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The incidence and seasonal variation of necrotizing fasciitis in Korea: a nationwide cross-sectional study
Journal Pre-proof The incidence and seasonal variation of necrotizing fasciitis in Korea: a nationwide cross-sectional study Hee Kyoung Choi, GiHyeon Seo, Euna Han PII:
S1198-743X(20)30003-3
DOI:
https://doi.org/10.1016/j.cmi.2020.01.002
Reference:
CMI 1888
To appear in:
Clinical Microbiology and Infection
Received Date: 31 December 2019 Accepted Date: 2 January 2020
Please cite this article as: Choi HK, Seo G, Han E, The incidence and seasonal variation of necrotizing fasciitis in Korea: a nationwide cross-sectional study, Clinical Microbiology and Infection, https:// doi.org/10.1016/j.cmi.2020.01.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
1
The incidence and seasonal variation of necrotizing fasciitis in Korea: a nationwide
2
cross-sectional study
3
Hee Kyoung Choia,b, GiHyeon Seoc, Euna Hana*
4
a
College of Pharmacy, Yonsei Institute of Pharmaceutical Research, Yonsei University, Seoul, Republic of Korea
5
b
Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Ansan,
6
Republic of Korea
7
c
8
Republic of Korea
Healthcare Review and Assessment Committee, Health Insurance Review and Assessment Service, Seoul,
9 10 11 12
* Corresponding Author:
13
Euna Han, PhD
14
College of Pharmacy, Yonsei Institute of Pharmaceutical Research
15
Yonsei University
16
162-1 Songdo-dong, Yeonsu-gu, Incheon, Korea
17
Phone: +82-32-749-4511; Fax: +82-32-749-4105
18
E-mail: [email protected]
19 20
1
21
ABSCTRACT
22
Objectives: NF is a rare but fatal disease, and there is no known annual incidence of NF in Korea. The aim of
23
this study was to investigate the incidence and seasonal variation of necrotizing fasciitis (NF) in Korea.
24
Methods: We analyzed claims from the nationwide Korean Health Insurance Review and Assessment Service
25
database. Patients who were hospitalized with an NF diagnosis code and received surgical intervention were
26
classified as NF cases. Poisson regression models were used to assess the relationships of incidence rates with
27
year, age, and sex. A multivariate Poisson regression model was used to investigate variations in monthly NF
28
incidence trends.
29
Results: From 2012 to 2017, the overall average annual NF incidence rate was found to be 0.86 per 100,000
30
population. NF incidence increased with age and was 2.5-times higher among males across all age groups. Two-
31
thirds of cases occurred among patients with diabetes. The peak NF incidence occurred during the summer.
32
Multivariate Poisson regression modeling using national meteorological variables suggested that mean
33
temperatures and number of NF cases in the previous month were associated with the number of NF cases in the
34
current month.
35
Conclusions: Clinicians should consider NF when encountering an elderly male with diabetes in the summer.
36 37 38 39 40 41 42 43 44 2
45
Introduction
46
Necrotizing fasciitis (NF) is a rare but potentially fatal infectious disease, which exerts a heavy economic
47
burden on patients and the healthcare system [1-3]. Early suspicion is essential for successful treatment of NF
48
and aggressive surgical intervention with appropriate antimicrobial therapy is required. NF occurs worldwide,
49
and the annual incidence of NF varies from 0.3 to 15 per 100,000 population [4-9]. In particular, there is a wider
50
variation in NF incidence in western Asia, and this is thought to be due to environmental or lifestyle factors,
51
such as climate [4], extensive sea coasts, and raw fish ingestion [10]. NF is associated with older age, male sex,
52
obesity, diabetes, trauma, steroid use, nonsteroidal anti-inflammatory drug, chronic kidney disease, liver
53
cirrhosis, and alcohol use disorder or chronic alcoholism [7, 10-15].
54
Although several epidemiologic studies from Korea on NF have been reported, these studies have relied on
55
hospital-based data and did not estimate NF incidence rates [10, 12]. Moreover, they may not be representative
56
of the entire Korean population. Therefore, we aimed to investigate the annual incidence and other
57
epidemiologic features of NF at the national level, using claims data from the Korean Health Insurance Review
58
and Assessment Service (HIRA), the only public agency that reviews National Health Insurance Service (NHIS)
59
claims before reimbursement decisions are made. We also analyzed the relationship between the number of
60
monthly NF cases and national monthly mean meteorological variables.
61 62
Methods
63
Data sources
64
We used claims data from the HIRA database. The NHIS program was initiated in 1987 and achieved universal
65
coverage of the entire Korean population by 1989. Accordingly, the HIRA database contains all information
66
regarding the diagnoses, prescribed medications, and procedures of approximately 50 million Koreans [16].
67
HIRA provided the claims data with the concealed individual patient identifiers.
68 69
Case definitions 3
70
We define NF patients as those who were hospitalized because of NF and underwent surgical treatment
71
accordingly. We used a method used in a previous study conducted in Taiwan [4], which requires an NF
72
diagnosis code and a surgical intervention code to identify NF. Supplementary Table S1 lists the diagnosis and
73
procedure codes. The disease codes in the claims data are encoded according to the Korean Standard
74
Classification of Diseases (KCD), which is a modified adaptation of the 10th revision of the International
75
Statistical Classification of Diseases and Related Health Problems (ICD-10) for the Korean medical context.
76
Most KCD codes are the same as the corresponding ICD-10 codes, with a few exceptions.
77
We retrieved data from claims reviewed during the 2011–2018 period and analyzed only the episodes that
78
started between 2012 and 2017. NF episodes were defined by the following process (Figure S1). First, we
79
identified claims with NF diagnosis codes and procedure codes as NF admission claims. Second, we
80
reconstructed the claims at the episode level. Third, we excluded episodes suspected to be related to previous
81
episodes. Patients may be readmitted for secondary treatment, such as skin grafting or a repeated surgical
82
procedure. Thus, a readmission within 180 days of the previous episode’s discharge date was considered as the
83
same episode. Fourth, admission episodes with an initial admission date before January 1, 2012, were excluded.
84
Covariates
85
Demographics included sex, age, and presence of comorbidities. Age at diagnosis was grouped by 10-year
86
intervals starting at 20 years of age. Comorbidities were classified based on the ICD-10 codes: fibrosis and
87
cirrhosis of the liver (K74) and diabetes mellitus (E10–E14, O24) in the same claim. The involved sites were
88
classified according to diagnosis codes. National monthly mean meteorological variables were pulled from
89
public data provided by the Korea Meteorological Administration, including mean temperatures, minimum
90
temperature, maximum temperature, rainfall, and rainy days [17].
91
Analysis
92
The annual NF incidence rates per 100,000 population was calculated using the age- and sex-specific
93
frequencies of identified NF cases as the numerators and the age- and sex-specific midyear populations
94
(provided by the Statistic Korea database [18]) as the denominators. Poisson regression models were used to
95
assess the relationships between crude incidence rates and year, age, and sex. 4
96
We performed a cross-correlation analysis using the Spearman rank test to investigate the lagged effects of
97
monthly meteorological variables on the monthly NF incidence with a time lag of zero to three months.
98
Multivariate Poisson regression model was used to investigate the variations in the trends of monthly NF cases
99
as follows: = , , ,
IRR = =
, ! "
% & ⋯ &( ⋯ ) &) % & ⋯ & ⋯ ) &)
100
Where Y is the number of NF cases; t represents months; E represents days in a month; β denotes the coefficient
101
estimates; Tmax, Tmin, and Tmean are the monthly maximum, minimum, and mean temperatures (°C),
102
respectively; Rains is the rainfall intensity (mm); and n represents the n-month lag time from t. Although NF is
103
not a transmitted disease, some pathogens causing NF are associated with poor hygiene or contaminated water
104
or food. Therefore, we included the number of cases (Yt –1) from the previous month in the Poisson regression
105
model. Stata software version 14 (StataCorp, College Station, TX, USA) was used for all analyses.
106
Ethics
107
This study was approved by the Institutional Review Board of Yonsei University (approval number: 7001988-
108
201901-HR-517-01E). A waiver of informed consent was approved by the IRB of Yonsei University.
109 110
Results
111
From 2012 to 2017, 1,960 patients experienced 2,014 NF episodes. Most patients (97.4%) experienced one
112
episode. Compared with patients who experienced a single episode, patients who experienced multiple episodes
113
were younger and more likely to have diabetes. More than 60% of the episodes were attributed to male patients.
114
The ≥70-year age group experienced the most NF episodes, followed by patients in their 50s. Two-thirds of the
115
episodes occurred in patients with underlying diabetes. The commonly involved sites were the lower extremities
116
and the pelvis (ankle or foot, lower leg, pelvic region, and thigh). (Table 1).
117
Table 2 shows the estimated NF incidence rates stratified by age and sex. Incidence increased with age, ranging 5
118
from 0.03 per 100,000 in the 0–19-year age group to 2.17 per 100,000 in the ≥70-year age group. Figure 1
119
shows the age- and sex-specific annual NF incidence rates. The incidence rates increased with age for both
120
sexes and increased with year. The incidence rates were 2.5 times higher among males than among females
121
across all age groups (incidence rate ratio [IRR]: 2.54, 95% confidence interval [CI]: 2.31–2.79). The NF
122
incidence peaked in 2014 and was the lowest in 2012 for both males and females. The overall annual incidence
123
rate was 0.86/100,000 (95% CI: 0.82–0.90).
124
The number of NF cases peaked during the summer (i.e., July, August, and September) (Figure S2). Table 3
125
shows the correlation between the monthly number of NF cases and the national monthly mean temperatures.
126
The maximum, mean, and minimum average temperatures had a positive correlation with 0 to 2 months of lag
127
time. The rainfall intensity of the previous month showed a positive correlation with the monthly NF incidence.
128
We chose the 1-month lag of the maximum temperature, 1-month lag of the minimum temperature, 1-month lag
129
of the mean temperature, and 1-month lag of the rainfall intensity for the Poisson regression analysis. Table 4
130
shows the relationship between the monthly NF incidence and these meteorological factors. If a mean
131
temperature in the previous month increased by one point, the rate ratio for the NF cases would be expected to
132
increase by a factor of 1.56 while holding all other variables in the model constant. However, a rise in the
133
maximum or minimum temperature in the previous month had an inverse effect on the NF incidence of a given
134
month. Meanwhile, if the NF incidence in the previous month increased by one point, the rate ratio for the NF
135
incidence would be expected to increase by a factor of 1.02.
136 137
Discussion
138
The overall mean annual incidence rate of NF during 2012–2017 was 0.86/100,000. NF incidence ranges from
139
0.3 to 15 cases per 100,000 population [4, 5, 7-9, 11]. A previous study using the claims data from 2005 to 2010
140
showed an annual incidence rate of 11.6 cases per 100,000 population in Taiwan [4]. In the present study, the NF
141
incidence was lower than that found in Taiwan [4] and Thailand [8] but higher than incidence rates in Western
142
Countries [5, 7, 9]. This could be attributed to the higher incidence of NF caused by V. vulnificus and A.
143
hydrophila in Taiwan and Korea. Taiwan and Korea have higher rates of V. vulnificus and A. hydrophila 6
144
infection because they have extensive sea coasts as well as higher rates of raw seafood ingestion and liver
145
cirrhosis [10].
146
NF is divided two microbiologic categories: polymicrobial (type I) and monomicrobial (type II) infections [11].
147
Monomicrobial NF is most commonly caused by group A Streptococcus, followed by other beta-hemolytic
148
streptococci and S. aureus. Aeromonas hydrophila and Vibrio vulnificus can cause monomicrobial NF. Type I
149
NF usually occurs in older adults with underlying comorbidities, whereas type II NF can occur at any age and in
150
patients with no underlying diseases. The most important predisposing factor is diabetes [1, 6, 13]. Liver disease
151
[10, 13], alcoholism [10, 13, 14] and alcohol use disorder [15] are also common underlying diseases associated
152
with NF. A retrospective study conducted at three university hospitals in Korea showed that diabetes was the
153
most common disease (45.8%) associated with NF, followed by chronic liver disease (26.5%). In contrast,
154
another Korean study at a single university hospital serving the surrounding 3,000 islands region showed that
155
alcoholism (53.5%) and liver cirrhosis (50.7%) were the most common comorbidities and that only 15.2% of
156
patients had diabetes [10]. This finding may be attributed to differences in the characteristics of both regional
157
and national studies. The proportion of underlying disease in our study was similar to that in a previous US
158
study using nationwide administrative data (i.e., diabetes: 55% and liver disease: 1.4–4%) [6]. We did not have
159
denominators to calculate the incidence rates according to underlying diseases; therefore, we would not directly
160
assess the risk posed by comorbid conditions. However, the prevalence of these comorbidities among the NF
161
cases was much higher than that in the Korean general population. The prevalence of diabetes in Korea was
162
estimated to be 13.7% in 2016 [19], while the liver cirrhosis prevalence was estimated to be 0.01% between
163
1998 and 2013 [20].
164
The NF incidence was higher among the elderly and showed male predominance in this study. These results are
165
concordant with those in the previous reports [5, 7, 13]. The commonly involved sites were the extremities,
166
pelvis, and perineum, which is similar to what has been reported from previous studies [10, 21].
167
Previous studies reported a rising incidence of NF [4, 5]; however, we could not find such an increasing trend in
168
Korea.
169
We found that NF incidence peaked during summer. Some studies suggested that the cellulitis [22] and NF [4] 7
170
incidence rates increase during the warm season. In a study conducted in Taiwan, the number of NF cases
171
peaked in August, and the peak correlated with the monthly temperature [4]. The Poisson regression model in
172
the present study indicated that the NF cases in a given month could be influenced by the number of NF cases in
173
the previous month. This may provide evidence to inform preventive policies by local communities and health
174
authorities.
175
We attempted to extract all potential NF cases occurring in Korea from 2012 through 2017 using national
176
insurance claims with all Koreans as compulsory beneficiaries. Therefore, the findings of the present study
177
account for real-world evidence for the whole Korean population.
178
This study had some limitations. First, we could not obtain information about causative bacteria and could not
179
distinguish between monomicrobial and polymicrobial infections. Second, we did not include automobile
180
insurance claim data. One of the risk factors for NF is major trauma; hence, our analysis may have
181
underestimated the incidence. However, the burden of automobile insurance is minimal relative to that of health
182
insurance. For example, in 2016, there were 1,399,039,549 health insurance claims compared with 15,525,771
183
automobile insurance claims, representing approximately 1.1% of the number of health insurance claims [23].
184
Therefore, the proportion of NF cases covered by automobile insurance was not expected to be high. Third,
185
patients with extremely severe NF, who died before a surgical procedure, may not have been identified as
186
having NF because a procedure code was required as part of the case definition. Finally, we could not assess
187
other important risk factors, such as recent medications, obesity, raw fish intake and trauma. These individual
188
patient-level factors could not be identified due to the limitations of claims data. Therefore, our study aimed to
189
reveal time-series changes in the incidence of NF in the entire country, rather than identify the causes or risk
190
factors associated with individual patients.
191 192
Conclusions
193
NF predominantly occurs among older individuals and males. Seasonality and trends were correlated with the
194
previous month’s mean temperature and number of NF cases, which may suggest the need for preventive
195
intervention and may be a clue for hospital physicians to suspect of NF early. Additional studies are needed to 8
196
identify the modifiable risk factors associated with NF.
197 198
Transparency declaration
199
Conflict of interest
200
None declared.
201
Funding
202
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-
203
profit sectors.
204
Acknowledgements
205
This study was presented at the ID week in October 2-6, 2019 at the Walter E. Washington Convention Center,
206
in Washington, DC
207
Access to data
208
According to HIRA data protection regulation, administrative data is made available for specific research
209
projects. Thus, authors cannot share the data we used for this study with other researchers. However, data may
210
be available after obtaining HIRA’s permission on reasonable request.
211
Contribution
212
EH and HKC had full access to all the data in the study and takes responsibility for the integrity of the data and
213
the accuracy of the data analysis. Conception and design EH, GHS, HKC. Drafting of the manuscript HKC.
214
Critical revision of the manuscript EH, GHS, HKC. All authors have read and approved the final manuscript.
215 216
Figure legends
217
Figure 1. Annual age-specific incidence rates of necrotizing fasciitis (NF)
218
(A) Female and (B) Male 9
219 220 221
Appendix A. Supplementary data
222
Supplementary Table S1. ICD-10 diagnosis codes and procedure codes associated with necrotizing fasciitis
223
Figure S1. Selection process to define the necrotizing fasciitis (NF) episodes
224
Figure S2. Seasonality of necrotizing fasciitis
225 226 227 228
10
229
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230
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Korean
Health
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288 289 290
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291
Table 1. Characteristics of the necrotizing fasciitis episodes from 2012 through 2017 Characteristic
2,014 episodes
Number of patients
1960
Number of patients who experienced one episode
1910 (97.4%)
Number of patients who experienced two episodes
46 (2.3%)
Number of patients who experienced three episodes
4 (0.2%)
Male
1388 (68.9%)
Age, years ± standard deviation [range]
59.8 ± 14.6 [0.2–99]
0–19
21 (1.0%)
20–29
29 (1.4%)
30–39
114 (5.7%)
40–49
296 (14.7%)
50–59
513 (25.5%)
60–69
475 (23.6%)
≥70
566 (28.1%)
Diabetes
1378 (68.4%)
Liver cirrhosis
62 (3.1%)
Involved sites Multiple sites
82 (4.1%)
Shoulder region
13 (0.7%)
Arm and hand
163 (8.1%)
Pelvic region and thigh
277 (13.8%)
Lower leg
511 (25.4%)
Ankle and foot
731 (36.3%)
Other or unspecified
238 (11.8%)
Procedure Fasciotomy
292
1733 (86.0%)
Amputation of the pelvis
1 (0.1%)
Amputation of the thigh
108 (5.4%)
Amputation of the upper arm, forearm, or lower leg
172 (8.5%)
NF, necrotizing fasciitis; NA, not applicable
293 294 13
295
Table 2. Incidence rate (per 100,000 population) of necrotizing fasciitis by sex and age Total Age
296
group,
Incidence
Male 95% CI
Incidence
Female 95% CI
rate
Incidence
95% CI
years
rate
0–19
0.03
0.01-0.05
0.05
0.03–0.07
0.02
0.01–0.03
20–29
0.07
0.05–0.10
0.10
0.06–0.14
0.04
0.03–0.06
30–39
0.24
0.20–0.29
0.35
0.28–0.41
0.14
0.11–0.16
40–49
0.56
0.50–0.63
0.80
0.71–0.90
0.32
0.27–0.36
50–59
1.07
0.98–1.16
1.53
1.39–1.67
0.60
0.54–0.67
60–69
1.67
1.52–1.82
2.42
2.20–2.65
0.95
0.85–1.06
≥70
2.17
1.99–2.35
3.44
3.13–3.75
1.35
1.22–1.49
CI, confidence interval
297 298 299 300 301 302 303 304 305 306 307 14
rate
308
Table 3. Spearman’s coefficient of rank correlation for time-lag effects on the monthly number of necrotizing
309
fasciitis Spearman’s coefficient according to given meteorological variable
310
Lag time
Mean
Maximum
Minimum
(months)
temperature
temperature
temperature
(°C)
(°C)
(°C)
0
0.3485***
0.3566**
0.3370**
0.1770
0.0032
1
0.4007***
0.4184***
0.3922***
0.3652**
0.2108
2
0.3401**
0.3512**
0.3350**
0.2091
0.1826
3
0.1861
0.1994
0.1682
0.0662
-0.0303
*p < 0.05; **p < 0.01; ***p < 0.001
311 312 313 314 315 316 317 318 319 320 321
15
Rainfall (mm)
Rainy (days)
days
322 323
Table 4. Poisson regression model results on the associations between temperature variation and the monthly
324
number of necrotizing fasciitis cases
325
IRR
95% CI
P value
Mean_lag1
1.56
1.03–2.37
0.035
Max_lag1
0.79
0.64–0.99
0.040
Min_lag1
0.81
0.67–0.99
0.037
NF_lag1
1.02
1.01–1.03
<0.001
Rains_lag1
1.00
1.00–1.00
0.422
IRR, incidence rate ratio; CI, confidence interval
326 327 328 329 330
16
A
B Figure 1.
S1198-743X(20)30003-3
DOI:
https://doi.org/10.1016/j.cmi.2020.01.002
Reference:
CMI 1888
To appear in:
Clinical Microbiology and Infection
Received Date: 31 December 2019 Accepted Date: 2 January 2020
Please cite this article as: Choi HK, Seo G, Han E, The incidence and seasonal variation of necrotizing fasciitis in Korea: a nationwide cross-sectional study, Clinical Microbiology and Infection, https:// doi.org/10.1016/j.cmi.2020.01.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
1
The incidence and seasonal variation of necrotizing fasciitis in Korea: a nationwide
2
cross-sectional study
3
Hee Kyoung Choia,b, GiHyeon Seoc, Euna Hana*
4
a
College of Pharmacy, Yonsei Institute of Pharmaceutical Research, Yonsei University, Seoul, Republic of Korea
5
b
Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Ansan,
6
Republic of Korea
7
c
8
Republic of Korea
Healthcare Review and Assessment Committee, Health Insurance Review and Assessment Service, Seoul,
9 10 11 12
* Corresponding Author:
13
Euna Han, PhD
14
College of Pharmacy, Yonsei Institute of Pharmaceutical Research
15
Yonsei University
16
162-1 Songdo-dong, Yeonsu-gu, Incheon, Korea
17
Phone: +82-32-749-4511; Fax: +82-32-749-4105
18
E-mail: [email protected]
19 20
1
21
ABSCTRACT
22
Objectives: NF is a rare but fatal disease, and there is no known annual incidence of NF in Korea. The aim of
23
this study was to investigate the incidence and seasonal variation of necrotizing fasciitis (NF) in Korea.
24
Methods: We analyzed claims from the nationwide Korean Health Insurance Review and Assessment Service
25
database. Patients who were hospitalized with an NF diagnosis code and received surgical intervention were
26
classified as NF cases. Poisson regression models were used to assess the relationships of incidence rates with
27
year, age, and sex. A multivariate Poisson regression model was used to investigate variations in monthly NF
28
incidence trends.
29
Results: From 2012 to 2017, the overall average annual NF incidence rate was found to be 0.86 per 100,000
30
population. NF incidence increased with age and was 2.5-times higher among males across all age groups. Two-
31
thirds of cases occurred among patients with diabetes. The peak NF incidence occurred during the summer.
32
Multivariate Poisson regression modeling using national meteorological variables suggested that mean
33
temperatures and number of NF cases in the previous month were associated with the number of NF cases in the
34
current month.
35
Conclusions: Clinicians should consider NF when encountering an elderly male with diabetes in the summer.
36 37 38 39 40 41 42 43 44 2
45
Introduction
46
Necrotizing fasciitis (NF) is a rare but potentially fatal infectious disease, which exerts a heavy economic
47
burden on patients and the healthcare system [1-3]. Early suspicion is essential for successful treatment of NF
48
and aggressive surgical intervention with appropriate antimicrobial therapy is required. NF occurs worldwide,
49
and the annual incidence of NF varies from 0.3 to 15 per 100,000 population [4-9]. In particular, there is a wider
50
variation in NF incidence in western Asia, and this is thought to be due to environmental or lifestyle factors,
51
such as climate [4], extensive sea coasts, and raw fish ingestion [10]. NF is associated with older age, male sex,
52
obesity, diabetes, trauma, steroid use, nonsteroidal anti-inflammatory drug, chronic kidney disease, liver
53
cirrhosis, and alcohol use disorder or chronic alcoholism [7, 10-15].
54
Although several epidemiologic studies from Korea on NF have been reported, these studies have relied on
55
hospital-based data and did not estimate NF incidence rates [10, 12]. Moreover, they may not be representative
56
of the entire Korean population. Therefore, we aimed to investigate the annual incidence and other
57
epidemiologic features of NF at the national level, using claims data from the Korean Health Insurance Review
58
and Assessment Service (HIRA), the only public agency that reviews National Health Insurance Service (NHIS)
59
claims before reimbursement decisions are made. We also analyzed the relationship between the number of
60
monthly NF cases and national monthly mean meteorological variables.
61 62
Methods
63
Data sources
64
We used claims data from the HIRA database. The NHIS program was initiated in 1987 and achieved universal
65
coverage of the entire Korean population by 1989. Accordingly, the HIRA database contains all information
66
regarding the diagnoses, prescribed medications, and procedures of approximately 50 million Koreans [16].
67
HIRA provided the claims data with the concealed individual patient identifiers.
68 69
Case definitions 3
70
We define NF patients as those who were hospitalized because of NF and underwent surgical treatment
71
accordingly. We used a method used in a previous study conducted in Taiwan [4], which requires an NF
72
diagnosis code and a surgical intervention code to identify NF. Supplementary Table S1 lists the diagnosis and
73
procedure codes. The disease codes in the claims data are encoded according to the Korean Standard
74
Classification of Diseases (KCD), which is a modified adaptation of the 10th revision of the International
75
Statistical Classification of Diseases and Related Health Problems (ICD-10) for the Korean medical context.
76
Most KCD codes are the same as the corresponding ICD-10 codes, with a few exceptions.
77
We retrieved data from claims reviewed during the 2011–2018 period and analyzed only the episodes that
78
started between 2012 and 2017. NF episodes were defined by the following process (Figure S1). First, we
79
identified claims with NF diagnosis codes and procedure codes as NF admission claims. Second, we
80
reconstructed the claims at the episode level. Third, we excluded episodes suspected to be related to previous
81
episodes. Patients may be readmitted for secondary treatment, such as skin grafting or a repeated surgical
82
procedure. Thus, a readmission within 180 days of the previous episode’s discharge date was considered as the
83
same episode. Fourth, admission episodes with an initial admission date before January 1, 2012, were excluded.
84
Covariates
85
Demographics included sex, age, and presence of comorbidities. Age at diagnosis was grouped by 10-year
86
intervals starting at 20 years of age. Comorbidities were classified based on the ICD-10 codes: fibrosis and
87
cirrhosis of the liver (K74) and diabetes mellitus (E10–E14, O24) in the same claim. The involved sites were
88
classified according to diagnosis codes. National monthly mean meteorological variables were pulled from
89
public data provided by the Korea Meteorological Administration, including mean temperatures, minimum
90
temperature, maximum temperature, rainfall, and rainy days [17].
91
Analysis
92
The annual NF incidence rates per 100,000 population was calculated using the age- and sex-specific
93
frequencies of identified NF cases as the numerators and the age- and sex-specific midyear populations
94
(provided by the Statistic Korea database [18]) as the denominators. Poisson regression models were used to
95
assess the relationships between crude incidence rates and year, age, and sex. 4
96
We performed a cross-correlation analysis using the Spearman rank test to investigate the lagged effects of
97
monthly meteorological variables on the monthly NF incidence with a time lag of zero to three months.
98
Multivariate Poisson regression model was used to investigate the variations in the trends of monthly NF cases
99
as follows: = , , ,
IRR = =
, ! "
% & ⋯ &( ⋯ ) &) % & ⋯ & ⋯ ) &)
100
Where Y is the number of NF cases; t represents months; E represents days in a month; β denotes the coefficient
101
estimates; Tmax, Tmin, and Tmean are the monthly maximum, minimum, and mean temperatures (°C),
102
respectively; Rains is the rainfall intensity (mm); and n represents the n-month lag time from t. Although NF is
103
not a transmitted disease, some pathogens causing NF are associated with poor hygiene or contaminated water
104
or food. Therefore, we included the number of cases (Yt –1) from the previous month in the Poisson regression
105
model. Stata software version 14 (StataCorp, College Station, TX, USA) was used for all analyses.
106
Ethics
107
This study was approved by the Institutional Review Board of Yonsei University (approval number: 7001988-
108
201901-HR-517-01E). A waiver of informed consent was approved by the IRB of Yonsei University.
109 110
Results
111
From 2012 to 2017, 1,960 patients experienced 2,014 NF episodes. Most patients (97.4%) experienced one
112
episode. Compared with patients who experienced a single episode, patients who experienced multiple episodes
113
were younger and more likely to have diabetes. More than 60% of the episodes were attributed to male patients.
114
The ≥70-year age group experienced the most NF episodes, followed by patients in their 50s. Two-thirds of the
115
episodes occurred in patients with underlying diabetes. The commonly involved sites were the lower extremities
116
and the pelvis (ankle or foot, lower leg, pelvic region, and thigh). (Table 1).
117
Table 2 shows the estimated NF incidence rates stratified by age and sex. Incidence increased with age, ranging 5
118
from 0.03 per 100,000 in the 0–19-year age group to 2.17 per 100,000 in the ≥70-year age group. Figure 1
119
shows the age- and sex-specific annual NF incidence rates. The incidence rates increased with age for both
120
sexes and increased with year. The incidence rates were 2.5 times higher among males than among females
121
across all age groups (incidence rate ratio [IRR]: 2.54, 95% confidence interval [CI]: 2.31–2.79). The NF
122
incidence peaked in 2014 and was the lowest in 2012 for both males and females. The overall annual incidence
123
rate was 0.86/100,000 (95% CI: 0.82–0.90).
124
The number of NF cases peaked during the summer (i.e., July, August, and September) (Figure S2). Table 3
125
shows the correlation between the monthly number of NF cases and the national monthly mean temperatures.
126
The maximum, mean, and minimum average temperatures had a positive correlation with 0 to 2 months of lag
127
time. The rainfall intensity of the previous month showed a positive correlation with the monthly NF incidence.
128
We chose the 1-month lag of the maximum temperature, 1-month lag of the minimum temperature, 1-month lag
129
of the mean temperature, and 1-month lag of the rainfall intensity for the Poisson regression analysis. Table 4
130
shows the relationship between the monthly NF incidence and these meteorological factors. If a mean
131
temperature in the previous month increased by one point, the rate ratio for the NF cases would be expected to
132
increase by a factor of 1.56 while holding all other variables in the model constant. However, a rise in the
133
maximum or minimum temperature in the previous month had an inverse effect on the NF incidence of a given
134
month. Meanwhile, if the NF incidence in the previous month increased by one point, the rate ratio for the NF
135
incidence would be expected to increase by a factor of 1.02.
136 137
Discussion
138
The overall mean annual incidence rate of NF during 2012–2017 was 0.86/100,000. NF incidence ranges from
139
0.3 to 15 cases per 100,000 population [4, 5, 7-9, 11]. A previous study using the claims data from 2005 to 2010
140
showed an annual incidence rate of 11.6 cases per 100,000 population in Taiwan [4]. In the present study, the NF
141
incidence was lower than that found in Taiwan [4] and Thailand [8] but higher than incidence rates in Western
142
Countries [5, 7, 9]. This could be attributed to the higher incidence of NF caused by V. vulnificus and A.
143
hydrophila in Taiwan and Korea. Taiwan and Korea have higher rates of V. vulnificus and A. hydrophila 6
144
infection because they have extensive sea coasts as well as higher rates of raw seafood ingestion and liver
145
cirrhosis [10].
146
NF is divided two microbiologic categories: polymicrobial (type I) and monomicrobial (type II) infections [11].
147
Monomicrobial NF is most commonly caused by group A Streptococcus, followed by other beta-hemolytic
148
streptococci and S. aureus. Aeromonas hydrophila and Vibrio vulnificus can cause monomicrobial NF. Type I
149
NF usually occurs in older adults with underlying comorbidities, whereas type II NF can occur at any age and in
150
patients with no underlying diseases. The most important predisposing factor is diabetes [1, 6, 13]. Liver disease
151
[10, 13], alcoholism [10, 13, 14] and alcohol use disorder [15] are also common underlying diseases associated
152
with NF. A retrospective study conducted at three university hospitals in Korea showed that diabetes was the
153
most common disease (45.8%) associated with NF, followed by chronic liver disease (26.5%). In contrast,
154
another Korean study at a single university hospital serving the surrounding 3,000 islands region showed that
155
alcoholism (53.5%) and liver cirrhosis (50.7%) were the most common comorbidities and that only 15.2% of
156
patients had diabetes [10]. This finding may be attributed to differences in the characteristics of both regional
157
and national studies. The proportion of underlying disease in our study was similar to that in a previous US
158
study using nationwide administrative data (i.e., diabetes: 55% and liver disease: 1.4–4%) [6]. We did not have
159
denominators to calculate the incidence rates according to underlying diseases; therefore, we would not directly
160
assess the risk posed by comorbid conditions. However, the prevalence of these comorbidities among the NF
161
cases was much higher than that in the Korean general population. The prevalence of diabetes in Korea was
162
estimated to be 13.7% in 2016 [19], while the liver cirrhosis prevalence was estimated to be 0.01% between
163
1998 and 2013 [20].
164
The NF incidence was higher among the elderly and showed male predominance in this study. These results are
165
concordant with those in the previous reports [5, 7, 13]. The commonly involved sites were the extremities,
166
pelvis, and perineum, which is similar to what has been reported from previous studies [10, 21].
167
Previous studies reported a rising incidence of NF [4, 5]; however, we could not find such an increasing trend in
168
Korea.
169
We found that NF incidence peaked during summer. Some studies suggested that the cellulitis [22] and NF [4] 7
170
incidence rates increase during the warm season. In a study conducted in Taiwan, the number of NF cases
171
peaked in August, and the peak correlated with the monthly temperature [4]. The Poisson regression model in
172
the present study indicated that the NF cases in a given month could be influenced by the number of NF cases in
173
the previous month. This may provide evidence to inform preventive policies by local communities and health
174
authorities.
175
We attempted to extract all potential NF cases occurring in Korea from 2012 through 2017 using national
176
insurance claims with all Koreans as compulsory beneficiaries. Therefore, the findings of the present study
177
account for real-world evidence for the whole Korean population.
178
This study had some limitations. First, we could not obtain information about causative bacteria and could not
179
distinguish between monomicrobial and polymicrobial infections. Second, we did not include automobile
180
insurance claim data. One of the risk factors for NF is major trauma; hence, our analysis may have
181
underestimated the incidence. However, the burden of automobile insurance is minimal relative to that of health
182
insurance. For example, in 2016, there were 1,399,039,549 health insurance claims compared with 15,525,771
183
automobile insurance claims, representing approximately 1.1% of the number of health insurance claims [23].
184
Therefore, the proportion of NF cases covered by automobile insurance was not expected to be high. Third,
185
patients with extremely severe NF, who died before a surgical procedure, may not have been identified as
186
having NF because a procedure code was required as part of the case definition. Finally, we could not assess
187
other important risk factors, such as recent medications, obesity, raw fish intake and trauma. These individual
188
patient-level factors could not be identified due to the limitations of claims data. Therefore, our study aimed to
189
reveal time-series changes in the incidence of NF in the entire country, rather than identify the causes or risk
190
factors associated with individual patients.
191 192
Conclusions
193
NF predominantly occurs among older individuals and males. Seasonality and trends were correlated with the
194
previous month’s mean temperature and number of NF cases, which may suggest the need for preventive
195
intervention and may be a clue for hospital physicians to suspect of NF early. Additional studies are needed to 8
196
identify the modifiable risk factors associated with NF.
197 198
Transparency declaration
199
Conflict of interest
200
None declared.
201
Funding
202
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-
203
profit sectors.
204
Acknowledgements
205
This study was presented at the ID week in October 2-6, 2019 at the Walter E. Washington Convention Center,
206
in Washington, DC
207
Access to data
208
According to HIRA data protection regulation, administrative data is made available for specific research
209
projects. Thus, authors cannot share the data we used for this study with other researchers. However, data may
210
be available after obtaining HIRA’s permission on reasonable request.
211
Contribution
212
EH and HKC had full access to all the data in the study and takes responsibility for the integrity of the data and
213
the accuracy of the data analysis. Conception and design EH, GHS, HKC. Drafting of the manuscript HKC.
214
Critical revision of the manuscript EH, GHS, HKC. All authors have read and approved the final manuscript.
215 216
Figure legends
217
Figure 1. Annual age-specific incidence rates of necrotizing fasciitis (NF)
218
(A) Female and (B) Male 9
219 220 221
Appendix A. Supplementary data
222
Supplementary Table S1. ICD-10 diagnosis codes and procedure codes associated with necrotizing fasciitis
223
Figure S1. Selection process to define the necrotizing fasciitis (NF) episodes
224
Figure S2. Seasonality of necrotizing fasciitis
225 226 227 228
10
229
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230
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291
Table 1. Characteristics of the necrotizing fasciitis episodes from 2012 through 2017 Characteristic
2,014 episodes
Number of patients
1960
Number of patients who experienced one episode
1910 (97.4%)
Number of patients who experienced two episodes
46 (2.3%)
Number of patients who experienced three episodes
4 (0.2%)
Male
1388 (68.9%)
Age, years ± standard deviation [range]
59.8 ± 14.6 [0.2–99]
0–19
21 (1.0%)
20–29
29 (1.4%)
30–39
114 (5.7%)
40–49
296 (14.7%)
50–59
513 (25.5%)
60–69
475 (23.6%)
≥70
566 (28.1%)
Diabetes
1378 (68.4%)
Liver cirrhosis
62 (3.1%)
Involved sites Multiple sites
82 (4.1%)
Shoulder region
13 (0.7%)
Arm and hand
163 (8.1%)
Pelvic region and thigh
277 (13.8%)
Lower leg
511 (25.4%)
Ankle and foot
731 (36.3%)
Other or unspecified
238 (11.8%)
Procedure Fasciotomy
292
1733 (86.0%)
Amputation of the pelvis
1 (0.1%)
Amputation of the thigh
108 (5.4%)
Amputation of the upper arm, forearm, or lower leg
172 (8.5%)
NF, necrotizing fasciitis; NA, not applicable
293 294 13
295
Table 2. Incidence rate (per 100,000 population) of necrotizing fasciitis by sex and age Total Age
296
group,
Incidence
Male 95% CI
Incidence
Female 95% CI
rate
Incidence
95% CI
years
rate
0–19
0.03
0.01-0.05
0.05
0.03–0.07
0.02
0.01–0.03
20–29
0.07
0.05–0.10
0.10
0.06–0.14
0.04
0.03–0.06
30–39
0.24
0.20–0.29
0.35
0.28–0.41
0.14
0.11–0.16
40–49
0.56
0.50–0.63
0.80
0.71–0.90
0.32
0.27–0.36
50–59
1.07
0.98–1.16
1.53
1.39–1.67
0.60
0.54–0.67
60–69
1.67
1.52–1.82
2.42
2.20–2.65
0.95
0.85–1.06
≥70
2.17
1.99–2.35
3.44
3.13–3.75
1.35
1.22–1.49
CI, confidence interval
297 298 299 300 301 302 303 304 305 306 307 14
rate
308
Table 3. Spearman’s coefficient of rank correlation for time-lag effects on the monthly number of necrotizing
309
fasciitis Spearman’s coefficient according to given meteorological variable
310
Lag time
Mean
Maximum
Minimum
(months)
temperature
temperature
temperature
(°C)
(°C)
(°C)
0
0.3485***
0.3566**
0.3370**
0.1770
0.0032
1
0.4007***
0.4184***
0.3922***
0.3652**
0.2108
2
0.3401**
0.3512**
0.3350**
0.2091
0.1826
3
0.1861
0.1994
0.1682
0.0662
-0.0303
*p < 0.05; **p < 0.01; ***p < 0.001
311 312 313 314 315 316 317 318 319 320 321
15
Rainfall (mm)
Rainy (days)
days
322 323
Table 4. Poisson regression model results on the associations between temperature variation and the monthly
324
number of necrotizing fasciitis cases
325
IRR
95% CI
P value
Mean_lag1
1.56
1.03–2.37
0.035
Max_lag1
0.79
0.64–0.99
0.040
Min_lag1
0.81
0.67–0.99
0.037
NF_lag1
1.02
1.01–1.03
<0.001
Rains_lag1
1.00
1.00–1.00
0.422
IRR, incidence rate ratio; CI, confidence interval
326 327 328 329 330
16
A
B Figure 1.