Efficacy of photodynamic therapy in the treatment of oral candidiasis: a systematic review and meta-analysis

Oral candidiasis (OC) is a fungal infectious disease of the oral mucosa caused by Candida [1]. In recent years, with the application of broad-spectrum antibiotics, glucocorticoids, and immunosuppressants, organ transplantation, and tumor treatment, the number of patients with impaired immune function has increased, and the incidence of oral candidiasis has continued to increase, becoming the most common infectious disease of the oral mucosa [2]. Patients with oral candidiasis are often associated with burning, unpleasant bitter or salty taste, altered taste, and sometimes pain and discomfort, difficulty swallowing, nausea, vomiting, and diarrhea. These symptoms may affect the patient's ability to eat and lead to changes in the patient's quality of life [3].

The current effective treatments for oral Candida infections are topical and systemic treatments. For mild cases of infection, topical antifungal drugs such as nystatin are recommended [4]. The treatment period of nystatin is long, usually 14–28 days or even longer, with occasional adverse effects such as nausea, diarrhea or loss of appetite after taking it [5]. For patients who are immunocompromised or at risk of disseminated candidiasis, systemic antifungal therapy, such as azoles, can be used [6]. However, the increasing use of azoles has led to an increase in Candida resistance to antifungal drugs [7], necessitating the search for new therapeutic approaches. Alternative antifungal drugs that have been considered include colloidal solutions of metal nanoparticles (silver, gold), ozone therapy, photo biomodulation and photodynamic therapy, of which photodynamic therapy is a promising new therapy [8].

Photodynamic therapy (PDT) is a treatment method in which a photosensitizer is applied to the diseased tissue and a photochemical reaction is produced by irradiation with a specific wavelength light source to achieve a therapeutic effect. Reactive oxygen species (ROS) produced in photochemical reactions can react with a variety of biomolecules such as phospholipids, nucleic acids and proteins of cells to produce toxicity thereby inactivating cells and other microorganisms [9‐11]. In recent years, as PDT continues to be used in clinical practice, its anti-Candida effect has received increasing attention. The main benefits of PDT over conventional antifungal therapy include its broad antimicrobial spectrum, short therapeutic course, strong targeting, high selectivity, and low impact on surrounding normal tissue cells [1]. Additionally, studies have shown that Candida is susceptible to photoinactivation, including drug-resistant strains, which can treat recurrent infections brought on by drug-resistant Candida [12‐14]. Therefore, PDT shows potential applications in the treatment of oral infections.

The light source chosen for PDT is usually a low-energy laser with a power of less than 500mW and a wavelength range of 630 ~ 750 nm, which can be precisely regulated in terms of output power and produces only a localized effect, and therefore does not require any special protection and will not burn the surrounding tissues [15]. A variety of light sources have been used for PDT therapy, and semiconductor lasers, which have the advantages of being easy to operate, portable, and cost-effective, have been more and more widely used; in addition, non-laser light sources, such as incandescent lamps, quartz halogen lamps, and light-emitting diodes, have been used to a certain extent as well [16]. Photosensitizer is an important factor in the successful application of photodynamic therapy, commonly used in the clinic is the second generation of photosensitizers, mostly porphyrin compounds derivatives, such as 5-amino ketoglutaric acid; as well as stains and dyes, such as bracketed toluidine blue, methylene blue, rose red, erythrosine, and peacock green, which have strong photoinactivation effect [17]. Photosensitizers increase the inhibition rate with incubation time, reaching a peak plateau at 30 ~ 90 min [18].

The current clinical effectiveness of PDT for oral candidiasis is variable, and Mima [19] and Senna [20] conducted a randomized controlled trial of PDT for oral candidiasis comparing the efficacy of PDT with that of mycophenolate and found no significant difference between the two in terms of clearance of oral Candida, but the PDT group required a shorter course of treatment to achieve the same effect. Maciel [21] et al. compared PDT combined with a low-energy laser with miconazole gel in the treatment of oral Candida and showed that although the PDT group had some efficacy, its cure rate was significantly lower than that of the miconazole group. Therefore, this study used Meta-analysis to systematically evaluate PDT for the treatment of oral Candida and to provide a basis for clinical application.

Different from previous systematic reviews, this study is not limited to single-drug control and outcome indicators, but compares PDT with nystatin, fluconazole, and miconazole, and more comprehensively evaluates the effects of PDT and antifungal drugs on oral candida. disease treatment effect. The possible mechanisms of PDT in combination with nystatin for the treatment of oral candidiasis were also explored, as well as the recurrence after treatment and the safety of the treatment approach.

This Meta-analysis is based on the PRISMA 2020 Statement: Updated Guidelines for the Reporting of Systematic Reviews guidance [22] for asking questions, registered with INPLASY (registration number INPLASY2022120053), asking “Is photodynamic treatment of oral Candida effective compared to conventional antifungal drugs?”.

The results of this meta-analysis showed that compared with nystatin, when the treatment area was on the palate, there was a statistically significant difference in the reduction of Candida colonies between the two groups (P < 0.05), suggesting that PDT is more effective in removing oral Candida in the palate, but there was no statistically significant difference in the denture area. The process of microbial adhesion to the denture surface is related to the surface properties of the material, such as hydrophobicity and surface roughness [34], and the porous structure and irregular inner surface of the acrylic resin denture act as a reservoir for microorganisms, as well as difficulties in hygienic maintenance and disinfection [35], resulting in more rapid regeneration of Candida in the patient's denture than in the treated palate [36]. The use of PDT technique in the study affected only the palatal mucosa, while treatment with drugs could act on other areas such as the oral mucosa and the tongue, possibly due to dilution of saliva resulting in a weakened effect on Candida and the penetration of the mycelium into the epithelial cells before starting colonization of the palate within 48 h [37]. All of these reasons may cause PDT to be more effective on the palate than on the denture site. The role of PDT in reducing Candida counts is insufficient if the denture surface is not mechanically cleaned [38]. Other topical medications such as nystatin can be used for treatment, but the movement of the oral muscles makes it difficult to keep the medication in the treated area thus reducing the level of treatment [27]. However, systemic antifungals like amphotericin B can be used, but they are not very effective in removing fungal colonies from the surface of the denture [39]. Therefore, it is recommended that all wearers clean all surfaces of the denture regularly to minimize denture-related fungal infections [38]. At the 15-day follow-up of the denture site, there was a statistically significant difference in the reduction of Candida colonies between the two groups, but there was no statistically significant difference at 30 and 60 days, which may be due to the recolonization of Candida on the denture surface after treatment.

Azoles are commonly used in the treatment of Candida infections, but with the massive and unregulated use of antifungal drugs, the resistance rate of Candida to azoles is now gradually increasing, and the phenomenon of cross-resistance between azoles is obvious [40]. Mechanisms of Candida resistance to azoles include altered drug targets, overexpression of drug efflux pumps, altered metabolic pathways and initiation of adaptive stress responses. Mutation or overexpression of the azole target enzyme gene ERG11 in Candida albicans maintains target enzyme activity and produces drug resistance [41]. The results of this Meta showed that the efficacy of PDT in oral candidiasis was similar to that of fluconazole and that miconazole was superior to PDT, but considering that the increasing use of azoles has led to an increase in the resistance of Candida to them, and the fact that PDT can treat recurring infections caused by drug-resistant Candida, this is one of the advantages of PDT over azoles.

For the treatment of candidiasis, the use of topical antifungal agents provides temporary relief, but recurrence is a common problem, especially in the case of immunodeficiency [21]. Mima [19] et al. showed recurrence of palatal inflammation in 75% and 78% of patients in the NYT and PDT groups, respectively, during follow-up, Scwingel [33] et al. showed recurrence of signs and symptoms in 72% of patients in the control group on day 30, and Macial [21] et al. found recurrence in 25% of patients in the experimental group and 12.5% in the control group, which may be related to improper denture cleaning and Candida recolonization in patients with denture stomatitis. With regard to safety, no adverse reactions were reported in Macial [21], while there were varying degrees of nausea and burning tongue in the studies of Yue Zhao [31] and Jinmei Tan [32], which may be related to immunodeficiency in HIV-infected patients.

Due to the widespread use of antifungal drugs such as nystatin and drug resistance in some patients, the clinical effectiveness of their treatment of oral candidiasis still needs to be improved [42]. PDT has a wide antibacterial spectrum, short therapeutic course and strong targeting, and can cause death of Candida by changing the permeability of Candida [43]. Combining the two methods may have more significant effects, so it is of great clinical significance to explore the combined application of PDT and mycobacterium. The results of this Meta-analysis showed that the combination of PDT and nystatin was more effective than nystatin alone in the treatment of oral candidiasis, and the recurrence rate was lower, which may be related to the mechanism of fungal inactivation by PDT interacting with the mechanism of antifungal drugs. Nystatin is a polyene antibiotic that interacts with ergosterol in fungal cell membranes, making them porous and susceptible to cracking, thus exerting its antifungal action [44]. PDT, on the other hand, is a photochemical reaction to excite a photosensitizer to produce reactive oxygen species, which can react with a variety of biomolecules such as proteins and phospholipids of fungal cells to produce activity and eventually inactivate the cells [45]. Therefore, the synergistic effect of the two treatment measures makes the combination more effective than a single antifungal drug. Regarding the safety of the combination therapy, the results of the Chen Chong [29] study showed that the incidence of adverse reactions during treatment was similar in both groups, and the adverse reactions resolved on their own without treatment, suggesting that the combination therapy was safe and reliable. The combination of PDT and antifungal drugs is recommended in clinical treatment and may be a more reliable measure for reducing the recurrence of oral candidiasis.

Smoking was identified as one of the important risk factors for increased oral Candida carriage in the included studies [46]. A meta-analysis by Nader [47] showed that smokers had significantly higher rates of oral Candida carriage than non-smokers. Smoking reduces the activity of oral leukocytes, decreases gingival exudate, and reduces the load of immunoglobulins and leukocytes, thus contributing to the colonization of Candida in the oral cavity [48]. Abduljabbar [38] conducted a clinical trial on the presence of smoking as a risk factor in patients with denture stomatitis and found that PDT was significantly more effective in non-smokers than in smokers.

This Meta has some limitations to consider, the lack of an appropriate number of RCTs included in each subgroup, as well as the small sample size included in some studies and the differences in follow-up time between studies to the extent that bias may result in subgroup analysis. There is a lack of standardization in the use of PDT across studies, such as differences in photosensitizers, activation wavelengths, power output, irradiation duration, and energy dose. In addition, the choice of the optimal synergistic treatment modality of PDT with other drugs still needs to be studied in depth.

PDT was effective in the treatment of oral candidiasis; PDT was more effective than nystatin for the treatment of denture stomatitis in the palate, while there was no significant difference between the two for the denture site; The efficacy of PDT for oral candidiasis was similar to that of fluconazole; PDT was less effective than miconazole for oral candidiasis; Compared with nystatin alone, the combination of PDT and nystatin is more effective in treating oral candidiasis with less risk of recurrence.