Abstract
Background
COVID-19 related immune dysregulation including impaired interferon signaling, reduced cytotoxic T-cell activity, and sustained inflammatory imbalance may contribute not only to delayed screening but also to true biological persistence of high-risk HPV (HR-HPV). This study investigated whether prior COVID-19 infection influences cervical HR-HPV persistence and associated cytological abnormalities.
Methods
In this retrospective study, 738 h-HPV positive women without baseline high-grade lesions or immunocompromising conditions were included. The study group comprised 372 women with PCR confirmed symptomatic COVID-19, while those without confirmed infection served as controls. Patients with prior excisional cervical procedures, other STDs, pregnancy, or incomplete follow-up data were excluded. HR-HPV DNA and cervical cytology were assessed at standardized follow-ups at at mean intervals of approximately 10 and 19 months, and persistence rates were compared.
Results
Cervical HR-HPV persistence was significantly higher in COVID-19 positive patients at both follow-up visits (p = 0.007 and p = 0.021). Persistence of HPV 16 was also significantly higher in the COVID-19 positive group (p = 0.021), whereas HPV 18 persistence did not differ between groups (p = 0.851). Cervical cytology and colposcopy findings were comparable between groups at both visits (p = 0.873, p = 0.606, and p = 0.927, p = 0.751). Importantly, after adjusting for potential confounders including age, smoking status, baseline cytology, and COVID-19 vaccination, a history of COVID-19 infection remained a significant independent risk factor for HR-HPV persistence (aOR: 1.81, p < 0.001).
Conclusion
Prior COVID-19 infection was associated with increased HR-HPV persistence, particularly HPV 16. If confirmed by larger prospective studies, these findings may warrant intensified follow-up protocols for women with concurrent HR-HPV positivity and a history of COVID-19 infection. Prospective immunologic studies are additionally required to clarify how COVID-19 related immune alterations may influence HPV clearance.
Keywords: Human papillomavirus, COVID-19, SARS-CoV-2, HR-HPV persistence, Cervical cancer screening
Background
Human papillomavirus (HPV) is an oncogenic DNA virus that plays a central role in the pathogenesis of cervical cancer. Among the more than 200 HPV types identified, approximately 40 infect the anogenital mucosa, of which 14 are classified as high-risk (HR) genotypes due to their established oncogenic potential. The most prevalent HR types include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 [1, 2]. Cervical HR-HPV infection is strongly associated with cervical cytology abnormalities, which encompass a spectrum ranging from low-grade lesions, such as atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL), to high-grade lesions, including high-grade squamous intraepithelial lesions (HSIL) and cervical intraepithelial neoplasia (CIN), which may progress to invasive cervical cancer if left untreated.
Although both innate and adaptive immune responses are integral to viral clearance, persistent HPV infection can initiate oncogenic transformation. Most HPV infections resolve spontaneously within 1–2 years; however, approximately 10–15% evolve into persistent infections [3]. Persistence of HR-HPV, particularly genotypes 16 and 18, is a critical determinant of progression to CIN, cervical cancer, and other anogenital malignancies [4]. HPV 16 alone accounts for nearly half of cervical cancer cases globally, while types 16 and 18 collectively contribute ~ 66%. A further five genotypes (31, 33, 45, 52, and 58) account for an additional ~ 15% of cervical cancers and 11% of all HPV associated malignancies [5].
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), profoundly disrupted healthcare systems worldwide, including cervical cancer screening and HPV vaccination programs. Multiple studies have documented substantial reductions in screening participation, along with delays in diagnosis and follow-up, resulting in increased detection of CIN 2 and CIN 3 lesions in the post-pandemic period changes largely attributed to deferred evaluation [4].
Beyond these indirect disruptions, emerging evidence indicates that COVID-19 may exert direct biological effects on HR-HPV persistence through immunomodulatory mechanisms. COVID-19 infection induces broad dysregulation of both innate and adaptive immunity, including attenuation of interferon signaling and diminished cytotoxic T-lymphocyte activity, both of which are essential for the recognition and clearance of HPV infected cells [6]. Such immune perturbations may enhance HPV survival, replication, and integration within host epithelial tissues. While these indirect effects of the pandemic are well recognized, the specific mechanisms through which COVID-19 induced immune modulation may influence HR-HPV persistence and progression remain poorly understood, and the clinical implications of these interactions require direct investigation. This need highlights the importance of evaluating the direct biological impact of COVID-19 on HR-HPV infection and related disease outcomes.
Consistent with this hypothesis, metagenomic sequencing studies have revealed unexpectedly high rates of HPV coinfection and extensive genotype diversity among COVID-19 positive individuals [7]. Furthermore, large-scale epidemiological analyses demonstrate significantly elevated risks of HPV related carcinoma in situ and invasive cancers among individuals with prior COVID-19 infection, potentially reflecting the long term impact of COVID-19 associated immune dysfunction on HPV persistence and disease progression [8].
Despite these observations, methodologically rigorous longitudinal studies assessing HR-HPV clearance following COVID-19 infection remain scarce. A pioneering study on this relationship recently highlighted that COVID-19 induced immune dysregulation significantly hinders viral clearance [9]. However, the precise mechanisms through which this impairment influences long-term HR-HPV persistence and cervical cytological abnormalities are not yet fully delineated. This gap in knowledge underscores the scientific rationale and novelty of the present study.
Taken together, current evidence supports a multifactorial interplay between COVID-19 and HR-HPV, wherein COVID-19 induced immune dysregulation provides a biologically plausible pathway for impaired HPV clearance and increased risk of persistent HR-HPV infection [8]. The present study aims to elucidate the potential impact of prior COVID-19 infection on cervical HR-HPV persistence and related cytological abnormalities.
Materials and methods
Ethical statement
This non-randomized retrospective study was covered between March 15, 2020, and March 15, 2023, at the Department of Gynecologic Oncology, Ankara Bilkent City Hospital. Data was obtained from the elec tronic database system, patient files and pathology reports. The study was approved by the No. 1 Medical Research Scientific and Ethical Evaluation Board of Ankara Bilkent City Hospital (approval number: 1–25-1711). The study protocol adhered to the ethical standards of the 1975 Helsinki Declaration.
Study participants
A total of 738 female patients aged 18 years or older who were cervical HR-HPV DNA positive, had no high-grade cervical preinvasive lesions, had no other sexually transmitted infections (STDs), and had no history of immunocompromising disease or medication were evaluated for inclusion. Patients were excluded if they had missing HR-HPV or cytology results at baseline or during follow-up, became pregnant during the study period, had immunocompromising conditions (such as HIV infection, congenital or acquired immunodeficiency, or autoimmune disease) or were receiving immunosuppressive therapy, had previously undergone excisional, ablative, or destructive cervical procedures, had a history of hysterectomy, were diagnosed with high-grade cervical lesions (HSIL/CIN2+) or cervical cancer at baseline or during follow-up, had sexually transmitted infections other than HPV, received HPV vaccination before or during follow-up, or had insufficient medical records. Immunocompromised status was defined as the presence of any condition known to impair immune function, including HIV infection, congenital or acquired immunodeficiency, autoimmune disease, current immunosuppressive therapy, active cancer treatment, or prior organ or bone marrow transplantation.
COVID-19 severity was categorized into five groups. Individuals who tested positive for COVID-19 but exhibited no clinical symptoms or signs of lower respiratory tract involvement were classified as having asymptomatic infection. Those presenting with upper respiratory tract symptoms without hypoxemia were considered to have mild disease. Individuals showing clinical or radiological evidence of pneumonia while maintaining adequate oxygenation were classified as having moderate disease. Patients demonstrating significant respiratory compromise accompanied by reduced oxygen saturation were considered to have severe disease. Finally, those developing acute respiratory distress syndrome (ARDS), septic shock, or multi-organ failure requiring intensive care support were classified as having critical illness [10].
The COVID-19 positive group (n = 372) included patients who tested positive for COVID-19 by polymerase chain reaction (PCR) and exhibited COVID-19 compatible symptoms (e.g., fever, cough, dyspnea, sore throat, myalgia, loss of taste or smell, or diarrhea) that could not be attributed to another condition; these individuals were classified as having mild or moderate disease. The COVID-19 negative group (n = 366) consisted of patients with no PCR confirmed COVID-19 infection and either no COVID-19 compatible symptoms or symptoms attributable to other conditions. Patients with asymptomatic infection, severe disease, or critical illness were excluded. Regarding the temporal sequence, all participants were confirmed to be HR-HPV positive at the time of enrollment (baseline). In the study group, PCR-confirmed symptomatic COVID-19 infection occurred within a mean interval of 3.2 (± 1.4) months following this initial HR-HPV diagnosis. This timing ensures that the study specifically evaluates the impact of COVID-19 related immune response on the persistence or clearance of a pre-existing HR-HPV infection.
In our clinic, follow-up is conducted in accordance with ASCCP guidelines [11]. During the COVID-19 pandemic, follow up intervals for patients positive for HR-HPV were standardized and theoretically reduced to six month increments to mitigate potential surveillance delays. However, while these visits were scheduled as such, the actual mean timings of the data points analyzed in this study corresponded to follow-up periods of 10.40 ± 3.54 and 19.03 ± 6.26 months, respectively. At each follow-up visit, HR-HPV DNA and cytology results were evaluated in both groups. HR-HPV persistence was strictly defined as the continuous detection of the same high-risk genotype at baseline and during the follow-up period (typically at least 6–12 months apart). Cases involving the clearance of a baseline genotype followed by the acquisition of a new, different HR-HPV genotype were not classified as persistent infections.
At the first follow-up visit, 85 of 372 patients in the COVID-19 positive group (22.8%) and 74 of 366 patients in the negative group (20.2%) were excluded for not meeting follow-up criteria. At the second follow-up visit, an additional 17 positive patients (4.6%) and 9 negative patients (2.5%) were excluded. Consequently, 287 COVID-19 positive and 292 COVID-19 negative patients were analyzed at the first follow-up assessment, while 270 positive and 283 negative patients were included in the second follow-up analysis (Fig. 1).
Fig. 1.
Flowchart of patient enrollment and exclusion. 1: -Women aged 18–65 years. -No abnormalities detected in cervico-vaginal smear. -Absence of high-grade cervical preinvasive lesions. -Exclusion of patients with other sexually transmitted diseases (STDs). -No history of diseases or medications affecting immune response. 2: -“Patients with documented mild or moderate COVID-19 disease confirmed by polymerase chain reaction testing
We have now analyzed whether the excluded patients differed from those included in the final analysis with respect to baseline demographic and clinical characteristics. No statistically significant differences were found between excluded and included patients in terms of age, parity, smoking status, socioeconomic status, menopausal status, cervical cytology results, or HR-HPV genotype distribution. This indicates that the exclusions were unlikely to introduce selection bias. To avoid confounding, we did not perform genotype-specific COVID-19 analyses for cases involving multiple high-risk HPV types, including concurrent HPV 16 and 18 infections, as it was impossible to determine which specific genotype was responsible for the persistence or clearance.
Baseline demographic and clinical variables compared between groups included age, parity, smoking habit, intrauterine device use, socioeconomic status, education level, menopausal status, COVID-19 vaccination status, cervical cytology results, HR-HPV genotype, and colposcopy outcomes. Socioeconomic status was self-reported by patients on a 10-point scale based on perceived social differences (e.g., income, education, reputation), with scores of 1–3 classified as low socioeconomic status [12]. Patients who had received at least one dose of the Pfizer/BioNTech mRNA vaccine or the Sinovac Life Sciences (inactivated) vaccine were considered vaccinated.
Cervical cytology and biopsies were assessed by expert pathologists according to the Bethesda System. Cervical cytology results were classified as: NILM (negative for intraepithelial lesion or malignancy), ASC-US (atypical squamous cells - undetermined significance), LSIL (low-grade squamous intraepithelial lesion), ASC-H (atypical squamous cells, cannot exclude high-grade SIL), HSIL (high-grade squamous intraepithelial lesion), or inadequate. Colposcopic assessments were performed in accordance with the 2011 International Federation for Cervical Pathology and Colposcopy (IFCPC) terminology. In addition, for clarity and consistency with contemporary standards, the correspondence between CIN categories and the two-tiered Lower Anogenital Squamous Terminology (LAST) system was acknowledged, whereby CIN 1 is classified as low-grade squamous intraepithelial lesion (LSIL) and CIN 2–3 are classified as high-grade squamous intraepithelial lesion (HSIL) [13].
DNA analysis
HPV detection was performed using the HPV Genotyping Detection Kit (Fluorescence PCR method; detection limit: 1000 copies/mL). Liquid-based cytology was performed using the NOVAprep® system (Novaprep Inc., Russia) and Max-prep® system (Corebiotech Co., Ltd., Korea). HPV DNA was identified using the QIAscreen HPV PCR kit (Qiagen Inc., Germany).
Nasopharyngeal and/or oropharyngeal samples for COVID-19 were tested using RT-PCR, with two commercial kits (BioSpeedy COVID-19 RT-qPCR Detection Kit, Bioeksen, Istanbul, Turkey targeting RdRp; and Coronex COVID-19 Multiplex RT-qPCR Kit, DS Bio & Nano Technology, Ankara, Turkey targeting Orf1ab and N genes). Both kits included internal control targeting human RNaseP. PCR runs were performed using Rotor-Gene Q (Qiagen, Hilden, Germany).
Statistical analysis
Normality of quantitative variables was assessed using the Kolmogorov–Smirnov test. Non-normally distributed variables were compared with the Mann–Whitney U test. Categorical variables were analyzed using Pearson’s Chi-square and Fisher’s exact tests. In the multivariable model, HR-HPV persistence at the first follow-up was defined as the primary outcome (dependent variable), while COVID-19 history, age, smoking status, HPV genotypes (HPV 16 and HPV 18), baseline cytology, and vaccination status were included as independent variables. To identify independent predictors of HR-HPV persistence, a multivariable logistic regression analysis was performed using variables that were clinically relevant or significant in univariate analyses. Results were presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI). Results were expressed as median (Q1–Q3) and n (%). A p-value < 0.05 was considered statistically significant. Statistical analyses were conducted using IBM SPSS version 22 (IBM Corporation, Armonk, NY, USA).
Results
In the entire cohort, the mean age was 40.92 ± 10.9 years (range, 19–65), and the mean parity was 1.99 ± 1.12. The mean durations of the first and second follow-up visits were 10.40 ± 3.54 months and 19.03 ± 6.26 months, respectively. There was no significant difference between the COVID-19 positive and COVID-19 negative groups with respect to follow-up intervals (Table 1).
Table 1.
Demographic and clinicopathological characteristics of HR-HPV positive patients with and without a history of COVID-19 infection
| Characteristics | Entire group (n = 579) | COVID-19 Infection | p Value | ||
|---|---|---|---|---|---|
| Negative (n = 292) | Positive (n = 287) | ||||
| Mean ± SD | Mean ± SD | Mean ± SD | |||
| Age (years) | 40.92 ± 10.9 | 40.7 ± 10.8 | 41.1 ± 10.9 | 0.792 | |
| Parity | 1.99 ± 1.12 | 2.02 ± 1.14 | 1.95 ± 1.43 | 0.464 | |
| First follow-up time (months) | 10.40 ± 3.54 | 10.07 ± 3.10 | 10.79 ± 3.89 | 0.792 | |
| Second follow-up time (months) | 19.03 ± 6.26 | 19.90 ± 5.98 | 18.25 ± 6.11 | 0.577 | |
| n (%) | n (%) | n (%) | |||
| Smoking | 196 (33.8) | 106 (36.3) | 90 (31.3) | 0.208 | |
| IUD presence | 157 (27.1) | 75 (25.2) | 82 (28.5) | 0.435 | |
| Socio-economics status (low) | 125 (21.6) | 66 (22.6) | 59 (20.5) | 0.549 | |
| Education level1 | 313 (54.1) | 146 (50) | 167 (58.1) | 0.293 | |
| Menopausal status (premenopause) | 461 (79.6) | 235 (80.4) | 226 (78.7) | 0.604 | |
| COVID-19 vaccination status* | 563 (97.2) | 285 (97.6) | 278 (96.8) | 0.856 | |
| Smear | NILM | 218 (37.6) | 113 (38.7) | 105 (36.6) | 0.217 |
| AS-CUS | 237 (40.1) | 109 (37.3) | 128 (44.6) | ||
| LSIL | 85 (14.7) | 50 (17.1) | 35 (12.2) | ||
| Not available | 39 (6.7) | 20 (6.9) | 19 (6.6) | ||
| HR-HPV type | 16 | 160 (27.6) | 83 (28.4) | 77 (26.8) | 0.751 |
| 18 | 44 (7.6) | 20 (6.9) | 24 (8.4) | ||
| 16 and 18 | 23 (4) | 13 (4.4) | 10 (3.5) | ||
| Other than 16/18 | 352 (60.8) | 176 (60.3) | 176 (61.3) | ||
| Colposcopy | Normal | 317 (54.7) | 158 (54.1) | 159 (55.4) | 0.755 |
| CIN1 | 262 (45.2) | 134 (45.9) | 128 (44.6) | ||
Continuous variables were analyzed using the Mann–Whitney U test, and categorical variables were analyzed using Pearson’s Chi-square test. Statistical significance was defined as p < 0.05
*Vaccinated
1: Bachelor's degree and above
n Number of HR-HPV positive patients, SD Standard deviation, IUD Intrauterine device, p Significance value, NILM Negative for intraepithelial lesion or malignancy, AS-CUS Atypical squamous cells of undetermined significance, LSIL Low-grade squamous intraepithelial lesion, CIN1 Cervical intraepithelial neoplasia 1, HR-HPV High risk-human papilloma virus
Among these patients, 196 (33.8%) were smokers, 157 (27.1%) were intrauterine device users, 125 (21.6%) had low socioeconomic status, 313 (54.1%) had a university degree or higher, 461 (79.6%) were premenopausal, and 563 (97.2%) were vaccinated against COVID-19. Cytology results showed 218 (37.6%) NILM, 237 (40.1%) ASC-US, and 85 (14.7%) LSIL. HPV genotyping revealed 160 (27.6%) patients with HPV 16, 44 (7.6%) with HPV 18, 23 (4%) with HPV 16 and 18, and 352 (60.8%) with other cervical high-risk HPV genotypes. Colposcopy findings demonstrated 158 (54.1%) normal results and 134 (45.9%) CIN 1 lesions. No significant differences were observed between the COVID-19 positive and COVID-19 negative groups in terms of age, parity, smoking status, intrauterine device use, socioeconomic status, education level, menopausal status, COVID-19 vaccination status, cytology results, HR-HPV genotype, or colposcopic findings (Table 1). No statistically significant baseline differences were found between excluded and included patients across demographic, clinical, or cytological variables.
No significant differences were observed between HR-HPV positive patients with and without prior COVID-19 infection regarding cytology results at 6 and 12 months of follow-up (p = 0.823 and p = 0.606, respectively (Table 2).
Table 2.
Smear results at first and second follow-up in HR-HPV positive patients with and without prior COVID-19 infection
| Characteristics | COVID-19 Infection | p Value | |||
|---|---|---|---|---|---|
| Negative (n = 292) | Positive (n = 287) | ||||
| n (%) | n (%) | ||||
| Smear |
First follow-up |
NILM | 202 (69.3) | 195 (67.9) | 0.873 |
| ASC-US | 50 (17.1) | 56 (19.5) | |||
| LSIL | 22 (7.5) | 24 (8.4) | |||
| ASC-H | 5 (1.7) | 4 (1.4) | |||
| HSIL | 3 (1) | 2 (0.7) | |||
| Not available | 10 (3.4) | 6 (2.1) | |||
|
Negative (n = 77) 1 |
Positive (n = 106) 2 |
||||
| n (%) | n (%) | ||||
|
Second follow-up |
NILM | 46 (59.7) | 52 (49.1) | 0.606 | |
| ASC-US | 13(16.9) | 20 (18.9) | |||
| LSIL | 10 (13) | 16 (15.1) | |||
| ASC-H | 1 (1.3) | 3 (2.8) | |||
| HSIL | 4 (5.2) | 5 (4.7) | |||
| Not available | 3 (3.9) | 10 (9.4) | |||
Pearson’s Chi-square test; significance threshold p < 0.05
1Nine patients who underwent excisional procedures were excluded
217 patients who underwent excisional procedures were excluded
n Number of HR-HPV positive patients, p Significance value, NILM Negative for intraepithelial lesion or malignancy, AS-CUS Atypical squamous cells - undetermined significance, LSIL Low-grade squamous intraepithelial lesion, ASC-H Atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion. HSIL High-grade squamous intraepithelial lesion
No significant differences were observed between HR-HPV positive patients with and without prior COVID-19 infection regarding colposcopic findings and colposcopy-guided biopsy results at 6 and 12 months of follow-up (p = 0.927 and p = 0.751, respectively (Table 3).
Table 3.
Colposcopy and biopsy results at first and second follow-up in HR-HPV positive patients with and without prior COVID-19 infection
| Characteristics | COVID-19 Infection | p Value | ||||
|---|---|---|---|---|---|---|
| Negative (n = 89)1 | Positive (n = 125)2 | |||||
| n (%) | n (%) | |||||
| Colposcopy and biopsy |
First follow-up |
Normal colposcopy | 10 (11.2) | 15 (12) | 0.927 | |
| Biopsy | Normal | 31 (34.8) | 39 (31.2) | |||
| CIN 1 | 27 (30.3) | 36 (28.8) | ||||
| CIN 2 | 5 (5.6) | 11 (8.8) | ||||
| CIN 3 | 4 (4.5) | 6 (4.8) | ||||
| Not available | 12 (13.6) | 18 (14.4) | ||||
|
Negative (n = 38) 3 |
Positive (n = 56) 4 |
|||||
| n (%) | n (%) | |||||
| Second follow-up | Normal colposcopy | 5 (13.1) | 11 (19.6) | 0.751 | ||
| Biopsy | Normal | 16 (42.1) | 24 (42.8) | |||
| CIN 1 | 9 (23.6) | 13 (23.2) | ||||
| CIN 2 | 2 (5.3) | 3 (5.4) | ||||
| CIN 3 | 2 (5.3) | 3 (5.4) | ||||
| Not available | 4 (10.5) | 2 (3.6) | ||||
Pearson’s Chi-square test; significance threshold p < 0.05
186 patients with HR-HPV positivity and 3 patients with HR-HPV-negative smear ASC-H/HSIL
2123 patients with HR-HPV positivity and 2 patients with HR-HPV-negative smear results for ASC-H/HSIL
337 patients with HR-HPV positivity and 1 patient with HR-HPV-negative smear results for ASC-H/HSIL
455 patients with HR-HPV positivity and 1 patient with HR-HPV-negative smear results for ASC-H/HSIL
n Number of HR-HPV positive patients, p Significance value, CIN1 Cervical intraepithelial neoplasia 1, CIN2 Cervical intraepithelial neoplasia 2, CIN3 Cervical intraepithelial neoplasia 3
At first follow-up, 86 (29.5%) patients in the COVID-19 negative group tested HR-HPV positive, while 206 (70.5%) remained negative. In the COVID-19 positive group, 123 (42.8%) were HR-HPV positive, while 164 (57.2%) remained negative. HR-HPV persistence was significantly higher in the COVID-19 positive group (p = 0.007). At second follow-up, 37 (13.1%) in the COVID-19 negative group were HR-HPV positive, while 246 (86.9%) remained negative. In the COVID-19 positive group, 55 (20.3%) were HR-HPV positive, while 215 (79.7%) remained negative. HR-HPV persistence was again significantly higher in the COVID-19 positive group (p = 0.021) (Table 4) (Fig. 2).
Table 4.
HR-HPV status at first and second follow-up in patients with and without prior COVID-19 infection
| Characteristics | COVID-19 Infection | p Value | |||
|---|---|---|---|---|---|
| Negative (n = 292) | Positive (n = 287) | ||||
| n (%) | n (%) | ||||
| HR-HPV |
First follow-up |
Positive | 86 (29.5) | 123 (42.8) | 0.007* |
| Negative | 206 (70.5) | 164 (57.2) | |||
|
Negative (n = 283) 1 |
Positive (n = 270) 2 |
||||
| n (%) | n (%) | ||||
| Second follow-up | Positive | 37 (13.1) | 55 (20.3) | 0.021* | |
| Negative | 246 (86.9) | 215 (79.7) | |||
Pearson’s Chi-square test; *significance threshold p < 0.05
1 9 patients who underwent excisional procedures were excluded
2 17 patients who underwent excisional procedures were excluded
n Number of High Risk-Human Papilloma Virus positive patients, p Significance value, HR-HPV High risk-human papilloma virus
Fig. 2.
Temporal distribution of HR-HPV results by COVID-19 infection status
Of the 77 HPV 16 positive patients in the COVID-19 positive group, 42 (54.5%) were still HPV 16 positive after first follow-up and 21 (27.2%) after second follow-up. Of the 83 HPV 16 positive patients in the COVID-19 negative group, 24 (28.8%) were still HPV 16 positive after first follow-up and 9 (10%) after second follow-up. For HPV 16 positive patients, persistence was also significantly higher in the COVID-19 positive group (p = 0.021) (Table 5; Fig. 3). Of the 24 HPV 18 positive patients in the COVID-19 positive group, 13 (54.1%) were still HPV 18 positive after first follow-up and 7 (29.2%) after second follow-up. Of the 20 HPV 18 positive patients in the COVID-19 negative group, 8 (40%) were still HPV 18 positive after first follow-up and 5 (25%) after second follow-up. For HPV 18 positive patients, persistence was similar in the COVID-19 positive and COVID-19 negative groups (p = 0.851) (Table 5.; Fig. 3).
Table 5.
Genotype distribution of cervical HR-HPV positivity during follow-up in patients with and without prior COVID-19 infection
| Characteristics | COVID-19 Infection | p Value | ||
|---|---|---|---|---|
| Negative | Positive | |||
| n (%) | n (%) | |||
| HPV 16 positive | Initially | 83 (100) | 77 (100) | 0.021* |
| First follow-up | 24 (28.8) | 42 (54.5) | ||
| Second follow-up | 9 (10.8) | 21 (27.2) | ||
| HPV 18 positive | Initially | 20 (100) | 24 (100) | 0.851 |
| First follow-up | 8 (40) | 13 (54.1) | ||
| Second follow-up | 5 (25) | 7 (29.2) | ||
Pearson’s Chi-square test; *p-value <0.05 was considered statistically significant
n Number of High Risk-Human Papilloma Virus Positive patients, p Significance value, HPV Human papilloma virus
Fig. 3.
Distribution of HR-HPV genotypes over time by COVID-19 infection status
The independent predictors of HR-HPV persistence were evaluated using a multivariable logistic regression model. After adjusting for potential confounders including age, smoking status, baseline cytology, and COVID-19 vaccination, a history of COVID-19 infection remained a significant independent risk factor for HR-HPV persistence aOR: 1.81, 95% CI: 1.32–2.48, p < 0.001). Additionally, HPV 16 positivity was found to be the strongest predictor of viral persistence (aOR: 2.28, 95% CI: 1.64–3.17, p < 0.001). Other variables, including age (p = 0.412), smoking status (p = 0.304), HPV 18 positivity (p = 0.238), baseline cytology (p = 0.385), and vaccination status (p = 0.592), did not show a statistically significant independent association with HR-HPV persistence in this model (Table 6).
Table 6.
Multivariable logistic regression analysis of factors associated with HR-HPV persistence at Follow-up
| Variable | aOR | 95% CI | p Value |
|---|---|---|---|
|
COVID-19 History (Positive vs. Negative) |
1.81 | 1.32–2.48 | < 0.001* |
|
Age (Continuous) |
1.01 | 0.99–1.03 | 0.412 |
|
Smoking Status (Yes vs. No) |
1.18 | 0.86–1.62 | 0.304 |
|
HPV 16 Positive (Yes vs. No) |
2.28 | 1.64–3.17 | < 0.001* |
|
HPV 18 Positive (Yes vs. No) |
1.35 | 0.82–2.22 | 0.238 |
|
Baseline Cytology (Abnormal vs. NILM) |
1.22 | 0.78–1.91 | 0.385 |
|
COVID-19 Vaccination (Yes vs. No) |
0.91 | 0.64–1.29 | 0.592 |
aOR Adjusted Odds Ratio, CI Confidence Interval. The model is adjusted for age, smoking status, HPV genotypes, baseline cytology, and COVID-19 vaccination status. *Statistically significant (p < 0.05)
Discussion
In this study, we investigated the potential impact of COVID-19 infection on HR-HPV persistence and cervical cytological abnormalities. As presented in Tables 1, 2 and 3, baseline demographic, cytological, and colposcopic variables were comparable between COVID-19 positive and negative groups (all p > 0.05), indicating similar initial risk profiles. However, longitudinal analyses revealed a significantly higher HR-HPV persistence in the COVID-19 positive group at both the first and second follow-up visits (42.8% vs. 29.5%, p = 0.007; and 20.3% vs. 13.1%, p = 0.021). When evaluated by genotype, only HPV 16 demonstrated statistically significant persistence (p = 0.021). These epidemiological findings necessitate mechanistic exploration to understand how COVID-19 may influence HPV clearance [8, 14].
COVID-19 affects both innate and adaptive immune responses. Immune dysregulation including T-cell depletion and excessive proinflammatory cytokine secretion may interfere with the host immune mechanisms required for HPV elimination. The hyperinflammatory yet immunosuppressive immune profile characterizing COVID-19 may impede cytotoxic T-cell mediated clearance in the cervical epithelium, thereby promoting persistent HPV infection [15]. HPV clearance depends heavily on Th1-mediated cellular immunity, particularly interferon-γ (IFN-γ) and interleukin-12 (IL-12), which activate CD8⁺ cytotoxic responses against infected epithelial cells. COVID-19 related elevations in IL-6 may suppress Th1 polarization and diminish CD8⁺ T-cell activity [16]. Additionally, T-cell exhaustion with PD-1 upregulation a phenomenon observed in both COVID-19 and HPV-related lesions may contribute to reduced viral clearance [17]. Collectively, these immunological alterations provide a biologically plausible explanation for the increased HR-HPV persistence, particularly HPV 16, observed in our cohort. Supporting this biological plausibility, Akdemir et al. recently reported that COVID-19 infection significantly impairs HPV clearance rates, suggesting that the systemic immune dysregulation leads to a failure in viral elimination [9].
Beyond systemic immune effects, COVID-19 induces endothelial injury across multiple organ systems through inflammatory and thrombotic pathways. Varga et al.. emphasized that although direct infection of cervical epithelial cells by COVID-19 is unlikely, inflammatory infiltration of endothelial cells may indirectly influence cervical immunity [18]. Several intersecting mechanisms including cytokine-induced vascular permeability (IL-6, TNF-α), endothelial activation and leukocyte transmigration (ICAM-1, VCAM-1, E-selectin), local hypoxia due to microthrombi (HIF-1α), and downregulation of MHC-I expression can impair mucosal barrier integrity, antiviral defenses, and antigen presentation [19]. Although cervix specific data remain limited, these pathways create an immune environment conducive to mucosal viral persistence. These findings further align with broader virome-level observations reported in COVID-19 patients.
COVID-19 has also been associated with diverse mucocutaneous manifestations, including urticaria, maculopapular rashes, varicella like eruptions, purpuric lesions, livedoid changes, and thrombotic ischemic lesions [20]. Although cervical tissue has not been directly studied, several authors have proposed that similar inflammatory alterations may theoretically influence cervical epithelial immunity and, in turn, affect HPV persistence. Vavoulidis et al.. suggested that systemic immune dysregulation may promote a pro-oncogenic cervical microenvironment, while Elmas et al.. highlighted that mucocutaneous inflammation and vascular injury may extend to genital mucosa [21]. Because these mechanisms are extrapolated from non-cervical tissues, they remain speculative; however, they are pathophysiologically consistent with known mucosal antiviral responses. COVID-19 related increases in IL-6, TNF-α, and IL-1β, along with interferon pathway dysregulation and endothelial permeability changes, may theoretically weaken cervical mucosal immunity and favor persistent HPV infection [15, 22]. These biologically plausible parallels should nonetheless be interpreted cautiously until supported by cervix-specific evidence.
Short-term immunological disturbances provide only a partial explanation; however, a long-term immune dysregulation model may also be relevant. The cytokine storm induced by COVID-19 characterized by elevated IL-6, IL-1β, and TNF-α may impair mucosal viral clearance or accelerate the progression of pre-existing cervical lesions through sustained immune activation or epithelial injury [18, 22]. Ye et al.. further demonstrated that these cytokine-mediated effects contribute to immune exhaustion, weakened antiviral responses, and potential viral immune escape [23]. Women recovering from COVID-19 may develop post-COVID syndrome involving neuroinflammation, coagulation disturbances, autoimmunity, and viral persistence. Circulating antigen–antibody complexes and microthrombi induce endothelial injury and promote the reactivation of latent viruses such as Epstein Barr virus and HHV-6 [24, 25]. This convergence of clinical and mechanistic evidence supports the plausibility of a prolonged post-viral susceptibility to HR-HPV persistence. The significantly higher HR-HPV persistence observed in COVID-19 positive women in our study aligns with this model.
These immunological considerations have prompted several researchers to reconsider the role of COVID-19 in cervical disease progression. Becker et al. hypothesized that COVID-19 may adversely influence cervical dysplasia through immune exhaustion rather than direct epithelial infection, recommending closer follow-up for patients with dysplasia and concurrent immunological disturbances [14]. Although preliminary, these perspectives emphasize the need to contextualize cervical disease within broader COVID-19 related immune alterations. In contrast, Erkayman et al.. reported a regression of cutaneous HPV-related verrucae vulgares following symptomatic COVID-19 infection, illustrating that HPV host interactions may vary across HPV types and immune landscapes [26].
Disruptions to healthcare access during the pandemic have been proposed as an additional risk factor for HPV persistence and progression [4]. However, both groups in our study had comparable access to follow-up and interventions, suggesting that the increased HR-HPV persistence observed among COVID-19 positive patients is unlikely to be attributable solely to delays in care. The relatively similar cytological and colposcopic findings between groups indicate that virological persistence may precede morphological changes, underscoring the importance of long-term surveillance.
The genotype-specific pattern observed in our study warrants particular attention. HPV 16 possesses strong immune evasion capabilities, including downregulation of antigen presentation and suppression of interferon-related path Compared witways [27]. COVID-19 related disturbances such as impaired CD8⁺ T-cell responses, reduced type I/III interferon signaling, and cytokine imbalance characterized by elevated IL-6 and TNF-α may further facilitate persistence of immune evasive HPV genotypes [28]. These interactions provide a mechanistic rationale for the significant HPV 16 persistence identified in our cohort. Consistent with our findings, Akdemir et al. observed that patients with a history of COVID-19 had significantly lower clearance rates specifically for HPV 16 and 18 compared to the control group, reinforcing the hypothesis that COVID-19 may exacerbate the persistence of these high-risk genotypes [9]. However, due to the retrospective design and limited genotype-specific data beyond HPV 16 and 18, pooled analysis of other HR-HPV types was not feasible.
Metagenomic studies have reported increased viral diversity in COVID-19 patients, including concurrent HPV genotypes, though these observations are based on systemic and respiratory samples rather than cervical specimens [29]. These findings further align with broader virome-level alterations indicating that COVID-19 may disrupt antiviral homeostasis beyond a single pathogen. The similar educational and socioeconomic profiles of both groups in our cohort reduce the likelihood of confounding by social determinants of health. While COVID-19 has disproportionately affected disadvantaged populations and exacerbated HPV related disparities [30], the demographic similarity of our cohort strengthens the argument that COVID-19 may exert a direct or indirect biological effect on HR-HPV persistence, independent of social or behavioral confounders.
Although this study provides valuable preliminary evidence, several limitations should be noted. First, to date, a definitive impact of COVID-19 vaccination on the clearance or persistence of high-risk HPV has not been established in the literature. Furthermore, current scientific evidence regarding the potential impact of COVID-19 vaccination on HR-HPV clearance remains limited and indirect, with no definitive association established in the literature to date. The balanced distribution of vaccination status between our study groups ensures that this factor did not act as a confounder in the observed HR-HPV persistence rates. Second, while the retrospective design may allow for some unmeasured confounding, the statistically similar distribution of baseline characteristics across groups significantly strengthens the reliability of our findings. Third, genotype-specific interactions between COVID-19 and high-risk HPV types other than HPV 16 and 18 remain unknown, limiting broader genotype level conclusions. Fourth, metagenomic data supporting increased viral diversity in COVID-19 patients were derived from non-cervical specimens, reducing their applicability to cervical tissue. Finally, proposed mechanistic links between COVID-19 related immune dysregulation and HR-HPV persistence remain theoretical due to the absence of cervix specific immunological or longitudinal experimental data. These limitations should be considered when interpreting the findings.
Ultimately, the most significant contribution of our study is the demonstration, through a multivariable logistic regression model (Table 5.), that COVID-19 history is an independent risk factor for HR-HPV persistence (aOR: 1.81, p < 0.001). By adjusting for potential confounders such as age, smoking, and vaccination status, we have shown that the association between COVID-19 and delayed HPV clearance likely stems from direct biological mechanisms rather than demographic or lifestyle variations. These findings underscore the need for further mechanistic research to clarify how COVID-19 related immune alterations impact the cervical microenvironment.
Conclusion
In conclusion, this study demonstrates that women with a history of COVID-19 exhibit higher HR-HPV persistence, particularly for HPV 16. Crucially, after adjusting for all potential confounders, COVID-19 remained an independent risk factor, with a 1.81 times higher odds of HR-HPV persistence (aOR: 1.81). These findings suggest that COVID-19 related systemic and mucosal immune alterations may significantly influence the natural history of HR-HPV. Although cytological and colposcopic outcomes were comparable between groups, the virological divergence indicates that persistent infection may precede detectable morphological changes, necessitating enhanced long-term monitoring.
While linking mechanisms remain hypothetical, biologically plausible pathways including interferon suppression, impaired T-cell clearance, and mucosal dysregulation likely contribute to these observations. Our retrospective design and lack of cervix-specific immunological data highlight the need for prospective, longitudinal studies integrating mucosal immunoprofiling and viral kinetics.
Clinically, women with recent COVID-19 may benefit from intensified surveillance, such as closer follow-up intervals or repeat genotyping. Overall, our results support the hypothesis that COVID-19 exerts direct or indirect biological effects on HR-HPV persistence.
Acknowledgements
Not applicable.
Abbreviations
- ARDS
Acute Respiratory Distress Syndrome
- ASC-H
Atypical Squamous Cells, Cannot Exclude HSIL
- ASC-US
Atypical Squamous Cells of Undetermined Significance
- CD8⁺ T cell
Cytotoxic T lymphocyte
- CIN
Cervical Intraepithelial Neoplasia
- COVID-19
Coronavirus Disease 2019
- HIF-1α
Hypoxia-Inducible Factor 1-alpha
- HPV
Human Papillomavirus
- HR-HPV
High-Risk Human Papillomavirus
- HSIL
High-grade Squamous Intraepithelial Lesion
- ICAM-1
Intercellular Adhesion Molecule 1
- IFCPC
International Federation for Cervical Pathology and Colposcopy
- IFN-γ
Interferon-gamma
- IL-1β
Interleukin-1 beta
- IL-6
Interleukin-6
- IL-12
Interleukin-12
- IUD
Intrauterine Device
- LAST
Lower Anogenital Squamous Terminology
- LSIL
Low-grade Squamous Intraepithelial Lesion
- MHC-I
Major Histocompatibility Complex class I
- PCR
Polymerase Chain Reaction
- PD-1
Programmed Cell Death Protein 1
- RT-PCR
Reverse Transcription Polymerase Chain Reaction
- SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
- STD
Sexually Transmitted Disease
- VCAM-1
Vascular Cell Adhesion Molecule 1
Authors’ contributions
M.Ş., A.B. and A.T.T designed the study. Y.Ö.U., T.A. and O.A.analyzed and interpreted the patient data regarding the study. M.Ş., M.Ü., F.K and H.R.Y wrote the main manuscript text and prepared tables and graphs. A.T.T supervised the work. All authors review and approved the final manuscript before its submission.
Funding
No funding was received for the conduct of this study.
Data availability
The data used in this manuscript can be requested from the corresponding author.
Declarations
Ethics approval and consent to participate
The study was approved by the No. 1 Medical Research Scientific and Ethical Evaluation Board of Ankara Bilkent City Hospital (approval number: 1-25-1711). Written informed consent was obtained from all participants, and the study was conducted in accordance with the Declaration of Helsinki.
Consent for publication
Not Applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
The data used in this manuscript can be requested from the corresponding author.