Cervicitis

Etiology

The etiology of cervicitis can be broadly classified into infectious and noninfectious categories.

Infectious Cervicitis

In 30% to 50% of infectious cases, Neisseria gonorrhea or Chlamydia trachomatis are present.[2] Chlamydia cervicitis is 4 to 5 times more common than gonococcal cervicitis.[3] Other less common infectious agents that can cause cervicitis include human papillomavirus, HSV, Trichomonas vaginalis, syphilis [4], tuberculosis [5], and Mycoplasma genitalium.[6] Mycoplasma, a more recently described sexually transmitted infection, is frequently implicated in cervicitis affecting patients with HIV infection.[7] Neisseria and Chlamydia primarily infect the columnar epithelium of the endocervix, whereas HSV and trichomonas affect the squamous epithelium of the ectocervix.[8][9] 

Bacterial vaginosis (BV) has also been associated with cervicitis, whether due to BV-associated bacteria themselves or due mainly to the absence of lactobacilli in the vagina.[10] Alternatively, glycosidases and proteinases produced by the BV-associated bacteria may degrade the cervicovaginal mucus and contribute to the association of BV with cervicitis.[11]

Noninfectious Cervicitis

Over half of all cases of cervicitis are STI-negative cervicitis.[12] The noninfectious causes include mechanical or traumatic irritation and chemical irritants. Surgical instruments or foreign objects like pessaries, condoms, diaphragms, cervical caps, or tampons can cause mechanical trauma to the cervix. Chemical irritants may cause allergic reactions and include items like soaps, laundry products, spermicides, latex, vaginal douches, and contraceptive creams.[1][13] Systemic inflammatory diseases, such as lichen planus, lupus, sarcoidosis, Wegener granulomatosis [14], inflammatory bowel disease, rheumatoid arthritis, and Behcet syndrome, have rarely been implicated in cervicitis. Atrophy of the vaginal and uterine lining from the hypoestrogenic state seen with natural or surgical menopause can mimic cervicitis.[1] 

The exact etiology cannot be determined in more than half of all cases of cervicitis. Differentiating the cervical inflammation caused by mechanical or chemical irritants from that caused by infectious etiologies is not clinically possible. Taylor et al demonstrated that 61% of women enrolled in a randomized trial were negative for Chlamydia, Gonorrhea, Trichomonas, or Mycoplasma by nucleic acid amplification testing (NAAT).[15] Many such studies have proven that we cannot determine the etiological agent for cervicitis in a large proportion of cases.[10][16]

Cervicitis Risk Factors

Aside from age, additional risk factors include:

• Having a new sex partner
• Having multiple sex partners
• Having a sex partner who has concurrent sexual partners
• Having a sex partner diagnosed with an STI
• Having HIV infection 

Other behaviors associated with an increased risk of cervicitis include:

• Inconsistent condom use outside a mutually monogamous relationship
• Current or previous STIs
• Previous incarceration
• Exchanging money or drugs for sex

Epidemiology

The exact prevalence of cervicitis is difficult to determine due to the lack of a standard definition, underdiagnosis due to lack of symptoms [17], and the variation of prevalence by population. Since sexual activity is the main risk factor for infectious causes, cervicitis may affect 30% to 40% of the patients seen in STI clinics.[9][18] The highest incidence of cervicitis is seen in sexually active women aged 15 to 24.[19] 

Additional risk factors for cervicitis, aside from age, include:

• Having a new sex partner
• Having multiple sex partners
• Having a sex partner who has concurrent sexual partners
• Having a sex partner diagnosed with an STI
• Having HIV infection 

Other behaviors associated with an increased risk of cervicitis include:

• Inconsistent condom use outside a mutually monogamous relationship
• Current or previous STIs
• Previous incarceration
• Exchanging money or drugs for sex

Pathophysiology

Cervicitis, which is caused by infection, triggers an immune response. This triggers the release of proinflammatory cytokines, recruitment of neutrophils, and subsequent tissue damage, characterized by epithelial cell disruption, neutrophil infiltration, and cytokine release. This immune response disrupts the cervical mucus barrier, impairing its protective function against ascending infections. Noninfectious causes of cervicitis (eg, chemical or mechanical irritants) can also alter the local microenvironment, leading to epithelial injury and inflammation of the cervix.

Histopathology

The histopathology of cervicitis reveals inflammation of the cervical epithelium and stroma, with varying degrees of cellular infiltration, depending on the duration and cause of the condition. When viewed microscopically, cervical gram stains with >30 white blood cells (WBCs) per high power field (HPF) are labeled as cervicitis.[9] Acute cervicitis is characterized by an abundance of neutrophils within the epithelium and underlying stroma, often accompanied by epithelial erosion or ulceration.

In chronic cervicitis, lymphocytes, plasma cells, and macrophages predominate, with less neutrophilic activity. Hyperplasia of the endocervical epithelium and squamous metaplasia may occur as a reparative response to chronic irritation. Infectious agents, eg, Chlamydia trachomatis or Neisseria gonorrhea, often induce epithelial vacuolization or necrosis. The presence of mucopurulent exudate and stromal edema is also a common histologic finding. Histopathology and gram staining have no clinical utility in diagnosing women with physical findings of cervicitis because they show nonspecific inflammatory infiltrates.[20]

History and Physical

Clinical History

A thorough medical history is instrumental in the identification of risk factors for cervicitis. Both symptomatic and asymptomatic women who come in for screening should be asked about their sexual history in detail. One screening method for sexual history is the "5 Ps": partners, practices, prevention of pregnancy, protection from STIs, and previous STIs. Typical symptoms reported include purulent or mucopurulent vaginal discharge and painful or painless intermenstrual or postcoital bleeding. Cervicitis symptoms are similar to those of vaginitis, including dyspareunia and vaginal itching. An in-depth inquiry should be carried out for the associated symptoms of dysuria for concomitant urethritis and lower abdominal pain suggestive of PID or endometritis.[7]

Physical Examination

All patients with suspicion of cervicitis should undergo pelvic and vaginal examinations. Up to 80% of patients with cervicitis are asymptomatic.[4] Classical cervical examination findings consistent with cervicitis include mucopurulent discharge at the os or friability.[12] However, many patients are asymptomatic or have only minimal symptoms.[2] Therefore, a normal physical exam does not rule out an infection. Additionally, red dots on the cervix from punctate hemorrhages (ie, strawberry cervix) are suggestive of trichomonas, while vesicles and ulcers may indicate an HSV infection. Mycoplasma cervicitis is asymptomatic in many patients, which, therefore, remains undiagnosed.[21] Upper genital involvement should be suspected in the case of high fever, abdominal or adnexal tenderness, and cervical motion tenderness.

Evaluation

Once a clinical diagnosis of cervicitis has been established, an investigation of the causative organism begins. The most sensitive and specific test for the most common organisms, chlamydia and gonorrhea, is the nucleic acid amplification testing (NAAT). NAAT can be performed on endocervical cells, vaginal fluid, or urine samples.[22] If warranted, NAAT on endocervical samples may be used to test for Mycoplasma Genitalium.[23]

Patients diagnosed with infectious cervicitis should also be evaluated for vaginitis caused by trichomonas and bacterial vaginosis, as a concurrent vaginal infection may be present. When bacterial vaginosis is present with cervicitis, it may be the source of the inflammation seen with cervicitis.[24] Saline microscopy, amine whiff test, and vaginal pH may be performed to look for yeast and BV, whereas NAAT is the preferred test for trichomonas since the sensitivity of microscopy for trichomonas is only about 50%.[8] 

If these organisms are not identified, FDA-approved NAAT testing for mycoplasma may be performed. M genitalium can be found in 10% to 30% of patients with cervicitis, but it is difficult to diagnose.[24] Patients with persistent or recurrent cervicitis or PID may be tested for Mycoplasma genitalium.[23] Testing for HSV is not recommended, as its utility is unknown unless there is high clinical suspicion. U. parvum, U. urealyticum, Mycoplasma hominis, or genital culture for group B streptococcus is not routinely recommended.

A few rare cases of cervicitis caused by Group B Streptococcus (GBS) have been reported in the literature, particularly in healthy young patients. Although GBS is typically nonpathogenic, genetic and environmental factors can enable it to act as a pathogen and cause cervicitis. In patients with negative initial test results and no other identifiable cause of cervicitis, GBS should be considered as a potential diagnosis.[24]

Treatment / Management

The resolution of symptoms is dependent on the etiology of cervicitis. According to the Centers for Disease Control and Prevention (CDC) guidelines, empiric treatment is recommended for women at higher risk of STIs, which include women younger than 25, those with a new sexual partner, a partner with an STI, irregular use of condoms, or multiple concurrent sexual partners.[4] For these women, antimicrobials to cover for chlamydia and gonorrhea are given. Empiric treatment is also suggested for women with no identifiable pathogen on testing. Treatment can be deferred until the confirmatory tests are available for women at lower risk of STIs.[8][9][25] According to CDC guidelines, the recommended empiric regimen is as follows:(B3)

• Doxycycline 100 mg orally twice a day for 7 days
• For patients with a severe allergy to penicillins/cephalosporins, a recommended alternative therapy is  oral azithromycin 1 g in a single dose [8][9][25]
• For patients at risk for gonorrhea or living in an area with a high gonorrhea prevalence, concurrent treatment for gonococcal infection with a single dose of ceftriaxone 500 mg intramuscularly should be considered [26]
(B3)

The following infectious pathogens should be treated with established recommended regimens if identified by laboratory investigations:

• Chlamydia: Doxycycline 100 mg orally twice a day for 7 days is preferred
  • Alternative treatments are azithromycin 1 g as a single dose with a test of cure recommended at 4 weeks posttreatment or levofloxacin 500 mg oral daily for 7 days.
• Gonorrhea: Ceftriaxone intramuscular 500 mg intramuscular (1 g if weight over 150 kg) is preferred.
  • Doxycycline 100 mg orally twice daily for 7 days is recommended if chlamydia has not been ruled out.
  • Alternative treatments are gentamycin 240 mg intramuscular once or cefixime 800 mg orally once.[17]
• Mycoplasma
  • Antimicrobial resistance is prevalent with this pathogen.[7]
  • The CDC recommends 2-stage treatment because doxycycline alone only cures 30%.
  • If resistance testing is unavailable or resistance to azithromycin is identified, doxycycline 100 mg 2 times daily orally for 7 days is recommended, followed by moxifloxacin 400 mg once daily orally for 7 days.
  • If resistance testing is available and sensitivity to macrolides is noted, doxycycline 100 mg 2 times daily orally for 7 days is recommended, followed by azithromycin 1 g on day 1, then 500 mg on days 2 to 4.[23][17][23]
• Trichomonas: The recommended treatment is 500 mg metronidazole orally twice daily for 7 days.
• Bacterial vaginosis: The recommended treatment is 500 mg metronidazole twice daily for 7 days or intravaginal 0.75% metronidazole gel once daily for 5 days.
• Herpes simplex virus: The recommended treatment is oral 400 mg acyclovir 3 times daily for 7 to 10 days.[17]

Partner Management

Treatment of sexual partners exposed within the preceding 3 to 6 months is recommended if a sexually transmitted disease is diagnosed, and partners should abstain from sexual activity until both patient and partner have completed the 7-day therapy.[8] If single-dose therapy is used, then abstinence should be used until 7 days after therapy is complete and until symptoms have resolved. Patients with infectious cervicitis should also be tested for syphilis, hepatitis, and HIV. Expedited partner therapy (EPT) can be considered for male partners when direct evaluation is not feasible. Information should be given regarding the infection, details on transmission and prevention, and possible complications.[4] 

Persistent or Recurrent Cervicitis

For cases of persistent cervicitis after antimicrobial therapy, reevaluation is crucial to exclude reexposure, treatment failure, or other infections like M. genitalium. Testing for M. genitalium is advised when symptoms persist despite treatment with azithromycin or doxycycline and when reexposure or nonadherence is unlikely. If symptoms clearly indicate cervicitis and no infectious cause is identified, referral to a gynecologic specialist may be necessary to investigate noninfectious causes, eg, cervical dysplasia or polyps.

Management Considerations in Special Populations

Patients with HIV and cervicitis are given the same treatment as patients without HIV. Polymycrobial cervicitis is common among females who are immunocompromised.[27] Therefore, prompt treatment in these women reduces viral shedding and may reduce the risk of HIV transmission.[28] Specifically, Mycoplasma genitalium infection of the cervix increases HIV viral shedding, and the presence of M. genitalium is associated with an increase in transmission of HIV.[29](B2)

Follow-Up Care

Following treatment for chlamydia, gonorrhea, or trichomoniasis, patients should return in 3 months for repeat testing because of the high rates of reinfection with these organisms. The CDC recommends partner therapy, which should be offered if available. The legal permissibility of partner therapy varies by state.[17] If the patient has an IUD in place, clinicians should leave it in place during treatment for cervicitis. However, an IUD should not be placed until after treatment if an active cervicitis infection is diagnosed at the time of planned insertion.

Differential Diagnosis

Women with cervicitis usually have a high risk of concurrent STIs and should be evaluated for them. If testing for infection is negative, then noninfectious causes are investigated, including tests for contact dermatitis and systemic diseases like lichen planus. In postmenopausal women, genitourinary syndrome of menopause may mimic cervicitis. However, it usually presents with other symptoms, including atrophic vulvovaginitis and subsequent vaginal dryness and dyspareunia.[30]

Extragenital organ cancers have been found to metastasize to the cervix in very rare cases. Unusual causes for cervicitis in these cases have included metastatic papillary thyroid cancer, breast cancer, colorectal cancer, and stomach cancer.[31]

Prognosis

The overall prognosis of infectious causes of cervicitis is favorable. After treatment has begun, recovery is seen within a few days to a week. In the case of treatment failure and recurrent infection, the first step is to confirm the eradication of the causative organisms by repeat testing. A thorough history is taken for an assessment of reexposure (eg, new or untreated sexual partner) and noninfectious causes (eg, chemical irritants and systemic diseases). Once the infection has been ruled out, no clear options for further management have been established. Persistent antibiotic therapy is not recommended due to a lack of evidence of benefit and concerns for antibiotic resistance.[8]

The term chronic cervicitis is used for women with persistent discharge for at least 3 months despite the resolution/exclusion of infection. Usually, chronic cervicitis is caused by noninfectious sources, and no standard approach is recommended in these cases. This cervicitis of unknown etiology may respond to antibiotics, silver nitrate, or loop electrosurgical excision procedures.[32] Allergens, such as house dust mites, which are prevalent in the environment, have been shown to trigger an immune response in the uterine cervix of sensitized individuals upon exposure. This response may contribute to chronic cervicitis in some cases. However, the underlying mechanisms driving chronic cervicitis require further investigation.[33]

Complications

The main complications that result from cervicitis are potential adverse pregnancy effects, PID, and endometritis.[11] Other untoward outcomes include chronic pelvic pain, ectopic pregnancy, and infertility.[4] Ascension of infection into the upper genital tract and development of pelvic inflammatory disease is the most common complication of cervicitis. PID can cause inflammation and scarring of the fallopian tubes and can further have both acute and chronic sequelae, which include abscess formation, chronic pain and infection, ectopic pregnancy, and infertility. One study showed that with a delay of care, PID due to chlamydia can increase the risk of infertility by 3-fold.[34]

Cervicitis-associated inflammation can lead to an increased risk of both HIV transmission and susceptibility to HIV infection. Studies have also demonstrated a correlation between cervical inflammation and the development of squamous intraepithelial lesions, suggesting that cervicitis may promote the development of cervical cancer. In pregnancy, cervicitis may be linked to complications such as preterm birth, spontaneous abortion, prelabor rupture of membranes, fetal loss, intrauterine growth restriction, and postpartum endometritis.[11] Newborn conjunctivitis is the main complication, but arthritis, scalp abscesses, meningitis, endocarditis, stomatitis, and pneumonia may also result.[4]