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Abstract

Introduction: Photodynamic therapy (PDT) is a two-stage treatment method making use of light energy and a photosensitizer in the presence of oxygen. PDT has already proved to bring good anti-inflammatory and anti-proliferative effects in the treatment of actinic keratosis, squamous cell carcinoma in situ as well as in superficial and nodular basal cell carcinoma. In PDT-treated lesions, infected or cancerous keratinocytes are effectively destroyed due to selective apoptosis and necrosis induced by a release of reactive oxygen species. PDT is distinguished by several features, most notably its non-invasiveness, selectivity for the target tissue, which causes fewer side effects and brings excellent cosmetic results. PDT is an effective option for treating viral diseases using a photosensitizer capable of selective accumulation in virus-infected cells not only within visible lesions, but also in subclinical disease areas where the virus is in latent form. Objectives and methods: This literature review presents recent reports on PDT for the treatment of viral skin infections, with a particular focus on the efficacy of this method. Results: The viruses that most commonly cause skin diseases include the human papilloma virus (HPV), herpes simplex virus (HSV), varicella-zoster virus (VZV), molluscum contagiosum virus (MCV). PDT inhibits the proliferation of virus-infected cells, induces apoptosis, damages lesional blood vessels, regulates local immunity and controls viral loads. An additional advantage of PDT is the short healing period and little damage to the treated tissue. Furthermore, wider use of PDT may contribute to reducing the risk of developing drug resistance. Conclusion: The safety of PDT makes this method an effective way to treat viral skin diseases in difficult locations, as well as in children and immunocompromised patients.

Keywords

photodynamic therapy PDT viral skin diseases

Introduction

Even though scientific studies on viral pathogenesis are constantly revised and updated, viral infections remain tricky, treacherous, and insidious. Despite their seemingly successful treatment, pathogenic viruses are still able to outfox the host`s defence mechanisms and trigger a full-blown infection or lie dormant until they are brought back to life. Therefore, it is necessary to identify and annihilate the underlying virus-host interactions at the molecular level.

More often than not, unsatisfactory results of applied conventional treatment of viral skin infections, caused by the human papilloma virus (HPV), herpes simplex virus (HSV), varicella-zoster virus (VZV), molluscum contagiosum virus (MCV) and other pathogenic viruses evoke feelings of frustration in the patient whose quality of life becomes considerably compromised. Therefore, researchers are on the lookout for more effective, less invasive and safer methods of treatment for various viral infections, including viral skin infections which are one of the most common types of infection. In light of the above, it appears that the photodynamic therapy (PDT), a two-stage treatment regimen making use of light energy and a photosensitizer (i.e. porphyrins: 5-aminolevulinic acid (5-ALA), or its ester methyl-5-ALA (MAL) as well as the synthetic dyes: methylene blue, toluidine blue and rose Bengal, in the presence of oxygen, is a promising alternative therapeutic option since it has already proved to bring good anti-inflammatory and anti-proliferative effects in the treatment of actinic keratosis (AK), squamous cell carcinoma (SCC) in situ as well as in superficial and nodular basal cell carcinoma (BCC). In PDT-treated lesions, infected or cancerous keratinocytes are effectively destroyed due to selective apoptosis and necrosis induced by a release of reactive oxygen species (ROS), particularly singlet oxygen; furthermore, PDT is a non-invasive therapeutic method, specific to the target tissue, which causes fewer side effects and brings excellent cosmetic results.

A growing number of scientific studies provides evidence that the endogenous, molecular oxygen, generated during PDT, is capable of killing pathogens, including viruses.

Materials and methods

We conducted our literature review in search of recent reports on photodynamic therapy for the treatment of viral skin infections, with a particular focus on the efficacy of this method.

PDT mechanisms of action in viral skin infections

The mechanisms of action regarding photodynamic therapy (PDT) in the treatment of viral diseases are similar to the mechanisms observed in the treatment of oncological diseases or bacterial and fungal infections. The effectiveness of PDT depends on the efficiency of a selected photosensitizer which, after topical application, must be able to penetrate keratinocytes and finally reach the fast-proliferating, virus-infected cells. Its participation in the heme biosynthesis pathway leads to the formation and accumulation of a photoactive molecule – protoporphirin IX (PpIX) during incubation time, which, according to Ross et al., is 3 h for condyloma acuminate, assessed on the basis of fluorescence of the treated tissue.¹ Stirred by the light, PpIX generates ROS which will be able not only to destroy the virus-infected keratinocytes but also the virus itself, that is, the proteins and glycoproteins in the envelope, surface glycoproteins in non-enveloped viruses, viral nucleic acids (single- or double-stranded, either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and enzymes within the capsid. Therefore, photosensitizing agents must bind specifically to viral components, such as the envelope, protein coat or to nucleic acids. Although viruses do not have the ability to produce PpIX, it is known that ALA and its derivatives contribute to the selective accumulation of PpIX in cells infected with HSV, HPV and other viruses.²

Apparently, PDT inhibits replication of the virus in the late stages of its infection cycle and is able to reduce the microbial load, thereby minimising the probability of survival and transmission of the virus and the recurrence of infection.

On the one hand, a topically applied photosensitizer may be of diagnostic value (photodynamic/fluorescence diagnostics), on the other hand, however, which is of pivotal therapeutic value, it is capable of generating ROS that are indispensable for the apoptosis and necrosis of virus-infected cells and the virus itself.

In type I mechanism, ROS, such as the hydroxyl radical, trigger the peroxidation of lipids which compromises the structural integrity of the virus-infected cells, thereby increasing the permeability of Na+ and K− ions. Moreover, the same ROS interacts with the genetic material through oxidation of deoxyribose in DNA or ribose in RNA, ultimately leading to its degradation and the inhibition of replication because it blocks the Nuclear Factor kappa B (NF-κB) and MAPK signalling pathways³PI3K/Akt, Wnt/Beta-catenin, ERK/MAPK, NF-κB, YY1, AP-1, JAK/STAT and CXCL12/CXCR4 signalling pathways have an important role in the progression of cervical cancer, in patients infected with HPV.⁴ It is worth noting that Xie et al. demonstrated that ALA-PDT induced apoptosis and autophagy in HPV-infected cells by affecting the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR signal pathways.⁵

Type II mechanism completes photo-inactivation of the virus. In the process of photo-sensibility, the most active form of ROS, that is, singlet oxygen, is generated to destroy the proteins and enzymes of the virus through the cyclo-addition of tryptophane, methionine and lysine residues. The singlet oxygen-mediated damage to nucleic acids mainly affects the guanine base causing formation of 8-hydroxyguanosine. As a consequence, the nucleotide degradation, gene mutations, and splitting of the DNA or RNA strands take place.

ALA is mainly localised to the mitochondria; thus, inhibition of mitochondrial enzymes is a key event in cell death during PDT. Miao et al. showed that ALA-PDT causes damage to mitochondrial membranes in cells infected with HPV16.⁶ The large amount of ROS produced during PDT leads to membrane depolarization, cytochrome c release, caspase-3 activation which result in cell death. ALA-PDT could also induce endoplasmic reticulum stress-specific apoptosis which may be due to the migration of PpIX from the mitochondria to the endoplasmic reticulum (ER). Furthermore, Li et al. demonstrated that ALA-PDT affected the ER and induced apoptosis via the activation of caspase 12 in high-risk HPV (HR-HPV) infected cells of cervical cancer (HeLa cells) while the Ca2+-CamKKβ-AMPK pathway and authophagy may be one of the mechanisms of PDT resistance.⁷

While PDT is in progress, the lymphocytes, macrophages and dendritic cells (DCs) are stimulated to produce and release cytokines, that is, Il-1, IL-6, TNF-alpha, IFN-alpha, IFN-beta and metalloproteinase 1, which leads to diffuse inflammation in the treated skin area. Destruction of the virus-infected cells results in the expression and secretion of damage-associated molecular patterns, cytokine release, activation of neutrophils and maturation of DCs as well as the subsequent activation of the adaptive immune system.⁸

In PDT for genital warts, activation of the immune response is primarily due to the participation of the CD4+T cells and DCs. Bu et al. demonstrated that in patients with condyloma acuminata, ALA-PDT decreases the level of Treg cells and increases the level of TGF-beta as well as lymphotactin (LTN) that are responsible for stimulating the immune response in both Th1, Th2 cells and leukocytes at the site of HPV infection. Bu et al. revealed that after 5-ALA PDT, the number of CD4+CD25+Foxp3 + Treg cells and CD4+CD25+ Treg cells, known to suppress the immune responses and induce immune tolerance, significantly decreased to the levels observed in a healthy group, whereas the serum levels of TGF-beta 1 and lymphotactin increased significantly.⁹ Xie et al. confirmed the occurrence of local immune-suppression within the genital warts. On PDT completion, the authors observed an increase in the count of CD4+T cells after 4 h as well as their transition from the middle superficial layer of the dermis to the superficial dermis, together with an increase in IFN-gamma mRNA. The increased IFN-gamma mRNA expression was transitory and returned to the baseline after 24 h. A gradual increase in the count of CD123+ pDCs and expressions of IFN-alpha and IFN-beta, due to activation of the MyD88 pathway, was observed, which is indicative of an intensified antiviral immune response due to application of PDT. In contrast, HPV infection induces the down-regulation of IFN type I level, furthermore, 24 h after PDT completion, the count of CD3+T cells increased, while the count of CD8+T cells remained the same.¹⁰ Radakovic et al. observed resolution of distant viral warts and suggested that PDT may result in a specific systemic immune response.¹¹

Destruction of superficial dilated capillaries in the dermal papillae, as a result of PDT, leads to cutting off /interruption to the blood and nutrients supply, to rapidly developing viral changes in the skin.

Photosensitizers in PDT of viral skin infections

In photodynamic therapy of viral infections, photosensitizers are used to photoinactivate viruses through singlet oxygen-mediated oxidation of virus envelope lipids, capsid, core proteins and nucleic acids.¹² The most commonly used photosensitizers in the treatment of viral skin diseases are 5-aminolevulinic acid (ALA) and its methyl ester (MAL) as precursors of protoporphyrin IX. Other photosensitizers (Figure 1) include, for example, chlorin-based molecules, benzoporphyrins, phthalocyanines, porphycenes, phenothiazines, hypericins, perylenes and metallo-derivative of tetrapyrrole compounds.^12,13

Figure 1.

Structures of photosensitizers used in antiviral PDT (author: Prof. Dorota Kowalczuk).

The reason for the failure of viral disease therapy, with particular regard to cutaneous warts, is the reduced penetration of 5-ALA due to significant epidermal hyperkeratosis. Methods of increasing the effectiveness of treatment include, for example, adding penetration enhancers (absorption promoters) to the formulation, that is, ethylenediaminetetraacetic acid (EDTA, 2%) and dimethyl sulfoxide (DMSO, 2%). When treating viral warts, it is also important to have an appropriate pre-treatment procedure to remove the keratinized epidermal layers using keratolytic preparations or mechanically, by cutting their outer layers with a scalpel. PDT is also being combined with other types of treatment, such as carbon dioxide laser therapy, cryotherapy, polytherapy with isotretinoin or topical antiviral agents. Combination therapy is more effective than PDT monotherapy, especially in the treatment of recalcitrant viral skin diseases.

The efficacy of curcumin in the treatment of HPV infections has also been confirmed. Kutluay et al. showed on cultured cells that curcumin reduces the immediate-early gene expression in HSV and reduces HSV-1 infectivity. Similarly, hypericin inhibits viral infectivity in relation to various viruses, including HSV.¹⁴ However, it should be remembered that the effectiveness of photodynamic therapy against viruses depends not only on the photosensitizing molecule used, but also on the type of virus, the dose and wavelength of light, and the therapeutic conditions.

PDT in papillomaviruses skin infections

Human papillomaviruses (HPV) are non-enveloped, icosahedral, double-stranded deoxyribonucleic acid (dsDNA) viruses belonging to the Papovaviridae family. More than 200 different genotypes of this virus have been identified, of which, types such as 16, 18, 30, 33 and 45, are classified as high-risk HPV (HR-HPV) genotypes. The virus infects dividing cells of the basal layer of the epithelium and/or epidermis. In host cells, HPV uses pioneer factors, for example, KLF4, OCT4, and SOX2 mediated by HPV proteins E6 and E7 for its transcription and replication.

The most common forms of HPV diseases are cutaneous and genital verrucae/warts. These are most often located on the hands, feet, around the nails and on the face (i.e. hand and foot warts, periungual warts, plane warts) and in the genital area (i.e. condyloma acuminatum). The basic methods for treating viral warts include cryosurgery, cryotherapy, curettage, electrosurgery, carbon dioxide laser, Q-switched Nd-YAG, or pulsed dye laser, excision, salicylic acid, topical immunomodulators, for example, imiquimod, antimitotic agents (podophyllin, retinoids or intralesional injection of bleomycin) and oral retinoids such as oral isotretinoin.¹⁵ Despite the availability of many treatments, the complete elimination of the virus is still a challenge. HPV DNA can survive in epithelial cells for years or even decades without causing any clinical symptoms but posing a risk of developing precancerous lesions and malignant tumours. The use of PDT in the treatment of condylomatic lesions was first presented by Kennedy et al. in 1990.¹⁶ PDT is also used in cases of warts resistant to other treatment methods. In the results of studies published in recent years, ALA was most often used in PDT procedures at concentrations of 10–20%. The incubation period, under occlusion with photosensitizer, ranged from 3 to 8 h. After removing the dressing and washing off any residual photosensitizer, the lesions were irradiated with LED light 630 nm+/−10 nm or Tungsten lamp 400–700 nm or IPL Quantum or 580–720 nm of incoherent multiple band light source, using a dose of 50–126 J/cm². The procedure was carried out in 1 to 10 sessions between 1 and 6 weeks apart, the most common being 3 sessions every week.

PDT is an effective treatment for viral warts and has a high cure rate and low recurrence rate. The efficacy of PDT in the treatment of warts, as assessed by various authors, ranges from 28% to 95%. The cure rate for periungual and subungual warts is 90% and for hand and foot warts is 56–100%. Wang et al. showed that the therapeutic effect of PDT in viral foot warts positively correlates with the degree of necrosis and apoptosis of keratinocytes. Irradiation doses higher than 50 J/cm² allow higher clearance rates to be achieved following 5-ALA PDT treatments.¹⁷

Wu et al. compared the effects of treating viral foot warts using ALA-PDT (treatment group) and cryosurgery (control group), obtaining an efficacy of 86.96% and 39.47%, respectively, with a recurrence rate after 3 months of 20% and 53.33%, respectively.¹⁸

A limiting factor in the efficacy of wart treatment is the presence of hyperkeratotic lesions, which impairs the penetration and uptake of ALA by virus-infected cells. In order to increase the effectiveness of PDT, it is a pre-treatment of warts with Azone, shaving, curettage, micro-needling having been recommended or the use of other methods that allow keratinized tissue to be removed before the photosensitizer is applied. The most important side effect of PDT is burning and stinging during exposure to light, which may be due to the inflammation caused by cell necrosis and the interaction between δA nerve fibres or C nerve fibre.¹⁹ In some patients, burning and itching persists up to 48 h after treatment.²⁰

Flat warts are most often caused by HPV types 3 and 10 and occur mainly in children and young adults, affecting the forehead, cheeks, back of the hands and the forearms. Up to 78% of lesions resolve spontaneously within 2 years, although there are occasionally cases that are refractory to treatment. In the PDT procedures described for facial flat warts, 5–20% 5-ALA or MAL was most commonly used. After an incubation period of 3–6 h, the lesions were irradiated with LED light 630 nm+/−10 nm at a dose of 37 J/cm² to 126 J/cm², 50–100 mW/cm². Typically, between 1 and 6 sessions were required with intervals of 1-2 weeks. The rate of complete resolution of facial flat warts with PDT ranges from 64.6% to 100%. Recurrence rate after 6 months was 5.88%.²¹

Hassan et al. applied PDT using intralesional injection of 4% methylene blue solution and after 15 min irradiation with intense pulsed light (IPL) (16–22 J/cm3) in 30 patients with viral warts. The treatments were performed twice a week in a maximum of 4 sessions. Efficacy was compared to a group of 30 patients who received IPL alone. Clearance of skin lesions was demonstrated in 43.3% of patients treated with methylene blue compared to 20% treated with IPL alone.²²

Despite the high potential for spontaneous resolution, there are cases of viral warts that persist for months or even years and are resistant to standard treatment methods. In patients with recalcitrant warts, PDT, in combination with keratolytic treatments is an effective treatment modality and the main limiting factor for the use of this treatment modality, especially in the paediatric population, is pain during irradiation. One of the modifications of PDT is the replacement of the irradiation step by using daylight, or so-called Daylight Photodynamic Therapy (DL-PDT). Borgia et al. conducted a study comparing the efficacy and safety of conventional photodynamic therapy (C-PDT) with daylight PDT (DL-PDT) in the treatment of resistant, flat facial warts in a group of 30 patients under 18 years of age. All patients were treated with 10% 5-ALA as a photosensitizer and 3 treatment sessions were performed 1 month apart. In the DL-PDT method, the incubation period with the photosensitizer was shortened to half an hour. At 24 weeks from the start of treatment, the authors observed similar efficacy of both PDT methods. DL-PDT was better tolerated, did not require a long incubation period, was almost painless and was therefore assessed particularly well by adolescent patients.²³ In turn, Fathy et al. obtained complete resolution of plane warts in 13 out of 20 patients treated after using DL-PDT using 10% methylene blue (10% liposomal-loaded methylene blue gel) as a photosensitizer. For this photosensitizer, the incubation period before exposure to sunlight was 15 min.²⁴ When using the DL-PDT procedure, it is necessary to apply a sunscreen against UVA and UVB with SPF 50+, which is applied to the skin 30 min before the application of the photosensitizer.

Condyloma acuminatum, one of the most common sexually transmitted diseases, is caused in 90% of cases by HPV types 6 and 11, which belong to the low-risk HPVs. Lesions are localised in the genital, anal and urethral areas. High-risk HPV infections, on the other hand, are associated not only with the occurrence of condyloma acuminatum, but also with the risk of developing bowenoid papulosis, persistent cervical high-risk HPV infection and cervical intraepithelial neoplasia (CIN). The treatment procedure for HPV-induced genital lesions usually involves a 3-4-h incubation period with a photosensitizer, viz. 10–20% 5-ALA followed by 630 ± 10 nm exposure to LED light using 80–150 J/cm², 60–100 mW/cm². The treatments are repeated every 1-2 weeks and most often, it is necessary to carry out 1–10 sessions. In most studies, 10% 5-ALA showed the optimal therapeutic profile in terms of efficacy and safety. The efficacy of PDT of condyloma acuminata is estimated at 85.7–100% with a recurrence rate of 8.62–16.2%. Sometimes a combination therapy is recommended, for example: pre-treatment with super-pulsed CO2 laser prior to 5% 5-ALA-PDT. Considering the location of the condylomas, the highest efficacy of PDT is found for lesions in the urethral area and the lowest with the highest recurrence rate in the anal area.²⁵ Furthermore, HPV infections of the urethral orifice area have a higher risk of treatment failure due to the limited choice of possible therapeutic modalities on account of safety and fear of complications, that is, bleeding, infection, burning, oedema, urination disorders (oliguria, dysuria) and especially the risk of urethral stricture, whereas 5-ALA PDT causes only mild burning during irradiation. The undoubted advantage of PDT is the absence of scarring at the treatment site regardless of the severity of the verrucae. Therefore, PDT is the therapy of choice for warts located within the natural orifices, that is, the urethra and anus.

The high efficacy of PDT is due to its effect, not only on clinically visible condyloma acuminatum, but also on latent and subclinical virus-shedding areas. Hu et al. showed that PDT effectively eliminates HPV and significantly reduces viral loads after 3 cycles of treatment. The rate of HPV DNA negativity, after a single PDT treatment, was higher in patients with latent or subclinical infection compared to patients with clinical disease present, indicating that latent HPV infection is more easily treated.²⁶ Owczarek et al. showed that for genital warts in men, refractory to podophyllotoxin or cryosurgery treatment, determination of HPV DNA type is an indicator of the severity of infection and allows the prognosis of the length of treatment. Six months after 4 PDT sessions, 16 out of 21 patients (76.19%; p = .0007) were completely cured. HPV DNA negativity was found in 66.67% (p = .03) of patients, with the rate of virus eradication being higher for low-risk HPV compared to high-risk HPV, 76.92% (10/13; p = .0003) and 50% (4/8; p = .05), respectively. Hence, ALA-PDT can also be an effective treatment in cases of previous therapeutic failures. The persistence of clinical lesions and the presence of high-risk HPV should be an indication for prolonged treatment.²⁷ Wang et al. showed that patients infected with several HPV types and/or high-risk viruses required significantly more 5-ALA PDT sessions compared to patients with one HPV type and/or low-risk virus type identified.²⁸ In turn, Hu et al. found that multiple sexual partners, recurrent HPV infections and severe pain during PDT were associated with a higher likelihood of the virus surviving after three cycles of ALA-PDT. Infection with single HPV strains and the subclinical stage of the disease were associated with a higher likelihood of efficacy after three cycles of ALA PDT.²⁹ Li et al. observed resolution of all lesions in 66 patients with refractory condyloma acuminatum of the anogenital region after treatment with ALA-PDT (1–9 sessions weekly) in combination with tretinoin or isotretinoin at a dose of 10 mg twice daily for 45–90 days. Retinoids reduce viral replication and activate the process of apoptosis. Combination therapy reduces the risk of recurrence, accelerates the healing process and reduces scarring.³⁰ A meta-analysis that included 1903 patients with condyloma acuminatum showed that 5-ALA PDT significantly reduces the risk of recurrence at 12 and 24 weeks after treatment. 5-ALA PDT combined with CO2 laser treatment further enhances efficacy and reduces the risk of recurrence. The selectivity of PDT in HPV-induced infections makes this method a good treatment option for condyloma acuminatum, with a success rate of 66–100% in women, while this is 73–100% in men, with a recurrence rate of around 17%.

PDT is also an effective and safe treatment for HPV infections in immunosuppressed patients. Higher efficacy of combination therapy such as cryotherapy with PDT, compared to cryotherapy alone in the treatment of condylomas in immunosuppressed patients is emphasized. 5-ALA PDT is a particularly preferred treatment for HPV infection in HIV-positive patients. It has been described as highly effective in the treatment of giant condylomas in AIDS patients, as well as acquired epidermodysplasia verruciformis (AEV), which is an HPV infection found in HIV-positive people.

PDT in herpes viruses skin infections

Herpesviridae is a family of more than 100 species of viruses, including eight human pathogens, characterized by the presence of a core containing double-stranded DNA (dsDNA), icosapentahedral capsid, tegument and envelope. In humans, they cause infections that persist throughout the host’s life. Of this group of viruses, cutaneous infections are mainly caused by alphaherpesviruses, such as herpes simplex virus-1 (HSV-1) responsible for oral and labial herpes, herpes simplex virus-2 (HSV-2) responsible for genital herpes, varicella-zoster virus (VZV) being the aetiological agent of chickenpox and shingles. The life cycle of Herpesviridae runs in two phases, that is, a lytic phase during which viral replication occurs and a latent phase during which the virus remains dormant in neurons. It has been shown that there are so-called pioneer factors involved in herpes virus infection. For example, KLF4 is a pioneer factor involved in activating the virus genes responsible for reactivating and initiating HSV-1 replication, while the pioneer factor RUNX1 plays a role in silencing it and in its transition to the latent phase.³¹ The most common treatment for herpes is oral or topical acyclovir, an antiviral drug that inhibits HSV, which should be administered within 72 h of the onset of symptoms of infection. Another treatment option is valacyclovir, which shows greater bioavailability and whose active metabolite is acyclovir. Chronic use of the above-mentioned drugs can lead to the development of resistance, so other therapeutic options are being sought.

PDT in the treatment of herpes infections was first introduced in the early 1970s, particularly for the treatment of genital lesions. PDT for the treatment of herpes labialis is best used in the acute, vesicular phase of the disease. Most commonly described, is the use of methylene blue at a concentration of 0.005–0.01% as a photosensitizer, which, under red light irradiation inactivates the virus by oxidative damage to its DNA, inducing fragmentation of the viral DNA. Methylene blue is applied to the lesions after first piercing the blisters with a sterile needle. After 3 min, the lesions are irradiated with an LED lamp or a laser (diode laser). The use of a 660 nm laser using 100–150 mW/cm² power and a dose of 100–300 J/cm² for 30 s per point for 3 J of energy has been described. Lago et al. observed a beneficial effect of the application of 20 s duration and 2 J energy after 24 and 72 h of consecutive irradiation (in the phase of the crust formed).³² Osiecka et al. used 5-ALA and 630 nm LED light irradiation at a dose of 120 J/cm² in the treatment of herpes using the PDT method.³³ Ajmal et al. in adolescent patients (14–19 years) with herpes labialis observed that PDT reduces pain scores and decreases levels of pro-inflammatory cytokines such as TNF-alpha and Il-6, which may be related to the immunomodulatory effect of PDT. In addition, photobiomodulation applied at the stage of disease with a crust formed, by affecting collagen fibres, accelerates the healing process and shortens the time needed to achieve remission of lesions.³⁴ Ramalho et al. observed that on the first day of treatment, there was a significantly greater reduction in the size of the herpes and a reduction in swelling and tingling of the lesion in patients treated with acyclovir in combination with PDT compared to those treated with acyclovir alone.³⁵

PDT in poxvirus skin infections

Poxviridae is a family of 38 virus species, with a core envelope and double-stranded DNA (dsDNA). The dermatotrophic species is molluscum contagiosum virus (MCV), which causes a disease in humans called molluscum contagiosum. The disease is most common in children aged 1–10 years, while in immunocompromised patients and adults it occurs mainly as a sexually transmitted disease. Lesions usually appear on the face, neck, hands, armpits and the genital area and tend to resolve spontaneously within 6–12 months. Cryotherapy, curettage, laser therapy, podophyllotoxin, potassium hydroxide, salicylic acid, benzoyl peroxide and tretinoin are used in the treatment. An alternative method of treatment is PDT. Single case reports are available of patients who were treated with a protocol involving incubation with 5-ALA for 3-4 h and irradiation with 630 nm LED or blue light at a dose of 37 J/cm² - 120 J/cm². From 1 to 5 sessions were carried out with an interval of 15 days. Satisfactory effectiveness was obtained.

Conclusions

PDT is an effective alternative treatment for skin viral diseases caused by HPV, HSV and MCV. The undoubted advantage is the destruction of lesions and subclinical areas infected by the virus with little damage to the surrounding normal tissue. The method is highly efficient and has a low recurrence rate (the recurrence rate of PDT is low). Wider use of PDT can contribute to reducing the risk of developing drug resistance, which is increasingly observed, not only in the context of bacterial resistance to antibiotics, but also in relation to antiviral drugs. The safety of the procedure makes PDT a buoyant method for treating viral skin diseases in difficult locations (i.e. around natural orifices), in children and in immunocompromised patients.

It is worth noting that most studies have focused on the use of PDT to treat bacterial or fungal infections, and there is limited information on its effectiveness against viral infections.

It can be assumed that with the introduction of modifications to PDT, including new photosensitizers and modern light sources, as well as new treatment protocols, this therapeutic method will be increasingly used to treat viral skin diseases.

ORCID iD

Paulina Szczepanik-Kułak https://orcid.org/0000-0002-3205-5407

Statements and declarations

Footnotes

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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A review of photodynamic therapy for the treatment of viral skin diseases

Abstract

Keywords

Introduction

Materials and methods

PDT mechanisms of action in viral skin infections

Photosensitizers in PDT of viral skin infections

PDT in papillomaviruses skin infections

PDT in herpes viruses skin infections

PDT in poxvirus skin infections

Conclusions

ORCID iD

Statements and declarations

Footnotes

Funding

Conflicting interests

References