ISSN 0030- 6096

O S A K A
C I T Y

Vol.

67

No.1

M E D I C A L

2021

J O U R N A L

V o l . 6 7 ,N o . 12 0 2 1

PUBLISHED BYOSAKA CITY MEDICAL ASSOCIATIONOSAKA JAPANOsaka City Medical Journal
Vo l . 6 7 , N o . 1 ,June 2021

CONTENTS
page
Smoking is Associated with the Severity of Rhododendrol-induced
Leukoderma and with the Occurrence of Leukomelanoderma
YOSHIE FUKUNAGA, KAZUYOSHI FUKAI, AYANO UMEKOJI-HAYASHI,
TAKUMA ISHIHARA, AYUMI SHINTANI, and DAISUKE TSURUTA････････････････････････････････

1

Systematic Stepwise Treatment Strategy and Its Short-term Outcomesfor Patients with Corona Virus Disease 2019 Complicated byAcute Respiratory Distress Syndrome
KENICHIRO UCHIDA, KENJI MATSUO, SAE KAWATA,
AYAKO KIRITOSHI, RYO DEGUCHI, HOSHI HIMURA,NAOHIRO HAGAWA, MASAHIRO MIYASHITA, KATSUMI YAMAMOTO,TOSHIKI MAEDA, SHINICHIRO KAGA, TOMOHIRO NODA,TETSURO NISHIMURA, HIROMASA YAMAMOTO, YUKA NONOSE,YUMI KATAOKA, KAZUHIRO OSHIMA, HIROSHI KAKEYA,TOSHIHIKO SHIBATA, and YASUMITSU MIZOBATA ････････････････････････････････････････････････

9Complications after Open Reduction and Internal Fixation of
Olecranon Fractures: Elderly vs Young
MASAHIRO MIYASHITA, KENTA MINATO, MAKOTO FUKUDA,
and MASATAKA YASUDA･･･････････････････････････････････････････････････････････････････････････････････ 21
Optimal Surgery for Abdominal Intermediate-risk Neuroblastoma:
Retrospective Study in a Single Institution
KENJI SANTO, AKIHIRO YONEDA, SHUICHIRO UEHARA,TATSUO NAKAOKA, MASAFUMI KAMIYAMA, TETSURO NAKAMURA,
TAKESHI INOUE, and JUNICHI HARA･･････････････････････････････････････････････････････････････････ 29
Laparoscopic Percutaneous Extraperitoneal Closure for Inguinal Hernia in
Young Adults: Assessment of Safety, Efficacy, and Reliability
YUKARI SAKAE, YOSHIKI MOROTOMI, KOHEI NOGUCHI,
TAKEO YASUDA, TOSHIHIKO SHIBATA, and TATSUO NAKAOKA ･･･････････････････････････････ 37
The Clinical Course of Patients with Influenza after Administration of
Various Anti-influenza Drugs during the 2019-2020
Influenza Season in Osaka, JapanNAOMI MARUYAMA, NAOKO YOSHII, YOSHIHIRO TOCHINO,
MASASHI FUJIOKA, KAZUHISA ASAI, TAKASHI HAMAZAKI,HIROSHI KAKEYA, and TOMOYA KAWAGUCHI ･･････････････････････････････････････････････････････ 45

Osaka City Med. J. Vol. 67, 1-8, 2021

Smoking is Associated with the Severity of Rhododendrol-induced
Leukoderma and with the Occurrence of Leukomelanoderma
YOSHIE FUKUNAGA1), KAZUYOSHI FUKAI1,2), AYANO UMEKOJI-HAYASHI3), TAKUMA ISHIHARA4),AYUMI SHINTANI5), and DAISUKE TSURUTA1)
Departments of Dermatology1) and Medical Statistics5), Osaka City University
Graduate School of Medicine; Department of Dermatology2), Osaka City General Hospital;
Department of Dermatology3), Baba Memorial Hospital; andInnovative and Clinical Research Promotion Center4), Gifu University Hospital

Abstract
Background
Rhododendrol (RD) is a skin whitening ingredient that was developed in Japan. Among the 800000
users of RD-containing cosmetics, 20000 patients developed localized leukoderma (RD-induced
leukoderma). Forty-two % of those users showed perilesional hyperpigmentation (leukomelanoderma),and 14% of them were associated with vitiligo vulgaris afterwards.
Methods
For this retrospective cohort study, we abstracted data from our dermatology medical records of
101 patients who developed leukoderma after using the cosmetics containing RD from July 2013 to
December 2014. Age, BMI, the number of RD-containing products they used, smoking history, anddepigmentation scores at their baseline visit as well as blood test data for anti-nuclear and/or antithyroid antibodies were analyzed. Multivariable logistic regression and linear regression were used
for analyses of leukomelanoderma, vitiligo vulgaris and characteristics at the baseline visit.
Results
Age, the number of RD-containing products used, BMI, anti-nuclear, and anti-thyroid antibodies
were not significantly correlated with the presence of leukomelanoderma, but it appeared thatleukomelanoderma was more likely to occur in patients with current smoking. In addition, smokers
showed a significant increase in their depigmentation score at the baseline visit.
Conclusions
Our study demonstrates that smoking is associated with the severity of RD-induced leukoderma
and the occurrence of leukomelanoderma.
Key Words: ‌Rhododendrol; Leukoderma; Vitiligo vulgaris; Leukomelanoderma;
Smoking

Received May 29, 2020; accepted November 24, 2020.
Correspondence to: Yoshie Fukunaga, MD.
Department of Dermatology, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585 Japan
Tel: +81-6-6645-3826; Fax: +81-6-6645-3825
E-mail: yoshieosw@gmail.com-1-

Fukunaga et al

Introduction
Rhododendrol (RD, 4-[4-hydroxyphenyl]-2-butanol) is a skin whitening ingredient that wasdeveloped in 2006 by Kanebo Cosmetics. Cosmetics containing RD were on sale from 2008 in Japan.
However, it turned out that among the users of RD-containing cosmetics, a considerable number ofusers developed leukoderma in 2013. As many as 20000 users, approximately 2% of the 800000 usersof RD-containing cosmetics, developed RD-induced leukoderma. After discontinuing use of thosecosmetics, most leukodermas showed spontaneous repigmentation. However, some users noted that
their leukodermas still persisted for several years, and new leukodermas appeared in non-RD
exposed skin areas, suggesting the development of vitiligo vulgaris1).
The Japanese Dermatological Association (JDA) established a Special Committee on the Safety of
Cosmetics Containing Rhododendrol and reported a nationwide epidemiological survey 2-4) after
developing a scoring system to evaluate the severity of leukodermas. The median depigmentation
score at the baseline visit was 6 (range 0-48) among the 1315 patients whose questionnaire of thesecond nationwide survey was available, and most of those were at a relatively lower score 3).
Hyperpigmentation in depigmented or surrounding area was observed in 42% of 1235 patients whose
responded to the questionnaire, and one third of them improved afterward3).
Fourteen % of patients who were subjects of the third nationwide survey observed, expansions of
the areas of depigmentation or the development of vitiligo vulgaris at non-exposed areas4). RD wasdeveloped and was thought to reduce melanin synthesis, as a competitive inhibitor of tyrosinase, theenzyme critical to melanin synthesis5,6). RD itself is degraded by tyrosinase and gives rise to harmful
metabolites that are toxic to melanocytes7). In susceptible subjects, the damaged melanocytes induced
T-cell responses which activated site-specific cytotoxic lymphocytes (CTLs). Those, CTLs may cause
the spread of depigmentation to non-exposed sites8).
Cigarette smoke contains a variety of reactive oxygen species (ROS) such as superoxide andhydroxyl radicals and other chemicals that increase the burden of oxidative stress9). Oxidative stressinduced by ROS has been implicated in the pathogenesis of autoimmune diseases because it may
damage autoimmune target cells and produce novel antigens10). It has also been reported that vitiligo
vulgaris develops due to the overproduction of ROS in melanocytes11).
In this retrospective cohort study, we collected data of patients who visited our institution for thetreatment of RD-induced leukoderma. Their data was analyzed to identify risk factors of theseverity of RD-induced leukoderma and the occurrence of perilesional hyperpigmentation(leukomelanoderma).

Methods
Patients
After approval by the Institutional Review Board of Osaka City University Medical School (#3810),
we assembled a retrospective cohort of 101 patients with RD-induced leukoderma, who had visited
our Dermatology Department from July 2013 to December 2014. From their medical records, wecollected their age, BMI, the number of RD-containing products used, smoking history, anddepigmentation scores at their baseline visit. Blood tests were conducted to assess whether they had
anti-nuclear and/or anti-thyroid antibodies at their baseline visit. In addition, whether the patientsdeveloped vitiligo vulgaris or hyperpigmentation at surrounding areas (i.e. leukomelanoderma)during the course of treatment was also recorded.

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Smoking and Rhododendrol-induced Leukoderma

Evaluation of the depigmentation score and leukomelanoderma
The Depigmentation score as defined by the JDA was calculated as the sum of the six parts ofindividual area scores: forehead, periorbital areas, cheeks (right and left sides), nose and mouth, neckand hands. Each individual area score was the multiplication of the degree (i.e. complete
depigmentation: 2, incomplete depigmentation: 1) and the area of depigmentation: 0 (0%), 1 (1%25%), 2 (26%-50%), 3 (51%-75%) and 4 (76%-100%). The maximum total depigmentation score was
48. The presence or absence of leukomelanoderma was visually assessed independently by twodermatologists using photographs.
Statistical analysis
We assessed the factors associated with 1) the severity of the leukoderma, which is quantified by
the depigmentation score at the baseline visit, 2) the occurence of leukomelanoderma, and 3) the
occurrence of vitiligo vulgaris. Multivariable logistic regression was used for binomial outcomes ofthe occurrence or non-occurrence of leukomelanoderma as well as vitiligo vulgaris during thetreatment course. Multivariable linear regression was used for continuous outcome of the first
depigmentation score to assess the effects of various risk factors including age, smoking history,
number of RD-containing roducts used, BMI, anti-nuclear, and anti-thyroid antibodies. The
depigmentation score at the baseline visit was natural log-transformed to provide normality in theresiduals, and coefficients obtained by the regression model were back-transformed indicating the %increase in the first depigmentation score by an interquartile range (IQR) increase in corresponding
covariates. The non-linearity of continuous risk factor variables was assessed using a restricted cubic
spline. No significant non-linearity was observed. Missing data were imputed using the multiple
imputation method because the exclusion of patients who had missing data might cause a selection
bias. Demographic and clinical characteristics of the patients were presented using median and IQR
for continuous variables and frequencies and percentages for categorical variables. All statisticalanalyses used a two tailed significance level of 0.05. All statistical calculations were performed using
R software, version 3.5.1 (www.r-project.org).

Results
Characteristics of the patients
We enrolled 101 patients who developed leukoderma after using cosmetics containing RD, andtheir demographics are listed in Table 1. It shows median or percentage value of each risk factor that
we hypothesize, depigmentation score, and complication with vitiligo vulgaris and leukomelanoderma.
Regarding smoking history, twelve of patients (12%) had it, however, there was no former-smoker but
current-smoker.
Depigmentation scores at the baseline visit
Histogram plots of depigmentation scores at the baseline visit are shown in Figure 1. The medianvalue of the depigmentation score at the baseline visit was 14 (IQR, 4-32) (Table 1).
Development of leukomelanoderma and vitiligo vulgaris
Results of the multivariable logistic regression are shown in Figure 2. We analyzed theassociation of leukomelanoderma and vitiligo vulgaris with each of the candidate risk factors. Age,
number of RD-containing products used, BMI, anti-nuclear, and anti-thyroid antibodies were notsignificantly correlated with the outcome, but it appeared that leukomelanoderma was more likely tooccur in patients with current smoking (odds ratio 21.53, 95% CI 2.39-193.78; p＝0.006).

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Fukunaga et al
Table 1. ‌Demographic and clinical characteristics of patients at thebaseline visit
Variable

N=101

Age in years, median (IQR)
Female, n (%)
Smoking, n (%)
Number of products, median (IQR)
BMI, median (IQR)
Positive for anti-nuclear antibody, n (%)
Positive for anti-thyroid antibody, n (%)
Depigmentation score, median (IQR)
Complication of vitiligo vulgaris, n (%)
Complication of leukomelanoderma, n (%)

60 (48, 70)
101 (100)
12 (12)
9.5 (5, 17)21.6 (19.58, 23.48)
11 (12)26 (28)14 (4, 32)
10 (10)48 (48)

IQR, interquartile range.

Figure 1. Histograms of depigmentation scores at the baseline visit (n ＝101). Most patients presented with arelatively low depigmentation score.

The effect of smoking
As indicated by linear regression analysis (Table 2), patients who have smoking history had
significant increases in the depigmentation score at the baseline visit (coefficient 1.239, p ＝0.012).
The other factors such as age, the number of RD-containing products used, BMI, anti-nuclear, andanti-thyroid antibodies did not appear to show a significantly different effect on the first
depigmentation score at the baseline visit. Box plots were used to compare the depigmentation scoresat the baseline visit between smokers and non-smokers (Fig. 3). That analysis showed that themedian of the depigmentation score at the baseline visit was significantly higher among patients witha smoking history (median score 26 for the smokers, 13 for non-smokers, p＝0.03).

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Smoking and Rhododendrol-induced Leukoderma

Figure 2. Result of multivariable logistic regression for leukomelanoderma and vitiligo vulgaris including age,smoking, number of rhododendrol (RD) -containing products used, BMI, anti-nuclear, and anti-thyroid antibodies.
Odds ratios reflect a comparison between the 25th and the 75th percentile values for each variable. Age, smoking,number of RD-containing products used, BMI, anti-nuclear, and anti-thyroid antibodies were not significantly
correlated with leukomelanoderma and/or vitiligo vulgaris, but leukomelanoderma was likely to occur in patients who
had a smoking history (odds ratio 21.53, 95% CI 2.39-193.78; p＝0.006).

Table 2. ‌Linear regression analysis of the effect of each factor on the depigmentation scores at thebaseline visit
VariableAge (IQR: 48-70)
Smoking
Number of products (IQR: 5-17)
BMI (IQR: 19.6-23.5)
Positive for anti-nuclear antibody
Positive for anti-thyroid antibody

Coefficient

95% CI

p value

1.295
1.239
1.004
0.915
0.788
1.258

[0.897, 1.869][1.239, 5.505][0.856, 1.177][0.685, 1.223][0.387, 1.644][0.695, 2.277]

0.165
0.012
0.960
0.546
0.522
0.444

Coefficients are indicated as % increase in depigmentation scores at the baseline visit by IQR increase in thecorresponding covariates. IQR, interquartile range.

Discussion
This study shows that smoking is associated with the increase of the depigmentation score at thebaseline visit and also the development of leukomelanoderma. To the best of our knowledge, only one
clinical study exists regarding the risk factors related to RD-induced leukoderma12). Patients with ahistory of atopic dermatitis or patients who had a higher depigmentation score at the baseline visit
significantly developed vitiligo vulgaris after the RD-induced leukoderma12). However, this is the firstreport referring to an association between smoking and RD-induced leukoderma.

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Figure 3. Box plots of depigmentation scores at the baseline visit by smokers and non-smokers. Mann-Whitney U
test showed the median depigmentation score of smokers at the baseline visit is higher than non-smokers (medianscore 26 for smokers, 13 for non-smokers, p＝0.03).

RD is a competitive inhibitor of tyrosinase and reduces melanin production, but it is also cytotoxic
to human melanocytes5). One of the mechanisms for its cytotoxicity is the effect of RD-quinone
through binding with sulfhydryl proteins, and the other is the pro-oxidant activity of RD-derived
melanins that leads to oxidative stress13). Within human melanocytes, tyrosinase oxidizes RD to RDquinone and RD-cyclic-quinone which is cytotoxic to melanocytes. When these toxic substances
combine with thiol-containing chemicals such as glutathione (GSH) and cysteine (Cys), they will bedetoxified to RS-catechol and RS-cyclic-catechol 7,14,15). RD-catechol and RD-cyclic catechol which aremetabolites of RD-quinone generate superoxide in the process of their oxidization. It has also beenreported that superoxide dismutase (SOD) oxidizes superoxide to hydrogen peroxide (H 2O2) andoxygen. H2O2 which is one type of ROS, is detoxified by combining with a thiol group14). In smokers,
the plasma levels of GSH and Cys have been shown to be significantly lower than in nonsmokers16).
Thus, metabolites of RD and ROS are supposed to be less detoxified in smokers, given that GSH and
Cys are exhausted from the detoxification of smoking-related chemicals.
Leukomelanoderma is a combined form of dyspigmentation, composed of speckled pattern ofhyperpigmentation along with wider areas of hypopigmentation (Fig. 4). Leukomelanoderma can becaused by the medication history, such as oral thiazide-based diuretics17,18), and by the application ofhydroquinone19). The mechanism of leukomelanoderma induced by medication may be due to sun
exposure, the color of the skin and the genetic predisposition, however, none of these are obvious18).

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Smoking and Rhododendrol-induced Leukoderma

Figure 4. Clinical appearance of leukomelanoderma. Speckled hyper- and hypo-pigmentation are intermixed on arelatively wide range of the skin. This patient was 69-year-old woman who had a smoking history at the first visit.
Her depigmentation score was 28.

In regard to hydroquinone, the combination of post-inflammatory pigmentation induced by contact
dermatitis and hydroquinone-induced leukoderma has been postulated 19). In fact, contact dermatitis
due to RD was suggested by positive patch testing, as reviewed by the first epidemiological reportfrom the JDA2). The presence of leukomelanoderma considerably lowers the quality of life of patients.
It has been reported that perilesional hyperpigmentation was seen in 42% of patients with RDinduced leukoderma3), and in this study cohort, 48% of the patients had leukomelanoderma.
Tobacco smoking induces several undesirable characteristics of skin aging such as wrinkles andincreased skin pigmentation20-23). Melanin indices of the skin among current smokers are higher whencompared with never and former smokers23). Human epidermal melanocytes are activated by watersoluble tobacco smoke through the Wnt/β-catenin signaling pathway and produce more melanin in
vitro24).
A limitation of this study is that the number of patients who smoked was small. Although thepercentage (12%) was higher than the women s value (8.2%) of a national health and nutrition survey
in 2016 in Japan, it may be difficult to generalize our results because the sample size was small.
In conclusion, our study has shown that smoking induces more severe RD-induced leukoderma.
The depigmentation score at the baseline visit of smokers is higher, suggesting that cytotoxic
substances may accumulate in the course of the metabolism of RD because of the low levels of GSH
and Cys in the plasma16). In addition, smoking may lead to a higher risk of leukomelanoderma
probably due to post-inflammatory pigmentation caused by contact dermatitis.
Acknowledgement
All authors have no COI to declare regarding the present study.
I am grateful to Elizabeth and Vince Hearing for carefully proofreading the manuscript.

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Fukunaga et al

References
1. Nishigori C, Aoyama Y, Ito A, et al. Guide for medical professionals (i.e., dermatologists) for the managementof Rhododenol-induced leukoderma. J Dermatol 2015;42:113-128.
2. Aoyama Y, Ito A, Suzuki K, et al. The first epidemiological report of Rhododendrol-induced leukoderma inJapan based on a nationwide survey. The Japanese Journal of Dermatoology 2014;124:2095-2109. (InJapanese)
3. Suzuki K, Aoyama Y, Ito A, et al. The second epidemiological report of Rhododendrol-induced leukoderma inJapan based on a nationwide survey. The Japanese Journal of Dermatoology 2014;124:3125-3142. (InJapanese)
4. Ito A, Aoyama Y, Suzuki K, et al. The third epidemiological report of Rhododendrol-induced leukoderma inJapan based on a nationwide survey. The Japanese Journal of Dermatoology 2015;125:2401-2014. (InJapanese)
5. Sasaki M, Kondo M, Sato K, et al. Rhododendrol, a depigmentation-inducing phenolic compound, exerts
melanocyte cytotoxicity via a tyrosinase-dependent mechanism. Pigment Cell Melanoma Res 2014;27:754-763.
6. Iwadate T, Kashiwakura Y, Masuoka N, et al. Chemical synthesis and tyrosinase inhibitory activity ofrhododendrol glycosides. Bioorg Med Chem Lett 2014;24:122-125.
7. Okura M, Yamashita T, Ishii-Osai Y, et al. Effects of rhododendrol and its metabolic products on melanocytic
cell growth. J Dermatol Sci 2015;80:142-149.
8. Tokura Y, Fujiyama T, Ikeya S, et al. Biochemical, cytological, and immunological mechanisms of
rhododendrol-induced leukoderma. J Dermatol Sci 2015;77:146-149.
9. van der Toorn M, Rezayat D, Kauffman HF, et al. Lipid-soluble components in cigarette smoke induce
mitochondrial production of reactive oxygen species in lung epithelial cells. Am J Physiol Lung Cell Mol
Physiol 2009;297:L109-114.
10. Di Dalmazi G, Hirshberg J, Lyle D, et al. Reactive oxygen species in organ-specific autoimmunity. Auto Immun
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11. Xie H, Zhou F, Liu L, et al. Vitiligo: How do oxidative stress-induced autoantigens trigger autoimmunity? J
Dermatol Sci 2016;81:3-9.
12. Yoshikawa M, Sumikawa Y, Hida T, et al. Clinical and epidemiological analysis in 149 cases of rhododendrolinduced leukoderma. J Dermatol 2017;44:582-587.
13. Ito S, Wakamatsu K. Biochemical mechanism of rhododendrol-induced leukoderma. Int J Mol Sci 2018;19:552.
14. Ito S, Ojika M, Yamashita T, et al. Tyrosinase-catalyzed oxidation of rhododendrol produces
2-methylchromane-6,7-dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity.
Pigment Cell Melanoma Res 2014;27:744-753.
15. Ito S, Gerwat W, Kolbe L, et al. Human tyrosinase is able to oxidize both enantiomers of rhododendrol.
Pigment Cell Melanoma Res 2014;27:1149-1153.
16. Moriarty SE, Shah Jh, Lynn M, et al. Oxidation of glutathione and cysteine in human plasma associated withsmoking. Free Radic Biol Med 2003;35:1582-1588.
17. Seishima M, Shibuya Y, Kato G, et al. Photoleukomelanoderma possibly caused by etretinate in a patient withpsoriasis. Acta Derm Venereol 2010;90:85-86.
18. Masuoka E, Bito T, Shimizu H, et al. Dysfunction of melanocytes in photoleukomelanoderma following
photosensitivity caused by hydrochlorothiazide. Photodermatol Photoimmunol Photomed 2011;27:328-330.
19. Yanagishita-Nakatsuji S, Fukai K, Ohyama A, et al. Probable allergic contact dermatitis from hydroquinone
presenting as leukomelanoderma: report of two cases. J Dermatol 2017;44:e330-e331.
20. Yin L, Morita A, Tsuji T. Skin aging induced by ultraviolet exposure and tobacco smoking: evidence fromepidemiological and molecular studies. Photodermatol Photoimmunol Photomed 2001;17:178-183.
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24. Nakamura M, Ueda Y, Hayashi M, et al. Tobacco smoke-induced skin pigmentation is mediated by the arylhydrocarbon receptor. Exp Dermatol 2013;22:556-558.

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Osaka City Med. J. Vol. 67, 9-20, 2021

Systematic Stepwise Treatment Strategy and Its Short-term
Outcomes for Patients with Corona Virus Disease 2019 Complicatedby Acute Respiratory Distress Syndrome
KENICHIRO UCHIDA1), KENJI MATSUO1), SAE KAWATA1), AYAKO KIRITOSHI1), RYO DEGUCHI1),HOSHI HIMURA1), NAOHIRO HAGAWA1), MASAHIRO MIYASHITA1), KATSUMI YAMAMOTO1),TOSHIKI MAEDA1), SHINICHIRO KAGA1), TOMOHIRO NODA1), TETSURO NISHIMURA1),
HIROMASA YAMAMOTO1), YUKA NONOSE2), YUMI KATAOKA2), KAZUHIRO OSHIMA3), HIROSHI KAKEYA3),TOSHIHIKO SHIBATA4), and YASUMITSU MIZOBATA1)
Departments of Traumatology and Critical Care Medicine1), Infection Control Science3),and
Cardiovascular Surgery4), Osaka City University Graduate School of Medicine; andThe Nursing Department2), Osaka City University Hospital

Abstract
Background
Corona Virus Disease 2019 (COVID-19) continues to be a global crisis, and mortality fromCOVID-19 remains uncontrolled in several countries. Once the patients acquire acute respiratory
distress syndrome (ARDS) concomitantly and require ventilatory support, mortality is reported toreach up to 30%-90%. The aim of this study was to assess our treatment strategy and its outcomes.
Methods
This was a single-center, retrospective study, and all patients admitted due to ARDS following
COVID-19 were reviewed. We administrated aggressive prolonged prone positioning with highpositive end expiratory pressure. Low dose methylprednisolone was used for all patients.
Extracorporeal membrane oxygenation was indicated for the patients in whom PaO2/FiO2 (P/F) ratio＜80 under our initial treatment strategy.

Results
From March 2020 to June 2020, total of nine patients were hospitalized with polymerase chain
reaction-positive Severe Acute Respiratory Syndrome Coronavirus 2 infection concomitant with
ARDS. The median age was 72 (47.5-78) years old and all patients were male. The P/F ratio at thetime of admission was 116 (69-140). The median Sequential Organ Failure Assessment score was 8(7-11), and two patients were in a state of septic shock and had already been administrated
vasopressors. By performing our strategic treatment, five patients were recovered from ARDS andwere successfully extubated without any complications. The total in-hospital mortality rate during
Received June 23, 2020; accepted November 24, 2020.
Correspondence to: Kenichiro Uchida, MD, PhD, FACS.
Department of Traumatology and Critical Care Medicine, Osaka City University Graduate School of
Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8586, Japan
Tel: +81-6-6645-2121; Fax: +81-6-6646-3064
E-mail: cvs.uchida@gmail.com-9-

Uchida et al

this study period was 33.3%.
Conclusions
Our systematic stepwise intensive care strategy for ARDS following COVID-19 achieved
permissive outcomes compared to the high mortality rate in the world including elsewhere in Japan.
Key Words: ‌ARDS; COVID-19; Mortality; Prone position; Methylprednisolone

Introduction
Patients with Corona Virus Disease 2019 (COVID-19), which has become a global epidemic since
December 2019, are often asymptomatic or accompanied by mild fever and respiratory symptoms1).
However, depending on the patient s background, such as older age and their underlying diseases,
COVID-19 can become severe at a rate of about 5%-10%1,2) and can develop into acute respiratory
distress syndrome (ARDS) that requires precise respiratory management and extracorporeal
circulation. Once these patients concomitantly acquire ARDS, the mortality rate reportedly rises to
32%-97.2%1,3-6). Although the use of drugs such as favipiravir and hydroxychloroquine is currently
drawing attention, its effectiveness is still unestablished. And treatment for ARDS following
COVID-19 must be modified based on a general ARDS strategy7,8) because of the extremely rapid
deterioration of the respiratory condition and its comorbidities such as hypercoagulopathy and organ
infarctions. Furthermore, every step of all required clinical procedures such as endotracheal
intubation must be thoroughly modified to avoid secondary infections of essential health care
workers.
We retrospectively assessed our treatment strategy and its outcomes in patients with ARDS
related to COVID-19.

Methods
In this single-center, retrospective review, we assessed patients admitted to the Trauma andCritical Care Center of Osaka City University Hospital. The records of all patients admitted with
COVID-19 concomitant with ARDS were reviewed and included nine patients who were evaluated foroutcomes and complications. The cla ssification of severity of ARDS was referenced by Berlin
definition9).
Outlines of our stepwise treatment strategy for ARDS secondary to COVID-19 is shown in
Figure 1.
Treatment for COVID-19
For the patients with polymerase chain reaction (PCR) -positive Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) infection, favipiravir and hydroxychloroquine were available
drugs in our institution. Favipiravir was administered 3600 mg as the initial dose on the 1st day and1600 mg per day was continued for the next 14 days. Hydroxychloroquine was administered 400 mg
per day and was continued for the next 14 days as well. In view of the potential for communityacquired pneumonia, ceftriaxone (CTRX) and azithromycin (AZM) were administered together until
the sputum culture was confirmed. If the result of sputum culture was negative, we terminated these
antibiotics and if causative bacteria such as methicillin-resistant staphylococcus aureus had alreadybeen detected in previous hospital, we added or continued sensitive drugs for these bacteria.

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Short-Term Outcomes for COVID-19 with ARDS

Figure 1. Our stepwise approach to treat ARDS secondary to COVID-19. ARDS, acute respiratory distress syndrome;
mPSL, methylprednisolone; PCR, polymerase chain reaction; SARS-CoV-2, Severe Acute Respiratory SyndromeCoronavirus 2; PEEP, positive end-expiratory pressure; P/F, PaO2/FiO2; PIP, positive inspiratory pressure; and V-V/V-A
ECMO, veno-venous/veno-arterial extracorporeal membrane oxygenation.

Infusion management
Infusion control was based on serum lactate level, stroke volume variation (SVV) between therange of 10%-18%, and echocardiographic evaluation such as measuring the length of left ventricular
end-diastolic diameter between the range of 35-40 mm and the length of inferior vena cava diameter
between the range of 8-15 mm.
If we could not obtain a sufficient mean atrial pressure despite maintaining intravenous volume,
norepinephrine and/or dobutamine was administered based on the cardiac function of the patients. If
the administration speed of norepinephrine exceeded 0.1 µg/kg/h, we considered adding vasopressinto control systemic peripheral vascular resistance.
Respiratory management
To limit aerosolization from the patients, we adopted a prompt endotracheal intubation strategy if
the patients required oxygen at more than 5 L/min. Based on the general recommendations for
ARDS, the ventilator adjustment strategy was managed by maintaining high positive end-expiratory
pressure (PEEP) and low tidal volume at 4-8 mL/kg of ideal body weight, allowing permissive
hypercapnia. To prevent the occurrence of ventilator-induced lung injury, maximum airway pressure
was controlled so as not to exceed 30 cm H2O7,8,10).
Administration of spontaneous awakening trial under sedation
We used continuous intravenous administration of propofol, dexmedetomidine, midazolam, andfentanyl in combination to maintain the Richmond Agitation and Sedation Scale score at a level of −3
to −5. And we tapered the sedatives once a day to assess the best consciousness level and neurologicaldeficits of the patients.

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Uchida et al

Administration of prolonged prone positioning
If a PaO 2/FiO 2 (P/F) ratio ≧150 could not be obtained even under maximum appropriate
ventilatory support, aggressive prone position therapy was introduced (Fig. 1). To obtain maximum
effects of this treatment, the prone position was continued for ＞14 hours but ＜16 hours to avoid
complications such as pressure ulcers11,12).
Administration of extracorporeal membrane oxygenation (ECMO)
In patients in whom a P/F ratio of ＞80 could not be obtained even with the addition of prone
position therapy and there were no absolute contraindications for the patients, we introduced venovenous ECMO as an additional treatment option.
Use of corticosteroids
We immediately started low-dose methylprednisolone at 1 mg/kg/day if the patients met thediagnostic criteria for ARDS.
On the basis of one report 13), we considered the administration of a high dose of methylprednisolone
at 1 g/day for 3 days as a steroid pulse only in patients in whom we could not obtain adequate
oxygenation even after administration of best current treatment strategy for 14 days (Fig. 1).
Prophylactic administration of low molecular weight heparin
If there were no hemorrhagic complications on admission, we started low molecular weight
heparin from the 1st day of admission because of the reports of a high incidence of complications ofhypercoagulopathy specified to COVID-1913-15). If the patients were complicated by disseminatedintravascular coagulopathy (DIC) as calculated by acute DIC score during their clinical course16), weconverted to the use of recombinant human soluble thrombomodulin and added antithrombin (AT-Ⅲ)
if the value of AT-Ⅲ in the blood examination was ＜70%.
Statistical analysis
Statistical values are expressed as the median (interquartile range 25%-75%) or number (%).

Results
From March 2020 to June 2020, total of nine patients were hospitalized with PCR-positive SARSCoV-2 infection and respiratory failure associated with ARDS. The previous medical histories of thepatients are shown in Table 1. The median age of the patients was 72 (47.5-78) years old, and all
patients (100%) were male. The number of days from disease onset to admission to our hospital was
9 (5.5-13.5) days. All nine patients (100%) met the criteria for ARDS based on the Berlin definition.
Three patients had already been treated with Ciclesonide in previous hospital. The history ofsmoking was the most frequent background (88.9%) and their median Sequential Organ Failure
Assessment score was calculated as 8 (7-11)17). Three patients (33.3%) were complicated by DIC. Twopatients were already suffering acute kidney failure, and two patients were in shock and had alreadybeen administered vasopressors at a previous hospital. The other comorbidities and underlying
diseases detected on admission were concomitant methicillin-resistant Staphylococcus aureus
pneumonia in one patient, massive cerebral infarction in one patient (Table 2).
The results of the main blood tests and radiological type of COVID-19 infection obtained atadmission are shown in Table 3. The P/F ratio at the time of admission was 116 (69-140), and seven(77.8%) of patients had already been intubated at a previous hospital. lactate dehydrogenase (LDH)on admission was 408 (387.5-847.5) international unit (IU/L), krebs von der lungen 6 (KL-6) was 887(466.5-2833.5) Unit/mL, and C-reactive protein (CRP) was 17.7 (8.66-25.01) mg/dL. Type of- 12 -

Short-Term Outcomes for COVID-19 with ARDS
Table 1. Demographic Data of the Patients
N＝9Sex

9 (Male 100%)

Age, years
Type of admission
Transferred from other hospital
Physiological data on arrival
GCS
HR (beats per min)Systolic blood pressure (mm Hg)
Body temperature (℃)
Past medical history / Underlying disease
Current/Ex-smoker
Alcohol abuser
Hypertension
Diabetes
Hyperlipidemia
StrokeCardiac failure
COPD
Chronic kidney disease
Post nephrectomy
Current malignant lymphoma treatment
SOFA score on admission

72 (47.5-78)
9 (100%)6 (3-15)98.0 (87.5-128.5)
158.0 (137.5-163.5)
37.5 (36.6-38.0)
8 (88.9%)
1 (11.1%)
3 (33.3%)
4 (44.4%)
1 (11.1%)
0
3 (33.3%)
1 (11.1%)
1 (11.1%)
1 (11.1%)
1 (11.1%)
8 (7-11)

Statistical data are presented as median (25%-75% interquartile range) or
number. GCS, Glasgow Coma Scale; HR, heart rate; COPD, chronic obstructive
pulmonary disease; and SOFA, Sequential Organ Failure Assessment.

Table 2. Concomitant Complications on Arrival
N＝9
Concomitant complications on arrival
ARDS
MRSA pneumonia
Massive cerebral infarction
Cardiac failure
Acute kidney injury
Endotracheal intubation/Ventilator
Septic shock requiring Vasopressor
DIC

9 (100%)1 (11.1%)
1 (11.1%)
2 (22.2%)
2 (22.2%)
7 (77.8%)
2 (22.2%)
3 (33.3%)

Statistical data are presented as number (percent). ARDS, acute respiratory
distress syndrome; MRSA, methicillin-resistant Staphylococcus aureus; andDIC, disseminated intravascular coagulopathy.

COVID-19 infection classified by computed tomography (CT) scan was three in Type L that showed
only ground-glass densities are present, and six in Type H that showed a remarkable increase in lungweight.
The details of the clinical data were described in Table 4. Prone position therapy was performed- 13 -

Uchida et al
Table 3. Examination Results
N＝9
P/F ratio
Base excess−4.0 (−4.9- −2.7)

116 (69-140)

pH
Lactate level (mmol/L)

7.34 (7.29-7.37)
0.9 (0.7-1.3)

WBC (/μL)

6600 (3700-16300)

Plt (×104/μL )CRP (mg/dL)
Cr (mg/dL)
BUN (mg/dL)

12.9 (8.05-19.5)
17.7 (8.66-25.01)
0.97 (0.76-1.58)
19 (14.5-53)

CK (IU/L)

227 (99.5-347.0)

LDH (IU/L)
KL-6 (Unit/mL)
HgbA1c (%)
T-Bil (mg/dL)
Fibrinogen (mg/dL)
FDP (μg/mL)
PT-INR

408 (387.5-847.5)
887 (466.5-2833.5)
6.1 (5.75-7.7)
0.5 (0.35-1.0)
539 (431.0-666.5)
6.4 (5.1-99.2)
1.08 (0.98-1.4)

Type of COVID-19 infection classified by CT scan
Type LType H

3 (33.3%)
6 (66.7%)

Statistical data are presented as median (25%-75% interquartile range). P/F,
PaO2/FiO2; WBC, white blood cell count; Plt, platelet count; CRP, C-reactive protein;Cr, creatinine; BUN, Blood urea nitrogen; CK, Creatinekinase; IU/L, international
unit; LDH, lactate dehydrogenase; KL-6, krebs von der lungen 6; HgbA1c,
hemoglobin A1c; T-Bil, total bilirubin; FDP, fibrinogen degradation products; andPT-INR, prothrombin time-international normalized ratio.

in six (66,7%) patients, and it could be performed for 16 (14.5-16.5) hours/day. Three patients (33.3%)
were received steroid pulse dose therapy for three days after being treated 14 days our best tacticaltreatment. The respiratory condition of two patients improved significantly shortly afteradministration of high-dose steroids, but ARDS in the other one patient did not show significant
improvement. As the results, two of these three patients had worsened the respiratory conditions
and died during admission. The concomitant complications observed during admission wereventricular fibrillation in one patient (11.1%), bacterial pneumonia in three patients (33.3%), tension
pneumothorax in one patient (11.1%) and mediastinal emphysema in two patients (22.2%). One ofthese patients (11.1%) with mediastinal emphysema had detected tracheoesophageal fistula andtreated conservatively. Acute renal injury requiring renal replacement therapy were concomitantwith four patients (44.4%) and intravenous thrombosis were detected in one patient (11.1%).
One patient was considered to be indicated on ECMO therapy based on the P/F ratio at the time ofadmission. However, as a massive cerebral infarction was also detected by computed tomographyscan on admission, we decided not to administrate ECMO, and conservative best medical treatment
was continued for this patient. Thus, ECMO was not required in any patient (0%), and renal
replacement therapy was administered in 3 patients due to acute kidney injury (33.3%).
Recovery from ARDS and successful extubation was achieved in five patients over 7 (5.5-10.5)
days, and they were transferred to another hospital at 10 (6.5-13.5) days after admission. One- 14 -

Short-Term Outcomes for COVID-19 with ARDS
Table 4. Clinical Courses
N＝9
Successful extubation
Length of ventilator support from admission, days
Length of stay in ICU, days
Length of ventilator support from admission, days
Length of stay in ICU, days
Required prone positioning
Length of prone positioning, days (hours)
Requiring blood transfusion
Low-dose steroid use
High-dose steroid use after 14 days from admission
Vasopressor use
Max catecholamine index
CRRT
ECMO
Tracheostomy
Concomitant comorbidities during admission
Ventricular fibrillation
Tension pneumothorax
Bacterial pneumonia
Mediastinal emphysema
Tracheoesophageal fistula
Endotracheal re-intubation
Acute kidney injury requiring CRRT
Deep venous thrombosis
Systemic fungal infection
Mild pressure sore (prone-positioned patient)
CPC grade obtained on disposition
Ⅰ
Ⅱ
Ⅲ
Ⅳ
Ⅴ
In - hospital mortality

5 (50%)
7 (5.5-10.5)
10 (6.5-13.5)
17.5 (7.5-27)
18.5 (10-27)
6 (66.7%)
16 (14.5-16.5)
1 (11.1%)
9 (100%)3 (33.3%)
9 (100%)5.5 (4.5-9)
4 (44.4%)
0
1 (11.1%)
1 (11.1%)
1 (11.1%)
3 (33.3%)
2 (22.2%)
1 (11.1%)
1 (11.1%)
4 (44.4%)
1 (11.1%)
1 (11.1%)
3/6 (50%)
5 (55.6%)
00
1 (11.1%)
3 (33.3%)
3 (33.3%)

Statistical data are presented as median (25%-75% interquartile range) or number.
CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane
oxygenation; and CPC, Cerebral Performance Category.

patient (Patient 7 in Fig. 2) improved respiratory conditions and transferred to another hospital withintubated. Another one (Patient 6 in Fig. 2) patient was performed tracheostomy because of
prolonged ventilation time on thirty-nine days after admission for treating respiratory conditions andtracheoesophageal fistula. The obtained Cerebral Performance Category (CPC) of the nine patientsat the points of disposition was 1 in five patients (55.6%), 2 in zero, 3 in zero, 4 in one (11.1%), and 5
in three patients (33.3%). Mild pressure sores developed after long-term prone position therapy inthree patients (50%) on the anterior lower jaw and anterior thoracic wall in all three. Eight patients(88.9%) converted to negative on a follow-up PCR SARS-CoV-2 test after 14 days of treatment. Finalin-hospital mortality was three patients (33.3%) during this study period.
Figure 2 shows the timeline of all patients. We had checked PCR again after 14 days of treatment- 15 -

Uchida et al

Figure 2. The timeline of all patients. PCR, polymerase chain reaction.

except being extubated and transferred patients. One patient (Patient 5 in Fig. 2) with a current
history of lymphoma died due to multiple organ failure and recurrent exacerbation of respiratory
function probably because of the patient s immunocompromised condition. The conversion of PCRnegative for SARS-CoV-2 test and viral seroconversion tested by serum antibody was not observed
only this patient after 14 days of treatment. The cause of the death of another patient (Patient 8 inFig. 2) was the result of a do not attempt resuscitation (DNAR) request obtained from the patient s
family due to failure of the patient to regain consciousness following a massive cerebral infarctionthat was detected on admission. The other one patient (Patient 6 in Fig. 2) had once recovered from
ARDS, but died because of decreased respiratory conditions due to pulmonary fibrosis and multiple
organ failure including systemic fungal infection at the 57 days after admission. The CT scan of thispatient at the time of admission and after 14 days treatment were shown in Figure 3.

Discussion
Although there are currently several recommended treatment strategies for COVID-19 andconcomitant ARDS, the mortality rate remains high globally, especially among patients requiring
mechanical ventilation. As a clinical finding, the lung compliance of our patients was significantly
poor, and almost all patients required a high intra-tracheal pressure close to 30 cm H2O to obtain thetargeted tidal volume.
Respiratory disfunction due to ARDS is mainly due to the collapse of bilateral dorsal lung alveoli
and atelectasis; hence, the prone position was recommended to correct the ventilation/perfusion (V/Q)
mismatch from ARDS7,8,15). We also consider this positioning to allow the most invasive and secure
therapy for these patients, and thus we continued the prone position for 14-16 hours if it was
indicated for the particular patient. We consider this prolonged prone position strategy especially forType H patients was the most effective and important treatment for COVID-19 patients since the- 16 -

Short-Term Outcomes for COVID-19 with ARDS

Figure 3. Lung computed tomography image of the same patient on the time of admission (A) and after 14 days
treatment (B). (A) CT shows predominant bilateral and peripheral consolidation with areas of air bronchogram(a, b) and focal ground-glass opacities associated with smooth interlobular and intralobular septal thickening in
the right lower lobes (crazy-paving pattern). (B) The CT scan of the same patient after 14 days of treatment. CT
shows advanced stage of bilateral dependent consolidation and pulmonary fibrosis with bronchiectasis were detected
especially in the anterior lung regions (a). A less common but bilateral and predominant peripheral consolidation
pattern with round cystic changes is also detected internally (b).

respiratory condition of the patients improved significantly during prone positioning.
ECMO is always available for patients with ARDS in our institution, and we recognize that its
administration is effective for acute respiratory or circulatory disfunction. For COVID-19 patients,
ECMO indications were recommended as a P/F ratio of less than 60 18), but given the consideration forthe difficulty of procedures in unfamiliar environments with wearing full personal protective equipment
and of communication between the staffs, we defined the ECMO indication as the P/F ratio of lessthan 80. However, by performing our treatment strategy faithfully, no patients developed the criteria
for ECMO induction during the study period.
The systemic administration of steroids for ARDS is still an issue under global discussion. The- 17 -

Uchida et alrisks and benefits of using steroids for ARDS have been discussed on a global scale, and there is still
no strong recommendation for their use19-21). Recently, low-dose use of corticosteroid was weakly
recommended for general ARDS 19) and also in association with COVID-19 22,23). The provisionalguideline issued by World Health Organization (WHO)15) stopped recommending the administration ofsteroid drugs on the basis of several observational studies. However, there are several opinions
indicating the usefulness of low-to-moderate doses of steroids in the acute phase19,22,24). Based on thefindings of Meduri et al24), we also administer a low dose of steroids in the acute phase of ARDS in our
institution.
Although historically there have been some negative opinions regarding high-dose steroid
administration for ARDS prolonged to over 14 days after onset25,26), one report notes that high-dose
administration of methylprednisolone permitted the patients to be weaned and the ventilator to bewithdrawn13). In our study, we administrate high-dose methylprednisolone only for the patients
without obtaining improvement after 14 days treatment. Although the respiratory condition of twopatients seemed to have improved significantly shortly after administration of high-dose steroids, but
the final respiratory conditions and their outcomes did not show significant improvement.
Recently the use of dexamethasone reported to decrease 28-day mortality among those who werereceiving invasive mechanical ventilation27). Although the administration of dexamethasone for ARDS
patients had not been highly recommended so far, WHO guidelines updated the recommendation forusing dexamethasone for ARDS following COVID-19 on the basis of this study15). We have to consider
the indication of dexamethasone especially for receiving invasive mechanical ventilation.
As the treatment drugs for COVID-19, after we had experienced a case of ventricular fibrillation,
probably due to prominent QT interval prolongation in patients who use hydroxychloroquine in
combination with AZM, and some similar reports from around the world 28) , based onelectrocardiography at admission and drug-induced corrected QT (QTc) interval prolongation risk
score29), concomitant use of hydroxychloroquine and AZM was discontinued in the patients withmoderate risk or higher. And as the sedation strategy, because man y complications ofhypercoagulation and cerebral infarction in relation to COVID-19 are reported30-32), we tapered thesedatives once a day to assess the best consciousness level and neurological deficits of the patientsand no one had fresh cerebral complications during admission. The incidences of mediastinal
emphysema and tracheoesophageal fistula were considered to be occurred due to long-term intubation
with high intra tracheal pressure and direct cuff pressure of endotracheal tube to wall of trachea33,34).
Normally, the cuff pressure is controlled at 20-25 mm Hg35), but the cuff pressure of this patient wasrecorded up to 30 mm Hg in order to limit the aerosolization and to withstand high-PEEP ventilation.
As another considerable factor, although we usually perform tracheostomy around 14 days after being
intubated, we suspended performing this procedure due to minimize aerosolization for the COVID-19
patients. As the limitations of current report, since this is the single-center study and small
preliminary report describing our treatment strategy and its short-term outcomes, and further multiinstitutional evaluation will be needed.
We conclude that our systematic stepwise intensive care strategy for treating ARDS secondary to
COVID-19 achieved permitted outcomes compared to the high mortality rate seen around the world
including elsewhere in Japan. We have to follow up these patients continuously to assess their longterm outcomes.

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Short-Term Outcomes for COVID-19 with ARDS

Acknowledgements
All authors have no COI to declare regarding the present study.
Written informed consent for this report was obtained from patients and if not available from thepatient, the consent was obtained from their family members.
We sincerely dedicate this paper to all essential health workers who have fought against
COVID-19 not only directly but also secondarily in Osaka City University Hospital. The excellent
results are due to the tremendous cooperation and teamwork of all of the involved staff such as inpreventing nosocomial infections, redistributing staff, and temporarily limiting elective operations.
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Osaka City Med. J. Vol. 67, 21-27, 2021

Complications after Open Reduction and Internal Fixation of
Olecranon Fractures: Elderly vs Young
MASAHIRO MIYASHITA1,2), KENTA MINATO1), MAKOTO FUKUDA1), and MASATAKA YASUDA1)
Department of Orthopaedic Surgery1), Baba Memorial Hospital; andDepartment of Trauma and Critical Care Medicine2), Osaka City University
Graduate School of Medicine

Abstract
Background
Although tension band wiring (TBW) is used commonly for simple olecranon fractures, we often
encounter redisplacements in the elderly. We hypothesized that elderly patients have more
complications after olecranon fracture operations than young patients. Therefore, we comparedoutcomes of these procedures including complications in young and elderly patients.
Methods
We retrospectively investigated outcomes including complications of 31 patients aged ≧65 years
and 40＜65 years who underwent olecranon fracture operations at two hospitals. Average follow-up
was 10 months. Complications included redisplacement (fracture site displaced ≧2 mm), non-union
and infection. We statistically compared the outcomes of TBW (simple TBW and ring pin) and locking
plate between elderly and young patients.
Results
Redisplacement occurred in 21 elderly patients (67%), 2 of whom (6%) had huge displacements
resulting in nonunion. The postoperative redisplacement rate using TBW in the elderly wassignificantly higher than that in young patients (71% vs 27%, p ＜0.001). The postoperative
redisplacement rate using locking plate in the elderly was not significantly higher than in young
patients (33% vs 10%, p＝0.07). There was no statistically significant difference in redisplacement
rate and distance among simple TBW, ring pin and locking plate. We confirmed no deep infections,but only superficial infection in one patient in each group.
Conclusions
Elderly patients had more complications after olecranon fractures, including redisplacement rateand distance, especially when TBW was used. However, there were no statistically significant
differences in redisplacement rate and distance among the implants.
Key Words: ‌Fracture: Olecranon; Complication; Elderly patient; Osteoporosis;
Displacement
Received June 23, 2020; accepted November 24, 2020.
Correspondence to: Masahiro Miyashita, MD.
Department of Trauma and Critical Care Medicine, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-2121; Fax: +81-6-6645-3986
E-mail: miya@med.osaka-cu.ac.jp- 21 -

Miyashita et al

Introduction
With an increasingly aging society, fracture fixation modalities for patients with osteoporotic bone
are changing. Although tension band wiring (TBW) is used commonly for simple olecranon fractures,some reports recommend plate or suture anchor fixation for highly comminuted fractures in theelderly. Complications such as redisplacement, infection and non-union may lead the loss of function
and some cases may relate in the mortalities of the elderly1-4). We report outcomes including
complications of olecranon fractures in the elderly compared to those of young patients. We
hypothesized that elderly patients have more complications after surgical operations of olecranon
fractures than young patients.

Methods
We received institutional review board approval for this study. We used electronic medical charts
to identify 96 patients who underwent surgery for olecranon fractures between January 2011 andDecember 2016 at our hospital and another related hospital. All charts were reviewed in 71 patients(37 men, 34 women). We divided the patients into two groups, Group O aged ≧65 years (31 patients)
and Group Y aged ＜65 years (40 patients). Average age at surgery was 58 years (range, 15-95).
Minimum follow-up period was 6 months postoperatively. We excluded patients who showed no rangeof motion (ROM) data at the final follow-up. The right and left sides were affected in 21 and 50
patients, respectively. Average follow-up period was 10 months (range, 6-17). According to the Mayoclassification 5), one patient had TypeⅠ, 27 TypeⅡA, 38 TypeⅡB, and five TypeⅢB fractures. All
patients with TypesⅠ and ⅡA fractures were treated with TBW. Types ⅡB and ⅢB fractures weretreated with locking plate in 13 patients and TBW in 30 patients (Table 1). Simple TBW, ring pin(TBW with eyelet preventing wire backout), and three kinds of locking plates were used. Although
we usually chose locking plates for highly comminuted fractures, the implants were chosen according
to the operators preference. We usually used splint for 1 or 2 weeks after surgery. Redisplacement
was defined when the fracture site was displaced ≧2 mm postoperatively on a plain X-ray
examination6). Redisplacement distance was defined as the gap between fracture fragments, and we
calculated the average values of redisplacement cases.
We investigated complications including redisplacement rate and distance as primary outcomes.
We statistically compared the outcomes of TBW and locking plate between groups O and Y.
Furthermore, we statistically compared the outcomes of TBW only for simple fractures (TypeⅠ and
ⅡA). We also investigated the redisplacement rate and distance statistically for three different
implants (TBW, ring pin, and locking plate). Secondary outcomes were active ROM of the elbow atfinal follow-up and other complications, such as non-union, implant irritation, reoperation andinfection. Statistical analyses were performed with Fisher s exact test, Mann–Whitney U test andKruskal-Wallis test. All statistical analyses were performed with EZR, which is for R. More precisely,
it is a modified version of R commander designed to add statistical functions frequently used inbiostatistics. P＜0.05 was considered statistically significant.

Results
Demographic data were not statistically significantly different between the groups. Follow-up was
longer in group Y (Tables 1 and 2). Redisplacement rates in cases using TBW were 71% in group O
and 27% in group Y (p ＜0.001). Redisplacement rates in cases using TBW for simple fracture were

- 22 -

Complications of Olecranon Fractures in the Elderly
Table 1. Mayo classification

TypeⅠ
TypeⅡATypeⅡB
TypeⅢB

≧65 y

＜65 y

Total

0 (0%)
15 (48.4%)
14 (45.2%)2 (6.5%)

1 (2.5%)
12 (30%)24 (60%)3 (7.5%)

1
27
38
5
＊

p＝0.384

TBW (simple TBW and TBW with eyelet)

TypeⅠ
TypeⅡATypeⅡB
TypeⅢB

≧65 y

＜65 y

Total

0 (0%)
15 (53.6%)
12 (42.9%)
1 (3.6%)

1 (3.3%)
12 (40%)15 (50%)2 (6.7%)

1
27
27
3
＊

p＝0.618

Locking plate

TypeⅠ
TypeⅡATypeⅡB
TypeⅢB

≧65 y

＜65 y

Total

0 (0%)
0 (0%)
2 (66.6%)
1（33.3%)0 (0%)
0 (0%)
9 (90%)
1 (10%)

0
0
11
2
＊

＊

p＝0.423

Fisher s exact test. TBW, tension band wiring.

Table 2. ‌Demographic data, follow-up period, complications and ROM
Group OGroup Y

Male

19

15

Female

12

25

Right

10

29

Left

21

11

TBW

14

16

Ring pin
Plate

14
3

Follow-up

Sex

＊

0.058

＊

0.794

14
10

＊

0.252

8M

10 M

＊＊

0.02

Rediplacement rate

64%

23%

＊

Rediplacement distance

3 mm

2 mm

＊＊

0.16

flexion

140°

140°

＊＊

0.285

extension

8°

10°

＊＊

0.04

non-union20

irritation

1

0

reoperation

3

1

1

1

Affected side

Implant

ROM

infection＊

p value

Fisher s exact test,＊＊＜0.001Mann-Whitney U test. M, month; ROM, range of motion; and TBW, tension band wiring.

- 23 -

Miyashita et al

66% in group O and 23% in group Y (p＝0.03). Redisplacement rate in cases using locking plate was
not significantly different between group O and Y (Table 3).
Displacement occurred on an average of 1.9 weeks after surgery. Redisplacement distance incases using TBW was 4.8 mm in group O and 3.3 mm in group Y (p＝0.281), and redisplacement
distance in cases using TBW for simple fracture was 5.1 mm in group O and 2 mm in group Y (p＝0.019) (Table 3). Redisplacement rate and distance were not significantly different among TBW, ringpin, and locking plate (Table 4). Although ROMs of flexion were not significantly different between
the groups, ROMs of extension in group O were significantly worse than those in group Y (Table 2).
Two patients in group O had huge displacements resulting in non-union without reoperation.
Reoperation was not possible in one because of multiple general diseases, while the other refusedreoperation. Redisplacement occurred in 2 cases of plate fixation and 28 cases of TBW. Reoperation
was performed for three patients in group O and one in group Y. We confirmed no deep infections, but
only superficial infection in one patient in each group (both recovered with use of oral antibacterial
agents).
Two cases of complications after surgical operations are presented. Patient 1 is an 84-year-old
woman sustained a TypeⅡA fracture fixed using TBW. Wire back-out from the bone fragment
occurred at 1 month postoperatively. Reoperation was performed because of skin irritation. The wireback-out reocurred, but we delayed removal of the implant after bony union was confirmed. ROM atlast follow-up was −15°
extension and 110°flexion (Fig. 1). Patient 2 is an 86-year-old man sustained
a TypeⅡB fracture fixed using a locking plate (VA-LCP® OLECRANON PLATE 2.7/3.5). Because ofpoor capturing of the proximal locking screw to the bone fragment, redisplacement occurred at 1 week
Table 3. ‌Displacement rate and distanceGroup OGroup Yp value

rate

71%

27%

＊

distance

3 mm

2 mm

＊＊

0.281

rate

66%

23%

＊

0.03

distance

3.5 mm

2 mm

＊＊

0.019

rate

33%

10%

＊

p value

TBW (simple TBW and ring pin)
Displacement＜0.001TBW for simple fracture (TypeⅠ and ⅡA)
Displacement

Locking plate
Displacement＊

Fisher s exact test,

＊＊

0.073

Mann-Whitney U test. TBW, tension band wiring.

Table 4. ‌Redisplacement rate and distance by each implant
Displacement
Rate
Distance＊

Fisher s exact test,

＊＊

Group

TBW

Ring pin

Plate

O
Y

9 (64%)
5 (31%)

11 (79%)3 (21%)

1 (33%)
1 (10%)

＊

0.29

＊

0.51

O

4.0 mm

2.0 mm

20 mm

＊＊

0.09

Y

2.0 mm

2.0 mm

2.0 mm＊＊0.33

Kruskal-Wallis test. TBW, tension band wiring.

- 24 -

Complications of Olecranon Fractures in the Elderly

Figure 1. An 84-year-old elderly female with type ⅡA fracture. A, Preoperative X-ray. B, Immediate postoperative
X-ray. C, One month postoperative X-ray. D, Immediate post-reoperation X-ray. E, Two weeks post-reoperation X-ray.
F, Final follow-up X-ray.

Figure 2. An 86-year-old elderly male with type ⅡB fracture. A and B, Preoperative X-ray and computed
tomography. C, Immediately postoperative X-ray. D, One week postoperative X-ray. E, Final follow-up X-ray.

- 25 -

Miyashita et al

postoperatively. The patient refused reoperation, resulting in non-union. ROM at last follow-up was−15°
extension and 145°flexion (Fig. 2).

Discussion
Olecranon fracture is not an osteoporotic fracture7,8), but we often encounter failures after open
reduction and internal fixation in the elderly with olecranon fractures. Several reports haveevaluated various implants such as ring pins to prevent wire backout and nails and double plates toachieve rigid fixations. However, to our knowledge no reports compared the distance or rate ofredisplacement between each implant. Which implant is best to fix osteoporotic bone has been
controversial. Patients with redisplacement resulting in union recover very well, and patients with ahuge redisplacement who subsequently underwent reoperation had severe contracture and worse
recovery. Otherwise, patients with a huge redisplacement and resulted in non-union gained wide
ROMs (Figs. 1 and 2). Whether to perform reoperation should be considered carefully.
According to our results, the redisplacement rate was higher in elderly than young patients.
There was a statistically significant difference only in the rates of redisplacement in cases using TBW
between in the elderly and young, but there were significant differences in both distance and rate ofredisplacement in cases using TBW for simple fractures. And there were no significant differences in
distance and rate of redisplacement using locking plate. Wilson et al reported that precontoured
plates provide significantly greater compression than TBW in the treatment of transverse fractures ofthe olecranon9). Hume et al reported that plate fixation achieved good functional results more often
than TBW in a prospective randomized study. Loss of reduction was more frequent with TBW (53%)
than with plate fixation (5%)10). Recently, plates with multidirectional locking screws are available forcomminuted olecranon fractures. We considered that the locking plate osteosynthesis is an effective
and safe tool for comminuted olecranon fractures in the elderly11-13). However, we are concerned thatsurgery time may be longer and the occurrence of complications, such as infection, might beincreased.
The main factor of redisplacement seemed to be our technical errors. There was a possibility of
inadequate fracture fixations due to insufficient evaluation of preoperative fracture patterns. Somepatients experienced immediate postoperative wire loosening. On the other hand, one patient with
an ipsilateral trochanteric femoral fracture had redisplacement when she performed gait exercise of
the lower extremity, although fracture fixation was strong enough. Jin et al reported that TBW using
Kirschner wire with eyelets produced excellent clinical and radiographic outcomes14). However, nosignificant improvement in the post operative pain relief was observed. Similarly, in our results,
there were no significant differences in redisplacement rate and distance between TBW and ring pin.
Two non-union patients in our study gained wide ROM. Duckworth et al reported that nonoperative
functional treatment of displaced olecranon fractures in the elderly (＞70 years old) provided goodresults and a high rate of satisfaction15). Gallucci et al also reported similar results in the elderly(average age 76)16). Duckworth et al reported no significant difference between groups in a prospective
randomized controlled trial comparing nonoperative and operative management for acute isolated
displaced fractures of the olecranon in patients aged ≧75 years17). The postoperative rehabilitation
protocol was free ROM exercise with a sling following 1 week immobilization with a cast or splint.
For olecranon fractures in the elderly, in particular for severely comminuted fractures, nonoperative
management might be a choice of treatment. Furthermore, operative treatment might not be chosen- 26 -

Complications of Olecranon Fractures in the Elderlyin patients with comorbidities and when huge redisplacement occur, we must consider carefully
whether to perform a reoperation.
This study has following limitations. At first, the sample size was small. Secondly, several
operators chose different kinds of implants and method of fixations. There were many biases instatistical analyses because the fracture types were not unified.
In conclusion, the postoperative redisplacement rates of olecranon fractures using TBW in theelderly were significantly higher than those in young patients. There were no statistically significant
differences in redisplacement rate and distance among three different implants.
Acknowledgements
All authors have no COI to declare regarding the present study.
References
1. Bateman DK, Barlow JD, VanBeek C, et al. Suture anchor fixation of displaced olecranon fractures in theelderly: a case series and surgical technique. J Shoulder Elbow Surg 2015;24:1090-1097.
2. Cha SM, Shin HD, Kim KC, et al. Fixation of posterior process fractures of the olecranon using a modified
suture bridge technique: report of 2 cases. J Hand Surg Am 2014;39:2434-2437.
3. Kiviluoto O, Santavirta S. Fractures of the olecranon: analysis of 37 consecutive cases. Acta Orthop Scand
1978;49:28-31.
4. Morwood MP, Ruch DS, Leversedge FJ, et al. Olecranon fractures with sagittal splits treated with dual
fixation. J Hand Surg Am 2015;40:711-715.
5. Ates Y, Atlihan D, Yildirim H. Current concept in the treatment of fractures of the radial hand, the olecranon,
and the coronoid. J Bone Joint Surg Am 1996;78:969.
6. Wolfgang G, Burke F, Buch D, et al. Surgical treatment of displaced olecranon fractures by tension band
wiring technique. Clin Orthop Relat Res 1987;224:192-204.
7. Cummings SR, Kelsey JL, Nevitt MC, et al. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol
Rev 1985;7:178-208.
8. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoprotic fractures. Lancet 2002;359:1761-1767.
9. Wilson J, Bajwa A, Kamath V, et al. Biomechanical comparison of interfragmentary compression in transverse
fractures of the olecranon. J Bone Joint Surg Br 2011;93:245-250.
10. Hume MC, Wiss DA. Olecranon fractures. A clinical and radiographic comparison of tension band wiring andplate fixation. Clin Orthop Relat Res 1992;285:229-235.
11. Edwards SG, Matrin BD, Fu RH, et al. Comparison of olecranon plate fixation in osteoporotic bone: do current
technologies and designs make a difference? J Orthop Trauma 2011;25:306-311.
12. Erturer RE, Sever C, Sonmez MM, et al. Results of open reduction and plate osteosynthesis in comminuted
fracture of the olecranon. J Shoulder Elbow Surg 2011;20:449-454.
13. Wagner FC, Konstantinidis L, Hohloch N, et al. Biomechanical evaluation of two innovative locking implants
for comminuted olecranon fractures under high-cycle loading conditions. Injury 2015;46:985-989.
14. Kim JY, Lee YH, Gong HS, et al. Use of Kirschner wires with eyelets for tension band wiring of olecranon
fractures. J Hand Surg Am 2013;38:1762-1767.
15. Duckworth AD, Bugler KE, Clement ND, et al. Nonoperative management of displaced olecranon fractures in
low-demand elderly patients. J Bone Joint Surg Am 2014;96:67-72.
16. Gallucci GL, Piuzzi NS, Slullitel PA, et al. Non-surgical functional treatment for displaced olecranon fracturesin the elderly. Bone Joint J 2014;96:530-534.
17. Duckworth AD, Clement ND, McEachan JE, et al. Prospective randomised trial of non-operative versus
operative management of olecranon fractures in the elderly. Bone Joint J 2017;99:964-972.

- 27 -

Osaka City Med. J. Vol. 67, 29-35, 2021

Optimal Surgery for Abdominal Intermediate-risk Neuroblastoma:
Retrospective Study in a Single Institution
KENJI SANTO1), AKIHIRO YONEDA1), SHUICHIRO UEHARA1), TATSUO NAKAOKA1), MASAFUMI KAMIYAMA1),TETSURO NAKAMURA1), TAKESHI INOUE2), and JUNICHI HARA3)
Departments of Pediatric Surgery1), Pathology2), and Pediatric Hematology and Oncology3),
Osaka City General Hospital

Abstract
Background
The treatment outcome of intermediate-risk neuroblastoma has improved and it is an important
issue to reduce the treatment complication. To identify the optimal surgery, we evaluate the surgicalrisk factors for abdominal intermediate-risk neuroblastoma treatment.
Methods
Twelve patients with abdominal intermediate-risk neuroblastoma, according to the risk
stratification in the Children s Oncology Group, treated at our hospital between 1995 and 2016 were
included. The patients were divided into two groups according to the presence (group A, n ＝5) or
absence (group B, n＝7) of surgical complications. Clinical features were compared between groups A
and B.
Results
The median age at diagnosis was 7 (range 4-8 months) and 7 (0.1-23 months) months in groups A
and B. Surgical complications were nephrectomies (n＝2), renal atrophy (n＝1), bowel obstruction (n＝1), and ejaculation disorder (n＝1). All tumors in group A and 29% (n＝2) of tumors in group B had≧95% resection. All patients had tumors with image-defined risk factors at diagnosis. Only one oftumors in group B changed to image-defined risk factors not present status after chemotherapy. All
patients were alive without disease after a median follow-up of 175 months (44-263 months).
Conclusions
Resection of ≧95% could be a surgical risk factor in abdominal intermediate-risk neuroblastoma
treatment. Due to the positive outcomes, less aggressive surgery minimizing surgical complications
for abdominal intermediate-risk neuroblastoma is recommended even if residual tumors persist.
Key Words: ‌Neuroblastoma; Pediatrics; Complications; Intermediate-risk; Surgery

Received July 2, 2020; accepted November 24, 2020.
Correspondence to: Kenji Santo, MD.
Department of Pediatric Surgery, Osaka City General Hospital,
2-13-22 Miyakojima-hondori, Miyakojima-ku, Osaka 534-0021, Japan
Tel: +81-6-6929-1221; Fax: +81-6-6929-1221
E-mail: santokenji@gmail.com- 29 -

Santo et al

Introduction
Neuroblastoma, the most commonly occurring extracranial malignant solid tumor in children, is aheterogeneous tumor that exhibits various behaviors, including spontaneous regression andmetastatic diseases with poor outcome. Neuroblastoma is classified into low-, intermediate-, or highrisk categories based on the clinical and biological features, with the risk category correlating withoutcome. Identification of risk groups has allowed tailoring of therapy to improve outcomes andminimize the risk of deleterious consequences of therapy1).
A recent large, prospective, multicenter trial by the Children s Oncology Group (COG) revealed
that the rate of overall survival of patients with intermediate-risk tumors exceeded 90%, with aconsequent reduction in the application of treatment2). On the other hand a relatively high surgicalcomplication rate of 28% with four deaths was observed in their trial.
Iehara et al3) retrospectively reviewed 20 patients with intermediate-risk neuroblastoma after 15
years of the median follow-up time. They concluded that the presence of a residual mass at the endof treatment did not influence the patients prognoses. Although these results suggested that
aggressive surgery is not necessary, optimal surgery for intermediate-risk neuroblastoma has notbeen clearly discussed previously.
A previous study showed the potential prognostic importance of clinical characteristics, including
the primary tumor site. Patients with abdominal primaries have a less favorable prognosis thanthose with cervical, pelvic, and thoracic primaries 4). Furthermore, Image-Defined Risk Factors(IDRFs) were separately defined according to the anatomical sites5). Therefore, to identify the optimal
surgery for intermediate-risk neuroblastoma, we conducted a retrospective study to evaluate thesurgical risk factors of abdominal intermediate-risk neuroblastoma treatment.

Methods
Of the 148 patients with neuroblastoma treated at our hospital between January 1995 andDecember 2016, 17 were classified as intermediate-risk neuroblastoma cases following the COG risk
classification. Intermediate-risk neuroblastoma was defined as International Neuroblastoma Staging
System (INSS)6) stage 3 or 4 disease without MYCN amplification in an infant (＜1 years), stage 3
disease with favorable histopathological features in a child (≧1 years), and stage 4S disease with adiploid tumor-cell DNA index, unfavorable histopathological features, or both2). We did not recruit inaccordance with the current International Neuroblastoma Risk Group (INRG) risk classification7)
because no information of 11q LOH was available in patients treated prior to the publication of the
INRG risk classification. Of these patients, 12 with abdominal neuroblastoma were selected. We
divided the patients into two groups according to the presence (group A, n＝5) or absence (group B, n＝7) of surgical complications. We retrospectively evaluated the risk factors in the surgical treatmentof abdominal intermediate-risk neuroblastoma. The study design was approved by the ethics review
board of our institution (No. 1804002).
IDRFs were determined according to the Guidelines for imaging and staging of neuroblastic
tumors5). Therefore, isolated contact with renal vessels was considered an IDRF-positive condition inthis study. Surgical complications were defined as major complications of surgery that occurred
during the intraoperative or postoperative period. With respect to nephrectomy, expanded resection
was also allowed at that time, and it was not considered a complication. However, we classified
planed nephrectomy as complications according to the current neuroblastoma treatment policy. The- 30 -

Optimal Surgery for Intermediate-risk NB
Table 1. Patients’ characteristics
group A
(N＝5)

group B
(N＝7)

4 (80)

4 (57)

4 (80)
1 (20)0 (0)1 (20)

6 (86)
1 (14)0 (0)
1 (14)

4 (80)
1 (20)

6 (86)
1 (14)

5 (100)7 (100)3 (60)0 (0)2 (40)

6 (86)
1 (14)0 (0)Sex, n (%)
Male
INSS, n (%)
34
4S
Intraspinal extension, n (%)
Primary therapy, n (%)
Chemotherapy
Surgical resection
INPC, n (%)
FH, NBDNA ploidy, n (%)
Hyperdiploidy
Diploidy
Unknown

INSS, International Neuroblastoma Staging System; INPC, International Neuroblastoma
Pathology Classification; FH, Favorable histology; and NB, Neuroblastoma.

extent of resection was classified into the following three categories: resection of ≧95%, 50%-95%, and＜50% of the tumor volume 8).

Two surgeons decided the extent of resection according to thepreoperative and postoperative images and surgical records.
Age of onset, INSS stage, initial treatment, pathological findings [International Neuroblastoma
Pathology Classification (INPC)], tumor biology (MYCN amplification, DNA diploidy), primary tumor
location, tumor size, IDRFs, association with renal pedicles, extent of resection, and prognoses werecompared retrospectively between the two groups.
Data were expressed as medians and ranges. To obtain pairwise comparisons of the data, theFisher exact test and Student s t-tests was applied. A p value of 0.05 indicated statisticalsignificance. All analyses were performed using R version 3.4.0 (R Core Team. R: A language andenvironment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria,
http://www.R-project.org/)9).

Results
The patients characteristics are shown in Table 1. Four patients (80%) in group A and six
patients (86%) in group B had stage 3 tumors. Intraspinal extensions were present in one patient inboth groups. Of the patients in groups A and B, 80% (n＝4) and 86% (n＝6) received chemotherapy as
an initial treatment, respectively. None of the patients had MYCN amplified or an INPC unfavorable
tumor in both groups.
The median age at diagnosis was 7 months (range: 4-8 months) in group A and 7 months (0.1-23
months) in group B (Table 2 and Table 3). The treatment protocols were not uniform. The drugs ofchemotherapy were used in this study, cyclophosphamide (CPM), vincristine (VCR), pirarubicin(THP), cisplatin (CDDP), carboplatin (CBDCA), dacarbazine (DTIC) and etoposide (VP). The surgical- 31 -

Santo et al
Table 2. Clinical features in group A
Age atPreoperative chemotherapy
Case diagnosis(cycle)(month)1

4

2

5

VCR＋CPM (7)VCR＋CPM＋THP (2)Chemotherapy after surgery(cycle)Median follow-up
Complications period(month)NA

Nephrectomy167

VCR＋CPM＋THP＋CDDP (1)Nephrectomy177

VCR＋CPM＋THP (5)Bowelobstruction

172

VCR＋CPM＋THP＋CDDP (2)
3

8

NA

4

7

VCR＋CPM＋THP (2)57VCR CPM＋THP (3)＊VCR＋CPM＋THP (5)Renal atrophy

205

VCR＋CPM (5)Retrograde
ejaculation

263

VCR＋CPM＋THP＋CDDP (3)VCR, vincristine; CPM, cyclophosphamide; THP, pirarubicin; CDDP, cisplatin; and NA, not applicable.

Table 3. Clinical features in group B

Case

Age atdiagnosis(month)

6

2

7

7

Median follow-up
period(month)Preoperative chemotherapy(cycle)Chemotherapy after surgery(cycle)VCR＋CPM (3)CBDCA＋VP (1)CBDCA＋CPM＋THP (1)NA

52

VP＋CPM (2)44

VP＋CBDCA＋THP (2)VP＋CBDCA (1)
CPM＋THP (1)87

VCR＋CPM＋THP (4)VCR＋CPM＋THP (2)

104

9

23

VCR＋CPM＋THP＋CDDP (5)VCR＋CPM＋THP＋CDDP (3)CPM＋DTIC (1)118

CPM＋THP＋CDDP (1)
10

0.1

NA

VCR＋CPM (18.5)

190

11

7

VCR＋CPM＋THP (2)VCR＋CPM＋THP＋CDDP (9)

NA

215

12

7

VCR＋CPM (3)VCR＋CPM＋THP (4)VCR＋CPM＋THP (3)208

VCR, vincristine; CPM, cyclophosphamide; CBDCA, carboplatin; VP, etoposide; THP, pirarubicin; CDDP, cisplatin;
DTIC, dacarbazine; and NA, not applicable.

complications in group A were planed nephrectomies (n＝2), renal atrophy (n＝1), bowel obstruction (n＝1), and ejaculation disorder (n＝1). All the patients were alive without disease after a medianfollow-up of 175 months (44-263 months). Tumors characteristics showed in Table 4. Group A had
three adrenal tumors (60%), and group B had two (29%). Two retroperitoneal tumors were found ingroup A (40%); and five, in group B (71%). All the patients had tumors with IDRFs at diagnosis inboth groups. Only one of tumors in group B changed from IDRFs present to IDRFs not present
status after preoperative chemotherapy. Three tumors encased renal vessels and two tumors
contacted with them in group A. Three tumors encased, three contacted, and one separated in group
B. Only one tumor in group B changed from contact to separate status after preoperative
chemotherapy.
The size of the primary tumor was 80 mm (45-110 mm) in group A and 55 mm (32-86 mm) ingroup B. The preoperative tumor size was 58.5 mm (30-103 mm) in group A and 40 mm (36-80 mm)- 32 -

Optimal Surgery for Intermediate-risk NB
Table 4. Tumors’ characteristics
group A
(N＝5)

group B
(N＝7)

AdrenalRetroperitoneal
IDRFs at diagnosis, n (%)
Preoperative IDRFs, n (%)
Primary relationship with RP, n (%)

3 (60)
2 (40)
5 (100)5 (100)2 (29)
5 (71)
7 (100)6 (86)

Separate
Contact
EncasePreoperative relationship with RP, n (%)

0 (0)2 (40)
3 (60)

1 (14)
3 (43)
3 (43)

Separate
Contact
EncasePrimary tumor size, mm (range)
Preoperative tumor size, mm (range)

0 (0)2 (40)
3 (60)
80 (45-110)
58.5 (30-103)

2 (29)
2 (29)
3 (43)
55 (32-86)
40 (36-80)

Resection of ≧95%, n (%)

5 (100)2 (29)

Primary tumor location, n (%)

p-value
0.56

1
1
NA

NA

0.13
0.43
0.028

IDRFs, Image-Defined Risk Factors; RP, renal pedicles; and NA, not applicable.

in group B. No tumors were increased in size in group A, while three tumors were increased in sizein group B during preoperative chemotherapy.
All the tumors were resected by at least 95% of the tumor volume in group A, including fivecomplete resections, whereas two complete resections, five 50%-95% resections, and one nonsurgicaltreatment were performed in group B. Thus, all the tumors were resected ≧95% in group A, whereas
29% (n＝2) of the tumors were resected ≧95% in group B. Significantly more tumors in group A thanin group B were resected ≧95% (p＝0.028).

Discussion
In this study, the risk factor in the surgical treatment of patients with abdominal intermediaterisk neuroblastoma could be tumor resection of ≧95%. As all the patients in this study were alive
without disease, complete resection could be unnecessary in patients with abdominal intermediaterisk neuroblastoma. This finding is in accordance with some previous reports. Two large studies
showed that the extent of resection was not associated with event-free and overall survival inunresectable neuroblastoma without MYCN amplification10,11). The presence of a residual mass at theend of treatment has been reported to have no influence on patient prognosis after a long-term followup in patients with intermediate-risk neuroblastoma3,12). These findings supported our opinions thatconservative surgery that allows residual tumors to avoid complications was acceptable.
One patient (case 11) who did not undergo surgery for family wishes at the first treatment
required additional surgery 8 years after the treatment in this study. Although the pathologicalfinding of the biopsy sample at the time of initial diagnosis was neuroblastoma, it was changed toganglioneuroma. This result suggests that the residual tumor may have had a differentiation
tendency. Marachelian et al showed that the post-chemotherapy histopathology of intermediate-risk
neuroblastoma was characterized by regression or maturation13).

- 33 -

Santo et al

IDRFs have been propounded for predicting the surgical risks of localized neuroblastoma by the
INRG task force. The report showed 94% of patients with INSS Stage 3 had IDRFs14). In this study,
all patients in both groups had tumors with IDRFs at diagnosis. A study from Germany showed thatthe surgical complication rates were 26.6% and 14.5% (among 366 patients who underwent resection
other than biopsy) in patients with localized neuroblastoma tumors identified as IDRF-present and
IDRF-absent at diagnosis, respectively15). IDRFs at diagnosis were associated with higher rates ofoperative complications. To avoid surgical complications, a biopsy followed by neoadjuvant
chemotherapy is recommended as the initial treatment in patients with IDRF-present tumors, rather
than surgical resection. Moreover, due to the positive outcome in this study, conservative surgery to
avoid complications is recommended even if residual tumors remain after surgery.
The European Unresectable Neuroblastoma study revealed that the unchanged IDRF pattern wasobserved in 50% of patients and the appearance of new IDRFs during chemotherapy in approximately
20% of patients11). A study from Japan reported that tumors should shrink to ＜20% of the volume at
the time of diagnosis for negative IDRFs and that major surgical complications were observed even in
the patients who had disappearance/numerical reduction of IDRFs 16). In this study, IDRFs
disappeared after chemotherapy in only one of patients in group B. Therefore, patients withintermediate-risk neuroblastoma whose tumors had IDRFs at diagnosis may have a potential risk forundergoing surgery even after neoadjuvant chemotherapy.
A previous study showed that the primary tumor size was associated with the risk ofnephrectomy17). Contrary to expectations, surgical complications were not associated with theprimary and preoperative tumor sizes in this study. None of the tumors in group A increased in size,
whereas three tumors in group B increased in size.
In Guidelines for imaging and staging of neuroblastic tumors, isolated contact with renal vessels
is considered an IDRF-positive condition5). On the other hand, only encasement of the renal pedicles
is considered an IDRF-positive in Japan Neuroblastoma Study Group (JNBSG)18). The previous
report showed if isolated contact with renal vessels was considered an IDRF-positive condition, thesensitivity increased but the specificity decreased for the predictor of the complication18). In thisstudy, three patients with renal complications in group A had tumors encasing renal pedicles and thetumors were completely resected. In group B, three patients had tumors encasing renal vessels, but
no tumors were resected completely. No renal complications were observed on contact in both groups.
Therefore, complete resection could be unnecessary in patients with tumors encasing renal pedicles
and isolated contact with renal vessels could not be surgical risk.
This study has the following limitations: The number of the patients was limited, and thetreatment protocols were not uniform. To better investigate the risk factors in the surgical treatmentof patients with intermediate-risk neuroblastoma, larger prospective studies with uniform
therapeutic protocols should be designed.
In conclusion, aggressive resection of ≧95% of the tumor could be a surgical risk factor in thetreatment of abdominal intermediate-risk neuroblastoma. As all the patients in this study were alive
without disease, conservative surgery to avoid complications could be acceptable even if residual
tumors persist.
Acknowledgements
All authors have no COI to declare regarding the present study.

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Optimal Surgery for Intermediate-risk NB

References
1. Park JR, Bagatell R, London WB, et al. Children s Oncology Group s 2013 blueprint for research:neuroblastoma. Pediatr Blood Cancer 2013;60:985-993.
2. Baker DL, Schmidt ML, Cohn SL, et al. Outcome after reduced chemotherapy for intermediate-risk
neuroblastoma. N Engl J Med 2010;363:1313-1323.
3. Iehara T, Yagyu S, Tsuchiya K, et al. Residual tumor in cases of intermediate-risk neuroblastoma did not
influence the prognosis. Jpn J Clin Oncol 2016;46:661-666.
4. Cotterill SJ, Pearson AD, Pritchard J, et al. Clinical prognostic factors in 1277 patients with neuroblastoma:
results of The European Neuroblastoma Study Group Survey 1982-1992. Eur J Cancer 2000;36:901-908.
5. Brisse HJ, McCarville MB, Granata C, et al. Guidelines for imaging and staging of neuroblastic tumors:consensus report from the International Neuroblastoma Risk Group Project. Radiology 2011;261:243-257.
6. Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis,
staging, and response to treatment. J Clin Oncol 1993;11:1466-1477.
7. Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG) classification
system: an INRG Task Force report. J Clin Oncol 2009;27:289-297.
8. Kubota M. The role of surgery in the treatment of neuroblastoma. Surg Today 2010;40:526-532.
9. Kanda Y. Investigation of the freely available easy-to-use software EZR for medical statistics. Bone Marrow
Transplant 2013;48:452-458.
10. Twist CJ, Schmidt ML, Naranjo A, et al. Maintaining outstanding outcomes using response- and biology-based
therapy for intermediate-risk neuroblastoma: a report from the Children s Oncology Group study ANBL0531.
J Clin Oncol 2019;37:3243-3255.
11. Avanzini S, Pio L, Erminio G, et al. Image-defined risk factors in unresectable neuroblastoma: SIOPEN study
on incidence, chemotherapy-induced variation, and impact on surgical outcomes. Pediatr Blood Cancer 2017;10.1002/pbc.26605.
12. Amano H, Uchida H, Tanaka Y, et al. Excellent prognosis of patients with intermediate-risk neuroblastoma
and residual tumor postchemotherapy. J Pediatr Surg 2018;53:1761-1765.
13. Marachelian A, Shimada H, Sano H, et al. The significance of serial histopathology in a residual mass foroutcome of intermediate risk stage 3 neuroblastoma. Pediatr Blood Cancer 2012;58:675-681.
14. Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging
system: an INRG Task Force report. J Clin Oncol 2009;27:298-303.
15. Simon T, Hero B, Benz-Bohm G, et al. Review of image defined risk factors in localized neuroblastoma
patients: results of the GPOH NB97 trial. Pediatr Blood Cancer 2008;50:965-969.
16. Yoneda A, Nishikawa M, Uehara S, et al. Can neoadjuvant chemotherapy reduce the surgical risks for localizedneuroblastoma patients with image-defined risk factors at the time of diagnosis? Pediatr Surg Int 2016;32:
209-214.
17. Shamberger RC, Smith EI, Joshi VV, et al. The risk of nephrectomy during local control in abdominal
neuroblastoma. J Pediatr Surg 1998;33:161-164.
18. Yoneda A, Nishikawa M, Uehara S, et al. Can image-defined risk factors predict surgical complications inlocalized neuroblastoma? Eur J Pediatr Surg 2016;26:117-122.

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Osaka City Med. J. Vol. 67, 37-43, 2021

Laparoscopic Percutaneous Extraperitoneal Closure for
Inguinal Hernia in Young Adults:
Assessment of Safety, Efficacy, and Reliability
YUKARI SAKAE1,2), YOSHIKI MOROTOMI1,3), KOHEI NOGUCHI2), TAKEO YASUDA4),TOSHIHIKO SHIBATA1), and TATSUO NAKAOKA1)
Department of Pediatric Surgery1), Osaka City University Graduate School of Medicine;
Department of Surgery2), Izumiotsu Municipal Hospital:
Department of Pediatric Surgery3), Kitano Hospital; andDepartment of Surgery4), Tsukazaki Hospital

Abstract
Background
Inguinal hernias can occur in both children and adults. Indirect hernias in children, are primarily
treated with simple high ligation of the hernia sac. However, no conclusive guidelines exist on age
limits for the indication of this surgical approach. We investigated indications for laparoscopic
percutaneous extraperitoneal closure (LPEC) in adults with indirect hernias.
Methods
This study was conducted at two centers from April 1, 2008 to March 31, 2019. The following
indications were considered for LPEC: 1) indirect hernia without coexistence of direct or femoral
hernias and a hernia orifice diameter ≦20 mm and 2) patients younger than 45 years of age withouta history of abdominal surgery who could tolerate general anesthesia. LPEC was performed in 32
patients who met the criteria, and the following parameters were investigated: hernia orifice
diameter, operative time, hospital stay, postoperative pain, surgical site infection (SSI), time to return
to work or school, and recurrence.
Results
The median hernia orifice diameter was 8 mm, and the median operative times were 31.5 and 32
min for unilateral and bilateral hernias, respectively. The median hospital stay was short (3 days),and no patient required analgesics postoperatively. There were no SSIs, recurrence, or hernia onset
on the opposite side during the median follow-up period of 1812 days.
Conclusions
LPEC should be considered a superior treatment for indirect hernias in individuals aged less than
45 years with a hernia orifice diameter ≦20 mm.
Received August 6, 2020; accepted November 24, 2020.
Correspondence to: Tatsuo Nakaoka, MD.
Department of Pediatric Surgery, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3841; Fax: +81-6-6646-6057
E-mail: nakaoka34@yahoo.co.jp- 37 -

Sakae et al

Key Words: ‌Inguinal hernia; Laparoscopic percutaneous extraperitoneal closure; Highligation; Young adults

Introduction
Inguinal hernias can occur in both children and adults. Indirect hernias originating in the patent
processus vaginalis (PPV), the most common inguinal hernias in children, are primarily treated withsimple high ligation of the hernia sac. However, no conclusive guidelines exist on age limits for theindication of this surgical approach. Although the European Hernia Society guidelines on thetreatment of inguinal hernia in adult patients strongly recommend the use of a mesh for inguinal
hernia in patients aged ≧18 years1), the International Guidelines for Groin Hernia Management do
not offer a unified opinion on whether mesh-based techniques are indicated in all patients, including
those with small lateral hernias (European Hernia Society L1 and L2)2). In pediatric surgery,laparoscopic percutaneous extraperitoneal closure (LPEC) has been commonly performed in recent
years to perform high ligation similar to that achieved using the Potts method under laparoscopy 3).
In the present study, we investigated the indications for LPEC in young adult patients with indirect
hernias.

Methods
Patients
Considering LPEC might be indicated for adult indirect hernias sharing the same etiology as
pediatric inguinal hernias, the following criteria were considered indications for LPEC in young
adults: 1) indirect hernia without coexistence of direct or femoral hernias and a small hernia gate
(hernia orifice diameter ≦20 mm), 2) adolescents and adults aged 15-45 years without a history ofabdominal surgery, and 3) ability to tolerate general anesthesia.
From April 1, 2008 to March 31, 2019, 53 of 273 patients with indirect hernia met the inclusion
criteria. Preoperative diagnosis was achieved by computed tomography or ultrasound. The twoavailable hernia repair methods, transabdominal peritoneal repair (TAPP) and LPEC, were explained
to the patients, and we performed LPEC in the patients who provided consent to undergo LPEC. The
final decision for LPEC was reached based on intra-operative findings. Specifically, the hernia gateswere evaluated under laparoscopy, and the indications for TAPP versus LPEC were evaluated. If thepatient was determined not to fulfill the indications for LPEC, TAPP was planned to perform as thealternative approach. The present study included 32 patients who provided consent and underwent
LPEC (Fig. 1).
The following parameters were evaluated in the present study: hernia orifice diameter, operative
time, hospital stay, postoperative pain, surgical site infection (SSI), time to return to work or school,
and recurrence. Prognosis was surveyed via telephone or mail.
All procedures performed in studies involving human participants were in accordance with the
ethical standards of the institutional and/or national research committee and with the 1964 Helsinki
Declaration and its later amendments or comparable ethical standards. The study was approved by
the Bioethics Committee of Tsukazaki Hospital (#181035) and Bioethics Committee of Izumiotsu
Municipal Hospital (#R2-5). All procedures used in this study conformed to the tenets of the
Declaration of Helsinki. Informed consent was obtained from all individual participants included in
the study.

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Laparoscopic Percutaneous Extraperitoneal Closure in Young Adults

Figure 1. Study flowchart. From April 2008 to March 2019, 53 of a total of 273 patients with symptomatic indirect
hernias met the study inclusion criteria. After details on transabdominal peritoneal repair (TAPP) and laparoscopic
percutaneous extraperitoneal closure (LPEC) were provided, 32 patients provided consent and underwent LPEC.

LPECLPEC was performed following the method described by Takehara et al 4). Briefly, a 3-mm
laparoscope was placed through an umbilical incision and 3-mm grasping forceps were inserted in theright abdominal regions through an abdominal incision. A 19-gauge LPEC needle with a 2-0
Surgilon ® suture (COVIDIEN, Tokyo, Japan) was used for ligation. The pneumoperitoneum wasmaintained at 10 mm Hg using a carbon dioxide insufflator. The LPEC needle with a wire loop to
hold the 2-0 Surgilon® suture was inserted at the midpoint of the right or left inguinal line. Half ofthe circuit suturing was performed extraperitoneally, without involving or injuring the spermatic
duct or gonadal vessels, and the peritoneum was punctured at the medial edge of the internalinguinal ring. The 2-0 Surgilon® was placed into the abdominal cavity, and circuit suturing of themedial side of the internal ring was performed extraperitoneally using the same technique. The
LPEC needle was introduced into the abdominal cavity through the same puncture hole. After the
suture was held in the wire loop inside the LPEC needle, the LPEC needle was removed from theabdomen. Next, the orifice of the hernia sac was closed extraperitoneally with complete circuit
suturing around the internal inguinal ring using an LPEC needle. Of note, we performed the method
by Takehara et al twice to create double ligation of the internal inguinal ring (double LPEC) toprevent recurrence due to loosened ligatures in all study patients (Fig 2). The circuit suturing wastied extracorporeally, and the internal inguinal ring was completely closed without skipping any
areas.
The maximum diameter of the hernia orifice was measured using scale-marked sutures.

Results
Thirty-two patients, including 18 male (56%) and 14 female (44%) patients, who fulfilled the- 39 -

Sakae et al

Figure 2. Double laparoscopic percutaneous extraperitoneal criteria (LPEC) in a young adult male patient. The
orifice of hernia sac is closed extraperitoneally twice with complete circuit suturing around the internal inguinal ringusing an LPEC needle.

Table 1. Clinical characteristics of the study patients
Male

FemaleTotal

1828.5 (20.75-33.5) [15-43]

14
28 (24-33) [16-40]

32
28 (23-33) [15-43]

Affected side
Right
Left
Bilateral

7
6
5

7
2
5

14
8

BMI (kg/m2)＊

21.9 (19.4-25.5) [16-28.3]

19.4 (18.3-22.9) [18-24.4]

21.5 (18.7-23.7) [16-28.3]

Number of patients
Age＊

10

quartile range [range]. Abbreviations: BMI, body mass index.

＊

criteria were included in the present study. The median age was 28 [15-43] years (28.5 [15-43] and 28[16-40] years in male and female patients, respectively). There were 14, 8, and 10 patients withright-sided, left-sided, and bilateral hernias, respectively. The median body mass index was 21.5 [1628.3] kg/m2 (21.9 [16-28.3] and 19.4 [18-24.4] kg/m2 in male and female patients, respectively). The
American Society of Anesthesiologists physical status was class 1 for all patients. The study cohort
included eight male smokers, whereas none of the female patients were smokers. None of thepatients had a medical history or were on oral medications (Table 1).
The median hernia orifice diameter was 8 [2-20] mm. The median operative times for unilateraland bilateral hernias were 31.5 [20-51] and 32 [20-72] min, respectively, and the median hospital stay
was 3 days. All wounds were small in all patients, and no patient required analgesics postoperatively
or developed SSI (Fig. 3). The majority of the patients returned to school or work within three days
after the operation (Table 2).
The median follow-up period was 1812 days, no patients developed recurrence or new hernia onset- 40 -

Laparoscopic Percutaneous Extraperitoneal Closure in Young Adults

Figure 3. Surgical scars one week after bilateral surgery in a patient with bilateral patient indirect hernias toillustrate that the scars were very small in patients undergoing laparoscopic percutaneous extraperitoneal closure(LPEC).

Table 2. Surgical outcomes
LPEC [n＝32]
Median diameter of the hernial orifice (mm)＊Median duration of unilateral surgery (min)＊Median duration of bilateral surgery (min)＊Surgical site infection
Median hospital stay (days)
Recurrence
Discomfort in wound site
Follow-up period (days)＊＊

TAPP [n＝241]

8 (7-10) [2-20]

20 (15-28.8) [5-40]

31.5 (23.8-38.5) [20-51]

91 (72-106) [49-129]

32 (28.5-42) [20-72]
03
0
1 (3.2%)92.5 (72.3-111.8) [50-163]
6
5
7
NA

1812 (1040-2386) [321-3965]

NAquartile range (range). Abbreviations: NA, Not applicable.

on the opposite side. One patient underwent two transvaginal births after LPEC, and one patient
had two deliveries by caesarian section; however, to date, none of the patients experienced recurrence.
There were no cases with seroma as a complication. Although one female patient experienced
discomfort in the inguinal region three years postoperatively, she did not require analgesics and wasable to perform daily activities of living.

Discussion
Indirect hernias originating in the PPV, the most common inguinal hernias in children, are treatedby high ligation in which the hernia sac is ligated directly on the internal inguinal ring. However, theage limit for this surgical method remains inconclusive. We considered the possibility that simple
high ligation can be used to treat external inguinal hernias in selected young adults. In the present
study, no recurrence of hernia was observed in young adult patients who underwent LPEC forindirect hernias.

- 41 -

Sakae et al

LPEC, a high-ligation method for pediatric hernia developed by Takehara et al in 19954), is arelatively new operative method that achieves simple high ligation that is as effective as conventional
methods and has become a widely used method for the treatment of pediatric inguinal hernia. On theother hand, surgical techniques for adult inguinal hernia predominantly use a mesh, such as meshplug; an anterior approach, TAPP, totally extraperitoneal repair (TEP); and laparoscopic posterior
approaches.
Adolescent inguinal hernias are treated using high ligation or posterior wall suture repair andtension-free repair method using a mesh. The 2015 Inguinal Hernia Treatment Guidelines of theJapanese Hernia Society recommend a tension-free repair method using a mesh indiscriminately foryoung, middle-aged, and older adults alike. The European Hernia Society guidelines strongly
recommend the use of a mesh, particularly in male patients ≧18 years of age to avoid higher
recurrence rates1). The choice of method depends on the surgeon. However, adult indirect hernias
caused by PPV in the absence of a weakened abdominal wall are considered to be curable with highligation, and whether abdominal wall reinforcement with artificial materials should be indicatedindiscreetly for all patients remains controversial5). The Nyhus classification, which determines theoperative method preoperatively, indicates that type Ⅰ hernia without internal inguinal ring s
dilatation common in children and young adults can be treated with high ligation6).
Hayakawa et al classify indirect hernia originating from an origin other than a PPV as de novo
hernia7). De novo hernia, a direct type of indirect hernia caused by the surrounding fascial tissue
pushing through a weakened hernia orifice, can be diagnosed based on whether the displaced
peritoneum can be smoothly replaced back into the abdominal cavity7). However, we have neverencountered this condition in young patients and we consider that LPEC is not indicated in theseacquired hernias; thus, the decision can be easily made under laparoscopy.
Regarding the measurement of hernia orifice diameter, we often perform LPEC in pediatricpatients with an inguinal hernia orifice diameter of 20 mm without recurrence; therefore, in thepresent study the LPEC indications for indirect hernias included a hernia orifice diameter ≦20 mm.
We predict that the indication for LPEC might be extended to patients with larger hernia orifices
based on the lack of recurrence in the present study.
We consider that the patient age is the most important indication for LPEC, because the definitionof a young adult is ambiguous. In a study of 1983 inguinal hernia patients who were 18 years of age
or older, Neumayer et al reported that patients mean age ± SD were approximately 45 years to 71
years8), indicating possible weakening of the transversal fascia around 45 years; therefore, the age
cutoff was 45 years for LPEC in the present study.
The most important advantage of LPEC is that there is no need for insertion of foreign objects andit involves no risk of mesh infections. Additionally, the first surgery does not become an obstacle for
repeat surgery in cases of recurrence because the inguinal canal is not opened during the firstsurgery. The operative time is short, and can be performed during a short hospital stay. The
surgeries were performed the day after admission in all cases, and the patients were discharged on
postoperative days 1-2 according to the patient s request. However, surgery can be performed on the
day of admission and the patient can be discharged the following day, further shortening the hospital
stay; therefore, LPEC provides an economic advantage. Moreover, the wound size was small, and no
SSI occurred in the current study cohort. Selection of the operative method, LPEC or TAPP, isimportant, but incorrect indications are not made under laparoscopy because it enables the- 42 -

Laparoscopic Percutaneous Extraperitoneal Closure in Young Adults

observation of the hernia type.
According to the 14th Nationwide Survey of Endoscopic Surgery including Japanese endoscopic
surgeons in Japan, the recurrence rates of TAPP, TEP, and mesh plug for adult patients with inguinal
hernia were 1.9%, 1.6%, and 3.9%, respectively9). However, the recurrence rate was 0% in the present
study. We performed double LPEC to avoid the loosening of ligatures, which might have prevented
recurrence in the current cohort.
In this study, we did not compare LPEC with TAPP, because the patient s background was so
different. Of course, we should consider the effect of the size of the hernial orifice diameters andpatient s age, the operative time, hospital stays were significantly shorter in LPEC than in TAPP. We
considered that LPEC was superior to TAPP, in safety and efficacy.
This study has several limitations. First, the sample size of 32 patients was small. However,
although the exact rate is unknown, the incidence of inguinal hernia is substantially lower in young
adults compared with middle-aged and elderly patients. Second, the median follow-up period was1812 days, which was a relatively short period. Thus, follow-up should be conducted for a longer
duration, and future investigations should include larger patient cohorts in multicenter studies.
Based on the current study results, we propose LPEC as an indication for indirect hernias without
coexistence of direct or femoral hernias and a hernia orifice diameter ≦20 mm in adults younger than
45 years of age without a history of abdominal surgery who can tolerate general anesthesia. For
these patients, LPEC can be considered a superior treatment option as it does not require the use of amesh; LPEC is also associated with shorter operative time and hospital stay, reduced postoperative
pain, no SSI or recurrence, earlier return to work or school, and lower medical costs. Furthermore,
the relationships among patient age, hernia orifice size, and potential for treatment with simple highligation should be assessed in future studies.
Acknowledgments
All authors have no COI to declare regarding the present study.
References
1. Simons MP, Aufenacker T, Bay-Nielsen M, et al. European Hernia Society guidelines on the treatment of
inguinal hernia in adult patients. Hernia 2009;13:343-403.
2. HerniaSurge Group. International guidelines for groin hernia management. Hernia 2018;22:1-165.
3. Miyake H, Fukumoto K, Yamoto M, et al. Comparison of percutaneous extraperitoneal closure (LPEC) andopen repair for pediatric inguinal hernia: experience of a single institution with over 1000 cases. Surg Endosc
2016;30:1466-1472.
4. Takehara H, Yakabe S, Kameoka K. Laparoscopic percutaneous extraperitoneal closure for inguinal hernia inchildren: clinical outcome of 972 repairs done in 3 pediatric surgical institutions. J Pediatr Surg 2006;41:19992003.
5. Hirayama Y, Iwaya A, Iinuma Y, et al. The technique and operative results of an advanced laparoscopic
percutaneous extraperitoneal closure method for young adult patients with an indirect inguinal hernia. Nihon
Rinsho Geka Gakkai Zasshi 2016;77:23-28. (In Japanese)
6. Nyhus LM. Individualization of hernia repair: a new era. Surgery 1993;114:1-2.
7. Hayakawa T. Transabdominal preperitoneal laparoscopic herniorrhaphy: classification and concept of the denovo type indirect hernia. Shokakigeka 2016;39:485-493. (In Japanese)
8. Neumayer L, Giobbie-Hurder A, Jonasson O, et al. Open mesh versus laparoscopic mesh repair of inguinal
hernia. N Engl J Med 2004;350:1819-1827.
9. Watanabe M, Inomata M, Akira S, et al. 14th Nationwide Survey of Endoscopic Surgery in Japan. Nihon
Naishikyogeka Gakkai Zasshi 2018;23:727-890. (In Japanese)- 43 -

Osaka City Med. J. Vol. 67, 45-55, 2021

The Clinical Course of Patients with Influenza after Administrationof Various Anti-influenza Drugs during the 2019-2020
Influenza Season in Osaka, JapanNAOMI MARUYAMA1), NAOKO YOSHII1), YOSHIHIRO TOCHINO2), MASASHI FUJIOKA3), KAZUHISA ASAI1),
TAKASHI HAMAZAKI4), HIROSHI KAKEYA5), and TOMOYA KAWAGUCHI1)
Departments of Respiratory Medicine1), Medical Education and General Practice2),
Department of Pediatrics4), and Infection Control Science5),
Osaka City University Graduate School of Medicine; andFujioka Pediatric Clinic3)

Abstract
Background
In Japan, four neuraminidase inhibitors (NAIs) and one cap-dependent endonuclease inhibitor,
baloxavir marboxil (baloxavir), are currently available for treatment of influenza. We investigatedprescription trends of each anti-influenza drug and the clinical course of patients with influenza who
were treated with anti-influenza drugs, including baloxavir, during the 2019-2020 influenza season.
Methods
A multicenter observational study in Osaka was conducted with postcard questionnaires. Patients
who were diagnosed with influenza responded to a postcard questionnaire containing questions about
their background characteristic, and their body temperature. We analyzed the factors that wereassociated with early fever alleviation and biphasic fever, and compared the duration of fever amongfour anti-influenza drug groups excluding peramivir, because few patients were prescribed this drug.
Results
A total of 252 patients with influenza were enrolled and analyzed (97 patients aged ＜10 years,
and 155 patients aged ≧10 years). Baloxavir was prescribed to three of the 97 patients aged ＜10years (3.1%) and to 19 of the 155 patients aged ≧10 years (12.3%). The duration of fever in patientswith influenza was not significantly different among the four groups that received oseltamivir,
laninamivir, zanamivir, or baloxavir. We found no significant difference between the frequency of
biphasic fever episodes and the choice of anti-influenza drugs.
Conclusions
Our study showed no significant association between baloxavir and early fever alleviation or thefrequency of biphasic fever episodes. One cause may be that no statistically association was detected
Received October 27, 2020; accepted January 12, 2021.
Correspondence to: Naomi Maruyama, MD.
Department of Respiratory Medicine, Osaka City University Graduate School of Medicine,
1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3916; Fax: +81-6-6646-6808
E-mail: m8528571@med.osaka-cu.ac.jp- 45 -

Maruyama et aldue to the decrease in the number of prescriptions of baloxavir.
Key Words: ‌Influenza; Neuraminidase inhibitor; Baloxavir marboxil; Biphasic fever

Introduction
Influenza is an acute viral respiratory disease that is epidemic in the winter months. The
seasonal epidemic of influenza is a major cause of morbidity and mortality globally, and the majority
of deaths occur in the elderly. In Japan, about 10-15 million people are infected with influenza every
year. Thousands of deaths occur each year due to influenza, and tens of thousands die during apandemic1).
Baloxavir marboxil (baloxavir) was newly released as a cap-dependent endonuclease inhibitor in
March 2018 in Japan, and is now available in addition to four existing neuraminidase inhibitors(NAIs), oseltamivir, zanamivir, peramivir, and laninamivir. An international clinical trial showedthat baloxavir has good therapeutic activity against influenza A and B virus infections 2,3). A few
clinical studies reported that the duration of fever in influenza patients treated with baloxavir isshorter than in those taking NAIs4,5). The number of baloxavir prescriptions increased explosively
due to the convenience of the single oral dose and the effect; more than 5.2 million people were
estimated to be prescribed baloxavir during the 2018-2019 influenza season6). We also reported thatbaloxavir was prescribed to about 40% of influenza patients5).
On the other hand, in a clinical trial, the emergence of viruses with amino acid substitutions at
position 38 of polymerase acidic protein, which reduces the susceptibility to baloxavir, occurs at ahigh rate, and sometimes in association with rebounds in viral titers and possibly prolongation ofsymptoms2). In October 2019, the Japanese Association for Infectious Disease and the Japan
Pediatric Society suggested that doctors carefully consider the administration of baloxavir forchildren aged ＜12 years7,8).
There are few reports which examine the clinical effects of baloxavir and compare with NAIs inclinical practice. Our objective was to investigate prescription trends of each anti-influenza drug andthe clinical course of patients with influenza who were treated with anti-influenza drugs, including
baloxavir, during the 2019-2020 influenza season.

Methods
ProceduresThis multicenter observational study was conducted in 52 hospitals or clinics in Osaka prefecture,
Japan. Physicians, pediatricians, and otorhinolaryngologists participated in this study. Patientswith influenza who were diagnosed using an antigen detection kit and who were treated with an antiinfluenza drug from December 1, 2019 through April 30, 2020 were enrolled. After obtaining oral
informed consent from the patients or their guardians, clinicians completed the sections on age, sex,
type of influenza (A or B), and the prescribed anti-influenza drug, and then handed the postcard
questionnaire to the patients. Patients mailed the postcard to the Department of Respiratory
Medicine, Osaka City University Graduate School of Medicine after they filled out the questionnaire.
The study protocol was approved by the Institutional Ethics Committee (Osaka City University
Graduate School of Medicine, Approval No. 2019-035).
Questionnaire items
Patients recorded their peak body temperature before first visiting the hospital or clinic, and their- 46 -

Clinical Course of Patients with Influenza

body temperature twice a day (morning and afternoon) for 4 days from first visit. They also
completed the questionnaire regarding their vaccination status this year; underlying diseases;
adverse events of anti-influenza drugs such as coughing, vomiting, diarrhea, abdominal pain,
abnormal behavior, and headache; and the episode of biphasic fever.
Definition of the duration of fever, fever reduction and biphasic fever
We defined the duration of fever as the time from anti-influenza drugs administration until the
fever was alleviated for more than one day with no relapse thereafter. Fever reduction was defined
as a temperature below 37.5℃ in patients aged ＜10 years or below 37.0℃ in patients aged ≧10years9,10). Biphasic fever was defined as developing a fever again after alleviation of the fever for morethan 1 day11,12).
Statistical analysis
Statistical analyses were performed with JMP, ver. 10 (SAS Institute, Inc., Cary, NC, USA). The
Kruskal-Wallis test followed by the Steel-Dwass test for multiple comparisons were used to compare
the duration of fever with each anti-influenza drug. We conducted univariate analysis followed bymultivariate analysis with logistic regression models to examine the factors (sex, age, type of
influenza virus, underlying disease, vaccination status, and type of anti-influenza drug) that wereassociated with the alleviation of fever in 2 days after treatment with anti-influenza drugs began.
Independent variables with p ＜0.20 in univariate analysis and those reported to be associated withearly fever alleviation were included in the multivariate model11,13). The logistic regression model wasused to determine the factors (sex, age, type of influenza, underlying diseases, vaccination status, andtype of anti-influenza drug) influencing the episodes of biphasic fever, and no multiplicity adjustment
was performed in the analyses. To evaluate the frequency of adverse events in each anti-influenza
drug, a Chi-square test was used. Three patients were prescribed peramivir, and they were excluded
from statistical analyses which compared the duration of fever, examined the factors that wereassociated with the early fever alleviation, or biphasic fever episodes, and evaluated the frequency ofadverse events.

Results
Patient characteristics
A total of 900 postcards were handed to patients with positive results on the rapid diagnostic kits.
The response rate was 28.9% (260/900). Eight patients were excluded from the analyses because ofincomplete questionnaire data for age, sex, type of influenza, body temperatures, or prescribed antiinfluenza drug (Fig. 1). Thus, a total of 252 patients were enrolled and analyzed: 97 patients aged
＜10 years (Type A, 80; Type B, 17), and 155 patients aged ≧10 years (Type A, 147; Type B, 8)(Table 1). The anti-influenza drugs prescribed for the patients aged ＜10 years were oseltamivir for
54, laninamivir for 24, zanamivir for 17, peramivir for 0, and baloxavir for 3, and those for thepatients aged ≧10 years were oseltamivir for 41, laninamivir for 77, zanamivir for 15, peramivir for
3, and baloxavir for 19. Of all patients, 51 had underlying disease (Hypertension, 10; Hyperlipidemia,
2; Diabetes mellitus, 3; Bronchial asthma, 8; Allergy, 18; Other, 20). A total of 110 patients hadreceived the influenza vaccine this year.
Factors related to early alleviation of fever
Multivariate analysis revealed that laninamivir was significantly associated with alleviation offever in 2 days compared to oseltamivir (odds ratio, 1.91; 95% confidence interval: 1.05-3.54; p＝0.034)- 47 -

Maruyama et al

Figure 1. Flow of participants through the study. A total of 900 postcards were handed to patients with influenza.
The number of postcards which were returned was 260. Eight patients were excluded from the analyses because ofincomplete questionnaire data for age, sex, type of influenza, body temperatures, or prescribed anti-influenza drug.
Thus, a total of 252 patients were enrolled and analyzed.

Table 1. ‌Clinical characteristics of the study subjects
Characteristics
Age, Mean years±SD
Range

Gender, male/female
Type of influenza virus
Underlying diseases

Vaccinated this year
Anti-influenza drugs

0-4 years
5-9 years
10-19 years
20-39 years
40-59 years
60 yearsmale
femaleType A
Type B
Hypertension
Hyperlipidemia
Diabetes mellitus
Bronchial asthma
Allergy
Yes/No/Unspecified
Oseltamivir
Laninamivir
Zanamivir
Peramivir
Baloxavir＜10 years (n＝97)

10 years≦ (n＝155)

Total (n＝252)

6.17±2.46
24
73
0
0
0
0
51
46
80
17
0

31.6±20.4
0
0
74
14
52
15
69
86
147
8
10

21.8±20.3
24 (9.5)
73 (28.9)
74 (29.4)
14 (5.6)
52 (20.6)
15 (6.0)120 (47.6)
132 (52.4)
227 (90.1)
25 (9.9)
10 (4.0)0023
46/48/3

2
3
6
15
64/85/6

53
24
17
0
3

41
77
15
3
19

2 (0.7)3 (1.2)8 (3.2)18 (7.1)
110 (43.6) /133
(52.8) /9 (3.6)
94 (37.3)
101 (40.1)
32 (31.7)
3 (3.0)22 (21.8)

Data are number or proportion (%) of patients. Abbreviation: SD, standard deviation.

- 48 -

Clinical Course of Patients with Influenza
Table 2a. Factors influencing alleviation of fever in 2 days
Variable
GenderUnivariate analysis
FemaleMale＜10 years≧10 years

Multivariate analysisn/N (%)
65/130 (50.0)
72/119 (60.5)
54/97 (55.7)
83/152 (54.6)

O.R.
1
1.53
1
0.96

95% CI
0.93-2.54
0.58-1.60

p value
0.096
0.87
0.60

Type of influenza
virusType A
Type B

122/224 (54.5)
15/25 (60.0)1
0.80

0.34-1.85

Underlying
diseasesNo
Yes

103/186 (55.4)
28/51 (54.9)

1
0.98

-

-

0.53-1.84

0.95

Vaccinated this
year

No
Yes

73/131 (55.6)
60/110 (54.5)

1
0.95

0.57-1.59

0.85

Anti-influenza
drug

Oseltamivir
Laninamivir
Zanamivir
Baloxavir

45/94 (47.9)
62/101 (61.4)
16/32 (50.0)
14/22 (63.6)

1
1.73
1.09
1.91

0.98-3.07
0.48-2.44
0.74-5.17

0.058
0.84
0.18

O.R.

95% CI

p value

1.58

0.94-2.65

0.08

0.80

0.45-1.41

0.44

1.24

0.52-3.07

0.63

1.91
0.99
2.10

1.05-3.54
0.44-2.26
0.79-5.96

0.034
0.99
0.14

Abbreviation: O.R., odds ratio; and CI, confidence intervals.

(Table 2a).
Table 2b showed sub-group analysis for factors influencing alleviation of fever in 2 days by age
group. Laninamivir was significantly associated with alleviation of fever in 2 days compared tooseltamivir in patients aged ＜10 years (odds ratio, 2.93; 95% confidence interval: 1.08-8.69; p＝0.035).
We also analyzed the factors influencing alleviation of fever in 2 days in patients with influenza A(n＝227). No statistically significant association was found between alleviation of fever in 2 days andsex, age group, underlying disease, vaccination status, or choice of anti-influenza drugs in patientwith influenza A.
Duration of fever after administration of the first dose of anti-influenza drug
The duration of fever in influenza patients was not significantly different among the four groups
that received oseltamivir, laninamivir, zanamivir, or baloxavir (Fig. 2). The median durations of fever
in influenza patients who received each anti-influenza drug was 2.0 to 2.5 days.
Episodes of biphasic fever
Biphasic fever occurred in 10 of 249 patients (4.0%). No statistically significant association was
found between the frequencies of biphasic fever and sex, age group, type of influenza, underlying
disease, vaccination status, or choice of anti-influenza drugs (Table 3).
Adverse events for each anti-influenza drug
The frequency of each adverse event after administration of the anti-influenza drug is shown in
Table 4. There was no statistically significant difference in the frequency of all adverse events, suchas coughing, diarrhea, vomiting, abdominal pain, headache, and abnormal behavior among the fourgroups that received oseltamivir, laninamivir, zanamivir, or baloxavir.

Discussion
In this study, the duration of fever was not significantly different among the four groups that- 49 -

Maruyama et al
Table 2b. Sub-group analysis for factors influencing alleviation of fever in 2 days by age groups＜10 years

Variable

Gendern/N (%)

O.R.

95% CI

p value

Female21/45 (46.7)

1

-

-

Male

30/49 (61.2)

1.80

0.80-4.14

0.16Type A

42/80 (52.5)

1

-

-

Type B

9/14 (64.3)

1.63

0.52-5.70

0.41

Underlying diseases

NoYes

46/83 (55.4)
6/11 (54.6)

1
0.97

0.27-3.59

0.96

Vaccinated this year

No
Yes

25/48 (52.1)
25/44 (56.8)

1
1.21

0.53-2.77

0.65

Anti-influenza drug

Oseltamivir
Laninamivir
Zanamivir
Baloxavir

24/53 (45.3)
17/24 (70.8)
10/17 (58.8)
3/3 (100.0)

1
2.93
1.73
-

1.08-8.69
0.58-5.41
-

0.035
0.33

Type of influenza virus-≧10 years

Variablen/N (%)

O.R.

95% CI

p value

Female43/84 (51.2)

1

-

-

Male

40/68 (58.8)

1.58

0.94-2.65

0.35Type of influenza virus

Type A
Type B

80/144 (55.6)
3/8 (37.5)

1
1.24

0.52-3.07

0.32

Underlying diseases

NoYes

57/103 (55.3)

1

-

-

22/40 (55.0)

0.99

0.47-2.07

0.97

Vaccinated this year

No
Yes

48/83 (57.8)

1

-

-

33/64 (51.6)

0.78

0.40-1.50

0.45

21/41 (51.2)

1

-

-

Anti-influenza drug

Oseltamivir
Laninamivir
Zanamivir
Baloxavir

45/77 (58.4)
6/15 (40.0)
11/19 (57.9)

1.34
0.63
1.31

1.05-3.54
0.44-2.26
0.79-5.96

0.45
0.46

Gender0.63

Abbreviation: O.R., odds ratio; and CI, confidence intervals.

received oseltamivir, laninamivir, zanamivir, or baloxavir, and the frequencies of biphasic fever
episodes and each adverse event in influenza patients who were treated with baloxavir was similar tothat in patients treated with other anti-influenza drugs. In addition, laninamivir significantly
contributed to early fever alleviation compared to oseltamivir in patients aged ＜10 years. The
number of patients with influenza who were prescribed baloxavir decreased compared to the previous
season (8.7% vs 37.5%)5).
In international clinical trials, the virus titer was significantly lower from the second day ofadministration in the baloxavir group than in the oseltamivir group2). Our recent report also showedthat the baloxavir group had a significantly shorter duration of fever than the NAI group in thosewith influenza A in the 2018-2019 season5). However, a previous study reported the emergence ofviruses with reduced susceptibility to baloxavir following baloxavir treatment, and these viruses wereassociated with transient rises in infectious virus titers, prolongation of virus detectability, initial- 50 -

Clinical Course of Patients with Influenza

Figure 2. Comparison of the duration of fever in patients with influenza who received each anti-influenza drug.
Data are the median days of fever in patients who received each anti-influenza drug; oseltamivir (median 2.5 days;
interquartile range (IQR) 2.0-3.0), laninamivir (median 2.0 days; IQR 1.5-2.5), zanamivir (median 2.3 days; IQR 1.63.4), and baloxavir (median 2.0 days; IQR 1.4-2.5).

Table 3. ‌Factors influencing episodes of biphasic fever according to age group, type of influenza, andanti-influenza drugn/N (%)

O.R.

95% CI

p value＜10 years

5/130
5/119
4/99 (4.0)

1
0.91
1

0.26-3.23
-

0.89
-

≧10 years

6/155 (3.9)

0.94

0.26-3.73

0.92

GenderMale
FemaleType of influenza virus

Type A
Type B

9/227 (4.0)
1/25 (4.0)

1
1.00

0.05-5.72

0.99

Underlying diseases

No
Yes

7/186
3/51

1
0.89

0.48-1.66

0.89

Vaccinated this year

No
Yes

3/131
7/110

1
2.90

0.79-13.7

0.11

Anti-influenza drug

Oseltamivir
Laninamivir
Baloxavir

5/94 (5.3)
4/101 (4.0)
1/22 (4.5)

1
0.73
0.85

0.18-2.86
0.04-5.63

0.65
0.88

Abbreviation: O.R., odds ratio; and CI, and confidence intervals.

Table 4. ‌Adverse events in each anti-influenza drug

Coughing n (%)
Diarrhea n (%)
Vomiting n (%)
Abdominal pain n (%)
Headache n (%)
Abnormal behavior n (%)

Oseltamivir(N=94)

Laninamivir(N=101)

Zanamivir(N=32)

Baloxavir(N=22)

p value32 (34.0)
25 (26.6)
16 (17.0)
12 (12.77)
2 (2.1)3 (3.2)39 (38.6)
16 (15.8)
7 (6.9)8 (7.92)
1 (1.0)2 (2.0)18 (56.2)
8 (25.0)
2 (6.3)2 (6.25)
2 (6.3)0 (0.0)6 (27.3)
6 (27.3)
2 (9.1)2 (9.1)0 (0.0)0 (0.0)

0.10
0.27
0.11
0.61
0.27
0.62

- 51 -

Maruyama et aldelay in symptom alleviation, and uncommonly, with symptom rebound2,3). Our study showed nodifference between the duration of fever or the frequency of biphasic fever episodes in the patients
who received baloxavir and those in the patients who received oseltamivir, laninamivir, or zanamivir.
Further studies will be needed to address the clinical effects of baloxavir, which contributed toshortening of the duration of fever or time to alleviation of symptoms, and the frequency of viruses
with reduced susceptibility to baloxavir and their effects on clinical outcomes.
We have shown no difference between the frequency of adverse events after administration of theanti-influenza drug. Abdominal symptoms such as vomiting, diarrhea, and abdominal pain inpatients who were treated with oseltamivir were previously reported as adverse events andbronchospasm after inhalation of laninamivir or zanamivir were also reported as adverse events9,14,15).
However, it is difficult to accurately evaluate abdominal symptoms, coughing, and others as adverse
events of anti-influenza drugs because they also occur with the symptoms of influenza. The frequencyof adverse events after administration of baloxavir was similar to that of other influenza drugs.
Because baloxavir is still a new drug, further studies on adverse events of baloxavir are needed in the
future.
We have shown that laninamivir significantly contributed to early fever alleviation compared tooseltamivir in patients aged ＜10 years. We also found that all patients aged ≦4 years wereprescribed laninamivir with a nebulizer. Laninamivir is not sold overseas, because the time toalleviation of symptoms in patients treated with laninamivir was not significantly different from thatin patients who received a placebo in a phase Ⅱ trial, although the drug is effective in reducing thevirus16). However, in Japan, some previous reports have shown that laninamivir has a similar efficacy
and safety as oseltamivir for the treatment of influenza10,17,18). Because laninamivir is a single-dose
inhalation drug that has an advantage over oseltamivir for medication adherence especially inchildren who frequently refuse to take an oral drug, it may be significantly associated with early fever
reduction in patients aged ＜10 years. Nebulizers were used for inhaling laninamivir beginning in
October 2019 in addition to a dry powder inhaler. We consider that nebulized administration oflaninamivir can be widely prescribed to infants and elderly patients who may have difficulty using adry powder inhaler.
The number of patients who were prescribed baloxavir was significantly reduced in our survey ofthe 2019-2020 season compared to the 2018-2019 season5), similar to national trends in Japan19). We
consider that one cause of the decrease in the number of prescriptions of baloxavir is the suggestions
from the Japanese Association for Infectious Diseases and the Japan Pediatric Society based on some
reports of the emergence of viruses with reduced susceptibility to baloxavir in children and their
human-to-human transmission7,8,20,21). The decrease in the number of prescriptions of baloxavir may
have affected the results in our study. The frequency and odds ratio of alleviation of fever in 2 daysin patients who were prescribed baloxavir was higher than those in patients who were prescribedlaninamivir, however no significant difference could be detected due to the small number ofprescriptions of baloxavir.
Some limitations of this study should be recognized. First, the response rate of the postcard
questionnaires was not high. Therefore, the sample may not be representative of all patients with
influenza. The proportion of our patients who were in their 20 s and 30 s was lower than that in thedata from the Ministry of Health, Labour and Welfare (MHLW) (5.5% vs 16.1%). However, theproportion of patients aged 5-9 years and 10-14 years was higher than those in the MHLW data

- 52 -

Clinical Course of Patients with Influenza(53.2% vs 38.7%). The proportions of the other age groups in our subjects were similar to those in the
MHLW data22). We suggest that the working populations who were in their 20 s and 30 s may not
return many postcards because they didn t have enough time to answer and mail the postcard
questionnaire. Second, the answers including body temperature were self-reported data, and thereliability of the answer is a limitation. Third, the use of antipyretics was not considered, and theduration of fever may shorter than the actual one. Based on the above limitations, we should
consider adding or modifying questionnaire items and other questionnaire methods such as an online
survey for the further development of the study in the future. Fourth, this study was anobservational study, not a randomized controlled study. The selection of the anti-influenza drug wasat the discretion of each physician, introducing invisible selection bias. Making an accuratecomparison of the effects of each anti-influenza drug may be difficult, because their prescription
numbers were different. Fifth, we could not confirm the influenza subtype in this study. For the
2019-2020 season, the National Institute of Infectious Disease reported that more than 90% of theinfluenza subtype was type A (H1N1 pdm09), which almost constituted an epidemic23).
In conclusion, our study showed no significant association between baloxavir and early fever
alleviation or the frequency of biphasic fever episodes that have been reported in the previous study.
One cause may be that no statistically association was detected due to the decrease in the number ofprescriptions of baloxavir. Further studies will need to address the clinical effects of baloxavir, which
contributes to the shortening of the duration of fever or the time to alleviation of symptoms, and theassociation between baloxavir and biphasic fever episodes. Because epidemic influenza virus
subtypes change from season to season, annual influenza surveys are also important for investigating
the appropriate use and efficacy of anti-influenza drugs.
Acknowledgements
All authors have no COI to declare regarding the present study.
We gratefully acknowledge the cooperation of following clinics and hospitals; Aihara second
Hospital, Asakayama General Hospital, Ikuno Clinic for Internal Medicine, Ikuwakai Memorial
Hospital, Ishikiriseiki Hospital, Ishitani Clinic, Imamura Clinic, Izumiotsu Municipal Hospital,
Izumi City General Hospital, Osaka Ekisaikai Hospital, Osaka Minato Central Hospital, Oshimaclinic for Internal Medicine, Kayou Internal Medicine and Pediatric Clinic, Kyowa Hospital,
Kourigaoka Yukeikai Hospital, Gotoh Otolaryngology Clinic, Sakazaki Child Clinic, Shirai Hospital,
Sunami Internal Medicine Clinic, Sumiyoshi Democratic Clinic, Takeda Children s Clinic, Takechi
Pediatric and Internal Medicine Clinic, Tane General Hospital, Tooyama Otolaryngology Clinic,
Tooyama Internal Medicine Clinic, Tochino Otolaryngology Clinic, Nakajima Pediatric Clinic,
Nagayoshi General Hospital, Nihonseimei Hospital, Nishiyodo Hospital, Hata Internal Medicine
clinic, Hananomachi Family Clinic, Hara Clinic, Hirai Clinic, PL Hospital, Higashisano Hospital,
Higashisumiyosi Morimoto Hospital, Fujii Internal Medicine and Pediatric Clinic, Fujioka Pediatric
Clinic, Fujitani Clinic, Fijito Clinic, Fuchu Hospital, Bellifecare Clinic, Masaki Clinic, Minamiura
Pediatric Clinic, Moriguchi Ikuno Memorial Hospital, Yamagami Clinic, Yamada Internal Medicine
Clinic, Yamamoto Internal Medicine Clinic, Yamamoto Third Hospital, and Yodogawa Christian
Hospital.

- 53 -

Maruyama et al

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[Revised: June 8, 2021]

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Editorial Committee

Kazuo Ikeda, MD (Chief Editor)
Yasuhiro Fujiwara, MD

Wakaba Fukushima, MD

Masayuki Hosoi, MD

Koki Inoue, MD

Shoji Kubo, MD

Yukio Miki, MD

Yukio Nishiguchi, MD

Masahiko Ohsawa, MD

Atsushi Shioi, MD

Toshiyuki Sumi, MD

Kishiko Sunami, MD

Daisuke Tsuruta, MD

Junji Uchida, MD

The volumes and issues published in 1954-2018 were as follows: Vol 1 (one issue), Vols 2-5 (2issues, each), Vols 6-7 (one issue, each), Vols 8-9 (2 issues, each), Vol 10 (one issue), Vol 11 (2issues), Vol 12 (one issue), Vol 13 (2 issues), Vols 14-20 (one issue, each), Vol 21 (2 issues), Vol 22(one issue), Vols 23-65 (2 issues, each), Vol 66 (one issue)

Publisher : Osaka City Medical Association,
Osaka City University Medical School,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan