Efficacy of photodynamic therapy on candida colonization and clinical symptoms in denture stomatitis: a systematic review and meta-analysis

Denture stomatitis (DS) is a very common oral inflammatory condition affecting 15% to 70% of removable denture wearers [1‐4]. A considerable portion of DS cases are asymptomatic and discovered incidentally during dental examination as an erythema and/or edema of the oral mucosa covered by the denture [4]. However, some DS patients may complain of pain, itching and/or burning [4]. Although DS is a relatively common disorder, its exact etiology has not yet been entirely understood [4, 5]. By and large, there is an agreement that DS is a multifactorial disease [4]. Candida Albicans has been found to be strongly associated with, and even reported to be implicated in pathogenesis of DS [3, 4, 6, 7]. Dentures are usually fabricated from polymethyl methacrylate resin with its inherited porosity disadvantage [8]. The fungal species, mainly Candida Albicans, colonize the porous surface of the acrylic resin, causing oral mucosal inflammation [8]. Other systemic and local predisposing factors include, but not limited to, trauma from ill-fitting denture, poor oral and/or denture hygiene, smoking, decreased salivary flow, medications, increased age of denture, continuous wearing of the denture, and systemic diseases, like diabetes mellitus [5‐7, 9, 10]. These factors appear to increase the ability of opportunistic fungal pathogens, mainly Candida albicans, to colonize both the denture and oral mucosal surfaces causing inflammation [3, 4, 11].

Beside adjusting and managing the aforementioned predisposing factors, topical and systemic antifungal medications are still the mainstay treatment of DS [12]. However, these medications are not always effective in eradicating the fungal colonies from the dentures, and may be associated with a high risk of recurrence after antifungal therapies [12‐15]. Another significant limitation of antifungal therapies is that fungal species may develop resistance against these medications especially in patients with long-term use [16]. Moreover, the long-term use of these medications, especially systemic antifungals, is usually associated with various side effects including the risk of drug interactions, a matter that limits their use. The above argument justifies seeking for alternative novel therapies for DS that are safe, effective, and well-tolerated, without the disadvantages of conventional therapies.

Photodynamic therapy (PDT) has been proposed as a novel, promising treatment modality for several oral mucosal conditions, including DS [17‐19]. PDT is a two-stage treatment involving application of a light-sensitive chemical substance –called a photosensitizer- followed by application of a visible light radiation [14, 20]. In the presence of oxygen, the interaction between the photosensitizer and radiation results in production of singlet oxygen and other oxygen reactive species causing cell damage and death of the microorganism, with minimal damaging effects on the host cells [14]. Additionally, PDT has been suggested to have anti-inflammatory and immunomodulatory properties, a matter that explains its therapeutic effects [17, 21].

In context of DS, a number of clinical trials have evaluated the efficacy of PDT, and reported promising results [14, 15, 22‐26]. A 2018-study by de Senna et al. [15] compared the efficacy of PDT with topical antifungal therapy in DS, and found equivalent efficacy in reducing candida count and clinical signs of DS. Two more recent clinical studies among DS patients in Saudi Arabia also replicated these results [23, 25]. On the other hand, one study by Alves et al., 2020 found PDT to be inferior to topical nystatin in reducing candida colonization in DS patients [14]. A recent 202- study by Al-Aaali et al. [27] investigated the efficacy of PDT on fungal growth and oral health related quality of life in DS patients. The results revealed superiority of miconazole gel over PDT, but a combination therapy (PDT + Miconazole) showed significantly better results than Miconazol [27]. In this context, a few systematic reviews attempted to summarize the available evidence regarding the efficacy of PDT in the management of DS, and reported conflicting results [28‐30]. It is worth mentioning, however, that the aforementioned reviews included only very limited number of studies (3–5 studies) and failed to include all potentially eligible studies, and thus the results might be inconclusive. Additionally, more recent relevant clinical trials on the efficacy of PDT in DS have been published over the past two years [22, 27, 31], again with interesting results.

In light of the fact that the above mentioned limitations of the previous systematic reviews [14, 22, 24, 25] and the lack of a comprehensive systematic review addressing the effect of PDT in comparison to the topical and/or systemic antifungal in treatment of DS, the present systematic review and meta-analysis sought to analyze and update the current evidence in this regard.

Recently, PDT has been proposed as a novel and promising therapeutic modality for various oral inflammatory diseases, including DS [17‐19, 30, 38]. The present systematic review aimed to answer the focused question: “Is PDT efficacious in the management of DS as compared to the topical antifungal medications?”. The qualitative analysis of the included studies answered explicitly that PDT is as efficacious as the topical antifungal therapies, and that adjunctive PDT therapy is more efficacious than antifungal alone in the management of DS, although the statistical significant is at borderline. More specifically, the pooled results of seven studies revealed nearly equivalent efficacy of PDT and topical antifungal therapies in reducing the candida colony count and improvement of clinical signs of DS. Moreovere, the pooled two studies found better efficacy of adjunctive use of PDT (PDT + antifungal therapy) in the management of DS than antifungal alone. Nevertheless, despite these promising results, the findings of the present systematic review should be interpreted with caution given the substantial heterogeneity among the included studies and low quality in some of the included studies, as discussed in the following sections.

One of the primary outcome measures assessed in the present systematic review was the mycological efficacy of PDT. The findings revealed that PDT was very efficacious in reducing the candida colonization count from the palatal mucosa, which was equivalent to or even better than topical antifungal medications. The antimicrobial properties of PDT can be ascribed to the synergistic interaction between the photosensitizer and the radiation that results in production of singlet oxygen and other oxygen reactive species that cause cell damage and death of the microorganism [14, 20]. The findings of the present systematic review support previous systematic reviews and meta-analyses that reported strong antimicrobial efficacy of PDT, with no reported side effects [19, 28, 38, 39]. However, the present results are different from a recent meta-analysis of three studies on DS subjects, which found inferior outcomes with PDT as compared to nystatin [30]. It should be noted, however, that the latter meta-analysis included only three studies, while in our review eight studies were pooled, and this may explain the differences in the results.

Another key outcome assessed in the present systematic review was the clinical efficacy (i.e., reducing clinical signs and symptoms associated with DS) of PDT. Overall, the included studies revealed a good efficacy of PDT in reducing the size of the lesions and ameliorating the symptoms, a finding which is consistent with the previous literature. In addition to its antimicrobial action, PDT have been shown to have potent anti-inflammatory, immunomodulatory effects as well as healing promoting properties through biomodulation in irradiated tissues [21, 40]; this together may explain the therapeutic effects of PDT in alleviating the clinical signs of DS. There is growing evidence indicates that PDT is highly efficacious in the management of various oral inflammatory diseases including oral lichen planus, oral mucositis, herpes labialis [17, 41, 42], which further substantiate the results of the present review.

It is pertaining to mention that the efficacy of PDT is governed by several important factors including type of the photosensitizers, source of light, oxygen availability, laser parameters, duration and frequency of the treatment [43]. Among these, the type of the photosensitizers is the most important factor that influences the therapeutic efficacy of PDT. Unfortunately, the included studies showed a wide heterogeneity in the type of the photosensitizers and other related parameters such as the concentration and irradiation times of the photosensitizers, which, in turn, may have influenced the treatment outcomes. Another key factor that has a great influence on PDT efficacy is the source of light and the related factors (wavelengths, power density, and energy density). Again, the included studies showed great variability in this respect. For example, some studies used LED while others used diode lasers. Similarly, the wavelengths of the used laser/LED varied greatly across the studies, ranging from 455 to 940 nm. Such a discrepancy in PDT parameters is an obvious limitation, making comparability between studies very difficult, and thus no firm conclusion can be drawn. Further, lack of standardized methodologies precludes investigators from creating a standard protocol for the management of oral fungal infections including DS.

Although the findings of the present systematic review support the efficacy of PDT in the management of DS, some methodological shortcomings must be considered. One important limitation is the small sample sizes and the low quality of some of the included studies, and thus no concrete evidence can be concluded. Another key limitation is the marked heterogeneity across the included studies with respect to type of comparison group (the type of topically applied antifungal, dose, frequency, and duration), severity of DS, age and gender of the participants, frequency and duration of PDT sessions, follow-up period, outcome measures, type of photosensitizers, and other PDT-related parameters. Specifically, the wide discrepancy in PDT parameters impedes generating a common protocol that can be considered as a standard for use of PDT in DS treatment. Finally, most of the included studies (five studies) were conducted in one country (Brazil), and thus the generalizability of the results is questionable. Hence, conducting large-scale multicenter clinical trials is warranted.

In conclusion, the results of the present updated systematic review and meta-analysis reveal that PDT is as efficacious as topical antifungal in the management of denture stomatitis, suggesting that PDT can be used as an alternative or as an adjunct to the topical antifungal medications for the management of DS. Further well-designed randomized clinical trials with large sample sizes and standardized photodynamic therapy parameters are required to discern the efficacy of PDT in the management of DS.