Oral lichen planus: Pathogenesis, clinical features, and diagnosis

INTRODUCTION — Lichen planus (LP) is a chronic inflammatory disorder that affects the skin and mucous membranes. Oral LP is a mucosal subtype of LP that most commonly occurs in middle-aged adults. Oral LP may occur alone or in conjunction with other forms of LP (picture 1A-E). (See "Lichen planus", section on 'Clinical features'.)

The clinical findings of oral LP range from reticular, white plaques to mucosal erythema, erosions, and ulceration (picture 2A-E). Although reticular lesions are often asymptomatic, pain frequently accompanies the other manifestations of oral LP.

The pathogenesis, clinical manifestations, and diagnosis of oral LP will be reviewed here. Discussion of the management of oral LP and reviews of other forms of LP are provided separately. (See "Oral lichen planus: Management and prognosis" and "Lichen planus" and "Lichen planopilaris" and "Vulvar lichen planus" and "Overview of nail disorders", section on 'Lichen planus' and "Lichenoid drug eruption (drug-induced lichen planus)".)

EPIDEMIOLOGY — Epidemiologic data on oral lichen planus (LP) vary. Population-based studies performed in Asia, Europe, North America, and the Middle East have found disease prevalence rates between less than 1 percent and 3 percent [1]. Systematic reviews and meta-analyses estimate a global prevalence of 1 percent [2,3].

Oral LP most commonly occurs in middle-aged adults. Large retrospective studies from Europe and the United States indicate that the average age of patients presenting with oral LP is around 50 to 60 years [3-6]. Oral LP is rare in children [7-11].

In contrast to cutaneous LP, which is more likely to occur in males than females, females may be more likely to develop oral LP than males [1,4,5,12-15]. In a retrospective study of 723 patients with oral LP seen in an outpatient dermatology office in the United States, 75 percent of the patients were females [4]. Moreover, a retrospective study of 808 patients referred to an oral medicine department in Italy found that 60 percent of the patients were females [5]. In a systematic review and meta-analysis of observational studies, the pooled prevalence of oral LP in clinic-based studies was 1.7 percent in females and 1.1 percent in males [3].

Oral LP can occur in patients with LP involving other sites, such as the genitalia and skin. (See 'Extraoral findings' below.)

PATHOGENESIS — The pathogenic mechanisms that lead to oral lichen planus (LP) are not fully understood.

Inciting factors — A common theory on the pathogenesis of oral LP is that an immune reaction against an exogenous or endogenous antigen triggers the onset of an aberrant immune response to an intrinsic epithelial antigen and the onset of the disease. Exposures to infections, trauma, drugs, and contact allergens as well as autoimmune disorders and abnormal histamine metabolism and transport in oral keratinocytes have been proposed as potential contributing factors [16-18]. However, a causative role for any of these factors in oral LP is unconfirmed.

In particular, the relevance of hepatitis C virus in the pathogenesis of LP is uncertain. An increased prevalence of hepatitis C virus infection among patients with LP has been detected in numerous geographic locations, such as southern Europe and Japan [19,20]. Some Italian studies have identified the HLA-DR6 allele as a potential risk factor for hepatitis C virus-associated oral LP [21,22]. Other studies have not found an association [23]. The relationship between LP and the hepatitis C virus is discussed in greater detail separately. (See "Lichen planus", section on 'Hepatitis C virus'.)

Although associations between oral LP and thyroid disease, type 2 diabetes, and dyslipidemia have been reported [24-27], definitive links between oral LP and these disorders are not established.

Mechanism — Oral LP is considered to be a T cell-mediated, chronic, inflammatory reaction that results in a cytotoxic response against epithelial basal cells [16]. The inflammatory infiltrate in oral LP is primarily composed of CD8⁺ T cells. A potential pathway for CD8⁺ T cell-mediated cytotoxicity in oral LP is described below [16]:

●CD8⁺ T cells are activated by antigens presented on major histocompatibility complex (MHC) 1 molecules on keratinocytes or by encounters with activated CD4⁺ helper T cells or cytokines produced by activated CD4⁺ helper T cells.

●Activated CD8⁺ T cells induce keratinocyte apoptosis through mechanisms such as secretion of tumor necrosis factor (TNF)-alpha, secretion of granzyme B, or Fas-Fas ligand interactions.

●Activated CD8⁺ T cells produce chemokines that attract additional inflammatory cells, thereby promoting continued inflammation.

Other factors that have been proposed as contributors to oral LP include the upregulation of matrix metalloproteinases, which disrupt the epithelial basement membrane zone and allow entry of immune cells into the epidermis; the release of proinflammatory mediators and proteases by mast cells; and perturbations in the innate immune response that may involve toll-like receptors and interleukin (IL) 17 [16,28-31].

Genetic factors — Genetic factors that influence immune function may contribute to oral LP. An Italian study found a significant increase in a genetic polymorphism of the first intron of the interferon (IFN)-gamma promoter in patients with oral LP compared with controls [32]. A separate study performed in China found an association between a polymorphism in the TNF-alpha gene and risk for oral LP in a subset of patients [33].

CLINICAL MANIFESTATIONS — Oral lichen planus (LP) may be divided into clinical subtypes: reticular, erythematous (atrophic), erosive, and ulcerative [4,34,35]. More than one subtype may be present in an individual patient separately over time or concurrently. The clinical findings of oral LP are usually seen bilaterally in a symmetric distribution.

Clinical subtypes

●Reticular oral lichen planus – Reticular oral LP is the most common clinical presentation of oral LP but is often underdiagnosed as it is typically asymptomatic. Reticular oral LP is characterized by the presence of white lines, papules, or plaques in a reticulated or lacy pattern on the oral mucosa (picture 2A, 2D-E). The term "Wickham striae" is often used to describe this clinical presentation. The most common site of reticular oral LP is the posterior buccal mucosa [36]. Other common sites are the labial mucosa, tongue, and vermillion of the lower lip (picture 3).

Reticular oral LP may occur in conjunction with erythematous or erosive disease. As an example, in a retrospective study of 723 patients with oral LP, erythematous and erosive manifestations were the predominant findings in 37 and 40 percent of patients, respectively [4]. In almost all cases, reticular disease also was present. The remaining 23 percent of patients had isolated reticular oral LP.

Large, painful, hyperkeratotic plaques on the tongue are a less common manifestation [4,34].

●Erythematous (atrophic) oral lichen planus – Erythematous oral LP typically occurs in conjunction with reticular lesions. However, unlike reticular LP (which is often asymptomatic), the erythematous, erosive, and ulcerative forms of oral LP (including desquamative gingivitis) are typically symptomatic. Patients may note pain, burning, swelling, or irritation. Patients may experience mucosal bleeding in response to mild trauma, such as toothbrushing [35]. Areas of mucosal atrophy, appearing as red patches among the white papules, patches, or plaques of reticular LP, are usually present (picture 2C). Erythematous lesions are common on the gingiva, palate, floor of the mouth, and labial mucosa.

●Erosive/ulcerative oral lichen planus – Erosive oral LP is characterized by mucosal erosions (picture 2B). Erosive oral LP is usually accompanied by both reticular and erythematous lesions (picture 4) [35]. One specific presentation of erosive oral LP is desquamative gingivitis, a term which refers to widespread erosions of the gingiva (most often maxillary and mandibular labial or facial gingiva). While desquamative gingivitis is a frequent presentation of erosive oral LP, desquamative gingivitis may be seen in a variety of other inflammatory mucosal disorders, including mucous membrane pemphigoid, pemphigus vulgaris, paraneoplastic pemphigus, and allergic contact mucositis (picture 5). Around 10 percent of patients with oral LP have isolated gingival disease [37].

Ulcerative oral LP manifests as mucosal ulcers that are often covered by a pseudomembrane. Ulcerative disease is often seen on the tongue and buccal mucosa. A diagnostic biopsy for hematoxylin and eosin and immunofluorescence may differentiate oral ulcers.

Additional clinical findings include the Koebner phenomenon (the development of new lesions at sites of trauma from dental appliances or routine dental cleanings) and mucoceles (a minor salivary gland cyst that results from obstruction of the salivary gland duct) [38,39]. (See "Oral lesions", section on 'Mucoceles'.)

Lesions of erosive LP may resolve with altered pigmentation or scarring/fibrosis of the mucosal tissue. Residual postinflammatory hyperpigmentation, manifesting as brown to black pigment on the oral mucosa, has been reported in association with oral LP and may be noted after appropriate treatment of oral LP. Hyperpigmentation is most likely to occur in patients with highly pigmented skin [40]. This may be very distressing to the patient due to the cosmetic results, despite the resolution of the erythema and pain. Patients should be forewarned of this unusual, but significant, complication of treatment.

Extraoral findings — While oral LP may occur in isolation, it often occurs in conjunction with other clinical manifestations of LP. Thus, patients with oral LP should be asked about other sites of involvement, including cutaneous findings and other sites of mucosal disease. As an example, a retrospective study of 584 patients with oral LP found that cutaneous LP, nail LP, and lichen planopilaris were present in 16, 2, and 1 percent of patients, respectively, while genital involvement was detected in 77 of 399 examined females (19 percent) and in 8 of 174 males (5 percent) [41]. In another retrospective study of 274 patients with biopsy-confirmed LP, 37 of the 147 patients with oral LP (25 percent) had simultaneous cutaneous and/or genital involvement [42].

Brief descriptions of extraoral forms of LP are provided below.

Extraoral cutaneous findings

●Cutaneous lichen planus – Cutaneous LP is typically characterized by the appearance of polygonal, violaceous, pruritic, flat-topped papules on the trunk or extremities (picture 1A, 1D-E). Volar wrists and sacral back are common areas of involvement. Oral LP is common among individuals with cutaneous LP; it is estimated that more than 50 percent of individuals with cutaneous LP also have oral lesions [34,43]. (See "Lichen planus", section on 'Clinical features'.)

●Lichen planopilaris – Lichen planopilaris is a form of scarring alopecia characterized by atrophic plaques and subtle follicular hyperkeratosis (picture 1B). (See "Lichen planopilaris".)

●Nail lichen planus – Nail involvement in LP may manifest as horizontal grooves, ridges, and splitting in the nail plate (trachyonychia (picture 1C)) or with pterygium formation, which are all signs of matrix involvement (picture 6) [44]. (See "Overview of nail disorders", section on 'Lichen planus'.)

Extraoral mucosal findings

●Genital (vulvar, vaginal, or penile) lichen planus – The clinical findings of vulvar LP include erythema; erosions; and white, reticulated plaques (picture 7) [45,46]. Scarring and agglutination of tissues is a common finding and may result in functional impairment. Lesions may be asymptomatic, pruritic, or painful and may be accompanied by dysuria or dyspareunia. Annular lesions are a common manifestation of penile LP (picture 8A-B).

The terms "vulvovaginal-gingival syndrome" and "peno-gingival syndrome" describe patients who have both genital LP and gingiva-predominant oral LP [47,48]. These syndromes can be particularly recalcitrant to treatment. Anal erythema, erosions, or papules may be noted in patients with anal LP [48]. (See "Vulvar lichen planus", section on 'Clinical manifestations'.)

●Laryngeal lichen planus – Patients with laryngeal involvement may report soreness of the throat, odynophagia, and hoarseness. Lesions may be visualized on laryngoscopy [49,50].

●Esophageal lichen planus – Esophageal LP typically presents with symptoms of dysphagia and odynophagia [51]. Patients may also have symptoms of gastroesophageal reflux. Esophageal stricture formation is common, often requiring repeat esophageal dilation. The proximal esophagus is more frequently involved compared with the distal esophagus, though involvement of both can occur. In a study of 72 reported cases of esophageal LP, 89 percent of patients had oral LP as well [51].

●Ocular lichen planus – Ocular LP presents with symptoms of erythema and irritation of the palpebral and bulbar conjunctiva, which can eventually progress to a cicatrizing conjunctivitis and blindness (picture 9) [52,53].

●Nasal lichen planus – LP of the nasal mucosa usually presents with erythema and erosions; reticular findings are rare. Recurrent nosebleeds and chronic congestion may also occur.

●Otic lichen planus – Infrequently, LP involves the external auditory canal, with erosive disease and cicatricial change resulting in stenosis and conductive hearing loss. Otic LP is most often seen in conjunction with oral, vulvovaginal, and/or esophageal disease [54].

DIAGNOSIS — When a diagnosis of oral lichen planus (LP) is being considered, it is critical to perform a thorough review of systems; review of the patient history (including both medical and dental history); and review of medications (nonprescription and prescription), allergies, and functional habits. The diagnosis is confirmed by physical examination and histologic findings.

Clinical evaluation — The clinical evaluation should include a patient history that assesses the following:

●History of LP involving other body sites

●History of other skin disorders that may present with similar findings (eg, autoimmune blistering diseases)

●Presence of associated symptoms (eg, pain, burning)

●Presence of symptoms suggestive of other sites of mucosal involvement (eg, dysphagia, odynophagia, reflux, hoarseness, stridor, ocular irritation, dysuria, dyspareunia, hematuria)

●Review of medication list (both prescription and nonprescription over the counter) to evaluate for the possibility of an oral lichenoid drug eruption (may occur weeks to months after drug initiation) (table 1)

●History of dental restorations, use of dental appliances, or oral exposure to substances that may cause oral lichenoid contact eruptions (table 2)

A full examination that includes the evaluation of the mucosal and cutaneous surfaces, including the conjunctiva, nasal and otic mucosa genitalia (vulva, vagina, penis), scalp, and nails, should be performed. Thorough examination may lead to the detection of extraoral manifestations of LP that provide additional support for the diagnosis or the identification of clinical findings that suggest another diagnosis. In addition, the presence of dental restoration materials (eg, amalgam fillings, permanent or removable appliances) that could contribute to a lichenoid contact reaction should be noted. (See 'Extraoral findings' above and 'Differential diagnosis' below.)

Biopsy — Tissue biopsies of oral LP may help to confirm the diagnosis and are particularly of value for erythematous and erosive LP, which share clinical features with multiple other mucosal disorders, including oral malignancy [55].

Thus, we biopsy all patients who exhibit features of erythematous and/or erosive subtypes. Bullous lesions may also be biopsied. Biopsies to confirm oral LP are less essential in patients who present with classic reticular LP, particularly in patients in whom a diagnosis of LP has already been confirmed through biopsy of an extraoral manifestation of this disorder.

A 4 mm punch biopsy of lesional tissue that extends into the submucosa usually provides a sufficient specimen for histologic examination [56,57]. If reticular LP is present in conjunction with erythematous or erosive manifestations, biopsy of the reticular area is preferred for diagnosis of oral LP. Biopsies taken from reticular areas have intact epithelium and may be less likely to yield nonspecific findings [4]. However, erythematous or erosive lesions should be biopsied when considering possible malignancy transformation. (See "Oral lichen planus: Management and prognosis", section on 'Risk of oral squamous cell carcinoma'.)

The histologic findings of oral LP can offer strong support for the diagnosis but are not pathognomonic. Clinical correlation is required. Common histologic findings of oral LP include (picture 10A-B) [34,58]:

●Parakeratosis and slight acanthosis of the epithelium

●Saw-toothed rete ridges

●Liquefaction degeneration of the basal layer with apoptotic keratinocytes (referred to as Civatte, colloid, hyaline, or cytoid bodies)

●An amorphous band of eosinophilic material at the basement membrane

●A lichenoid (band-like), mixed, lymphohistiocytic infiltrate in the submucosa

●Wedge-shaped hypergranulosis

In cases where the clinical and histologic findings are inconclusive, direct immunofluorescence (DIF) microscopy of perilesional mucosa may be used to exclude autoimmune vesiculobullous disorders (eg, pemphigus, pemphigoid, linear immunoglobulin A [IgA] bullous dermatosis). In oral LP, DIF usually demonstrates globular deposits of immunoglobulin M (IgM) and IgA in the submucosa (cytoid bodies) along with shaggy or fibrillar deposition of fibrinogen along the basement membrane zone. Indirect immunofluorescence (IIF) has no constructive role in the evaluation of LP. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Direct immunofluorescence'.)

Oral lichenoid lesions are difficult to differentiate clinically or histopathologically. These lesions may be due to oral lichenoid contact mucositis or stomatitis, oral lichenoid drug reactions, or lichenoid tissue reactions [55].

Additional evaluation — Additional tests may be ordered based upon clinical suspicion for other conditions. The possibility of Candida infection or herpes simplex virus reactivation should be considered in patients who experience acute exacerbations of disease severity despite previously effective treatment. Erosions or ulcers that fail to resolve or exhibit atypical features should be biopsied to rule out malignancy. (See "Esophageal candidiasis in adults", section on 'Diagnosis' and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis' and "Oral lichen planus: Management and prognosis", section on 'Risk of oral squamous cell carcinoma'.)

Screening for hepatitis C virus infection in patients with LP is reviewed separately. In general, it appears reasonable to screen patients with oral LP for hepatitis C virus infection, particularly in patients from areas of high prevalence. (See "Lichen planus", section on 'Additional testing'.)

DIFFERENTIAL DIAGNOSIS — An evaluation to determine the underlying cause of red or white oral lesions should be performed in all patients who present with such lesions. The differential diagnosis of oral lichen planus (LP) is particularly broad, given the various clinical manifestations of the condition (see 'Clinical subtypes' above). Careful review of the patient history, examination findings, and biopsy results is useful for distinguishing oral LP from other disorders.

Select disorders in the differential diagnosis of oral LP are reviewed below:

●Leukoedema – Leukoedema is a common, benign finding in the oral cavity that presents as white-gray, somewhat translucent plaques on the mucosa (picture 11) [59,60]. The buccal mucosa is the most common site for involvement. Symptoms are absent, and no treatment is necessary. (See "Oral lesions", section on 'Leukoedema'.)

●Oropharyngeal candidiasis – Oropharyngeal candidiasis (also known as thrush) is a common infection that has a predilection for infants, older adults with dentures, immunosuppressed individuals, and individuals utilizing intraoral corticosteroid therapy. Patients present with white plaques or erythematous patches on the buccal mucosa, palate, tongue, or oropharynx that may be mistaken for reticular LP (picture 12A-C). The diagnosis can be made quickly by performing a potassium hydroxide (KOH) preparation. Oropharyngeal candidiasis may coexist with oral LP as a result of topical corticosteroid therapy. (See "Oropharyngeal candidiasis in adults", section on 'Diagnosis' and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation' and "Esophageal candidiasis in adults".)

●Leukoplakia – Leukoplakia is a manifestation of squamous epithelial hyperplasia that may be a precursor to oral squamous cell carcinoma. White patches or plaques develop on the oral mucosa (picture 13A-B). A biopsy of leukoplakia is indicated to rule out malignancy. (See "Oral lesions", section on 'Leukoplakia' and "Oral leukoplakia", section on 'Introduction'.)

●Oral squamous cell carcinoma – Oral squamous cell carcinoma can present as erythematous or mixed red and white patches, papules or plaques, ulcers, or exophytic masses (picture 14). A biopsy is necessary for diagnosis. (See "Oral lichen planus: Management and prognosis", section on 'Risk of oral squamous cell carcinoma' and "Oral lesions", section on 'Oral squamous cell carcinoma'.)

●Oral lichenoid drug reaction – Lichenoid drug eruptions may be caused by a variety of systemic medications (table 1) and share clinical features with oral LP (picture 15). Histologic findings of a deep mixed infiltrate with lymphocytes, plasma cells, and neutrophils (with or without eosinophils) and perivascular inflammation favor this diagnosis [34,55]. (See "Lichenoid drug eruption (drug-induced lichen planus)".)

●Oral lichenoid contact reaction (allergic contact mucositis) – Oral lichenoid contact reactions may be caused by a variety of substances (picture 16 and table 2). Mercury-containing amalgam used for dental restoration is the most common cause [34]. The clinical and histologic features of oral lichenoid contact reactions are similar to oral LP [61]. Patch testing and recognition of the proximity of an offending substance to the eruption can aid with diagnosis [55]. (See "Oral lesions", section on 'Contact stomatitis'.)

●Autoimmune blistering diseases – Mucous membrane pemphigoid, pemphigus vulgaris, and other autoimmune blistering diseases may present with oral erosions and desquamative gingivitis similar to that seen in erosive LP (picture 17). Biopsies for routine histologic examination and direct immunofluorescence (DIF) are useful for distinguishing these disorders from oral LP. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Mucosal features' and "Linear IgA bullous dermatosis", section on 'Mucosal involvement' and "Epidermolysis bullosa acquisita", section on 'Clinical manifestations' and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

●Graft-versus-host disease – Lacy, reticulated plaques or erosions that resemble oral LP may occur in chronic graft-versus-host disease (GVHD) (picture 18A-C). The histologic findings of these disorders are also similar. The patient history is useful for differentiating chronic GVHD from oral LP. Oral involvement in acute GVHD is less well characterized than chronic GVHD, but has been associated with erythematous, erosive, ulcerative, or lichenoid oral lesions [62]. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Chronic cutaneous graft-versus-host disease' and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Acute cutaneous graft-versus-host disease'.)

●Multiple mucoceles – The presence of multiple intact vesicles, particularly on the soft palate or nonattached mucosa, may occur as a result of an intense, inflammatory infiltrate that obstructs the minor salivary glands. (See "Oral lesions", section on 'Mucoceles'.)

Examples of other disorders that may present with oral white plaques include syphilis (picture 19), oral hairy leukoplakia (picture 20), oral condyloma (picture 21), and white sponge nevus (picture 22). Additional disorders in the differential diagnosis of erythematous and erosive oral LP include aphthous stomatitis (picture 23), erythroplakia (picture 24), and syphilis (picture 25).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lichen planus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Lichen planus (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Oral lichen planus (LP) is a subtype of LP that most commonly occurs in middle-aged adults. Females are more likely to develop oral LP than males. Individuals of all ethnic backgrounds may be affected. (See 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of oral LP is not fully understood but appears to involve an immune-mediated cytotoxic reaction against epithelial cells. Activated CD8⁺ T cells may play a key role. The inciting factors for oral LP are unknown. (See 'Pathogenesis' above.)

●Clinical manifestations – The clinical findings of oral LP can be divided into reticular, erythematous (atrophic), and erosive subtypes. Many patients with reticular LP also have concurrent, erythematous or erosive lesions. The buccal mucosa is the most common site for reticular oral LP. Nonspecific erythema is prominent on the gingiva. (See 'Clinical manifestations' above.)

●Extraoral findings – Oral LP may occur as the only manifestation of LP or in conjunction with other features of the disorder. Oral LP is common among individuals with cutaneous LP, and many females with oral LP have associated genital (vaginal or vulvar) involvement. (See 'Extraoral findings' above.)

●Diagnosis – The diagnosis of oral LP can usually be made based upon the review of clinical and histologic findings. Direct immunofluorescence (DIF) is helpful for ruling out autoimmune blistering diseases, which involve the mucosa in challenging cases. (See 'Diagnosis' above.)

Patients with oral LP may have involvement of other mucosal surfaces, which can result in functional limitations if untreated. Thus, the patient evaluation should include inquiries regarding the presence of ocular, nasal, laryngeal, esophageal, or anogenital symptoms. (See 'Extraoral findings' above and 'Clinical evaluation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Bethanee J Schlosser, MD, PhD, who contributed to an earlier version of this topic review.