Sexually Transmitted Diseases

0025-712,5/90 $0.00

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Vaginal Infections in Adult Women

J. D. Sobel, MD*

Vaginal infections in adult women are among the most common in clinical practice. Vaginal discharge is among the 25 most common reasons for consulting physicians in private office practice in the United States. 136 Vaginitis was found in 28% of women attending sexually transmitted diseases (STD) clinics in one survey,25 and in still others has been described in approximately one third of women attending STD clinics. Vaginitis is the most frequent complaint seen in self-referred cases in gynecologic clinics. 72 Approximately 40% of women with vaginal symptoms will have some type of vaginitis. 44 The three common clinical entities of vulvovaginal candidiasis (VVC) , trichomoniasis, and bacterial vaginosis (BV) account for over 90% of the cases of vaginitis. A small number of remaining cases are due to a variety of poorly defined entities that are listed in Table 1. In the United States, cases of Trichomonas vaginitis declined slowly from 1966 to 1987, and over this same period, vaginitis due to other causes increased dramatically from less than 3 million per year to nearly 10 million per year. Several recent studies indicate that even in the varied clinical setting of STD clinics, student health clinics, and private practice, bacterial vaginosis is the most common form of vaginal infection (30% to 35%), followed closely by VVC (20% to 25%), and, finally, trichomoniasis, which occurs significantly less frequently. 7.45 68 In 15% to 20% of patients, a mixed infection caused by two or more causative agents will be present. Trichomoniasis accounts for approximately 10% of cases, and the remainder are caused by the less frequent mechanisms listed in Table 1. N one of the epidemiologic studies have defined the prevalence of asymptomatic infection or mixed infections; hence, the true prevalence of vaginitis remains considerably underestimated. 'Professor of Medicine and Chief, Division of Infectious Diseases, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan

Medical Clinics of North America-Vo\. 74, No. 6, November 1990

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Table 1. Causes of Vaginitis in Adult Women Bacterial vaginosis (40%-50%) Vulvovaginal candidiasis (20%-25%) Trichomonas vaginitis (15%-20%) Miscellaneous Atrc,phic vaginitis Postpuerperal atrophic vaginitis Foreign body Ulcerative vaginitis associated with Staphylococcus aureus and toxic shock syndrome Desquamative inflammatory vaginitis (erosive lichen planus) Streptococcal vaginitis (beta-hemolytic) Collagen vascular disease. Beh"et syndrome. pemphigus. and so forth Idiopathic

DIFFERENTIAL DIAGNOSIS AND APPROACH TO WOMEN WITH ASYMPTOMATIC AND SYMPTOMATIC VAGINITIS

Symptoms related to vaginitis include vaginal discharge, pruritus, and a variety of manifestations of inflammation of the vagina, introitus, and vulva, depending upon the extent and severity of the inflammatory reaction. These symptoms include soreness, irritation, discomfort, dysuria, and dyspareunia. Primary care physicians frequently fail to inquire about the association of these symptoms with sexual relations and thus lose valuable insight into the chronicity and cause of symptoms. Coitus constitutes a nonspecific but useful "stress test" in establishing the presence, site, and extent of mild vaginal and introital inflammation. Vaginal discharge can also be caused by mucopurulent cervicitis; therefore, it is essential to evaluate the cervix in all patients with vulvovaginal complaints. Mucopurulent cervicitis caused by Chlamydia trachomatis and Neisseria gonorrhoeae is characterized by a yellow endocervical exudate and confirmed by the simple identification of yellow exudate on a white cotton-tipped swab specimen of endocervical secretions. The cervix is friable, edematous, and bleeds easily on physical contact. Mucopurulent cervicitis must be differentiated from cervicitis caused by herpes simplex virus (HSV), from vaginitis, and from simple ectropion of the cervix (ectopy). The latter is a normal finding without a mucopurulent exudate, although ectopy is associated with increased numbers of polymorphonuclear leukocytes (PMNs) in the vaginal discharge as determined by microscopy. A thorough history is obtained, including detailed description and duration of symptoms; sexual history, including recent change of sexual partner; past therapy; and response to therapy. Specific details include a description of the vaginal discharge-its color and consistency and, most importantly, the presence or absence of an offensive odor. Although the odor associated with VVC is absent, minimal, or nonoffensive, most women will describe it as unpleasant. However, women with BV or trichomoniasis have little hesitation in volunteering the offensive, embarrassing nature of the discharge, which characteristically increases in severity immediately following unprotected coitus. Physical examination includes careful inspection and palpation (with a cotton swab) of the vulva as well as the vaginal vestibule. The latter area is

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frequently ignored; as a result, the diagnosis of focal vulvitis, or vestibulitis, is frequently missed. Inspection with a vaginal speculum includes examination of the vaginal mucosa for erythema, petechiae, ulceration, edema, atrophy, and adherent discharge. The pooled vaginal secretions are also assessed with regard to color, consistency, and volume. Finally, as mentioned previously, no vaginal examination is complete without evaluation of the cervix. After inspection, the middle third of the vagina is swabbed to obtain a valid specimen of secretions suitable for rapid pH estimation. Thereafter, swabs of mucosa secretions are obtained for saline and 10% potassium hydroxide (KOH) microscopic examination. Bacterial and fungal cultures are not required on a routine basis and are only indicated in selected cases. An additional swab is obtained for the immediate performance of a 10% KOH amine elaboration test (whiff). In the presence of suspected cervicitis, cervical specimens should also be obtained for identification of C. trachomatis, N. gonorrhoeae, and HSV. The saline microscopy examination has many purposes, including identification of clue cells, trichomonads, and yeast or hyphae, and estimation of whether PMNs are present and whether they are increased. Most investigators consider a ratio of PMN s to epithelial cells of one or less as within normal limits. Likewise, exfoliated vaginal epithelial cells are studied in order to identifY an increase in basal or parabasal cells, which may indicate a relative estrogen deficiency or reflect a "desquamating" inflammatory reaction in the wall of the vagina. The final useful component of saline microscopy includes examination of the vaginal flora, particularly as evident in the intercellular spaces. The normal appearance of the vaginal flora consists of rodlike organisms that are unclumped and in moderate numbers. This description is preserved in VVC, but it dramatically changes in both trichomoniasis and BV, in which the normal flora is lost and replaced by larger numbers of coccobacillary that are often clumped microorganisms. Gram stain examination of vaginal secretions, although a useful permanent research and epidemiologic tool, is not required on a routine basis and adds little to a good saline wet-mount examination. Given the low sensitivity of the saline examination in detecting Candida species, a 10% KOH microscopic examination should always be performed, even if the saline wet mount identifies other causes of vaginitis, because mixed infections are common. In the majority of symptomatic women, a thorough history, careful physical examination, and the aforementioned rapid laboratory tests should provide an immediate and reliable clinical diagnosis. In a small percentage of women, the diagnosis will be deferred pending the availability within a few days of results of additional studies, especially cultures. Each of the previously described tests has a variable sensitivity and specificity depending on the specific clinical entity in question, and each test is discussed later. Nevertheless, as outlined in Table 2, within a few minutes an accurate, reliable diagnosis can be reached utilizing the guidelines outlined. In spite of the simplicity of the laboratory tests, relatively few practitioners perform a thorough evaluation, although the time involved is minimal. Practitioners prefer to rely on the clinical response to empirical

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Table 2. Diagnostic Features of Vaginitis in Adult Women NOR\1AL

CA:VUIDA

BACTERIAL

TRICHOMONAS

VAGINITIS

VAGINOSIS

VAGINITIS

None or physiologic leukorrhea

Vulvar pruritus,

Variable, scant to moderate Clear or white Floccular nonhomogeneous

Scant to moderate White Clumped but variable

"Bubbles " Appearance of vulva and vagina

Absent Normal

pH of vaginal fluid Amine test (10% KOH) Saline microscopy

50 J.Lg/mL) indicate clinically significant resistance. Increased doses of metronidazole and longer duration of therapy are necessary to cure these refractory patients. These patients should be given maximal

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tolerated doses of daily oral metronidazole for 10 to 14 days. In rare cases, high-dose intravenous metronidazole therapy (as high as 2 to 4 g of metronidazole daily) may be necessary with careful monitoring for drug toxicity. 36 . Most patients taking metronidazole complain of an unpleasant or metallic taste. Other common side effects include nausea (10%), transient neutropenia (7.5%), and a disulfiram-like effect when alcohol is ingested. Caution should be used when 5-nitroimidazoles are used in patients taking warfarin. 51 Long-term and high-dose therapy increases the risk of neutropenia and peripheral neuropathy. In experimental studies metronidazole has been shown to be mutagenic for certain bacteria, indicating a carcinogenic potential,51 although cohort studies have not established an increase in cancer morbidity. Thus, the risk to humans of short-term, low-dose metronidazole treatment is extremely small. Superinfection with Candida species resulting in symptomatic yeast vaginitis is relatively uncommon, (16%) although a recent study of metronidazole use in bacterial vaginosis indicates much higher rates of Candida superinfection.ll2 Treatment of trichomoniasis in pregnancy is unsatisfactory.1l6 Metronidazole readily crosses the placenta; hence, it is prudent to avoid its use in the first trimester of pregnancy because of concern for teratogenicity. The drug can be administered during the second and third trimesters, however. 1l8 Accordingly, there is little to offer the severely symptomatic patient in early pregnancy other than the pallliative use of vinegar douches and sitz baths. Topical clotrimazole and Betadine jelly may offer some benefit, although sound evidence for efficacy is lacking. BACTERIAL VAGINOSIS Bacterial vaginosis is the most prevalent cause of vaginal infection in women of childbearing age. Previously called nonspecific vaginitis, the entity was formerly diagnosed by a process of exclusion. Bacterial vaginosis is anything but nonspecific, and diagnostic criteria are no longer negative. Historically, Curtis in 1911 30 and subsequently Schroder in the 1920s 123 recognized an entity in women characterized by a white discharge that they associated with a shift in vaginal flora from predominantly Lactobacillus to one dominated by anaerobes. The association of Gardnerella vaginalis with nonspecific vaginitis was first reported by Gardner and Dukes in 19555°; however, these authors ignored the potential role of organisms other than G. vaginalis. The term nonspecific vaginitis has been replaced by the term bacterial vaginosis to describe a specific problem characterized by the overgrowth of several species of facultative anaerobic bacteria and genital mycoplasma. As vaginal inflammation is not a feature of this infection, the term vaginosis appears better suited than vaginitis. Epidemiology The frequency of symptomatic and asymptomatic BV is a reflection of the population studied. Bacterial vaginosis was diagnosed in 17% to 19% of Women seeking gynecologic care in family practice or student health care

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settings. 4 • 7 The prevalence increases considerably in symptomatic women in STD clinics, reaching 24% to 37%.40 Bacterial vaginosis has been observed in 16% to 29% of pregnant women 56 ; the lowest figures have been described among private patients and the highest prevalence in STD and university clinics. Gardnerella vaginalis has been found in 10% to 31% of virgin adolescent girls, 19 but it is still found significantly more frequently among sexually active women, reaching a prevalence in some at risk populations of 50% to 60%.

Evaluation of epidemiologic factors has not revealed clues in the etiology of BV. Antibiotic use, age of menarche, catamenial use, and frequency of intercourse have not been associated with BV. Use of the intrauterine device (IUD) was found to be more common in women with BV,4 although the mechanism by which the IUD increases the risk of BV is unknown. Pathogenesis Bacterial vaginosis is the result of massive overgrowth of mixed flora, including peptostreptococci, Bacteroides species, G. vaginalis, Mobiluncus species, and genital mycoplasmas. There is little inflammation, and the disorder represents a disturbance of the vaginal microbial ecosystem rather than a true infection of tissues. The overgrowth of mixed flora is associated with a loss of the normal Lactobacillus-dominated vaginal flora. It is apparent that no single recognized bacterial species is responsible for bacterial vaginosis. Experimental studies in human volunteers29 and animal studies indicate that inoculation of the vagina with individual species of bacteria associated with BV, e.g., G. vaginalis, rarely result in BV. 29 • 50 In primate studies, vaginal inoculation with both G. vaginalis and Mobiluncus resulted in vaginal discharge in two monkeys.87 These studies support the concept of introduction of a group or complex of organisms, possibly via sexual intercourse, that act synergistically to induce BV. The role of sexual transmission, however, remains extremely controversial. In support of the role of sexual transmission, in addition to the aforementioned experimental studies, is the higher prevalence of BV among more sexually active young women than among sexually inexperienced women. 4 Not all studies reached the same conclusion, with HoIst reporting that women with BV did not have more sexual partners than normal women. 63 In favor of sexual transmission has been the observation that BV-associated microorganisms are more frequently isolated from the urethras of male partners with BV.50. 57, 63. !l0 The cause for the massive overgrowth of anaerobes, Gardnerella, Mycoplasma, and Mobiluncus species, is unknown. Theories include increased substrate availability, increased pH, and loss of the restraining effects of the normal dominant Lactobacillus flora. Skavin l23a reported inhibition of Gardnerella, Mobiluncus, and Bacteroides species in vitro by vaginal lactobacilli. Moreover, Eschenbach 42 recently reported that whereas normal women are colonized by H 2 0 2 -producing strains of lactobacilli, women with BV not only have reduced overall population numbers of lactobacilli but species present lack the ability to produce H 2 0 2 • 42 The H 2 0 2

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produced by lactobacilli may inhibit the pathogens associated with BY either directly by the toxicity of H 2 0 2 or as a result of the production of H 2 0 2 -halide complex in the presence of natural cervical peroxidase. Accompanying the bacterial overgrowth in BY is the increased production of amines by anaerobes facilitated by microbial decarboxylases. Amines in the presence of increased vaginal pH volatilize to produce the typical abnormal fishy odor, which is also produced when 10% KOH is added to vaginal secretions. The aromatic amines responsible for the characteristic odor were originally thought to be putrescine and cadaverine; recently, however, trimethylamine has been suggested as the dominant abnormal amine in BY.16 It is likely that bacterial polyamines produced together with the organic acids found in the vagina in BY (acetic and succinic acid) are cytotoxic, resulting in exfoliation of vaginal epithelial cells, which creates the vaginal discharge. Gardnerella vaginalis attaches avidly to exfoliated epithelial cells, especially at the alkaline pH found in BY. The adherent Gardnerella result in the formation of the pathognomonic clue cells. 27 Clinical Features

Up to 50% of women with bacterial vaginosis may be asymptomatic. The cardinal symptom is that of vaginal malodor, often described as fishy, that often appears after unprotected coitus. An abnormal vaginal discharge is usually described that is infrequently profuse. Pruritus, dysuria, abdominal pain, and dyspareunia are not manifestations of BY. Examination reveals a non viscous grayish white adherent discharge that is often visible on the labia and introital area. Apart from the discharge, no other abnormalities are apparent on examination. Until recently, BY has been considered to be largely of nuisance value only. New epidemiologic observations, however, suggest that a different perspective is justified, especially in relation to asymptomatic BY. Recently, BY-associated organisms have been isolated in amniotic fluid infection, 52 chorioamnionitis,58 postpartum endometritis, and bacteremia. 121 Gravett53 demonstrated that BY in pregnancy was significantly associated with preterm premature rupture of membranes, a finding subsequently confirmed by other investigators. 58, 88 In nonpregnant women, an association between asymptomatic BY and polymicrobial upper genital tract infection, including endometritis and salpingitis, has been suggested. 40 Diagnosis As with all forms of vaginitis, signs and symptoms are unreliable in the diagnosis of BY. The clinical diagnosis can be reliably made in the presence of three or more of the following four objective criteria: (1) adherent white non floccular homogeneous discharge; (2) positive amine test, with release of fishy odor upon addition of 10% KOH to vaginal secretions; (3) vaginal pH greater than 4.5; and (4) presence of clue cells on light microscopy. These clinical signs are simple, reliable, and easy to perform. Of the cardinal clinical signs, the abnormal discharge has the least specificity. The presence of clue cells is the single most reliable predictor of BY. 40, 50, 57 Clue cells are exfoliated vaginal squamous epithelial cells covered with G. vaginalis, which give the cells a granular or stippled

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appearance with a characteristic loss of clear cell borders. At least 20% of observed epithelial cells should be clue cells in order to be of diagnostic significance. Occasionally, one can demonstrate clue cells consisting exclusively of curved gram-negative rods belonging to Mobiluncus species. The offensive fishy odor may be apparent during the physical examination or may only become apparent during the amine test. Several investigators consider the positive amine test the least sensitive of the four clinical tests,40. 57 especially when compared with the Gram stain. Of the various signs, the vaginal fluid pH has the greatest sensitivity but the lowest specificity. More recently, Eschenbach 40 has suggested that a pH greater than 4.7 increases the specificity of vaginal fluid pH measurement. 40 The wet-mount examination is critical not only because it allows detection of clue cells and exclusion of Trichomonas but because the diagnosis of BV is supported by (1) the absence of PMNs and (2) the characteristic appearance of the background bacterial flora with the dominance of the coccobacillary organisms. Similar information may also be obtained by performing Gram stains. The latter test has a sensitivity of 93% and a specificity of 70%. 134 Although several tests have been developed based upon metabolic products of bacteria involved in BV, they have little role in the routine diagnosis of BV. These include detection of increased concentrations of succinic and acetic acid in vaginal secretions with corresponding decreased vaginal lactic acid and resultant altered succinic lactic acid ratio.IJ3 Similarly, measurement of vaginal polyamines, putrescine, cadaverine, and trimethylamine,26 which are increased in BV, remains a research tool, as does the proline aminopeptidase test. 138 Finally, although cultures for C. vaginalis will be positive in almost all cases of BV, one may detect C. vaginalis in 50% to 60% of women who fail to meet the diagnostic criteria for BV.40 Accordingly, vaginal culture has no part in the diagnosis ofBV. Treatment

Although many regimens were advocated and used prior to 1979, none of the oral systemic or topical agents were particularly effective or shown in controlled studies to be superior to placebo. Poor efficacy has been observed with triple-sulfa creams,86. 110 erythromycin, tetracycline,IIO acetic acid gel, and povidone-iodine vaginal douches. Moderate cure rates have been obtained with ampicillin (mean 66%) and amoxicillin. It has been suggested that the limitations of ampicillin are due to beta-lactamases produced by vaginal Bacteroides species; however, no convincing improvement in results has been seen using beta-lactamase inhibitors such as clavulanic acid in combination with amoxicillin. The foundation for successful therapy remains oral metronidazole, as confirmed in numerous studies. 11, 41, 86. 110. 136 Most studies using multiple divided-dose regimens of800 to 1200 mg/day for 1 week achieved immediate clinical cure rates in excess of 90% and approximately 80% at 4 weeks. Although single-dose therapy with 2 g of metronidazole achieves comparable immediate clinical response rates, higher recurrence rates have been reported. 41 , 136 The beneficial effect of metronidazole results predominantly from its antianaerobic activity and because C. vaginalis is susceptible to

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the hydroxymetabolites of metronidazole. Although Mycoplasma hominis is resistant to metronidazole, the organism is usually not detected at followup visits of successfully treated patients. Similarly, Mobiluncus curlisii is resistant to metronidazole but usually disappears following therapy. Several authors have recently reported highly successful therapy of BY with topical and oral clindamycin. 54 , 59 Clindamycin, used as a 2% cream or suppository over 7 days, has excellent anaerobic activity as well as moderate activity against C. vaginalis and M. hominis. Although additional studies are still in progress, clindamycin offers the first effective alternative to metronidazole, especially in pregnancy and in women who are allergic to or cannot tolerate metronidazole. In the past, it was not customary to treat asymptomatic BY, especially because patients often improved spontaneously over a period of months. 19 If BY has the potential to cause upper tract disease, especially in pregnancy, then a change in policy will be justified, but only when the results of recent epidemiologic studies are confirmed and when prospective intervention studies show that treatment of BY is safe and prevents premature rupture of membranes, prematurity, and postpartum infectious morbidity. After the first trimester, symptomatic BY is usually treated with metronidazole because currently no experience in this setting with clindamycin has been obtained. There is no good evidence that topical vaginal yogurt or H 20 z douche is an effective therapy for BY. The issue of treating male sexual partners remains controversial in spite of indirect evidence of sexual transmission. Unfortunately, no study to date has documented reduced recurrence rates of BY in women whose partners have been treated with a variety of regimens, including metronidazole. Accordingly, most clinicians do not routinely treat male partners. 1.38 Following successful clinical therapy with 7 days of metronidazole, approximately 30% of initially responding patients have recurrence of identical signs and symptoms within 3 months. 11 Hillier and Holmes 57 observed recurrence rates in up to 80% of patients within 9 months. The reasons for recurrence are unclear, but clinicians have traditionally blamed exogenous reinfection, probably by the sexual route, as the most likely explanation. More recently, Cook et aJ28 presented convincing evidence that relapse was due to failure to correct vaginal ecologic disturbance rather than reinfection. In this study, BY-associated organisms appeared to persist often in lower numbers. Another possible cause for relapse is the failure to establish a normal Lactobacillus-dominant flora following therapy. YULYOYAGIN AL CANDIDIASIS Epidemiology There are no reliable figures defining the incidence of YYC in the United States, mainly because this common clinical entity is not reportable. Statistical data in Great Britain reveal a sharp increase in the incidence of female YYC during the period 1975 to 1984. 5 In the United States, Candida is now the second most common cause of vaginal infections. 25

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Hurley 69 estimated that 75% of women will experience at least one episode of VVC during their childbearing period 69 and approximately 40% to 50% of these will experience a second attack. 70 A small subpopulation of women of undetermined magnitude, probably less than 5% of the adult female population, suffers from repeated, recurrent, often intractable episodes of Candida vaginitis. Point-prevalence studies indicate that Candida may be isolated from the genital tract of approximately 20% of asymptomatic, healthy women of childbearing age. 37 The natural history of asymptomatic colonization is unknown, although both animal and limited human studies suggest that vaginal carriage may continue for several months and perhaps years. Several factors are associated with increased rates of asymptomatic vaginal colonization with Candida (Table 4), including pregnancy (30% to 40%), use of high-estrogen content oral contraceptives, uncontrolled diabetes mellitus, and women frequenting STD clinics. 106 The rarity of Candida isolation in premenarchal women and the lower prevalence of Candida vaginitis after menopause emphasize the hormonal dependence of the infection. Pathogenesis

The Organism Between 85% and 90% of yeasts isolated from the vagina are Candida albicans strains. 95 The remainder are due to non-albicans Candida species, the commonest of which are Torulopsis glabrata and C. tropicalis. 65 Nonalbicans Candida species are capable of inducing vaginitis, and are often more resistant to conventional therapy. Although more than 200 strains of C. albicans have been identified by typing, there is no evidence of strain tropism selecting for strains with a predilection to colonize the vagina or to cause vaginitis. 102. 103 For Candida to colonize the vaginal mucosa, they must first adhere to the vaginal epithelial cells. Candida albicans adheres in significantly higher numbers to vaginal epithelial cells than do C. tropicalis, C. krusei, and C. pseudotropicalis. 75 This may explain the relative infrequency of the latter strains in vaginitis. There is considerable person-to-person variation in terms of vaginal cell receptivity to Candida organisms in adherence assays. 126 Nevertheless, vaginal cells from women with recurrent VVC do not show increased cell avidity or affinity kinetics for Candida. 140 Preliminary studies by Krivan using radiolabeled fungi and autoradiography suggest that Candida recognized at least terminal Gal f31-4Glc sequences in epithelial cell Table 4. Factors Associated with Increased Asymptomatic Vaginal Colonization with Candida and Candida Vaginitis* Pregnancy Uncontrolled diabetes mellitus High-estrogen-containing oral contraceptives Corticosteroid therapy Tight-fitting synthetic underclothing Antimicrobial therapy (oral, parenteral, or topical) *Vaginitis only.

Intrauterine device Increased frequency of coitus* "Candy binge"* Idiopathic Women frequenting STD clinics

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membrane glycolipids as its specific receptor,80 and the yeast adhesin appears to reside with the surface mannoprotein. Germination of Candida enhances colonization 126 and facilitates tissue invasion. Factors that enhance or facilitate germination tend to precipitate symptomatic vaginitis (e. g., estrogen therapy, pregnancy), whereas measures that inhibit germination (e. g., antibiotic elimination of bacterial flora) may prevent acute vaginitis in women who are asymptomatic carriers of yeast. 128 Little is known regarding the role of Candida proteolytic enzymes, toxins, and phospholipase in determining the virulence of the organisms. Slutsky et aP24 reported high-frequency heritable switching of colony morphology of Candida grown on amino acid-rich agar in vitro at 240C. 124 The variant phenotypes represent, among other things, a varying capacity to spontaneously form mycelia. Although there is as yet no evidence that phenotypic switching occurs in vivo at 37°C, it provides an attractive hypothesis for the possibility of spontaneous in vivo transformation from asymptomatic colonization to symptomatic vaginitis. Candida organisms gain access to the vaginal lumen and secretions predominantly from the adjacent perianal area. This is borne out by several epidemiologic9 . 70 and typing studies. 9g Candida-associated vaginitis is seen predominantly in women of childbearing age, and only in the minority of cases can a precipitating factor be identified to explain the transformation from asymptomatic carriage to symptomatic vaginitis in individual patients (see Table 4). Although Hurley 70 reported that C. albicans was never a commensal in the vagina and always a pathogen, other investigators have not corroborated this view and have demonstrated that many women carry C. albicans in the vagina without subjective symptomatology, often with low Candida concentration or titer. Host Factors. During pregnancy, the vagina is more susceptible to vaginal infection, resulting in both a higher incidence of vaginal colonization and vaginitis attack rate,12 and lower cure rates. The clinical attack rate is maximally increased in the third trimester, and symptomatic recurrences also are more common throughout pregnancy. 12. 95 It is generally thought that, by providing a higher glycogen content in the vaginal environment, the high levels of reproductive hormones provide an excellent carbon source for Candida growth and germination. 90 A more complex mechanism is likely, in that estrogens enhance vaginal epithelial cell avidity for Candida adherence and a yeast cytosol receptor or binding system for female reproductive hormones has been documented. III These hormones also enhance yeast mycelial formation. 76. 77, III Several studies have shown increased vaginal colonization rates with Candida following high estrogen-content oral contraceptive use. 31 Recent studies utilizing low estrogen-content oral contraceptives have not found an increase in Candida vaginitis. 31 Vaginal colonization with Candida is more frequent in diabetic women, and uncontrolled diabetes predisposes to symptomatic vaginitis. Glucose tolerance tests have been recommended in women with recurrent WC; however, the yield is low. Testing is not justified in otherwise healthy premenopausal women. Symptomatic VVC is frequently observed during or following courses

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of systemic antibiotics. Although no antimicrobial agent is free of this complication, the broad-spectrum antibiotics such as tetracycline, ampicillin, and cephalosporin are mainly responsible 21 , 107 and are thought to act by eliminating the normal protective vaginal bacterial flora. The natural flora provides a colonization-resistant mechanism and prevents Candida germination. Lactobacillus species have been singled out as providing this protective function. Auger and Joly6 found reduced titers of Lactobacillus species in vaginal cultures obtained from women with symptomatic vaginitis. Lactobacillus-Candida interaction includes competition for nutrients, stearic interference of Candida adherence, 126 and elaboration of bacteriocins that inhibit yeast proliferation and germination. Other factors that contribute to increased incidence of Candida vaginitis are the use of tight, poorly ventilated clothing and nylon underclothing, which increase perineal moisture and temperature. Chemical contact, local allergy, or hypersensitivity reactions may also predispose to symptomatic vaginitis. There is no evidence confirming that iron deficiency predisposes to infection. 33 During the phase of asymptomatic carriage, Candida organisms exist predominantly in the nonfilamentous form and in relatively low numbers (Table 5). Under these circumstances, there exists a delicate equilibrium between Candida, the resident protective bacterial flora, and other local vaginal defense mechanisms. Symptomatic vaginitis develops in the presence of factors that enhance Candida virulence factors (see Table 5) or as a result of loss of local defense mechanisms. Candida albicans may cause cell damage and the resulting inflammation by direct hyphae invasion of epithelial tissue. It is possible that proteases and other hydrolytic enzymes facilitate cell penetration with resultant inflammation, mucosal swelling, erythema, and exfoliation of vaginal epithelial cells. The characteristic nonhomogeneous vaginal discharge consists of a conglomerate of hyphae elements and exfoliated nonviable epithelial cells with few PMNs. Candida may also induce symptoms by hypersensitivity or allergic reaction, particularly in women with idiopathic recurrent VVC. Oral and vaginal thrush correlate well with depressed cell-mediated immunity in debilitated or immunosuppressed patients. This is particularly evident in patients with chronic mucocutaneous candidiasis and AIDS. Accordingly, one might anticipate that lymphocytes similarly contribute to normal vaginal defense mechanisms, preventing mucosal invasion by Candida.62, 137 Table 5. Comparison of Asymptomatic Vaginal Colonization and Symptomatic Vaginitis ASYMPTOMATIC COLONIZATION

Candida strain type Predominant phenotype Titer Proteolytic activity White or opaque colonies

SYMPTOMATIC VAGINITIS

Identical Blastospore and budding :SlO"/mL

Identical Germ tube and mycelia 2:104/mL

Fewer opaque

More opaque

+-+ +

+++-+++

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Pathogenesis of Recurrent and Chronic Candida Vaginitis Careful evaluation of women with recurrent vaginitis usually fails to reveal any precipitating or causal mechanism. 130 These desperate women avoid antibiotics, oral contraceptives, tightfitting clothing, and hormone therapy and have normal glucose tolerance tests. In the past, clinicians attributed the frequent episodes to repeated fungal reinoculation of the vagina from a persistent intestinal source93 or as a result of sexual transmission (Table 6). The intestinal reservoir theory is based upon the report of recovery of Candida on rectal culture in almost 100% of women with VVC. 34, 93 Biotyping of simultaneously obtained vaginal and rectal cultures almost invariably reveals identical strains. 92, gg This theory has been criticized in the last few years, as several authors have found much lower concordance between rectal and vaginal cultures in patients with recurrent VVC. 60, 99 In particular, in a maintenance study of women with recurrent vaginitis receiving ketoconazole, recurrence of Candida vaginitis occurred in the presence of negative rectal cultures for Candida,gg Additionally, two controlled studies using oral nystatin treatment, which reduces intestinal yeast carriage, failed to prevent symptomatic recurrence of vaginal candidiasis,94. 143 Penile colonization with Candida is present in approximately 20% of male partners of women with recurrent vaginal candidiasis. 32, 99, 117 Asymptomatic male genital colonization is four times more common in male sexual partners of infected women,117 Strain typing techniques indicate that infected partners usually carry identical strains,99 Recently, positive Candida cultures of prostatic ejaculate revealed an additional small reservoir in male partners of women with recurrent VVC,66, 105 In spite of this circumstantial evidence, confirmation that sexual transmission occurs is still lacking, and the contribution of sexual transmission to the pathogenesis of infection remains unknown. Based upon the prevalence of positive penile cultures, the role of sexual spread appears extremely limited; hence, routine therapy of male partners, even those of women with recurrent candidal vaginitis, is unlikely to reduce recurrence rates substantially. No single controlled study has shown that treatment of men prevents recurrence in women, Vaginal relapse infers that incomplete eradication or clearance of Candida from the vagina occurs following antimycotic therapy that may be Table 6. Pathogenesis of Recurrent Vulvovaginal Candidiasis Source More frequent vaginal inoculation Intestinal reservoir theory Sexual transmission Vaginal relapse Mechanism Enhanced Candida virulence* Host Depressed mucosal immunity (CMI) Immediate hypersensitivity reactivity (IgE) Loss of bacterial "colonization resistance" *Rarely due to antimycotic drug resistance,

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sufficient to reduce drastically the numbers of Candida in the lumen and alleviate signs and symptoms of inflammation. Accordingly, organisms would persist in small numbers in the vagina and result in continued carriage of the organism; when host environmental conditions permitted, the colonizing organisms would increase in number, undergo mycelial transformation, and a new clinical episode would result. Whether recurrence is due to vaginal reinfection or relapse, it is apparent that women with recurrent VVC differ from women with infrequent episodes by virtue of their inability to tolerate small numbers of Candida reintroduced or persisting in the vagina. On the basis of serotyping of organisms, women with recurrent and infrequent infection share the same distribution frequency of organisms as women without symptoms. 10.3. 104 Likewise, Candida strains isolated from women with intractable disease express identical virulence factors and antifungal susceptibility patterns. The switching colony phenomenon that may occur in vivo and may constitute an explanation for more virulent strains developing spontaneously has yet to be addressed in women with unexplained recurrent VVC. 124 . 131 Host factors responsible for the frequent episodes are not clearly delineated, and more than one mechanism may be operative. There is no evidence of complement, phagocytic cells, or immunoglobulin deficiency in these patients. Recurrent VVC is not due to drug resistance; only three such cases have been reported. 122 Current theories as to the pathogenesis of recurrent disease remain unproven but include (1) qualitative and quantitative deficiency in the normal protective vaginal bacterial flora, and (2) an acquired, often transient, antigen-specific deficiency in T-Iymphocyte function that permits unchecked yeast proliferation and germination. 62. 137 According to Witkin, 149 reduced T-Iymphocyte reactivity to Candida antigen is the result of the elaboration by the patient's macrophages of prostaglandin E 2 , which blocks lymphocyte proliferation possibly by inhibiting interleukin2 production. Abnormal macrophage function could be the result of local IgE Candida antibodies or a serum factor. 14&-148 This hypothesis requires confirmation; nevertheless, numerous investigators have observed decreased Candida-specific lymphocyte reactivity in vitro. 149 Finally, another hypothesis involves an acquired acute hypersensitivity reaction to Candida antigen that is accompanied by elevated vaginal titers of Candida-antigen specific IgE. 81. 89. \08 This theory has a clinical basis in that patients with recurrent VVC often present with severe vulvar manifestations (rash, erythema, swelling, and pruritus) with minimal exudative vaginal changes, little discharge, and lower titers of organisms. Allergic responses to Candida have been reported to involve the male genitalia following coitus with a Candida-infected woman that are characterized by the acute onset of erythema, edema, severe pruritus, and irritation of the penis. 22 As yet only a minority of women with recurrent VVC have been shown to have elevated Candida-specific vaginal IgE. 149 So far only limited uncontrolled studies have found that using Candida antigen desensitization is helpful in reducing the frequency of recurrent episodes of vaginitis. 119 Clinical Manifestations Acute pruritus and vaginal discharge are the usual presenting complaints, but neither is specific to VVC and neither is invariably associated

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with disease. The most frequent symptom is that of vulvar pruritus which is present in virtually all symptomatic patients. Vaginal discharge is not invariably present and is frequently minimal. Although described as typically cottage cheese-like in character, the discharge may vary from watery to homogeneously thick. Vaginal soreness, irritation, vulvar burning, dyspareunia, and external dysuria are commonly present. Odor, if present, is minimal and nonoffensive. Examination frequently reveals erythema and swelling of the labia and vulva, often with discrete pustulopapular peripheral lesions. The cervix is normal, and vaginal mucosal erythema is present together with adherent whitish discharge. Characteristically, symptoms are exacerbated in the week preceding the onset of menses, with some relief experienced with the onset of menstrual flow. Diagnosis The relative lack of specificity of symptoms and signs precludes a diagnosis that is based on history and physical examination alone. 100 Most patients with symptomatic VVC may be readily diagnosed on the basis of simple microscopic examination of vaginal secretions. A wet-mount or saline preparation should routinely be done, and has a sensitivity of 40% to 60%. 9 The 10% KOH preparation is extremely valuable and even more sensitive than the wet mount in diagnosing the presence of germinated yeast. Vaginal pH estimations reveal a normal pH in the presence of Candida vaginitis (4.0 to 4.5), and the finding of a vaginal pH in excess of 5.0 should strongly alert clinicians to the possibility of bacterial vaginosis, trichomoniasis, or a mixed infection. Although routine cultures are unnecessary, vaginal culture should be performed in the presence of negative microscopy.8 Reliable clinical cultures can also be obtained using Nickerson's media or semiquantitative slide-stix cultures. The Pap smear is unreliable, being positive in only about 25% of patients. 120 Although vaginal culture is the most sensitive method currently available for detecting Candida, when cultures are positive, it should not be assumed that Candida are responsible for the vaginal symptoms. Odds 100 have shown that positive direct microscopy usually correlated with relatively high yeast concentrations in vaginal secretions as confirmed by quantitative vaginal cultures. There is no reliable serologic technique for the diagnosis of symptomatic Candida vaginitis. Recently, success was reported in achieving rapid and reliable diagnosis of Candida vaginitis utilizing a latex agglutination slide technique employing polyclonal antibodies reactive with multiple Candida species and directed against yeast mannan. 43 One study revealed a sensitivity of 81% and a specificity of 98.5%.43 A recent study by Sobel et aP25 failed to verify the high sensitivity of this test; moreover, the rapid slide test offered no advantage over standard microscopy. Treatment

Topical Agents for Acute Candida Vaginitis Antimycotics are available for local use as creams, lotions, aerosol sprays, vaginal tablets, suppositories, and coated tampons. There is little

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to suggest that formulation of the topical antimycotic influences clinical efficacy, so, for the most part, the patient's preference should dictate which vehicle is used to deliver the local therapy. Extensive vulvar inflammation dictates local vulvar application of cream. Antifungal agents that have been used in the topical treatment of Candida vaginitis are listed in Table 7. Nystatin creams and vaginal suppositories have been used extensively for almost three decades. 71 The average mycologic cure rate of 7- and 14day courses is approximately 75% to 80%. Azole derivatives appear to achieve slightly higher clinical and mycologic cure rates than the polyenes (nystatin), on the order of 85% to 90%.2. 14. 18. 38. 100 Although multiple comparative studies have been performed comparing clinical efficacy of the various azoles, there is little evidence that one azole agent is superior to others. The newest addition is terconazole, a lipophilic triazole agent that, like the imidazoles, inhibits fungal cytochrome P-450s involved in ergosterol biosynthesis1 42 but also inhibits chitin synthetase. Terconazole is at least as effective as miconazole and clotrimazole, and some trials indicate that it gives possibly more rapid relief of vulvovaginal symptoms. 78 Topical azoles are remarkably free of local and systemic side effects; nevertheless, the initial application of topical agents is not infrequently accompanied by local burning and discomfort. There has been a major trend toward shorter treatment courses with progressively higher antifungal doses, culminating in single-dose therapeutic regimens. In several studies, both short courses and single-dose regimens have been shown to be effective for most of the azole and polyene antifungals.1. 17 Although single-dose and short (3 day) courses of therapy imply short duration of treatment, the formulation of these agents, together with the high doses inserted, result in the persistence of active compounds in inhibitory concentration for several days. This has been well documented for clotrimazole, in which a single administration of a 500-mg suppository achieves measurable local therapeutic inhibitory concentrations for at least Table 7. Topical Azole Therapy of Vaginal Candidiasis DRUG

Butoconazole Clotrimazole

Miconazole

Econazole* Fenticonazole* Tioconazole Terconazole

FOR\IULATIOl\

DOSAGE

2% cream 2% cream 10% cream lOO-mg vaginal tab lOO-mg vaginal tab 500-mg vaginal tab 2% cream lOO-mg vaginal supp 200-mg vaginal supp 1200-mg vaginal supp 150-mg vaginal tab 2% cream 2% cream 6.5% cream 2% cream

5 g x 3 days 5 g x 7-14 days 5-g single application 1 tab x 7 davs 2 tab x 3 days 1 tab once 5 g x 7 days 2 supp x 7 days 2 supp x 3 days 1 supp once 1 tab x 3 days 5 g x 7 days 5 g x 3 days 5-g single dose 5 g x 3 days

*Not available in United States.

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2 to 3 days. ll5 Similar information is now available for miconazole. lOl Although numerous studies indicate that single-dose therapy is effective, anecdotal evidence suggests that individual failures are by no means uncommon. Studies in patients with severe and more intractable infection have not as yet been undertaken. It seems reasonable to use single-dose and short-course therapy in patients with infrequent episodes of mild to moderate severity in pregnant and nonpregnant women. None of the oral antimycotic agents have FDA approval in the United States for specific use in VVC. Nevertheless, ketoconazole (400 mg daily for 5 days), itraconazole (200 mg daily for 3 days or a 400-mg single day), and fluconazole (150 mg in a single daily dose) have all been shown to be highly effective in achieving clinical and mycological cure in acute Candida vaginitis. 10. 1.3. 15.24 Clinical results of oral therapy are at least as good if not superior to conventional topical antimycotic therapy. lOO Several studies indicate that, given the choice, most women prefer oral therapy.139 Any therapeutic advantage of oral therapy must be weighed against the potential for side effects and toxicity. Ketoconazole therapy is accompanied by gastrointestinal upset (10%) and rarely anaphylaxis, but the major concern is the risk of hepatotoxicity, which occurs in approximately 1 in every 10,000 to 15,000 women treated. 83 Similar side effects appear to be much less frequent with itraconazole and fluconazole. Management ofVVC during pregnancy is more difficult because clinical response tends to be slower and recurrences more frequent. Dl ~ost topical antifungal agents are effective, especially when prescribed for longer periods of 1 to 2 weeks. Although systemic absorption of topical antifungals is minimal, the potential risk of vaginal antimycotic therapy to the developing fetus during the first trimester of pregnancy must be weighed against the benefit derived by the patient. Although longer duration of therapy may be necessary to eradicate yeast infection, single high-dosage therapy with clotrimazole has been shown to be effective in pregnancy. 84 Treatment of Recurrent and Chronic VVC The management of women with recurrent and chronic VVC remains problematic. 127 The first step the clinician should take is to confirm the diagnosis of VVC. Thereafter, it is necessary to identify and eradicate possible underlying or predisposing causes. Uncontrolled diabetes must be controlled if any chance of clinical success is to be achieved. Similarly, the use of corticosteroids, other immunosuppressive agents, and hormones such as estrogens should be discontinued where possible. The continued use of oral contraceptives is controversial, however; many investigators have not found it beneficial or even necessary to discontinue low-dose estrogen oral contraceptive use when long-term antimycotic agents were prescribed. Similarly, a glucose tolerance test in otherwise asymptomatic healthy premenopausal women is rarely helpful. Most women with recurrent VVC already avoid tightfitting clothing and synthetic underwear. Douching with commercial preparations and vinegar is of no value and should be discouraged. Unfortunately, in the majority of women with recurrent or chronic VVC, no underlying or predisposing factor can be identified. 12D. 130 The majority of women with recurrent VVC require a long-term maintenance suppressive prophylaxis regimen. Several studies have con-

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firmed the success of maintenance regimens in reducing the frequency of symptomatic episodes of VVC during long-term prophylactic therapy.33a. 129. no Because of the chronicity of therapy, the convenience of oral treatment is apparent, and the best suppressive prophylaxis has been achieved with daily low-dosage ketoconazole 100 mg daily over 6 months. 130 The benefits of successful suppressive therapy must be weighed against the potential toxicity of oral therapy. Low-dosage ketoconazole is remarkably free of dose-dependent side effects but is not free from idiosyncratic toxic reactions such as hepatitis. In all three reports of successful maintenance prophylaxis, cessation of antifungal prophylaxis was associated with resurgence of symptomatic infection in approximately half the women studied. Another approach was described by Dennerstein, who reported a reduced rate of recurrence in chronic VVC in 15 patients during a 3-month period of depot medroxyprogesterone acetate therapy. 35 Chronic and recurrent VVC do not appear to be the result of resistant vaginal yeast. 99 Rarely, however, in women who fail to respond to conventional therapy, one encounters unusual organisms, e. g., Saccharomyces cerevisiae, Torulopsis glabrata, and C. tropicalis, which are known to have relatively higher MICs to azoles. 67 These patients will respond to oral imidazoles, topical flucytosine, or topical boric acid. Topical flucytosine should be limited to isolated cases only because of a tendency for resistance to be acquired. 67 Another widely utilized measure to prevent recurrence is adding oral nystatin to the concomitant vaginal therapy. Short-term studies of simultaneous vaginal and oral therapy with nystatin have produced conflicting results. Milne and Warnock94 failed to show any benefit of concomitant nystatin therapy, whereas a multicenter study98 showed a modest reduction of vaginal reinfection. However, the latter study did not extend further than 2 months following initial therapy. Prophylactic antifungal medication is not routinely recommended to accompany antibiotic therapy in most women; however, in women with recurrent VVC, it may be prudent to administer topical antimycotic therapy together with antibiotics. Finally, in dealing with women with chronic or recurrent VVC, it is necessary to emphasize the importance of reassurance, support, and counseling.

ATROPHIC VAGINITIS

It is important to distinguish between the symptomatic patient with an inflamed atrophic vagina and the patient with simple atrophy who has no symptoms and no specific inflammation. Clinically significant atrophic vaginitis is actually quite rare, and the majority of women with an atrophic vagina are asymptomatic. Because of reduced endogenous estrogen, the epithelium becomes thin and lacking in glycogen, which contributes to reduced lactic acid production and increased vaginal pH. The latter environment encourages the overgrowth of nonacidophilic coliform organisms and the disappearance of Lactobacillus species. In spite of these major but usually gradual changes, symptoms are usually absent especially in the absence of coitus.

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Typical symptoms include vaginal soreness, dyspareunia, and occasional spotting or discharge. Burning is a frequent complaint, often precipitated by intercourse. The vaginal mucosa is thin with diffuse redness, occasional petechiae, or ecchymoses with little or no vaginal folds. Vulvar atrophy may also be present. Discharge, if present, may be bloodlike, thick, or watery, and the pH of the vaginal secretions ranges from 5.5 to 7.0. The wet smear frequently shows increased PMNs associated with small, round epithelial cells. These latter parabasal cells represent immature squamous cells that have not been exposed to sufficient estrogen. The Lactobacillus-dominated flora is replaced by mixed flora of gram-negative rods. Bacteriologic cultures in these patients are not necessary and can be misleading. The treatment of atrophic vaginitis is primarily topical vaginal estrogen, especially in the absence of systemic symptoms. One half to one applicator used nightly for 1 to 2 weeks is usually sufficient to alleviate the atrophic vaginitis. UNUSUAL VAGINITIS SYNDROMES

The need for precise diagnosis cannot be underestimated. To many women, vaginal discharge means infection, and to many clinicians, the need for accurate diagnosis is not a priority, resulting in the use of empirical therapy. Nevertheless, physicians who are committed to accurate diagnosis recognize that, not infrequently, patients with objective vulvovaginal inflammation do not fit into any of the categories previously described in this article. The most commonly missed entity is that of focal vulvitis or vulvar vestibulitis. 48 . 109, 156 This entity has only been recognized during the last decade; it represents an inflammatory reaction involving tissue external to the hymen and presents in a focal, multifocal, or diffuse pattern. Of unknown etiology, the inflammation sometimes is localized to the opening of the Bartholin's or Skene's glands, hence the term vestibular adenitis, although frequently no glandular tissue is seen on biopsy. Patients present with chronic soreness, vulvar burning, and penetration dyspareunia. These chronic vestibular manifestations are usually unremitting and entirely nonspecific. Anecdotally, some investigators have suggested that focal vulvitis may represent a form of human papillomavirus infection. Treatment is difficult and often requires ablative local surgery or laser treatment. Palliation can be achieved with topical 4% aqueous lidocaine. Presence of a forgotten foreign body in the vagina may be associated with the overgrowth of mixed aerobic and anaerobic bacteria. Chemical or allergic vulvovaginitis is extremely common and is usually misdiagnosed as VVC. The most frequent expressions of allergy are vulvar pruritus, burning, and discomfort that are often intense in nature. Few physicians have the time to take a detailed history of possible causal irritants or allergens. Finally another poorly defined entity causing vaginal symptoms is that of erosive lichen planus, also called desquamative inflammatory vaginitis. 49 Accompanying vulvar disease may also coexist. This idiopathic inflammatory reaction predominantly involves the vagina, and produces a nonoffensive

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purulent vaginal discharge and severe dyspareunia. Examination reveals diflllse erythema of the vaginal mucosa with a copious purulent discharge. Vaginal pH is slightly elevated, and the predominant laboratory finding is that of a marked increase in PMNs, accompanied by increased numbers of basal and parabasal cells and increased numbers of epithelial cell nuclei, indicating both exfoliation and cytolysis. After trichomoniasis is excluded by culture, therapeutic options are limited by lack of understanding of the etiology. Topical corticosteroids are occasionally helpful, and some physicians even advocate short courses of systemic oral prednisone. In uncontrolled studies, some physicians have reported excellent results with topical clindamycin, suggesting an infectious etiology.

SUMMARY Often trivialized by the medical profession, vaginitis in adult women is not only extremely common but is the source of considerable distress and often results in marked suffering. Epidemiologic studies described in this article indicate the high prevalence of vaginitis and the large number of causes. Although the majority of infections in women are due to bacterial vaginosis, VVC, and trichomoniasis, it is clear that many other causes exist, and we have yet to discover the etiology of many clinical syndromes. Considerable progress has been made in understanding the pathogenesis of the three common vaginitides. Although excellent progress has been made by the pharmaceutical industry in providing new drugs for vaginitis, any further progress will require a better understanding of etiology and pathogenesis. Vaginitis causes major symptoms and is more than a nuisance problem. Clinicians owe it to their patients to attempt to make an accurate diagnosis and not to rely on empiric therapy.

REFERENCES 1. Adamson CD: Three day treatment of vulvovaginal candidiasis. Am J Obstet Cynecol 158:1002-1005, 1988 2. Adamson CD, Brown D Jr, Standard JV, et al: Three day treatment with butaconazole vaginal suppositories for vulvovaginal candidiasis. J Reprod Med 31:131-132, 1986 3. Alderete JF, Carza CE: Specific nature of Trichomonas vaginalis parasitism of host cell surfaces. Infect Immun 50:701, 1985 4. Amsel R: Nonspecific vaginitis: Diagnostic criteria and microbiolic and epidemiologic associations. Am J Med 74:14, 1983 5. Annual Reports of Chief Medical Officer, Department of Health and Social Security, 1976--1984 (England and Wales) 6. Auger P, Joly J: Microbial flora associated with Candida albicans vulvovaginitis. Ob stet Cynecol 55:397, 1980 7. Berg AO, et al: Establishing the cause of genitourinary symptoms in women in a family practice: Comparison of clinical examination and comprehensive microbiology. JAMA 251:620, 1984 8. Bergman et al: Clinical comparison of microscopic and culture techniques in the diagnosis of Candida vaginitis. J Fam Pract 18:549, 1984 9. Bertholf ME, Stafford MJ: Colonization of Candida albicans in vagina, rectum, and mouth. J Fam Pract 16:919-924, 1983

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10. Bingham JS: Single blind comparison ofketoconazole 200 mg oral tablets and clotrimazole 100 mg vaginal tablets and 1% cream in treating acute candidosis. Br J Vener Dis 60:175-177, 1984 11. Blackwell AL, et al: Anaerobic vaginosis (nonspecific vaginitis): Clinical, microbiological and therapeutic findings. Lancet ii:1379, 1983 12. Bland PB: Experimental vaginal and cntaneous moniliasis. Clinical and laboratory studies of certain monilias associated with vaginal oral and cutaneous thrush. Arch Dermatol Syphio 36:760-768, 1937 13. Bloch B, Smythe E: Ketoconazole in the treatment of vaginal candidiasis. S Air Med J 67:178-179, 1985 14. Bradbeer CS, Thin RN: Comparison of econazole and isoconazole as single-dose treatment for vaginal candidosis. Genitourin Med 61:396-398, 1985 15. Brammer KW (Multicenter Study Group): Treatment of vaginal candidiasis with a single oral dose of fluconazole. Eur J Clin Microbiol Infect Dis 7:364-367, 1988 16. Brand JM, Galask RP: Trimethylamine: The substance mainly responsible for the fishy odor often associated with bacterial vaginosis. Obstet Gynecol 63:682, 1986 17. Breuker G, Jurezok F, Lenaerts M, et al: Single-dose therapy of vaginal mycoses with clotrimazole vaginal cream 10%. Mykosen 29:427-436, 1986 18. Brewster E, Preti PM, Ruffman R, et al: Effect of Fenticonazole in vaginal candidiasis: A double-blind clinical trial versus clotrimazole. J Int Med Res 14:306-310, 1986 19. Bump RC, et al: The prevalence, six-month persistence, and predictive values of laboratory indicators of bacterial vaginosis (non-specific vaginitis) in asymptomatic women. Am J Ob stet Gynecol 150:917, 1986 20. Burch TA, et al: Epidemiological studies on human trichomoniasis. Am J Trop Med Hyg 8:312, 1959 21. Caruso LJ: Vaginal moniliasis after tetracycline therapy. Am J Obstet Gynecol 90:374, 1964 22. Catterall RD: Urethritis and balanitis due to candida. In Winner HI, Hurley R (eds): Symposium on Candida Infections. London, Churchill Livingstone, 1966, pp 113-118 23. Catterall RD: Trichomonal infection of the genital tract. Med Clin North Am 56:1203, 1972 24. Cauwenbergh G: Itraconazole: The first orally active antifungal for single-day treatment of vaginal candidosis. Curr Ther Res 41:210-214, 1987 25. Centers for Disease Control: Nonreported sexually transmitted diseases. MMWR 28:61, 1979 26. Chen KCS, et al: Biochemical diagnosis of vaginosis: determination of diamines in vaginal fluid. J Infect Dis 145:337, 1982 27. Cook RL, et al: Clue cells in bacterial vaginosis: immunofluorescent identification of the adherent gram-negative bacteria as Gardnerella vaginalis. J Infect Dis 160:490, 1989 28. Cook R, Redondo-Lopez V, Schmitt C, et al: Recurrent bacterial vaginosis: Factors predicting recurrence, in press 29. Crisswell BS, et al: Haemophilus vaginalis: Vaginitis by inoculation from culture. Obstet Gynecol 33:195, 1969 30. Curtis AH: On the etiology and bacteriology ofleucorrhoea. Surg Gynecol Obstet 18:229, 1914 31. Davidson F, Oates JK: The pill does not cause "thrush." Br J Ob stet Gynecol 92:1265, 1985 32. Davidson F: Yeasts and circumcision in the male. Br J Vener Dis 53:121-123, 1977 33. Davidson F, et al: Recurrent genital candidosis and iron metabolism. Br J Vener Dis 53:123-125, 1977 33a. Davison F, Mould RF: Recurrent genital candidosis in women and the effect of intermittent prophylactic treatment. Br J Vener Dis 54: 176-183, 1978 34. De Sousa HM, Van Uden N: The mode of infection in yeast vulvovaginitis. Am J Ob stet Gynecol 80:1096-1099, 1960 35. Dennerstein GJ: Depot-Provera in the treatment of recurrent vulvovaginal candidiasis. J Reprod Med 31:801-803, 1986 36. Dombrowski MP: Intravenous therapy of metronidazole-resistant Trichomonas vaginalis. Obstet Gynecol 69:524, 1987 37. Drake TE, Maibach HI: Candida and candidiasis: Cultural conditions, epidemiology, and pathogenesis. Postgrad Med 53:83-87, 1973

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