Many excellent reviews are dedicated to different aspects of Candida research.
Our perception of VVC is based only on interpretation of indirect indices: epidemiology of colonization and disease, macroscopic appearance of lesions, symptoms, investigation of vaginal smears using microscopy, culture or molecular genetic identification of microorganisms, and simulation of infection/colonization in vitro and in experimental animal models.
This is the first study that directly visualizes Candida microorganisms in vaginal biopsies, and the results substantially contradict widespread assumptions. We found no biofilm elements in vaginal biopsies obtained from women with VVC. Results were identical in women with acute sporadic or recurrent VVC.
This is in contrast to biofilms seen in bacterial vaginosis. Moreover, Candida cells on the surface were single, nonconfluent, and what is most important nonadherent to the vaginal epithelium. This cannot be explained by processing sample biases.
Carnoy solution, which we used for fixation of the biopsy samples, demonstrated its high efficiency in preserving biofilms and even bacteria-free slime on different mucosal surfaces.
However, in appropriate and representative specimens obtained in VVC, we were unable to detect any contiguous Candida layer on the mucosal or epithelial surface. It is possible that the cementing properties of the extracellular matrix, which is produced by Candida, is very low, unable to maintain Candida attachment to the vaginal surface and not different from those produced by any other microorganisms growing in a colony on a culture plate.
The fixation or adherence of Candida microorganisms to the vaginal surface is possible or likely through hyphal mucosal invasion. Visually apparent white membranes, which cover the vaginal epithelium in vulvovaginal candidiasis and appear to be biofilms, are actually deep inflammatory infiltrates.
In the past, few studies have included vaginal biopsies in women with VVC. In the absence of such critical tissue status information, vaginal candidiasis has been considered as entirely superficial mucosal infection and the lack of even superficial invasion emphasized. In fact, some clinicians refer to Candida vaginitis as infection of vaginal secretions only. Moreover, the histological appearance of nonvaginal Candida lesions presented in some publications are all definitively invasive (Gow and Hube,
page 407, Figure 1, A, B, and C, and Figure 2; Jabra-Rizk et al,
page 2729, Figure 9, B and C; Gao et al,
page 737, Figure 9; Allison et al,
page 8, Figure 6) and similar to our findings.
A most prominent feature in our study is a deep infiltration of vaginal tissue. The infiltration is not homogeneous with some regions affected more heavily than others and some remaining completely free. The removal of such lesions is impossible without stripping the integrity of the epithelial layer. In spite of the depth of infiltration, it is not full thickness, and disseminated infection is not reported clinically.
Candida colonization and infection occur in polymicrobial environments. Our findings suggest possible bacteria-yeast interactions in tissue invasion. With regard to VVC, Gardnerella spp. was claimed to promote and lactobacilli to supress Candida biofilms.
While our data support a contributory promoting role for Gardnerella, little was forthcoming to support lactobacilli being beneficial or protective.
On the contrary, lactobacilli were visualized accompanying Candida infection even more often than Gardnerella. The concentrations or density of lactobacilli within the vaginal epithelium was high, both for L. iners and other Lactobacillus species including L. crispatus. Because the lactobacilli were homogeneously distributed within the lesion and in some cases even enriched at the forefront of Candida infiltration, a pathogenic fungal-bacterial symbiosis seems more likely than a secondary saprophytic relationship.
Obviously pathogenic consortia include a variety of different types of bacteria as demonstrated in polymicrobial BV biofilms. The interaction between fungi and bacteria may contribute to the switch from saprophytic to invasive forms of fungal growth. Quorum-sensing research investigates stimuli that synchronize a correlated response of the microorganism to population density. Presently it is mainly focused on cross talking within single groups of microorganisms,
this but should be widened to polymicrobial populations.
In our series, 26% of the lesions did not hybridize with the Candida albicans-specific Caal FISH probe but were positive with the universal yeast probe. At present, we cannot designate the origin of these fungi. Either the Caal FISH probe hybridizes less stringently to other representatives of Candida, or the infiltration is indeed caused by non-Candida yeasts in some cases, which were clinically diagnosed as VVC. However, the extent of the infiltration by Candida albicans and other yeasts was identical, even in the absence of hyphae (Figure 6), indicating similar pathogenic potential.
Our data point to vaginal epithelial surface or mucosal invasion as an unrecognized feature of VVC. Although vaginal biopsies were not obtained in asymptomatic women without VVC but colonized with Candida, it is likely that such common saprophytic colonization occurs in the absence of any tissue invasion. Most importantly, no evidence of in situ, in vivo Candida biofilm existence emerged.
The clinical relevance of these findings is largely unknown, but the absence of finding a biofilm in VVC implies that antibiofilm therapy is not indicated because it may be required in BV. The finding of tissue invasion in VVC may have relevance to recolonization of vagina with candida organisms following antifungal therapy (ie, the vaginal mucosa may serve as organism reservoir to explain recolonization following treatment
The work has not been published previously and is not under consideration for publication elsewhere. The publication is approved by all authors, and tacitly or explicitly by the responsible authorities in which the work was carried out, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright holder. Each author named in the byline participated actively and sufficiently in the study reported. The author contributions included the following: Drs Swidsinski, Guschin, XY, and Tertychnyy designed the study; Drs Dörffel, Tang, Tertychnyy, Luo, and Jiang conducted the study; Drs Sobel and Verstraelen critically revised the manuscript; Drs Swidsinski, Guschin, and Dörffel performed the fluorescent in situ hybridization; and Drs Tertychnyy, Tang, Luo, and Jiang analyzed the data. All authors contributed to the conception of the work, revising of the data, shaping of the manuscript, and approved the final draft submitted.
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Published online: October 25, 2018
Accepted: October 17, 2018
Received in revised form: September 28, 2018
Received: July 3, 2018
The study was supported by a Charité University research promotion grant (2016) and The German Federation of Industrial Research Associations ZIM Project ZF4143701AJ5 . Both funding sources were not involved in the study design, collection, analysis and interpretation of data, in writing a report, or the decision to submit the article for publication.
The authors report no conflict of interest.
Cite this article as: Swidsinski A, Guschin A, Tang Q, et al. Vulvovaginal candidiasis: histologic lesions are primarily polymicrobial and invasive and do not contain biofilms. Am J Obstet Gynecol 2019;220:91.e1-8.