Vaginitis in the Age of the Microbiome

Symptomatic vaginal maladies constitute a common gynecological disorder for which nearly 5–10 million women seek care annually in the United States alone. ¹ Those affected may also be at increased risk for the acquisition of sexually transmitted diseases, the precipitation of pelvic inflammatory disease, and the promotion of preterm birth. ^{2 –5} Regrettably, however, the management of vaginitis is in need of an update now that the relevant microbiome can be accurately defined. A case in point is bacterial vaginosis (BV) for which annual recurrence rates as high as 58% have been observed. ⁶

This compromised state of affairs appears to be due to therapeutic protocols informed by subjective, selective, and qualitative diagnostic paradigms that fail to accurately identify the offending organism. Herein we propose that the informed diagnosis and treatment of vaginitis is contingent upon a careful quantitative survey of the vaginal microbiome in search of the organismal culprit. The realization of this vision will require the development of point-of-care technology for the conduct of real-time analysis of the vaginal microbiome.

Vaginitis, an inflammatory disorder of the vaginal canal, constitutes a common malady. Vulvovaginal candidiasis (VVC) impacts 75% of women at least once in their lifetime. BV, in turn, affects up to 50% of reproductive-aged women. ⁷ Attributable to overgrowth of a resident organism, vaginitis is frequently triggered by a disruption of the extant ecological equilibrium. The pathogenesis of BV is a case in point wherein a decrease in Lactobacillus species gives rise to the expansion of Gardnerella vaginalis, Atopbium vaginae, Prevotella, and other anaerobic bacterial species.

Similar mechanisms likely undergird the evolution of acute VVC the symptomatology of which is attributable to the overgrowth of Candida species. Little is known, however, as to the potential pathogenic role of other putative vaginal organisms the very presence and identity of which remain to be carefully characterized. ⁸ It is in this context that advances in high-throughput genomic sequencing techniques could be brought to bear with an eye toward characterizing the vaginal microbiome. Only in so doing will the future therapy of vaginitis be based on objective and quantitative measures intent on reducing, if not eliminating the likelihood of symptomatic recurrence.

The current clinical workup of vaginitis is inherently subjective and selective. A random sample of vaginal discharge cannot capture the underlying dysbiosis of vaginitis nor confirm its causality. Such samples are presently subjected to microscopy, pH measurement, potassium hydroxide testing, and culture. These diagnostic efforts, however, are invariably focused on a limited number of putative offenders. No consideration is being given to other taxa of the vaginal microbiome the morphology, genomic sequence, and culture conditions of which have yet to be discerned. Absent the ability to survey the entirety of the vaginal microbiome, accurate diagnosis and treatment of vaginitis are unlikely to advance.

Apart and distinct from the aforementioned shortcomings, the current clinical workup of vaginitis is qualitative in nature and, therefore, therapeutically compromised. ⁹ Indeed, current diagnostic efforts are limited to documenting the absence or presence of putative offending organisms rather than the quantification thereof. To the extent that the manifestations of vaginitis are attributable to a relative overgrowth of a pathogenic organism, it is paramount that the makeup of the entirety of the microbiome be carefully documented and that any and all deviation(s) from baseline be captured. The major assumptions inherent to this approach are that overgrown element(s) of the microbiome may constitute potential infectious culprits.

Knowledge of the baseline native vaginal microbiome of a patient is imperative. Some women are asymptomatically colonized with Candida species in symbiosis with other vaginal microbiota. ¹⁰ Yet other asymptomatic women may harbor appreciable numbers of gram-negative bacteria in association with BV. ^11,12 The composition of the vaginal microbial communities further fluctuates in response to changes in the circulating level of female sex hormones such as estrogen and progesterone, with increased stability when estrogen levels are highest. ¹³ It follows that the vaginal microbiome displays markedly distinct profiles through the menstrual cycle as well as broadly in prepubertal, postpubertal, pregnancy, and menopausal stages. ^{14 –16} Vaginal dysbiosis is also the byproduct of exogenous administered sex hormones, antibiotics, and immune modulators. ^17,18

The science of the microbiome has made significant strides. The study of the vaginal microbiome has been similarly advanced by high-throughput genomic sequencing. Technologies, such as shotgun metagenomic sequencing, have made it possible to identify the vaginal taxonomy of bacteria, archaea, fungi, and viruses. ¹⁹ It is through these efforts that it became apparent that the vaginal microbiome of adult women segregates into five distinct groups referred to as community state types (CSTs). ²⁰

Although not all CSTs are deemed pathogenic, some CSTs may play a role in the recurrence of vaginal infections. Using 16S rRNA taxon-directed qPCR (quantitative PCR) to characterize shifts in the CSTs, Shipitsyna et al. were able to assess the relative abundance of extant vaginal organisms and thereby establish quantitative cutoffs to define overgrowth. ²¹ In a related study, Gajer et al. characterized the stability of the vaginal CSTs of healthy women over time using twice weekly samples for a 16-week period. ¹³

In an era characterized by metagenomics and increasingly personalized medicine, the clinical framework for vaginitis must advance as well. There remains a dire need for accurate and objective methods for the diagnosis of bacterial, fungal, and protozoal vaginitides and thus of the cures thereof. High-throughput genomic technologies may provide rapid and comprehensive assessment of the state of vaginal health and reduce the burden of disease. ^22,23 In the future, a diagnostic point-of-care device is likely to afford the clinician with a complete quantitative analysis of the vaginal microbiome replete with evidence of dysbiosis, that is, the overgrowth of potential offending organisms.

Given temporal fluctuations that can affect the range of “normal,” a multifaceted clinical approach to vaginitis that incorporates patient physiology and sociobehavioral factors can help contextualize a patient's baseline homeostatic ecosystem relative to expected shifts such as those occurring with menstrual cycles. ¹³ Individualized therapeutic strategies could then be applied in a manner that will maximize the odds of cure. Until such time, regrettably, meaningful progress in the management of vaginitides is bound to be constrained.