS (n＝7)

Age (y)Female24112 (8-18)
3 (43)

Total IgE (IU/mL)
Specific IgE (UA/mL)
Peach
Pru p 1
Pru p 3
Pru p 4
Pru p 7
Japanese cedar
Alder
PPT (＋)

35

1192 (360-2700)

0
0
0
0
0.67
6.38
0

27.7 (0.1-84.4)
44.8 (0-100)
0 (0-0.34)
0 (0-46)
0 (0-0.29)
75.3 (0.14-100)
76.1 (8.07-100)

22 (0-4)

Values in OAS are expressed as median (range) or numbers (percentages). SR,
systemic reaction; and OAS, oral allergy syndrome.

Figure 2. Comparison of BAT-CD203c SI in peach allergy and healthy control. BAT-CD203c was performed on the SR
patient, the seven OAS patients, and six healthy controls. BAT-CD203c SI in the extract at (b) 100 μg/mL wassignificantly higher in the OAS patients than in healthy controls. In the SR patient, BAT-CD203c SI in the extract at
both (a) 10 and (b) 100 μg/mL was positive, and BAT-CD203c SI in the extract at (a) 10 μg/mL was markedly higher
than that in the OAS patients and healthy controls. ＊p＜0.05. BAT, basophil activation test; SI, stimulation index; SR,
systemic reaction; OAS, oral allergy syndrome; HC, healthy control; and N.S., not significant.

- 35 -Hashimoto et al

Discussion
In this study, we found that BAT-CD203c using crude antigen extracts showed high sensitivity inthe diagnosis of PFAS. Moreover, the higher the BAT-CD203c SI, the lower the threshold dose. We
suggest that BAT-CD203c using peach extracts may distinguish between systemic and oral symptoms
in peach allergy.
It has been reported that BAT has a high sensitivity and specificity in the diagnosis of peanut,
milk, egg, and wheat allergies15-17) and has a high diagnostic accuracy for PFAS18-21). In this study, we
showed that BAT has a high sensitivity for the diagnosis of PFAS, a result consistent with those ofprevious studies. There have been no reports examining the correlation between threshold doses and
BAT-CD203c. In this study, we reported for the first time that there was a significant negative
correlation between threshold doses on the basis of the results of OFC and BAT-CD203c SI for PFAS.
Therefore, BAT may be useful for predicting the threshold doses of food allergens for PFAS. There
have been some reports examining the difference in BAT between systemic and oral symptoms for
PFAS20,21). However, there has been no consensus on this topic. In fruit and vegetable allergies, lipid
transfer protein (LTP) and GRP have been reported as food antigens that result in systemic
symptoms and sometimes anaphylaxis9,10). Pru p 3 as peach LTP and Pru p 7 as peach GRP have been
identified8,23). Fruit peels contain more LTP, whereas fruit pulp contains more GRP. It has beensuspected that the causative antigen of severe peach allergy in Japan is mainly Pru p 7 because mostJapanese people eat peeled peaches10). In recent years, it has been reported that cypmaclein, a cypress
GRP, is cross-reactive with Pru p 724). In this study, the patient who had systemic symptoms after
eating raw peaches was diagnosed as having GRP allergy because of an increase in the Pru p
7-specific IgE level. In this patient, BAT-CD203c in the peach extract at 10 μg/mL was markedly
higher than that in the patients who had only oral symptoms and healthy controls. This suggeststhat BAT-CD203c may be useful in predicting the risk of systemic symptoms in PFAS.
Currently, there is no unified standard for the concentration of antigen extracts used in BAT. In
this study, BAT was performed in extracts at two concentrations (10 and 100 μg/mL), and the results
at each concentration were analyzed. As a result, there were some differences in the results between
the two concentrations. First, the sensitivity of BAT in diagnosing PFAS was high at 100 μg/mL,
whereas it was low at 10 μg/mL, except for tomatoes. Second, BAT-CD203c SI in peach OAS wassignificantly higher only at 100 μg/mL than in healthy controls. Third, there was a significant
negative correlation between threshold doses and BAT-CD203c SI in the extract at 10 μg/mL. Fourth,
BAT-CD203c SI in the peach extract at 10 μg/mL was markedly higher in the SR patient than in the
OAS patients and healthy controls; however, the SI at 100 μg/mL did not differ between the SR
patient and the OAS patients. Therefore, we suggest that BAT in extracts at a higher concentration(100 μg/mL) and a lower concentration (10 μg/mL) may be useful for diagnosing PFAS and forpredicting the severity of PFAS, respectively. BAT should be performed simultaneously at multiple
antigen concentrations for one causative food. In contrary, PPT, which was reported to have highsensitivity in the diagnosis of PFAS, was less sensitive than BAT and the crude antigen-specific IgEtest in this study. This result is possibly attributed to the fact that some patients did not comply withdiscontinuation of antihistamines before PPT and that the doctor who performed PPT was not thesame person at the two medical institutions.
This study has several limitations. First, in this study, the sensitivity of each test could beobtained, but the specificity could not be obtained, which was insufficient to evaluate the diagnostic- 36 -

Clinical Testing for Pollen-food Allergy Syndrome

accuracy. However, by comparing the sensitivities of the tests in this study, it was found that BAT isa useful test for the exclusion diagnosis of PFAS. Second, the number of patients in this study was
small, and only one patient had systemic symptoms due to the ingestion of a raw peach. Therefore, it
was insufficient to compare BAT-CD203c SI in SR patients with that in OAS patients. Long-term
prospective studies are required in the future. Third, in this study, open OFCs were performed
instead of DBPCFC. This may have affected the results because PFAS mainly causes subjective
symptoms such as itching and tingling in the oropharyngeal area. The medical institutions where
DBPCFC can be performed are limited; therefore, large multicenter studies will be needed in the
future.
In conclusion, BAT-CD203c has high sensitivity for the diagnosis of PFAS and may be useful for
predicting the severity of PFAS. We suggest that BAT is a reliable tool for predicting PFAS.
Acknowledgements
All authors have no COI to declare regarding the present study.
This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. The authors thank Shinichi Takeda, Tomoko Fujisaka, Aya Ikemoto, and Shigeyoshi
Imai for their analysis of the samples using a f low cytometer and Reiko Tokuda, Mizuho Nagao, andTakao Fujisawa of the Department of Pediatrics, Mie National Hospital for their technical guidancein BAT. We would like to thank Editage (www.editage.com) for English language editing.
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- 38 -

Osaka City Med. J. Vol. 68, 39-49, 2022

Association between Job Stressors and Extended Long-term
Sickness Absence due to Mental Disorders among
Public Servants in JapanYOSHIKI SHIRAHAMA, SHINICHI IWASAKI, YASUHIKO DEGUCHI, AYA KADOWAKI, AKIHIRO NIKI,
TOMOYUKI HIROTA, YOKO NAKAMICHI, and KOKI INOUE
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine

Abstract
BackgroundLong-term sickness absence due to mental disorders in the workplace is a public health concern.
The period of sickness absence due to mental disorders tends to be much longer relative to otherdiagnoses. Few studies have investigated the period of an extended long-term sickness absence due
to mental disorders and the job factors associated with it.
Methods
This study examined differences in job stressors, stress responses, and social support between
workers who took extended (≧8 months) and the usual (3-8 months) long-term sickness absence due
to mental disorders. Data from responses to the last Brief Job Stress Questionnaire by municipal
workers in the Kinki region of Japan before their sickness absence were analyzed for the period
between 2011 and 2015. Workers who took long-term sickness absence due to mental disorders weredivided into two cohorts (usual or extended long-term sickness absence; 123 individuals each): leaveof longer or shorter than eight months (the median leave period). The Brief Job Stress Questionnaire
subscales for propensity between the two cohorts were compared using the Mann-Whitney U test.
Results
Workers with extended long-term sickness absence had higher quantitative workloads, poorer
physical environments, and less job control, than workers with usual long-term sickness absence.
Conclusions
To reduce long-term sickness absence due to mental disorders, it is necessary to pay particularattention to job stressors and implement appropriate improvements, such as increasing freedom of
discretion and reducing the workload.
Key Words: ‌Job stressors; Sickness absence; Mental disorder; Brief Job Stress
Questionnaire; Public servant

Received September 15, 2021; accepted November 30, 2021.
Correspondence to: Yoshiki Shirahama, MD.
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3821; Fax: +81-6-6636-0439
E-mail: skybluegreen.2112@gmail.com- 39 -

Shirahama et al

Introduction
Sickness absence is a significant public health and economic concern. It not only has aconsiderable social impact, but also reduces individualsʼ quality of life. Sickness absence results in a
substantial loss of productivity and insurance costs among the working population, and is a criticalrisk factor for permanent exclusion from the labor market and for disability retirement1,2). Reducing
and preventing sickness absence is crucial, as it exerts a considerable economic burden on individuals,
employers, and society3).
Mental disorders (MD) among workers are a global concern. In Japan, over 60% of workers havereportedly experienced intense occupational worry or stress4), and 32% of Japanese companies haveshown a growing number of employees who exhibit mental health problems5). The Japanese Ministryof Health, Labour and Welfare reported that in approximately 10% of all companies, employees aretaking a sickness absence of over a month or quitting their jobs due to MD6). It has been the second
largest cause of sickness absence in Japan. In Finland, an increase in sickness absence due to MD
was observed between 2016 and 2019 in all age groups of both genders7,8). Both changing andpersistent common mental disorders at the two time points, which were separated by five years,
elevated the risk of sickness absence due to MD, as well as all-cause sickness absence9). Additionally,
sickness absence due to MD has increased in a number of countries in recent times10,11).
The period of sickness absence due to MD tends to be longer concerning other diagnoses resulting
in absence, such as musculoskeletal diseases12-15). In Japan, MD are the most common causes of longterm sickness absence (LTSA), followed by cancer, with both accounting for more than half of all
LTSAs16). A study in the UK found that MD, largely neurosis and neurosis ill-defined, was the second
largest cause of long periods of sickness absence (＞21 days), accounting for 16% of absences among
men and 18% among women17). On the other hand, study of employees in a Japanese manufacturing
company reported on their sickness absence days due to MD18); the mean sickness absence period was
330.2 days for major depressive disorder, 237.8 days for adjustment disorder, and 506.2 days foranxiety disorders. In the Japanese workforce, as of 1997, the average length of absence due to MD
and non-MD were 119.5 and 47.3 days, respectively 12). As shown above, MD tend to have longer
periods of sickness absence from work than non-MD in Japan.
Public service jobs, including typical jobs in various fields such as general affairs, accounting,personnel affairs, and taxes, are among the most popular in Japan. We presumed these to represent
typical work in the country. Japanese public servants with sickness absence are provided sufficient
welfare benefits, such as being paid a part of their wages. This may permit ease of taking sickness
absence. Additionally, in comparison to private sector workers, public servants often work underuniform conditions, including having high education levels, stable wages, and guaranteed job stability
with no threat of unemployment until retirement19,20). Because of these benefits, public servants may
tend to take long sickness absences without being able to return to work early. The Japan National
Personnel Authority21) in 2017 reported that the most frequent reason given (65.5%) for sickness
absence lasting over one month was “Mental and behavioral disorders” among public servants.
Another survey by the Japan Local Government Employee Safety and Health Association22), examined
760000 local public servants in 2018 and found that 2551 per 100000 public servants took more than
one month of sickness absence; the most frequent reason given for sickness absence was “Mental andbehavioral disorders” accounting for 57.7% of the absence lasting more than one month. This rate iscontinually increasing.
- 40 -

Job Stress and Extended Long-term Sickness Absence

Several studies have reported factors associated with prolonged periods of sickness absence. A
longitudinal study in Germany demonstrated a prospective association between high job strain and
LTSA (＞6 weeks)23). A longitudinal cohort study in Norway among 543 sick listed employees revealed
that low decision control as well as psychologically demanding jobs were independent predictors ofdelayed return to work24). In Japan, diagnosis and employee rank were factors predicting the durationof sickness absence due to MD25).
A meta-analysis has shown that exposure to psychosocial stressors at work was associated with anincreased risk of a varied duration of sickness absence due to mental disorders26). However, few
studies have investigated the association between an extended LTSA due to MD and job stressors andfocused on very long-term sickness absences among public servants. According to the job stress model
proposed by the National Institute for Occupational Safety and Health, job stressors bring acutestress responses, or strains, to workers. Such short-term strains, in turn, are presumed to have an
impact on longer-term indicators of mental and physical health, such as sickness absences27).
Therefore, we hypothesize that workers with extended LTSA due to MD experience much higher job
stressors than the workers with usual LTSA-MD among public servants. We conducted a study on
the differences in job stressors between the shorter and longer leave periods among LTSA-MD
workers.

Methods
Participants
Public servants working for the municipal or ward office of City A in the Kinki region of Japananswered the Brief Job Stress Questionnaire (BJSQ) as a part of the annual Stress Check Program28).
The Japanese government launched this occupational health policy with approximately 50 employees
in 2015, to screen workers with high psychosocial stress in the workplace. We requested themunicipal office of City A for a list of workers who took a sickness absence of 90 days or more between
2011 and 2015 in the city, and for the BJSQ data collected immediately before their leave. Bothabsence data and BJSQ data were anonymized by the office staff before the acquisition. Figure 1
shows an inclusion-exclusion f lowchart. Of the 810 workers who took long-term leave of 90 days or
more, the following employees were excluded: 216 who provided incomplete responses, 161 who took
leave for reasons other than MD, and 99 who retired whilst on leave. A total of 334 workers who had
MD and provided complete answers on their last BJSQ before taking sickness absence, were analyzed
in this study.
The median sickness absence period for all participants was eight months. Participants weredivided into two cohorts based on their sickness absence period: eight months or longer (extended
LTSA) and less than eight months (usual LTSA). The presence of overcontrol bias due to common
method variance was tested using Harmanʼs single-factor test.
Ethics statement
The Human Subjects Review Committee at Osaka City University approved the protocol of thisstudy (authorization number: 3337). As the data already existed, the review committee did not
require written informed consent. We obtained the BJSQ data of the workers anonymously (withencrypted ID). The health care center of City “A” provided a list of workers who took LTSA annuallyfor a mental health checkup and evaluated and improved the psychological work environment.
Long-term sickness absence due to mental disorders- 41 -

Shirahama et al

Figure 1. Flow chart for the selected study population.

LTSA-MD is defined as MD related sickness absence for greater than 90 days. The reason for
LTSA-MD was confirmed using a medical certificate issued by a doctor. The diagnoses on thesecertificates are not necessarily based on the International Classification of Diseases, Tenth Revision(ICD-10)29). The medical certificate for each LTSA in this study was confirmed by the researchers/
issuing doctors with over 10 yearsʼ experience, who diagnosed and classified MD (F code) that
resulted in the LTSA-MD. The medical certificates occasionally had two or more diagnoses. In suchcases, if the multiple diagnoses were from a single ICD-10 category, they were classified into thatcategory. If the multiple diagnoses belonged to different categories, we classified them into thecategory of causal disease (Priority order; F0, F1, F7, F8, and F9＞F6＞F2 and F3＞F4 and F5).
Brief Job Stress Questionnaire
The BJSQ utilized questions from the Job Content Questionnaire and Generic Job Stress
Questionnaire, which were developed by the National Institute for Occupational Safety and Health.
A large-scale investigation among Japanese workers confirmed the questionnaireʼs validity andreliability30). The BJSQ evaluated 57 items on a four-point Likert scale, ranging from 1 (disagree) to 4
(agree). The items were grouped into scales of: job stressors (17 items), stress responses (29 items),social support (9 items), and work and life satisfaction (2 items). Job stressors represented
psychological stressors related to work, and comprise quantitative workload, qualitative workload,
physical demands, interpersonal conf lict, poor physical environment, job control, skill utilization,
suitable jobs, and meaningfulness of work subscales. Stress responses represented psychological andphysiological stress reactions and consist of vigor, irritability, fatigue, anxiety, depression, and- 42 -

Job Stress and Extended Long-term Sickness Absence

physical stress response subscales. Social support represented social support in the workplace andcomprised support from supervisors, from coworkers, and from family/friends subscales. Higherscores on each BJSQ subscale indicated higher levels of stress. Average scores were calculated foreach subscale by dividing the total scores by the number of items for each subscale.
Demographic and occupational variables
Gender and age were the demographic variables, whereas job rank (manager/chief/staff) and job
categories (clerical, technical, professional) were the occupational variables.
Statistical analysis
Propensity score matching was used for the two groups to minimize bias due to confounding
factors, such as the diagnosis that led to the leave, the period from the administration of BJSQ to thestart of the sickness absence, and background factors. The propensity score was calculated by logistic
regression analysis using the period in which the participants took LTSA. Extended and usual LTSA
were the dependent variables, whereas age, gender, position, occupation type, diagnosis resulting insickness absence, and the period from the time they answered BJSQ to the start of LTSA, wereindependent variables.
Matching was performed by nearest-neighbor, with one non-restoration extraction with the caliperof ×0.2 as the standard deviation of the propensity score. Chi-square tests were performed tocompare the number of participants classified before and after propensity score matching for each
subscale of the BJSQ in the two groups.
Between-group comparisons were performed using the Mann-Whitney U test, as the data were notnormally distributed. A value of p ＜0.05 was regarded as a statistically significant difference
between groups. The data were analyzed using IBM SPSS version 26 (IBM, USA).

Results
Participant characteristics
Of the 334 study participants, 237 were men (71%) and 97 were women (29%). The mean age ±standard deviation (SD) was 41.9±7.8 years. A total of 136 employees were in the usual LTSA groupand 198 were in the extended LTSA group before propensity score matching. Among all participants,
the most frequent ICD-10 codes diagnosed for LTSA-MD were F3 (mood disorders; N＝226, 67.7%),
followed by F4 (stress-related and somatoform disorders; N＝86, 25.7%). The remaining workers in
the cohort (6.6%) were diagnosed under codes F0 (organic, including symptomatic, mental disorders),
F1 (mental and behavioral disorders due to psychoactive substance use), F2 (schizophrenia,
schizotypal and delusional disorders), F8 (disorders of psychological development), or F9 (behavioral
and emotional disorders with onset usually occurring in childhood and adolescence). The
demographic and occupational characteristics of the pre-matched and matched participants in theusual and extended LTSA groups are summarized in Table 1, respectively. In the cohort with usual
LTSA, after matching, there were 101 men and 22 women, with a mean age±SD of 42.4±7.7. In thecohort with extended LTSA, there were 103 men and 20 women, with a mean age±SD of 42.8±7.0.
After propensity score matching, no significant differences were found for diagnosis, gender, age,position, and job category between the two LTSA groups.
Comparison of BJSQ subscales between shorter and longer LTSAFor Harmanʼs single-factor test, the largest factor did not account for a majority of the variance(26.6%), indicating that overcontrol bias due to common method variance was not of great concern.
- 43 -

Shirahama et al
Table 1. Demographic and occupational characteristics before and after propensity score matching
Before matching (n＝334)
Usual LTSA
Extended LTSA
Period of sickness absence (months),
mean±SDN
ICD-10 code
F3
F4
Other mental disorders
Gender (men:women)
Age
Position (job title)
Manager
Chief
Staff
Job category
Clerical worker
Technical worker
Professional worker

After matching (n＝246)
Usual LTSA
Extended LTSA

5.9±1.617.5±8.6

5.9±1.617.7±8.7

136

198

123

123

106 (77.9%)
24 (17.7%)
6 (4.4%)
114:2242.4±8.0

120 (60.6%)
62 (31.3%)
16 (8.1%)
123:7541.7±7.6

93 (75.6%)
24 (19.5%)
6 (4.9%)101:2242.4±7.7

92 (74.8%)
24 (19.5%)
7 (5.7%)
103:2042.8±7.0

15
13
108

25
34
139

13
13
97

16
14
93

97
26
13

137
35
26

89
23
11

92
21
10

LTSA, Long-term sickness absence; and ICD-10, The International Classification of Diseases, Tenth Revision.

The BJSQ subscale scores in the usual and extended LTSA groups are summarized in Table 2.
Workers in the extended LTSA group showed a more significant quantitative workload, poorer
physical environment, and less job control among job stressors compared with workers with usual
LTSA. No significant differences were found for the remaining subscales. In addition, there were no
significant differences for the subscales of the stress response, social support, and satisfaction.

Discussion
This study divided the participants into two groups (usual and extended LTSA-MD) based on the
period of their sickness absence and compared the scores of the scales of job stressors, stress response,and social support. The results revealed that workers with extended LTSA-MD had a moresignificant quantitative workload, poorer physical environments, and less job control. There were no
significant differences for other job stressors, stress response, social support, and satisfaction with thelength of sickness absence.
This study hypothesized that greater job stressors prolonged the period of sickness absence, which
was partly supported by our findings. It demonstrated that a greater quantitative workload andlower job control were correlated with a longer period of sickness absence, which followed the job
demand control model developed by Karasek31). According to this model, a combination of high job
demands and low job control, referred to as high job strain, predicts adverse health effects. The
findings of this study were largely consistent with the model in terms of workload and job control.
The meta-analysis on the risk of sickness absences due to mental disorders (not limited to long-term)
showed that exposure to job strain elevated the risk of sickness absences by 47% 26). Some
aforementioned longitudinal studies reported the association between high job strain and LTSA23,24).
Particularly, Norwegian employees who report high levels of job strain are at an increased risk of- 44 -

Job Stress and Extended Long-term Sickness Absence
Table 2. Subscale scores on the Brief Job Stress Questionnaire
Range

Usual LTSA

Extended LTSA

p-value

Job stressor
Quantitative workload
Qualitative workload
Physical demands

3-12
3-12
1-4

7.8±2.4
8.6±2.2
1.9±1.0

8.8±2.3

0.01＊

9.0±2.1

0.20

2.1±1.1

0.07

Interpersonal conf lict3-12

6.4±1.8

6.5±2.0

0.55

Poor physical environment

1-4

2.4±1.0

2.7±1.0

0.03＊

Lack of job control

3-128.0±2.2

8.5±2.0

0.03＊

Skill utilization
Suitable jobs

1-4
1-4

2.6±0.8
2.8±0.9

2.5±0.90.45

2.8±0.9

0.72

Meaningfulness of work

1-4

2.6±0.9

2.6±0.9

0.62

Stress response
Vigor

3-12

9.8±2.0

9.8±2.3

0.84

Irritability

3-12

6.5±2.7

Fatigue
Anxiety3-12
3-12

7.8±2.7

6.5±2.5
8.3±2.9

0.95
0.11
0.23

6–24

7.3±2.912.8±5.0

7.8±2.9

Depression

13.4±5.0

0.36

Physical stress response

11-4422.0±6.923.0±6.9

0.25

Social support
Support from supervisor

3-127.8±2.3

7.8±2.0

0.77

Support from coworker

3-12

7.7±2.3

7.8±2.2

0.69

Support from family/friends

3-12

5.8±2.6

5.8±2.50.55

2-8

5.0±1.5

4.9±1.5

0.53

Other factors
Job satisfaction

Each score is expressed as mean±standard deviation. ＊Denotes a significant difference in scores between the usualand extended LTSA cohorts (p＜0.05). LTSA, Long-term sickness absence.

LTSA (＞16 days)32). Several studies also focused on the association between the period of LTSA andjob factors. A one-year follow-up study in Belgium reported a significant indirect association between
job strain-mediated bullying and LTSA (＞15 consecutive days)33). Our results were consistent withthe findings of these studies on the association between job strain and LTSA. Milner et al foundcontemporaneous associations between various work stressors and mental health, while only job
demands (consistent with quantitative workload, qualitative workload, physical demands,
interpersonal conf lict, and poor physical environment in the BJSQ) had a lagged effect on mental
health one year later34). This lagged effect may explain the reason for the extended LTSA-MD.
However, there was no significant difference between usual and extended LTSA with regard tosocial support. The demand-control-support model states that social support acts as a buffer against
the negative impact of a more significant strain on workers35). Furthermore, according to the National
Institute for Occupational Safety and Health in Japan, social support acts as a buffer to control stressresponses in the workplace and illness caused by stress36). Interestingly, not only physical workload
but also social support from colleagues have been associated with the length of sickness absence 37).
Moreover, low psychological job demands, high social support from coworkers, supervisor support(Odds Raito; OR＝3.4, 95% Confidence Interval; CI: 1.6-7.3), and low strain (low job demands andhigh control) were predictive of shorter periods before returning to work after absence 38). A
comparative study showed that the combination of high job strain and low social support at work was- 45 -

Shirahama et alassociated with sickness absences due to mental disorders for more than 15 days39). Our results are
not consistent with these findings. Some studies have reported that social support has little
correlation with long-term leave. For instance, a study in Belgium in 2004 did not find any effect ofsocial support on LTSA due to mental health problems40). The meta-analysis mentioned above showedthat the association between low social support at work and a risk of sickness absence was found;however, it is not statistically significant26). Similarly, a study in the Republic of Slovenia indicatedthat workplace support from coworkers and leaders was not associated with the period of sickness
absence in understanding the inf luencing factors of LTSA-MD41); therefore, the associations of social
support with LTSA remain unclear.
In contrast to this study, previous studies focused on LTSA not only due to MD but also somatic
disorders (not LTSA-MD); moreover, the boundary between short- and long-term absences varied ineach study, ranging between six weeks and three months42). This boundary range is remarkably
shorter than that considered in this study (eight months). To date, no research has attempted to
examine LTSA-MD of such length.
We used job stressors data before the workersʼ sickness absence. The data included prolonged
stressful periods experienced by workers before extended LTSA-MD. These factors are predicted to behigher in extended LTSA-MD (quantitative workload, poor physical environment, and low job control)
than the usual LTSA-MD and have extended long-lasting effects. We assumed that the factors thatwere not different between extended and usual LTSA-MD (social support) do not have major longlasting effects. Our results also showed that almost all other BJSQ subscales did not show thedifferences between extended and usual LTSA. We assume these factors similarly do not have major
long-lasting effects. Kristel et al reported that workers with subjective health complaints do notdiffer from the reference group concerning return-to-work predictors from long-term sickness
absences43). This is in line with the results of stress responses, which did not differ between usual andextended LTSA in this study. By contrast, a Hordaland study reported that anxiety and depression
were stronger predictors of a longer duration of sickness absences44). However, the longest sickness
absence duration used in the study was more than 90 days. It is significantly shorter than the
duration we used in our study. The results of the present study are significant for understanding
extended LTSA-MD, as MD often induces long periods of sickness absences.
Our study also showed that workers with extended LTSA-MD worked in a significantly poorer
physical environment than usual LTSA-MD workers. In the BJSQ, a poor physical environment
means, “The environment of your workplace (noise, light, humidity, and ventilation) is not so good”30).
We found no studies focusing on the association between poor work environment and the period ofsickness absence. Fletcher et al found effects for lagged environmental work stressors on health overa five-year period, with these stressors contributing to a sustained decline in worker health45). Thesefindings are consistent with our results. We presume that the workers in the poor physicalenvironmental workplace are demotivated to return to work earlier. Our results can explain the longlasting effect of poor physical environment in the workplace and hesitation to return to work. As
mentioned above, Japanese public servants are provided with sufficient financial support and benefits
during leaves of absence. These may be contributing factors as to why a worker may maintain a longleave of absence.
Meta-analysis revealed that, compared to the control group, clinical or work-focused interventions
aimed at improving return to work reduced the number of sickness absence days in the intervention- 46 -

Job Stress and Extended Long-term Sickness Absencegroup46).
This study had several strengths. First, the defined period of sickness absence was much longer
than in most other studies. To the best of our knowledge, few studies have focused on sickness
absence for more than eight months. Second, this investigation was a nested case-control study,
allowing the evaluation of temporal causal relationships with a control cohort to increase therobustness of our evaluations. Third, participants were selected from about 20000 employees ×5
years, who belong to a single large workplace. Therefore, compared to other studies that gathered
participants from multiple companies, there is less variation in work content and occupations; it isthought that the bias by company unit is also less. Fourth, we used propensity score matching
method to reduce the bias from the time separation between the period participants answered BJSQ
and the end of sickness absence. Because it is difficult to require answering questionnaire, such as
job stressors, during sickness absence in general, we could obtain data before the sickness absence.
Further, no other study used propensity scores to compare sickness absence periods. Fifth, thediagnosis, which constituted the reason for the employeesʼ absence, were objectively confirmed mental
disorders by psychiatrists rather than being subjectively measured (e.g., through a mental healthquestionnaire).
On the other hand, this study encountered the following limitations. First, data were obtained
only from public servants from a single city in Japan, making it difficult to generalize the findings toother jobs and locations. Second, the BJSQ was collected before their period of absence. However,their responses may have altered during the leave; because such information could not be obtained,
these possibilities remain ambiguous. Third, past MD or comorbidities could not be determined, as
participantsʼ medical certificates identified only the present disease. Fourth, differences in specificroles within a workerʼs occupation were not considered; work atmosphere and content may further
affect workersʼ job stressors. Fifth, the frequency of sickness absence could not be considered. Sixth,
in this study, it is difficult to predict the period of sickness absence for those who retired whilst on
leave. Therefore, we excluded them, but it is possible that this underestimates or overestimates theimpact of job stressors on extended LTSA. Finally, all data were self-reported; as such, personality
differences or response tendencies may have inf luenced the results. Further research using methods
to measure workersʼ stress through objective investigations, such as semi-structured interviews, isrequired.
Conclusions
Our findings showed that workers who took extended LTSA-MD for more than eight months had amore significant quantitative workload, poorer physical environments, and less job control.
Mitigating lost time and productivity by monitoring workersʼ stress levels, and identifying andintervening when workplace stress is exceptionally high, could serve as a possible solution to mitigate
LTSA-MD.
Acknowledgements
All authors have no COI to declare regarding the present study.
We would like to thank all participants for their cooperation.
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