Background: The aim of this study was to explore the correlation
between high-risk human papillomavirus (HR-HPV) infection and changes in vaginal
microecology, as well as the severity of cervical intraepithelial lesions (CIN).
Methods: A retrospective analysis was conducted on 221 inpatients (aged
23–80 years) who underwent simultaneous testing of vaginal secretions for
microecological parameters, HR-HPV genotyping, and cervical tissue biopsy at the
Department of Gynecology, Second Affiliated Hospital of Xinjiang Medical
University, Urumqi, from October 2021 to January 2023. The study subjects were
analyzed to determine the association between HR-HPV infection and alterations in
vaginal microecology, as well as CIN. Results: Among the 221 cases, 69
were positive for HR-HPV, resulting in a positivity rate of 31.22% (69/221). Out
of the 139 cases with normal vaginal microecology, 26 were positive for HR-HPV,
yielding a positivity rate of 18.71% (26/139). Among the 82 cases with abnormal
vaginal microecology, 43 were positive for HR-HPV, resulting in a positivity rate
of 52.44% (43/82). Out of the 162 cases with normal cervix, 26 were positive for
HR-HPV, resulting in a positivity rate of 16.00% (26/162). Among the 59 cases
with abnormal cervix, 43 were positive for HR-HPV, resulting in a positivity rate
of 72.88% (43/59). In the cases of abnormal cervix, 10 presented cervical
inflammation, with a HR-HPV positivity rate of 70.00% (7/10); 20 cases had
cervical intraepithelial lesions (CIN) I, with a HR-HPV positivity rate of
70.00% (14/20); 20 cases had CIN II, with a HR-HPV positivity rate of 75.00%
(15/20); and 9 cases had CIN III, with a HR-HPV positivity rate of 77.80% (7/9).
Moreover, among the 162 cases with normal cervix, 36 had abnormal vaginal
microecology, resulting in an abnormality rate of 22.22% (36/162). Among the 59
cases with abnormal cervix, 46 had abnormal vaginal microecology, resulting in an
abnormality rate of 77.97% (46/59). In the cases of abnormal cervix, 10 had
cervical inflammation, with an abnormal vaginal microecology rate of 70.00%
(7/10); 20 cases had CIN I, with an abnormal vaginal microecology rate of 70.00%
(14/20); 20 cases had CIN II, with an abnormal vaginal microecology rate of
80.00% (16/20); and 9 cases had CIN III, with an abnormal vaginal microecology
rate of 100.00% (9/9). The differences in HR-HPV positivity rates between the
group with normal vaginal microecology and the group with abnormal vaginal
microecology were statistically significant (p
Cervical cancer is the most prevalent infection-associated neoplasm among women. Infection with high-risk human papillomavirus (HR-HPV) has been implicated in the development of cervical intraepithelial neoplasia and cervical cancer, and there may be synergistic effects in their progression [1, 2]. Similar to other mucosal sites in the body, the female genital tract harbors a distinct microbial community, primarily dominated by Lactobacillus genus, which plays a vital role in maintaining health and homeostasis. Growing evidence suggests that dysbiosis of the reproductive tract, along with specific bacteria and cytokines, may contribute to HPV infection and the advancement of cervical intraepithelial lesions (CIN). Therefore, this study aims to examine the relationship between CIN, HPV infection, and changes in vaginal microecology, offering novel insights for the prevention and treatment of these conditions.
A total of 221 inpatients, aged 23–80 years, were selected as study subjects from October 2021 to January 2023 at the Department of Gynecology, Second Affiliated Hospital of Xinjiang Medical University. These patients underwent simultaneous microecological testing of vaginal secretions, genotyping of HPV, and cervical tissue biopsy. The study received approval from the Ethics Committee of the Second Affiliated Hospital of Xinjiang Medical University, and all participants provided informed consent. Inclusion criteria consisted of a history of sexual intercourse, informed consent, and cooperation, while exclusion criteria included irregular vaginal or menstrual bleeding, pregnancy or lactation, presence of other tumors, severe gynecological or endocrine diseases, and inability to cooperate.
Specimen collection: The patient assumed a cystotomy position, and the lateral wall of the vagina and the cervical area were fully exposed. A sterile cotton swab was used to collect an appropriate amount of secretion from the upper 1/3 of the lateral wall, which was then placed in a test tube.
Detection method: The vaginitis joint detection kit and Bpr-2014A vaginitis automatic detection workstation (Master Biotechnology Co., Ltd, Suzhou, Jiangsu, China), was employed according to manufacturer’s instructions.
Test content and significance: The microscopic detection after Gram staining assessed the density, diversity, dominant flora, and presence of special pathogens such as spores, budding spores, fungal hyphae, and trichomonas. An aerobic vaginitis (AV) score greater than 3 diagnosed the presence of AV. Additionally, the normal range of vaginal pH was considered to be between 3.8 and 4.5. An abnormal vaginal microecology was diagnosed if there were abnormalities in any of the flora densities, diversity, dominant flora, pH, or Lactobacillus function.
Specimen collection: The cervix was exposed, excess secretions were wiped away using a sterile cotton swab, and a special cervical brush was inserted into the cervical canal. By rotating it clockwise five times, exfoliated epithelial cells at the squamocolumnar junction of the cervix were collected and placed in a specimen bottle containing HPV preservation solution.
Detection method: The HR-HPV typing nucleic acid assay kit (Beijing Bohui Innovation Biotechnology Group Co., Beijing, China), was used to detect specific DNA nucleic acid fragments of 18 HR-HPV subtypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82, 83).
Statistical analysis was performed using SPSS 19.0 (IBM Corporation, Armonk, NY,
USA). Descriptive statistics, Chi-square (
A significant difference was observed in the HR-HPV positivity rate between the
groups with abnormal and normal vaginal microecology. The positive rate in the
abnormal microecology group was significantly higher than that in the normal
|HR-HPV positive rate (%)||Total||p|
|Vaginal microecology||Positive||43 (52.44)||82||27.332||0.000|
HR-HPV, high-risk human papillomavirus.
Significant differences were observed in the HR-HPV positivity rates across
different cervical lesions. These rates demonstrated an increase in conjunction
with the severity of the different analyzed cervical lesions (p
|Cervical lesions||Number||HR-HPV positive rate (%)||p|
|Normal||162||26 (16.00)||136 (84.00)|
|Cervical inflammation||10||7 (70.00)||3 (30.00)||17.681||0.000|
|CIN I||20||14 (70.00)||6 (30.00)||30.218||0.000|
|CIN II||20||15 (75.00)||5 (25.00)||35.448||0.000|
|CIN III||9||7 (77.80)||2 (22.20)||20.861||0.000|
|Total||221||69 (31.20)||152 (68.80)||65.309||0.000|
CIN, cervical intraepithelial lesions; HR-HPV, high-risk human papillomavirus.
Significant disparities in vaginal microecology were observed among distinct
cervical lesions. Notably, as the severity of cervical lesions increased, the
positive rate of vaginal microecology also showed a corresponding escalation.
These findings are statistically significant (p
|Cervical lesions||Number||Vaginal microecology||p|
|Positive (%)||Negative (%)|
|Normal||162||36 (22.22)||126 (77.78)|
|Cervical inflammation||10||7 (70.00)||3 (30.00)||20.395||0.000|
|CIN I||20||14 (70.00)||6 (30.00)||29.120||0.000|
|CIN II||20||16 (80.00)||4 (20.00)||26.600||0.000|
|CIN III||9||9 (100.00)||0 (0)||11.467||0.000|
|Total||221||82 (37.10)||139 (62.90)||60.311||0.000|
CIN, cervical intraepithelial lesions; HR-HPV, high-risk human papillomavirus.
HPV, a double-stranded closed-loop DNA virus, exhibits the ability to self-replicate and encode within vaginal epithelial cells during their differentiation process. By manipulating cell growth patterns, the virus can effectively evade the immune system. Over time, persistent infection in the host can lead to the development of various cervical tissue lesions . Among the 100+ identified HPV types, approximately 40 can infect the genital tract . These types are classified as high- or low-risk based on their propensity to induce intraepithelial lesions in the cervix [5, 6]. In our study, out of the 69 cases of HPV infection, the most common types were HPV16, HPV52, and HPV58, which are also prevalent in China. Persistent infection with HPV16, HPV52, and HPV58, showed a strong association with viral load and grade II and III CIN [7, 8, 9]. Notably, HPV58 infection is particularly prevalent among 90% of patients with CIN, or cervical squamous cell carcinoma in our country. It is important to note that while HR-HPV infection is widespread, only a small proportion (5–10%) of these infections are considered genuinely risky, indicating persistence [10, 11, 12]. However, there is some ambiguity in defining the duration of persistence required to represent a “risk”. Approximately 75% of HR-HPV infections leading to cervical squamous cell carcinoma occur before the age of 30, with cancer development peaking after 10 years. This suggests that, on average, 10–20 years of persistent infection is necessary for the development of cervical squamous cell carcinoma [13, 14]. The extended timeframe allows for preventive measures and interventions, including HPV testing, cytological screening, and local treatment of identified precancerous lesions.
HR-HPV serves as a significant risk factor for the development of pre-cancerous and cancerous conditions in the cervix. Due to its high sensitivity for cervical disease, it is commonly employed as an early detection tool for cervical lesions. The lower genital tract of women encompasses a crucial microecological environment, where various microflora coexist in a state of relative balance within the vagina of healthy individuals . Among these, Lactobacillus species play a predominant role and contribute to the maintenance of vaginal microecological equilibrium by producing lactic acid, hydrogen peroxide, and other enzymes under optimal temperature and pH conditions [16, 17]. Findings from this study indicate that an imbalance in vaginal microecology tends to facilitate the expression of HPV, thereby leading to cervical tissue lesions. Disruption of the vaginal mucosa and abnormal elevation of pH weaken the local vaginal microecology, impairing its ability to inhibit pathogenic microorganisms. Concurrently, lactobacilli, which play a critical role in maintaining homeostasis, are suppressed within the vaginal flora, resulting in an increased prevalence of Candida and Trichomonas. Consequently, the rate of HPV virus infection significantly rises, and individuals infected with HR-HPV are at a substantially higher risk of developing various cervical lesions, which pose significant health risks .
CIN do not typically present with distinctive clinical symptoms, and high-grade lesions are more commonly observed in patients over the age of 46 [1, 19]. HPV is implicated in approximately 5% of global cancer cases, including cervical, vaginal, oropharyngeal, and other malignancies. Among these, cervical cancer exhibits the highest incidence, accounting for around 260,000 annual deaths . Worldwide, cervical cancer remains the most prevalent form of cancer within the female reproductive system, posing a severe threat to women’s lives and overall health.
Despite the availability of the HPV vaccine, the burden of cervical cancer is projected to remain high in the next 30–50 years due to low immunization rates in low- and middle-income countries, and inadequate cervical cancer screening worldwide . Recent evidence suggests that the composition of vaginal flora in cervical disease may influence the persistence of HPV infection and disease progression. A deeper understanding of the impact of vaginal flora composition could contribute to the development of more advanced markers for detecting microflora and provide valuable insights and targets for the development of novel preventive and therapeutic interventions.
In conclusion, this study highlights the increased risk of developing CIN associated with both HR-HPV infection and vaginal microecological abnormalities. Vaginal microecological imbalances may potentially synergize with HR-HPV infection in the development of cervical lesions. Therefore, it is recommended to conduct concurrent vaginal microecological testing in HR-HPV-positive patients to assess the presence of vaginal microecological abnormalities. However, further investigation is warranted to elucidate the synergistic mechanism involving vaginal microecology, HR-HPV infection, and CIN. Additionally, it is crucial to determine whether the treatment of vaginal microecological abnormalities can influence the conversion of HR-HPV infection.
In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study if our institution approved the request.
QHZ: Conception, data curation, formal analysis, investigation, methodology, writing - original draft, Writing - review & editing. YSL: Participate in the completion of writing - original draft, interpretation of data. CSX: Conception, funding acquisition, resources. All authors contributed to editorial changes in the manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript.
The study received approval from the Ethics Committee of the Second Affiliated Hospital of Xinjiang Medical University (approval number: 2022H024), and all participants provided informed consent.
This study was funded by Natural Science Foundation of Xinjiang Uygur Autonomous Region (2022D01A309) and Department of Gynecology, Second Affiliated Hospital of Xinjiang Medical University, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia (SKL-HIDCA-2022-GJ4).
The authors declare no conflict of interest.
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