Volume 92, Issue 12 pp. 3889-3894
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Effectiveness of a combination therapy of traditional Chinese medicine and CO2 laser treatment for condyloma acuminatum

Huaxiang Xu

Huaxiang Xu

Department of the Medical Cosmetology, Jiangxi Provincial People's Hospital, Nanchang, China

Department of Dermatology & STD, Jiangxi Provincial People's Hospital, Nanchang, China

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Qinglin Shen

Qinglin Shen

Institute of Clinical Medicine, Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, Nanchang, China

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Bing Fan

Corresponding Author

Bing Fan

Department of Radiology, Jiangxi Provincial People's Hospital, Nanchang, China

Correspondence Bing Fan, Department of Radiology, Jiangxi Provincial People's Hospital, 330006 Nanchang, China.

Email: [email protected]

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Changqing Xi

Changqing Xi

Department of Traditional Chinese Medicine, Yichang Yiling Hospital, Yichang, China

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Lili Wang

Lili Wang

Department of Dermatology & STD, Yichang Yiling Hospital, Yichang, China

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First published: 22 April 2020
Citations: 5

Abstract

Background

Condyloma acuminatum (CA) is both highly infectious and frequently recurring and requires long-term, repeated treatments, which seriously affect the physical and psychological health of patients. The purpose of the present study was to investigate the effectiveness of a combination therapy of traditional Chinese medicine and CO2 laser on CA and the relationship between CA relapse and cellular immunity.

Methods

The study cohort consisted of 160 CA patients who underwent ambulatory treatment between January 2017 and January 2019 in the Department of Dermatology and Venerology of our hospital. The 160 patients were randomly divided into two groups: a combination therapy group (80 cases), who underwent CO2-laser treatment followed by three courses of oral traditional Chinese medicine and a control group (80 cases), who were only treated with the CO2 laser to remove warts. The efficacy of the CO2-laser treatment was evaluated on the first month after treatment and relapse was evaluated at monthly follow-ups for 6 months. Additionally, 20 normal volunteers were also recruited. Three months before and after treatment, the cellular immunity factors of peripheral blood T lymphocyte subsets, including CD4+, CD8+, CD4+/CD8+, and interleukin-2 (IL-2), were detected and compared between CA patients and normal volunteers, the combination therapy and control groups, and the relapse and cure groups to determine whether there were statistical differences.

Results

Compared with normal volunteers, CA patients exhibited lower CD4+, CD4+/CD8+, and IL-2 levels and higher CD8+ levels (P < .05). In addition, the rates of relapse for the combination therapy and control groups were 25.7% and 40.8%, respectively. However, the comprehensive immunity factors showed no statistical difference (P > .05) before treatment. Three months after treatment, factors including CD4+ and CD4+/CD8+ were higher in the combination therapy group than in the control group (P < .05), and CD8+ and IL-2 showed no statistical difference (P > .05); factors including CD4+, CD4+/CD8+, and IL-2 were higher and CD8+ was lower in the cure group than in the relapse group (P < .05).

Conclusion

The therapy combination of traditional Chinese medicine and CO2-laser treatment can reduce the relapse rate of CA. It might be that traditional Chinese medicine combined with CO2-laser treatment regulate liver meridian, Qi and blood, and restore the balance between various subgroups.

Highlights

The therapy combination of traditional Chinese medicine and CO2-laser treatment can reduce the relapse rate of CA. It might be traditional Chinese medicine combined with CO2-laser treatment regulate liver meridian, Qi and blood.

ABBREVIATIONS

  • AIDS
  • acquired immunodeficiency syndrome
  • CA
  • condyloma acuminatum
  • HPV
  • human papillomavirus
  • IL-2
  • interleukin-2
  • PBS
  • phosphate-buffered saline
  • 1 BACKGROUND

    Condyloma acuminatum (CA) is a sexually transmitted disease caused by human papillomavirus infection, which primarily manifests as verrucous lesions.1, 2 The incidence of CA is 30 million cases per year worldwide and has been on the rise in recent times, on the basis of statistics from the World Health Organization. This disease is both highly infectious and frequently recurring and requires long-term, repeated treatments, which seriously affect the physical and psychological health of patients.2, 3 Although the clinical implementation of CO2-laser treatment has become relatively effective, it cannot eliminate latent or subclinical infections, resulting in a high rate of relapse.4 However, in recent years, the development of traditional Chinese medicine has made some advances in the treatment of CA, although a combination of traditional Chinese medicine with CO2 laser therapy is not well-documented.5 This study investigated the use of the CO2-laser technique along with traditional Chinese medicine in a combination treatment for CA and compared it with CO2-laser monotherapy with regard to clinical efficacy and rate of relapse. The relationship between relapse of CA and cellular immunity was also explored by detecting peripheral blood T lymphocyte subsets and interleukin interleukin-2 (IL-2) of patients both before and after treatment. Thus, we aimed to provide a theoretical foundation of the efficacious therapeutics and recurrence mechanisms for CA.

    2 METHODS

    2.1 Patient selection

    This study was a prospective, randomized, controlled clinical study and was approved by the hospital ethics committee. All patients were properly informed and provided their written consent. Inclusion criteria (a) patients with a preliminary diagnosis of CA who had not received any treatment; (b) patients with single or multiple lesions, with each single lesion having a diameter of less than 2.0 cm; (c) patients who volunteered for this study, with the persistence to finish treatment courses and attend follow-ups as required. Exclusion criteria (a) patients with a local combination of other sexually transmitted diseases, including syphilis or AIDS, or infectious dermatoses, for instance an uncured fungal infection; (b) patients with severe systemic diseases and liver and renal dysfunctions; (c) patients during pregnancy or lactation; (d) patients failing to take the prescribed medication.

    A total of 160 CA patients who underwent ambulatory treatment between January 2017 and January 2019 in the Department of Dermatology and Venerology of our hospital were involved in this study and randomly divided into two groups. The combination therapy group (80 cases) underwent oral traditional Chinese medicine combined with CO2-laser treatment, while the control group (80 cases) were treated with a CO2 laser only. Several cases were excluded, including three coinfected with syphilis, one coinfected with AIDS, nine coinfected with repeated fungal infection, and six cases with patient withdrawal or loss on follow-up. Eventually 141 patients were enrolled (70 in the combination therapy group and 71 in the control group). The patients had lesions that were distributed in various areas, including the urethral orifice, balanus, coronary sulcus, frenum, phallosome, crissum, vaginal orifice, and labia majora/minora. In addition, various factors, including gender, age, duration of disease, number of lesions, and wart area, were not statistically different (P > .05) between the two groups, demonstrating comparable baseline data (Table 1). In addition, 20 normal volunteers were recruited, aged from 25 to 47 years, with an average of (35.2 ± 8.2) years.

    Table 1. Baseline comparison between combination therapy and control groups (x ± s)
    Combination therapy group (n = 70) Control group (n = 71) P
    Gender
    Male 43 41 χ2 = 0.198 .656
    Female 27 30
    Age, y 39.2 ± 10.9 38.2 ± 11.1 t = 0.547 .585
    Duration of disease, months 4.2 ± 3.1 3.9 ± 2.5 t = 0.672 .568
    Number of lesions 3.0 ± 2.7 3.2 ± 2.5 t = 0.617 .681
    Wart area, mm2 120.2 ± 63.9 131.3 ± 72.3 t = 0.964 .160

    2.2 Therapeutic technique

    Routine disinfection was applied to the patients’ wart areas and the surrounding normal skin mucous membrane, followed by local infiltration anesthesia with 2% lidocaine and high temperature gasification and elimination of warts by the UltraPulse CO2-laser system (GP900D). The area of gasification was applied 2 mm beyond the wart and down to the basal layer of the lesion, and the wound was disinfected with iodide and compressed to stop bleeding. Patients in the treatment group were then provided oral home-made traditional Chinese medicine with the following formula: Cortex Phellodendri 15 g, Rhizoma Atractylodis 30 g, the seed of Job's tears 30 g, Herba Artemisiae Scopariae 15 g, Spina Gleditsiae 15 g, Herba Taraxaci 15 g, Radix Paeoniae Rubra 15 g, Radix Isatidis 15 g, Folium Isatidis 15 g, Spica Prunellae 15 g, Nidus Vespae 15 g, and Paris Polyphylla Smith 15 g. For those patients with Qi deficiency, Radix Astragali 30 g was added; for patients with heavy dampness, Poria 15 g and Polyporus 15 g were added. Each set of medication was decocted to 600 mL in the decoction room of our hospital and was administered at 100 mL each time, three times a day for three courses, with the duration of each course being 10 days. While, patients in the control group were only treated with the CO2 laser to remove warts.

    2.3 Research methods and evaluation criteria

    Samples of 3 to 4 mL fasting peripheral blood were collected from all patients and normal volunteers before treatment. After adding heparin for anticoagulation and phosphate-buffered saline (PBS) and mixing thoroughly, the liquid was centrifuged at 1500 rpm for 20 minutes, and lymphocytes in the separation layer were drawn up with a syringe pump. Subsequently, PBS was added, and the mixture went through a second centrifugation at 1500 rpm for 10 minutes, after which the supernatant was discarded. The residue was then preserved at low temperature. Eventually, the peripheral blood T lymphocyte subsets, including CD3+, CD4+, CD8+, CD4+/CD8+, and IL-2, were detected using a FACS-Calibur flow cytometer. Three months after treatment, re-examination of peripheral blood was performed on all patients, and the differences in these factors were compared. In addition, the occurrence of relapse was checked at monthly follow-ups for 6 months. Relapse was considered to be the appearance of new warts in or within 2 cm around the original lesion after treatment, with positive acetowhite test results. Patients who showed no signs of new warts were considered cured.

    2.4 Statistical methods

    Statistics were analyzed via SPSS 13.0, with measurement data presented as (x ± s). The comparative analysis between CA patients and normal volunteers and the cure and relapse groups were performed by independent t tests. Furthermore, enumeration data were expressed as percentages, with the relapse rates between groups compared using χ2 tests. Differences were considered statistically significant at P < .05.

    3 RESULTS

    3.1 Comparison of rate of relapse between combination therapy and control groups

    A total of 141 patients were included in this study, with 84 males and 57 females aged from 23 to 70 years and an average age of 38.7 ± 11.0 years. The duration of disease ranged from 12 days to 18 months, with an average of 4.0 ± 2.8 months.

    Among the 141 patients, 94 were cured and 47 relapsed, and the rate of relapse was 40.8% (29/71) in the control group and 25.7% (18/70) in the combination therapy group. There was no statistical difference between the two groups (χ2 = 3.631, P = .057).

    3.2 Comparison of peripheral blood T lymphocytes between CA patients and normal volunteers

    The 141 CA patients all exhibited lower CD4+, CD4+/CD8+, and IL-2 levels and higher CD8+ levels compared with normal volunteers, and the differences were statistically significant (P < .05) (Table 2).

    Table 2. Comparison of peripheral blood T lymphocytes between CA patients (n = 141) and normal volunteers (n = 20)
    Group CD3+ (%) CD4+ (%) CD8+ (%) CD4+/CD8+ IL-2 (KU/L)
    CA 68.84 ± 4.99 37.84 ± 4.64 32.30 ± 5.70 1.24 ± 0.35 7.01 ± 2.41
    Normal volunteers 70.46 ± 5.43 44.44 ± 4.39 28.35 ± 5.72 1.65 ± 0.45 9.78 ± 2.44
    t 1.341 5.991 2.901 4.664 4.811
    P .182 .000 .004 .000 .000
    • Abbreviations: CA, condyloma acuminatum; IL-2, interleukin-2.

    3.3 Comparison of peripheral blood T lymphocytes between combination therapy group and control group

    When the combination therapy and control groups were compared before treatment, the levels of CD4+ (37.87 ± 4.46% vs 37.82 ± 4.84%), CD8+ (32.13 ± 6.32% vs 32.47 ± 5.06%), CD4+/CD8+ (1.24 ± 0.35 vs 1.25 ± 0.35), and IL-2 (7.08 ± 2.55 vs 6.93 ± 2.27 KU/L) were not statistically different (P > .05). Three months after treatment, the levels of CD4+ and CD4+/CD8+ were significantly higher in the combination therapy group compared with those in the control group (P < .05); however, the levels of CD3+, CD8+, and IL-2 were not statistically different (P > .05) (Table 3).

    Table 3. Comparison of peripheral blood T lymphocytes between combination therapy (n = 70) and control (n = 71) groups after 3 months
    Group CD3+ (%) CD4+ (%) CD8+ (%) CD4+/CD8+ IL-2 (KU/L)
    Combination therapy 69.00 ± 4.72 42.73 ± 4.24 28.66 ± 5.60 1.56 ± 0.40 8.70 ± 2.04
    Control 68.58 ± 5.19 40.08 ± 4.20 29.72 ± 5.81 1.42 ± 0.44 8.42 ± 1.76
    t 0.510 3.718 1.104 1.910 0.843
    P .611 .000 .271 .049 .401
    • Abbreviations: CA, condyloma acuminatum; IL-2, interleukin-2.

    3.4 Comparison of peripheral blood T lymphocytes between cure and relapse groups

    The levels of CD3+, CD4+, CD4+/CD8+, and IL-2 were higher in the cure group than in the relapse group, and the levels of CD8+ were lower in the cure group. All differences were statistically significant (P < .05) (Table 4).

    Table 4. Comparison of peripheral blood T lymphocytes between cure (n = 94) and relapse (n = 47) groups after 3 months
    Group CD3+ (%) CD4+ (%) CD8+ (%) CD4+/CD8+ IL-2 (KU/L)
    Cure 69.48 ± 4.88 42.67 ± 4.04 28.97 ± 5.49 1.60 ± 0.43 9.28 ± 1.59
    Relapse 67.42 ± 4.86 38.85 ± 4.05 31.64 ± 5.39 1.28 ± 0.34 7.13 ± 1.67
    t 2.373 5.294 3.763 4.543 7.464
    P .019 .000 .000 .000 .000
    • Abbreviations: CA, condyloma acuminatum; IL-2, interleukin-2.

    4 DISCUSSION

    Various treatments for CA, including surgical excision, cryotherapy, imiquimod cream, and photodynamic therapy, all involve the universal challenges of thoroughly clearing human papillomavirus (HPV) infections and radically curing CA lesions.4, 6-12 However, infection by HPV is intrinsically interconnected with the body's immune functions. Specifically, T cellular immunity plays significant roles in the activation of HPV and the occurrence, cure, and relapse of CA. In addition, previous studies have reported the existence of cellular immunity dysfunction in CA patients,13, 14 including disproportional peripheral blood T lymphocyte subsets, an abnormal rate of natural killer cells, and an imbalance of cellular factors, for example, interleukins. These aberrations of cellular immunity will eventually protect the virus from immune system attack. Furthermore, T lymphocytes, the primary antiviral cells, include both CD8+ and CD4+ cells. In particular, CD8+ cells are capable of immune suppression and can inhibit the function of peripheral T lymphocytes. During normal immune function, the ratio of CD4+/CD8+ cells is maintained within a certain range. Once the balance is disturbed, the reduced immune function results in inefficient elimination of the virus, ultimately leading to disease progression.9, 15

    The CO2-laser method is a prevailing clinical therapy and has been demonstrated to be safe and effective through clinical practice; however, it can only remove visible lesions, not subclinical infections. Indeed, the rate of reoccurrence has been reported to be as high as 30% to 75% after CO2-laser monotherapy.4, 16, 17 In recent years, the use of traditional Chinese medicine has achieved positive results in the treatment of CA18-20; however, the use of a combination therapy of traditional Chinese medicine with CO2-laser treatment is not well-documented. Therefore, this study utilized the CO2-laser technique combined with traditional Chinese medicine to treat CA and compared the efficacy and relapse rate of the approach with CO2-laser monotherapy. The relationship between CA relapse and cellular immunity was also explored by detecting variations in the ratio of peripheral blood T lymphocytes. Therefore, we hoped to provide a theoretical foundation for effective therapeutics and recurrence mechanisms for CA.

    The results of this study suggest that, compared with normal volunteers, CA patients exhibit a higher percentage of CD8+ cells, and lower levels of CD4+, CD4+/CD8+, and IL-2, indicating a close connection between CA occurrence and the body's immune function. Specifically, the cellular immunity function of CA patients decreased and the antiviral immunity affected, leading to failed HPV elimination.21, 22 After the combination therapy of traditional Chinese medicine and CO2 laser was used, the percentage of peripheral blood CD8+ cells decreased, while the percentage of CD4+ cells, the ratio of CD4+/CD8+ cells, and the levels of IL-2 all increased, suggesting immune function recovery. Moreover, the percentage of CD4+ cells increased significantly compared with the control group, and almost reached normal levels. This result may be due to the pharmacological actions of traditional Chinese medicine. Furthermore, compared with the relapse group, the cure group possessed a significantly higher percentage of CD4+ cells, ratio of CD4+/CD8+ cells, and concentration of IL-2 and a significantly lower percentage of CD8+ cells. As the hypofunction of cellular immunity is a primary factor in CA relapse, it could result in inefficient clearance and immune escape of HPV and, ultimately, recurrence.23-25 Nevertheless, traditional Chinese medicine combined with CO2-laser treatment effectively enhances the cellular immunity functions of the body, promoting normal differentiation of T lymphocytes, restoring the balance between various subgroups, and remarkably reducing CA recurrence.

    According to the theory of traditional Chinese medicine, CA is a result of unhygienic sexual intercourse and an external pathogenic toxin, which leads to the external invasion of pathogenic dampness and heat into the genital mucosa, leading to stagnated heat in the liver meridian, disharmony between Qi and the blood, and intermingling of pathogenic dampness and heat.5, 20, 26, 27 While, CO2-laser therapy causes protein denaturation and coagulation necrosis and can effectively remove warts by cauterization. Furthermore, in traditional Chinese medicine, Rhizoma Atractylodis can dispel pathogenic wind and dampness to strengthen the spleen; Cortex Phellodendri can clear heat and dry dampness, remove toxic substances, cure sores, repel fire, and clear hecticness; Herba Artemisiae Scopariae can clear heat, promote diuresis, and remove jaundice; the seed of Job's tears functions to clear heat, promote diuresis, eliminate wind and dampness, and strengthen the spleen and stomach; Radix Paeoniae Rubra clears heat, cools the blood, and promotes blood circulation to remove stasis; Spina Gleditsiae functions to reduce swelling, detoxify, apocenosis, and destroy parasites; Radix Isatidis, Folium Isatidis, Herba Taraxaci, and Paris Polyphylla Smith have heat-clearing, detoxifying, detumescent, and hemostatic properties; Spica Prunellae can clear heat and purge fire, eliminate stagnation to reduce swelling, and improve eyesight; Nidus Vespae counteracts toxic substances, destroys parasites, dispels pathogenic wind, and relieves pain; Polyporus deals with edema by promoting diuresis; Poria helps to strengthen the spleen, calm the heart, promote diuresis, and excrete dampness; and Radix Astragali is effective for liver protection, antiaging, and boosting the immune system.18, 27, 28 The combined actions of the above medicines have the effects of detoxifying, counteracting blood stasis, clearing heat and dampness, dispersing stagnated liver Qi to relieve depression, body strengthening and consolidating, and boosting immunity and are we believe they influence the HPV infection and help to clear the virus. Nevertheless, among the comprehensive ingredients of traditional Chinese medicine, it is still unknown which ingredients play pivotal roles in fighting HPV. Generally, the decrease in the CA recurrence rate is closely bound with the enhancement of the patients’ immunity, and traditional Chinese medicine has a positive effect on this process.

    5 CONCLUSION

    Overall, the combination therapy of traditional Chinese medicine and CO2-laser treatment might regulate liver meridian, Qi and blood, restore the balance between various subgroups, and reduce CA recurrence.

    This study had some limitations. There are various risk factors that lead to the recurrence of CA, including HPV type, viral load, local pathological factors, and multiple sexual partners. However, this study only took a limited sample size into consideration, with no logistic assessment on the above multiple factors. Future studies should include an increased sample size for stratification analysis. Furthermore, a fundamental research is needed to investigate the complicated pharmacological mechanisms underlying traditional Chinese medicine.

    CONFLICT OF INTERESTS

    The authors declare that there are no conflict of interests.

    AUTHOR CONTRIBUTIONS

    H.X. carried out the data collection, literature review, and drafting of the manuscript. Q.S. contributed to the drafting of the manuscript and aided in the literature review. C.X. and L.W. participated in the data collection and the drafting of the manuscript. B.F. helped to design the work and revised the final version of the manuscript. All authors read and approved the final manuscript.

    ETHICS STATEMENT

    Ethical approval for this investigation was obtained from the Research Ethics Committee of Jiangxi Provincial People's Hospital, and the reference number was 2017-067.

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