The Centers for Disease Control and Prevention (CDC) estimates that approximately 2.5 million new cases of syphilis, chlamydia, and gonorrhea were reported in the United States in 2022[1]. Young adults 15 to 24 years of age account for nearly one-half of the reported cases [1]. The exact number of cases is difficult to ascertain, as these diseases do not always result in the affected patient seeking medical care, especially if symptoms are mild or absent. Some STIs, such as human papillomavirus (HPV), herpes simplex virus, and Trichomonas vaginalis, are not routinely reportable to the CDC [2]. Lack of access to medical care and the stigma associated with STIs are also obstacles that may prevent patients from seeking medical treatment, and disruptions in the availability of care and screening services during the COVID-19 pandemic have likely caused an increase in undiagnosed infections. Patients who are untreated remain infectious and can transmit the STI to others [1].

When cases of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), HPV, herpes simplex virus, and trichomoniasis are added to the cases of syphilis, gonorrhea, and chlamydia, the public health burden of STIs is readily apparent. In total, it is estimated that 68 million men and women in the United States have an STI on any given day [5]. The annual direct medical costs for the treatment of STIs in the United States are estimated to be $16 billion. This does not take into account the costs associated with lost productivity [5].

Gonorrhea (the result of infection with Neisseria gonorrhoeae) is the second most common reportable STI in the United States [3]. In 2022, 648,056 cases of gonorrhea were reported to the CDC, with more than half occurring in people 15 to 24 years of age [3,7]. N. gonorrhoeae is a gram-negative aerobic bacterium that thrives in a warm, moist environment. The humidity, temperature range, and pH level of the mucous membranes of the oral cavity, genitals, and perirectum make these areas ideal environments for the replication of N. gonorrhoeae and a reservoir for its transmission.

The histology of certain tissues makes them more susceptible to infection with N. gonorrhoeae. For example, the columnar epithelium that makes up the mucosal lining of the cervix and urethra and the transitional epithelium of the mucosal lining of the oropharynx and rectum are common entry points for gonococcal infection. In contrast, the stratified squamous epithelium that composes the skin and the mucosal lining of the oral cavity proper appears more resistant to N. gonorrhoeae [9].

Treatment of uncomplicated gonorrhea usually consists of a single-dose antibiotic regimen that is compatible with the patient's medical history. The CDC recommends an intramuscular (IM) dose of 500 mg ceftriaxone. Other regimens of cephalosporin (e.g., ceftizoxime, cefotaxime), while potentially safe and effective against uncomplicated urogenital and anorectal infections, have not been shown to have any advantage over ceftriaxone, and there is evidence that their effectiveness may be waning [11]. Oral azithromycin is no longer recommended due to a widespread increase in macrolide resistance [17]. The CDC currently recommends the use of ceftriaxone 500 mg IM in a single dose for persons weighing <150 kg (1g IM in a single dose for persons weighing >150 kg) for the treatment of uncomplicated gonorrhea of the pharynx [11]. Alternative treatments for pharyngeal gonorrhea are unreliable.

The classic lesion associated with the primary stage of syphilis is a chancre located at the site of inoculation. These painless lesions are firm and round and can occur on the external genitals, vagina, anus, rectum, lips, tongue, or oral mucosa. These infectious lesions may be solitary or multiple and can exhibit variance in their size. An estimated 40% to 75% of extragenital chancres occur in the mouth [24]. The chancre can appear two to three weeks after the initial exposure and may be associated with a lymphadenopathy. The surface of the chancre commonly ulcerates and forms a hemorrhagic covering that harbors a large reservoir of T. pallidum.

The secondary stage of syphilis usually develops 2 to 12 weeks after initial exposure [24]. The systemic manifestations of secondary syphilis are the result of the hematogenous dissemination of T. pallidum. Patients may experience fever, painful joints, malaise, and generalized lymphadenopathy. Mucocutaneous involvement is also common and features the development of a non-pruritic rash. The rash often develops on the palms of the hands and soles of the feet, but the symmetrical, red-brown lesions can occur anywhere in the body [24]. Oral lesions occur in approximately 30% of patients with secondary syphilis. The classic oral lesion at this stage is a grayish-white erosion with an erythematous base known as a mucous patch (Image 1). These shallow ulcerations can extend to 1 cm in diameter and usually occur bilaterally, most often involving the mobile surfaces of the oral cavity (e.g., the tongue) [25]. Extension of these lesions onto the gingiva and hard palate is rare. However, the hard palate may develop macular lesions that appear as firm, flat or minimally elevated erythematous lesions. Although the oral and cutaneous lesions that occur during secondary syphilis are more pronounced and more widespread than those of primary syphilis, they will resolve without medical intervention, again leading many patients to believe that the disease is "cured." However, syphilis will continue to progress in the absence of medical treatment.

Approximately one-third of patients who have not undergone medical treatment will advance to the tertiary stage of syphilis [25]. This stage can occur decades after the initial infection. Patients with late-stage syphilis are noninfectious, but the disease that results can be widespread, serious, and potentially fatal [21]. The characteristic lesion of tertiary syphilis is a gumma, which may appear on the skin, mucous membranes, neural tissue, bone, and/or any visceral organ. The gumma is a long-standing granulomatous lesion with a necrotic central core. Oral gummata are not common, but when they do occur, they usually involve the tongue and the palate. The necrotic core of palatal gummata can be expansive and perforate the nasal cavity or the maxillary sinus. These lesions can range in size from a few millimeters to large masses more than 1 cm in diameter. As with the oral lesions of the primary and secondary stages of syphilis, a gumma cannot be identified by visual means only. Referral for a medical evaluation and a biopsy is necessary to distinguish it from other lesions, such as squamous cell carcinoma. Dental treatment should be deferred until the identification of the lesion is ascertained. Syphilitic involvement of the tongue can manifest as an interstitial glossitis. The tongue may appear erythematous, with a loss of surface papillae and the development of a fissured and lobulated appearance.

Syphilis can be transferred from an infected mother directly to the developing fetus in utero via the placenta or via direct contact with a genital lesion during childbirth. The highest incidence of mother-to-child transmission occurs during the primary stage, with risk progressively decreasing during the advanced stages of the disease. Syphilitic involvement of the developing fetus can result in spontaneous abortion, stillbirth, and neonatal disease. Untreated syphilis in pregnant women results in infant death in up to 40% of cases [4]. Congenital syphilis can also lead to specific oral and facial manifestations in affected children, including perforations in the hard palate (Image 2) and Hutchinson triad. The triad consists of interstitial keratitis, eighth nerve deafness, and Hutchinson teeth. The dental malformation known as Hutchinson teeth is caused by an inhibition of the proper developmental function of the ameloblasts (enamel-forming cells) via an inflammatory process mediated by T. pallidum [27]. Disruption in the formation of the crowns of the teeth occurs during later development of the teeth, which spares the deciduous teeth from this anomaly [28]. This condition affects the permanent incisors, resulting in characteristic semilunar notches on their incisal edges.

HPV is a family of more than 200 genotypes, of which more than 40 types infect the mucosal epithelium [29]. Unlike gonorrhea and syphilis, HPV infection is not reportable to the CDC, and most cases are asymptomatic and subclinical. The CDC estimates that 13 million people acquire HPV infections each year in the United States and that 42 million Americans are currently infected, making it the most common STI in the country [30]. Orogenital contact is the primary means by which the HPV is transferred to the structures in and around the oral and maxillofacial complex. Approximately 90% of this viral pathogen is cleared by the immune system within two years, but the remainder can cause oral and systemic problems with a high degree of morbidity, including squamous papilloma, verruca vulgaris, condyloma acuminatum, and certain cancers [29].

Squamous papilloma is the most common benign neoplasm of oral epithelial origin. It is usually associated with HPV types 6 and 11, although HPV type 16 has occasionally been isolated from these lesions [29,30]. The lesions can occur anywhere within the oral cavity but have a predilection for the soft palate, the uvula, and the tongue. The size of squamous papilloma lesions can vary but are usually less than 1 cm in diameter. They may be attached to the underlying tissue by a movable, stalk-like base (pedunculated) or a fixed, broad base (sessile). The lesions are generally asymptomatic and usually have the same color as the contiguous oral mucosa; however, they may appear white due to keratinization of the superficial layer. The lesions cannot be diagnosed by visual means alone, so histopathologic examination is essential to rule out a malignant neoplasm. Surgical excision is the treatment of choice, and recurrence of these lesions is uncommon.

HPV types 2, 4, 6, and 40 are the primary etiologic agents for the development of verruca vulgaris, also known as the common wart [32]. Verruca vulgaris is a relatively common cutaneous lesion, but oral lesions can also occur. When these lesions develop intra-orally, they are most likely to affect keratinized tissues such as the lip, the hard palate, and the gingiva. Verruca vulgaris lesions are contagious, and their origin in and around the mouth is usually via autoinoculation (e.g., when a cutaneous wart on a finger is brought into contact with the oral or peri-oral structures). Transmission of an existing oral lesion to the genitals is infrequent but can occur through oral-genital contact.

Lesions of the oral mucosa caused by infection with HPV subtype 13 or 32 is known as focal epithelial hyperplasia or Heck disease. The lesions appear as small, single or multiple papules. They may appear anywhere in the oral cavity, especially on the labial and buccal mucosa, lower lip, and tongue, and less often on the upper lip, gingiva, and palate [46]. Removal is usually not necessary, and the lesions often resolve on their own. However, if the papules are impairing the patient's ability to eat or maintain good oral hygiene or if they are causing aesthetic concern, they may be removed via excisional biopsy or cryosurgery [46].

Patients with infectious mononucleosis develop a classic triad of symptoms: fever, pharyngitis, and lymphadenopathy. Possible oral manifestations of infectious mononucleosis include palatal petechiae, tonsillar enlargement, and pharyngitis, although these physical findings alone are not diagnostic. While other viral pathogens, such as cytomegalovirus, can cause similar symptoms, EBV has been implicated as the etiologic factor in 90% of the cases of infectious mononucleosis [48]. The diagnostic criteria for infectious mononucleosis include laboratory testing of a blood sample. In a normal blood smear, approximately 1% to 2% of the cells evaluated are large reactive lymphocytes, while these cells comprise approximately 10% to 40% of blood smears of patients with infectious mononucleosis [49]. Antibody testing may be useful in conjunction with the assessment of somatic and oral manifestations to confirm the diagnosis of infectious mononucleosis; however, the CDC recommends that the Monospot rapid latex agglutination test should no longer be used due to high numbers of false-positive and false-negative results [47,50].

Treatment of infectious mononucleosis involves palliative relief of the symptoms with analgesics and antipyretic medications, bed rest, and adequate fluid and nutritional intake. Elective dental treatment is contraindicated during the active course of the disease, and emergency dental treatment should be limited to the relief of pain and the control of acute odontogenic infections; definitive dental treatment should be deferred until the active disease has resolved. The use of amoxicillin or ampicillin is contraindicated in patients with acute infectious mononucleosis as there is an increased risk of an antibiotic-induced rash (maculopapular exanthems), which could be mistaken for an allergic reaction [51]. If an antibiotic is required to treat an odontogenic infection while a patient is still experiencing symptoms of infectious mononucleosis, an alternate antibiotic compatible with the patient's medical history should be used.

Aside from the oral lesions, primary HSV-1 infection may present with cervical lymphadenopathy, malaise, fever, and irritability. While the initial infection is self-limited in immunocompetent patients and resolves within two weeks, the virus is not eliminated from the body. Instead, the virus migrates to the trigeminal ganglion, where it remains in a state of latency. The reactivation of HSV-1 (recurrent herpes labialis) occurs secondary to psychologic or emotional stress, overexposure to sunlight, illness, injury, or immunosuppression. Prior to an outbreak, most patients experience a prodromal sensation of itching, burning, or tightness of the skin when viral replication causes the death of the target host cell followed by ballooning degeneration of the affected host cells. HSV-1 infections are not strictly considered an STI, though the virus can be transmitted through close contact with saliva (e.g., kissing) and sexual activity (e.g., oral sex) during prodrome and outbreaks.

Chlamydia is an STI caused by the bacterium Chlamydia trachomatis. It is the most commonly reported STI in the United States, with more than 1.6 million cases reported to the CDC in 2022 [3]. In addition, many cases of chlamydia go unreported and undetected due to the lack of symptoms. When symptoms are present, they may develop many weeks after the initial infection. Chlamydial infections in women can develop in the cervix and/or the urethra, with associated vaginal discharge or pain during urination. Men may experience a discharge from the urethra, a burning sensation during urination, or a painful swelling in one or both testicles (epididymitis). A urine sample or a swab of fluid from the penis or the vagina is taken to definitively diagnose a chlamydial infection. Without treatment, chlamydial infection can spread to the uterus and the fallopian tubes, leading to pelvic inflammatory disease, endometriosis, and an increased risk of premature births and infertility [56]. Occasionally, untreated chlamydial infections in men can cause the development of reactive arthritis (Reiter syndrome), which features inflammation of the joints, the urethra, and the eyes [57].

The diagnosis and staging of HIV and AIDS is based on the CDC's case definition for HIV infection [61]. This system uses a combination of laboratory evidence of HIV infection, CD4+ cell count, and the presence of AIDS-defining conditions to assign stages to the infection. Stage 3 HIV infection, designated as AIDS, is defined by laboratory confirmation of HIV infection and a CD4+ T-lymphocyte count less than 200 cells/mcL or less than 14%. At this stage, opportunistic infections are present and can have a high degree of morbidity and even mortality. The most common oral manifestations of AIDS include:

Over time, periodontal pathology in patients with HIV/AIDS progresses to necrotizing ulcerative gingivitis. This condition features the rapid destruction of the gingival tissues, with necrosis of the interdental papilla (Image 6). Mild bleeding is present in the involved tissues. The progression from gingivitis to periodontal disease in patients with healthy immune systems is usually a slow process, but in those with AIDS, progression from necrotizing ulcerative gingivitis to necrotizing ulcerative periodontitis is often rapid and aggressive. Necrotizing ulcerative periodontitis is typified by destruction of the supporting alveolar bone, causing moderate-to-severe pain. Occasionally, the bacteria can extend into the alveolar and buccal mucosa and cause a necrotizing stomatitis [12].

Kaposi sarcoma is the most common malignant disease in patients with HIV/AIDS [13]. It is caused by infection with human herpesvirus-8, also known as Kaposi sarcoma-associated herpesvirus. Although cutaneous lesions are more common, oral lesions of Kaposi sarcoma occur in approximately 50% of patients. When these lesions appear in the oral cavity, the most common sites are the hard palate, the gingiva, and the tongue. The lesions of Kaposi sarcoma do not blanch upon compression and are generally asymptomatic until they enlarge and interfere with normal function or become traumatized or ulcerated. These singular or nodular lesions can be a combination of blue, red, and purple and are often elevated from the tissue surface. Biopsy is required to confirm diagnosis.