Abstract
Background
Hypertrophic scar (HS) and keloid (KD) are common dermal fibroproliferative growth caused by pathological wound healing. HS's prevalence is currently undetermined in China. Though it primarily occurs in dark-skinned individuals, KD can develop in all races, and its prevalence among Chinese people is poorly documented.
Objective
To explore the present epidemiological status of them in Chinese college students.
Methods
We conducted a university-based cross-sectional study at one university in Fujian, China. A total of 1785 participants aged 16–34 years (mean age, 20.0 ± 2.0; 58.7% female) were enrolled and statistical analyses were performed.
Results
HS and KD were observed in 5.2% (95% confidence interval [CI]: 4.2–6.2) and 0.6% (95% CI: 0.3–1.0) of the population respectively. There was a significant difference by sex in HS (P < 0.05), but not in KD. The prevalence of HS and KD both showed a significant difference by age (P < 0.05), but not in ethnic and native place distribution. The occurrence of HS and KD were both concentrated in individuals 9–20 years old (HS: 77.2%; KD: 81.8%). They were mainly distributed in the upper limbs (52.1%; 64.3%), and the main cause was trauma (51.0%; 35.7%). In addition, male sex was a risk factor for HS (adjusted P < 0.001), and KD was associated with age ≥22 years and family history (adjusted P < 0.050).
Conclusion
HS and KD are common in Chinese college students, and more attention and research is warranted.
Keywords: Hypertrophic scar, Keloid, Epidemiology, College students
1. Introduction
Hypertrophic scar (HS) and keloid (KD)—two kinds of skin fibrosis disease—are caused by the proliferation of fibroblasts and the formation of extracellular matrix secondary to abnormal physiologic wound healing [1,2]. It can develop following many kinds of skin injury in the dermis, such as trauma, surgery, acne, and burn [3]. Patients with HS and KD can suffer from pruritus, pain and contracture, which can both physically and psychologically affect their quality of life [4,5]. HS is coded as EE60.1 and KD is EE60.0 according to International Classification of Diseases, 11th. Both forms of scarring rise above the skin level, but HS does not extend beyond the initial site of injury, while KD typically develop beyond the original wound margins [6,7].
The highest incidences of HS and KD are in the second to third decade—adolescents and young adults [3]. They occur at similar rates in both sexes in Africa [3]. In the USA, 40–70% of surgery patients and up to 91% of burn injury patients develop HS [3], but its epidemiology is currently undetermined in China. KD can develop in all races, and it is mainly found in dark-skinned individuals, often combined with a positive family history [3,8]. The prevalence rates of KD were 0.09–16% in the United Kingdom and Africa [9,10]. Two community-based clinical surveys of skin diseases in children aged between 6 and 11 years in Taiwan found that the prevalence of KD ranged from 0.33% to 0.6% [11,12]. A previous case-control study of outpatients of dermatological departments in China revealed that KD typically occurred between the ages of 10 and 29 years, the prevalence of KD in first-degree relatives was 7.62%, and a positive family history was associated with greater severity and multiple sites of KD [13]. To date, the prevalence of KD in the young population in China has not been elucidated. Thus, we conducted this university-based cross-sectional study with the aim of exploring the epidemiological and clinical aspects of HS and KD of young population in China.
2. Materials and methods
2.1. Study participants
As reported, HS and KD mainly occur in individuals between 10 and 30 years old in China [13]. University is a place where many young people gather, and college students come from all over China. Therefore, it is a rather better place for epidemiological surveys of HS and KD in Chinese young people.
The university-based cross-sectional study was conducted from May to August 2019 using purposive sampling to survey students from one university in Xiamen, China. This university has a population of approximately 40,000 Chinese students from all around China [14]. A total of 1798 participants from 14 colleges were included. Among them, 13 students—3 were foreign students and 10 were tourists to the university—who did not meet our criteria were excluded from the study. The final sample size was 1785 (744 males and 1041 females, age range 16–34 years), and they came from all 44 province-level administrative regions (PARs) in China.
3. Procedure and data collection
A convenience sampling method was used to select the study participants. Five places (library, public study room, classroom, stadium and canteen) with a large volume of students on campus were chosen. Each investigator recruited participants for our study in these places. Written informed consent was obtained from all participants. The investigation was completed in accordance with the ethical principles originating from the Declaration of Helsinki and was approved by the Medical Ethics Committee of School of Medicine, Xiamen University (No. 201904291). Six investigators from university were trained to conduct face-to-face interviews, and 2 dermatologists from the hospital participated in the diagnostic process.
In the first stage, the investigators collected basic information on sex, ethnicity, date of birth, native place, family history of KD, college, grade, class and email in the overall sample through one unified-designed questionnaire filled by participants. Each participant voluntarily exposed skin lesions to an investigator in a safe and independent room nearby, where history collection, physical examination and photo taking for various lesions were conducted. Participants who were suspected of having HS or KD were diagnosed and provided further information on (1) classification of scars [physiological scars (Fig. 1a and b), HS (Fig. 1c and d) and KD (Fig. 1e and f)]; (2) anatomical sites of HS or KD (cranium, face, neck, chest, back, abdomen, waist, shoulder, arm, elbow, forearm, wrist, hand, hip, thigh, knee, thigh, ankle and foot); (3) quantity of HS or KD (single or multiple); (4) onset age of HS or KD; (5) cause of HS or KD (surgery, trauma, vaccination, ear-piercing, burn, acne, hair folliculitis, varicella, shingles, BCG and other causes) and detailed information about family history of KD. All images and information were numbered and stored carefully to protect the patients’ right to privacy. To reduce the possibility of recall bias, we supplied diagnostic materials and carefully considered the content of the questionnaire and the techniques of investigation. After that, the final diagnosis was confirmed by two board-certified dermatologists through all materials we collected.
Fig. 1.
Clinical appearances of scars (physiological scars, HSs and KDs) in this study. (a) Physiological scar on the right forehead caused by trauma. (b) Physiological scar on the back of the right palm caused by trauma. (c) HS on the back after surgery. (d) HS on the right elbow caused by burn. (e) KD on his right arm caused by chickenpox. (f) KD on the left elbow caused by trauma.
In the second stage of the study, all those with HS or KD were selected as cases in our study to reduce selection bias, and participants without HS and KD of the same college were selected by simple random sampling as controls. Each case was matched with 10 controls to achieve the most suitable analysis base. A total of 103 cases and 1030 controls were subjected to case-control analysis on the basis of the available data in the first stage, with the aim of further identifying the relevant factors for HS and KD (Fig. 2).
Fig. 2.
Flow diagram showing the process of cases and controls' inclusion.
3.1. Clinical definitions
There are currently no unified guidelines for the diagnostic criteria for HS and KD [3]. Peacock's definition is still used by certified dermatologists. HS is usually tough, raised at the site of injury, developing within 4–8 weeks of injury and accidently symptomatic [2]. It tends to regress over time after several years [2], and could generally be divided into two types—long-lasting, inactive, purely fibrotic raised scar and early keloid-like scar that usually spontaneously regress in two years. By contrast, KDs can appear many years later, raise and extend beyond the site of injury currently, and usually be symptomatic [2]. At the same time, differential diagnosis was performed to exclude lupus erythematosus, xanthomatosis, hemangioma, vascular malformation, cutaneous fibroma, skin carcinoma, condyloma acuminatum. In brief, the diagnosis of HS and KD is generally based on history collection, physical examination, and especially morphological findings.
The onset age was the time when the patient first developed HS or KD, and the duration was the time between onset age and diagnosis. Then number (single vs. multiple) was described according to the number of anatomical locations of the HS or KD [15]. Family history was considered positive if the patient's first-, second- and/or third-degree relatives had KD; family history was considered negative otherwise.
3.2. Statistical analyses
Data were numbered, entered, and double-checked using Microsoft Excel 2019. Statistical analysis was conducted using SPSS v. 22.0 (IBM SPSS Inc., Chicago, IL, USA) for Windows. The paired t-test was used to determine the degree of fitting of two known curves. The chi square test, its correction formula or Fisher's exact test were used for the comparison of proportions in epidemiology and case-control analysis. Qualitative results were described using numbers and frequencies, while quantitative results were shown by means ± standard deviations. Odds ratios (ORs) with their 95% confidence intervals (CIs) were used through univariable and multivariable logistic regression analyses to identify those factors associated with HS and KD. The variables with P < 0.250 in univariable analysis were introduced in the multivariable model. The results were considered statistically significant at P˂0.050.
4. Results
Since the enrollment plan of that university in each PAR has changed little recently, we chose the plan of 2020 to represent the native place distribution of the population [16]. The paired t-test conducted on the proportion of the sample and the population showed no differences between them (P > 0.950), meaning that the sample could reflect the overall situation to a certain extent.
4.1. Prevalence of HS and KD in the study population
A total of 1785 participants aged 16–34 years (mean age, 20.0 ± 2.0; 58.7% female) were enrolled in the study, among whom 92 had HSs and 11 had KDs. Thus, the prevalence of HS was 5.2% (95% CI, 4.2–6.2), and the prevalence of KD was 0.6% (95% CI, 0.3–1.0; Table 1).
Table 1.
Epidemiological characteristics of the HS and KD cases.
| Parameter | No. of cases |
||||
|---|---|---|---|---|---|
| Total | HS | P | KD | P | |
| Total | 1785 | 92 (5.2)a | 11 (0.6) | ||
| Gender | |||||
| Males | 744 | 57 (7.7) | <0.001c | 6 (0.8) | 0.575 |
| Females | 1041 | 35 (3.4) | 5 (0.5) | ||
| Ethnicity | |||||
| Han people | 1607 | 83 (5.2) | 0.950 | 11 (0.7) | 0.547 |
| Minority people | 178 | 9 (5.1) | 0 (0) | ||
| Native place | |||||
| Southern China | 1174 | 60 (5.1) | 0.909 | 9 (0.8) | 0.420 |
| Northern China | 611 | 32 (5.2) | 2 (0.3) | ||
| Age (years) | |||||
| ≤18 | 355 | 8 (2.3) | 0.014c | 0 (0) | 0.032c |
| 19 | 488 | 22 (4.5) | 3 (0.6) | ||
| 20 | 412 | 25 (6.1) | 3 (0.7) | ||
| 21 | 267 | 23 (8.6) | 1 (0.4) | ||
| 22 | 102 | 5 (4.9) | 0 (0) | ||
| ≥23 | 161 | 7 (4.3) | 4 (2.5) | ||
| Onset age (years) | |||||
| 1-4 | 6 | 6 (6.5)b | 0 (0) | ||
| 5-8 | 10 | 10 (10.9) | 0 (0) | ||
| 9-12 | 19 | 16 (17.4) | 3 (27.3) | ||
| 13-16 | 28 | 27 (29.3) | 1 (9.1) | ||
| 17-20 | 33 | 28 (30.4) | 5 (45.5) | ||
| 21-24 | 5 | 4 (4.3) | 1 (9.1) | ||
| 25-28 | 2 | 1 (1.1) | 1 (9.1) | ||
| Number | |||||
| Single | 97 | 88 (95.7) | 9 (72.7) | ||
| Multiple | 6 | 4 (4.3) | 2 (27.3) | ||
| Family history of KD | |||||
| Yes | 2 | 0 (0) | 2 (27.3) | ||
| No | 101 | 92 (100.0) | 9 (72.7) | ||
Data are presented as frequency (prevalence).
Data are presented as frequency (percentage).
Statistically significant result.
4.2. Epidemiological characteristics of HS and KD cases
There were significantly more male cases of HS than female cases (7.7% vs. 3.4%; P < 0.050), while KD cases were not significantly different between sexes (0.8% vs. 0.5%; P > 0.050). HS prevalence was similar between people of Han and minority ethnicities (5.2%; 5.1%) and between students from southern and northern China (5.1%; 5.2%). KD prevalence in Han people was higher than that in people from ethnic minorities (0.7% vs. 0%), and KD prevalence in those from southern China was also higher than in those from northern China (0.8% vs.0.3%), but these differences were not significant (P > 0.050; Table 1); this could be attributed to the small number of KD cases.
The prevalence of HS and KD both showed significant differences in age (P < 0.050); the highest prevalence of HS was at 21 years (8.6%) and KD was at 20 (0.7%), and the average age of HS and KD cases was 20.4 ± 1.8 and 21.6 ± 2.8 years, respectively. In addition, the onset ages were concentrated between 9 and 20 years (HS: 77.2%; KD: 81.8%), and the onset ages of HS and KD cases were 14.0 ± 5.3 and 17.4 ± 5.0 years on average. Moreover, the multiple-scar rates of HS and KD cases (4.3%; 27.3%) were lower than the single-scar rates. Additionally, the positive rate of family history was 2/11 (18%, 95% CI, 2%–52%) in KD cases, and patients with a family history didn't show a higher multiple-scar rate than those without a family history (1/2 vs. 1/9, P = 0.326; Table 1).
4.3. Clinical characteristics of HS and KD
They were detected at multiple anatomical sites, and both HS and KD were mainly distributed in the upper limbs (52.1%; 64.3%).The main cause of HS and KD was trauma (51.0%; 35.7%), and their duration of the largest proportion was between 0 and 2 years (31.3%; 35.7%; Table 2). Moreover, nearly 70% of the HS lasted for more than 2 years.
Table 2.
Clinical characteristics of HS and KD.
| Parameter | No. of HS and KD |
|
|---|---|---|
| HS | KD | |
| Total | 96 (100.0) | 14 (100.0) |
| Site | ||
| Cranium | 5 (5.2) | 0 (0) |
| Face | 9 (9.4) | 1 (7.1) |
| Neck | 5 (5.2) | 1 (7.1) |
| Chest | 5 (5.2) | 1 (7.1) |
| Abdomen | 1 (1.0) | 1 (7.1) |
| Back | 2 (2.1) | 1 (7.1) |
| Upper limbs | 50 (52.1) | 9 (64.3) |
| Lower limbs | 19 (19.8) | 0 (0) |
| Cause | ||
| Trauma | 49 (51.0) | 5 (35.7) |
| Surgery | 22 (22.9) | 4 (28.6) |
| Acne | 10 (10.4) | 3 (21.4) |
| Burn | 8 (8.4) | 0 (0) |
| Eczema | 1 (1.0) | 0 (0) |
| Piercing ears | 1 (1.0) | 0 (0) |
| Chickenpox | 0 (0) | 1 (7.1) |
| Other | 5 (5.2) | 1 (7.1) |
| Duration (years) | ||
| 0-2 | 30 (31.3) | 5 (35.7) |
| 3-5 | 20 (20.8) | 4 (28.6) |
| 6-8 | 18 (18.8) | 4 (28.6) |
| 9-11 | 12 (12.5) | 1 (7.1) |
| 12-14 | 6 (6.3) | 0 (0) |
| 15-17 | 6 (6.3) | 0 (0) |
| 18-20 | 4 (4.2) | 0 (0) |
Data are presented as frequency (percentage).
4.4. Factors associated with HS and KD
To further identify relevant factors, a total of 92 cases/920 controls of HS and 11 cases/110 controls of KD were subjected to case-control analysis. Associations with sex, nationality, birthplace, age and family history between cases and controls are summarized in Table 3. Male sex was significantly associated with HS (adjusted OR, 2.554; 95% CI, 1.641–3.976; adjusted P < 0.001). Age, specifically ≥22 years (adjusted OR, 7.779; 95% CI, 1.405–43.063; adjusted P = 0.019) and family history of KD (adjusted OR, 34.056; 95% CI, 2.512–461.654; adjusted P = 0.008) were associated with KD. Besides, male sex showed no association with KD (adjusted P = 0.800) and han people showed no association with HS (P = 0.947). HS (P = 0.804) and KD (P = 0.727) both revealed no regional differences between northern and southern China.
Table 3.
Factors associated with HS and KD.
| HS |
KD |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Positive cases |
OR value |
Adjusted OR valuea |
Adjusted |
Positive cases |
OR value |
Adjusted OR valuea |
Adjusted |
|||
| Relevant factors | (92/920) | (95% CI) | P | (95% CI) | P | (11/110) | (95% CI) | P | (95% CI) | P |
| Gender | ||||||||||
| Males | 57/354 | 2.604 (1.675–4.049) | <0.001b | 2.554 (1.641–3.976) | <0.001b | 6/45 | 1.733 (0.499–6.027) | 0.524 | 1.196 (0.301–4.754) | 0.800 |
| Females | 35/566 | 1 | – | 1 | – | 5/65 | 1 | – | 1 | – |
| Ethnicity | ||||||||||
| Han people | 83/828 | 1.025 (0.498–2.107) | 0.947 | 11/101 | – | |||||
| Minority people | 9/92 | 1 | – | 0/9 | – | |||||
| Native place | ||||||||||
| Southern China | 60/588 | 1.059 (0.675–1.660) | 0.804 | 9/81 | 1.611 (0.329–7.899) | 0.727 | ||||
| Northern China | 32/332 | 1 | – | 2/29 | 1 | – | ||||
| Age (years) | ||||||||||
| ≤19 | 30/371 | 1 | – | 1 | – | 3/59 | 1 | – | 1 | – |
| 20-21 | 48/399 | 1.154 (0.595–2.238) | 0.671 | 1.110 (0.569–2.165) | 0.759 | 4/39 | 2.017 (0.428–9.509) | 0.375 | 1.599 (0.290–8.811) | 0.590 |
| ≥22 | 14/150 | 1.488 (0.923–2.398) | 0.103 | 1.394 (0.860–2.259) | 0.177 | 4/12 | 6.556 (1.297–33.143) | 0.023b | 7.779 (1.405–43.063) | 0.019b |
| Family history of KD | ||||||||||
| Yes | – | 2/1 | 24.222 (1.999–293.570) | 0.022b | 34.056 (2.512–461.654) | 0.008b | ||||
| No | – | 9/109 | 1 | – | 1 | – | ||||
CI, confidence interval; OR, odds ratio.
Adjusted additional factors in the same multivariate model.
Statistically significant result.
In order to better analyze the factors related to KD, the age groups merged to a limited extent, which may affect the analysis results of HS. Although Table 3 revealed no differences in the age distribution of HS (adjusted P > 0.050), we tended that the correlation (P = 0.014) shown in Table 1 was the fact. Probably due to the insufficient sample size, KD patients in minority people (0/9) were not found, leading to our inability to perform analysis.
5. Discussion
HS and KD prevalences are poorly documented in the Chinese population, especially in the college students’ population. This is a university-based study enrolling 1785 participants (mean age, 20.0 ± 2.0 years; 58.7% female) from one university in Xiamen of southeast China. We identified 92 HS cases and 11 KD cases. The prevalence rate of HS and KD was 5.8% (95% CI, 4.7–6.9) in total, demonstrating that HS and KD commonly affect Chinese college students. Moreover, we observed no ethnic or regional differences in their prevalences.
According to global data, the incidence rates of HS are more than 40% following surgery and burn injury in the USA [17]. The KD prevalence rate in Africans (Zaire, 16%; Cameroon, 3.5%) is much higher than that in Europeans (UK, 0.09%) [9,10,17]. Skin phototypes and environmental elements (climate and lifestyle) mainly contribute to the prevalence differences of HS and KD around the world. In addition to racial differences, sampling methodology and diagnostic criteria may also influence prevalence findings. Our study involved university students coming from all different PARs of China to give more representative results. The results showed that the prevalence rate of HS (5.2%) in China was much higher than that of KD (0.6%) in China, and the KD prevalence rate was at a medium level in comparison with global rates. Even though unified guidelines for the diagnostic criteria of HS and KD have not yet been established, with the help of dermatologists, we identified a diagnosis system for HS and KD according to the clear definitions of Mancini and Peacock, the general description of HS and KD from Burd and Berman, and the KD scoring criteria founded by Lu et al. [2,6,7,[18], [19], [20]]. This was the up-to-date and rigorous diagnostic method at the beginning of our investigation and was used to adequately train our investigators.
The results suggested that HS prevalence was significantly different by sex (male: 7.7%, female: 3.4%) in China, in contrast to the equal sex distribution in Africa [3]. Most of the observed HSs (68.7%) belonged to the first type of HSs―long-lasting, inactive, purely fibrotic raised scars. HS and KD were two chronic skin diseases occurring mainly during the second decade in our population, less than the 10–29 years described by Lu et al. [13].
The positive rate of a family history of KD in this population (18%) was less than the 27.8% reported by Lu et al., in 2015 [13]. This difference was due to the different sampling methodologies. According to Lu's report, patients with a positive family history had KD with greater severity, while many patients without a family history we met had KD with lower severity and chose not to go to the hospital for treatment; thus, their diagnoses were missed in outpatient medical records. Furthermore, several studies have shown that the single-nucleotide polymorphism of some susceptible genes may be closely related to the formation of KD [[21], [22], [23]]. Our results provide additional support for the association between genetic factors and KD. Our results also showed that 82% of KD patients had no family history. HS and KD pathogenesis is complex and poorly understood. Beyond genetic factors, the formation of KD has also been associated with other factors, such as epigenetic modification (noncoding RNA, DNA methylation), systemic factors (adolescence, pregnancy, hypertension) and local factors (mechanical stimuli) [[24], [25], [26], [27]].
There are three key strengths in our study. First, university students come from all over China and naturally form a reasonable young-adult population for epidemiological surveys of HS and KD. Second, data were obtained from a rather large population within a short period of time, which was attributed to China's huge population base. Next, using the up-to-date and rigorous diagnostic method, well-trained investigators and professional dermatologists minimized the misdiagnosis rate. Conversely, there were several limitations. First, this was an exploratory non-probabilistic sampling study, and thus cannot be generalized to fully infer the characteristics of the population. Second, in terms of the analysis of KD, the sample size was relatively small, which may influence the description of its partial characteristics, such as ethnic and age differences in KD prevalence in China. Despite these limitations, the findings obtained from this study still provide fundamental information on the epidemiology of HS and KD in the Chinese young population and lay the foundation for more precise and further research on them in China.
Declaration
Author contribution statement
An-Hao Liu: Performed the experiments; Analyzed and interpreted the data; Wrote the paper; Xiao-Lu Sun: Performed the experiments; Analyzed and interpreted the data; Di-Zhi Liu; Fan Xu; Shi-Jie Feng; Shi-Yu Zhang; Lu-Zhou Li; Jia-Li Zhou; Yi-Ting Wang: Performed the experiments; Li Zhang; Xiao Lin; Shu-Bin Gao; Xin Yue; Xiao-Ming Liu; Guang-Hui Jin: Contributed reagents, materials, analysis tools or data; Bin Xu: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data; Wrote the paper.
Data availability statement
Data will be made available on request.
Funding statement
This study was supported by Xiamen University Undergraduate Innovation and Entrepreneurship Training Programs (2019X0754 and S202010384693 to A.H.L.), grants from the National Natural Science Foundation of China (81672793 to B.X.) and the Fundamental Research Funds for the Central Universities (20720180043 to B.X.).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
We are grateful to all the university students for their cooperation in this research and dedication for medicine and we would like to express our sincere gratitude to the dermatologists from hospital for their selfless and generous help.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2023.e15345.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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Data Availability Statement
Data will be made available on request.