INTRODUCTION
Human papilloma virus (HPV) infection can cause benign cutaneous and anogenital warts, which are usually considered mild and tend to be overlooked in many studies. 1 2 However, they can cause discomfort and psychological stress in affected patients. 3 There are several reports suggesting that immunocompromised individuals, such as transplant recipients, are at an increased risk of HPV infection and may experience more severe warts, impacting their quality of life. 4 5
Existing studies on warts and transplantation are often limited in scope and sample size. 4 6 7 Unfortunately, there are few population-based, large-scale studies comprehensively evaluating the risk of cutaneous and genital warts in patients with different types of transplantations.
In this study, we investigated the risk of cutaneous and genital warts in patients who had received transplantation including kidney transplantation (KT), liver transplantation (LT), and hematopoietic stem cell transplantation (HSCT) using the Korea National Health Insurance Service (NHIS) claims database.
METHODS
Korean NHIS database accounts for approximately 97% of the Korean population, while the remaining 3% is covered by the medical aid program integrated into the NHIS.
From the database of the NHIS, the patients who underwent solid organ transplantation (KT or LT) or HSCT from January 2010 to December 2017 were traced. We excluded subjects with previous diagnosed cutaneous or genital warts, and a 12-month lag period was applied. Finally, 27,564 transplantat patients (KT [n = 13,429], LT [n = 8,992], and HSCT [n = 5,143]) and 137,820 1:5 age- and sex-matched control subjects were followed for maximum 10 years from 2010 to 2019 to identify new onset cutaneous or genital warts (cutaneous warts: B07 and genital warts: A63.0). The index date for the control group was assigned based on the matched date of the transplantation group, and wart incidence was followed up from the matched date in the same manner as in the cases group.
Comorbid diseases (hypertension, dyslipidemia, type 2 diabetes mellitus and previous hematologic disorders [leukemia, lymphoma, multiple myeloma, and bone marrow failure disease]) were defined based on International Classification of Diseases-10 codes.
To evaluate the risk of warts, we performed multivariable Cox proportional hazard regression analyses after adjusting for confounding factors. Model 1 was not adjusted, while Model 2 was adjusted for age and sex. Model 3 was adjusted for age, sex, hypertension, diabetes mellitus, and dyslipidemia. Model 4 was adjusted for age, sex, hypertension, diabetes mellitus, dyslipidemia, and previous hematologic disorders. Cumulative incidence curves were plotted using the Kaplan-Meier method, and statistical significance was examined using the log-rank test. Subgroup analyses were performed according to age and sex. To examine the P values for interaction between transplantation and wart incidence across sex and age, we included multiplicative interaction terms in the model and assessed the significance through joint tests in the Cox Proportional-Hazard Model. We analyzed the number of outpatient visits with cutaneous and genital warts during the 2 years after the first diagnosis of warts in the transplantation and control groups.
Statistical analyses were performed with SAS software ver. 9.4 (SAS Institute, Cary, NC, USA). Two-sided P < 0.05 was considered to indicate statistical significance.
Ethics statement
This study was approved by the Institutional Review Board (IRB) of Seoul St. Mary’s Hospital, The Catholic University of Korea (IRB No. KC20ZISI0066), and was conducted in accordance with the principles of the Declaration of Helsinki. No informed consent was required from patients due to the nature of public data from NHIS.
RESULTS
Baseline demographic characteristics
A total of 27,564 patients who had undergone transplantation (KT, LT, or HSCT) and 137,820 age- and sex-matched control subjects were enrolled. The baseline characteristics of the study population are described in Supplementary Table 1 .
Risk of cutaneous and genital warts in patients with transplantation
The results presented in this study are primarily derived from Model 4, which adjusts for age, sex, hypertension, diabetes mellitus, dyslipidemia, and hematologic disorders. In multivariable Cox proportional hazards regression analysis, the risk of cutaneous warts significantly increased in patients with transplantation (adjusted hazard ratio [aHR], 3.73; 95% confidence interval [CI], 3.49–3.98) compared to that in the control group without transplantation ( Table 1 ). The risk of cutaneous warts was also greater in KT (aHR, 4.35; 95% CI, 4.04–4.69), LT (aHR, 2.78; 95% CI, 2.48–3.11), and HSCT patients (aHR, 2.77; 95% CI, 2.18–3.52) compared to that in the control group. Regarding the risk of genital warts, significantly higher risk was observed in patients with transplantation (aHR, 1.18; 95% CI, 1.07–1.29) compared to the control group without transplantation, and in patients with KT (aHR, 1.29; 95% CI, 1.16–1.44) compared to the control group ( Table 2 ). In patients with LT, no statistically significant difference was observed compared to the control group (aHR, 1.04; 95% CI, 0.88–1.23). In patients with HSCT, lower risk of genital warts was observed compared to the control group (aHR, 0.56; 95% CI, 0.35–0.89).
Table 1
Incidence rates and risks of cutaneous warts in transplant patients
Data are expressed as hazard ratios and 95% confidence intervals. Model 1 was not adjusted. Model 2 was adjusted for age and sex. Model 3 was adjusted for age, sex, comorbidities of type 2 diabetes mellitus, hypertension, and hyperlipidemia. Model 4 was adjusted for age, sex, comorbidities of type 2 diabetes mellitus, hypertension, hyperlipidemia, leukemia, lymphoma, multiple myeloma, and bone marrow failure disorders. IR = incidence rate, KT = kidney transplantation, LT = liver transplantation, HSCT = hematopoietic stem cell transplantation. a Incidence rate per 1,000 person-years.
| Transplantation | No. of patients | Cutaneous warts | Person-years | IR a | Model 1 | Model 2 | Model 3 | Model 4 | |
| Transplantation | |||||||||
| No | 137,820 | 2,671 | 847,715.4 | 3.15 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | |
| Yes | 27,564 | 1,577 | 139,356.5 | 11.32 | 3.66 (3.44–3.90) | 3.68 (3.46–3.92) | 3.69 (3.47–3.93) | 3.73 (3.49–3.98) | |
| Transplantation type | |||||||||
| No | 137,820 | 2,671 | 847,715.4 | 3.15 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | |
| KT | 13,429 | 945 | 74,344.4 | 12.71 | 4.08 (3.79–4.39) | 4.36 (4.04–4.69) | 4.36 (4.05–4.70) | 4.35 (4.04–4.69) | |
| LT | 8,992 | 343 | 44,924.9 | 7.64 | 2.47 (2.21–2.76) | 2.79 (2.50–3.13) | 2.79 (2.50–3.13) | 2.78 (2.48–3.11) | |
| HSCT | 5,143 | 289 | 20,087.1 | 14.39 | 4.86 (4.30–5.48) | 3.28 (2.90–3.71) | 3.27 (2.89–3.70) | 2.77 (2.18–3.52) |
Table 2
Incidence rates and risks of genital warts in transplantation patients
Data are expressed as hazard ratios and 95% confidence intervals. Model 1 was not adjusted. Model 2 was adjusted for age and sex. Model 3 was adjusted for age, sex, comorbidities of type 2 diabetes mellitus, hypertension, and hyperlipidemia. Model 4 was adjusted for age, sex, comorbidities of type 2 diabetes mellitus, hypertension, hyperlipidemia, leukemia, lymphoma, multiple myeloma, and bone marrow failure disorders. IR = incidence rate, KT = kidney transplantation, LT = liver transplantation, HSCT = hematopoietic stem cell transplantation. a Incidence rate per 1,000 person-years.
| Transplantation | No. of patients | Genital warts | Person-years | IR a | Model 1 | Model 2 | Model 3 | Model 4 | |
| Transplantation | |||||||||
| No | 137,820 | 3,199 | 847,100.1 | 3.78 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | |
| Yes | 27,564 | 595 | 143,444.6 | 4.15 | 1.12 (1.03–1.23) | 1.11 (1.02–1.22) | 1.12 (1.03–1.23) | 1.18 (1.07–1.29) | |
| Transplantation type | |||||||||
| No | 137,820 | 3,199 | 847,100.1 | 3.78 | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | |
| KT | 13,429 | 374 | 76,861.5 | 4.87 | 1.30 (1.17–1.45) | 1.28 (1.15–1.42) | 1.29 (1.16–1.44) | 1.29 (1.16–1.44) | |
| LT | 8,992 | 142 | 45,680.8 | 3.11 | 0.84 (0.71–1.00) | 1.04 (0.88–1.23) | 1.05 (0.88–1.24) | 1.04 (0.88–1.23) | |
| HSCT | 5,143 | 79 | 20,902.3 | 3.78 | 1.08 (0.87–1.35) | 0.75 (0.60–0.94) | 0.76 (0.61–0.95) | 0.56 (0.35–0.89) |
Cumulative incidence rates of cutaneous and genital warts
The Kaplan-Meier analysis for the cumulative incidence rate of cutaneous and genital warts showed a significantly increased risk in the transplant group compared to that in the controls without transplantation (log-rank test, P < 0.001 for cutaneous wart and P = 0.001 for genital wart, respectively) ( Supplementary Fig. 1 ).
Subgroups by age and sex
In subgroup analysis, the risk of cutaneous warts was higher in transplant patients than in the control group in all sex and age groups ( Table 3 ). The risk was highest in the 20–39 (aHR, 4.52; 95% CI, 3.92–5.22) and 40–59 year age groups (aHR, 4.56; 95% CI, 4.14–5.02). The risk of genital warts was higher in transplant patients who were male, and older than 40 years compared to the control group. The risk was highest in the 60+ age group (aHR, 2.09; 95% CI, 1.47–2.99).
Table 3
Risk of cutaneous and genital warts in subgroups by age and sex
Data are expressed as hazard ratios and 95% confidence intervals. Model 1 was not adjusted. Model 2 was adjusted for age and sex. Model 3 was adjusted for age, sex, comorbidities of type 2 diabetes mellitus, hypertension, and hyperlipidemia. Model 4 was adjusted for age, sex, comorbidities of type 2 diabetes mellitus, hypertension, hyperlipidemia, leukemia, lymphoma, multiple myeloma, and bone marrow failure disorder. KT = kidney transplantation, LT = liver transplantation, HSCT = hematopoietic stem cell transplantation.
| Transplantation | Sex | Age, yr | ||||||
| Male | Female | 0–19 | 20–39 | 40–59 | ≥ 60 | |||
| Cutaneous warts | ||||||||
| Transplantation | ||||||||
| No | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||
| Yes | 3.80 (3.50–4.14) | 3.62 (3.25–4.03) | 1.90 (1.59–2.28) | 4.52 (3.92–5.22) | 4.56 (4.14–5.02) | 3.82 (3.15–4.63) | ||
| P for interaction | 0.115 | < 0.001 | ||||||
| Transplantation type | ||||||||
| No | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||
| KT | 4.39 (3.98–4.83) | 4.27 (3.80–4.80) | 2.70 (2.02–3.60) | 4.87 (4.19–5.67) | 5.34 (4.80–5.94) | 4.86 (3.91–6.05) | ||
| LT | 2.98 (2.60–3.41) | 2.46 (2.01–3.03) | 1.50 (1.12–2.02) | 3.12 (2.26–4.31) | 3.32 (2.85–3.86) | 2.53 (1.87–3.42) | ||
| HSCT | 3.17 (2.38–4.24) | 2.10 (1.37–3.22) | 1.79 (1.32–2.43) | 4.12 (2.19–7.73) | 4.69 (2.48–8.88) | 6.46 (1.58–26.32) | ||
| P for interaction | 0.005 | < 0.001 | ||||||
| Genital warts | ||||||||
| Transplantation | ||||||||
| No | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||
| Yes | 1.69 (1.41–2.03) | 1.06 (0.95–1.18) | 0.84 (0.51–1.37) | 1.08 (0.93–1.25) | 1.16 (1.02–1.33) | 2.09 (1.47–2.99) | ||
| P for interaction | < 0.001 | 0.002 | ||||||
| Transplantation type | ||||||||
| No | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | 1 (Ref.) | ||
| KT | 1.79 (1.44–2.24) | 1.18 (1.05–1.34) | 0.93 (0.52–1.66) | 1.07 (0.91–1.27) | 1.15 (0.98–1.34) | 1.56 (0.94–2.59) | ||
| LT | 1.62 (1.22–2.15) | 0.87 (0.71–1.08) | 0.72 (0.27–1.93) | 1.11 (0.80–1.55) | 1.20 (0.95–1.51) | 2.74 (1.76–4.28) | ||
| HSCT | 1.17 (0.57–2.41) | 0.43 (0.23–0.79) | 0.62 (0.13–3.03) | 1.02 (0.43–2.40) | 0.95 (0.35–2.59) | 14.67 (0.16–1,349.06) | ||
| P for interaction | < 0.001 | 0.001 |
Number of medical visits for cutaneous and genital warts
The number of outpatient visits for cutaneous warts was significantly higher in the transplantation group (4.03 ± 0.14 versus 2.83 ± 0.11) ( Supplementary Table 2 ). The number of outpatient visits for genital warts was significantly higher in the transplantation group (3.46 ± 0.14 versus 2.44 ± 0.06) compared to the control group.
In both cutaneous and genital warts, the number of outpatient visits was significantly higher in the transplantation group, regardless of gender. For cutaneous warts, the higher number of visits was observed in the transplantation group among those younger than 60 years old, while for genital warts, it was higher in the transplantation group among those older than 20 years old.
DISCUSSION
In this nationwide population-based cohort study, a significantly increased risk of cutaneous and genital warts was observed in patients who received transplantation compared to those in the control group who did not receive transplantation. The risk of cutaneous warts was higher in all age and sex groups among transplant patients, with a more pronounced increase in those aged 20–39 and 40–59 years. For genital warts, male patients and those over 40 in the transplant group exhibited a higher risk compared to the control group. Furthermore, transplant patients required more outpatient visits for management of cutaneous and genital warts, highlighting the challenges of managing warts in transplant patients.
Previous studies have suggested a correlation between transplants and warts, with immunosuppressed transplant patients experiencing more frequent, severe, and treatment-resistant warts. 8 9 Due to the impairment of cell-mediated immunity in transplant patients using immunosuppressants, warts occur more frequently, are more severe, are resistant to treatment, and present a higher risk for malignancy compared to immunocompetent individuals. 10 The risk of warts in transplant patients is associated with the duration of immunosuppressive treatment. 11 Studies from Brazil, Poland, and the UK have reported a significant number of transplantation patients developing viral warts. 7 12 13 Despite these epidemiological findings, there is still a lack of comprehensive risk assessment studies focusing on warts in transplant patients. According to a previous population-based study in Korea, cutaneous wart infection and re-infection were highest in patients younger than 20 years and lower in patients older than 20 years. 1 The impact of immunosuppression on cutaneous wart risk may be more pronounced in transplant patients aged 20–39 and 40–59, as these age groups showed relatively lower wart prevalence in the general population compared to those under 20 years. Differences in the dosage and duration of immunosuppressive therapy might contribute to variations in risk, but these factors were not analyzed in this study. Future studies should aim to incorporate these variables to provide a more comprehensive understanding of the observed trends. Additionally, transplant patients aged over 40 exhibited a significant increase in genital warts risk, consistent with a Danish report showing a higher risk in renal transplantation recipients over the age of 30. This may be attributed to several factors. First, in immunocompromised individuals, latent HPV infections acquired earlier in life could reactivate. Second, younger transplant recipients might engage in less sexual activity due to health-related concerns, making their exposure to HPV lower compared to the general population in their 20s and 30s. Third, the HPV vaccination program introduced in Korea in 2007 likely contributed to the reduced incidence of genital warts in younger individuals. Further studies are needed to clarify the causal relationships underlying these findings.
The findings revealed that the risk of cutaneous warts was higher than that of genital warts. Among transplant patients, health-related effects, such as reduced sexual activity or exposure during the recovery period, may lower the risk of genital wart acquisition. Conversely, skin contact or trauma during daily activities and hospital care may increase the risk of cutaneous warts. These factors could contribute to a more significant increase in the risk of cutaneous warts among transplant patients. Further research is needed to establish clearer causal relationships and to better understand why this trend is more pronounced in HSCT patients.
Most of the previous studies have a limitation in that they only analyzed a small study population in a single institution or cohort. The strength of this study is its large-scale nature, comprehensively analyzing the risk of cutaneous and genital warts in transplant patients (KT, LT, and HSCT), and its representation of the entire Korean population. In particular, since transplant recipients are covered by the individual copayment beneficiaries program for rare and intractable disorders managed by the Korean Government, the diagnosis of transplantations is relatively reliable. Furthermore, the occurrence of cutaneous and genital warts was followed up for a relatively long period of time.
There are several limitations to this study. First, warts diagnoses were based on claim data from NHIS, which may not capture all cases. Undiagnosed warts may have been excluded. Moreover, it was difficult to completely rule out the possibility of selection bias. An additional limitation is that patients who underwent transplantation more recently had shorter observation periods, which may have led to an underestimation of wart incidence compared to those with longer follow-up periods from earlier transplantations. Finally, the NHIS database lacked detailed information on donors and recipients such as disease activity and severity, history of previous warts, type of warts, and use of immunosuppressants. The increased risk of warts may be influenced by factors such as the combination, dosage, and duration of immunosuppressive therapy after transplantation. A significant limitation of this study is that the effects of immunosuppressive therapy were not accounted for, highlighting the need for future research to address this aspect. It would be also beneficial to further explore the effectiveness of the HPV vaccine in reducing the incidence of warts among transplant recipients and whether patients who develop warts post-transplantation face a higher risk of cutaneous cancers.
Taken together, our study demonstrated that the risk of cutaneous and genital warts was significantly higher in patients who had undergone transplantation. Moreover, these patients necessitated more frequent outpatient visits for wart, emphasizing the importance of implementing preventive measures and comprehensive care for warts in this vulnerable population.
Disclosure: The authors have no potential conflicts of interest to disclose.
Data Availability Statement: National Health Insurance data used in this study are available from the Korea National Health Insurance Service (NHIS) under restricted access due to data protection legislation and are available upon reasonable request to and with the permission of NHIS ( https://www.nhis.or.kr/ ).
Author Contributions: Conceptualization: Han JH, Park YM, Bang CH. Data curation: Han JH, Oh HJ, Son JH, Kim YH, Jung JH, Lee JH. Formal analysis: Park YM. Investigation: Son JH. Methodology: Son JH. Supervision: Park YM. Validation: Park YM, Bang CH. Visualization: Bang CH. Writing - original draft: Han JH, Park YM, Bang CH. Writing - review & editing: Han JH, Oh HJ, Kim YH, Lee JH, Park YM, Bang CH.
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SUPPLEMENTARY MATERIALS
Supplementary Table 1
Baseline characteristics of the study population
Supplementary Table 2
Number of medical visits for cutaneous and genital warts
Supplementary Fig. 1
Cumulative incidence curves of cutaneous and genital warts in the transplantation and control groups without transplantation (log-rank P < 0.001 and P = 0.001).