Clinical Efficacy of 5‐Aminolevulinic Acid Photodynamic Therapy Combined With Interferon Spray in Treating Common and Plantar Warts

ABSTRACT

Background

Conventional treatments for common and plantar warts often have limited efficacy and high recurrence rates. 5‐Aminolevulinic acid photodynamic therapy (5‐ALA‐PDT) has attracted increasing attention as an alternative therapeutic option for these lesions. This study investigated the potential of 5‐ALA‐PDT as an alternative treatment option for patients with refractory common and plantar warts.

Objective

To explore the clinical efficacy of 5‐ALA‐PDT and recombinant human interferon alpha 2b (rhIFN‐α2b) spray combination therapy against common and plantar warts.

Methods

We enrolled 104 patients with common or plantar warts and randomly assigned them to the intervention (5‐ALA‐PDT combined with rhIFN‐α2b spray; n = 51) or control (cryotherapy; n = 53) group to compare treatment efficacy, recurrence rate, and adverse events.

Results

After three consecutive treatment cycles, the 4‐week complete recovery and total effective rates were 90.20% and 96.08% in the intervention group, versus 62.26% (p = 0.002) and 77.36% (p = 0.013) in the control group. Recurrence rates were significantly lower in the intervention group at 8 weeks (2.17% vs. 24.24%), 12 weeks (4.35% vs. 33.33%), and 6 months (4.35% vs. 39.39%; all p < 0.05). All adverse events were mild to moderate and localized.

Conclusion

5‐ALA‐PDT combined with rhIFN‐α2b spray exhibited superior clinical efficacy in treating common and plantar warts, significantly improving treatment efficacy, reducing medium‐term recurrence, and demonstrating good safety and tolerability.

1. Introduction

Cutaneous warts are benign proliferative skin disorders that commonly affect the hands and feet. They are generally caused by infection with human papillomavirus (HPV) in the skin and mucous membranes [1]. Beyond their aesthetic impact, warts may cause pain and ambulatory discomfort, leading to psychological distress in affected individuals [2]. Contemporary clinical management strategies primarily include physical interventions (e.g., cryotherapy, laser, microwave ablation), topical or systemic pharmacotherapy (e.g., salicylic acid, imiquimod), and immunomodulatory treatments [3]. However, the inherent limitations of conventional therapeutic approaches render them suboptimal for treating common and plantar warts, resulting in a notably high recurrence rate. 5‐Aminolevulinic acid photodynamic therapy (5‐ALA‐PDT) involves the topical application of a photosensitizer, followed by irradiation with a specific light source to selectively destroy infected cells by generating reactive oxygen species (ROS), such as singlet oxygen, while largely sparing adjacent normal tissues [4]. Recombinant human interferon alpha 2b (rhIFN‐α2b) is a cytokine with broad‐spectrum antiviral, immunomodulatory, and antiproliferative properties [5]. It can inhibit HPV replication and enhance immune cell activity. Theoretically, combining both methods could yield synergistic effects. Therefore, this study investigated the therapeutic efficacy of their combined application against common and plantar warts to determine its potential as an alternative therapeutic option with high cure rates and low recurrence in the clinical setting.

2. Materials and Methods

2.1. General Information

This study was approved by the Ethics Committee of Zhongshan Second People's Hospital (No. KY202201) and conducted in accordance with the Declaration of Helsinki (2013 revision). Written informed consent was obtained from all participants, with written consent from legal guardians for participants under 18 years of age.

The study included 104 patients with common or plantar warts presenting to the Dermatology and Aesthetic Medicine Center of Zhongshan Second People's Hospital (June 2022–May 2025). Inclusion criteria: ① Patients clinically diagnosed with common or plantar warts [1]; ② Age 16–60 years; ③ No prior wart treatment within the past 2 weeks; ④ All participants provided written informed consent; for those aged < 18 years, consent was additionally signed by their legal guardians. Exclusion criteria: ① Pregnant or lactating women; ② Patients with comorbid immunosuppressive diseases or those receiving immunosuppressants; and ③ Patients with allergy to lasers or porphyrin drugs. The patients were assigned to the intervention group (n = 51; receiving 5‐ALA‐PDT combined with rhIFN‐α2b spray) or the control group (n = 53; receiving liquid nitrogen cryotherapy) via randomization using a computer‐generated random number table (generated by an independent statistician not involved in the study). Allocation concealment was achieved using sequentially numbered, sealed, opaque envelopes. No stratification was performed, as baseline characteristics—including age, disease duration, and wart type—were balanced between the two groups (Table 1). The CONSORT flow diagram of patient enrollment, randomization, and follow‐up is provided as Figure 1.

TABLE 1.

Baseline characteristics of randomized participants.

Characteristics	5‐ALA‐PDT + rhIFN‐α2b (n = 51)	Cryotherapy (n = 53)	χ2/t	p
Sex			χ2 = 0.001	0.979
Male	29 (56.86)	30 (56.60)
Female	22 (43.14)	23 (43.40)
Age (years)	31.75 ± 10.08	33.34 ± 9.87	t = −0.82	0.417
Wart duration (months)	13.06 ± 5.96	12.03 ± 5.22	t = 0.94	0.350
Anatomical locations of warts			χ2 = 0.64	0.888
Palms/Soles/Periungual region	25 (49.02)	24 (45.28)
Limbs a /Trunk	15 (29.41)	14 (26.42)
Head/Neck	5 (9.80)	7 (13.21)
Multiple anatomical sites	6 (11.76)	8 (15.09)
Wart scores
Count score	10.61 ± 5.19	9.72 ± 4.52	t = 0.94	0.352
Diameter score	17.47 ± 8.05	16.53 ± 6.75	t = 0.65	0.519
Total score	28.08 ± 12.77	26.25 ± 11.03	t = 0.78	0.435

Note: Data are expressed as mean ± standard deviation or frequency and percentage 5‐ALA‐PDT, 5‐aminolevulinic acid photodynamic therapy; rhIFN‐α2b, recombinant human interferon alpha 2b.

^a Excluding palms, soles, and periungual region.

FIGURE 1.

CONSORT diagram of the trial. CONSORT, Consolidated Standards of Reporting Trials.

2.2. Methods

Patients in the intervention group received 5‐ALA‐PDT combined with rhIFN‐α2b spray. ① All warts were pretreated with CO₂ laser ablation (wavelength of 10,600 nm; continuous power of 0.1–5 W; pulse duration of 0.1–1 ms) to induce slight petechial hemorrhage. The resection range was set at 0.2–0.3 cm outside the wart lesion. ② Following cleaning of the affected area, 5‐ALA powder (Shanghai Fudan‐Zhangjiang Biopharmaceutical Co. Ltd., Shanghai, China) was used to prepare a fresh gel (20% concentration), which was evenly applied to the warts and up to 1.0 cm beyond the lesion boundary. The warts were then covered with plastic film and incubated for 3–4 h. ③ Subsequently, the lesions were illuminated with red LED light at 635 ± 10 nm (Wuhan Yage Optic and Electronic Technique Co. Ltd., Wuhan, China). Irradiation was performed for 30 min at a power density of 80 mW/cm² and an energy density of 144 J/cm². Cold air was simultaneously directed at the irradiation site for pain relief. Immediately post‐illumination, an ice pack was applied to the treatment site for 20 min. ④ The treatment site was protected from light for 24 h post‐irradiation. ⑤ rhIFN‐α2b spray (Tianjin Weiming Biopharmaceutical Co. Ltd., Tianjin, China) was applied starting from the second day after PDT, three times daily, with 1–2 sprays per application (100,000 IU of IFN per spray) to each ablation site, including the wound and surrounding skin. The treatment was administered for 4 weeks after the third 5‐ALA‐PDT session. ⑥ 5‐ALA‐PDT was administered at 1‐week intervals, for a total of 3 sessions.

Patients from the control group received cryotherapy with liquid nitrogen. A cotton swab dipped in liquid nitrogen was applied to each wart until the wart and a 0.2–0.3 cm margin of surrounding normal skin turned completely white (blanched). The freeze–thaw cycle was repeated once after the tissue had returned to its normal color. Each freeze lasted 15–30 s depending on wart thickness, until complete blanching was achieved. After the swab was removed and the lesion regained its normal color, the procedure was repeated to complete 1 treatment session. Cryotherapy was administered at 1‐week intervals for 3 treatment sessions.

All treatments were performed by the same medical team. Patients were instructed to avoid scratching the treatment site, keep it clean and dry, avoid exposure to direct sunlight, and seek medical attention promptly if discomfort occurred.

2.3. Indicators of Observation

All outcomes were assessed by an independent, board‐certified dermatologist blinded to treatment allocation, with all analyses performed on a per‐patient basis. Although distinct adverse event profiles may have introduced potential unblinding, assessment bias was minimized by using the same non‐treating assessor and objective primary outcomes (wart count and size). No unblinding events occurred during the study.

① Treatment efficacy: Treatment efficacy was evaluated based on a composite scoring system that accounted for both wart size and count. The wart count score was calculated as 1 point per wart. Wart size was scored based on maximum diameter: 0 points for 0 mm (complete clearance); 1 point for 0–4 mm; 2 points for > 4–8 mm; 3 points for > 8–12 mm; 4 points for > 12–16 mm; and 5 points for > 16–20 mm. The patient's overall score was the sum of the wart count and wart size scores [6]. The wart clearance rate was evaluated 4 weeks after the final treatment and calculated as follows: Wart clearance rate = [(pre‐treatment total score − post‐treatment total score) / pre‐treatment total score] × 100%. Clinical efficacy was classified into four categories based on the clearance rate:

• Complete recovery: 100% (complete elimination of all warts).

• Significant improvement: 60% to < 100% >

• Improvement: 30% to < 60%.

• No effect: < 30%.

The total effective rate was defined as the sum of the complete recovery, significant improvement, and improvement rates.

② Recurrence rate: Patients with complete recovery were followed at 8 weeks, 12 weeks, and 6 months after the final treatment to evaluate recurrence. Recurrence was defined as the reappearance of lesions at the original treatment site.

③ Pain severity and adverse events: Pain during treatment was rated on a 10‐point Visual Analog Scale (VAS; 0 = no pain, 10 = the worst imaginable pain). All treatment‐related adverse events were recorded from the first session until 12 weeks after the final treatment.

2.4. Sample Size Calculation

Sample size was calculated, assuming a 20% difference in complete clearance rates between groups, with a two‐sided type I error rate of 0.05 and a power of 80%. Estimates were reported with 95% confidence intervals (CIs). The minimum required sample size was 48 patients per group. To account for potential loss to follow‐up, we enrolled 104 patients: 51 in the 5‐ALA‐PDT + rhIFN‐α2b group and 53 in the cryotherapy group.

2.5. Statistical Analysis

All analyses were performed using SPSS 25.0. Continuous variables were expressed as mean ± standard deviation, and categorical variables as frequencies and percentages. Normality (Shapiro–Wilk test) and variance homogeneity (Levene's test) were tested. Continuous variables were compared using the independent‐samples t‐test (homogeneous variance) or Welch's corrected t‐test (heterogeneous variance). Categorical variables were analyzed with Pearson's chi‐square test. Fisher's exact test was performed for expected cell counts < 5. A two‐sided p < 0.05 was considered statistically significant.

3. Results

3.1. Baseline Clinical Data

No significant inter‐group differences were observed across baseline data, including sex, age, disease duration, lesion location, and pre‐treatment wart scores (all p > 0.05), indicating comparability between the two groups (Table 1).

3.2. Treatment Efficacy Outcomes

At the 4‐week follow‐up, complete recovery and total effective rates were significantly higher in the 5‐ALA‐PDT + rhIFN‐α2b group than in the cryotherapy group. Binary logistic regression analysis revealed that the intervention group had 5.58 times greater odds of complete recovery (odds ratio [OR] = 5.58, 95% CI: 1.90–16.37; p = 0.002) and 7.17 times greater odds of the total effective rate (OR = 7.17, 95% CI: 1.52–33.90; p = 0.013) (Table 2, Figure 2A).

TABLE 2.

Comparison of treatment efficacy between the two groups, n (%).

Effective rate	5‐ALA‐PDT + rhIFN‐α2b (n = 51)	Cryotherapy (n = 53)	P	OR	95% CI
Wart clearance rate
Complete recovery (100% clearance)	46 (90.20)	33 (62.26)	0.002	5.58	1.90–16.37
Significant improvement (60% to < 100% clearance)	2 (3.92)	6 (11.32)	—	—	—
Improvement (30% to < 60% clearance)	1 (1.96)	2 (3.77)	—	—	—
No effect (< 30% clearance)	2 (3.92)	12 (22.64)	—	—	—
Total effective rate a	49 (96.08)	41 (77.36)	0.013	7.17	1.52–33.90

Abbreviations: 5‐ALA‐PDT, 5‐aminolevulinic acid photodynamic therapy; rhIFN‐α2b, recombinant human interferon alpha 2b.

^a The total effective rate was defined as the sum of the complete recovery, significant improvement, and improvement rates. p‐values, odds ratios (ORs), and 95% confidence intervals (CIs) were calculated using binary logistic regression, with the cryotherapy group as the reference.

FIGURE 2.

Effective and recurrence rate outcomes. (A) Effective rates of the two treatment groups at 4 weeks after the final treatment. (B) Recurrence rates in the two treatment groups at 8 weeks, 12 weeks, and 6 months after final treatment. 5‐ALA‐PDT, 5‐aminolevulinic acid photodynamic therapy; rhIFN‐α2b, recombinant human interferon alpha 2b.

3.3. Recurrence Rate Outcomes

Recurrence rates were significantly lower in the 5‐ALA‐PDT + rhIFN‐α2b group at all three time points: 2.17% vs. 24.24% (OR = 0.07, p = 0.014), 4.35% vs. 33.33% (OR = 0.09, p = 0.003), and 4.35% vs. 39.39% (OR = 0.07, p = 0.001). Notably, no new recurrences occurred in the intervention group after the 12‐week follow‐up (Table 3, Figure 2B).

TABLE 3.

Comparison of recurrence rates between the two groups.

Recurrence rate	5‐ALA‐PDT + rhIFN‐α2b (n = 46 a )	Cryotherapy (n = 33 a )	p	OR	95% CI
8 weeks, n (%)	1 (2.17)	8 (24.24)	0.014	0.07	0.01–0.59
12 weeks, n (%)	2 (4.35)	11 (33.33)	0.003	0.09	0.02–0.45
6 months, n (%)	2 (4.35)	13 (39.39)	0.001	0.07	0.01–0.34

Abbreviations: 5‐ALA‐PDT, 5‐aminolevulinic acid photodynamic therapy; rhIFN‐α2b, recombinant human interferon alpha 2b.

^a The analysis was limited to patients who achieved complete recovery after treatment. p‐values, odds ratios (ORs), and 95% confidence intervals (CIs) were calculated using binary logistic regression, with the cryotherapy group as the reference.

3.4. Adverse Events Outcomes

All adverse events observed in both groups were mild to moderate and localized to treatment sites. No systemic adverse events were reported in either cohort (Table 4).

TABLE 4.

Comparison of adverse events between the two groups.

Adverse events	5‐ALA‐PDT + rhIFN‐α2b (n = 51)	Cryotherapy (n = 53)	χ2/t	p
Pain
Severity a (VAS score)	6.13 ± 1.04	4.19 ± 0.85	10.41	< 0.001
Duration b (hours)	5.91 ± 2.20	1.42 ± 0.62	14.04 c	< 0.001 c
Other local adverse events
Burning sensation	46 (90.20)	7 (13.21)	61.64	< 0.001
Redness and swelling	43 (84.31)	39 (73.58)	1.79	0.180
Blisters or hemorrhagic blisters	5 (9.80)	40 (75.47)	45.66	< 0.001
Itching	9 (17.65)	8 (15.09)	0.12	0.725
PIH	16 (31.37)	17 (32.08)	0.01	0.939
Scarring	1 (1.96)	6 (11.32)	—	0.113 d
Local photosensitive reactions	7 (13.73)	0 (0.00)	—	0.005 d
Systemic adverse events	0 (0.00)	0 (0.00)	—	—

Note: Data are expressed as mean ± standard deviation or frequency and percentage.

Abbreviations: 5‐ALA‐PDT, 5‐aminolevulinic acid photodynamic therapy; PIH, post‐inflammatory hyperpigmentation; rhIFN‐α2b, recombinant human interferon alpha 2b.

^a Pain severity during treatment = average of the Visual Analog Scale (VAS) scores of the 3 treatment sessions.

^b Pain duration after treatment = average pain duration of the 3 treatment sessions.

^c Welch's corrected t‐test was used due to significant heterogeneity of variance (Levene's test, p < 0.001).

^d Fisher's exact test was used for comparisons due to an expected cell frequency < 5.

Compared with the cryotherapy group, the 5‐ALA‐PDT + rhIFN‐α2b group reported significantly higher mean pain severity during treatment (VAS score: 6.13 ± 1.04 vs. 4.19 ± 0.85, t = 10.41; p < 0.001) and significantly longer mean pain duration after treatment (5.91 ± 2.20 h vs. 1.42 ± 0.62 h, Welch's corrected t = 14.04; p < 0.001).

In terms of local adverse events, burning sensation (90.20% vs. 13.21%, χ² = 61.64; p < 0.001) and local photosensitive reactions (13.73% vs. 0.00%, Fisher's exact test; p = 0.005) had significantly higher incidence in the 5‐ALA‐PDT + rhIFN‐α2b group. However, blisters or hemorrhagic blisters were significantly lower (9.80% vs. 75.47%, χ² = 45.66; p < 0.001). The 5‐ALA‐PDT + rhIFN‐α2b group also had a lower incidence of scarring than the cryotherapy group (1.96% vs. 11.32%, Fisher's exact test; p = 0.113), although the difference was not significant. No significant between‐group differences were found for redness and swelling, itching, or post‐inflammatory hyperpigmentation (PIH) (all p > 0.05) (Table 4).

3.5. Typical Case

A 32‐year‐old female patient was admitted with multiple painful verrucous growths on the sole of the left foot, present for 14 months. Early lesions appeared as scattered keratotic verrucous papules on the left sole, causing walking pain. The patient responded poorly to three cycles of cryotherapy and over 20 sessions of traditional Chinese herbal immersion administered at another hospital. The lesions gradually expanded and became confluent, further impairing walking. On admission, examination revealed multiple grayish‐yellow keratotic papules, partly merging into plaques, scattered across the left plantar surface and the first, second, and fifth toes. The lesions had rough surfaces, local petechial hemorrhage, and tenderness (Figure 3A). A diagnosis of multiple plantar warts was made. After providing informed consent, the patient received 5‐ALA‐PDT and rhIFN‐α2b (Figure 3B,D). Complete resolution of the warts was achieved at the 4‐week follow‐up after the third cycle (Figure 3E). Follow‐up at 6 months after therapy completion revealed no recurrence of warts at the original treated sites (Figure 3F).

FIGURE 3.

Treatment of a typical case of common and plantar warts. (A) Before treatment with 5‐ALA‐PDT + rhIFN‐α2b. (B) After one session of combination therapy. (C) After two sessions of combination therapy. (D) After three sessions of combination therapy. (E) Follow‐up at 4 weeks after therapy completion. (F) Follow‐up at 6 months after therapy completion. 5‐ALA‐PDT, 5‐aminolevulinic acid photodynamic therapy; rhIFN‐α2b, recombinant human interferon alpha 2b.

4. Discussion

Common and plantar warts are clinical subtypes of cutaneous warts, proliferative diseases caused by HPV infection of keratinocytes, with a prevalence of 7%–12% in the general population [7, 8]. Characterized by a thickened stratum corneum and a protracted clinical course, these lesions are particularly difficult to treat with conventional therapies and may harbor subclinical or latent infections that are visually indistinct, posing a substantial therapeutic challenge in dermatologic practice [9]. While cryotherapy remains the most commonly used treatment, freezing range and depth are difficult to control, causing serious adverse reactions or damage to normal tissues. Furthermore, cryotherapy carries a high recurrence rate. An observational study of 90 patients [10] found that the overall success rate for cryotherapy of warts on the hands and feet was 64.44%.

In this study, the combination of 5‐ALA‐PDT and rhIFN‐α2b spray demonstrated superior efficacy in treating common and plantar warts compared with conventional cryotherapy, achieving high wart clearance rates, likely due to synergistic effects. A review by Oluwafemi and Songca [11] noted that combining photosensitizers with therapeutic agents synergistically enhances therapeutic efficacy, especially in infections of the skin and mucosal membranes. In particular, 5‐ALA can selectively target HPV‐infected cells that exhibit abnormal, active proliferation. Through a series of enzymatic reactions, 5‐ALA is converted into the photosensitizing substance protoporphyrin IX (PpIX). Under irradiation at a specific wavelength, PpIX undergoes a photodynamic reaction upon light excitation and oxidative action, generating ROS that destroy HPV‐infected cells via oxidative damage while sparing normal cells [4, 12]. Consistent with this mechanism, Wang et al. [13] reported that 88% of 25 patients with plantar warts achieved complete response at 1‐month follow‐up after 5‐ALA‐PDT, with histological evidence of marked necrosis and apoptosis in epidermal keratinocytes post‐treatment. IFN‐α2b possesses broad‐spectrum antiviral, immunomodulatory, and antiproliferative properties. By binding to specific membrane receptors on cell surfaces, it neutralizes both DNA and RNA viruses, thereby effectively inhibiting viral replication and suppressing the abnormal proliferation of HPV‐infected epithelial cells [14, 15]. Taken together, 5‐ALA‐PDT and rhIFN‐α2b spray exert theoretically synergistic effects against common and plantar warts.

Recurrence rates at 8 weeks, 12 weeks, and 6 months post‐treatment among cured patients in the control group were significantly higher than those in the intervention group. This may be because cryotherapy targets only clinically visible lesions, failing to address subclinical infections, thereby leading to high recurrence. In contrast, the intervention combined 5‐ALA‐PDT and IFN‐α2b after thorough CO₂ laser ablation pre‐treatment of visible warts. CO₂ laser therapy is a commonly used minimally invasive technique for removing warts, which effectively vaporizes and cauterizes wart tissue using a high‐energy laser beam to destroy HPV‐infected skin cells [6]. CO₂ laser ablation plays a critical synergistic role in this combination regimen. Specifically, it removes the hyperkeratotic stratum corneum covering the warts, thereby enhancing the 5‐ALA penetration into the deeper layers of infected keratinocytes. Furthermore, it reduces the overall wart tissue volume, decreasing the burden on subsequent photodynamic treatment [16, 17]. Therefore, with thorough CO₂ laser pre‐treatment, the combination of 5‐ALA‐PDT and rhIFN‐α2b spray can eliminate subclinical and latent HPV infections to achieve a therapeutic effect that progresses from “focal clearance” to “field clearance”, thereby effectively minimizing recurrence [18].

The main adverse events in the intervention group included pain, burning sensation, redness and swelling, PIH, and local photosensitive reactions. In the cryotherapy group, the main adverse events were pain, redness and swelling, blisters or hemorrhagic blisters, PIH, and scarring. These results were generally consistent with previous reports [19]. Furthermore, PDT caused more severe and prolonged pain during treatment than cryotherapy. Thus, the significantly higher pain associated with PDT should be discussed with patients when obtaining informed consent. Active pain management strategies (e.g., topical anesthesia, cold air, oral analgesics) should be considered to improve tolerability.

Notably, two cases of multiple common warts in the narrow inter‐toe spaces in the intervention group did not respond to the treatment, likely due to restricted illumination angles during PDT caused by the wart locations, potentially constraining energy density that led to suboptimal therapeutic efficacy.

5. Limitations

This study has several limitations. First, the two treatment modalities are inherently imbalanced; the 5‐ALA‐PDT + rhIFN‐α2b combination requires more time, specialized equipment, and causes more severe pain than cryotherapy, which may affect patient acceptability. Second, the 6‐month follow‐up provides only medium‐term recurrence data. Extended follow‐up studies are needed to evaluate long‐term recurrence (≥ 12 months). Third, the combination therapy of CO₂ laser ablation, 5‐ALA‐PDT, and rhIFN‐α2b spray is the standard practice in our center. Efficacy was evaluated only for the full regimen, without separate groups for each component, preventing assessment of individual contributions to the overall therapeutic effect. Future factorial studies are needed to elucidate the individual and synergistic effects of these treatments. Fourth, the single‐center design limits generalizability. Larger, multi‐center studies with extended follow‐up are required to confirm the feasibility and safety of this combination therapy.

6. Conclusions

In conclusion, 5‐ALA‐PDT combined with rhIFN‐α2b spray demonstrated significant synergistic efficacy in treating common and plantar warts, improving wart clearance rates, reducing medium‐term recurrence, and exhibiting a favorable safety profile. This regimen represents a promising option, particularly for multiple or recurrent warts or those refractory to conventional therapies.

Author Contributions

Sheng‐Jiang Liang and Jia‐Min Miao contributed to the preparation and editing of the manuscript. All authors contributed to the article and have approved the submitted version.

All persons designated as authors participated in the work and take public responsibility for its content.

Funding

This work was supported by Zhongshan Science and Technology Bureau, 2022B1011.

Ethics Statement

This study received ethics approval from the Zhongshan Second People's Hospital (No. KY202201).

Consent

All patients or their legal guardians signed written informed consent.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.