Recurrent vulvovaginal candidiasis (RVVC) is a common cause of significant morbidity in women in all strata of society affecting millions of women worldwide. Previously, RVVC occurrence was limited by onset of menopause but the widespread use of hormone replacement therapy has extended the at-risk period. Candida albicans remains the dominant species responsible for RVVC, however optimal management of RVVC requires species determination and effective treatment measures are best if species-specific. Considerable progress has been made in understanding risk factors that determine susceptibility to RVVC, particularly genetic factors, as well as new insights into normal vaginal defense immune mechanisms and their aberrations in RVVC. While effective control of RVVC is achievable with the use of fluconazole maintenance suppressive therapy, cure of RVVC remains elusive especially in this era of fluconazole drug resistance. Vaccine development remains a critical challenge and need.
Originally termed “acute Candida vaginitis,” vaginal infection by Candida species has transformed into the concept of vaginal candidiasis or candidosis in the United Kingdom, due to recognition of a wider spectrum of symptomatic and asymptomatic disease. Subsequent recognition that the dominant site of inflammation and source of symptoms is the vulva led to the term “vulvovaginal candidiasis” (VVC). While most episodes of symptomatic disease appear as sporadic attacks of acute VVC, some women have more chronic or long-term daily manifestations and symptoms are infrequently diagnosed as mycotic in origin. Yet another subgroup has emerged with recurrent episodes, being entirely asymptomatic between episodes (recurrent VVC [RVVC]). The entity of RVVC has been defined as at least 3 symptomatic episodes in the previous 12 months, although some investigators demand yet an additional episode, ie, 4 attacks. This is an entirely arbitrary differentiation, not based on any data or study and likely women so identified by each definition are identical.
It has become impossible in any open, free society to perform epidemiologic studies and determine the frequency of women with RVVC. This is, firstly, a consequence of the widespread availability of over-the-counter (OTC) antifungal agents. Procurement of the easily available, numerous highly effective topical antimycotic agents, although controversial, can be considered a boon to women’s health. OTC availability clearly has given women access to rapid symptom relief, but is still not inexpensive and open access should have been accompanied by a diagnostic test that would have allowed a woman to correctly diagnose yeast as the cause of her symptoms. Regrettably self-diagnosis is unreliable, with significant overdiagnosis of VVC in the presence of extremely nonspecific and common symptoms. Numerous studies have shown the drawbacks of OTC availability of antifungal agents. Fortunately, the excessive use and overuse of such topical agents has had infrequent adverse consequences, safety has been maintained, and drug resistance as a consequence of frequent use remains rare.
The inadequacies of self-diagnosis of VVC are compounded by practitioner overdiagnosis and underdiagnosis, with US standards comparable to those of syndromic methods in nonindustrialized countries. Current clinical approaches are too often based on empiricism and trial and error. These factors have contributed to poor data availability of the frequency of both acute VVC and RVVC. Estimation of the prevalence of RVVC is similarly marred by physician diagnostic inaccuracies. A recent study using online computer technology reaffirmed a large earlier study reporting self-professed RVVC in 6-9% of women.
Of note, in an expanding population of postmenopausal women isolated studies have supported the clinical impression that a growing number of older women remain at risk of VVC and RVVC as the result of hormone replacement therapy, especially vaginal topical use. It is estimated that RVVC affects approximately 138 million women worldwide annually and 492 million over their lifetimes (David Denning, MD oral communication July 24, 2015). Unfortunately true population-based studies of RVVC are rare. Moreover, the natural history of RVVC over a lifetime has not been addressed. Foxman et al obtained data on duration of symptoms linked with age in 247 women. Most women reported duration of RVVC to be 1-2 years although a substantial number had symptoms for 4 or 5 years and some very much longer, with risk and symptoms lasting decades.
Microbiology
Given that C albicans remains responsible for >90% of episodes of acute sporadic VVC in most studies worldwide, it is not surprising that C albicans similarly is responsible for the majority of infections in women with RVVC. Approximately 85-95% of women with RVVC have azole-sensitive C albicans as the causative pathogen, implying that the host rather than the pathogen contributes dominantly to the pathophysiology of RVVC. Of the non- albicans Candida species, C glabrata is the most frequently isolated species from the vagina in symptomatic and asymptomatic women. Risk factors for C glabrata include type 2 diabetes, postmenopausal status, and older age. The recent introduction of glycosuria-inducing agents to treat type 2 diabetics is also reported to increased prevalence VVC due to C glabrata . In contrast to adults with invasive candidiasis and candidemia, azole exposure has not emerged as a risk factor for C glabrata in women with RVVC. It would appear that all non- albicans Candida species have substantially reduced capacity to express virulence characteristics and hence serve as vaginal pathogens. The implications are important in that the mere isolation of C glabrata and other non- albicans species in symptomatic women with vaginitis does not confirm causality. A cause-effect likelihood is far lower than that defined for C albicans , with likelihood of C glabrata , isolated from the vagina, being responsible for symptoms no higher that 20-30%. Accordingly, in such women other causes for symptoms require active exclusion, before embarking on antifungal therapy, which is less likely to eradicate these low virulence, innocent bystanders also more resistant to antifungal agents. Occasionally major geographic differences in Candida species distribution are reported and more reports usually indicate a higher frequency of C glabrata occurrence.
Pathogenesis of RVVC
Candida blastospores (yeast) migrate from the lower gastrointestinal tract to the adjacent vestibule and vagina. This is a similar route taken by vaginal Lactobacillus species. Colonization of the vagina follows usually in low numbers after adherence of Candida to vaginal epithelial cells. Colonization resistance is poorly studied and understood but colonization is enhanced by an estrogen-influenced environment following menarche and declines in the postmenopause period. In healthy women not prone to RVVC, asymptomatic colonization may persist for months and years as yeasts live in symbiosis with vaginal microbiota. Acute symptomatic VVC follows a breakdown in this relationship and entails either a triggered overgrowth of Candida organisms or alteration in the host protective defense mechanisms, which act to maintain low numbers of yeast organisms and at the same time deliberately down-regulate the mucosal immune inflammatory response aimed at tolerating the presence of low numbers of yeast. An increased rate of vaginal colonization represents but 1 phase of susceptibility to RVVC and causes may be genetic, biologic, or behavioral as shown in the Figure . Description of Candida virulence factors is outside the scope of this review.
The innate immune system provides the first barrier against vulvovaginal Candida infections. Pattern recognition receptors on innate immune cells sense molecular moieties on the surface of yeast, and thereafter induce an intracellular signal within epithelial cells that stimulates production of effector molecules such as proinflammatory cytokines or defensins. Toll-like receptors (TLRs) and C-type lectin receptors recognize numerous components of fungal cell walls. Single nucleotide polymorphisms in host genes are associated with an increased susceptibility to candidiasis. In recent years, it has become evident that interferon-gamma production, and interleukin (IL)-23-dependent, IL-17 and IL-22 signaling (IL-1/Th17 axis) are critical for protection against mucosal candidiasis in mice and possibly in human beings.
Primary or idiopathic RVVC defines women in whom secondary precipitating events or triggering factors are not apparent and hence genetic factors are likely to play a dominant or exclusive mechanism. Nevertheless, even when acute VVC episodes are consistently linked to secondary identifiable triggering mechanisms or events it is likely that genetic susceptibility is still relevant in pathogenesis of RVVC attacks. A genetic basis for RVVC was first suggested by anecdotal reports based on family history occurrence and subsequently by blood group studies. However more powerful were the descriptions of patients with chronic mucocutaneous candidiasis in which RVVC was a prominent clinical manifestation. Several genes emerged in accompanying genetic studies including dectin, providing a likely explanation for RVVC. Unfortunately subsequent controlled studies in otherwise healthy women, without chronic mucocutaneous candidiasis, with idiopathic RVVC failed to confirm the role of these genes. The only polymorphism emerging was a defect in epithelial cell membrane TLR2 due to substitution of amino acid proline by histidine. Exactly how these genetic alterations predispose to RVVC is unclear. Hypotheses relate to Candida epithelial cell receptor function or density and vaginal mucosal immunological inflammatory response. A common theory suggests that the normal regulated mucosal proinflammatory cytokine response, dependent on intracellular inflammasome regulation, is enhanced resulting in an exaggerated inflammatory reaction (hyperreactive) responsible for vulvovaginal symptoms. Experimental animal studies strongly suggest that inflammasome and IL-17 activation are essential for discriminating between colonization and invasion with C albicans at the level of mucosa. With each year, new genes emerge responsible for yet additional cytokines, more recently IL-22, that are critical in balancing resistance with tolerance to Candida and deficiencies thereof predisposing to RVVC. The emergence of genetic information appears to have preceded understanding of normal vaginal defense mechanisms. Another polymorphism to emerge in women with RVVC relates to mannose–binding lectin (MBL), which binds to Candida organisms and activates complement enhancing opsonization and hence might reduce vaginal colonization. Some investigators report reduced vaginal concentrations of MBL and impaired TLR receptor function in RVVC, both decreasing vaginal host defenses against Candida organisms. The role of MBL and TLR genetic polymorphisms remains controversial and has not been confirmed by all investigators.
Pathogenesis of RVVC
Candida blastospores (yeast) migrate from the lower gastrointestinal tract to the adjacent vestibule and vagina. This is a similar route taken by vaginal Lactobacillus species. Colonization of the vagina follows usually in low numbers after adherence of Candida to vaginal epithelial cells. Colonization resistance is poorly studied and understood but colonization is enhanced by an estrogen-influenced environment following menarche and declines in the postmenopause period. In healthy women not prone to RVVC, asymptomatic colonization may persist for months and years as yeasts live in symbiosis with vaginal microbiota. Acute symptomatic VVC follows a breakdown in this relationship and entails either a triggered overgrowth of Candida organisms or alteration in the host protective defense mechanisms, which act to maintain low numbers of yeast organisms and at the same time deliberately down-regulate the mucosal immune inflammatory response aimed at tolerating the presence of low numbers of yeast. An increased rate of vaginal colonization represents but 1 phase of susceptibility to RVVC and causes may be genetic, biologic, or behavioral as shown in the Figure . Description of Candida virulence factors is outside the scope of this review.
The innate immune system provides the first barrier against vulvovaginal Candida infections. Pattern recognition receptors on innate immune cells sense molecular moieties on the surface of yeast, and thereafter induce an intracellular signal within epithelial cells that stimulates production of effector molecules such as proinflammatory cytokines or defensins. Toll-like receptors (TLRs) and C-type lectin receptors recognize numerous components of fungal cell walls. Single nucleotide polymorphisms in host genes are associated with an increased susceptibility to candidiasis. In recent years, it has become evident that interferon-gamma production, and interleukin (IL)-23-dependent, IL-17 and IL-22 signaling (IL-1/Th17 axis) are critical for protection against mucosal candidiasis in mice and possibly in human beings.
Primary or idiopathic RVVC defines women in whom secondary precipitating events or triggering factors are not apparent and hence genetic factors are likely to play a dominant or exclusive mechanism. Nevertheless, even when acute VVC episodes are consistently linked to secondary identifiable triggering mechanisms or events it is likely that genetic susceptibility is still relevant in pathogenesis of RVVC attacks. A genetic basis for RVVC was first suggested by anecdotal reports based on family history occurrence and subsequently by blood group studies. However more powerful were the descriptions of patients with chronic mucocutaneous candidiasis in which RVVC was a prominent clinical manifestation. Several genes emerged in accompanying genetic studies including dectin, providing a likely explanation for RVVC. Unfortunately subsequent controlled studies in otherwise healthy women, without chronic mucocutaneous candidiasis, with idiopathic RVVC failed to confirm the role of these genes. The only polymorphism emerging was a defect in epithelial cell membrane TLR2 due to substitution of amino acid proline by histidine. Exactly how these genetic alterations predispose to RVVC is unclear. Hypotheses relate to Candida epithelial cell receptor function or density and vaginal mucosal immunological inflammatory response. A common theory suggests that the normal regulated mucosal proinflammatory cytokine response, dependent on intracellular inflammasome regulation, is enhanced resulting in an exaggerated inflammatory reaction (hyperreactive) responsible for vulvovaginal symptoms. Experimental animal studies strongly suggest that inflammasome and IL-17 activation are essential for discriminating between colonization and invasion with C albicans at the level of mucosa. With each year, new genes emerge responsible for yet additional cytokines, more recently IL-22, that are critical in balancing resistance with tolerance to Candida and deficiencies thereof predisposing to RVVC. The emergence of genetic information appears to have preceded understanding of normal vaginal defense mechanisms. Another polymorphism to emerge in women with RVVC relates to mannose–binding lectin (MBL), which binds to Candida organisms and activates complement enhancing opsonization and hence might reduce vaginal colonization. Some investigators report reduced vaginal concentrations of MBL and impaired TLR receptor function in RVVC, both decreasing vaginal host defenses against Candida organisms. The role of MBL and TLR genetic polymorphisms remains controversial and has not been confirmed by all investigators.
Clinical aspects of VVC
Cardinal symptoms include vulvovaginal pruritus, irritation, soreness, dyspareunia, and vaginal discharge. Clinical signs are best exemplified by vulva erythema, edema, excoriation, and fissure formation together with introital and vaginal erythema. A nonmalodorous clumpy white discharge is suggestive of VVC but is extremely nonspecific. Diagnosis should never be based on clinical findings alone given their lack of specificity. RVVC, by virtue of the frequent, numerous acute recurrences or chronicity has a profound effect on the quality of life of affected women with additional systemic symptoms including depression and anxiety.
Diagnosis of VVC
Vaginal pH is almost always normal in VVC and an elevated pH suggests an alternative diagnosis although mixed infections occasionally occur. Traditional bedside laboratory tests, include saline and 10% potassium hydroxide microscopy, are still extremely useful providing rapid confirmation when positive, but these tests are now infrequently performed in an era where more expensive and complex tests have become a new but not necessarily superior diagnostic routine. Saline and KOH microscopy unfortunately have low sensitivity (40-70%) even in experienced hands. When clinical suspicion points to VVC in the presence of negative microscopy and normal vaginal pH, culture should be obtained. No new reliable, rapid, or immediately available tests to indicate the presence of yeast are available. DNA homology probes are useful, providing reasonably accurate results within several hours. Polymerase chain reaction (PCR) methods to detect Candida genus presence as well as to determine specific species are now widely available. This service is provided by commercial companies with reliable results available within several days. Whether or not PCR will replace the traditional gold standard viz culture methodology is unclear. PCR methods are undoubtedly more sensitive than culture but have not been shown to offer any advantage to the clinician in practice; moreover this technique is more expensive.
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